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WO2001042368A1 - Substituted phthalocyanines and their precursors - Google Patents

Substituted phthalocyanines and their precursors Download PDF

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Publication number
WO2001042368A1
WO2001042368A1 PCT/GB2000/004708 GB0004708W WO0142368A1 WO 2001042368 A1 WO2001042368 A1 WO 2001042368A1 GB 0004708 W GB0004708 W GB 0004708W WO 0142368 A1 WO0142368 A1 WO 0142368A1
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Prior art keywords
substituted
optionally substituted
alkyl
phthalocyanine
formula
Prior art date
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PCT/GB2000/004708
Other languages
French (fr)
Inventor
Michael John Cook
Martin James Heeney
Original Assignee
Gentian As
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9929064.5A external-priority patent/GB9929064D0/en
Priority claimed from GBGB0025817.8A external-priority patent/GB0025817D0/en
Application filed by Gentian As filed Critical Gentian As
Priority to HU0301099A priority Critical patent/HUP0301099A3/en
Priority to CA002394891A priority patent/CA2394891A1/en
Priority to PL00355851A priority patent/PL355851A1/en
Priority to EEP200200298A priority patent/EE200200298A/en
Priority to EP00985506A priority patent/EP1238016A1/en
Priority to AU21922/01A priority patent/AU2192201A/en
Priority to JP2001543656A priority patent/JP2003516421A/en
Publication of WO2001042368A1 publication Critical patent/WO2001042368A1/en
Priority to NO20022663A priority patent/NO20022663L/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0076—PDT with expanded (metallo)porphyrins, i.e. having more than 20 ring atoms, e.g. texaphyrins, sapphyrins, hexaphyrins, pentaphyrins, porphocyanines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y10/00—Nanotechnology for information processing, storage or transmission, e.g. quantum computing or single electron logic
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B47/00—Porphines; Azaporphines
    • C09B47/04—Phthalocyanines abbreviation: Pc
    • C09B47/045—Special non-pigmentary uses, e.g. catalyst, photosensitisers of phthalocyanine dyes or pigments
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B47/00—Porphines; Azaporphines
    • C09B47/04—Phthalocyanines abbreviation: Pc
    • C09B47/06—Preparation from carboxylic acids or derivatives thereof, e.g. anhydrides, amides, mononitriles, phthalimide, o-cyanobenzamide
    • C09B47/067—Preparation from carboxylic acids or derivatives thereof, e.g. anhydrides, amides, mononitriles, phthalimide, o-cyanobenzamide from phthalodinitriles naphthalenedinitriles, aromatic dinitriles prepared in situ, hydrogenated phthalodinitrile
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B47/00—Porphines; Azaporphines
    • C09B47/04—Phthalocyanines abbreviation: Pc
    • C09B47/06—Preparation from carboxylic acids or derivatives thereof, e.g. anhydrides, amides, mononitriles, phthalimide, o-cyanobenzamide
    • C09B47/067—Preparation from carboxylic acids or derivatives thereof, e.g. anhydrides, amides, mononitriles, phthalimide, o-cyanobenzamide from phthalodinitriles naphthalenedinitriles, aromatic dinitriles prepared in situ, hydrogenated phthalodinitrile
    • C09B47/0673—Preparation from carboxylic acids or derivatives thereof, e.g. anhydrides, amides, mononitriles, phthalimide, o-cyanobenzamide from phthalodinitriles naphthalenedinitriles, aromatic dinitriles prepared in situ, hydrogenated phthalodinitrile having alkyl radicals linked directly to the Pc skeleton; having carbocyclic groups linked directly to the skeleton

Definitions

  • This invention relates to a process for the preparation of phthalonitrile sulfonate esters, a process for the preparation of substituted phthalonitriles using said phthalonitrile sulfonate esters, a process for the preparation of substituted phthalocyanines using said substituted phthalonitriles, a process for the preparation of phthalonitrile halides, a process for the preparation of substituted phthalocyanines using said phthalonitrile halides, novel phthalonitrile sulfonate esters, novel substituted phthalonitriles, novel substituted phthalocyanines and certain uses of said novel substituted phthalocyanines.
  • substituted phthalocyanines show a multitude of desirable properties and are thus useful for a wide variety of applications.
  • the desirable properties of substituted phthalocyanines can often be tuned by manipulation of the substituents on the ring system. In general these substituents fall into two categories, the so-called peripheral (2, 3, 9, 10, 16, 17, 23, 24) and the non-peripheral (1, 4, 8, 11, 15, 18, 22, 25) substituents, as shown in Scheme 1.
  • GB-B-2,229,190 discloses a group of non-peripherally substituted phthalocyanines, at least some of which, in thin films such as for example Langmuir-Blodgett films, in the liquid crystalline state, or when dissolved or dispersed in a carrier material, are transparent in the visible region and yet strong absorbers of UV or IR radiation. Hence they are capable of absorbing energy emitted by lasers and thus useful in laser addressed applications such as laser addressed optical storage devices and projection displays. Alteration of the substituents and the central ion M is a means for tuning the wavelength of absorption by the substituted phthalocyanines to match the wavelengths of the lasers.
  • GB-B-2,295,547 discloses the use of a similar group of non-peripherally substituted phthalocyanines as photosensitizers in photodynamic therapy.
  • EP-A-0, 906,758 discloses a variety of zinc-phthalocyanines substituted with hydrophilic substituents linked to the phthalocyanine ring via an oxygen atom as phototherapeutic or photodiagnostic agents.
  • dye compounds are administered to a tumour-bearing subject. These dye substances may be taken up by the tumour at least to a certain extent. Upon selective irradiation with an appropriate light source the tumour tissue is destroyed via the dye mediated photo-generation of cytotoxic species such as singlet oxygen or free radicals such as hydroxy or superoxide.
  • Alkoxy-substituted phthalonitriles have been synthesised by alkylation of hydroxy- substituted phthalonitriles (see Scheme 2) or nucleophilic aromatic substitution of nitro- or chloro-substituted phthalonitriles (Scheme 3).
  • Scheme 2 alkylation of hydroxy- substituted phthalonitriles
  • Scheme 3 nucleophilic aromatic substitution of nitro- or chloro-substituted phthalonitriles
  • a hydroxy-substituted phthalonitrile may be treated with a suitable base and a haloalkane to yield an alkoxy-substituted pthalonitrile.
  • a nitro- or chloro- substituted phthalonitrile may be treated with a suitable base and an alcohol to yield an alkoxy-substituted pthalonitrile.
  • the resulting 2,5-dialkylfuran may be treated with fumaronitrile followed by a suitable base to yield a 3,6- dialkylphthalonitrile.
  • thiophene may be 2,5-alkylated using suitable base and a haloalkane.
  • the resulting 2,5- dialkylthiophene may be oxidised to yield the corresponding 1,1 -dioxide. This may be reacted with fumaronitrile to yield a 3,6-dialkylphthalonitrile.
  • Substituted phthalocyanines have been prepared by the cyclisation of appropriately substituted phthalonitriles.
  • a substituted phthalonitrile may be reductively cyclised into a substituted phthalocyanine by treatment with a suitable base.
  • the substituted phthalocyanine may be metallated by treatment with a suitable metal compound.
  • the substituted phthalonitrile may be reductively cyclised directly into the metallated substituted phthalocyanine by treatment with a suitable metal compound in the presence of a suitable base.
  • a major disadvantage of the prior art syntheses of substituted phthalocyanines is that a large variety of potentially useful substituents cannot be introduced into phthalocyanine by these prior art syntheses, because their functionality is incompatible with the required reaction conditions.
  • the present invention provides a new synthetic route to substituted phthalocyanines via cyclisation of substituted phthalonitriles, prepared by substitution reactions of phthalonitrile sulfonate esters.
  • aryl iodides, bromides, triflates as well as nonaflates M. Rottlander, P. Knochel, J. Org. Chem., 1998, vol. 63, page 4523; B.H. Lipshutz, D.J. Buzard, C.S.
  • m are the same or different and each m is 0, 1 , 2, 3 or 4, provided that not all four m are 0 simultaneously;
  • R 1 are the same or different and each R 1 is C ⁇ -C 20 alkyl optionally substituted;
  • p are the same or different and each p is 0, 1, 2 or 3;
  • R 3 are the same or different and each R 3 is -F, -Cl, -Br or -I;
  • M is a metal atom in the M(II) oxidation state, a metal chloride, a metal bromide, a metal oxide, silicon with two axial substituents or two hydrogen atoms, one hydrogen being bonded to each of the two bonding nitrogen atoms;
  • R 6 is either C ⁇ -C 12 alkyl, optionally substituted with one or more of -F and/or -Cl, or aryl, optionally substituted with one or more of -CH 3 , -NO 2 , -OCH 3 , -F, -Cl and/or -Br; and when m is 2, 3 or 4, R 6 are the same or different;
  • alkyl is defined as a hydrocarbon with a sp 3 hybridised ⁇ -carbon, which may be straight chain or branched, and which may optionally be substituted, and which may comprise at least one double bond and/or at least one triple bond.
  • Aryl is defined as an aromatic hydrocarbon with a sp hybridised aromatic ⁇ -carbon, which may optionally be substituted. Examples of aryls are
  • Heteroaryl is defined as an aromatic hydrocarbon with a sp 2 hybridised aromatic ⁇ -carbon, which comprises at least one heteroatom N, O or S as part of the aromatic ringsystem, and which may optionally be substituted. Examples of heteroaryls are
  • Alkynyl is defined as a hydrocarbon with a sp hybridised ⁇ -carbon, which may be branched or unbranched, and which may optionally be substituted.
  • alkynyl groups are -C ⁇ C-H, -C ⁇ C-CH 3 , -C ⁇ C-C 6 H 5 and -C ⁇ C-C ⁇ C-H.
  • Terminal alkenyl and terminalally alkynyl refers to terminal “alkenyl” and “alkynyl” groups respectively.
  • an optionally substituted alkyl group may be substituted with one or more of -F, -Cl, -Br, -I, -OH, -R 4 -O-R 5 , -R 4 -S-R 5 , -NH 2 , -NHR 5 , -N(R 5 ) 2 , -N(R 5 ) 3 + and/or -R 4 -N-(R 5 ) 2 .
  • An optionally substituted alkenyl group may be substituted with one or more of -F, -Cl, -Br, -I, -OH, -R 4 -O-R 5 , -R 4 -S-R 5 , -NH 2 , -NHR 5 , -N(R 5 ) 2 , -N(R 5 ) 3 + and/or -R 4 -N-(R 5 ) 2 .
  • An optionally substituted alkynyl group may be substituted with -F, -Cl, -Br, -I, -OH, -R 4 -O-R 5 , -R 4 -S-R 5 , -NH 2 , -NHR 5 , -N(R 5 ) 2 , -N(R 5 ) 3 + , -R 4 -N-(R 5 ) 2 , -Si(R 5 ) 3 , -C 5 H 4 N, -C 4 H 3 S and/or -C 6 H 5 .
  • An optionally substituted aryl group may be substituted with one or more of Cj-Cio alkyl, C 2 -C ⁇ o alkenyl, -NO 2 , -OCH 3 , -CH 2 OH, -F, -Cl, -Br, -OH, -NH 2 , -NHR 5 , -N(R 5 ) 2 , -N(R 5 ) 3 + , -NHCOR 5 , -COR 5 , -COOR 5 and/or -CON(R 5 ) 2 .
  • An optionally substituted heteroaryl group may be substituted with one or more of Cj-Cio alkyl, C 2 -C 10 alkenyl, -NO 2 , -OCH 3 , -F, -Cl, -Br, -OH, -NH 2 , -NHR 5 , -N(R 5 ) 2 , -N(R ) 3 + , -NHCOR 5 , -COR 5 , -COOR 5 and/or -CON(R 5 ) 2 .
  • a "non-peripheral" substituent is defined as a substituent ⁇ to the point of fusion between the pyrrole ring and the R 2 containing aromatic ring in a compound of formula (I) or (V), or ⁇ to either one of the two cyano groups in a compound of formula (IV), (VI) or (VII).
  • a substituent is defined as
  • peripheral when it is not “non-peripheral".
  • the non-peripheral substituents are in positions 1, 4, 8, 11, 15, 18, 22 and 25 and the peripheral substituents are in positions 2, 3, 9, 10, 16, 17, 23 and 24.
  • a substituted phthalocyanine is made up of a core structure and four substituent- units X.
  • the four substituent-units X are shown encircled in formulas (I) and (V) below.
  • a substituted phthalocyanine can be mixed or non-mixed.
  • a non-mixed phthalocyanine is a phthalocyanine made up of four identical substituent-units X.
  • a mixed phthalocyanine is a phthalocyanine made up of at least two different substituent-units, preferably a mixed phthalocyanine is made up of two different substituent-units X 1 and X 2 , wherein the ratio of X'.X 2 may be 1 :3, 2:2 or 3:1. When the ratio of X':X 2 is 2:2, the pairs of identical substituent-units X or X may be adjacent to each other or opposite each other.
  • a non-mixed or a mixed phthalocyanine may be obtained.
  • M is an isotope of Cu, Ni, Pb, V, Pd, Pt, Co, Nb, Al, Sn, Zn, Mg, Ca, In, Ga, Fe, Ge, a lanthanide, Si with two axial substituents or 2H. More preferably, is an isotope of a diamagnetic metal, Si with two axial substituents or 2H. Even more preferably, M is an isotope of Zn, Al, Mg, Pd, Pt, Si with two axial substituents or 2H.
  • the phthalocyanine (I) is a non-mixed phthalocyanine or if the phthalocyanine (I) is substituted with -S-R 5 , the sum of m and p is not 4 or 8.
  • the compound of formula (I) and/or (V) may form a sandwich complex comprising two or more compounds of formula (I) and/or (V).
  • a multimer comprising two or more compounds of formula (I) and/or (V) covalently linked.
  • the covalently linked compounds of formula (I) and/or (V) are covalently linked via substituents R 1 , R 8 and/or R 9 .
  • R , R , R and p are defined as in the first aspect of the present invention, and m is 1, 2, 3 or 4,
  • R is defined as in the first aspect of the present invention.
  • the conversion of the sulfonate ester of formula (III) into the substituted phthalonitrile of formula (IV) comprises a cross-coupling of the sulfonate ester of formula (III) with an organozinc reagent R'ZnX or an organocopper reagent R'CuX catalysed by palladium or nickel, wherein R 1 is defined as in the first aspect of the present invention and X is a halogen.
  • the halogen is Cl, Br or I.
  • the conversion of the sulfonate ester of formula (III) into the substituted phthalonitrile of formula (IV) comprises a cross-coupling of the sulfonate ester of formula (III) with a trialkylborane B(R') 3 catalysed by palladium, wherein R 1 are the same or different and each R is C ⁇ -C 20 alkyl optionally substituted; -R 4 -O-R 5 ; -R 4 -S-R 5 ; -R 4 -N-(R 5 ) 2 ; -R 4 -P-(R 5 ) 2 ; -R 4 -aryl optionally substituted; -R 4 -heteroaryl optionally substituted; -R 4 -COR 5 ; -R 4 -COOR 5 or
  • B(R') 3 is 9-BBN, i.e. R'BCCHHM).
  • the conversion of the sulfonate ester of formula (III) into the substituted phthalonitrile of formula (IV) comprises a cross-coupling of the sulfonate ester of formula
  • R are the same or different and each R is Cj-Cio alkyl optionally substituted and both R 7 together with -O-B-O- may form a ring.
  • R ] B(OR 7 ) 2 is R'B ⁇ C ⁇ CH ⁇ C ⁇ O-), R ⁇ -OCH Z CH J O-) or
  • the conversion of the sulfonate ester of formula (III) into the substituted phthalonitrile of formula (IV) comprises a coupling of the sulfonate ester of formula (III) with a coupling partner R1H catalysed by palladium, wherein R 1 is C 2 -C 20 terminally alkenyl optionally substituted or C 2 -C 20 terminally alkynyl optionally substituted.
  • R 1 are the same or different and each R 1 is C ⁇ -C 2 o alkyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -R 4 -O-R 5 , -R 4 -S-R 5 , -NH 2 , -NHR 5 , -N(R 5 ) 2 , -N(R 5 ) 3 + and/or -R 4 -N-(R 5 ) 2 ; C 2 -C 20 alkenyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -R 4 -O-R 5 , -R 4 -S-R 5 , -NH 2 , -NHR 5 , -N(R 5 ) 2 , -N(R 5 ) 3 + and/or -R 4 -N-(R 5 ) 2 ; C
  • R 1 are the same or different and each R 1 is CrC 20 alkyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -NH 2 , -NHR 5 , -N(R 5 ) 2 and/or -N(R 5 ) 3 + ; C 2 -C 20 alkenyl; C 2 -C 20 alkynyl; -S-R 5 ; -N-(R 5 ) 2 ; -R 4 -aryl, optionally substituted with one or more of C ⁇ -C 10 alkyl, C 2 -C ⁇ o alkenyl, -NO 2 , -OCH 3 , -F, -Cl, -Br, -OH, -NH 2 , -NHR 5 , -N(R 5 ) 2 , -N(R 5 ) 3 + , -NHCOR 5 , -COR 5 ,
  • R 1 may be a peripheral or a non-peripheral substituent.
  • at least one R 1 is a non-peripheral substituent.
  • the compound of formula (I) and/or (IV) may be substituted with or conjugated to an amino acid, a fatty acid, a nucleic acid, a di-, tri- or up to decapeptide, a polypeptide, a protein, a saccharide, a polysaccharide or a polymer.
  • the compound of formula (I) and/or (IV) is substituted with or conjugated to an amino acid, a fatty acid, a nucleic acid, a di-, tri- or up to decapeptide, a polypeptide, a protein, a saccharide, a polysaccharide or a polymer via substituent R .
  • R , R , R and p are defined as in the first aspect of the present invention, and m is 1, 2, 3 or 4,
  • R is Preferably, R 6 are the same or different and each R 6 is -CH 3 , -C 2 H 5 , -C 3 H 7 , -CH(CH 3 ) 2 , -C 4 H 9 , -C 8 H 17 , -CHC1 2 , -CF 3 , -C 4 F 9 , -C 6 H 5 , -(C 6 H 4 )-4-CH 3 , -(C 6 H 4 )-2-NO 2 , -(C 6 H 4 )-3-NO 2 , -(C 6 H 4 )-4-NO 2 , -(C 6 H 4 )-2-Br, -(C 6 H 4 )-4-Br, -(C 6 H 4 )-4-Cl, -(C 6 H4)-4-F, -(C 6 H 3 )-2,5-Cl 2 , -(C 6 H 3 )-3,4-Cl 2 , -(C 6 H4)-4
  • p 0.
  • n are the same or different and each m is 0, 1, 2, 3 or 4;
  • R 1 are the same or different and each R 1 is C ⁇ -C 20 alkyl optionally substituted;
  • R 2 are the same or different and each R 2 is
  • p are the same or different and each p is 0, 1 , 2 or 3;
  • R are the same or different and each R is -F, -Cl, -Br or -I;
  • R are the same or different and each R is C ⁇ -C 20 alkyl optionally substituted;
  • q 1 or 2;
  • R 9 are the same or different and each R 9 is -Cl, -Br, -I, -alkyl optionally substituted, -alkenyl optionally substituted, -alkynyl optionally substituted, -aryl optionally substituted or -heteroaryl optionally substituted; and
  • M is a metal atom in the M(II) oxidation state, a metal chloride, a metal bromide, a metal oxide, silicon with two axial substituents or two hydrogen atoms, one hydrogen being bonded to each of the two bonding nitrogen atoms;
  • R 10 are the same or different and each R 10 is -Cl, -Br or -I, into a substituted phthalonitrile of formula (VII)
  • R are the same or diffferent and each R is -alkyl optionally substituted, -alkenyl optionally substituted, -alkynyl optionally substituted, -aryl optionally substituted or -heteroaryl optionally substituted;
  • R 9 being -Cl, -Br or -I into an R 9 being -alkyl optionally substituted, -alkenyl optionally substituted, -alkynyl optionally substituted, -aryl optionally substituted, or -heteroaryl optionally substituted.
  • a non-mixed or a mixed phthalocyanine may be obtained.
  • M is an isotope of Cu, Ni, Pb, V, Pd, Pt, Co, Nb, Al, Sn, Zn, Mg, Ca, In,
  • M is an isotope of a diamagnetic metal, Si with two axial substituents or 2H. Even more preferably, M is an isotope of Zn, Al, Mg, Pd, Pt, Si with two axial substituents or 2H.
  • R 1 are the same or different and each R 1 is C ⁇ -C 20 alkyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -R 4 -O-R 5 , -R 4 -S-R 5 , -NH 2 , -NHR 5 , -N(R 5 ) 2 , -N(R 5 ) 3 + and/or -R 4 -N-(R 5 ) 2 ; C 2 -C 20 alkenyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -R 4 -O-R 5 , -R 4 -S-R 5 , -NH 2 , -NHR 5 , -N(R 5 ) 2 , -N(R 5 ) 3 + and/or -R 4 -N-(R 5 ) ; C 2 -C 20 al
  • R 1 are the same or different and each R 1 is Cj-C 2 o alkyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -NH 2 , -NHR 5 , -N(R 5 ) 2 and/or -N(R 5 ) 3 + ; C 2 -C 20 alkenyl; C 2 -C 20 alkynyl; -S-R 5 ; -N-(R 5 ) 2 ; -R 4 -aryl, optionally substituted with one or more of C ⁇ -C 10 alkyl, C 2 -C ⁇ 0 alkenyl, -NO 2 , -OCH 3 , -F, -Cl, -Br, -OH, -NH 2 , -NHR 5 , -N(R 5 ) 2 , -N(R 5 ) 3 + , -NHCOR 5 , -
  • At least one R 1 is not C ⁇ -C 20 alkyl non-substituted.
  • R 1 may be a peripheral or a non-peripheral substituent.
  • at least one R 1 is a non-peripheral substituent.
  • the compound of formula (V) may be substituted with or conjugated to an amino acid, a fatty acid, a nucleic acid, a di-, tri- or up to decapeptide, a polypeptide, a protein, a saccharide, a polysaccharide or a polymer.
  • the compound of formula (V) is substituted with or conjugated to an amino acid, a fatty acid, a nucleic acid, a di-, tri- or up to decapeptide, a polypeptide, a protein, a saccharide, a polysaccharide or a polymer via substituent R 1 .
  • the phthalocyanine (V) is a non-mixed phthalocyanine or if the phthalocyanine (V) is substituted with -S-R 5 , the sum of m and p is not 4 or 8.
  • R 2 is
  • p 0.
  • R are the same or different and each R is C ⁇ -C 20 alkyl optionally substituted with -OH. More preferably, R are the same or different and each R is C ⁇ -C 20 alkyl. Even more preferably, R 8 are the same or different and each R 8 is C]-C 10 alkyl.
  • R 9 are the same or different and each R 9 is -Br, -I, -alkenyl optionally substituted, -alkynyl optionally substituted, -aryl optionally substituted or -heteroaryl optionally substituted.
  • the compound of formula (I) and/or (V) may form a sandwich complex comprising two or more compounds of formula (I) and/or (V).
  • a multimer comprising two or more compounds of formula (I) and/or (V) covalently linked.
  • the covalently linked compounds of formula (I) and/or (V) are covalently linked via substituents R 1 , R 8 and/or R 9 .
  • R are the same or different and each R is C ⁇ -C 20 alkyl optionally substituted with -OH. More preferably, R 8 are the same or different and each R 8 is C ⁇ -C 20 alkyl. Even more preferably, R 8 are the same or different and each R 8 is C J -CIQ alkyl.
  • n 1, 2, 3 or 4;
  • R 6 is either C]-C 12 alkyl, optionally substituted with one or more of -F and/or -Cl, or aryl, optionally substituted with -CH 3 , -NO 2 , -OCH 3 , -F, -Cl and/or -Br; and when m is 2, 3 or 4, R are the same or different; p is 0, 1, 2 or 3; and
  • R ,3 is either -F, -Cl, -Br or -I; and when p is 2 or 3, R are the same or different.
  • R is N
  • R are the same or different and each R is -CH 3 , -C 2 H 5 , -C 3 H 7 , -CH(CH 3 ) 2 , -C 4 H 9 , -C 8 H 17 , -CHC1 2 , -CF 3 , -C 4 F 9 , -C 6 H 5 , -(C 6 __ 4 )-4-CH 3 , -(C 6 H 4 )-2-NO 2 , -(C 6 H 4 )-3-NO 2 , -(C 6 H 4 )-4-NO 2 , -(C 6 H 4 )-2-Br, -(C 6 H 4 )-4-Br, -(C 6 H 4 )-4-Cl, -(C 6 H 4 )-4-F, -(C 6 H 3 )-2,5-Cl 2 , -(C 6 H 3 )-3,4-Cl 2 , -(C 6 H 3 )
  • p 0.
  • n 1, 2, 3 or 4;
  • R is C ⁇ -C 20 alkyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -R 4 -O-R 5 , -R 4 -S-R 5 , -NH 2 , -NHR 5 , -N(R 5 ) 2 , -N(R 5 ) 3 + and/or -R 4 -N-(R 5 ) 2 ; C 2 -C 20 alkenyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -R 4 -O-R 5 , -R 4 -S-R 5 , -NH 2 , -NHR 5 , -N(R 5 ) 2 , -N(R 5 ) 3 + and/or -R 4 -N-(R 5 ) 2 ; C 2 -C 20 alkynyl, optionally substituted
  • -R 5 is C ⁇ -C 20 alkyl, C 2 -C 20 alkenyl, aryl, heteroaryl or H, or two -R 5 together form a saturated or unsaturated ring; and when m is 2, 3 or 4, R 1 , -R 4 - and -R 5 are the same or different;
  • p 0, 1, 2 or 3;
  • R is either -F, -Cl, -Br or -I; and when p is 2 or 3, R are the same or different;
  • R 1 is C ⁇ -C 20 alkyl non-substituted, -CF 3 , -OR 5 , -CH 2 OR 5 or -S-aryl, m is 3 or 4 or p is 1 , 2 or 3.
  • At least one R 1 is not C ⁇ -C 20 alkyl non-substituted.
  • R 1 are the same or different and each R 1 is C ⁇ -C 20 alkyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR 5 , -SR 5 , -NH 2 , -NHR 5 , -N(R 5 ) 2 and/or -N(R 5 ) 3 + ; C 2 -C 20 alkenyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR 5 , -SR 5 , -NH 2 , -NHR 5 , -N(R 5 ) 2 and/or -N(R 5 ) 3 + ; C 2 -C 20 alkynyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR 5 , -SR 5 , -NH 2
  • R 1 are the same or different and each R 1 is C 1 -C 20 alkyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR 5 , -SR 5 , -NH 2 and/or -NHR 5 ; C 2 -C 2 o alkenyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR 5 , -SR 5 , -NH 2 and/or -NHR 5 ; C2-C 20 alkynyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR 5 , -SR 5 , -NH 2 and/or -NHR 5 ; -OR 5 ; -SR 5 ; -SO 2 R 5 ;
  • R 1 are the same or different and each R 1 is C 1 -C 20 alkyl substituted with at least one or more of -F, -Cl, -Br, -I, -OH, -NH 2 , -NHR 5 , -N(R 5 ) 2 and/or -N(R 5 ) 3 + ; C 2 -C 20 alkenyl; C 2 -C 2 o alkynyl; -S-R 5 ; -N-(R 5 ) 2 ; -aryl, optionally 25 substituted with one or more of C1-C 10 alkyl, C 2 -C ⁇ 0 alkenyl, -NO 2 , -OCH 3 , -F, -Cl, -Br, -OH, -NH 2 , -NHR 5 , -N(R 5 ) 2 , -N(R 5 ) 3 + , -NHCOR 5 , -COR
  • R 1 are the same or different and each R 1 is C 1 -C 20 alkyl fully substituted with -F, -Cl and/or -Br; C 2 -C 2 o alkenyl; C 2 -C 20 alkynyl; -S-R 5 ; or -aryl, optionally substituted with one or more of -CH 3 , -NO 2 , -OCH 3 , -F, -Cl, -Br, -OH and/or -NH 2 ; where -R 5 are the same or different and each -R 5 is C1-C2 0 alkyl, C 2 -C 20 alkenyl, aryl, heteroaryl or H, or two -R 5 together form a saturated or unsaturated ring.
  • R 1 may be a peripheral or a non-peripheral substituent.
  • at least one R 1 is a non-peripheral substituent.
  • the compound of formula (IV) may be substituted with or conjugated to an amino acid, a fatty acid, a nucleic acid, a di-, tri- or up to decapeptide, a polypeptide, a protein, a saccharide, a polysaccharide or a polymer.
  • the compound of formula (IV) is substituted with or conjugated to an amino acid, a fatty acid, a nucleic acid, a di-, tri- or up to decapeptide, a polypeptide, a protein, a saccharide, a polysaccharide or a polymer via substituent R 1 .
  • R 2 is A .
  • p 0.
  • R 1 are the same or different and each R 1 is C ⁇ -C 20 alkyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -R 4 -O-R 5 , -R 4 -S-R 5 , -NH 2) -NHR 5 , -N(R 5 ) 2 , -N(R 5 ) 3 + and/or -R 4 -N-(R 5 ) 2 ; C 2 -C 20 alkenyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -R 4 -O-R 5 , -R 4 -S-R 5 , -NH 2 , -NHR 5 , 5 -N(R 5 ) 2 , -N(R 5 ) 3 + and/or -R
  • R are the same or different and each R is
  • 25 p are the same or different and each p is 0, 1, 2 or 3; provided that not all four m and all four p are 0 simultaneously;
  • R are the same or different and each R is either -F, -Cl, -Br or -I;
  • 30 M is a metal atom in the M(II) oxidation state, a metal chloride, a metal bromide, a metal oxide, silicon with two axial substituents or two hydrogen atoms, one hydrogen being bonded to each of the two bonding nitrogen atoms;
  • R 1 provided that when all R 1 are the same and are C ⁇ -C 20 alkyl non-substituted, -CF 3 ,
  • the substituted phthalocyanine (I) of the eighth aspect of the present invention may be a non-mixed or a mixed phthalocyanine. 10
  • At least one R 1 is not C ⁇ -C 20 alkyl non-substituted.
  • R 1 are the same or different and each R 1 is C ⁇ -C 20 alkyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR 5 , -SR 5 , -NH 2 , -NHR 5 ,
  • C 2 -C 20 alkenyl optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR 5 , -SR 5 , -NH 2 , -NHR 5 , -N(R 5 ) 2 and/or -N(R 5 ) 3 + ;
  • C 2 -C 20 alkynyl optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR 5 , -SR 5 , -NH 2 , -NHR 5 , -N(R 5 ) 2 , -N(R 5 ) 3 + , -Si(R 5 ) 3 , - ILtN, -C 4 H 3 S and/or -C 6 H 5 ; -OR 5 ; -SR 5 ;
  • each -R 5 is C 1 -C 20 alkyl, C 2 -C 20 alkenyl, aryl, hetereoaryl or H, or two -R 5 together form a saturated or unsaturated ring.
  • R 1 are the same or different and each R 1 is C ⁇ -C 20 alkyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR 5 , -SR 5 , -NH 2 30 and/or -NHR 5 ; C 2 -C 20 alkenyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR 5 , -SR 5 , -NH 2 and/or -NHR 5 ; C 2 -C 2 o alkynyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR 5 , -SR 5 , -NH 2 and/or -NHR 5 ; -OR 5 ; -SR 5 ; -SO 2 R 5 ; -N-(R 5 ) 2 ;
  • R 1 are the same or different and each R 1 is C ⁇ -C 20 alkyl substituted with at least one or more of -F, -Cl, -Br, -I, -OH, -NH 2 , -NHR 5 , -N(R 5 ) 2 and/or -N(R 5 ) 3 + ; C 2 -C 20 alkenyl; C 2 -C 20 alkynyl; -S-R 5 ; -N-(R 5 ) 2 ; -aryl, optionally 10 substituted with one or more of C ⁇ -C ⁇ 0 alkyl, C 2 -C ⁇ 0 alkenyl, -NO 2 , -OCH 3 , -F, -Cl, -Br, -OH, -NH 2 , -NHR 5 , -N(R 5 ) 2 , -N(R 5 ) 3 + , -NHCOR 5 , -COR 5
  • R 1 are the same or different and each R 1 is Cj-C 2 o alkyl fully substituted with -F, -Cl and/or -Br; C 2 -C 20 alkenyl; C 2 -C 20 alkynyl; -S-R 5 ; or -aryl, optionally substituted with one or more of-CH 3 , -NO , -OCH 3 , -F, -Cl, -Br, -OH and/or -NH ; where -R 5 are the same or different and each -R 5 is C ⁇ -C 20 alkyl, C 2 -C 2 o alkenyl, aryl, heteroaryl or H, or two -R 5 together form a saturated or unsaturated ring.
  • R 1 may be a peripheral or a non-peripheral substituent.
  • at least one R 1 is a non-peripheral substituent.
  • the compound of formula (I) may be substituted with or conjugated to an amino
  • the compound of formula (I) is substituted with or conjugated to an amino acid, a fatty acid, a nucleic acid, a di-, tri- or up to decapeptide, a polypeptide, a protein, a saccharide, a polysaccharide or a polymer via substituent R 1 .
  • the phthalocyanine (I) is a non-mixed phthalocyanine or if the phthalocyanine (I) is substituted with -S-R 5 , the sum of m and p is not 4 or 8.
  • R 2 is ⁇ .
  • p 0.
  • M is an isotope of Cu, Ni, Pb, V, Pd, Pt, Co, Nb, Al, Sn, Zn, Mg, Ca, In,
  • M is an isotope of a diamagnetic metal, Si with two axial substituents or 2H. Even more preferably, M is an isotope of Zn, Al, Mg, Pd, Pt, Si with two axial substituents or 2H.
  • R 1 are the same or different and each R 1 is C 2 -C 20 alkyl fully substituted with -F, -Cl and/or -Br; C 2 -C 20 alkenyl; C 2 -C 20 alkynyl; -S-R 5 ; or -aryl, optionally substituted with one or more of -CH 3 , -NO 2 , -OCH 3 , -F, -Cl, -Br, -OH and/or -NH 2 ; where -R 5 are the same or different and each -R 5 is C]-C 20 alkyl, C 2 -C 20 alkenyl, aryl, hetereoaryl or H, or two -R together form a saturated or unsaturated ring; A R 2 is ⁇ ; and
  • M is an isotope of Zn, Al, Mg, Pd, Pt, Si with two axial substituents or 2H.
  • the compound of formula (I) and/or (V) may form a sandwich complex comprising two or more compounds of formula (I) and/or (V).
  • a multimer comprising two or more compounds of formula (I) and/or (V) covalently linked.
  • the covalently linked compounds of formula (I) and/or (V) are covalently linked via substituents R 1 , R 8 and/or R 9 .
  • the substituted phthalocyanine is conjugated to a carrier or entrapped or embedded in a macromolecular carrier.
  • the carrier is an amino acid, a fatty acid, a nucleic acid, a di-, tri- or up to decapeptide, a polypeptide, a saccharide, a polysaccharide or a polymer.
  • the substituted phthalocyanine is conjugated to a carrier, it is preferably conjugated to the carrier via substituent R 1 , R 8 or R 9 .
  • the macromolecular carrier is a polypeptide
  • the polypeptide is preferably an antibody.
  • the substituted phthalocyanine is preferably entrapped or embedded in a solid polymer or conjugated to a soluble polymer.
  • the solid polymer is selected from polyesters, poly(orthoesters), polyanhydrides, tyrosine derived pseudo-poly(amino acids) or polyphosphazenes, or the soluble polymer is selected from N-(2-hydroxypropyl)methacrylamide (HMPA) copolymers, polyvinylpyrrolidone (PVP), poly(ethylene glycol) (PEG) polymers, copolymers or block copolymers, amino acid derived polymers or polyesters.
  • the solid or soluble polymer is a biodegradable polymer.
  • the substituted phthalocyanine of the present invention is for use as a medicament.
  • the medicament is for use in the photodynamic therapy of a human or animal disease.
  • a pharmaceutical composition comprising a substituted phthalocyanine according to the present invention or a pharmaceutically acceptable salt thereof in a mixture or in association with a pharmaceutically acceptable carrier, diluent or excipient.
  • the pharmaceutical composition is in a form suitable for topical, subcutaneous, mucosal, parenteral, systemic, intra-articular, intra-venous, intra-muscular, intra-cranial, rectal or oral application.
  • the pharmaceutical composition of the present invention is for use in the photodynamic therapy of a human or animal disease.
  • the human or animal disease is characterised by benign or malignant cellular hyperproliferation or by areas of neovascularisation.
  • the human or animal disease is a viral, fungal or bacterial disease or a disease caused by prions.
  • the human or animal disease is a tumour, rheumatoid arthritis, inflammatory arthritis, hemophilia, osteoarthritis, vascular stenosis, vascular restenosis, atheromas, hyperplasia, intimal hyperplasia, benign prostate hyperplasia, psoriasis, mycosis fungoides, eczema, actinic keratosis or lichen planus.
  • the source of illumination is a laser or a non-coherent light source emitting light of optimal wavelength.
  • a substituted phthalocyanine of the present invention for the manufacture of a phototherapeutic agent for the use in photodynamic therapy.
  • the phototherapeutic agent is used for the treatment of a disease characterised by benign or malignant cellular hyperproliferation.
  • the phototherapeutic agent is used for the treatment of a viral, fungal or bacterial disease or a disease caused by prions.
  • the phototherapeutic agent is used for the treatment of a disease such as a tumour, rheumatoid arthritis, inflammatory arthritis, hemophilia, osteoarthritis, vascular stenosis, vascular restenosis, atheromas, hyperplasia, intimal hype ⁇ lasia, benign prostate hype ⁇ lasia, psoriasis, mycosis fungoides, eczema, actinic keratosis and lichen planus.
  • a disease such as a tumour, rheumatoid arthritis, inflammatory arthritis, hemophilia, osteoarthritis, vascular stenosis, vascular restenosis, atheromas, hyperplasia, intimal hype ⁇ lasia, benign prostate hype ⁇ lasia, psoriasis, mycosis fungoides, eczema, actinic keratosis and lichen planus.
  • a substituted phthalocyanine of the present invention for the manufacture of a photodiagnostic agent for the identification of areas that are pathologically affected by cellular hype ⁇ roliferation.
  • a material comprising a substituted phthalocyanine of the present invention, wherein the optical or physical properties of the material may be altered by incident radiation.
  • the incident radiation is electromagnetic radiation. More preferably, the incident radiation is electromagnetic radiation with a wavelength in the range of from 200nm to lOOOnm.
  • a substituted phthalocyanine (I) may be prepared by the cyclisation of a substituted phthalonitrile (IV) either by itself or together with any other phthalonitrile of formula (IV).
  • a phthalonitrile of formula (IV) may in turn be prepared from a phthalonitrile sulfonate ester (III), which in turn may be prepared from a suitable phthalonitrile alcohol (II).
  • a phthalonitrile sulfonate ester of formula (III) may be prepared from a phthalonitrile alcohol of formula (II) under suitable conditions.
  • the preparation of 3,6- (trifluoromethanesulfonyloxy) phthalonitrile (a triflate), 2,3-dicyano-l,4- (trifluoromethanesulfonyloxy)naphthalene (a triflate) and 3,6- (nonafluorobutanesulfonyloxy)phthalonitrile (a nonaflate) are now described as representative examples of the preparation of phthalonitrile sulfonate esters of formula (III).
  • Aryl triflates are usually prepared from phenols in excellent yields by treating them with triflic anhydride in the presence of a base such as triethylamine or pyridine at low temperature (K. Ritter, Synthesis, 1993, page 735; P.J. Stang, M. Hanack, L.R. Subramanian, Synthesis, 1982, page 82).
  • a base such as triethylamine or pyridine at low temperature
  • the hydroquinone could be triflated in high yield (91%) by using either 2,6-lutidine or 2,4,6-collodine as the base in the presence of CH 2 C1 2 .
  • 2,6-lutidine or 2,4,6-collodine as the base in the presence of CH 2 C1 2 .
  • triflic anhydride dropwise under argon.
  • a simple aqueous work-up followed by recrystallisation from CH 2 Cl 2 /petrol or EtOAc/cyclohexane afforded the previously unknown 3,6-(trifluoromethanesulfonyloxy)phthalonitrile as yellow crystals in good yield.
  • 2,3-dicyano-l,4-(trifluoromethanesulfonyloxy)naphthalene was prepared by a similar procedure.
  • Aryl nonaflates are usually prepared from phenols by treatment with nonafluorobutanesulfonyl fluoride.
  • attempts to nonaflate the 2,3- dicyanohydroquinone under the above conditions all meet with failure, possibly due to the poorer leaving group ability of the fluoride anion compared with the triflate anion.
  • sodium hydride as the base in THF led to a clean and high yielding reaction to afford after a simple aqueous work-up the previously unknown 3,6- (nonafluorobutanesulfonyloxy)phthalonitrile.
  • the present invention provides a phthalonitrile sulfonyl ester of formula (III) and a process for its preparation.
  • a substituted phthalonitrile of formula (IV) may be prepared from a sulfonate ester of formula (III) under various conditions, such as for example cross-coupling with an organozinc reagent or an organocooper reagent catalysed by palladium (Method A) or nickel (Method B), cross-coupling with a trialkylborane catalysed by palladium (Method C), cross-coupling with a boronic acid or ester catalysed by palladium (Method D), S N A ⁇ reaction with a nucleophiles (Method E), or coupling with a suitable coupling partner catalysed by palladium (Method F).
  • organozincs are unreactive to a wide range of functional groups (P. Knochel, R.D. Singer, Chem. Rev., 1993, vol. 93, page 2117). This is important since it allows a range of functional groups to be inco ⁇ orated in the reaction, either on the organozinc reagent itself, or on the coupling partner.
  • Functional groups which can be tolerated include ketones, esters, amides, nitriles, acetals, alkenes and alkynes. Besides aryl and alkenyl halides, aryl and alkenyl triflates can also be used as coupling partners (K. Ritter, Synthesis, 1993, page 735; P. Knochel, J.J.A. Perea, P. Jones, Tetrahedron, 1998, vol. 54, page 8275; E. Erdik, Tetrahedron, 1992, vol. 48, page 9577).
  • decylzinc iodide was prepared by adding a concentrated solution (ca. 3M) of 1-iododecane in THF to a suspension of zinc dust (3 equivalent) in THF at 40°C.
  • the zinc dust was activated with a few mol% of dibromoethane and TMSC1 prior to the addition of the halide. After 12 hours at 40°C the preparation of decylzinc iodide was complete.
  • the organozincs can be prepared by metathesis of a Grignard or organolithium reagent with anhydrous ZnBr 2 or ZnCl 2 in THF. This method was also applied for the generation of decylzinc chloride.
  • This route firstly the MgCl 2 by-product tends to clog the stirrer and makes transfer by cannula problematic and secondly the ZnCl 2 is very hygroscopic and therefore difficult to dry.
  • 1-octynylzinc chloride was successfully prepared by metathesis of 1-octynyllithium with ZnCl 2 at -78°C.
  • the third method of note is the insertion of more activated zinc (Rieke zinc), prepared by the reduction of zinc halides, into less active alkyl bromides or even aryl bromides.
  • Rieke zinc more activated zinc
  • treatment of ZnCl 2 with finely cut lithium in the presence of naphthalene produces highly reactive zinc which reacts, for example with methyl 3-bromobutyrate in refluxing THF to afford the secondary zinc reagent
  • aryl and heteroarylzinc halides are available by using one of the three methods above (P. Knochel, J.J.A. Perea, P. Jones, Tetrahedron, 1998, vol. 54, page 8275).
  • the direct zinc insertion into iododecane is preferred for the preparation of the simple alkylzinc reagent decylzinc iodide.
  • 1-octynylzinc chloride was best prepared by metathesis of 1-octynyllithium and ZnC ⁇ at -78°C.
  • a more exotic zinc reagent 6-chlorohexylzinc bromide [Cl(CH2) 6 ZnBr] was purchased from the Aldrich chemical company. This was prepared by insertion of Rieke zinc. Rieke zinc as a solution in THF can also be purchased from Aldrich.
  • the Pd(PPh 3 ) 4 catalysed cross-coupling of 3,6-(trifluoromethanesulfonyloxy)- phthalonitrile with decylzinc iodide is described as a representative example of cross- coupling reactions of method A.
  • Lithium chloride was added as a co-catalyst. Although its exact role is not known, it helps to prevent biaryl formation and stabilises the catalyst (M. Fujita, H. Oka, K. Ogura, Tetrahedron Lett., 1995, vol. 36, page 5247; K. Ritter, Synthesis, 1993, page 735).
  • Nickel catalysis (method B) is an attractive alternative to palladium catalysis, both in terms of the cost of the metal and the increased reactivity of Ni(0) towards oxidative insertion into a carbon-halogen or carbon-triflate bond.
  • Snieckus and co-workers have examined the cross-coupling reaction of organotriflates with arylzinc reagents under a variety of conditions (CA. Quesnell, O.B. Familoni, V. Snieckus, Synlett, 1994, page 349). They examined a number of nickel catalysts including Ni(acac) 2 , Ni(acac) 2 /PPh 3 and NiCl 2 (PPh 3 ) 2 .
  • NiCl 2 (PPh 3 ) 2 /2PPh 3 catalysed cross-couplings of 3,6-
  • Ni(0) catalyst was generated in situ by the treatment of NiCl 2 (PPh 3 ) 2 (10 mol%) and PPh 3 (20 mol%) in THF at room temperature with «-BuLi (20 mol%) to afford a blood-red Ni(0) catalyst [Ni(PPh 3 ) ].
  • DIBAL or MeMgBr can be used instead of w-BuLi to generate the catalyst (CA. Quesnell, O.B. Familoni, V. Snieckus, Synlett, 1994, page 349).
  • To this catalyst was added 3,6-(trifluoromethanesulfonyloxy)phthalonitrile as a solid at room temperature under a stream of argon.
  • alkynylzinc chloride reagent prepared from an alkynyllithium 5 reagent with ZnCl 2 , led to the preparation of alkynyl-substituted phthalonitriles.
  • 3,6- bis(l'-octynyl)phthalonitrile was prepared by the cross-coupling of 1-octynylzinc chloride.
  • Alkyl boron reagents are readily available from the hydroboration of alkenes, and thus a wide range of alkyl groups can theoretically be introduced.
  • the most common alkyl transfer reagent used is a 9-alkyl-9-BBN derivative, whereupon the primary alkyl group is transferred preferentially. This is prepared from an alkene and 9-BBN.
  • simple trialkylborons, prepared from alkenes and BH 3 is more economical due to the expense of 9-BBN.
  • the cross-coupling involves the treatment of an aryl triflate with a palladium catalyst, a boron reagent and a base at high temperature (50-90°C), typically in a solvent such as THF or 1,4-dioxane.
  • the base is essential for the reaction to proceed, greatly increasing the nucleophilicity of the organoboron and accelerating the subsequent transmetalation step with the organopalladium complex (K. Matos, J.A. Soderquist, J. Org. Chem., 1998, vol. 63, page 461).
  • a variety of bases have been used for the reaction, although some of the most successful such as NaOMe (A. Furstner, G. Seidel, J. Org.
  • the cross-coupling of an aryl compound with a boronic acid or ester is a general method to couple an aromatic ring to an unsaturated coupling partner.
  • the reaction involves the palladium or nickel catalysed coupling of a boronic acid or ester with an aryl halide or triflate under mild base catalysis.
  • the mild conditions allow the inclusion of a wide-range of functionality on either coupling partner.
  • 3,6-diphenylphthalonitrile in 79% yield.
  • 3,6-Bis(4- methoxyphenyl)phthalonitrile and 3,6-bis(3-methoxyphenyl)phthalonitrile were prepared in a similar way by cross-coupling of 3,6-(trifluoromethanesulfonyloxy)phthalonitrile with 4-methoxyphenylboronic acid and 3 -methoxyphenylboronic acid respectively.
  • S N A ⁇ Nucleophilic aromatic substitution reactions are unfavourable due to electronic and steric reasons. S N AT reactions that nevertheless occur are thought to proceed either via a Meisenheimer complex or a benzyne intermediate. Arenes containing strongly electron-withdrawing groups ortho and/or para to the site of substitution may undergo S N A ⁇ reactions via an addition / elimination process (Meisenheimer complex). Treating arenes with a strong base can induce S N AT reactions via an elimination / addition process (benzyne intermediate).
  • Amino-substituted phthalonitriles may also be synthesised via method E, using amines such as for example piperidine, mo ⁇ holine, pyrrolidine or piperazine as nucleophiles, and has been exemplified using the first one of these.
  • S N AT conditions could possibly be favoured by using Cs 2 CO 3 as the base and the nonaflate rather than the triflate (see for example L. Neuville, A. Bigot, M.E.T.H. Dau, J. Zhu, J. Org. Chem., 1999, vol. 64, page 7638).
  • palladium catalysed animation may be a viable route (A.J. Belfield, Tetrahedron, 1999, vol. 55, page 11399).
  • a non-metallated or metallated substituted phthalocyanine of formula (I) may be prepared from a substituted phthalonitrile of formula (IV) under suitable conditions.
  • 3,6- Bis(dodecylsulfanyl)phthalonitrile was successfully cyclised into both the metal-free and the zinc phthalocyanine using NH 3 (g) in DMAE.
  • the cyclisation to form metallated derivatives can also be brought about using DBU as base.
  • Metal free analogues are also available by acid catalysed hydrolysis of the magnesium derivatives, exemplified by the demetallation of the octakis(nonylsulfanyl)phthalocyaninato magnesium(II) derivative.
  • the Q-band of these phthalocyanines is significantly red-shifted, occurring between 780 and 830 nm.
  • octa-S-aryl phthalocyanines with the eight groups similarly located on the phthalocyanine core, have been prepared by displacement of eight chlorine groups on an octa-chloro phthalocyanine.
  • Such compounds were identified as near infra-red absorbing dyes useful for security printing (EP application no. 85301291.2).
  • 3,6-bis(substituted)phthalonitrile precursors can be similarly cyclotetramerised to give the corresponding metallated or unmetallated phthalocyanine.
  • 3,6-Bis(6'-imidazol-l-yl-hexyl)phthalonitrile provides access to the corresponding zinc octakis(6'-imidazol-l-yl-hexyl)phthalocyanine, a derivative soluble in aqueous acid.
  • 1 :3 and 2:2 mixed substituted phthalocyanines may also be prepared making use of methods A to F described above, by cyclising a substituted phthalonitrile of formula (IV) together with any other substituted phthalonitrile (IV) instead of with itself.
  • [ 1 ,4-diphenyl-8, 11,15,18,22,25-hexakis(decyl)phthalocyaninato] zinc(II) was prepared by cross cyclotetramerisation of 3,6-diphenylphthalonitrile and 3,6- didecylphthalonitrile and [l,4-bis(4-methoxyphenyl)-8,l 1,15,18,22,25- hexakis(decyl)phthalocyaninato] zinc(II) was prepared by cross cyclotetramerisation of 3 ,6-bis(4-methoxyphenyl)phthalonitrile and 3 ,6-didecylphthalonitrile.
  • l,4-bis(3-methoxyphenyl)phthalonitrile and 3,6-didecylphthalonitrile provide [ 1 ,4-bis(3-methoxyphenyl)-8, 11,15,18,22,25-hexakis(decyl)phthalocyaninato] zinc(II).
  • the 3,6-didecylphthalonitrile may be used in excess.
  • Byproducts of the reaction include the symmetrically substituted [1,4,8,11,15,18,22,25- octakis(decyl)phthalocyaninato] zinc(II) and the 2:2 mixed substituted phthalocyanines in which the pairs of common substituted isoindole units are either opposite or adjacent.
  • This isomer mixture has been characterised in the case of the mixed cyclisation of 3,6- diphenylphthalonitrile and 3,6-didecylphthalonitrile.
  • Phthalocyanines bearing functional groups on the pendant aromatic rings can provide access to further derivatives by standard chemistry. For example, demethylation of the methoxy groups by reagents such as BBr 3 in the cases cited would lead to the corresponding phenolic derivatives. These could be used to link two or more phthalocyanine molecules together via diester linkages to form dimeric or oligomeric derivatives.
  • mixed phthalocyanines may also be synthesised with, for example, hydroxyalkyl or hydroxyalkoxy side chains on one phthalonitrile and hydrophobic substituents on the other phthalonitrile with the former in excess.
  • a metallated or non-metallated substituted phthalocyanine of formula (I) provides a metallated or non-metallated substituted phthalocyanine of formula (I) and a process for its preparation.
  • a metallated or non-metallated substituted phthalocyanine (V) may be prepared by the cyclisation of a substituted phthalonitrile (VI) or (VII) either by itself or together with any other pthalonitrile of formula (IV).
  • a substituted phthalonitrile of formula (VI) may in turn be prepared from 2,3- dicyanohydroquinone, as shown in Scheme 9.
  • a phthalonitrile halide of formula (VI) may be prepared from 2,3- dicyanohydroquinone by halogenation and subsequent alkylation under suitable conditions.
  • bromination of 2,3-dicyanohydroquinone affords 4,5-dibromo-3,6- dihydroxyphthalonitrile.
  • the use of Guenther's method T. Guenther, Justus Liebigs Ann. Chem., 1906, vol. 349, pages 56-58
  • bromine in acetic acid provides a product which gives a low analysis for bromine.
  • bromination of 2,3-dicyanohydroquinone using NBS Roussel UCLFA, French Patent No. 1313082, 28th December 1962; Chem. Abs., 1962, vol.
  • the present invention provides a phthalonitrile halide of formula (VI) and a process for its preparation.
  • 4,5-dibromo-3,6-dibutoxyphthalonitrile and 4-bromo-3,6- dibutoxyphthalonitrile were independently cyclotetramerised, the former to give the octabromo-octabutoxy-phthalocyaninato nickel(II) complex and the latter to give the tetrabromo-octabutoxy-phthalocyaninato zinc complex (as a mixture of regioisomers).
  • Substituted phthalocyanines having one phthalonitrile-monomer different from the other three (1:3 mixed substituted phthalocyanines) may be synthesised, for example, by making use of solid-phase synthetic methods (ret. Letts., 1982, vol. 23(30), pages 3023- 3026; J. Org. Chem., 1991, vol. 56, pages 82-90).
  • solid-phase synthetic methods ret. Letts., 1982, vol. 23(30), pages 3023- 3026; J. Org. Chem., 1991, vol. 56, pages 82-90.
  • polystyrene-based resins as solid-phase has been discussed (EP-A-0,906,758).
  • phthalocyanines having four identical phthalonitrile-monomers may also be synthesised via solid-phase synthesis.
  • 1 :3 and 2:2 mixed substituted phthalocyanines can in principle be prepared by several methods, for example cross cyclotetramerisation (G. de la Torre, P. Vazquez, F. Agullo- Lopez, T. Torres, J. Chem. Mat., 1998, vol. 8, pages 1671-1683; J. Bakboord, M.J. Cook, E. Hamuryudan, J. Porphyrins Phthalocyanines, 2000, vol. 4, pages 510-517).
  • route B has been followed using cross cyclotetramerisation to yield 1 :3 mixed substituted phthalocyanines.
  • the second fraction contains two components, which are separated on a second column, one of which is the required l,4-dibutoxy-2,3-dibromo-8,l l,15,18,22,25-hexakis(decyl)-phthalocyaninato nickel(II), identified by a cluster at 1714 D in the low resolution FAB-mass spectrum, elemental analysis and an ⁇ -NMR spectrum consistent with the expected structure.
  • the pure metal-free compound is isolated by column chromatography.
  • the metal-free compound is readily converted into 1,4- dibutoxy-2-bromo-8,l l,15,18,22,25-hexakis(decyl)phthalocyaninato zinc(II) by reaction with zinc acetate.
  • the latter is also obtained by reaction of 3,6-didecylphthalonitrile with 3,6-dibutoxy-4-bromophthalonitrile in DBU in the presence of zinc acetate.
  • Sonogashira coupling is first applied to l,4-dibutoxy-2-bromo-8,l 1,15, 18,22,25- hexakis(decyl)-phthalocyaninato nickel(II) using Et 3 N as solvent.
  • Et 3 N hexakis(decyl)-phthalocyaninato nickel(II)
  • the compound is reacted with trimethylsilylethyne (6 equivalents) at 80°C for 36 hours in the presence of Pd(PPh 3 ) 2 Cl 2 (20 mol%>) and Cul (30 mol%) with additional catalyst added after 24 hours, no cross coupling occurs.
  • Stille coupling procedure satisfactorily converts l,4-dibutoxy-2,3- dibromo-8,l l,15,18,22,25-hexakis(decyl)-phthalocyaninato nickel(II) directly into the unprotected ethynylated phthalocyanine in 54%> yield.
  • Stille coupling offers a significant improvement over the Sonogashira method in terms of overall yield.
  • there is less difficulty in separating the fully and partially coupled products which requires careful chromatography in the case of the Sonogashira procedure.
  • Sonogashira coupling using Pd(PPh 3 ) 2 Cl 2 /Cu(I)I as catalyst, or coupling using other catalysts for example Pd 2 (dba) 3 -AsPh 3 , can be undertaken to convert 1 ,4-dibutoxy-2- bromo-8,l l,15,18,22,25-hexakis(decyl)phthalocyaninato zinc(II) into corresponding substituted ethynylated derivatives.
  • the versatility of the Suzuki reaction on the 4-bromo- and 4,5-dibromo-3,6- dibutoxyphthalonitriles in principle provides access to other amino acid derivatives, for example with phenylalanine groups para coupled directly to the phthalonitrile core, preferably using NH 2 and CO 2 H protected derivatives of phenylalanine boronic acid or its ester (see F. Firooznia, C. Gude, K. Chan and Y. Satoh, Tetrahedron Letters, 1998, vol. 39, 3985).
  • phthalonitriles of formula (VII) can be cyclotetramerised alone to form further phthalocyanines.
  • 3,6-Dibutoxy-4,5-(tris(isopropyl)silylethynyl)phthalonitrile is converted into the corresponding [octabutoxy- octa(tris(isopropyl)silylethynyl)phthalocyaninato] nickel(II) complex.
  • Reaction of the latter with tetrabutylammonium fluoride removes the TIPS groups to afford the octabutoxy-octaethynyl phthalocyaninato nickel(II) complex.
  • the present invention provides a non-metallated or metallated substituted phthalocyanine of formula (V) and a process for its preparation.
  • phthalocyanines are investigated for liquid crystallinity as a routine element of their characterisation. Hitherto, the columnar mesophase properties of non-peripherally substituted phthalocyanines have been described, both uniformly substituted with either eight alkyl (A.S. Cherodian, A.N. Davies, R.M. Richardson, M.J. Cook, N.B. McKeown, A.J. Thomson, J. Feijoo, G. Ungar, K.J. Harrison, Mol. Cryst. Liq. Cryst., 1991, vol. 196, pages 103-114; M.J. Cook, S.J. Cracknell, K.J. Harrison, J. Mater. Chem., 1991, vol.
  • the first mesophase observed upon cooling gives rise to a "fan-like" birefringence texture characteristic of a discotic hexagonal disordered phase (D hd ) in accordance with the examples referred to above.
  • D hd discotic hexagonal disordered phase
  • l,4-Dibutoxy-2-bromo-8,l l,15,18,22,25-hexakis(decyl)- phthalocyaninato nickel (II) exhibits a second mesophase, but only during cooling. This phase is mobile and distorts under external pressure. It gives rise to an indistinct texture and has not been identified. It is here denoted as D x .
  • transition temperatures are measured by polarised light microscopy on the first heating and cooling cycle.
  • the higher temperature mesophase is assigned as Dhd-
  • the lower temperature mesophase D x is unknown.
  • the symmetry of the molecule has a marked effect upon the mesophase behaviour.
  • the nona-substituted phthalocyanines are of C s symmetry, whilst the deca-substituted phthalocyanines have C 2v symmetry.
  • the C s phthalocyanines exhibit lower K— »D hd transitions than the analogous C 2v phthalocyanines. This can be attributed to the more symmetrical phthalocyanines forming better packed crystals.
  • the C s phthalocyanines exhibit higher clearing points (K- ⁇ I or D hd ⁇ I) than their C 2v counte ⁇ arts.
  • the D hd mesophase of the C s phthalocyanines is much more mobile and less viscous than for the C v phthalocyanines.
  • the C s phthalocyanines also have a tendency towards supercooling, crystallisation occurring upon standing overnight at room temperature.
  • the C 2v phthalocyanines crystallise directly upon cooling.
  • the transition to the crystal is characterised by a colour change, not a change in texture, the "fans" becoming a lighter green. Replacement of the bromine atoms with unprotected ethynyl groups increases clearing transitions.
  • Substituted phthalocyanines show a multitude of desirable properties and are thus useful for a wide variety of applications.
  • Certain substituted phthalocyanines of the present invention show high photodynamic properties and a marked abso ⁇ tion in the red region of the visible spectrum. These compounds are thus useful both as such and in the form of conjugates with macromolecular carriers (such as for example polymers or antibodies) in the treatment of viral, fungal or bacterial diseases and diseases characterised by areas of neovascularisation or by benign or malignant cellular hype ⁇ roliferation, in particular diseases such as tumours, rheumatoid arthritis, inflammatory arthritis, hemophilia, osteoarthritis, vascular stenosis, vascular restenosis, atheromas, hype ⁇ lasia, intimal hype ⁇ lasia, benign prostate hype ⁇ lasia, psoriasis, mycosis fungoides, eczema, actinic keratosis or lichen planus. Moreover, in so far as they are fluorophores, they may be used as diagnostic agents for the identification of areas that are pathologically affected.
  • organic molecules containing the chromofluorophore macrocycle of the phthalocyanine are photo-activated by irradiation, they are capable of generating hyper- reactive derivatives of oxygen, above all singlet-oxygen or radicals, which are characterised by a high degree of cytotoxicity, and hence are potentially interesting for therapeutic applications, such as photodynamic therapy and/or diagnostic applications (E. Ben-Hur and I. Rosenthal, Int. J. Radiat. Biol., 1985, vol. 47, pages 145-147).
  • Photosensitization is a process in which a photochemical reaction is induced to occur by the presence of a substance (the photosensitizer), which absorbs the light but is itself substantially unchanged at the end of the reaction, the absorbed light energy being passed on to the main reactants.
  • a substance the photosensitizer
  • the photosensitizer absorbs the light but is itself substantially unchanged at the end of the reaction, the absorbed light energy being passed on to the main reactants.
  • the photosensitizer absorbs the light but is itself substantially unchanged at the end of the reaction, the absorbed light energy being passed on to the main reactants.
  • the photosensitizer the photosensitizer
  • the photosensitizer is broken down and a photo-product is formed which may also possess suitable photodynamic properties.
  • oxygen can be made sensitive to the electromagnetic radiation it may not normally absorb by the presence of phthalocyanines or other "complex" organic molecules; some of which may have metals or metal salts inco ⁇ orated.
  • the substituted phthalocyanines are administered to a tumour-bearing subject, where they are taken up by the tumour at least to a certain extent.
  • photodynamic therapy may be carried out in a conventional manner, using light sources and delivery systems that are known in the art (for example see Phys. Med. Biol., 1986, vol. 31(4), pages 327-360).
  • the tumour tissue is destroyed via the dye mediated photogeneration of species such as singlet oxygen or other cytotoxic species such as free radicals, for example hydroxy or superoxide.
  • Phthalocyanines comprising hydroxyl, amine or quaternary ammonium substituents have been described for photosensitization of cancer cells (CC. Leznoff et al., Photochemistry and Photobiology, 1989, vol. 49(3), pages 279-284; D. Wohrle et al., Photochemistry and Photobiology, 1990, vol. 51(3), pages 351-356; D. Wohrle D. et al., Dyes and Pigments, 1992, vol.
  • a compound is to be successful as a photosensitizer for use in photodynamic therapy, including the following: a) High quantum yield of reactive species, such as singlet-oxygen or radicals; b) Relatively low toxicity to the subject; c) Capacity of being activated by radiation of high wavelength (preferentially in the red or near infra-red region of the spectrum), which is able to penetrate more deeply into the tissues as compared to radiation of shorter wavelength; d) Selective accumulation by the cells that are responsible for a given pathological condition and fast elimination from the tissues that are not affected by the the pathological condition; e) Possibility of being conjugated to macromolecular carriers, albeit maintaining the characteristics of photosensitization efficiency.
  • Certain substituted phthalocyanines are induced to act as photosensitizers by incident electromagnetic radiation of a suitable wavelength.
  • the electromagnetic radiation is somewhere in the range of ultra-violet to infra-red, even more preferably it is in the range visible-red to infra-red. Red light shows greater tissue penetration than light of shorter wavelengths.
  • a photosensitizer absorbs laser light of a suitable wavelength, but other light sources may also be used, such as a tungsten halogen lamp.
  • Metallated phthalocyanines have been found to have better photosensitizing activity compared to metal-free phthalocyanines when the metal is diamagnetic. Particularly zinc (II) phthalocyanines have been found to be useful in photodynamic therapy. Conversely a paramagnetic metal renders the phthalocyanine inactive (I. Rosenthal, E. Ben-Hur, "Phthalocyanines in Photobiology” in “Phthalocyanines, Properties and Applications", eds., CC Leznoff and A.B.P. Lever, V.C.H. Publishers, 1989). Hydrophilic substituents or the conjugation to hydrophilic carriers can accelerate the metabolism of the phthalocyanines, enabling a fast in vivo elimination of the chromophore, and thus preventing the onset of cutaneous phototoxicity.
  • Some substituted phthalocyanines show photodynamic activity even at low oxygen concentration, thus being useful for the specific treatment of anaerobic microorganisms or the treatment of tumour diseases known to be characterised by a hypoxic environment.
  • Substituted phthalocyanines may also be conjugated to carriers to improve their pharmacological characteristics.
  • the carriers are normally chosen from the group consisting of amino acids, fatty acids, nucleic acids, di-, tri- or up to decapeptides, polypeptides, proteins, saccharides, polysaccharides, polymers and antibodies, which may be tailored to attach themselves to the tumour site.
  • Antibodies may be prepared from cultured samples of the tumour. Examples include P.L.A.P. (Placental Alkaline Phosphatase), H.M.F.G. (Human Milk Fat Globulin), C.E.A. (Carcino Embryonic Antibody) and H.C.G. (Human Chorionic Gonadotrophin).
  • the phthalocyanine-carrier bond may occur between carboxyl or amine groups or by exploiting other known functional and reactive groups.
  • compositions comprising a substituted phthalocyanine of the present invention, as such or in form of a conjugate with a carrier, or a pharmaceutically acceptable salt thereof, in a mixture or in association with a pharmaceutically acceptable carrier, diluent or excipient, may be formulated according to well-known principles and may desirably be in the form of unit dosages determined in accordance with conventional pharmacological methods.
  • the unit dosage forms may provide a daily dosage of active compound in a single dose or in a number of smaller doses. Dosage ranges may be established using conventional pharmacological methods and are expected to lie in the range of from 1 to 60 mg/kg of body weight.
  • compositions may desirably be in a form suitable for topical, subcutaneous, mucosal, parenteral, systemic, intra-articular, intravenous, intra-muscular, intra-cranial, rectal or oral application.
  • Suitable carriers and diluents are well known in the art and the compositions may include excipients and other components to provide easier or more effective administration.
  • the present invention provides a substituted phthalocyanine of formula (I) or (V) optionally conjugated to a carrier for use as a medicament, particularly for use in photodynamic therapy.
  • the present invention further provides a pharmaceutical composition comprising a phthalocyanine of formula (I) or (V) or a pharmaceutically acceptable salt thereof, particularly for use in photodynamic therapy.
  • the present invention further provides use of a substituted phthalocyanine of formula (I) or (V) for the manufacture of a phototherapeutic or photodiagnostic agent.
  • Some substituted phthalocyanines of the present invention in thin films for example Langmuir-Blodgett films and spin coated films, in the liquid crystalline state, or when dissolved or dispersed in a carrier material, are largely transparent in the visible region and are yet strong absorbers of ultraviolet or infra-red radiation, preferably of infrared radiation within the range of 750nm and 870nm and preferably exhibit abso ⁇ tion maxima within that range.
  • Such substituted phthalocyanines can be used in laser addressed applications, in which laser beams are used to scan across the surface of the material to leave a written impression thereon.
  • Gallium arsenide lasers provide laser light at a wavelength of about 850nm, and are most useful for the above applications. With increasing Al content (x ⁇ l), laser wavelength may be reduced down to about 750nm.
  • the high stability of the phthalocyanine ring system suggests further possible uses for the substituted phthalocyanines of the present invention, especially when complexed with central metal ions M, the variable oxidation states of which may give rise to materials with semiconductor, photoconductor or electrochromic properties. Such properties may be exploited in sensors, catalysts and displays.
  • substituted phthalocyanines of the present invention are derived from their stereochemistry and orientational ability, for example some have liquid crystal characteristics, and others may be of value in Langmuir-Blodgett films and spin coated films. Others may absorb electromagnetic radiation and be useful in solution for this pu ⁇ ose, for example in liquid crystals.
  • M is a large metal ion such as Pd or Pt, are as one-dimensional conductors, for example potentially or molecular wires.
  • substituted phthalocyanines of the present invention may be polymerised. Polymerisation may take place across double bonds in unsaturated side chains or by ester or amide formation or any other suitable polymerisation technique, which will be apparent to those skilled in the art. Any polymerisation may be achieved with little or no effect on the phthalocyanine ring itself, as it possesses high stability.
  • the present invention provides a material comprising a substituted phthalocyanine of formula (I) or (V), wherein the optical or physical properties of the material may be altered by incident electromagnetic radiation.
  • Figure 1 shows a typical decay and fitted curve for [l,4-bis(3-methoxyphenyl)- 8,l l,15,18,22,25-hexakis(decyl)-phthalocyaninato] zinc(II) (sample AA35) in toluene/pyridine, excited at 355nm.
  • the residuals (xlO) are shown offset by 20 mV.
  • the ringing observed in the first 2-3 ⁇ s of the decay are due to sensitiser fluorescence.
  • Figure 2 shows a plot showing the linear relationship between singlet oxygen emission intensity and laser energy for samples of perinaphthenone and [l,4-bis(3- methoxyphenyl)-8,l l,15,18,22,25-hexakis(decyl)-phthalocyaninato] zinc(II) (sample
  • Figure 3 shows a plot showing the relationship between the intensity of singlet oxygen signal (normalised for incident laser energy) and the fraction of light absorbed by [1 ,4-bis(3-methoxyphenyl)-8, 11,15,18,22,25-hexakis(decyl)-phthalocyaninato] zinc(II) (sample AA35) (1-10- A ).
  • Zinc dust 120 g was stirred in 2% HCl (300ml) for 2 minutes and the acid removed (decanter). The resulting dust was stirred sequentially with 2%> HCl (300 ml), water (3 x 300 ml) and 95%> ethanol (2 x 200ml), the dust being allowed to settle before the waste solvents were decantered. Finally the zinc was washed with diethyl ether (200 ml), filtered and dried under vacuum for 24 hours. The resulting dust was stored over P 2 O 5 . Preparation of tt-decylzinc iodide (see B. H. Lipshutz in "Organometallics in Synthesis. A Manual.”, ed. M. Schlosser, John Wiley and Sons, 1994, Chichester):
  • bis(triphenyl)phosphine-nickel(II) dichloride (0.53 g, 0.0008 mol) and triphenylphosphine (0.42 g, 0.0016 mol) were dissolved in dry THF (20 ml).
  • n-BuLi (0.65 ml of a 2.5M solution in hexane, 0.0016 mol) was added dropwise to afford the active red catalyst.
  • the second fraction was re-chromatographed over silica gel [pretreated with dichloromethane :triethylamine (99:1)] again first eluting with dichloromethane and then dichloromethane :THF (95:5) collecting the first deep blue fraction, which was recrystallised from THF:acetone to give 1,4,8,11,15,18,22,25- octakis(hexylsulfanyl)phthalocyaninato chloroindium(III) (17mg, 3%) as a dark blue/black solid [mp 202-204°C Found: C, 60.66; H.7.11; N, 6.84.
  • the first fraction was unreacted starting material (3.4 mg).
  • the second fraction contained a mixture; subsequent green fractions containing minor amounts of material were discarded.
  • the second fraction was further purified by column chromatography over silica (eluent: petrol/CH 2 Cl 2 98.5:1.5 then 97:3) to afford l,4-dibutoxy-2,3-(2 '-trimethylsilylethynyl)-8,l 1,15, 18,22,25- hexakis(decyl)phthalocyaninato nickel (II) as second fraction (13.2 mg, 35 %>) after recrystallisation from THF-methanol [m.p.
  • tributyl(ethynyl)tin 60 mg, 190 ⁇ mol was added, and the reaction heated at 100°C for 16 hours. The reaction was cooled and the toluene removed under reduced pressure. The residue was triturated with acetone to remove excess tributyl(ethynyl)tin, and the residue was washed from the filter paper with THF.
  • the solvent was removed under reduced pressure and the residue washed with methanol (3x50ml).
  • the crude phthalocyanine mixture was separated by column chromatography over silica (eluent: petrol ether).
  • the first fraction is 1,4,8,11, 15, 18,22,25-octakis(decyl)phthalocyanine (50mg) identical with an authentic sample.
  • the eluent was then changed to petrol/CH 2 Cl2 (10:1) and a second fraction collected.
  • the first fraction contains [1,4,8,11,15,18,22,25- octakis(decyl)phthalocyaninato] zinc(II) (240mg, 5.8%>).
  • the eluent was then changed to petroleum ether (bp. 40-60°C)/dichloromethane 1 : 1 and a second fraction was collected. This fraction was further purified by preparative tic on silica (eluent: petroleum ether (bp. 40-60°C)/dichloromethane 3:2).
  • the mixture was refluxed for 20 hours in the dark.
  • the solvent was removed under reduced pressure and the residue washed with methanol (3x50ml).
  • the crude product was separated by column chromatography over silica (eluent: petroleum ether (bp. 40-60°C): CH2CI2 4:1).
  • the first fraction contains symmetrical 1,4,8,11,15, 18,22,25-octakis(decyl)phthalocyaninato zinc(II) (300mg).
  • the eluent was changed to petroleum ether (bp. 40-60°C): CH2CI2 (1:1) and a second fraction collected. This fraction was further purified by preparation TLC silica plates (eluent: petroleum ether (bp.
  • the solution was degassed 3 times with Ar, then stirred in the dark in an oil bath at 80°C for 24 hours.
  • the reaction was cooled and again, under an Ar atmosphere, was added bis(triphenylphosphine)- palladium(II) chloride (3.84mg), copper(I) iodide (1.56mg) and 2-methyl-3-butyn-2-ol (15mg, lOeq).
  • the tube was resealed and heated at 80°C for a further 24 hours.
  • the reaction was monitored by TLC. After the starting material was consumed, the reaction was cooled, filtered and washed with diethyl ether until the washings were clear. The organics were combined and concentrated under reduced pressure.
  • Cesium fluoride (0.66g, 4.4mmol), tetrakis(triphenylphosphine)palladium(0) (0.25g, 10mol%) and 2-(4-pyridyl)-4,4,5,5-tetramethyl-l,3-dioxaborolane (0.45g, 2.2mmol) were placed under nitrogen for 10 minutes.
  • 4-Bromo-3,6-dibutoxyphthalonitrile (0.38g, l.lmmol) in 1 ,2-dimethoxyethane (DME) (20ml) was added and the mixture was refluxed for 48 hours, adding fresh tetrakis(triphenylphosphine)palladium(0) catalyst (0.25g, 10mol%) every 24 hours.
  • the solid was filtered and washed with methanol.
  • the product was separated by column chromatography on silica (eluent: petroleum ether (bp. 40-60°C) to remove 1,4,8,1 l,15,18,22,25-octakis(decyl)phthalocyanine).
  • the eluent was changed (petroleum ether (bp.40-60°C)-dichloromethane 9:1) and a second green fraction was collected. This was purified through a second silica column (eluents: petroleum ether (bp. 40-60°C) followed by petroleum ether (bp. 40-60°C)-dichloromethane 19:1).
  • the green product was separated by column chromatography on silica (eluent: toluene).
  • the first fraction contained symmetrical 1,4,8,11,15, 18,22,25-octakis(decyl)phthalocyanine.
  • the second fraction which contained the required product, was collected and was precipitated from toluene by addition of methanol to afford l,4-dibutoxy-2-(p-hydroxymethylphenyl)- 8, 11 , 15, 18,22,25-hexakis(decyl)phthalocyanine as a dark green solid, 100 mg (0.062mmol, 10%).
  • the second blue fraction contained [l,4-dibutoxy-2-(p- hydroxymethylphenyl)-8,ll, 15, 18,22, 25-hexakis(decyl)phthalocyaninato] zincfllj, 37 mg (0.022mmol, 90%).
  • the product was purified by column chromatography over silica (eluent: petroleum ether (bp. 40-60°C): dichloromethane 4:1) to remove [1,4,8,11, 15, 18,22,25-octakis(decyl)phthalocyaninato] zinc(II).
  • the eluent was changed to petroleum ether (bp. 40-60°C): dichloromethane 1 :1) and [1, 4-bis(3-methoxyphenyl)-8, 11,15,18,22, 25-hexakis(decyl)phthalocyaninato] zinc(II) was isolated as a green solid and recrystallised from THF/acetone [MALDI ms shows cluster at 1632.
  • 4,5-Dibromo-3,6-dibutoxyphthalonitrile (0.5g, l.l ⁇ mmol) was heated in dry butanol (6ml) under nitrogen.
  • DBU (0.18g, 1.2mmol) was added and reflux continued for 1 hour.
  • Nickel acetate tetrahydrate (0.09g, 0.3mmol) was added and reflux continued for 24 hours. The reaction was cooled and the solvent evaporated under reduced pressure.
  • 4,5-(tris(isopropyl)silylethynyl)-3,6- dibutoxyphthalonitrile (0.51g, 0.81mmol) was reacted with DBU (0.7g, 0.48mmol) and nickel acetate tetrahydrate (0.07g, 0.24mmol) in dry butanol (6ml) for 20 hours.
  • cells were incubated with the compound of interest, formulated in a liposome suspension, and then exposed to light of a suitable wavelength and energy. The number of viable cells surviving this treatment was registered.
  • the cell line chosen is the HT 1080 fibrosarcoma cell line [ATCC number: CCL-
  • This cell line represents hype ⁇ roliferating cells and is thus a useful model for the rapid cell cycle occurring in psoriasis.
  • DOPC L- ⁇ -dioleoyl- phosphatidylcholine
  • Rotavapor is then connected to a water pump in order to generate reduced pressure and the solvent is evaporated at room temperature.
  • the flask is saturated with nitrogen and 4ml of nitrogen-saturated phosphate buffered saline (PBS) are added.
  • PBS nitrogen-saturated phosphate buffered saline
  • the lipid film containing the phthalocyanine is resuspended by gently shaking in the presence of glass beads.
  • the aqueous suspension is sonicated (10 Hz) for about 30 minutes.
  • the vial is saturated with nitrogen and kept in an ice bath.
  • the liposomes are kept at room temperature overnight.
  • the liposomes have a shelf-life at 4°C of at least three months.
  • they are filtered through a 0.2 ⁇ m filter and the phthalocyanine concentration is measured by diluting a small aliquot of the suspension into a known excess of THF and determining the absorbance of such solution.
  • the cells were routinely cultured with DMEM (Eagle's modified Dulbecco medium added with 100 units/ml penicillin, 100 ⁇ g/ml streptomicin, 0.25 ⁇ m/ml anfotericin, 2mM glutamine) containing 10%> FCS (foetal calf serum) and maintained in a humid atmosphere containing 5%. CO 2 at a temperature of 37°C Normally, the cells were detached by using a solution of 0.05%> trypsin - 0.02% EDTA in phosphate-buffered saline. The action of trypsin was blocked by addition of FCS. The cell pellet, obtained by centrifugation at 1,000 ⁇ m for 8 minutes was resuspended with DMEM and 10%> FCS and then seeded in 75 cm 2 tissue cultured flasks.
  • DMEM Eagle's modified Dulbecco medium added with 100 units/ml penicillin, 100 ⁇ g/ml streptomicin,
  • Dulbecco medium containing 10%. FCS (foetal calf serum) and incubated in 25 cm tissue culture flasks. After 24 hours the culture medium was removed and replaced by 5ml DMEM (enriched with 3%> FCS) containing either 5 ⁇ M or 10 ⁇ Mof the phthalocyanine. The phthalocyanine was added in an aqueous suspension of DOPC liposomes. After 1 hour incubation, the medium was removed, the cells were washed twice with 4ml of
  • PBS devoid of Ca and Mg ions.
  • the cell pellet was homogenised with 2% aqueous sodium dodecylsulphate (SDS) (2ml).
  • SDS sodium dodecylsulphate
  • the suspension thus obtained was divided into two portions: a) 1ml was diluted with a known volume of THF for the determination of the phthalocyanine concentration by spectrophotofluorimetric analysis (excitation at 650 nm, emission collected in the 660-780 nm interval)using a Perkin-Elmer LS50B spectrophotofluorimeter. b) 0.5ml was used for the determination of the protein content by the standard assay with bicinchoninic acid.
  • 1.8x10 cells were seeded in Petri dishes of 7cm diameter, incubated for 24 hours in DMEM containing 10%. FCS in a humid atmosphere containing 5%. CO 2 and at a temperature of 37°C The medium was removed and replaced by 1ml DMEM containing 2.5 ⁇ M to 10 ⁇ M phthalocyanine which was added in DOPC liposomes. After 1 hour incubation, the cells were washed twice with PBS containing Ca 2+ (0.9 mM CaCl 2 • 2 H 2 O) ions and Mg 2+ (0.5 mM MgCl 2 • 2 H 2 O) ions.
  • the light source - Waldmann PDT 1200 (Waldmann Medical Division, Villingen- Schwenningen, Germany) - is a non-coherent light source with a filter allowing light between 600 and 730 nm to pass. A built-in output meter is used to monitor the doses given. The lamp was operated at a fluence rate of 100 mW/cm .
  • the cells in the Petri dish were irradiated (100 mW/cm ) for 1, 5, 10, 15 minutes (6 up to 90 J/cm 2 ) with 1ml PBS containing Ca 2+ and Mg 2+ ions.
  • the irradiated cells were mixed with 2ml DMEM containing 10%. FCS and incubated overnight.
  • the photosensitised cells were assayed by the trypan blue test (Reference: C. Milanesi, F. Sorgato, G. Jori, "Photokinetic and ultrastructural studies on po ⁇ hyrin photosensitization of HeLa cells", Int. J. Radiat. Biol, vol. 55, pages 59-69, 1989) and the survival was expressed as the percentage of the survival typical of cells which had been treated by an identical procedure but were not exposed to light.
  • Preliminary studies showed that irradiation of the cells in the absence of the photosensitizer and dark incubation of the cells with phthalocyanines has no effect on cell survival.
  • UV-Vis spectra were recorded using a Hitachi U-3000 Spectrophotometer.
  • the phthalocyanines samples were dissolved in THF, unless otherwise stated, and held in a lcm x 1cm quartz cuvette. The data were recorded at ambient temperature, 20-23°C
  • Fluorescence spectra were recorded using a Hitachi U-4500 Fluorescence Spectrophotometer.
  • the phthalocyanines samples were dissolved in THF and held in a lcm x lcm quartz cuvette. The data were recorded at ambient temperature, 20-23 °C
  • the samples were held in a lcm x lcm fluorescence cuvette (Hellma).
  • the incident laser energy for each measurement was determined using a pyroelectric detector held behind the sample.
  • the laser energy was adjusted by placing cells containing aqueous sodium nitrite between the CoSO 4 filter and the light guide.
  • Typical pulse energies used here were in the range 25-500 ⁇ J per pulse, as measured using a second, calibrated pyroelectric detector, (Gentec ED-100). Shot to shot noise was estimated to be ⁇ 10% and sets of 20 shots gave an average value within ⁇ 3%>.
  • Phosphorescence from the sample was collected and passed through an interference filter centred at 1270nm (Infra Red Engineering Ltd) and then focussed onto the active area of a liquid nitrogen cooled germanium photodiode (North Coast EO-817P).
  • the signal form the detector was AC coupled to a digital oscilloscope (Tektronix TDS-320) which digitised and averaged the transients. Typically 32 laser shots were used for each sample. The averaged data was transferred to a PC where it was stored and analysed.
  • Stock solutions of the materials were prepared by taking a small sample of the materials supplied and dissolving them in toluene (Fischer Scientific, Analytical grade) containing l%(v/v) pyridine. The pyridine was added to ensure that the samples did not aggregate. Exact concentrations of these solutions were not determined.
  • Working solutions were prepared by dilution of the stock with toluene to give absorbances of 0.01- 0.100 at 355nm when placed in a UV-Vis spectrometer (ATI-Unicam UV-2) compared to a reference cell containing the pure solvent. UV-Vis spectra were recorded in long pathlength cells (2cm) to ensure a more accurate measure of absorbance. Care was taken to avoid high absorbances in the region of the Q-bands (600-750nm) where re-abso ⁇ tion of the fluorescence from the sample can lead to error.
  • the data were recorded at ambient temperature, 20-23 °C, and the solutions were aerated.
  • a typical decay is shown below.
  • a plot of A v's incident laser energy was drawn for each solution and the slope determined. The slope is proportional to the singlet oxygen quantum yield and the amount of light absorbed by the sample.
  • the slope of the graph for each sample was taken and plotted against (1-10 "A ), where A is the absorbance of the samples at the excitation wavelength. The slope of this graph is then proportional to the singlet oxygen quantum yield.
  • Fluorescence lifetimes were determined using the method of time-correlated single photon counting (Principles of Fluorescence Spectroscopy 2 nd Ed, J. Lakowicz, Kluwer Academic/ Plenum Press). Samples were excited using the output from a 635nm pulsed diode laser (IBH NanoLed). This produced a 1MHz train of pulses with a FWHM of 200ps. Fluorescence was collected at 90° to the excitation source and the emission wavelength selected by a monochromator (Jobin-Yvon Triax 190) and detected using a cooled red-sensitive photomultiplier/discriminator (IBH TXB-04).
  • the output from the detector was used as the start signal for a time to amplitude converter (Ortec 567) and the stop signal was derived from the laser power supply/driver.
  • the TAC output was processed by a pulse height analyser (Ortec Trump 8K). Typically decays were obtained using a record length of 1024 channels with a time-window of 55ps/channel. Instrument response functions were obtained using a scattering suspension and were typically 45 Ops FWHM. Decays were analysed by the method of iterative reconvolution of the response function with a sum-of-exponentials and the fit optimised by the method of non-linear least-squares analysis. The quality of fit was judged by the reduced chi-squared, randomness of residuals and auto-correlation function (Principles of Fluorescence Spectroscopy 2 nd Ed, J. Lakowicz, Kluwer Academic/ Plenum Press).
  • Rhodamine 101 in acidified ethanol ⁇ f 1.00.

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Abstract

This invention relates to a process for the preparation of phthalonitrile sulfonate esters, a process for the preparation of substituted phthalonitriles using said phthalonitrile sulfonate esters, a process for the preparation of substituted phthalocyanines using said substituted phthalonitriles, a process for the preparation of phthalonitrile halides, a process for the preparation of substituted phthalocyanines using said phthalonitrile halides, novel phthalonitrile sulfonate esters, novel substituted phthalonitriles, novel substituted phthalocyanines and certain uses of said novel substituted phthalocyanines.

Description

Substituted Phthalocyanines and Their Precursors
Field of the invention
This invention relates to a process for the preparation of phthalonitrile sulfonate esters, a process for the preparation of substituted phthalonitriles using said phthalonitrile sulfonate esters, a process for the preparation of substituted phthalocyanines using said substituted phthalonitriles, a process for the preparation of phthalonitrile halides, a process for the preparation of substituted phthalocyanines using said phthalonitrile halides, novel phthalonitrile sulfonate esters, novel substituted phthalonitriles, novel substituted phthalocyanines and certain uses of said novel substituted phthalocyanines.
Background of the invention
In recent years significant research has been conducted into the synthesis of substituted phthalocyanines. This has been driven in part by the fact that substituted phthalocyanines show a multitude of desirable properties and are thus useful for a wide variety of applications. The desirable properties of substituted phthalocyanines can often be tuned by manipulation of the substituents on the ring system. In general these substituents fall into two categories, the so-called peripheral (2, 3, 9, 10, 16, 17, 23, 24) and the non-peripheral (1, 4, 8, 11, 15, 18, 22, 25) substituents, as shown in Scheme 1.
Figure imgf000002_0001
Scheme 1
GB-B-2,229,190 discloses a group of non-peripherally substituted phthalocyanines, at least some of which, in thin films such as for example Langmuir-Blodgett films, in the liquid crystalline state, or when dissolved or dispersed in a carrier material, are transparent in the visible region and yet strong absorbers of UV or IR radiation. Hence they are capable of absorbing energy emitted by lasers and thus useful in laser addressed applications such as laser addressed optical storage devices and projection displays. Alteration of the substituents and the central ion M is a means for tuning the wavelength of absorption by the substituted phthalocyanines to match the wavelengths of the lasers.
GB-B-2,295,547 discloses the use of a similar group of non-peripherally substituted phthalocyanines as photosensitizers in photodynamic therapy. EP-A-0, 906,758 discloses a variety of zinc-phthalocyanines substituted with hydrophilic substituents linked to the phthalocyanine ring via an oxygen atom as phototherapeutic or photodiagnostic agents. In the photodynamic therapy of cancer, dye compounds are administered to a tumour-bearing subject. These dye substances may be taken up by the tumour at least to a certain extent. Upon selective irradiation with an appropriate light source the tumour tissue is destroyed via the dye mediated photo-generation of cytotoxic species such as singlet oxygen or free radicals such as hydroxy or superoxide.
Hitherto substituents have frequently been introduced into phthalocyanine by the cyclisation of appropriately substituted precursors, usually phthalonitrile derivatives.
Alkoxy-substituted phthalonitriles have been synthesised by alkylation of hydroxy- substituted phthalonitriles (see Scheme 2) or nucleophilic aromatic substitution of nitro- or chloro-substituted phthalonitriles (Scheme 3). As disclosed in GB-B-2,229,190 and EP-A- 0,906,578 and as shown in Scheme 2, a hydroxy-substituted phthalonitrile may be treated with a suitable base and a haloalkane to yield an alkoxy-substituted pthalonitrile. Alternatively, as disclosed in EP-A-0,906,578 and shown in Scheme 3, a nitro- or chloro- substituted phthalonitrile may be treated with a suitable base and an alcohol to yield an alkoxy-substituted pthalonitrile.
i ) base , haloalkane RX
Figure imgf000003_0001
Scheme 2 where Y = Cl or N02 i) base, alcohol ROH
Figure imgf000004_0001
Scheme 3
The preparation of alkyl-substituted phthalonitriles has been rather more complex. Two routes to 3,6-dialkylphthalonitriles have been developed to date, both relying upon construction of the aromatic ring by Diels-Alder chemistry, either by the reaction of a furan (see Scheme 4) or the reaction of a thiophene- 1,1 -dioxide derivative (see Scheme 5) with fumaronitrile. As disclosed in GB-B-2,229,190 and shown in Scheme 4, furan may be 2,5-alkylated using a suitable base and a haloalkane. The resulting 2,5-dialkylfuran may be treated with fumaronitrile followed by a suitable base to yield a 3,6- dialkylphthalonitrile. Alternatively, as disclosed in GB-B-2,229,190 and shown in Scheme 5, thiophene may be 2,5-alkylated using suitable base and a haloalkane. The resulting 2,5- dialkylthiophene may be oxidised to yield the corresponding 1,1 -dioxide. This may be reacted with fumaronitrile to yield a 3,6-dialkylphthalonitrile.
Figure imgf000004_0002
i) base, haloalkane RX ii) fumaronitrile NCCH=CHCN iii) base
Scheme 4
Figure imgf000004_0003
i) base, haloalkane RX ii) oxidising agent iii) fumaronitrile NCCH=CHCN
Scheme 5
Substituted phthalocyanines have been prepared by the cyclisation of appropriately substituted phthalonitriles. As disclosed in GB-B-2,229,190 and EP-A-0,906,578 and as shown in Scheme 6, a substituted phthalonitrile may be reductively cyclised into a substituted phthalocyanine by treatment with a suitable base. The substituted phthalocyanine may be metallated by treatment with a suitable metal compound. Alternatively, the substituted phthalonitrile may be reductively cyclised directly into the metallated substituted phthalocyanine by treatment with a suitable metal compound in the presence of a suitable base.
Figure imgf000005_0001
i) base ii) metal compound iii) metal compound, base
Scheme 6
A major disadvantage of the prior art syntheses of substituted phthalocyanines is that a large variety of potentially useful substituents cannot be introduced into phthalocyanine by these prior art syntheses, because their functionality is incompatible with the required reaction conditions. Hence, the present invention provides a new synthetic route to substituted phthalocyanines via cyclisation of substituted phthalonitriles, prepared by substitution reactions of phthalonitrile sulfonate esters. Although aryl iodides, bromides, triflates as well as nonaflates (M. Rottlander, P. Knochel, J. Org. Chem., 1998, vol. 63, page 4523; B.H. Lipshutz, D.J. Buzard, C.S. Yun, Tetrahedron Lett., 1999, vol. 40, page 201) have been used as substitution partners, their use in substitution reaction for the preparation of phthalonitriles has not been suggested before. To date substitution reactions of phthalonitrile sulfonate esters have not been used for the synthesis of substituted phthalocyanines.
Brief description of the invention
According to a first aspect of the present invention, there is provided a process for the preparation of a substituted phthalocyanine of formula (I)
Figure imgf000006_0001
wherein m are the same or different and each m is 0, 1 , 2, 3 or 4, provided that not all four m are 0 simultaneously;
R1 are the same or different and each R1 is Cι-C20 alkyl optionally substituted;
C2-C20 alkenyl optionally substituted; C2-C20 alkynyl optionally substituted;
-R4-O-R5; -R4-S-R5; -R4-SO3H; -R4-SO2R5; -R4-SO2N(R5)2; -R4-N-(R5)2;
-R4-P-(R5)2; -R4-P(O)(OR5)2; -R4-aryl optionally substituted; -R4-heteroaryl optionally substituted; -R4-COR5; -R4-COOR5 or -R4-CON(R5)2; where
-R4- are the same or different and each -R4- is a chemical bond, -(CH2)q- with q being an integer from 1 to 20, or -(CH2)aCH=CH(CH2)b- with a and b being integers from 0 to 20 and the sum of a and b being from 0 to 20; and -R5 are the same or different and each -R5 is Cι-C20 alkyl, C -C20 alkenyl, aryl optionally substituted, heteroaryl optionally substituted or H, or two -R5 together form a saturated or unsaturated ring; R2 are the same or different and each R2 is
Figure imgf000007_0001
p are the same or different and each p is 0, 1, 2 or 3;
R3 are the same or different and each R3 is -F, -Cl, -Br or -I; and
M is a metal atom in the M(II) oxidation state, a metal chloride, a metal bromide, a metal oxide, silicon with two axial substituents or two hydrogen atoms, one hydrogen being bonded to each of the two bonding nitrogen atoms;
comprising the steps of
(a) converting a phthalonitrile alcohol of formula (II)
Figure imgf000007_0002
into a sulfonate ester of formula (III)
Figure imgf000007_0003
wherein R6 is either Cι-C12 alkyl, optionally substituted with one or more of -F and/or -Cl, or aryl, optionally substituted with one or more of -CH3, -NO2, -OCH3, -F, -Cl and/or -Br; and when m is 2, 3 or 4, R6 are the same or different;
(b) converting the sulfonate ester of formula (III) into the substituted phthalonitrile of formula (IV)
Figure imgf000008_0001
(c) cyclising the substituted phthalonitrile of formula (IV) either by itself or together with any other phthalonitrile of formula (IV).
For the purpose of the present invention, "alkyl" is defined as a hydrocarbon with a sp3 hybridised α-carbon, which may be straight chain or branched, and which may optionally be substituted, and which may comprise at least one double bond and/or at least one triple bond. "Aryl" is defined as an aromatic hydrocarbon with a sp hybridised aromatic α-carbon, which may optionally be substituted. Examples of aryls are
Figure imgf000008_0002
"Heteroaryl" is defined as an aromatic hydrocarbon with a sp2 hybridised aromatic α-carbon, which comprises at least one heteroatom N, O or S as part of the aromatic ringsystem, and which may optionally be substituted. Examples of heteroaryls are
Figure imgf000008_0003
. "Alkenyl" is defined as a hydrocarbon with a sp2 hybridised α-carbon, which may be branched or unbranched, and which may optionally be substituted. Examples of alkenyl groups are -CH=CH2, -CH=CH-CH3, -CH=CH-C6H5, -CH=CH-CH=CH2 and -CH=CH-CH2-CH=CH2. "Alkynyl" is defined as a hydrocarbon with a sp hybridised α-carbon, which may be branched or unbranched, and which may optionally be substituted. Examples of alkynyl groups are -C≡C-H, -C≡C-CH3, -C≡C-C6H5 and -C≡C-C≡C-H. "Terminally alkenyl" and "terminally alkynyl" refers to terminal "alkenyl" and "alkynyl" groups respectively.
For the purpose of the present invention, an optionally substituted alkyl group may be substituted with one or more of -F, -Cl, -Br, -I, -OH, -R4-O-R5, -R4-S-R5, -NH2, -NHR5, -N(R5)2, -N(R5)3 + and/or -R4-N-(R5)2. An optionally substituted alkenyl group may be substituted with one or more of -F, -Cl, -Br, -I, -OH, -R4-O-R5, -R4-S-R5, -NH2, -NHR5, -N(R5)2, -N(R5)3 + and/or -R4-N-(R5)2. An optionally substituted alkynyl group may be substituted with -F, -Cl, -Br, -I, -OH, -R4-O-R5, -R4-S-R5, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -R4-N-(R5)2, -Si(R5)3, -C5H4N, -C4H3S and/or -C6H5. An optionally substituted aryl group may be substituted with one or more of Cj-Cio alkyl, C2-Cιo alkenyl, -NO2, -OCH3, -CH2OH, -F, -Cl, -Br, -OH, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -NHCOR5, -COR5, -COOR5 and/or -CON(R5)2. An optionally substituted heteroaryl group may be substituted with one or more of Cj-Cio alkyl, C2-C10 alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -NH2, -NHR5, -N(R5)2, -N(R )3 +, -NHCOR5, -COR5, -COOR5 and/or -CON(R5)2.
For the purpose of the present invention, a "non-peripheral" substituent is defined as a substituent α to the point of fusion between the pyrrole ring and the R2 containing aromatic ring in a compound of formula (I) or (V), or α to either one of the two cyano groups in a compound of formula (IV), (VI) or (VII). A substituent is defined as
"peripheral" when it is not "non-peripheral". For example, in Scheme 1 the non-peripheral substituents are in positions 1, 4, 8, 11, 15, 18, 22 and 25 and the peripheral substituents are in positions 2, 3, 9, 10, 16, 17, 23 and 24.
,A
When R is A, then the compounds of formula (II), (III) and (IV) of the present
invention are substituted benzenes. When R is
Figure imgf000009_0001
then the compounds of formula (II), (III) and (IV) of the present invention are substituted naphthalenes. When R2 is
Figure imgf000009_0002
then the compounds of formula (II), (III) and (IV) of the present invention are
substituted anthracenes. When R2 is
Figure imgf000009_0003
, then the compounds of formula (II), (III) and (IV) of the present invention are substituted phenanthrenes.
A substituted phthalocyanine is made up of a core structure and four substituent- units X. The four substituent-units X are shown encircled in formulas (I) and (V) below. As will be appreciated, depending on the substituents R1, R3, R8 and R9, a substituted phthalocyanine can be mixed or non-mixed. A non-mixed phthalocyanine is a phthalocyanine made up of four identical substituent-units X. A mixed phthalocyanine is a phthalocyanine made up of at least two different substituent-units, preferably a mixed phthalocyanine is made up of two different substituent-units X1 and X2, wherein the ratio of X'.X2 may be 1 :3, 2:2 or 3:1. When the ratio of X':X2 is 2:2, the pairs of identical substituent-units X or X may be adjacent to each other or opposite each other.
Figure imgf000010_0001
When preparing a substituted phthalocyanine (I) according to the first aspect of the present invention, a non-mixed or a mixed phthalocyanine may be obtained.
Preferably, M is an isotope of Cu, Ni, Pb, V, Pd, Pt, Co, Nb, Al, Sn, Zn, Mg, Ca, In, Ga, Fe, Ge, a lanthanide, Si with two axial substituents or 2H. More preferably, is an isotope of a diamagnetic metal, Si with two axial substituents or 2H. Even more preferably, M is an isotope of Zn, Al, Mg, Pd, Pt, Si with two axial substituents or 2H.
Preferably, if the phthalocyanine (I) is a non-mixed phthalocyanine or if the phthalocyanine (I) is substituted with -S-R5, the sum of m and p is not 4 or 8.
Optionally, the compound of formula (I) and/or (V) may form a sandwich complex comprising two or more compounds of formula (I) and/or (V). Optionally, there is provided a multimer comprising two or more compounds of formula (I) and/or (V) covalently linked. Preferably, the covalently linked compounds of formula (I) and/or (V) are covalently linked via substituents R1, R8 and/or R9.
According to a second aspect of the present invention, there is provided a process for the preparation of a substituted phthalonitrile of formula (IV)
Figure imgf000011_0001
wherein R , R , R and p are defined as in the first aspect of the present invention, and m is 1, 2, 3 or 4,
comprising the steps of
(a) converting a phthalonitrile alcohol of formula (II)
Figure imgf000011_0002
into a sulfonate ester of formula (III)
Figure imgf000011_0003
wherein R is defined as in the first aspect of the present invention, and
(b) converting the sulfonate ester of formula (III) into the substituted phthalonitrile of formula (IV).
Preferably, the conversion of the sulfonate ester of formula (III) into the substituted phthalonitrile of formula (IV) comprises a cross-coupling of the sulfonate ester of formula (III) with an organozinc reagent R'ZnX or an organocopper reagent R'CuX catalysed by palladium or nickel, wherein R1 is defined as in the first aspect of the present invention and X is a halogen. Preferably, the halogen is Cl, Br or I.
Or the conversion of the sulfonate ester of formula (III) into the substituted phthalonitrile of formula (IV) comprises a cross-coupling of the sulfonate ester of formula (III) with a trialkylborane B(R')3 catalysed by palladium, wherein R1 are the same or different and each R is Cι-C20 alkyl optionally substituted; -R4-O-R5; -R4-S-R5; -R4-N-(R5)2; -R4-P-(R5)2; -R4-aryl optionally substituted; -R4-heteroaryl optionally substituted; -R4-COR5; -R4-COOR5 or
-R4-CONR5 2; where -R4- are the same or different and each -R4- is -(CH2)q- with q being an integer from 1 to 20, or -(CH2)aCH=CH(CH2)b- with a and b being integers from 0 to 20 and the sum of a and b being from 0 to 20; and -R5 are the same or different and each -R5 is Cι-C20 alkyl, C2-C20 alkenyl, aryl, heteroaryl or H, or two -R5 together form a saturated or unsaturated ring.
Preferably, B(R')3 is 9-BBN, i.e. R'BCCHHM).
Or the conversion of the sulfonate ester of formula (III) into the substituted phthalonitrile of formula (IV) comprises a cross-coupling of the sulfonate ester of formula
(III) with a boronic acid RΕ(OH) or a boronic ester R1B(OR7)2 catalysed by palladium or nickel, wherein R1 is C2-C20 alkenyl, -aryl optionally substituted or -heteroaryl optionally substituted; and
R are the same or different and each R is Cj-Cio alkyl optionally substituted and both R7 together with -O-B-O- may form a ring.
Preferably, R]B(OR7)2 is R'B^C^CH∑C^O-), R^-OCHZCHJO-) or
R1B(-OC(CH3)2C(CH3)2O-). Or the conversion of the sulfonate ester of formula (III) into the substituted phthalonitrile of formula (IV) comprises an SNAΓ reaction of the sulfonate ester of formula
(III) with a nucleophile HO-R5, HS-R5 or HN(R5)2, HP(R5)2 or F, wherein -R5 are the same or different and each R5 is Cι-C20 alkyl, C2-C20 alkenyl, aryl, heteroaryl or H, or two -R5 together form a saturated or unsaturated ring.
Or the conversion of the sulfonate ester of formula (III) into the substituted phthalonitrile of formula (IV) comprises a coupling of the sulfonate ester of formula (III) with a coupling partner R1H catalysed by palladium, wherein R1 is C2-C20 terminally alkenyl optionally substituted or C2-C20 terminally alkynyl optionally substituted.
Preferably, R1 are the same or different and each R1 is Cι-C2o alkyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -R4-O-R5, -R4-S-R5, -NH2, -NHR5, -N(R5)2, -N(R5)3 + and/or -R4-N-(R5)2; C2-C20 alkenyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -R4-O-R5, -R4-S-R5, -NH2, -NHR5, -N(R5)2, -N(R5)3 + and/or -R4-N-(R5)2; C2-C20 alkynyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -R4-O-R5, -R4-S-R5, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, _R _N_(R5)25 -Si(R5)3, -C5H4N, -C4H3S and/or A 6H5; -R4-O-R5; -R4-S-R5; -R4-SO3H; -R4-SO2R5; -R4-SO2N(R5)2; -R4-N-(R5)2; -R4-P-(R5)2; -R4-P(O)(OR5)2; -R4-aryl, optionally substituted with one or more of Cι-C10 alkyl, C2-C10 alkenyl, -NO2, -OCH3, -CH2OH, -F, -Cl, -Br, -OH, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -NHCOR5, -COR5, -COOR5 and/or -CON(R5)2; -R4-heteroaryl, optionally substituted with one or more of C,-C10 alkyl, C2-C10 alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -NHCOR5, -COR5, -COOR5 and/or -CON(R5)2; -R4-COR5; -R4-COOR5 or -R4-CON(R5)2; where R4 and R5 are defined as in the first aspect of the present invention.
More preferably, R1 are the same or different and each R1 is CrC20 alkyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -NH2, -NHR5, -N(R5)2 and/or -N(R5)3 +; C2-C20 alkenyl; C2-C20 alkynyl; -S-R5; -N-(R5)2; -R4-aryl, optionally substituted with one or more of Cι-C10 alkyl, C2-Cιo alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -NHCOR5, -COR5, -COOR5 and/or -CON(R5)2; where R4 and R5 are defined as in the first aspect of the present invention. Preferably, at least one R is not Cι-C20 alkyl non-substituted.
R1 may be a peripheral or a non-peripheral substituent. Preferably, at least one R1 is a non-peripheral substituent.
The compound of formula (I) and/or (IV) may be substituted with or conjugated to an amino acid, a fatty acid, a nucleic acid, a di-, tri- or up to decapeptide, a polypeptide, a protein, a saccharide, a polysaccharide or a polymer. Preferably, the compound of formula (I) and/or (IV) is substituted with or conjugated to an amino acid, a fatty acid, a nucleic acid, a di-, tri- or up to decapeptide, a polypeptide, a protein, a saccharide, a polysaccharide or a polymer via substituent R .
According to a third aspect of the present invention, there is provided a process for the preparation of a phthalonitrile sulfonate ester of formula (III)
Figure imgf000014_0001
wherein R , R , R and p are defined as in the first aspect of the present invention, and m is 1, 2, 3 or 4,
comprising the step of
(a) converting a phthalonitrile alcohol of formula (II)
Figure imgf000014_0002
into a sulfonate ester of formula (III).
Preferably, R is Preferably, R6 are the same or different and each R6 is -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -C8H17, -CHC12, -CF3, -C4F9, -C6H5, -(C6H4)-4-CH3, -(C6H4)-2-NO2, -(C6H4)-3-NO2, -(C6H4)-4-NO2, -(C6H4)-2-Br, -(C6H4)-4-Br, -(C6H4)-4-Cl, -(C6H4)-4-F, -(C6H3)-2,5-Cl2, -(C6H3)-3,4-Cl2, -(C6H3)-3,4-(OCH3)2 or -(C6H3)-2,4-(NO2)2- More preferably, R6 are the same or different and each R6 is -CH3, -CF3 or -C4F9.
Preferably, p = 0.
According to a fourth aspect of the present invention, there is provided a process for the preparation of a substituted phthalocyanine of formula (V)
Figure imgf000015_0001
wherein m are the same or different and each m is 0, 1, 2, 3 or 4;
R1 are the same or different and each R1 is Cι-C20 alkyl optionally substituted;
C -C20 alkenyl optionally substituted; C2-C20 alkynyl optionally substituted;
-R4-O-R5; -R4-S-R5; -R4-SO3H; -R4-SO2R5; -R4-SO2N(R5)2; -R4-N-(R5)2;
-R4-P-(R5)2; -R4-P(O)(OR5)2; -R4-aryl optionally substituted; -R4-heteroaryl optionally substituted; -R4-COR5; -R4-COOR5 or -R4-CON(R5)2; where
-R4- are the same or different and each -R4- is a chemical bond, -(CH2)q- with q being an integer from 1 to 20, or -(CH2)aCH=CH(CH2)b- with a and b being integers from 0 to 20 and the sum of a and b being from 0 to 20; and -R5 are the same or different and each -R5 is Cι-C20 alkyl, C2-C20 alkenyl, aryl optionally substituted, heteroaryl optionally substituted or H, or two -R5 together form a saturated or unsaturated ring;
R2 are the same or different and each R2 is
Figure imgf000016_0001
p are the same or different and each p is 0, 1 , 2 or 3;
R are the same or different and each R is -F, -Cl, -Br or -I;
R are the same or different and each R is Cι-C20 alkyl optionally substituted;
q is 1 or 2;
R9 are the same or different and each R9 is -Cl, -Br, -I, -alkyl optionally substituted, -alkenyl optionally substituted, -alkynyl optionally substituted, -aryl optionally substituted or -heteroaryl optionally substituted; and
M is a metal atom in the M(II) oxidation state, a metal chloride, a metal bromide, a metal oxide, silicon with two axial substituents or two hydrogen atoms, one hydrogen being bonded to each of the two bonding nitrogen atoms;
comprising either the steps of (a) converting a phthalonitrile halide of formula (VI)
Figure imgf000016_0002
wherein R10 are the same or different and each R10 is -Cl, -Br or -I, into a substituted phthalonitrile of formula (VII)
Figure imgf000017_0001
wherein R are the same or diffferent and each R is -alkyl optionally substituted, -alkenyl optionally substituted, -alkynyl optionally substituted, -aryl optionally substituted or -heteroaryl optionally substituted; and
(b) cyclising the substituted phthalonitrile of formula (VII) either by itself or together with any other phthalonitrile of formula (IV)
Figure imgf000017_0002
to yield a substituted phthalocyanine of formula (V);
or alternatively comprising the steps of
(a) cyclising the phthalonitrile halide of formula (VI) either by itself or together with any other phthalonitrile of formula (IV) to yield a substituted phthalocyanine of formula (V); and
(b) optionally converting the R9 being -Cl, -Br or -I into an R9 being -alkyl optionally substituted, -alkenyl optionally substituted, -alkynyl optionally substituted, -aryl optionally substituted, or -heteroaryl optionally substituted.
When preparing a substituted phthalocyanine (V) according to the fourth aspect of the present invention, a non-mixed or a mixed phthalocyanine may be obtained.
Preferably, M is an isotope of Cu, Ni, Pb, V, Pd, Pt, Co, Nb, Al, Sn, Zn, Mg, Ca, In,
Ga, Fe, Ge, a lanthanide, Si with two axial substituents or 2H. More preferably, M is an isotope of a diamagnetic metal, Si with two axial substituents or 2H. Even more preferably, M is an isotope of Zn, Al, Mg, Pd, Pt, Si with two axial substituents or 2H.
Preferably, R1 are the same or different and each R1 is Cι-C20 alkyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -R4-O-R5, -R4-S-R5, -NH2, -NHR5, -N(R5)2, -N(R5)3 + and/or -R4-N-(R5)2; C2-C20 alkenyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -R4-O-R5, -R4-S-R5, -NH2, -NHR5, -N(R5)2, -N(R5)3 + and/or -R4-N-(R5) ; C2-C20 alkynyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -R4-O-R5, -R4-S-R5, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -R4-N-(R5)2, -Si(R5)3, -C5H4N, -C4H3S and/or -C6H5; -R4-O-R5; -R4-S-R5; -R4-SO3H; -R4-SO2R5; -R4-SO2N(R5)2; -R4-N-(R5)2; -R4-P-(R5)2; -R4-P(O)(OR5)2; -R4-aryl, optionally substituted with one or more of Ci-Cio alkyl, C2-C10 alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -NHCOR5, -COR5, -COOR5 and/or -CON(R5)2; -R4-heteroaryl, optionally substituted with one or more of Cι-C10 alkyl, C2-Ci0 alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -NHCOR5, -COR5, -COOR5 and/or -CON(R5)2; -R4-COR5; -R4-COOR5 or -R4-CON(R5)2; where R4 and R5 are defined as in the first aspect of the present invention.
More preferably, R1 are the same or different and each R1 is Cj-C2o alkyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -NH2, -NHR5, -N(R5)2 and/or -N(R5)3 +; C2-C20 alkenyl; C2-C20 alkynyl; -S-R5; -N-(R5)2; -R4-aryl, optionally substituted with one or more of Cι-C10 alkyl, C2-Cι0 alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -NHCOR5, -COR5, -COOR5 and/or -CON(R5)2; where R4 and R5 are defined as in the first aspect of the present invention.
Preferably, at least one R1 is not Cι-C20 alkyl non-substituted.
R1 may be a peripheral or a non-peripheral substituent. Preferably, at least one R1 is a non-peripheral substituent.
The compound of formula (V) may be substituted with or conjugated to an amino acid, a fatty acid, a nucleic acid, a di-, tri- or up to decapeptide, a polypeptide, a protein, a saccharide, a polysaccharide or a polymer. Preferably, the compound of formula (V) is substituted with or conjugated to an amino acid, a fatty acid, a nucleic acid, a di-, tri- or up to decapeptide, a polypeptide, a protein, a saccharide, a polysaccharide or a polymer via substituent R1.
Preferably, if the phthalocyanine (V) is a non-mixed phthalocyanine or if the phthalocyanine (V) is substituted with -S-R5, the sum of m and p is not 4 or 8.
Preferably, R2 is
Preferably, p = 0.
Preferably, R are the same or different and each R is Cι-C20 alkyl optionally substituted with -OH. More preferably, R are the same or different and each R is Cι-C20 alkyl. Even more preferably, R8 are the same or different and each R8 is C]-C10 alkyl.
Preferably R9 are the same or different and each R9 is -Br, -I, -alkenyl optionally substituted, -alkynyl optionally substituted, -aryl optionally substituted or -heteroaryl optionally substituted. Preferably, R9 is -Br, -I, -CH=CH2, -C≡CH, -C≡C-Si(R5)3, -C≡C-CsHtN, -C≡C-C4H3S, -C≡C-C6H5, -C5H5N, -C4H3S or -C6H5 optionally substituted. More preferably, R9 is -Br, -I, -CH=CH2, -C≡CH, -C≡C-SiMe3, -C≡C-Si'Pr3, -C≡C-CsHtN, -C≡C-C4H3S, -C≡C-C6H5, -C5H5N, -C4H3S, -C6H5, -C6H5-CH2OH or -C6H5-OCH3.
Optionally, the compound of formula (I) and/or (V) may form a sandwich complex comprising two or more compounds of formula (I) and/or (V).
Optionally, there is provided a multimer comprising two or more compounds of formula (I) and/or (V) covalently linked. Preferably, the covalently linked compounds of formula (I) and/or (V) are covalently linked via substituents R1, R8 and/or R9.
According to a fifth aspect of the present invention, there is provided a process for the preparation of a phthalonitrile halide of formula (VI)
Figure imgf000020_0001
wherein R are the same or different and each R is Cι.2o alkyl optionally substituted; q is 1 or 2; and R10 are the same or different and each R10 is -Cl, -Br or -I; comprising the steps of (a) halogenating 2,3-dicyanohydroquinone to afford the dihalogenated product,
(b) alkylating the dihalogenated product to yield the alkylated mono- or dihalogenated product.
Preferably, R are the same or different and each R is Cι-C20 alkyl optionally substituted with -OH. More preferably, R8 are the same or different and each R8 is Cι-C20 alkyl. Even more preferably, R8 are the same or different and each R8 is CJ-CIQ alkyl.
According to a sixth aspect of the present invention, there is provided a phthalonitrile sulfonate ester of formula (III)
Figure imgf000020_0002
wherein R is
Figure imgf000020_0003
m is 1, 2, 3 or 4;
R6 is either C]-C12 alkyl, optionally substituted with one or more of -F and/or -Cl, or aryl, optionally substituted with -CH3, -NO2, -OCH3, -F, -Cl and/or -Br; and when m is 2, 3 or 4, R are the same or different; p is 0, 1, 2 or 3; and
R ,3 is either -F, -Cl, -Br or -I; and when p is 2 or 3, R are the same or different.
Preferably, R is
Preferably, R are the same or different and each R is -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -C8H17, -CHC12, -CF3, -C4F9, -C6H5, -(C6__4)-4-CH3, -(C6H4)-2-NO2, -(C6H4)-3-NO2, -(C6H4)-4-NO2, -(C6H4)-2-Br, -(C6H4)-4-Br, -(C6H4)-4-Cl, -(C6H4)-4-F, -(C6H3)-2,5-Cl2, -(C6H3)-3,4-Cl2, -(C6H3)-3,4-(OCH3)2 or -(C6H3)-2,4-(NO2)2. More preferably, R6 are the same or different and each R6 is -CH3, -CF3 or -C4F9.
Preferably, p = 0.
According to seventh aspect of the present invention, there is provided a substituted phthalonitrile of formula (IV)
Figure imgf000021_0001
wherein m is 1, 2, 3 or 4;
R is Cι-C20 alkyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -R4-O-R5, -R4-S-R5, -NH2, -NHR5, -N(R5)2, -N(R5)3 + and/or -R4-N-(R5)2; C2-C20 alkenyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -R4-O-R5, -R4-S-R5, -NH2, -NHR5, -N(R5)2, -N(R5)3 + and/or -R4-N-(R5)2; C2-C20 alkynyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -R4-O-R5, -R4-S-R5, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -R4-N-(R5)2, -Si(R5)3, -CsI^N, -C4H3S and/or -C6H5; -R4-O-R5; -R4-S-R5; -R4-SO3H; -R4-SO2R5; -R4-SO2N(R5)2; -R4-N-(R5)2; -R4-P_(R 5)2; -R4-P(O)(OR5)2; -R4-aryl, optionally substituted with one or more of Cι-C10 alkyl, C2-Ci0 alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -NHCOR5, -COR5, -COOR5 and/or -CON(R5)2; -R4-heteroaryl, optionally substituted with one or more of Ci-Cio alkyl, C2-Cι0 alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -NHCOR5, -COR5,
-COOR5 and/or -CON(R5)2; -R4-COR5; -R4-COOR5 or -R4-CON(R5)2; where
-R4- is a chemical bond, -(CH )q- with q being an integer from 1 to 20, or -(CH2)aCH=CH(CH2)b- with a and b being integers from 0 to 20 and the sum of a and b being from 0 to 20; -R5 is Cι-C20 alkyl, C2-C20 alkenyl, aryl, heteroaryl or H, or two -R5 together form a saturated or unsaturated ring; and when m is 2, 3 or 4, R1, -R4- and -R5 are the same or different;
R2 is
Figure imgf000022_0001
p is 0, 1, 2 or 3; and
R is either -F, -Cl, -Br or -I; and when p is 2 or 3, R are the same or different;
provided that when R1 is Cι-C20 alkyl non-substituted, -CF3, -OR5, -CH2OR5 or -S-aryl, m is 3 or 4 or p is 1 , 2 or 3.
Preferably, at least one R1 is not Cι-C20 alkyl non-substituted.
Preferably, R1 are the same or different and each R1 is Cι-C20 alkyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR5, -SR5, -NH2, -NHR5, -N(R5)2 and/or -N(R5)3 +; C2-C20 alkenyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR5, -SR5, -NH2, -NHR5, -N(R5)2 and/or -N(R5)3 +; C2-C20 alkynyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR5, -SR5, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -Si(R5)3, -C5H4N, -C4H3S and/or -C6H5; -OR5; -SR5; -SO2R5; -N-(R5)2; -P-(R5)2; -P(O)(OR5)2; -aryl, optionally substituted with one or more of d-Cio alkyl, C2-Cι0 alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -OR5, -SO3H, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -NHCOR5, -COR5, -COOR5 and/or -CON(R5)2; -heteroaryl, optionally substituted with one or more of Cι-Cι0 alkyl, C2-C10 alkenyl, -NO2, -OCH3, -F, 5 -Cl, -Br, -OH, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -NHCOR5, -COR5, -COOR5 and/or -CON(R5)2; -COR5; -COOR5 or -CON(R5)2; where -R5 are the same or different and each -R5 is C1-C20 alkyl, C2-C20 alkenyl, aryl, hetereoaryl or H, or two -R5 together form a saturated or unsaturated ring.
10 More preferably, R1 are the same or different and each R1 is C1-C20 alkyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR5, -SR5, -NH2 and/or -NHR5; C2-C2o alkenyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR5, -SR5, -NH2 and/or -NHR5; C2-C20 alkynyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR5, -SR5, -NH2 and/or -NHR5; -OR5; -SR5; -SO2R5;
15 -N-(R5)2; -P-(R5)2; -aryl, optionally substituted with one or more of Cι-C10 alkyl, C2-Cιo alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -OR5, -SO3H, -NH2 and/or -NHR5; -heteroaryl, optionally substituted with one or more of C1-C10 alkyl, C2-C10 alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -NH2 and/or -NHR5; -COR5; -COOR5 or -CON(R5)2; where -R5 are the same or different and each -R5 is Cι-C20 alkyl, C2-C20 alkenyl, aryl, hetereoaryl
Figure imgf000023_0001
Even more preferably, R1 are the same or different and each R1 is C1-C20 alkyl substituted with at least one or more of -F, -Cl, -Br, -I, -OH, -NH2, -NHR5, -N(R5)2 and/or -N(R5)3 +; C2-C20 alkenyl; C2-C2o alkynyl; -S-R5; -N-(R5)2; -aryl, optionally 25 substituted with one or more of C1-C10 alkyl, C2-Cι0 alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -NHCOR5, -COR5, -COOR5 and/or -CON(R5)2; where -R5 are the same or different and each -R5 is C1-C20 alkyl, C2-C20 alkenyl, aryl, heteroaryl or H, or two -R5 together form a saturated or unsaturated ring.
30 Even more preferably, R1 are the same or different and each R1 is C1-C20 alkyl fully substituted with -F, -Cl and/or -Br; C2-C2o alkenyl; C2-C20 alkynyl; -S-R5; or -aryl, optionally substituted with one or more of -CH3, -NO2, -OCH3, -F, -Cl, -Br, -OH and/or -NH2; where -R5 are the same or different and each -R5 is C1-C20 alkyl, C2-C20 alkenyl, aryl, heteroaryl or H, or two -R5 together form a saturated or unsaturated ring.
R1 may be a peripheral or a non-peripheral substituent. Preferably, at least one R1 is a non-peripheral substituent.
The compound of formula (IV) may be substituted with or conjugated to an amino acid, a fatty acid, a nucleic acid, a di-, tri- or up to decapeptide, a polypeptide, a protein, a saccharide, a polysaccharide or a polymer. Preferably, the compound of formula (IV) is substituted with or conjugated to an amino acid, a fatty acid, a nucleic acid, a di-, tri- or up to decapeptide, a polypeptide, a protein, a saccharide, a polysaccharide or a polymer via substituent R1.
Preferably, R2 is A .
Preferably, p = 0.
According to an eighth aspect of the present invention, there is provided a substituted phthalocyanine of formula (I)
Figure imgf000024_0001
wherein m are the same or different and each m is 0, 1, 2, 3 or 4; R1 are the same or different and each R1 is Cι-C20 alkyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -R4-O-R5, -R4-S-R5, -NH2) -NHR5, -N(R5)2, -N(R5)3 + and/or -R4-N-(R5)2; C2-C20 alkenyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -R4-O-R5, -R4-S-R5, -NH2, -NHR5, 5 -N(R5)2, -N(R5)3 + and/or -R4-N-(R5)2; C2-C2o alkynyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -R4-O-R5, -R4-S-R5, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -R4-N-(R5)2, -Si(R5)3, -C5H4N, -C4H3S and/or -C6H5; -R4-O-R5; -R4-S-R5; -R4-SO3H; -R4-SO2R5; -R4-SO2N(R5)2; -R4-N-(R5)2; -R4-P-(R5)2; -R4-P(O)(OR5)2; -R4-aryl, optionally substituted with one or more 10 of Ci-Ci0 alkyl, C2-Cι0 alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -OR5, -SO3H,
-NH2, -NHR5, -N(R5)2, -N(R5)3 +, -NHCOR5, -COR5, -COOR5 and/or -CON(R5)2; -R4-heteroaryl, optionally substituted with one or more of C)-C10 alkyl, C2-C10 alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -NHCOR5, -COR5, -COOR5 and/or -CON(R5)2; -R4-COR5; 15 -R4-COOR5 or -R4-CON(R5)2; where
-R4- are the same or different and each -R4- is a chemical bond, -(CH2)q- with q being an integer from 1 to 20, or -(CH2)aCH=CH(CH2)b- with a and b being integers from 0 to 20 and the sum of a and b being from 0 to 20; and -R5 are the same or different and each -R5 is Cι-C20 alkyl, C2-C20 alkenyl, -20- ar l^3ptionally_-substituted,-heter£oaiy4-optionally-subsu^uted-or--H,-orAwo-
-R5 together form a saturated or unsaturated ring;
R are the same or different and each R is
Figure imgf000025_0001
25 p are the same or different and each p is 0, 1, 2 or 3; provided that not all four m and all four p are 0 simultaneously;
R are the same or different and each R is either -F, -Cl, -Br or -I; and
30 M is a metal atom in the M(II) oxidation state, a metal chloride, a metal bromide, a metal oxide, silicon with two axial substituents or two hydrogen atoms, one hydrogen being bonded to each of the two bonding nitrogen atoms;
5 provided that when all R1 are the same and are Cι-C20 alkyl non-substituted, -CF3,
-OR5, -CH2OR5 or -S-aryl, m is 3 or 4 or p is 1, 2 or 3.
The substituted phthalocyanine (I) of the eighth aspect of the present invention, may be a non-mixed or a mixed phthalocyanine. 10
Preferably, at least one R1 is not Cι-C20 alkyl non-substituted.
Preferably, R1 are the same or different and each R1 is Cι-C20 alkyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR5, -SR5, -NH2, -NHR5,
15 -N(R5)2 and/or -N(R5)3 +; C2-C20 alkenyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR5, -SR5, -NH2, -NHR5, -N(R5)2 and/or -N(R5)3 +; C2-C20 alkynyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR5, -SR5, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -Si(R5)3, - ILtN, -C4H3S and/or -C6H5; -OR5; -SR5; -SO R5; -N-(R5)2; -P-(R5)2; -P(O)(OR5)2; -aryl, optionally substituted with one or more
Figure imgf000026_0001
-NHR5, -N(R5)2, -N(R5)3 +, -NHCOR5, -COR5, -COOR5 and/or -CON(R5)2; -heteroaryl, optionally substituted with one or more of Cj-Cio alkyl, C2-Cιo alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -NHCOR5, -COR5, -COOR5 and/or -CON(R5)2; -COR5; -COOR5 or -CON(R5)2; where -R5 are the same or different and
25 each -R5 is C1-C20 alkyl, C2-C20 alkenyl, aryl, hetereoaryl or H, or two -R5 together form a saturated or unsaturated ring.
More preferably, R1 are the same or different and each R1 is Cι-C20 alkyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR5, -SR5, -NH2 30 and/or -NHR5; C2-C20 alkenyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR5, -SR5, -NH2 and/or -NHR5; C2-C2o alkynyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR5, -SR5, -NH2 and/or -NHR5; -OR5; -SR5; -SO2R5; -N-(R5)2; -P-(R5)2; -aryl, optionally substituted with one or more of Cι-C10 alkyl, C2-Cι0 alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -OR5, -SO3H, -NH2 and/or -NHR5; -heteroaryl, optionally substituted with one or more of C1-C10 alkyl, C2-C10 alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -NH2 and/or -NHR5; -COR5; -COOR5 or -CON(R5)2; where -R5 are the same or different and each -R5 is C1-C20 alkyl, C2-C20 alkenyl, aryl, hetereoaryl 5 or H, or two -R5 together form a saturated or unsaturated ring.
Even more preferably, R1 are the same or different and each R1 is Cι-C20 alkyl substituted with at least one or more of -F, -Cl, -Br, -I, -OH, -NH2, -NHR5, -N(R5)2 and/or -N(R5)3 +; C2-C20 alkenyl; C2-C20 alkynyl; -S-R5; -N-(R5)2; -aryl, optionally 10 substituted with one or more of Cι-Cι0 alkyl, C2-Cι0 alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -NHCOR5, -COR5, -COOR5 and/or -CON(R5)2; where -R5 are the same or different and each -R5 is Cι-C20 alkyl, C2-C20 alkenyl, aryl, heteroaryl or H, or two -R5 together form a saturated or unsaturated ring.
15 Even more preferably, R1 are the same or different and each R1 is Cj-C2o alkyl fully substituted with -F, -Cl and/or -Br; C2-C20 alkenyl; C2-C20 alkynyl; -S-R5; or -aryl, optionally substituted with one or more of-CH3, -NO , -OCH3, -F, -Cl, -Br, -OH and/or -NH ; where -R5 are the same or different and each -R5 is Cι-C20 alkyl, C2-C2o alkenyl, aryl, heteroaryl or H, or two -R5 together form a saturated or unsaturated ring.
-20-
R1 may be a peripheral or a non-peripheral substituent. Preferably, at least one R1 is a non-peripheral substituent.
The compound of formula (I) may be substituted with or conjugated to an amino
25 acid, a fatty acid, a nucleic acid, a di-, tri- or up to decapeptide, a polypeptide, a protein, a saccharide, a polysaccharide or a polymer. Preferably, the compound of formula (I) is substituted with or conjugated to an amino acid, a fatty acid, a nucleic acid, a di-, tri- or up to decapeptide, a polypeptide, a protein, a saccharide, a polysaccharide or a polymer via substituent R1.
30
Preferably, if the phthalocyanine (I) is a non-mixed phthalocyanine or if the phthalocyanine (I) is substituted with -S-R5, the sum of m and p is not 4 or 8. A Preferably, R2 is ^ .
Preferably, p = 0.
Preferably, M is an isotope of Cu, Ni, Pb, V, Pd, Pt, Co, Nb, Al, Sn, Zn, Mg, Ca, In,
Ga, Fe, Ge, a lanthanide, Si with two axial substituents or 2H. More preferably, M is an isotope of a diamagnetic metal, Si with two axial substituents or 2H. Even more preferably, M is an isotope of Zn, Al, Mg, Pd, Pt, Si with two axial substituents or 2H.
More preferably, p = 0;
R1 are the same or different and each R1 is C2-C20 alkyl fully substituted with -F, -Cl and/or -Br; C2-C20 alkenyl; C2-C20 alkynyl; -S-R5; or -aryl, optionally substituted with one or more of -CH3, -NO2, -OCH3, -F, -Cl, -Br, -OH and/or -NH2; where -R5 are the same or different and each -R5 is C]-C20 alkyl, C2-C20 alkenyl, aryl, hetereoaryl or H, or two -R together form a saturated or unsaturated ring; A R2 is ^ ; and
M is an isotope of Zn, Al, Mg, Pd, Pt, Si with two axial substituents or 2H.
Optionally, the compound of formula (I) and/or (V) may form a sandwich complex comprising two or more compounds of formula (I) and/or (V).
Optionally, there is provided a multimer comprising two or more compounds of formula (I) and/or (V) covalently linked. Preferably, the covalently linked compounds of formula (I) and/or (V) are covalently linked via substituents R1, R8 and/or R9.
Optionally the substituted phthalocyanine is conjugated to a carrier or entrapped or embedded in a macromolecular carrier. Preferably, the carrier is an amino acid, a fatty acid, a nucleic acid, a di-, tri- or up to decapeptide, a polypeptide, a saccharide, a polysaccharide or a polymer. When the substituted phthalocyanine is conjugated to a carrier, it is preferably conjugated to the carrier via substituent R1, R8 or R9. When the macromolecular carrier is a polypeptide, the polypeptide is preferably an antibody.
When the macromolecular carrier is a polymer, the substituted phthalocyanine is preferably entrapped or embedded in a solid polymer or conjugated to a soluble polymer. More preferably, the solid polymer is selected from polyesters, poly(orthoesters), polyanhydrides, tyrosine derived pseudo-poly(amino acids) or polyphosphazenes, or the soluble polymer is selected from N-(2-hydroxypropyl)methacrylamide (HMPA) copolymers, polyvinylpyrrolidone (PVP), poly(ethylene glycol) (PEG) polymers, copolymers or block copolymers, amino acid derived polymers or polyesters. Preferably, the solid or soluble polymer is a biodegradable polymer.
Preferably, the substituted phthalocyanine of the present invention is for use as a medicament. Preferably, the medicament is for use in the photodynamic therapy of a human or animal disease.
According to a ninth aspect of the present invention, there is provided a pharmaceutical composition comprising a substituted phthalocyanine according to the present invention or a pharmaceutically acceptable salt thereof in a mixture or in association with a pharmaceutically acceptable carrier, diluent or excipient.
Preferably, the pharmaceutical composition is in a form suitable for topical, subcutaneous, mucosal, parenteral, systemic, intra-articular, intra-venous, intra-muscular, intra-cranial, rectal or oral application.
Preferably, the pharmaceutical composition of the present invention is for use in the photodynamic therapy of a human or animal disease. Preferably, the human or animal disease is characterised by benign or malignant cellular hyperproliferation or by areas of neovascularisation. Preferably, the human or animal disease is a viral, fungal or bacterial disease or a disease caused by prions. Preferably, the human or animal disease is a tumour, rheumatoid arthritis, inflammatory arthritis, hemophilia, osteoarthritis, vascular stenosis, vascular restenosis, atheromas, hyperplasia, intimal hyperplasia, benign prostate hyperplasia, psoriasis, mycosis fungoides, eczema, actinic keratosis or lichen planus.
Preferably, the source of illumination is a laser or a non-coherent light source emitting light of optimal wavelength.
According to a tenth aspect of the present invention, there is provided a use of a substituted phthalocyanine of the present invention for the manufacture of a phototherapeutic agent for the use in photodynamic therapy. Preferably, the phototherapeutic agent is used for the treatment of a disease characterised by benign or malignant cellular hyperproliferation. Preferably, the phototherapeutic agent is used for the treatment of a viral, fungal or bacterial disease or a disease caused by prions. Preferably, the phototherapeutic agent is used for the treatment of a disease such as a tumour, rheumatoid arthritis, inflammatory arthritis, hemophilia, osteoarthritis, vascular stenosis, vascular restenosis, atheromas, hyperplasia, intimal hypeφlasia, benign prostate hypeφlasia, psoriasis, mycosis fungoides, eczema, actinic keratosis and lichen planus.
According to an eleventh aspect of the present invention, there is provided a use of a substituted phthalocyanine of the present invention for the manufacture of a photodiagnostic agent for the identification of areas that are pathologically affected by cellular hypeφroliferation.
According to a twelfth aspect of the present invention, there is provided a material comprising a substituted phthalocyanine of the present invention, wherein the optical or physical properties of the material may be altered by incident radiation. Preferably, the incident radiation is electromagnetic radiation. More preferably, the incident radiation is electromagnetic radiation with a wavelength in the range of from 200nm to lOOOnm.
Detailed description of the invention
As can be seen in Scheme 7, a substituted phthalocyanine (I) may be prepared by the cyclisation of a substituted phthalonitrile (IV) either by itself or together with any other phthalonitrile of formula (IV). A phthalonitrile of formula (IV) may in turn be prepared from a phthalonitrile sulfonate ester (III), which in turn may be prepared from a suitable phthalonitrile alcohol (II).
Figure imgf000031_0001
Scheme 7
A phthalonitrile sulfonate ester of formula (III) may be prepared from a phthalonitrile alcohol of formula (II) under suitable conditions. The preparation of 3,6- (trifluoromethanesulfonyloxy) phthalonitrile (a triflate), 2,3-dicyano-l,4- (trifluoromethanesulfonyloxy)naphthalene (a triflate) and 3,6- (nonafluorobutanesulfonyloxy)phthalonitrile (a nonaflate) are now described as representative examples of the preparation of phthalonitrile sulfonate esters of formula (III).
Aryl triflates (trifluoromethanesulfonyls) are usually prepared from phenols in excellent yields by treating them with triflic anhydride in the presence of a base such as triethylamine or pyridine at low temperature (K. Ritter, Synthesis, 1993, page 735; P.J. Stang, M. Hanack, L.R. Subramanian, Synthesis, 1982, page 82). However, the reaction of 2,3-dicyanohydroquinone with either triethylamine or pyridine and triflic anhydride at -20°C was ineffective due to the low solubility of the starting material in both solvents. Addition of a co-solvent such as CH2C12 was also ineffective. However, the hydroquinone could be triflated in high yield (91%) by using either 2,6-lutidine or 2,4,6-collodine as the base in the presence of CH2C12. Thus, to a solution of dicyanohydroquinone in a 3:1 CH2Cl2/lutidine mixture at -20°C was added triflic anhydride dropwise under argon. After stirring for one day at room temperature, a simple aqueous work-up followed by recrystallisation from CH2Cl2/petrol or EtOAc/cyclohexane afforded the previously unknown 3,6-(trifluoromethanesulfonyloxy)phthalonitrile as yellow crystals in good yield. 2,3-dicyano-l,4-(trifluoromethanesulfonyloxy)naphthalene was prepared by a similar procedure.
Aryl nonaflates (nonafluorobutanesulfonyls) are usually prepared from phenols by treatment with nonafluorobutanesulfonyl fluoride. However, attempts to nonaflate the 2,3- dicyanohydroquinone under the above conditions all meet with failure, possibly due to the poorer leaving group ability of the fluoride anion compared with the triflate anion. However, using sodium hydride as the base in THF led to a clean and high yielding reaction to afford after a simple aqueous work-up the previously unknown 3,6- (nonafluorobutanesulfonyloxy)phthalonitrile.
Thus the present invention provides a phthalonitrile sulfonyl ester of formula (III) and a process for its preparation.
A substituted phthalonitrile of formula (IV) may be prepared from a sulfonate ester of formula (III) under various conditions, such as for example cross-coupling with an organozinc reagent or an organocooper reagent catalysed by palladium (Method A) or nickel (Method B), cross-coupling with a trialkylborane catalysed by palladium (Method C), cross-coupling with a boronic acid or ester catalysed by palladium (Method D), SNAΓ reaction with a nucleophiles (Method E), or coupling with a suitable coupling partner catalysed by palladium (Method F). These methods shall now be described in turn.
Methods A and B - Cross-coupling between a phthalonitrile sulfonate ester of formula (III) and an organozinc reagent or an organocopper reagent catalysed by palladium or nickel to yield an alkyl-substituted phthalonitrile of formula (IV): The cross-coupling reaction between an aryl iodide and an organozinc reagent catalysed by palladium (Negishi reaction) was first reported in 1977 by Negishi and co- workers (E. Negishi, A.O. King, N. Okukado, J. Org. Chem., 1977, vol. 42, page 1821). The reaction was somewhat overlooked until renewed interest in the late 80 's (P. Knochel, J.J.A. Perea, P. Jones, Tetrahedron, 1998, vol. 54, page 8275). Unlike organolithiums or Grignard reagents, which also undergo cross-coupling reactions, organozincs are unreactive to a wide range of functional groups (P. Knochel, R.D. Singer, Chem. Rev., 1993, vol. 93, page 2117). This is important since it allows a range of functional groups to be incoφorated in the reaction, either on the organozinc reagent itself, or on the coupling partner. Functional groups which can be tolerated include ketones, esters, amides, nitriles, acetals, alkenes and alkynes. Besides aryl and alkenyl halides, aryl and alkenyl triflates can also be used as coupling partners (K. Ritter, Synthesis, 1993, page 735; P. Knochel, J.J.A. Perea, P. Jones, Tetrahedron, 1998, vol. 54, page 8275; E. Erdik, Tetrahedron, 1992, vol. 48, page 9577).
Polyfunctional organozinc halides are readily prepared by direct insertion of zinc into alkyl iodides. Thus decylzinc iodide was prepared by adding a concentrated solution (ca. 3M) of 1-iododecane in THF to a suspension of zinc dust (3 equivalent) in THF at 40°C. The zinc dust was activated with a few mol% of dibromoethane and TMSC1 prior to the addition of the halide. After 12 hours at 40°C the preparation of decylzinc iodide was complete.
Several alternatives also exist. The organozincs can be prepared by metathesis of a Grignard or organolithium reagent with anhydrous ZnBr2 or ZnCl2 in THF. This method was also applied for the generation of decylzinc chloride. However a number of problems exist with this route, firstly the MgCl2 by-product tends to clog the stirrer and makes transfer by cannula problematic and secondly the ZnCl2 is very hygroscopic and therefore difficult to dry. However, 1-octynylzinc chloride was successfully prepared by metathesis of 1-octynyllithium with ZnCl2 at -78°C.
The third method of note is the insertion of more activated zinc (Rieke zinc), prepared by the reduction of zinc halides, into less active alkyl bromides or even aryl bromides. Thus treatment of ZnCl2 with finely cut lithium in the presence of naphthalene produces highly reactive zinc which reacts, for example with methyl 3-bromobutyrate in refluxing THF to afford the secondary zinc reagent (L. Zhu, R.M. Wehmeyer, R.D. Rieke, J. Org. Chem., 1991, vol. 56, page 1445; MN. Hanson, R.D. Rieke, J. Am. Chem. Soc, 1995, vol. 117, page 10775; MN. Hanson, R.D. Rieke, Tetrahedron, 1997, vol. 53, page 1925).
Many aryl and heteroarylzinc halides are available by using one of the three methods above (P. Knochel, J.J.A. Perea, P. Jones, Tetrahedron, 1998, vol. 54, page 8275). The direct zinc insertion into iododecane is preferred for the preparation of the simple alkylzinc reagent decylzinc iodide. 1-octynylzinc chloride was best prepared by metathesis of 1-octynyllithium and ZnC^ at -78°C. A more exotic zinc reagent 6-chlorohexylzinc bromide [Cl(CH2)6ZnBr] was purchased from the Aldrich chemical company. This was prepared by insertion of Rieke zinc. Rieke zinc as a solution in THF can also be purchased from Aldrich.
Initially the cross-coupling reaction was attempted under the more usual conditions of palladium catalysis (method A). Various palladium catalysts have been used for the reaction including Pd(PPh3)4 (E. Erdik, Tetrahedron, 1992, vol. 48, page 9577), bis(tri-o- tolylphosphine)palladium(II) dichloride (E. Νakamura, I. Kuwajima, Tetrahedron Lett., 1986, vol. 27, page 83), PdCl2(dppf) (T. Hayashi, M. Konishi, Y. Kobori, M. Kumada, T. Higuchi, K. Hirotsu, J. Am. Chem. Soc, 1984, vol. 106, page 158) and bis(tri-ø- furylphosphine)palladium(II) dichloride (V. Farina, B. Krishnan, J. Am. Chem. Soc, 1991, vol. 113, page 9585). The latter three catalysts bearing loosely bound bulky phosphine ligands help to prevent the formation of biaryls by phenyl transfer from triphenylphosphine and give excellent results.
The Pd(PPh3)4 catalysed cross-coupling of 3,6-(trifluoromethanesulfonyloxy)- phthalonitrile with decylzinc iodide is described as a representative example of cross- coupling reactions of method A. Lithium chloride was added as a co-catalyst. Although its exact role is not known, it helps to prevent biaryl formation and stabilises the catalyst (M. Fujita, H. Oka, K. Ogura, Tetrahedron Lett., 1995, vol. 36, page 5247; K. Ritter, Synthesis, 1993, page 735). Thus, to a solution of 3,6-(trifluoromethanesulfonyloxy)phthalonitrile, Pd(PPh3)4 (5 mol%) and LiCl (3 equivalent) in THF was added decylzinc iodide (2.5 equivalent) and the reaction refluxed under argon for 12 hours. After cooling and filtration to remove precipitated palladium, TLC analyses showed a mixture of 3,6-didecylphthalonitrile (by comparison with a known sample), and a slower running component, presumably 3-decyl- 6-(trifluoromethanesulfonyloxy)-phthalonitrile. Thus, as expected, palladium has been shown to be a viable catalyst in cross-coupling reactions of method A.
Nickel catalysis (method B) is an attractive alternative to palladium catalysis, both in terms of the cost of the metal and the increased reactivity of Ni(0) towards oxidative insertion into a carbon-halogen or carbon-triflate bond. Snieckus and co-workers have examined the cross-coupling reaction of organotriflates with arylzinc reagents under a variety of conditions (CA. Quesnell, O.B. Familoni, V. Snieckus, Synlett, 1994, page 349). They examined a number of nickel catalysts including Ni(acac)2, Ni(acac)2/PPh3 and NiCl2(PPh3)2. All catalysts were active to varying degrees, although PPh3 stabilised Ni(0) catalysts were among the most reactive. More recently a report by Lipshutz and co- workers demonstrated the nickel catalysed cross-coupling of aryl chlorides and one aryl triflate with alkylzinc reagents using a NiCl2(PPh3)2/2PPh3 catalyst (B.H. Lipshutz, P.A. Blomgren, S-K. Kim, Tetrahedron Lett, 1999, vol. 40, page 197).
The NiCl2(PPh3)2/2PPh3 catalysed cross-couplings of 3,6-
(trifluoromethanesulfonyloxy)phthalonitrile with decylzinc iodide, 6-chlorohexylzinc bromide and 1-octynylzinc chloride are described as representative examples of cross- coupling reactions of method B.
The Ni(0) catalyst was generated in situ by the treatment of NiCl2(PPh3)2 (10 mol%) and PPh3 (20 mol%) in THF at room temperature with «-BuLi (20 mol%) to afford a blood-red Ni(0) catalyst [Ni(PPh3) ]. DIBAL or MeMgBr can be used instead of w-BuLi to generate the catalyst (CA. Quesnell, O.B. Familoni, V. Snieckus, Synlett, 1994, page 349). To this catalyst was added 3,6-(trifluoromethanesulfonyloxy)phthalonitrile as a solid at room temperature under a stream of argon. The resulting solution was cooled to -78°C, and decylzinc iodide (2.5 equivalent) containing LiCl (2.5 equivalent) was added as a solution in THF. The reaction was allowed to warm to room temperature and stirred at that temperature for 16 hours. The reaction was then quenched with 5% HCl, and extracted with ethyl acetate. The organics were washed with further acid and base, dried and concentrated until precipitation began. The resulting solution was allowed to crystallise to afford 3,6-didecylphthalonitrile contaminated with PPh3. The PPh3 could be removed by 5 stirring the solid in acetonitrile, in which 3,6-didecylphthalonitrile is insoluble. A further filtration afforded the product as white crystals in 60-70% yield.
By using 6-chlorohexylzinc bromide as the zinc reagent under identical conditions to those described above, 3,6-bis(6'-chlorohexyl)phthalonitrile was readily produced in
10 61%) yield. The introduction of a halogenated alkyl chain is not readily performed by the thiophene and furan routes of the prior art described earlier. 3,6-Bis(4'- chlorobutyl)phthalonitrile, 3 ,6-bis(4-pivaloyloxybutyl)phthalonitrile, 3 ,6-bis(4-t- butyldimethylsilyloxybutyl)phthalonitrile, and 3,6-bis(l , 1 -H-2,2-H- perfluorodecyl)phthalonitrile were prepared similarly. Of course, those practiced in the art
15 will recognize that functionality within the substituent chain can be changed by standard functional group interconversion chemistry. To exemplify this, 3,6-bis(6'- chlorohexyl)phthalonitrile was reacted with imidazole to form the 3,6-bis(6'-imidazol-l- yl-hexyl)phthalonitrile. Terminal hydroxy groups at the end of the substituents are readily accessible from some of the functionality described. Conversion of appropriately 0 substituted phthalonitriles can be used to generate dimeric or oligomeric structures by standard reactions, for example terminal alcohol groups reacting with diesters or diacid chlorides.
The use of an alkynylzinc chloride reagent, prepared from an alkynyllithium 5 reagent with ZnCl2, led to the preparation of alkynyl-substituted phthalonitriles. Thus, 3,6- bis(l'-octynyl)phthalonitrile was prepared by the cross-coupling of 1-octynylzinc chloride.
In general the chemistry is readily performed, although the careful exclusion of water from the reaction is necessary. Lipshutz indicates that for the less reactive aryl 0 chlorides the addition of the organozinc reagent is best performed at -78°C An attempt to reproduce the coupling using decylmagnesium chloride rather than decylzinc iodide failed, with only polymeric products being formed. The much more reactive Grignard reagent is probably attacking the nitrile functionality. Method C - Cross-coupling between a phthalonitrile sulfonate ester of formula (III) and a trialkylborane catalysed by palladium to yield an alkyl-substituted phthalonitrile of formula (IV):
The reaction of aryl halides and aryl triflates with boron reagents has been extensively investigated by Suzuki and co-workers (N. Miyaura, A. Suzuki, Chem. Rev., 1995, vol. 95, page 2457). The cross-coupling of an aryl compound with an alkylboron reagent (Suzuki-Miyaura reaction) is a powerful tool for the formation of aryl-alkyl carbon bonds and has been investigated for both aryl halides (N. Miyaura, T. Ishiyama, H. Sasaki, M. Ishikawa, M. Sato, A. Suzuki, J. Am. Chem. Soc, 1989, vol. I l l, page 314) and aryl triflates (T. Oh-e, N. Miyaura, A. Suzuki, J. Org. Chem, 1993, vol. 53, page 2201).
Alkyl boron reagents are readily available from the hydroboration of alkenes, and thus a wide range of alkyl groups can theoretically be introduced. The most common alkyl transfer reagent used is a 9-alkyl-9-BBN derivative, whereupon the primary alkyl group is transferred preferentially. This is prepared from an alkene and 9-BBN. However the use of simple trialkylborons, prepared from alkenes and BH3, is more economical due to the expense of 9-BBN.
The cross-coupling involves the treatment of an aryl triflate with a palladium catalyst, a boron reagent and a base at high temperature (50-90°C), typically in a solvent such as THF or 1,4-dioxane. The base is essential for the reaction to proceed, greatly increasing the nucleophilicity of the organoboron and accelerating the subsequent transmetalation step with the organopalladium complex (K. Matos, J.A. Soderquist, J. Org. Chem., 1998, vol. 63, page 461). A variety of bases have been used for the reaction, although some of the most successful such as NaOMe (A. Furstner, G. Seidel, J. Org. Chem., 1997, vol. 62, page 2332) and NaOH (T. Oh-e, N. Miyaura, A. Suzuki, J Org. Chem, 1993, vol. 53, page 2201) are clearly incompatible with the nitrile functionality. Thus, weaker bases, such as K2CΟ3 and K3PΟ4, were investigated (K. Matos, J.A. Soderquist, J. Org. Chem., 1998, vol. 63, page 461). Again several palladium catalysts have been used for the reaction, the most successful being PdCl2(dppf). The results gained under a variety of conditions, all using tridecylborane, are summarised below, see Table 1. All reactions had LiCl (3 equivalent) added as a co- catalyst. The best results were obtained when tridecylborane was produced in situ, that is a solution of borane (0.33 equivalent) in THF was added to 1-decene at 0°C After stirring for 4 hours the formation of the tridecylborane was complete and the base was added. After stirring for a further 1 hour to allow formation of the borate complex, palladium catalyst and 3,6-(trifluoromethanesulfonyloxy)phthalonitrile were added and the reaction refluxed for 10 hours. The solvents were removed under reduced pressure and the residue purified by column chromatography to afford 3,6-didecylphthalonitrile in moderate yields. The low yields obtained are perhaps due to the effect of the base on the phthalonitrile, as considerable black baseline material was also formed.
Figure imgf000038_0001
a e . n ca es r ecy orane was orme n s tu.
Method D - Cross-coupling between a phthalonitrile sulfonate ester of formula (III) and a boronic acid or ester catalysed by palladium or nickel to yield a substituted phthalonitrile of formula (IV):
The cross-coupling of an aryl compound with a boronic acid or ester (Suzuki reaction) is a general method to couple an aromatic ring to an unsaturated coupling partner.
The reaction involves the palladium or nickel catalysed coupling of a boronic acid or ester with an aryl halide or triflate under mild base catalysis. The mild conditions allow the inclusion of a wide-range of functionality on either coupling partner.
The Pd(PPh3) catalysed cross-couplings of 3,6-bis(trifluoromethanesulfonyloxy)- phthalonitrile with phenylboronic acid, 3-methoxyphenylboronic acid and 4- methoxyphenylboronic acid respectively are described as representative examples of cross- coupling reactions of method D. To a solution of 3,6-(trifluoromethanesulfonyloxy)- phthalonitrile in toluene was added LiCl (2.5 equivalent) and Pd(PPh3)4 (6 mol%) under argon. Phenylboronic acid was added, followed by aqueous Na2CO3 as a base, and the > reaction was refluxed for 14 hours. A simple aqueous work-up followed by recrystallisation from toluene afforded 3,6-diphenylphthalonitrile in 79% yield. 3,6-Bis(4- methoxyphenyl)phthalonitrile and 3,6-bis(3-methoxyphenyl)phthalonitrile were prepared in a similar way by cross-coupling of 3,6-(trifluoromethanesulfonyloxy)phthalonitrile with 4-methoxyphenylboronic acid and 3 -methoxyphenylboronic acid respectively.
Method E - SNAΓ reaction of a phthalonitrile sulfonate ester of formula (III) with a nucleophile to yield a substituted phthalonitrile of formula (IV):
Nucleophilic aromatic substitution (SNAΓ) reactions are unfavourable due to electronic and steric reasons. SNAT reactions that nevertheless occur are thought to proceed either via a Meisenheimer complex or a benzyne intermediate. Arenes containing strongly electron-withdrawing groups ortho and/or para to the site of substitution may undergo SNAΓ reactions via an addition / elimination process (Meisenheimer complex). Treating arenes with a strong base can induce SNAT reactions via an elimination / addition process (benzyne intermediate).
The SNAT reactions of 3,6-bis(trifluoromethanesulfonyloxy)phthalonitrile with alkyl thiols from hexylthiol through to dodecylthiol are described as representative examples of reactions of method E. Typically, the reaction of 3,6- bis(trifluoromethanesulfonyloxy)phthalonitrile in DMF with dodecanethiol and K2CO3 resulted in an SNAΓ substitution of the triflate after stirring for 72 hours at room temperature. The reaction of 3,6-bis(trifluoromethanesulfonyloxy)phthalonitrile with the other alkyl thiols under similar conditions also resulted in an S AT substitution of the triflate. These reactions represent a facile synthesis of the previously unknown 3,6- bis(alkylsulfanyl)phthalonitrile series.
Amino-substituted phthalonitriles may also be synthesised via method E, using amines such as for example piperidine, moφholine, pyrrolidine or piperazine as nucleophiles, and has been exemplified using the first one of these. SNAT conditions could possibly be favoured by using Cs2CO3 as the base and the nonaflate rather than the triflate (see for example L. Neuville, A. Bigot, M.E.T.H. Dau, J. Zhu, J. Org. Chem., 1999, vol. 64, page 7638). Alternatively palladium catalysed animation may be a viable route (A.J. Belfield, Tetrahedron, 1999, vol. 55, page 11399).
Method F - Coupling between a phthalonitrile sulfonate ester of formula (III) and an unsaturated coupling partner catalysed by palladium to yield a substituted phthalonitrile of formula (IV):
The coupling of an alkene and an aryl halide or triflate is known as the Heck reaction. Again the reaction is palladium catalysed and generally occurs at high temperature in the presence of an amine base.
The palladium catalysed coupling of 3,6-bis(trifluoromethanesulfonyloxy)- phthalonitrile with 1-decene is described as a representative example of coupling reactions of method F. The reaction was attempted using 3,6-bis(trifluoromethanesulfonyloxy)- phthalonitrile and 1-decene under typical conditions. Thus 3,6- bis(trifluoromethanesulfonyloxy)phthalonitrile, 1-decene, Pd(PPh3)4 (6 mol%), LiCl and Et3N were heated to 100°C in DMF for 24 hours. This resulted in extensive formation of baseline material, from which none of the expected product could be isolated. After testing different solvents (DMF, CH3CN) and catalysts (Pd(PPh3)4, PdCl2(dppf), Pd(OAc)2 PPh3) without success, it was reasoned that the organic base (Et3N) was interfering with the reaction, possibly by attack at the triflate. Repeating the reaction with the hindered base, 2,6-lutidine, led to the expected di-alkenylphthalonitrile being isolated. Yields may possibly be improved by the use of different bases, both organic (for example DBU) and inorganic (for example Cs2CO3), and new catalysts (for example palladacycles, Ni(PPh3)4, etc.).
Thus the present invention provides a substituted phthalonitrile of formula (IV) and a process for its preparation. A non-metallated or metallated substituted phthalocyanine of formula (I) may be prepared from a substituted phthalonitrile of formula (IV) under suitable conditions. 3,6- Bis(dodecylsulfanyl)phthalonitrile was successfully cyclised into both the metal-free and the zinc phthalocyanine using NH3(g) in DMAE. The cyclisation to form metallated derivatives can also be brought about using DBU as base. This has afforded zinc phthalocyanines from the homologous series of 3,6-bis(alkylsulphanyl)phthalonitriles where the alkyl groups range from undecyl through to hexyl and magnesium phthalocyanines bearing eight decylsulfanyl groups through to hexylsulfanyl groups. DBU catalysed reactions of 3,6-bis(hexylsulfanyl)phthalonitrile with lead acetate and indium trichloride afforded the corresponding lead and chloroindium octakis(hexylsulfanyl)phthalocyanines. Metal free analogues are also available by acid catalysed hydrolysis of the magnesium derivatives, exemplified by the demetallation of the octakis(nonylsulfanyl)phthalocyaninato magnesium(II) derivative. The Q-band of these phthalocyanines is significantly red-shifted, occurring between 780 and 830 nm. Hitherto, octa-S-aryl phthalocyanines, with the eight groups similarly located on the phthalocyanine core, have been prepared by displacement of eight chlorine groups on an octa-chloro phthalocyanine. Such compounds were identified as near infra-red absorbing dyes useful for security printing (EP application no. 85301291.2).
Other 3,6-bis(substituted)phthalonitrile precursors can be similarly cyclotetramerised to give the corresponding metallated or unmetallated phthalocyanine. 3,6-Bis(6'-imidazol-l-yl-hexyl)phthalonitrile provides access to the corresponding zinc octakis(6'-imidazol-l-yl-hexyl)phthalocyanine, a derivative soluble in aqueous acid. 3,6- Bis(l,l-H-2,2-H-perfluorodecyl)phthalonitrile is converted into the corresponding octa( 1 , 1 -H-2,2-H-perfluorodecyl)phthalocyanine, soluble in fluorinated solvents.
Of course, 1 :3 and 2:2 mixed substituted phthalocyanines may also be prepared making use of methods A to F described above, by cyclising a substituted phthalonitrile of formula (IV) together with any other substituted phthalonitrile (IV) instead of with itself. For example, [ 1 ,4-diphenyl-8, 11,15,18,22,25-hexakis(decyl)phthalocyaninato] zinc(II) was prepared by cross cyclotetramerisation of 3,6-diphenylphthalonitrile and 3,6- didecylphthalonitrile and [l,4-bis(4-methoxyphenyl)-8,l 1,15,18,22,25- hexakis(decyl)phthalocyaninato] zinc(II) was prepared by cross cyclotetramerisation of 3 ,6-bis(4-methoxyphenyl)phthalonitrile and 3 ,6-didecylphthalonitrile.
Similarly, l,4-bis(3-methoxyphenyl)phthalonitrile and 3,6-didecylphthalonitrile provide [ 1 ,4-bis(3-methoxyphenyl)-8, 11,15,18,22,25-hexakis(decyl)phthalocyaninato] zinc(II). In these reactions, the 3,6-didecylphthalonitrile may be used in excess. Byproducts of the reaction include the symmetrically substituted [1,4,8,11,15,18,22,25- octakis(decyl)phthalocyaninato] zinc(II) and the 2:2 mixed substituted phthalocyanines in which the pairs of common substituted isoindole units are either opposite or adjacent. This isomer mixture has been characterised in the case of the mixed cyclisation of 3,6- diphenylphthalonitrile and 3,6-didecylphthalonitrile.
1 :3 and 2:2 Phthalocyanines bearing functional groups on the pendant aromatic rings can provide access to further derivatives by standard chemistry. For example, demethylation of the methoxy groups by reagents such as BBr3 in the cases cited would lead to the corresponding phenolic derivatives. These could be used to link two or more phthalocyanine molecules together via diester linkages to form dimeric or oligomeric derivatives.
Reaction of 3,6-bis(6'-imidazol-l-yl-hexyl)phthalonitrile with 3,6- didecylphthalonitrile, the latter in excess, produced a mixture of the self-cyclised product from 3,6-didecylphthalonitrile and the 1:3 product substituted with two 6'-imidazol-l-yl- hexyl groups and six decyl groups. The reaction was performed using DBU with zinc acetate to form the zinc phthalocyanine complexes.
Other examples of mixed phthalocyanines may also be synthesised with, for example, hydroxyalkyl or hydroxyalkoxy side chains on one phthalonitrile and hydrophobic substituents on the other phthalonitrile with the former in excess.
Thus the present invention provides a metallated or non-metallated substituted phthalocyanine of formula (I) and a process for its preparation. As can be seen in Scheme 8, a metallated or non-metallated substituted phthalocyanine (V) may be prepared by the cyclisation of a substituted phthalonitrile (VI) or (VII) either by itself or together with any other pthalonitrile of formula (IV).
( route A
Figure imgf000043_0002
Figure imgf000043_0001
route B route A + ( IV) + ( IV)
Figure imgf000043_0003
Scheme 8
A substituted phthalonitrile of formula (VI) may in turn be prepared from 2,3- dicyanohydroquinone, as shown in Scheme 9.
Figure imgf000044_0001
Scheme 9
A phthalonitrile halide of formula (VI) may be prepared from 2,3- dicyanohydroquinone by halogenation and subsequent alkylation under suitable conditions.
For example, bromination of 2,3-dicyanohydroquinone affords 4,5-dibromo-3,6- dihydroxyphthalonitrile. The use of Guenther's method (T. Guenther, Justus Liebigs Ann. Chem., 1906, vol. 349, pages 56-58), bromine in acetic acid, provides a product which gives a low analysis for bromine. However, bromination of 2,3-dicyanohydroquinone using NBS (Roussel UCLFA, French Patent No. 1313082, 28th December 1962; Chem. Abs., 1962, vol. 57, 11283h), followed by sodium metabisulfite reduction of the 2,3- dibromo-4,5-dicyanobenzoquinone so formed, gives 4,5-dibromo-3,6- dihydroxyphthalonitrile in 66% yield.
Alkylation of 4,5-dibromo-3,6-dihydroxyphthalonitrile unexpectedly and fortuitously provides access to both 4,5-dibromo-3,6-dibutoxyphthalonitrile and 4-bromo- 3,6-dibutoxyphthalonitrile. Thus iodobutane in the presence of potassium carbonate in MEK gives a mixture of 4,5-dibromo-3,6-dibutoxyphthalonitrile (6%) and 4-bromo-3,6- dibutoxyphthalonitiile (39%>). The latter is formed exclusively (42%) by delaying addition of iodobutane to the basic solution. This implies that the role of the base is to eliminate HBr from 4,5-dibromo-3,6-dihydroxyphthalonitrile, presumably via its tautomer. The resulting mono-bromobenzoquinone may then be reduced back to the mono- bromohydroquinone, which then undergoes conventional Williamson's ether synthesis. Conditions could not be found which favoured the formation of 4,5-dibromo-3,6- dibutoxyphthalonitrile over 4-bromo-3,6-dibutoxyphthalonitrile in this type of alkylation reaction. Instead, 4,5-dibromo-3,6-dibutoxyphthalonitrile is obtained conveniently and in satisfactory yield (84%) from 4,5-dibromo-3,6-dihydroxyphthalonitrile using Mitsunobu conditions.
Thus the present invention provides a phthalonitrile halide of formula (VI) and a process for its preparation.
A non-metallated or metallated substituted phthalocyanine of formula (V) may be prepared from a phthalonitrile halide of formula (VI) via two routes. Firstly (route A), the phthalonitrile halide (VI) may be converted into a substituted phthalonitrile (VII), which in turn is cyclised either by itself or together with any other phthalonitrile of formula (IV) to yield a substituted phthalocyanine of formula (V, with R9 = R11). Alternatively (route B), the phthalonitrile halide (VI) may be cyclised either by itself or together with any other phthalonitrile of formula (IV) to yield a substituted phthalocyanine halide of formula (V, with R9 = R10). The substituted phthalocyanine halide (V, with R9 = R10) may optionally be converted into a substituted phthalocyanine of formula (V, with R9 = R11).
For example, 4,5-dibromo-3,6-dibutoxyphthalonitrile and 4-bromo-3,6- dibutoxyphthalonitrile were independently cyclotetramerised, the former to give the octabromo-octabutoxy-phthalocyaninato nickel(II) complex and the latter to give the tetrabromo-octabutoxy-phthalocyaninato zinc complex (as a mixture of regioisomers).
Substituted phthalocyanines having one phthalonitrile-monomer different from the other three (1:3 mixed substituted phthalocyanines) may be synthesised, for example, by making use of solid-phase synthetic methods (ret. Letts., 1982, vol. 23(30), pages 3023- 3026; J. Org. Chem., 1991, vol. 56, pages 82-90). The use of polystyrene-based resins as solid-phase has been discussed (EP-A-0,906,758). Obviously, phthalocyanines having four identical phthalonitrile-monomers may also be synthesised via solid-phase synthesis. 1 :3 and 2:2 mixed substituted phthalocyanines can in principle be prepared by several methods, for example cross cyclotetramerisation (G. de la Torre, P. Vazquez, F. Agullo- Lopez, T. Torres, J. Chem. Mat., 1998, vol. 8, pages 1671-1683; J. Bakboord, M.J. Cook, E. Hamuryudan, J. Porphyrins Phthalocyanines, 2000, vol. 4, pages 510-517). To demonstrate the utility of routes A and B described above, route B has been followed using cross cyclotetramerisation to yield 1 :3 mixed substituted phthalocyanines. Two appropriately substituted phthalonitriles (VI) and (IV) are reacted together; the desired product is separated from the resulting mixture by chromatography. For example, mixed cyclotetramerisation of 4,5-dibromo-3,6-dibutoxyphthalonitrile and 3,6- didecylphthalonitrile in a ratio of 1 :9 is undertaken using lithium butoxide in butanol in the presence of nickel acetate. Chromatographic separation readily removes the self- condensation product of 3,6-didecylphthalonitrile, viz 1,4,8,11,15,18,22,25- octadecylphthalocyaninato nickel(II), as the first fraction. The second fraction contains two components, which are separated on a second column, one of which is the required l,4-dibutoxy-2,3-dibromo-8,l l,15,18,22,25-hexakis(decyl)-phthalocyaninato nickel(II), identified by a cluster at 1714 D in the low resolution FAB-mass spectrum, elemental analysis and an Η-NMR spectrum consistent with the expected structure. 1 ,4-Dibutoxy-2- bromo-8,l l,15,18,22,25-hexakis(decyl)-phthalocyaninato nickel(II) is synthesised similarly by mixed cyclotetramerisation of 4-bromo-3,6-dibutoxyphthalonitrile and 3,6- didecylphthalonitrile .
The latter cyclisation is also investigated in the absence of a nickel salt in order to obtain metal-free 1 ,4-dibutoxy-2-bromo-8, 11,15,18,22,25-hexakis(decyl)phthalocyanine. In this work, lithium butoxide in butanol is used as base at different temperatures and over different reaction times, with and without the addition of Pd(0) as Pd(PPh3)4 as a co- catalyst. Ratios of phthalonitriles of 4:1, 3:1 (3,6-didecylphthalonitrile in excess) and 1 :1 are investigated. A 1 : 1 ratio of precursors in dry butanol /lithium butoxide heated under reflux for 20 hours affords a mixture of octakis(decyl)phthalocyanine and the 1 :3 product, l,4-dibutoxy-2-bromo-8,l l,15,18,22,25-hexakis(decyl)phthalocyanine (as the lithiated derivatives). Also present are 2:2 products and compounds in which butoxy groups have displaced bromo substituents as judged by mass spectrometry. Unexpectedly, the addition of Pd(PPh3)4 as co-catalyst enhances yields of both the octakis(decyl)phthalocyanine and the 1 :3 product, l,4-dibutoxy-2-bromo-8,l l,15,18,22,25-hexakis(decyl)phthalocyanine. Furthermore, the latter is the major product. However, it is contaminated with up to ca. 15%) of the palladium metallated derivative, l,4-dibutoxy-2-bromo-8,l 1,15, 18,22,25- hexakis(decyl)phthalocyaninato palladium(II). The pure metal-free compound is isolated by column chromatography. The metal-free compound is readily converted into 1,4- dibutoxy-2-bromo-8,l l,15,18,22,25-hexakis(decyl)phthalocyaninato zinc(II) by reaction with zinc acetate. The latter is also obtained by reaction of 3,6-didecylphthalonitrile with 3,6-dibutoxy-4-bromophthalonitrile in DBU in the presence of zinc acetate.
The conversions of l,4-dibutoxy-2,3-dibromo-8,l l,15,18,22,25-hexakis(decyl)- phthalocyaninato nickel(II) and l,4-dibutoxy-2-bromo-8,l l,15,18,22,25-hexakis(decyl)- phthalocyaninato nickel(II) into their ethynylated derivatives are investigated using both the Sonogashira coupling method (K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett., 1975, vol. 16, pages 4467-4470; S. Thorand, N. Krause, J. Org. Chem., 1999, vol. 63, pages 8551-8553) leading to the trimethylsilyl (TMS) protected ethynylated phthalocynines, and the Stille procedure (D.E. Rudisill, J.K. Stille, J. Org. Chem., 1989, vol. 54, pages 5856-5866) leading directly to the unprotected ethynylated phthalocynines.
Sonogashira coupling is first applied to l,4-dibutoxy-2-bromo-8,l 1,15, 18,22,25- hexakis(decyl)-phthalocyaninato nickel(II) using Et3N as solvent. When the compound is reacted with trimethylsilylethyne (6 equivalents) at 80°C for 36 hours in the presence of Pd(PPh3)2Cl2 (20 mol%>) and Cul (30 mol%) with additional catalyst added after 24 hours, no cross coupling occurs. However, change of solvent to THF/Et3N (5:1), an increase in the amount of Cul (39 mol%), and addition of PPh3 satisfactorily converts l,4-dibutoxy-2- bromo-8,l l,15,18,22,25-hexakis(decyl)-phthalocyaninato nickel(II) into the TMS protected ethynylated phthalocynine, which is obtained in 62%) yield after chromatographic purification. The product gives a cluster corresponding to the molecular ion at 1653 D in the FAB mass spectrum and a Η-NMR signal at 0.49 ppm for the nine trimethylsilyl protons.
Stille coupling of l,4-dibutoxy-2-bromo-8,l l,15,18,22,25-hexakis(decyl)- phthalocyaninato nickel(II) using tributyl(ethynyl)tin and Pd(PPh3)4 as catalyst, stabilised by added PPh3 and lithium chloride, affords the unprotected ethynylated phthalocyanine in 48%o yield. The product is characterised by elemental analysis and Η-NMR spectroscopy.
The Sonogashira conditions used above are applied to the conversion of 1,4- dibutoxy-2,3-dibromo-8, 11,15,18,22,25-hexakis(decyl)-phthalocyaninato nickel(II) into the TMS protected ethynylated phthalocyanine giving a 35%> yield. The product is identified by a cluster at 1747 D in the MALDI-tof mass spectrum and a characteristic 18 proton singlet in the Η-NMR spectrum for the trimethylsilyl protons. 13C-NMR spectroscopy provides further confirmation of the structure. All 16 of the expected aromatic 13C signals are well resolved and the two ethynyl carbons give signals at 104.74 and 100.97 ppm. Deprotection of the TMS protected ethynylated phthalocyanine using aqueous KOH in THF/methanol medium affords the unprotected ethynylated phthalocyanine in 79% yield. This is characterised by a cluster at 1606 D in the FAB-mass spectrum, elemental analysis and 1H and 13C-NMR spectra which show signals fully consistent with the structure.
The Stille coupling procedure, used above, satisfactorily converts l,4-dibutoxy-2,3- dibromo-8,l l,15,18,22,25-hexakis(decyl)-phthalocyaninato nickel(II) directly into the unprotected ethynylated phthalocyanine in 54%> yield. Thus, in this case Stille coupling offers a significant improvement over the Sonogashira method in terms of overall yield. Furthermore, there is less difficulty in separating the fully and partially coupled products, which requires careful chromatography in the case of the Sonogashira procedure.
Sonogashira coupling, using Pd(PPh3)2Cl2/Cu(I)I as catalyst, or coupling using other catalysts for example Pd2(dba)3-AsPh3, can be undertaken to convert 1 ,4-dibutoxy-2- bromo-8,l l,15,18,22,25-hexakis(decyl)phthalocyaninato zinc(II) into corresponding substituted ethynylated derivatives. Reaction with 2-methyl-3-butyn-2-ol provided the corresponding substituted-ethynylphthalocyanine; reactions with other functionalised ethynes, for example ethyl propiolate, N-methylpropargylamine and l-C-ethynyl-2,3,4,6- tetraacetylglucopyranose would yield further novel phthalocyanines.
Route A was also followed. 4-Bromo-3,6-dibutoxyphthalonitrile and 4,5-dibromo- 3,6-dibutoxyphthalonitrile were cross-coupled with boronic acids using a palladium catalyst (Suzuki reaction). For example, 4-bromo-3,6-dibutoxyphthalonitrile and Pd(PPh3)4 (10mol%>) were stirred in DME under nitrogen for 10 minutes. 2- Thiopheneboronic acid was added, followed by a 2M aqueous solution of Na2CO . The mixture was refluxed for 12 hours. After cooling, a simple work-up followed by recrystallisation afforded 4-(2-thienyl)-3,6-dibutoxyphthalonitrile in 62%) yield. 4-Pyridyl- 3,6-dibutoxyphthalonitrile, 4-phenyl-3,6-dibutoxyphthalonitrile, 4,5-diphenyl-3,6- dibutoxyphthalonitrile, 4-(p-hydroxymethylphenyl)-3,6-dibutoxyphthalonitrile and 4-{p- N,N-dimethylaminophenyl)-3 ,6-dibutoxyphthalonitrile, 4-(p-aminophenyl)-3 ,6- dibutoxyphthalonitrile, 4-(p-methoxyphenyl)-3 ,6-dibutoxyphthalonitrile and 4-(p- carboxyphenyl)-3,6-dibutoxyphthalonitrile were prepared in a similar way. The functionalised phenyl rings in these 4-aryl-3,6-dibutoxyphthalonitriles provide access to further derivatives by functional group interchange. Thus mesylation of 4-(p- hydroxymethylphenyl)-3,6-dibutoxyphthalonitrile followed by reaction with tyrosine methyl ester in the presence of base affords the corresponding 4-p-benzyloxy-O-tyrosine methyl ester phthalonitrile.
The versatility of the Suzuki reaction on the 4-bromo- and 4,5-dibromo-3,6- dibutoxyphthalonitriles in principle provides access to other amino acid derivatives, for example with phenylalanine groups para coupled directly to the phthalonitrile core, preferably using NH2 and CO2H protected derivatives of phenylalanine boronic acid or its ester (see F. Firooznia, C. Gude, K. Chan and Y. Satoh, Tetrahedron Letters, 1998, vol. 39, 3985).
Application of the Heck reaction (coupling alkenes to aromatic rings) and the Negishi reaction to 4-bromo- and 4,5-dibromo-3,6-dibutoxyphthalonitriles as precursors provides further means of incoφorating functional groups at the 4- and 4,5-positions of 3,6-dibutoxyphthalonitrile. Thus reactions of 4-bromo-3,6-dibutoxyphthalonitrile with 4- chlorobutylzinc bromide and with 4-ethoxy-4-oxobutylzinc bromide afford the corresponding functionalised phthalonitriles, which are again in principle precursors to other functionally substituted alkyl substituents or can be linked to form dimeric phthalonitriles. Reaction of 3,6-dibutoxy-4(4'-ethoxy-4'-oxobutyl)phthalonitrile with 3,6- didecylphthalonitrile and zinc acetate, catalysed by DBU in butanol as solvent, afforded [1,4- dibutoxy- 2- (4'- butoxy- 4'- oxobutyl)- 8, 11, 15, 18, 22, 15- hexakis(decyl)phthalocyaninato] zinc(II). This reaction demonstrates that transesterification proceeds under the reaction conditions to incoφorate the butoxy group derived from the solvent at the ester moiety, a process which enables other alkoxy or substituted alkoxy groups to be incoφorated at this ester site through judicious choice of solvent. 1 :3 Mixed substituted phthalocyanines are then obtained from the 4-substituted- and 4,5-disubstituted-3,6-dibutoxyphthalonitriles using cross cyclotetramerisation as described above for route B. In this way various metallated and non-metallated 1,4- dibutoxy-2-substituted-8, 11,15,18,22,25-hexakis(decyl)phthalocyanines and 1 ,4-dibutoxy- 2,3-disubstituted-8,l l,15,18,22,25-hexakis(decyl)phthalocyanines were prepared.
Of course, phthalonitriles of formula (VII) can be cyclotetramerised alone to form further phthalocyanines. 3,6-Dibutoxy-4,5-(tris(isopropyl)silylethynyl)phthalonitrile is converted into the corresponding [octabutoxy- octa(tris(isopropyl)silylethynyl)phthalocyaninato] nickel(II) complex. Reaction of the latter with tetrabutylammonium fluoride removes the TIPS groups to afford the octabutoxy-octaethynyl phthalocyaninato nickel(II) complex.
Thus the present invention provides a non-metallated or metallated substituted phthalocyanine of formula (V) and a process for its preparation.
Some phthalocyanines are investigated for liquid crystallinity as a routine element of their characterisation. Hitherto, the columnar mesophase properties of non-peripherally substituted phthalocyanines have been described, both uniformly substituted with either eight alkyl (A.S. Cherodian, A.N. Davies, R.M. Richardson, M.J. Cook, N.B. McKeown, A.J. Thomson, J. Feijoo, G. Ungar, K.J. Harrison, Mol. Cryst. Liq. Cryst., 1991, vol. 196, pages 103-114; M.J. Cook, S.J. Cracknell, K.J. Harrison, J. Mater. Chem., 1991, vol. 1, pages 703-704; AN. Belushkin, M.J. Cook, D. Frezzato, S.D. Haslam, A. Ferrarini, D. Martin, J. McMurdo, P.L. Νordio, R.M. Richardson, A. Stafford, Mol. Physics, 1998, vol. 93, pages 593-607) or eight alkyloxymethyl groups (A.Ν. Cammidge, M.J. Cook, K.J. Harrison, A.J. Thomson, J. Chem. Soc. Perkin Trans. 1, 1991, pages 3053-3058), and 1 :3 non-uniformly substituted derivatives bearing at least six alkyl chains (I. Chambrier, M.J. Cook, S.J. Cracknell, J. McMurdo, J. Mater. Chem., 1993, vol. 3, pages 841-849; M.J. Cook, J. McMurdo, D.A. Miles, R.H. Poynter, J.M. Simmons, S.D. Haslam, R.M. Richardson, K. Welford, J. Mater. Chem., 1994, vol. 4, pages 1205-1213). Νon- peripherally substituted octa-alkoxy derivatives do not show mesophase behaviour (M.J. Cook, A.J. Dunn, S.D. Howe, A.J. Thomson, J. Chem. Soc. Perkin Trans. 1, 1988, pages 2453-2458). The liquid crystal behaviour of the prepared 1:3 phthalocyanines is examined by optical polarising microscopy, and the results are summarised in Table 2; K refers to the crystal state, D to a mesophase (discotic) and I is the isotropic liquid. All but 1,4- dibutoxy-2,3-(2'-trimethylsilylethynyl)-8, 11,15, 18,22,25-hexakis(decyl)-phthalocyaninato nickel (II) exhibit mesophase behaviour, indicating that inclusion of two alkoxy groups in the non-peripheral positions does not inhibit liquid crystallinity. Without exception, the first mesophase observed upon cooling gives rise to a "fan-like" birefringence texture characteristic of a discotic hexagonal disordered phase (Dhd) in accordance with the examples referred to above. l,4-Dibutoxy-2-bromo-8,l l,15,18,22,25-hexakis(decyl)- phthalocyaninato nickel (II) exhibits a second mesophase, but only during cooling. This phase is mobile and distorts under external pressure. It gives rise to an indistinct texture and has not been identified. It is here denoted as Dx.
Figure imgf000051_0001
Table 2 - Transition temperatures measured for various l,4-dibutoxy-2,3-substituted-
8,1 l,15,18,22,25-hexakis(decyl)-phthalocyaninato nickel (II) compounds
[The transition temperatures are measured by polarised light microscopy on the first heating and cooling cycle. The higher temperature mesophase is assigned as Dhd- The lower temperature mesophase Dx is unknown.]
The symmetry of the molecule has a marked effect upon the mesophase behaviour. Thus the nona-substituted phthalocyanines are of Cs symmetry, whilst the deca-substituted phthalocyanines have C2v symmetry. The Cs phthalocyanines exhibit lower K— »Dhd transitions than the analogous C2v phthalocyanines. This can be attributed to the more symmetrical phthalocyanines forming better packed crystals. Secondly, the C s phthalocyanines exhibit higher clearing points (K-→I or Dhd→I) than their C2v counteφarts. The Dhd mesophase of the Cs phthalocyanines is much more mobile and less viscous than for the C v phthalocyanines. The Cs phthalocyanines also have a tendency towards supercooling, crystallisation occurring upon standing overnight at room temperature. By contrast, the C2v phthalocyanines crystallise directly upon cooling. The transition to the crystal is characterised by a colour change, not a change in texture, the "fans" becoming a lighter green. Replacement of the bromine atoms with unprotected ethynyl groups increases clearing transitions.
Substituted phthalocyanines show a multitude of desirable properties and are thus useful for a wide variety of applications.
Certain substituted phthalocyanines of the present invention show high photodynamic properties and a marked absoφtion in the red region of the visible spectrum. These compounds are thus useful both as such and in the form of conjugates with macromolecular carriers (such as for example polymers or antibodies) in the treatment of viral, fungal or bacterial diseases and diseases characterised by areas of neovascularisation or by benign or malignant cellular hypeφroliferation, in particular diseases such as tumours, rheumatoid arthritis, inflammatory arthritis, hemophilia, osteoarthritis, vascular stenosis, vascular restenosis, atheromas, hypeφlasia, intimal hypeφlasia, benign prostate hypeφlasia, psoriasis, mycosis fungoides, eczema, actinic keratosis or lichen planus. Moreover, in so far as they are fluorophores, they may be used as diagnostic agents for the identification of areas that are pathologically affected.
Once organic molecules containing the chromofluorophore macrocycle of the phthalocyanine are photo-activated by irradiation, they are capable of generating hyper- reactive derivatives of oxygen, above all singlet-oxygen or radicals, which are characterised by a high degree of cytotoxicity, and hence are potentially interesting for therapeutic applications, such as photodynamic therapy and/or diagnostic applications (E. Ben-Hur and I. Rosenthal, Int. J. Radiat. Biol., 1985, vol. 47, pages 145-147).
Photosensitization is a process in which a photochemical reaction is induced to occur by the presence of a substance (the photosensitizer), which absorbs the light but is itself substantially unchanged at the end of the reaction, the absorbed light energy being passed on to the main reactants. For example when hydrogen is exposed to light of wavelength 253.6nm no absoφtion of the light takes place and the hydrogen remains completely unaffected. If mercury vapour is added to the hydrogen, the mercury atoms are excited. When such an excited mercury atom collides with a hydrogen molecule, it can transfer some of its energy to the hydrogen, and cause it to dissociate into atoms. The hydrogen has apparently been made sensitive to the light, which it does not absorb. In some cases the photosensitizer is broken down and a photo-product is formed which may also possess suitable photodynamic properties. Similarly, oxygen can be made sensitive to the electromagnetic radiation it may not normally absorb by the presence of phthalocyanines or other "complex" organic molecules; some of which may have metals or metal salts incoφorated.
In the photodynamic therapy of tumours, the substituted phthalocyanines are administered to a tumour-bearing subject, where they are taken up by the tumour at least to a certain extent. Following administration to the patient, photodynamic therapy may be carried out in a conventional manner, using light sources and delivery systems that are known in the art (for example see Phys. Med. Biol., 1986, vol. 31(4), pages 327-360). Upon selective irradiation with an appropriate light source the tumour tissue is destroyed via the dye mediated photogeneration of species such as singlet oxygen or other cytotoxic species such as free radicals, for example hydroxy or superoxide.
Biological studies of substituted phthalocyanines in photodynamic therapy have been conducted with water soluble sulfonated metallo-phthalocyanines (I. Rosenthal, Photochem. Photobiol., 1991, vol. 53(6), pages 859-870). Phthalocyanines comprising hydroxyl, amine or quaternary ammonium substituents have been described for photosensitization of cancer cells (CC. Leznoff et al., Photochemistry and Photobiology, 1989, vol. 49(3), pages 279-284; D. Wohrle et al., Photochemistry and Photobiology, 1990, vol. 51(3), pages 351-356; D. Wohrle D. et al., Dyes and Pigments, 1992, vol. 18, pages 91-102; H. Dummin, J. Photochem. Photobiol., 1997, vol. 37(3), pages 219-229). Experiments of cancer phototherapy with phthalocyanines on laboratory animals have also been reported (H. Barr et al., Br. J. Surg., 1990, vol. 77, pages 93-96; K. Schieweck et al., Proc. SPIE, 1994, vol. 2078, pages 107-118; C Ometto et al., Br. J. Cancer, 1996, vol. 74, pages 1891-1899; J. Rousseau et al., J. Photochem. Photobiol., B: Biol., 1990, vol. 6, pages 121-132). Minnoch et al. (J. Photochem. and Photobiol., 1996, vol. 32(3), pages 159-164) and Brown et al. (Photochem. and Photobiol, 1967, vol. 65(3)) have described the in vitro activity of four phthalocyanine derivatives both on micro-organisms and on cell lines.
There are various criteria, which have to be met at least to some extent, if a compound is to be successful as a photosensitizer for use in photodynamic therapy, including the following: a) High quantum yield of reactive species, such as singlet-oxygen or radicals; b) Relatively low toxicity to the subject; c) Capacity of being activated by radiation of high wavelength (preferentially in the red or near infra-red region of the spectrum), which is able to penetrate more deeply into the tissues as compared to radiation of shorter wavelength; d) Selective accumulation by the cells that are responsible for a given pathological condition and fast elimination from the tissues that are not affected by the the pathological condition; e) Possibility of being conjugated to macromolecular carriers, albeit maintaining the characteristics of photosensitization efficiency.
Certain substituted phthalocyanines are induced to act as photosensitizers by incident electromagnetic radiation of a suitable wavelength. This includes all suitable wavelengths of the electromagnetic spectrum. Preferably the electromagnetic radiation is somewhere in the range of ultra-violet to infra-red, even more preferably it is in the range visible-red to infra-red. Red light shows greater tissue penetration than light of shorter wavelengths. Preferably a photosensitizer absorbs laser light of a suitable wavelength, but other light sources may also be used, such as a tungsten halogen lamp.
Metallated phthalocyanines have been found to have better photosensitizing activity compared to metal-free phthalocyanines when the metal is diamagnetic. Particularly zinc (II) phthalocyanines have been found to be useful in photodynamic therapy. Conversely a paramagnetic metal renders the phthalocyanine inactive (I. Rosenthal, E. Ben-Hur, "Phthalocyanines in Photobiology" in "Phthalocyanines, Properties and Applications", eds., CC Leznoff and A.B.P. Lever, V.C.H. Publishers, 1989). Hydrophilic substituents or the conjugation to hydrophilic carriers can accelerate the metabolism of the phthalocyanines, enabling a fast in vivo elimination of the chromophore, and thus preventing the onset of cutaneous phototoxicity.
Some substituted phthalocyanines show photodynamic activity even at low oxygen concentration, thus being useful for the specific treatment of anaerobic microorganisms or the treatment of tumour diseases known to be characterised by a hypoxic environment.
Substituted phthalocyanines may also be conjugated to carriers to improve their pharmacological characteristics. The carriers are normally chosen from the group consisting of amino acids, fatty acids, nucleic acids, di-, tri- or up to decapeptides, polypeptides, proteins, saccharides, polysaccharides, polymers and antibodies, which may be tailored to attach themselves to the tumour site. Antibodies may be prepared from cultured samples of the tumour. Examples include P.L.A.P. (Placental Alkaline Phosphatase), H.M.F.G. (Human Milk Fat Globulin), C.E.A. (Carcino Embryonic Antibody) and H.C.G. (Human Chorionic Gonadotrophin). The phthalocyanine-carrier bond may occur between carboxyl or amine groups or by exploiting other known functional and reactive groups.
Pharmaceutical compositions, comprising a substituted phthalocyanine of the present invention, as such or in form of a conjugate with a carrier, or a pharmaceutically acceptable salt thereof, in a mixture or in association with a pharmaceutically acceptable carrier, diluent or excipient, may be formulated according to well-known principles and may desirably be in the form of unit dosages determined in accordance with conventional pharmacological methods. The unit dosage forms may provide a daily dosage of active compound in a single dose or in a number of smaller doses. Dosage ranges may be established using conventional pharmacological methods and are expected to lie in the range of from 1 to 60 mg/kg of body weight. Other active compounds may be used in the compositions or administered separately, or supplemental therapy may be included in a course of treatment for a patient. The pharmaceutical compositions may desirably be in a form suitable for topical, subcutaneous, mucosal, parenteral, systemic, intra-articular, intravenous, intra-muscular, intra-cranial, rectal or oral application. Suitable carriers and diluents are well known in the art and the compositions may include excipients and other components to provide easier or more effective administration.
Thus the present invention provides a substituted phthalocyanine of formula (I) or (V) optionally conjugated to a carrier for use as a medicament, particularly for use in photodynamic therapy. The present invention further provides a pharmaceutical composition comprising a phthalocyanine of formula (I) or (V) or a pharmaceutically acceptable salt thereof, particularly for use in photodynamic therapy. The present invention further provides use of a substituted phthalocyanine of formula (I) or (V) for the manufacture of a phototherapeutic or photodiagnostic agent.
Some substituted phthalocyanines of the present invention, in thin films for example Langmuir-Blodgett films and spin coated films, in the liquid crystalline state, or when dissolved or dispersed in a carrier material, are largely transparent in the visible region and are yet strong absorbers of ultraviolet or infra-red radiation, preferably of infrared radiation within the range of 750nm and 870nm and preferably exhibit absoφtion maxima within that range. Such substituted phthalocyanines can be used in laser addressed applications, in which laser beams are used to scan across the surface of the material to leave a written impression thereon. The technique relies upon localised absoφtion of laser energy, which causes localised heating and in turn alters the optical properties of the otherwise transparent material in the region of contact with the laser beam. Thus as the beam traverses the material, a written impression of its path is left behind. Important applications are in laser addressed optical storage devices and in laser addressed projection displays, in which light is directed through a cell containing the material and is projected onto a screen. Such devices have been described by F J Khan (Appl. Phys. Lett., 1973, vol. 22, page 111) and by Harold and Steele (Proceedings of Euro Display, Sep. 1984, vol. 84, pages 29-31 , Paris, France), in which the material in the device was a smectic liquid crystal material. Devices, which use a liquid crystal material as the optical storage medium, are an important class of such devices.
The use of semiconductor lasers, especially GaxAlι-xAs lasers (where x if from 0 to 1 and is preferably 1), has proven particularly popular in the above applications, because they can provide laser energy at a range of wavelengths in the near infra-red, which cannot be seen (and thus cannot interfere with the visible display), and yet can provide a useful source of well-defined, intense heat energy. Gallium arsenide lasers provide laser light at a wavelength of about 850nm, and are most useful for the above applications. With increasing Al content (x<l), laser wavelength may be reduced down to about 750nm.
The high stability of the phthalocyanine ring system suggests further possible uses for the substituted phthalocyanines of the present invention, especially when complexed with central metal ions M, the variable oxidation states of which may give rise to materials with semiconductor, photoconductor or electrochromic properties. Such properties may be exploited in sensors, catalysts and displays.
Further possible uses of the substituted phthalocyanines of the present invention are derived from their stereochemistry and orientational ability, for example some have liquid crystal characteristics, and others may be of value in Langmuir-Blodgett films and spin coated films. Others may absorb electromagnetic radiation and be useful in solution for this puφose, for example in liquid crystals. Other possible uses, where M is a large metal ion such as Pd or Pt, are as one-dimensional conductors, for example potentially or molecular wires.
Furthermore, the substituted phthalocyanines of the present invention may be polymerised. Polymerisation may take place across double bonds in unsaturated side chains or by ester or amide formation or any other suitable polymerisation technique, which will be apparent to those skilled in the art. Any polymerisation may be achieved with little or no effect on the phthalocyanine ring itself, as it possesses high stability.
Thus the present invention provides a material comprising a substituted phthalocyanine of formula (I) or (V), wherein the optical or physical properties of the material may be altered by incident electromagnetic radiation.
Brief description of the Figures
Figure 1 shows a typical decay and fitted curve for [l,4-bis(3-methoxyphenyl)- 8,l l,15,18,22,25-hexakis(decyl)-phthalocyaninato] zinc(II) (sample AA35) in toluene/pyridine, excited at 355nm. The residuals (xlO) are shown offset by 20 mV. The ringing observed in the first 2-3 μs of the decay are due to sensitiser fluorescence.
Figure 2 shows a plot showing the linear relationship between singlet oxygen emission intensity and laser energy for samples of perinaphthenone and [l,4-bis(3- methoxyphenyl)-8,l l,15,18,22,25-hexakis(decyl)-phthalocyaninato] zinc(II) (sample
AA35). The slopes 0.38 and 0.25, for these and more solutions of different absorbances are used to determine ΦΛ-
Figure 3 shows a plot showing the relationship between the intensity of singlet oxygen signal (normalised for incident laser energy) and the fraction of light absorbed by [1 ,4-bis(3-methoxyphenyl)-8, 11,15,18,22,25-hexakis(decyl)-phthalocyaninato] zinc(II) (sample AA35) (1-10-A).
Synthetic Experimental Details
Preparation of 3,6-bis(trifluoromethanesulfonyloxy)phthalonitrile:
A 2-necked flask equipped with a thermometer and a pressure equalising addition funnel was flame dried under argon. 2,3-Dicyanohydroquinone (5.2 g, 0.0325 mol) was dissolved in a mixture of dry CH C12 (30 ml) and dry 2,6-lutidine (16 ml), and the resulting yellow solution was cooled to -20°C A solution of trifluoromethanesulfonic anhydride (22.1 g, 0.078 mol) in dry CH2C1 (10 ml) was added dropwise over 30 minutes. The resulting solution was allowed to warm to room temperature and stirred for 14 hours. The CH2C12 was removed under reduced pressure and ethyl acetate (50 ml) was added. The resulting solution was washed with 5% HCl (2 x 20 ml), 5%> NaOH (2 x 20 ml, to remove starting material and mono-triflated compound) and brine (20 ml), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was recrystallised from ethyl acetate/cyclohexane to afford 3,6-bis(trifluoromethanesulfonyloxy)phthalonitrile (12.71 g, 92%) as pale yellow crystals [m.p. 109-111°C Found C, 28.46; H, 0.29; N, 6.50. Cι0H2N2O6S2F6 requires C, 28.31 ; H, 0.48; N, 6.60. Η NMR (270 MHz, CDC13) δ 7.87 (s, 2H) ppm. 13C NMR (270 MHz, CDC13) δ 148.89 (ArC-O), 128.66 (ArC-H), 118.55 (q, J = 321 Hz, -CF3), 1 12.88, 109.32 ppm. vmax (KBr) 3116 (m), 2254 (m, CN), 1473 (s), 1440 (s), 1231 (s), 1132 (s) cm"1. MS (70 eV, El) 423.9 (5.81%, M)+]. Preparation of 2,3-dicyano-l ,4-bis(trifluoromethanesulfonyloxy)naphthalene:
In a similar procedure to above, 2,3-dicyano-l, 4-dihydroxynaphthalene (1.99 g, 9.47 mmol) was dissolved in dry CH2C12 (25 ml) and dry 2,6-lutidine (10 ml), and the resulting brown solution cooled to -20°C A solution of trifluoromethanesulfonic anhydride (5.89 g, 3.5 ml, 2.2 eq) in dry CH2C12 (5 ml) was added dropwise over 30 minutes. The reaction was allowed to warm to room temperature and stirred for 18 hours. Work-up as above afforded the crude product, which was recrystallised from methanol to afford 2,3-dicyano-l, 4-bis(trifluoromethanesulfonyloxy)naphthalene (2.65 g, 59%>) as pale yellow crystals [mp 114-115°C Found: C, 35.58; H, 0.74; N, 5.82. C14H4N2O6S2F6 requires C, 35.45; H, 0.85; N, 5.90%. Η NMR (270 MHz, CDC13) δ 8.38 (2H, dd), 8.12 (2H, dd) ppm. 13C NMR (270 MHz, CDC13) δ 147.22 (ArC-O), 133.62 (ArC-H), 129.54, 123.85 (ArC-H), 118.46 (CF3, q, J= 321 Hz), 110.39, 106.04 ppm].
Preparation of 3 ,6-bis(nonafluorobutanesulfonyloxy)phthalonitrile:
2,3-Dicyanohydroquinone (2.53 g, 0.0158 mmol) and 18-crown-6 (one crystal) were dissolved in dry THF (60 ml) and cooled to 0°C Sodium hydride (60%) dispersed in mineral oil, 1.45 g, 0.0363 mmol) was added portionwise. To the resulting yellow precipitate was added nonafluorobutanesulfonyl fluoride (10.85 g, 0.036 mmol) dropwise at 0°C. The reaction was allowed to warm to room temerature and stirred for 24 hours to afford a pale green solution. The reaction was diluted with diethyl ether (50 ml), and washed with 5% NaOH (30 ml), 5% HCl (30 ml) and brine (30 ml), dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was recrystallised from CH2Cl2/CH3OH (99:1) to afford 3,6-bis(nonafluorobutanesulfonyloxy)phthalonitrile as white crystals [1H NMR (300 MHz, acetone-d6) δ 7.85 (s, 2H) ppm].
Preparation of Zinc dust (D.D. Perrin, W.L.F. Armarego, "Purification of Laboratory Chemicals", 3rd edition):
Zinc dust (120 g) was stirred in 2% HCl (300ml) for 2 minutes and the acid removed (decanter). The resulting dust was stirred sequentially with 2%> HCl (300 ml), water (3 x 300 ml) and 95%> ethanol (2 x 200ml), the dust being allowed to settle before the waste solvents were decantered. Finally the zinc was washed with diethyl ether (200 ml), filtered and dried under vacuum for 24 hours. The resulting dust was stored over P2O5. Preparation of tt-decylzinc iodide (see B. H. Lipshutz in "Organometallics in Synthesis. A Manual.", ed. M. Schlosser, John Wiley and Sons, 1994, Chichester):
To a flame-dried 2-necked flask, equipped with a reflux condensor and a rubber septum under argon, was added acid washed zinc dust (10 g, ca. 3 equivalent) and dry THF (3 ml). Dibromoethane (1.14 g, 6.07 mmol) in THF (2 ml) was added via syringe and the mixture was heated to ebullition with a hot air gun. The reaction was allowed to cool and then heated again. This process was repeated once more, then trimethylsilyl chloride (0.66 g, 6.07 mmol) was added. The mixture was again heated with a hot air gun and allowed to cool. The rubber septum was replaced by a pressure-equalising addition funnel charged with 1-iododecane (13.68 g, 51 mmol) in dry THF (25 ml), and the reaction heated to 40- 45°C The iododecane was added dropwise over 30 minutes, and then stirred for 12 hours at 40°C The reaction was cooled and the excess zinc allowed to settle (4 hours). The resulting grey zinc reagent was transferred via a cannula to a dry storage vessel. The remaining zinc was washed with THF (10 ml), allowed to settle and transferred into the storage vessel to afford n-decylzinc iodide in THF (37 ml, at 1.24M assuming a 90%) conversion). [NB. Complete reaction of iododecane can be checked by hydrolysing the zinc reagent and running a GC]
Preparation of 3,6-didecylphthalonitrile: Method A
To a flame dried 2-necked flask under argon was added 3,6- bis(trifluoromethanesulfonyloxy)phthalonitrile (1 g, 2.36 mmol), lithium chloride (0.30 g, 7.0 mmol), tetrakis(triphenylphosphine) palladium(O) (136 mg, 5 mol%>) and dry THF (10 ml). After stirring for 10 minutes at room temperature, decylzinc iodide in THF (7.0 mmol, 20 ml of a 0.35M solution in THF) was added via a syringe and the resulting solution was stirred at room temperature for 30 minutes, and then refluxed for 12 hours. The solution was cooled, filtered and the solvent removed under reduced pressure. TLC (petrol/CH2Cl2 1 :1) showed a mixture of 3,6-didecylphthalonitrile and a slower running fraction which was presumably 3-decyl-6-(trifluoromethanesulfonyloxy)phthalonitrile.
Preparation of 3,6-didecylphthalonitrile: Method B
To a flame-dried 2-necked flask was added bis(triphenylphosphine)-nickel (II) dichloride (0.154 g, 10 mol%) and triphenylphosphine (0.124 g, 20 mol%ι) under argon at room temperature. Dry THF (5 ml) was added followed by o-butyllithium (0.2 ml, 20 mol%>, 2.5M in hexanes) to afford a blood red slurry. 3,6-
Bis(trifluoromethanesulfonyloxy)-phthalonitrile (1 g, 2.36 mmol) was added as a solid under a fast stream of argon, and the resulting pale brown solution was cooled to -78°C Decylzinc iodide in THF (7.0mmol, 5.6ml of a 1.24M solution in THF) containing lithium chloride (0.30g, 7.0mmol) was added via a syringe and the resulting solution was warmed to room temperature over ca. 1 hour. The reaction was stirred at room temperature for 16 hours. 5%> HCl (10ml) was carefully added, followed by ethyl acetate (20ml). The organic layer was separated, and washed with 5%> HCl (10ml) and brine (10ml). The aqueous waste was back extracted with ethyl acetate (10ml), and the combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was stirred in acetonitrile (10 ml) for 30 minutes and filtered to afford pure 3,6- didecylphthalonitrile (0.61%, 70%ι), which was identical to a known sample.
Preparation of 3,6-bis(4'-chlorobutyl)phthalonitrile: Method B
A mixture of triphenylphosphine (625mg, 2.4mmol), lithium chloride (1.5g, 35mmol) and bis(triphenylphosphine)nickel (II) chloride (780mg, 1.2mmol) was stirred in dry THF (25ml) under nitrogen for 10 minutes. H-BuLi (2.5M in hexanes, 1ml) was added to the blue solution at room temperature. The solution turned deep red. Solid 3,6- bis(trifluoromethanesulfonyloxy)phthalonitrile (5g, 12mmol) was added at once under a fast stream of nitrogen and the pale brown solution was cooled to -78°C 4- Chlorobutylzinc bromide (0.5M in THF purchased from Aldrich, 50ml, 25mmol) was added via a syringe. The solution was allowed to warm to room temperature and stirring continued for 12 hours under nitrogen. 5%> HCl (50ml) was added and the mixture extracted with ethyl acetate (3x20ml). The combined organic layers were washed with 5% HCl (10ml), 5% NaOH (10ml), brine (10ml), and dried (MgSO4). The drying agent was removed by filtration and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica [eluent: petroleum ether (bp. 40-60°C) / dichloromethane, 1 :1] to remove triphenylphosphine. The eluent was changed to dichloromethane to obtain 3,6-bis(4 '-chlorobutyl)phthalonitrile (1.92g, 6.2mmol, 52%) as a pale yellow oil which solidifies on standing [mp 61 °C 1H-NMR (270 MHz, CDC13) δ 7.6 (s, 2H), 3.6 (t, 4H), 2.9 (t, 4H), 1.77 (m, 8H) ppm. m/z 308 (M, 21.47%), 310 (M+2, 15.42%)]. Preparation of 3,6-bis(6'-chlorohexyl)phthalonitrile: Method B
In a similar procedure to above, 3,6-bis(trifluoromethanesulfonyloxy)-phthalonitrile (0.5 g, 1.18 mmol) was added to the nickel catalyst [prepared from NiCl2(PPh3)2 (78 mg) and PPh3 (62.5 mg)]. The reaction was cooled to -78°C and 6-chlorohexylzinc bromide (0.5M in THF purchased from Aldrich, 5.5 ml, 2.75 mmol) was added via a syringe. The reaction was allowed to warm to room temperature and stirred for 16 hours. The reaction was quenched with 5%o HCl and worked-up as above. The resulting crude product was purified by column chromatography over silica (eluent: petrol/CH2Cl2 1 :1) to afford triphenylphosphine as the first fraction, and 3,6-bis(6'-chlorohexyl)phthalonitrile (0.26 g, 60.5%) as the second fraction [m.p. 44.5-45.5°C Found: C, 66.07; H, 7.17; N, 7.67. C20H26N2C12 requires C, 65.75; H, 7.17; N, 7.67. 1H NMR (300 MHz, CDC13) δ 7.48 (s, 2H), 3.54 (t, 4H, -OCH2), 2.87 (t, 4H, -CH2C1), 1.83-1.63 (m, 8H), 1.53-1.26 (m, 8H) ppm].
Preparation of 3,6-bis[6'-(imidazol-l-yl)hexyl]phthalonitrile: (from the above compound)
A mixture of 3,6-bis(6'-chlorohexyl)phthalonitrile (720mg, 1.97mmol), imidazole (270mg, 4mmol), potassium carbonate (10 eq.) and tetra-tt-butyl ammonium iodide (catalytic amount) in DMF (10ml) was heated at 60°C under nitrogen with stirring for 72 hours. After cooling, water (100ml) was added. A pale brown oil formed at the bottom of the flask and this was separated. Dichloromethane was added to the oil and the organic layer washed with water (2x20ml), brine (20ml) and dried (MgSO ). The drying agent was removed by filtration and the solvent removed under reduced pressure. The product was separated (silica gel, eluent: dichloromethane, followed by methanol). The methanol fraction was evaporated to yield 3,6-bis[6'-(imidazol-l-yl)hexyl]phthalonitrile (550mg, 1.3mmol, 66%) as a thick pale yellow oil [1H-NMR (270 MHz, CDC13 ) δ 7.62 (s, 2H), 7.59 (br s, 2H), 7.2 (br s, 4H), 4.2 (t, 4H), 2.91 (t, 4H), 1.86 (m, 4H), 1.75 (m, 4H), 1.4 (m, 8H) ppm. m/z 446 (M+H2O)].
Preparation of 3,6-bis(4'-ethoxy-4'-oxobutyl)phthalonitrile: Method B
A mixture of triphenylphosphine (375mg, 1.4mmol), lithium chloride (0.9g, 21 mmol) and bis(triphenylphosphine)nickel (II) chloride (470mg, 0.72mmol) was stirred in dry THF (15ml) under nitrogen for 10 minutes. «-BuLi (2.5M in hexanes, 0.6ml) was added to the blue solution at room temperature. The solution turned deep red. Solid 3,6- bis(trifluoromethanesulfonyloxy)phthalonitrile (3g, 7.1 mmol) was added at once under a fast stream of nitrogen and the pale brown solution was cooled to -78°C 4-Ethoxy-4- oxobutylzinc bromide (0.5M in THF purchased from Aldrich, 30ml, 15mmol) was added via a syringe. The solution was allowed to warm to room temperature and stirring continued for 12 hours under nitrogen. 5%> HCl (50ml) was added and the mixture extracted with ethyl acetate (3x20ml). The combined organics were washed with 5%> HCl (10ml), 5% NaOH (10ml), brine (10ml), and dried (MgSO4). The drying agent was removed by filtration and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica (eluent: dichloromethane) to remove triphenylphosphine. The eluent was changed to ethylacetate to obtain 3, 6-bis(4 '-ethoxy-4 '- oxobutyl)phthalonitrile (1.6g, 4.5mmol, 63%>) as a pale yellow oil which solidifies on standing [mp 51°C Η-NMR (270 MHz, CDC13) δ 7.6 (s, 2H), 4.15 (q, 4H), 2.95 (t, 4H), 2.4 (t, 4H), 2.04 (m, 4H), 1.25 (t, 6H) ppm. m/z 311 (M-OEt, 5.59%)].
Preparation of 3,6-bis(4'-pivaloylbutyl)phthalonitrile: Method B (a) 4-iodo-l-(pivaloyl)butane
To a stirred solution of dry THF (23.3g, 0.32mol) and pivaloyl chloride (12.06g, O.lmol) in dry acetonitrile (200ml) was added sodium iodide (30g, 0.2mol). The flask was protected by a drying tube and stirred for 12 hours at room temperature. The resulting orange solution was quenched with sat. sodium metabisulfite (200ml). The mixture was extracted with diethyl ether (3x80 ml). The combined organics were washed with 5% NaOH (80ml), sat. sodium bisulfite (80ml), brine (80ml), dried (MgSO4), filtered and concentrated under reduced pressure. The resulting crude oil was filtered through silica (eluent: diethyl ether/petrol 1:2). The first fraction afforded pure 4-iodo-l- (pivaloyl)butane (22.8 lg, 80.3%) [Η NMR (300 MHz, CDC13) δ 4.09 (t, 2H, J = 6.3 Hz), 3.22 (t, 2H, J = 6.8 Hz), 1.96-1.86 (m, 2H), 1.80-1.71 (m, 2H), 1.21 (s, 9H) ppm. IR (neat) 1729 (s, CO)]. The organozinc reagent from this compound was formed according to the procedure outlined above. (b) coupling reaction
To a flame dried 3 -necked flask under argon was added bis(triphenylphosphine)- nickel (II) dichloride (0.63g, 10mol%) and triphenylphosphine (0.50g, 20mol%). Dry THF (20ml) was added, followed by «-BuLi (2.5M in hexanes, 0.8ml, 20mol%) to afford a blood red slurry. 3,6-(Trifluoromethanesulfonyloxy)phthalonitrile (4g, 9.43mmol) and anhydrous LiCl (ca. 1.2g) were added together as solids under a fast stream of argon. The resulting pale brown solution was cooled to -78°C and 4-pivaloylbutylzinc iodide (0.024mol, 20ml of a 1.2M solution in THF) was added via a syringe. The solution was warmed to room temperature over ca. 1 hour, and the reaction stirred for 12 hours. Ethyl acetate (100ml) was added, and the solution washed twice with 5%> HCl (40ml), brine (40ml), dried (MgSO4), filtered and concentrated under reduced pressure. This was further purified by column chromatography over silica (eluent DCM). The first fraction contained PPh3. Subsequent fractions contained the product contaminated with triphenylphosphine and baseline material. A second column over silica (eluent: petrol/EtOAc 85:15 to 100:30) afforded 3,6-bis(4 '-pivaloylbutyl)phthalonitrile (2.57 g, 62%>) as the second fraction as a colourless oil [Found: C, 70.87; H, 8.21; N, 6.28. C26H36N2O4 requires C, 70.88; H, 8.24; N, 6.36. IR (neat) 2958, 2871, 2229 (CN), 1727 (ester). Η NMR (300 MHz, CDC13) δ 7.49 (s, 2H), 4.10 (t, 4H, J = 7.7 Hz), 2.91 (t, 4H, J = 7.2Hz), 1.78-1.61 (m, 8H), 1.20 (s, 18H) ppm. 13C NMR (300 MHz, CDC13) δ 178.63, 145.71, 133.48, 115.89, 114.86, 63.43, 38.58, 38.03, 33.80, 26.07, 27.00 ppm. MS (70 eV, El) 440.1 (2.7%, M+)].
Preparation of 3,6-bis(4'-tert-butyldimethylsilyloxybutyl)phthalonitrile: Method B
4-Iodo-l-(tert-butyldimethylsilyloxy)butane (S 'rttbe-9t_v 1999, 1231; Synthesis 1998, 56) was converted into the zinc derivative and used according to the reaction above to afford 3,6-bis(4'-tert-butyldimethylsilyloxybutyl)phthalonitrile (27.6%) as a colourless oil [IR (neat) 2229 (CN). 13C NMR (300 MHz, CDC13) δ 146.13, 133.351, 115.83, 115.13, 62.49, 33.99, 32.01, 26.86, 25.84, 18.20, -5.48 ppm. 1H NMR (300 MHz, CDC13) δ 7.45 (s, 2H), 3.61 (t, 4H), 2.86 (t, 4H), 1.78-1.67 (m, 4H), 1.60-1.52 (m, 4H), 0.86 (s, 9H), 0.02 (s, 6H) ppm].
Preparation of 3,6-bis(l,l-H-2,2-H-perfluorodecyl)phthalonitrile: Method B
Prepared as above from l,l-H-2,2-H-perfluorodecyl zinc iodide. After stirring at room temperature for 16 hours, the residue was dissolved in 250ml ether/THF (4:1) and washed with 5% HCl (40ml). An insoluble precipitate was formed and was filtered. The organic layer was washed with brine (40ml), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was stirred in acetonitrile (20ml) and filtered. The two filtrates were combined and recrystallised from α,α,α-trifluorotoluene to afford 3,6- bis(l, l-H-2,2-H-perfluorodecyl)phthalonitrile (1.56g, 58%) [Found: C, 33.01; H, 0.82; N, 2.93. C28Hι0N2F34 requires C, 32.96; H, 1.06; N, 2.75. IR (smear) 2229 (CN). 1H NMR (300 MHz, C6F6 containing 10% C6D6) δ 7.36 (s, 2H), 3.16 (t, 7.9 Hz), 2.57-2.41 (m, 4H) ppm].
Preparation of 3,6-bis( -octynyl)phthalonitrile: Method B
In a dry 2-necked flask under argon was added 1-octyne (2.20 g, 0.02 mol) and dry THF (10 ml). The reaction was cooled to -78°C and n-BuLi (2.5M solution in hexane, 8 ml, 0.02 mol) was added dropwise. The reaction was stirred for 30 minutes at -78°C. To the resulting yellow solution was added a solution of ZnCl2 in Et2O (1M, 20 ml, ALDRICH) over 10 minutes. The resulting white suspension was stirred at -78°C for 1 hour. Meanwhile, in another dry 2-necked flask the nickel catalyst was prepared. Thus, bis(triphenyl)phosphine-nickel(II) dichloride (0.53 g, 0.0008 mol) and triphenylphosphine (0.42 g, 0.0016 mol) were dissolved in dry THF (20 ml). n-BuLi (0.65 ml of a 2.5M solution in hexane, 0.0016 mol) was added dropwise to afford the active red catalyst. 3,6- (Trifluoromethanesulfonyloxy)phthalonitrile (3.40 g, 0.008 mol) was added as a solid under a fast stream of argon, the flask was cooled to -78°C, and the prepared solution of 1- octynylzinc chloride was added via a cannula. The reaction was allowed to warm to room temperature over ca. 1 hour and stirred at room temperature for 24 hours. The reaction was concentrated under reduced pressure and dissolved in ethyl acetate (100 ml). The ethyl acetate was washed with 5% HCl (2 x 20 ml), 5% NaOH (2 x 20 ml) and brine (20 ml), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was further purified by column chromatography over silica (eluent: Q^C^/petrol 1 :2 to 1 :10). The first fraction afforded triphenylphosphine, whilst the second fraction contained 3, 6-bis(l '- octynyl)phthalonitrile (1.31 g, 48%>) as a pale yellow oil which crystallised upon standing [Η NMR (60 MHz, CDC13) δ 7.60 (s, 2H), 2.3 (t, 4H), 1.7-1.2 (m, 16H), 0.9 (t, 6H) ppm].
Preparation of 3,6-didecylphthalonitrile: Method C
To a flame dried 2-necked flask under argon was added 1-decene (0.51 g, 3.64 mmol) and dry THF (5 ml). The solution was cooled to 0°C and BH3 in THF (1.2 mmol,
1.2 ml of a 1M solution in THF) was added dropwise. The reaction was stirred for 4 hours at 0°C Dry THF (4 ml) and anhydrous potassium phosphate (0.85 g, 4 mmol) were added and the reaction stirred for 1 hour at room temperature. Anhydrous lithium chloride (0.08 g, 1.9 mmol) and 3,6-bis(trifluoromethanesulfonyloxy)phthalonitrile (0.25 g, 0.59 mmol) were added, followed after 10 minutes by Pd(dppf)Cl2 [(l,l '-bis(diphenylphosphino) ferrocene)dichloropalladium (II)] (21 mg, 5 mol%>). The reaction was heated at reflux for 10 hours. The reaction was cooled and filtered to remove palladium salts. The filtrate was concentrated under reduced pressure. The crude black product was further purified by column chromatography over silica (eluent: toluene) to afford 3,6-didecylphthalonitrile (0.09 g, 38%).
Preparation of 3,6-diphenylphthalonitrile: Method D 3,6-Bis(trifluoromethanesulfonyloxy)phthalonitrile (0.5 g, 1.18 mmol) and anhydrous lithium chloride (0.13 g, 3 mmol) were stirred under argon in dry toluene (15 ml) for 30 minutes. Tetrakis(triphenylphosphine) palladium(O) (84.0 mg) was added and the mixture stirred for 10 minutes. Finally phenylboronic acid (0.43 g, mmol) was added followed by aqueous 2M Na2CO3 (2 ml). The reaction was heated under reflux for 14 hours, cooled and diluted with ethyl acetate (15 ml). The reaction was washed with 10% KOH (2 x 10 ml), 5% HCl (10 ml) and brine (10 ml), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was recrystallised from toluene to afford 3,6-diphenylphthalonitrile (0.26 g, 79%) [m.p. 221-223.5°C Η NMR (270 MHz, CDC13) δ 7.80 (s, 2H), 7.63-7.51 (m, 10H) ppm].
Preparation of 3,6-bis(4-methoxyphenyl)phthalonitrile: Method D
3 ,6-Bis(trifluoromethanesulfonyloxy)phthalonitrile (0.5 g, 1.18mmol) and anhydrous lithium chloride (0.13g, 3mmol) were stirred under argon in dry toluene (15ml) for 30 minutes. Tetrakis(triphenylphosphine)palladium(0) (84mg, 10mol%>) was added and the mixture stirred for 10 minutes. Finally, 4-methoxyphenylboronic acid (0.45g, 3.5mmol, 2.5eq.) was added, followed by aqueous 2M Cs2CO3 (2ml). The reaction was heated under reflux for 14 hours, cooled and diluted with ethylacetate (15ml). The organics were washed with aqueous solutions of 10%) KOH (2x10ml), 5% HCl (10ml), brine (10ml) and dried (MgSO4). The drying agent was removed by filtration and the solvent was removed under reduced pressure. The crude product was recrystallised from toluene to afford 3,6-bis(4-methoxyphenyl)phthalonitrile as white needles, 0.29g (0.86mmol, 73%). [mp. 213-215°C 1H NMR (300 MHz, CDC13) δ 7.74 (s, 2H), 7.55 (d, 4H, J= 8.5Hz), 7.06 (d, 4H, J= 8.6Hz), 3.89 (s, 6H) ppm. 13C NMR (300 MHz, CDC13) δ 161.07, 145.29, 134.0, 130.32, 128.91, 116.22, 115.49, 114.77, 55.56 (CH3) ppm. Found: C, 77.38; H, 4.68; N, 8.21%. C22H16N2O2 requires: C, 77.63; H, 4.74; N, 8.23%. m/z (El) 340 (21%), 262 (100%). vmax (nujol) 2224 (CN) cm"1].
Preparation of 3,6-bis(3-methoxyphenyl)phthalonitrile: Method D
3,6-Bis(trifluoromethanesulfonyloxy)phthalonitrile (0.5g, l .lδmmol) and anhydrous lithium chloride (0.13g, 3mmol) were stirred under argon in dry toluene (15ml) for 30 minutes. Tetrakis(triphenylphosphine)palladium(0) (84mg, 10mol%>) was added and the mixture stirred for 10 minutes. Finally, 3 -methoxyphenylboronic acid (0.45g, 3.5mmol, 2.5eq.) was added, followed by aqueous 2M Cs2CO3 (2ml). The reaction was heated under reflux for 14 hours, cooled and diluted with ethylacetate (15ml). The organics were washed with aqueous solutions of 10%) KOH (2x10ml), 5% HCl (10ml), brine (10ml) and dried (MgSO4). The drying agent was removed by filtration and the solvent was removed under reduced pressure. The crude product was recrystallised from toluene to afford 3,6-bis(3-methoxyphenyl)phthalonitrile (0.28g, 0.82mmol, 70%>) as white crystals [mp. 236-239°C. 13C NMR (300 MHz, CDC13) δ 160.22, 145.97, 137.84, 134.12, 130.45, 121.26, 115.96, 115.78, 115.55, 114.57, 55.59 ppm. Found C, 77.54; H, 4.64; N, 8.24. C22Hι6N2O2 requires C, 77.63; H, 4.74; N, 8.23%. Η NMR (300 MHz, CDC13) δ 7.79 (s, 2H), 7.45 (t, 2H, J= 8Hz), 7.16 (ddd, 2H, J= 1, 0.8, 4.9 and 1Hz), 7.11 (t, 2H, J= 2.5 and 1.6Hz), 7.06 (ddd, 2H, J= 1, 0.8, 4.9, and 1Hz), 3.89 (s, 6H) ppm. m/z (El) 340 (100%). vmax (nujol) 2224 (CN) cm"1].
Preparation of 3,6-bis(dodecylsulfanyl)phthalonitrile: Method E
3,6-Bis(trifluoromethanesulfonyloxy)phthalonitrile (2.00 g, 4.71 mmol) and dodecanethiol (4.51 g, 22.4 mmol) were stirred in dry DMF (20 ml) under nitrogen. Anhydrous potassium carbonate (5 g, excess) was added in portions over 4 hours, and the reaction stirred at room temperature for 72 hours. The reaction was poured into cold water (100 ml) and filtered. The filtrate was washed with water (50 ml) and methanol (50 ml). The mother liquor and washings were combined and extracted with ethyl acetate (2 x 100 ml). The combined organics were washed with 5% NaOH (50 ml) and brine (50 ml), dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting yellow solid was combined with the original filtrate and recrystallised from CH2Cl2/ethyl acetate. The resulting yellow needles were filtered and washed with petrol (to remove dodecanethiol traces) to afford 3,6-bis(dodecylsulfanyl)phthalonitrile (1.74 g, 70%) [m.p. 97.8-101.2°C Η NMR (270 MHz, CDC13) δ 7.49 (s, 2H), 3.01 (t, 4H), 1.70-1.20 (m, 40H), 0.88 (t, 6H) ppm].
Preparation of 3,6-bis(decylsulfanyl)phthalonitrile: Method E
In a typical procedure, finely crushed potassium carbonate (2.3g, excess) and decanethiol (3.30g, 19.0mmol) were stirred in dry DMF (10ml) under nitrogen. 3,6- Bis(trifluoromethanesulfonyloxy)phthalonitrile (2.00g, 4.7mmol) was added in portions over 2 hours, and the reaction stirred at room temperature for 72 hours. The reaction was poured into cold 5%o NaOH (150ml), and filtered. The mother liquor was extracted with ethyl acetate (3x50ml). The combined organic solutions were washed with 5%> NaOH (50ml), 5% HCl (50ml), brine (50ml), dried (MgSO4), filtered and concentrated under reduced pressure. The resulting yellow solid was combined with the original filtrate and recrystallised from DCM/ethyl acetate. The resulting yellow needles were washed with petrol and dried to afford 3,6-bis(decylsulfanyl)phthalonitrile (68%>) [Found: C, 71.31; H, 9.38; N, 5.85. C^H^S., requires: C, 71.14; N, 9.39; N, 5.93%. Η NMR (300 MHz, CDC13) δ 7.50 (s, 2H), 3.02 (t, 4H, J = 7.5 Hz), 1.68 (quint, 4H, 7.4 Hz), 1.47-1.25 (m, 28H), 0.88 (t, 6H, J = 6.7 Hz) ppm].
The following were prepared similarly:
3,6-Bis(dodecylsulfanyl)phthalonitrile [yield: 70%. Found: C, 71.94; N, 9.74; N, 5.03. C32H52N2S2 requires C, 72.67; N, 9.91; N, 5.30. Η NMR (270 MHz, CDC13) δ 7.49 (s, 2H), 3.01 (t, 4H, J = 7.4 Hz), 1.72-1.64 (m, 4H), 1.50-1.24 (m, 36H), 0.88 (t, 6H, J = 6.4 Hz) ppm].
3,6-Bis(undecylsulfanyl)phthalonitrile [yield: 63%. mp 92-93°C Found: C, 71.53; H, 9.62; N, 5.40. C30H4SN2S2 requires: C, 71.94; H, 9.66; H, 5.59. Η NMR (300 MHz, CDC13) δ 7.50 (s, 2H), 3.02 (t, 4H, J = 7.2 Hz), 1.72-1.64 (m, 4H), 1.50-1.25 (m, 32H), 0.88 (t, 6H, J = 6.7 Hz) ppm]. 3,6-Bis(nonylsulfanyl)phthalonitrile [yield: 65%. mp 86-88°C Found: C, 70.11; H, 8.91; N, 6.10. C26H40N2S2 requires: C, 70.22; H, 9.07; N, 6.30. Η NMR (300 MHz, CDC13) δ 7.51 (s, 2H), 3.02 (t, 4H, J = 7.4 Hz), 1.73-1.63 (m, 4H), 1.52-1.25 (m, 24H), 0.89 (t, 6H, J = 6.0 Hz) ppm. 13C NMR (75 MHz, CDC13) δ 141.60, 132.30, 117.37, 114.06, 33.91, 31.88, 29.44, 29.25, 29.20, 28.74, 22.70, 14.12 ppm].
3,6-Bis(octylsulfanyl)phthalonitrile [yield: 27%. mp 91-92°C Found: C, 69.20; H, 8.74; N, 6.56. C2 H36N2S2 requires: C, 69.19; H 8.72; N, 6.73%. Η NMR (300 MHz, CDC13) δ
7.50 (s, 2H), 3.03 (t, 4H, J = 7.4 Hz), 1.69 (quint, 4H, 7.4 Hz), 1.45 (quint, 4H), 1.28 (m, 16H), 0.89 (t, 6H, J = 6.7 Hz) ppm].
3,6-Bis(heptylsulfanyl)phthalonitrile [yield: 46%.. Found: C, 67.50; H, 8.21; N, 7.07. C22H32N2S2 requires: C, 68.01; H 8.31; N, 7.21%. Η NMR (300 MHz, CDC13) δ 7.51 (s, 2H), 3.03 (t, 4H, J = 7.5 Hz), 1.70 (quint, 4H, 7.4 Hz), 1.46 (m, 4H), 1.31 (m, 12H), 0.91 (t, 6H, J = 6.7 Hz) ppm].
3,6-Bis(hexylsulfanyl)phthalonitrile [yield: 53%.. mp 82-83.5°C Found: C, 66.60; H, 7.81; N, 7.72. C2oH28N2S2 requires: C, 66.62; H, 7.83; N, 7.77. 1H NMR (300 MHz, CDC13) δ
7.51 (s, 2H), 3.03 (t, 4H, J = 7.4 Hz), 1.73-1.63 (m, 4H), 1.50-1.24 (m, 12H), 0.90 (t, 6H, J = 6.9 Hz) ppm].
Preparation of l,4-bis(decylsulfanyl)-2,3-naphthalonitrile: Method E l,4-Bis(trifluoromethanesulfonyloxy)-2,3-naphthalonitrile (0.5g, 1.05 mmol) and decanethiol (3eq, 0.56g, 3.15mmol) were stirred in dry DMF (5ml) under nitrogen. Anhydrous caesium carbonate (1.14g, excess) was added in portions over 4 hours and the reaction stirred at room temperature for 72 hours. The reaction mixture was poured into cold water (25ml) and the mixture filtered. The solid was washed with water (25ml). The mother liquor and washings were combined and extracted with EtOAc (2x25ml). The combined extracts were washed with aqueous NaOH 5% (25ml), brine (25ml), dried (Na2SO4), and evaporated to dryness. The resulting yellow solid was combined with the earlier filtrate. Recrystallisation from acetone afforded l,4-bis(decylsulfanyl)-2,3- naphthalonitrile (0.30g, 46%) [mp 76°C Found: C, 73.35; H, 8.83; N, 5.24. C32H46N2S2 requires: C, 73.51; H 8.86; N, 5.35%. Η NMR (270 MHz, CDC13) δ 8.81 (m, 2H), 7.87 (m 2H), 3.07 (t, 4H, J = 7.3 Hz), 1.6-1.2 (m, 32H), 0.87 (t, 6H, J = 6.85) ppm].
Preparation of 3,6-bis-piperidinylphthalonitrile: Method E Dry piperidine (distilled over CaH2) (3ml) was stirred under argon. 3,6-
Bis(trifluoromethanesulfonyloxy)phthalonitrile (0.5g, 1.18mmol) was added and the reaction stirred for 72 hours. The flask was placed in the fridge and 3,6-bis- piperidinylphthalonitrile precipitated as yellow crystals. These were filtered and washed with acetonitrile (160mg, 0.54mmol, 46%) [1H NMR (270 MHz, DMSO-d6) δ 6.77 (s, 2H), 2.8 (br s, 8H), 1.5 (br s, 12H) ppm].
Preparation of 3,6-bis( -decenyl)phthalonitrile: Method F
3,6-Bis(trifluoromethanesulfonyloxy)phthalonitrile (0.5 g, 1.18 mmol) and anhydrous lithium chloride (0.13 g, 3 mmol) were dissolved in dry DMF (3 ml) under argon. 1-Decene (0.50 g, 3.6 mmol), tetrakis(triphenylphosphine)palladium(0) (72 mg, ca. 5mol%o) and 2,6-lutidine (0.5 ml) were added at 10 minute intervals, and the reaction was heated at 100°C for 16 hours. The reaction was cooled, poured into excess water (40 ml), and extracted with ethyl acetate (3 x 20 ml). The combined organics were washed with 5% NaOH (20 ml), 5%> HCl (20 ml) and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude black tar was purified by column chromatography over silica (eluent: petrol/CH2Cl2 1 :1 -» 0:1). The first fraction afforded triphenylphosphine and the second fraction afforded 3,6-bis(l '-decenyl)phthalonitrile (0.04 g, 8.4%>).
Formation of phthalocyanine derivatives from the above with the same substituents on each ring:
Preparation of 1,4,8,11,15, 18,22,25-octakis(l,l-H-2,2-H-perfluorodecyl)phthalocyanine:
3,6-Bis(l,l-H-2,2-H-perfluorodecyl)phthalonitrile (0.5g, 0.5mmol) was refluxed in DMAE (10ml) for 1 hour under a constant flow of NH3 gas. After that time, zinc acetate dihydrate (99.999%., 36mg, 0.33eq.) was added and reflux continued for 24 hours. After cooling, the solvent was removed under reduced pressure. The solid residue was washed with methanol then chromatographed on silica (eluent: trifluorotoluene). A green fraction was isolated and 1 ,4,8, 11 , 15, 18,22,25-octakis(l , l-H-2,2-H-perfluorodecyl)phthalocyanine recrystallised from trifluorotohiene (130mg, 25%) [Η NMR (270 MHz, C6F6+2%C6D6, 50°C) δ 8.04 (s, 8H), 5.15 (t, 16H), 3.21 (m, 16H) ppm].
Preparation of [1,4,8,11,15, 18,22,25-octakis[6-(imidazol-l-yl)hexyl]phthalocyaninato] zinc(II):
3,6-Bis[6'-(imidazol-l-yl)hexyl]phthalonitrile (950mg, 2.2mmol) was refluxed in butan-1-ol (15ml) in the presence of zinc acetate dihydrate (99.999%), 150mg, 0.7mmol). DBU (large excess) was added and reflux continued for 12 hours. The solvent was removed under reduced pressure. Water (40ml) was added to the residue and the solid green product was filtered and washed with water. This was then dissolved in hot methanol (10ml) and water (40ml) was added. The precipitated green [1, 4, 8, 11,15,18, 22,25-octakis[6-(imidazol-l-yl)hexyl]phthalocyaninato] zinc(II) was filtered and dried at 40°C overnight [λmax (abs.) 705 nm (THF)].
Preparation of [1,4,8,11,15, 18,22,25-octakis(dodecylsulfanyl)phthalocyaninato] zinc(II):
3,6-(Dodecylsulfanyl)phthalonitrile (1.03 g, 1.95 mmol) was heated to reflux in DMAE (20 ml) under the continual passage of ammonia gas. After 1 hour at reflux, zinc acetate dihydrate (0.13 g, 0.3 equivalent) was added. Reflux under the continual passage of ammonia gas was continued for 18 hours. The reaction was cooled and the solvent removed under reduced pressure. The residue was purified by column chromatography over silica (eluent: CH2Cl2:Et N 100:1). The first red/brown fraction was collected and concentrated under reduced pressure. The resulting puφle solid was recrystallised twice from THF/acetone/methanol to afford [1,4,8,11,15, 18,22,25-octakis(dodecylsulfanyl)- phthalocyaninato] zinc(II) (130 mg) [Found: C, 70.20; H, 9.57; N, 4.89. C128H208N8S8Zn requires C, 70.49; H, 9.61; N, 5.14. 1H NMR (270 MHz, C6D6/1 drop pyr-d5/50°C) δ 7.85 (s, 8H), 3.37 (t, 16H), 2.04 (quint, 16H), 1.66 (br quint, 16H), 1.45-1.25 (m, 128H), 0.96 (t, 24H) ppm. λmax (THF) 780 nm; λmax (toluene/1 %>pyridine) 777 nm]. [NB Reaction needs to be left longer than 16 hours at reflux since some starting material was recovered].
Preparation of 1,4,8,11,15,18,22,25-octakis(decylsulfanyl)phthalocyaninato zinc(II):
A solution of 3,6-bis(decylsulfanyl)phthalonitrile (l.Olg, 2.14mmol) was heated to reflux in dry pentanol (9ml) under nitrogen. DBU (0.23g, 1.50mmol) was added and the reaction heated for 1 hour. Zinc acetate dihydrate (99.999%) zinc, 0.14g, 0.64mmol) was added, and the reaction heated for a further 20 hours. The reaction was cooled and the solvents removed under reduced pressure. The residue was purified by column chromatography over silica (eluent: DCM/Et3N 100:1) and the first brown/red fraction collected and concentrated. The crude product was triturated with hot acetone (3x20 ml) to remove yellow coloured impurities and recrystallised from THF/methanol to afford 1,4,8,11, 15, 18,22,25-octakis(decylsulfanyl)phthalocyaninato zinc (II) (0.68g, 65.0%) [Found: C, 69.01; H, 9.05; N, 5.71. C112HI76N8S8Zn requires: C, 68.76; H, 9.07; N, 5.73. MS (MALDI) isotopic cluster at 1956 (M)+; aggregate at 3910. Η NMR (270 MHz, C6D6 containing 1% pyr-d5) δ 7.86 (s, 8H), 3.38 (t, 16H, J = 7.25 Hz), 2.11-2.01 (m, 16H), 1.68- 1.58 (m, 16H), 1.52-1.18 (m, 96H), 0.90 (t, 24H, J = 6.6 Hz) ppm. λmax (abs.) 781 nm (THF); λmaχ (em.) 804 nm (THF)].
The following were prepared similarly:
1,4,8,11, 15, 18, 22, 25-Octakis(undecylsulfanyl)phthalocyaninato zinc(II) [yield: 32.8%.. Found: C, 69.64; H, 9.33; N, 5.39. Cι20Hι92N8S8Zn requires: C, 69.97; H, 9.35; N, 5.42. 1H NMR (270 MHz, C6D6 containing 1% pyr-d5, 50°C) δ 7.86 (s, 8H), 3.37 (t, 16H, J = 7.4 Hz), 2.10-2.01 (m, 16H), 1.68-1.60 (m, 16H), 1.52-1.20 (m, 112H), 0.91 (t, 24H, J = 6.8Hz) ppm. λmax (abs.) 781 nm (THF); λmax(em.) 804 nm (THF)].
l,4,8,ll,15,18,22,25-Octakis(nonylsulfanyl)phthalocyaninato zinc(II) [yield: 14.8%. Found: C, 67.69; H, 8.71; N, 5.91. Cι04Hι60N8S8Zn requires: C, 67.73; H, 8.74; N, 6.08. 1H NMR (270 MHz, C6D6 containing 1% pyr-d5, 50°C) δ 7.87 (s, 8H), 3.40 (t, 16H, J = 7.4 Hz), 2.08-2.02 (m, 16H), 1.67-1.60 (m, 16H), 1.55-1.19 (m, 80H), 0.89 (t, 24H, J = 6.6 Hz) ppm. λmax (abs.) 782 nm (THF); λmax (em.) 802 nm (THF)] .
1,4,8, 11, 15,18,22,25-Octakis(octylsulfanyl)phthalocyaninato zinc(II) [yield: 12.0%). Found: C, 66.74; H, 8.51; N, 6.48. C96H144N8S8Zn requires: C, 66.63; H, 8.39; N, 6.48. 1H NMR (270 MHz, C6D6, 50°C) δ 7.84 (s, 8H), 3.34 (t, 16H, J = 7.4 Hz), 2.01 (m, 16H), 1.62 (m, 16H), 1.3 (broad m, 64H), 0.90 (t, 24H, J = 6.8Hz) ppm. λmax 783 nm (THF)].
1,4,8,11, 15, 18,22,25-Octakis(heptylsulfanyl)phthalocyaninato zinc(II) [yield: 10.6%. Found: C, 65.25; H, 8.03; N, 6.78. C88H128N8S8Zn requires: C, 65.32; H, 7.98; N, 6.93. 1H NMR (270 MHz, C6D6, 50°C) δ 7.82 (s, 8H), 3.32 (t, 16H, J = 7.4 Hz), 1.99 (m, 16H), 1.60 (m, 16H), 1.3 (broad m, 48H), 0.89 (t, 24H, J = 6.8Hz) ppm. λmax782 nm (THF)].
l,4,8,ll, 15, 18,22,25-Octakis(hexylsulfanyl)phthalocyaninato zinc (II) [yield: 32.8%. Found: C, 63.84; H, 7.43; N, 7.37. C80HI 12N8S8Zn requires: C, 63.73; H, 7.49; N, 7.43. 1H NMR (270 MHz, C6D6 containing 1% pyr-d5, 50°C) δ 7.81 (s, 8H), 3.30 (t, 16H, J = 7.4 Hz), 1.97 (m, 16H), 1.58 (m, 16H), 1.33 (m, 32H), 0.89 (t, 24H, J = 6.8Hz) ppm. λmax (abs.) 782 nm; λmax (em.) 801 nm (THF)].
Preparation of 1,4,8,11, 15, 18,22,25-octakis(decylsulfanyl)phthalocyaninato magnesium(II):
A solution of 3,6-bis(decylsulfanyl)phthalonitrile (0.3g, 0.64mmol) was heated to reflux in dry pentanol (3ml) under nitrogen. DBU (0.07g, 0.46mmol) was added and the reaction heated for 1 hour. Anhydrous magnesium chloride (18.2mg, 0.19mmol) was added, and the reaction heated for a further 20 hours. The reaction was cooled and the solvents removed under reduced pressure. The residue was purified by column chromatography over silica (eluent: DCM/Et3N 100:1) and the first brown/red fraction collected and concentrated. The crude product was triturated with hot methanol (3 x 10ml) to remove yellow coloured impurities and recrystallised from THF/methanol to afford 1,4,8, 11, 15, 18,22, 25-octakis(decylsulfanyl)phthalocyaninato magnesium(II) (0.21 g, 69.0%) [Found: C, 70.36; H, 9.38; N, 5.77. C Hι76N8S8Mg requires: C, 70.23; H, 9.26; N, 5.85. Η NMR (270 MHz, C6D6 containing 1% pyr-d5, 50°C) δ 7.86 (s, 8H), 3.38 (t, 16H, J = 7.4 Hz), 2.05 (quint, 16H, J = 7.4 Hz), 1.68-1.58 (m, 16H), 1.52-1.26 (m, 96H), 0.90 (t, 24H, J = 6.6 Hz) ppm. λmax(abs.) 776 nm (THF); λmax (em.) 793 nm (THF)].
The following were prepared similarly:
1 ,4,8, 11 , 15, 18,22,25-Octakis(nonysulfanyl)phthalocyaninato magnesium(II) [yield: 62.2%. Found: C, 69.44; H, 8,76; N, 5.99. C104Hι60N8S8Mg requires: C, 69.27; H, 8.94; N, 6.21. Η NMR (270 MHz, C6D6 containing 1% pyr-d5, 50°C) δ 7.86 (s, 8H), 3.38 (t, 16H, J = 7.25 Hz), 2.04 (quint, 16H, J = 7.4 Hz), 1.67-1.59 (m, 16H), 1.52-1.18 (m, 80H), 0.90 (t, 24H, J = 6.9 Hz) ppm. λmax (abs.) 772 nm (THF); λmax (em.) 796.8 nm (THF)]. 1 ,4,8,11,15, 18,22, 25-Octakis(octylsulfanyl)phthalocyaninato magnesium(Il) [yield: 48.3%>. Found: C, 68.29; H, 8.69; N, 6.50. C96H144N8S8Mg requires: C, 68.18; H, 8.58; N, 6.63. Η NMR (270 MHz, C6D6 containing 1% pyr-d5, 50°C) δ 7.86 (s, 8H), 3.37 (t, 16H, J = 7.4 Hz), 2.03 (quint, 16H, J = 7.4 Hz), 1.68-1.57 (m, 16H), 1.52-1.25 (m, 64H), 0.91 (t, 24H, J = 6.8 Hz) ppm. λmax (abs.) 774 nm (THF); λmax (em.) 794 nm (THF)].
1 ,4,8, 11 , 15, 18,22,25-Octakis(heptylsulfanyl)phthalocyaninato magnesium(Il) [yield: 7.4%>. Found: C, 68.29; H, 8.69; N, 6.50. C88Hι28N8S8Mg requires: C, 66.97; H, 8.18; N, 7.10. 1H NMR (270 MHz, C6D6 50°C) δ 7.84 (s, 8H), 3.35 (t, 16H, J = 7.4 Hz), 2.02 (quint, 16H, J = 7.4 Hz), 1.6 (m, 16H), 1.315 (m, 48H), 0.89 (t, 24H, J = 6.6 Hz) ppm].
1,4,8,11,15,18, 22, 25-Octakis(hexylsulfanyl)phthalocyaninato magnesium(II) [yield: 66.7%. Found: C, 65.51; H, 7.60; N, 7.64. C80H112N8S8Mg requires: C, 65.52; H, 7.70; N, 7.64. 1H NMR (270 MHz, C6D6 containing 1% pyr-d5, 50°C) δ 7.83 (s, 8H), 3.34 (t, 16H, J = 7.25 Hz), 2.00 (quint, 16H, J = 7.5 Hz), 1.65-1.57 (m, 16H), 1.45-1.25 (m, 32H), 0.89 (t, 24H, J = 6.9 Hz) ppm. λmax (abs.) 773 nm; λmax (em.) 792 nm (THF)].
Preparation of 1,4,8,11,15,18,22,25-octakis(nonylsulfanyl)phthalocyanine:
1 ,4,8, 11 , 15, 18,22,25-Octakis(nonylsulfanyl)phthalocyaninato magnesium(II) (50mg) was dissolved in trifluoroacetic acid (4ml) and stirred at room temperature under argon for 2 hours. The reaction was poured into water/ice (80ml) and extracted with DCM (2x50 ml). The DCM extract was washed with 5% NaOH (40ml), brine (40ml), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was further purified by column chromatography over silica (eluent: DCM/Et3N 99:1). The first fraction was collected and recrystallised from THF/acetone to afford 1,4,8,11, 15, 18,22,25- octakis(nonylsulfanyl)phthalocyanine [Found: C, 70.06; H, 9.20; N, 6.12. C104H162N8S8 requires: C, 70.14; H, 9.17; N, 6.29. 1H NMR (270 MHz, C6D6 containing 1% pyr-d5, 50°C) δ 7.70 (s, 2H), 3.21 (t, 16H, J = 7.25 Hz), 1.92 (quint, 16H, J = 7.4 Hz), 1.66-1.55 (m, 16H), 1.50-1.24 (m, 80H), 0.91 (t, 24H, J = 6.9 Hz), 0.07 (s, 2H) ppm].
Preparation of 1,4,8,11,15, 18,22,25-octakis(hexylsulfanyl)phthalocyaninato lead(II):
3,6-Bis(hexylsulfanyl)phthalonitrile (0.5g, 1.39mmol) was dissolved in dry pentan- l-ol (7ml), and heated to reflux under an atmosphere of nitrogen. DBU (0.14ml, 0.97mmol) was added and reflux continued for 1 hour. Lead (II) acetate (0.15g, 0.42mmol) was added and reflux continued for a further 18 hours. The solvent was removed under reduced pressure and the dark residue was filtered through silica gel (pretreated with dichloromethane :triethylamine 99:1) using dichloromethane as the eluent. The resultant solid was recrystallised from THF:acetone to give 1,4,8,11,15,18,22,25- octakis(hexylsulfanyl)phthalocyaninato lead(II) (87mg, 15%>) as dark red/brown crystals [mp 145-148°C Found C, 58.29; H, 6.65; N, 6.65. C80Hn2N8S8Pb requires C, 58.25; H, 6.84; N, 6.79%. Η NMR (270 MHz, C6D6, 1 drop pyridine d5, 50 °C) δ 7.76 (8H, s, Ar-H), 3.27 (16H, t, J= 7.42, -S-CH2-), 2.02-1.91 (16H, m, -S-CH2-CH2-), 1.64-1.53 (16H, m, -S- CH2-CH2-CH2), 1.32 (32H, m, -S-CH2-CH2-CH2-CH2-CH2-), 0.85 (24H, t, J = 0.7, R-CH3) ppm. m/z (MALDI) 1650 (M+l, 100%). λmax 827 nm (toluene)].
Preparation of 1 ,4,8, 11,15,18,22,25-octakis(hexylsulfanyl)phthalocyaninato chloroindium(III) : 3,6-Bis(hexylsulfanyl)phthalonitrile (0.5g, 1.39mmol) was dissolved in dry pentan- l-ol (7ml), and heated to reflux under an atmosphere of nitrogen. DBU (0.14ml, 0.97mmol) was added and reflux continued for 1 hour. Indium (III) chloride (93mg, 0.42mmol), was added and reflux continued for a further 18 hours. The solvent was removed under reduced pressure and the dark residue filtered through silica gel [pretreated with dichloromethane:triethylamine (99:1)] first eluting with dichloromethane to remove a yellow impurity and then with THF to remove the dark coloured baseline fraction. The second fraction was re-chromatographed over silica gel [pretreated with dichloromethane :triethylamine (99:1)] again first eluting with dichloromethane and then dichloromethane :THF (95:5) collecting the first deep blue fraction, which was recrystallised from THF:acetone to give 1,4,8,11,15,18,22,25- octakis(hexylsulfanyl)phthalocyaninato chloroindium(III) (17mg, 3%) as a dark blue/black solid [mp 202-204°C Found: C, 60.66; H.7.11; N, 6.84. C80Hπ2N8S8InCl requires C, 60.33; H, 7.09; N, 7.04%. 1H-NMR (270 MHz, C6D6, 1 drop pyridine d5, 50 °C) δ 7.79 (8H, s, Ar-H), 3.23 (16H, t, J = 7, -S-CHj-), 1.96-1.87 (16H, m, -S-C^-CH ), 1.65-1.55 (16H, m, -S-CH2-CH2-CH2), 1.45-1.32 (32H, m, -S-CH2-CH2-CH2-CH2-CH2-), 0.92-0.90 (24H, m, R-CHj) ppm. λmax 822 nm (THF)].
Preparation of 1,4,8,11,15, 18,22,25-octakis(dodecylsulfanyl)phthalocyanine: 3,6-(Dodecylsulfanyl)phthalonitrile (0.21 g, 0.40 mmol) was heated to reflux in DMAE (10 ml) under the continual passage of ammonia gas. After 2 hours at reflux, lithium chloride (19.8 mg, 0.48 mmol) was added. Reflux under the continual passage of ammonia gas was continued for 20 hours. The reaction was cooled and the solvent removed under reduced pressure. The residue was stirred in glacial acetic acid (10 ml) for 30 minutes, resulting in a bright red coloration. The acetic acid was removed under reduced pressure, and the residue was dissolved in CH2CI2 and washed with sat. Na2CO3, sat. NH4C1, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was further purified by column chromatography over silica (eluent: CH2Cl2:Et3N 100:1). The first red/brown fraction was collected and concentrated under reduced pressure. The resulting puφle solid was recrystallised from THF/acetone to afford 1,4,8, 11,15, 18,22,25-octakis(dodecylsulfanyl)phthalocyanine (44.1mg) [m.p. 88-88.5°C Found: C, 72.53; H, 9.97; N, 5.29. Cι28H21oN8S8 requires C, 72.60; H, 10.00; N, 5.29. λmax (toluene) 797 nm.].
Investigation of routes A and B:
Preparation of 4,5-dibromo-3 ,6-dihydroxyphthalonitrile:
To a stirred solution of 2,3-dicyanohydroquinone (3 g, 18.7 mmol) in tert-butanol (12 ml) at 45°C was added NBS (7 g, 38.8 mmol) portionwise over 15 minuntes. Stirring was continued for 2 hours and then additional NBS (7 g, 38.8 mmol) was added over 15 minutes. After a further 2 hours, the reaction was cooled to room temperature and poured into an aqueous solution of sodium metabisulfite (6 g in 60 ml, excess) at 0°C with vigorous stirring. The mixture was stirred for 10 minutes, the precipitate filtered, and washed with cold water (30 ml). The product was dried under vacuum at 60°C for 24 hours to yield 4,5-dibromo-3,6-dihydroxyphthalonitrile as a cream powder (3.94 g, 66.1%). This was used without further purification, but an analytical sample was prepared by recrystallisation from acetone/water [m.p. 248°C (dec). Found C, 30.47; H, 0.42; N, 8.70; Br, 50.22. C8H2N2O2Br2 (317.92) requires C, 30.22; H, 0.63; N, 8.81; Br 50.27. 13C NMR (270 MHz, acetone-d6) δ 151.74 (C-O), 123.08 (C-Br), 113.07 (CN), 102.46 (C-CN) ppm. vmax (nujol) 3250 (br), 2232 (m) cm"1.].
Preparation of 4,5-dibromo-3,6-dibutoxyphthalonitrile: A mixture of 4,5-dibromo-3,6-dihydroxyphthalonitrile (2.50 g, 7.86 mmol), triphenylphosphine (4.95 g, 18.9 mmol) and 1 -butanol (1.5 g, 20.2 mmol) was dissolved in dry THF (80 ml) and cooled to 0°C A solution of diisopropyl azodicarboxylate (4.35 g, 21.5 mmol) in THF (30 ml) was added dropwise over 30 minutes. The solution was allowed to warm to room temperature and stirred for an additional 10 hours. The THF was removed under reduced pressure to give a dark red oil, which was dissolved in diethyl ether (20 ml). The solution was filtered to remove undissolved triphenylphosphine oxide, concentrated and separated by column chromatography over silica (eluent: CH2Cl2/petrol 1 :2). The product was recrystallised from cyclohexane to afford 4,5-dibromo-3,6- dibutoxyphthalonitrile as white crystals (2.75 g, 83.6%) [m.p. 72-73 °C Found C, 44.51; H, 4.28; N, 6.47; Br, 37.33. Cι6H18N2O2Br2 (430.14) requires C, 44.68; H, 4.22; N, 6.51; Br, 37.15. 1H NMR (270 MHz, CDC13) δ 4.24 (t, J= 6.4 Hz, 4H), 1.92 (quint, J= 7.0 Hz, 4H), 1.67-1.53 (m, 4H), 1.04 (t, J = 7.3 Hz, 6H) ppm. 13C NMR (270 MHz, CDC13) δ 156.37 (ArC-O), 129.61 (ArC-Br), 112.33 (CN), 109.22 (ArC-CN), 76.43, 31.95, 18.92, 13.73 ppm. vmax (nujol) 2230 (m) cm"1. MS (70 eV, El): m/z (%): 432 (3.1), 430 (5.2), 428 (3.5) [M+].].
Preparation of 4-bromo-3 ,6-dibutoxyphthalonitrile :
A mixture of 4,5-dibromo-3,6-dihydroxyphthalonitrile (3 g, 9.4 mmol), finely crushed potassium carbonate (3 g, excess) and TBAB (0.26 g, 0.7 mmol) was refluxed in MEK (80 ml) for 12 hours. The reaction was cooled and 1 -iodobutane (3.70 g, 20 mmol) was added. Reflux was continued for a further 72 hours. Upon cooling, the reaction was filtered and washed with ethyl acetate. The organics were removed under reduced pressure and the residue dissolved in ethyl acetate (100 ml). This was washed with 5%. HCl (25 ml), sat. K2CO2 (25 ml), water (25 ml), brine (25 ml), dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography over silica (eluent: petrol/CH2Cl2 2:1) and recrystallised from cyclohexane to afford 4-bromo-3,6-dibutoxyphthalonitrile (1.43 g, 43%>) [m.p. 102.5- 104°C Found C, 54.71; H, 5.43; N, 7.89; Br, 22.67. Cι6H19N2O2Br, (351.24) requires C, 54.85; H, 5.47; N, 8.00; Br, 22.54. 1H NMR (270 MHz, acetone-d6) δ 7.88 (s, IH), 4.30 (t, 2H, J = 6.4 Hz), 4.18 (t, 2H, J= 6.4 Hz), 1.86 (m, 4H), 1.56 (m, 4H), 1.00 (t, 3H, J = 7.3 Hz), 0.99 (t, 3H, J = 7.3 Hz) ppm. 13C NMR (300 MHz, acetone-d6) δ 157.68 (ArC-O), 152.80 (ArC-O), 124.94, 123.33 (ArC-H), 112.81 (CN), 112.69 (CN), 1 11.39 (ArC-CN), 103.83 (ArC-CN), 75.75, 70.40, 31.81, 30.57, 18.70, 18.66, 13.07, 12.98 ppm. vmax (nujol) 2230 (m) cm"1. MS (70 eV, El): m/z (%): 350.1 (4.8), 352.1 (4.5) [M+].].
Preparation of l,4-dibutoxy-2,3-dibromo-8,l l,15,18,22,25-hexakis(decyl)- phthalocyaninato nickel(II):
To 3,6-didecylphthalonitrile (N.B. McKeown, I. Chambrier, M.J. Cook, J. Chem. Soc. Perkin Trans. 1, 1990, pages 1169-1177) (2.56 g, 6.27 mmol) and 4,5-dibromo-3,6- dibutoxyphthalonitrile (0.30 g, 0.70 mmol) in refluxing butanol (20 ml) under argon was added freshly cleaned lithium (ca. 50 mg, 7.5 mmol). The reaction was refluxed in the dark for 16 hours, cooled, nickel acetate tetrahydrate (0.53 g, 2.1 mmol) was added and reflux continued for 2 hours. After cooling the solvents were removed under reduced pressure and the residue triturated with methanol to afford a green solid. Purification by column chromatography over silica (eluent: petrol) afforded 1,4,8,11,15,18,22,25- octakis(decyl)phthalocyaninato nickel(II) (0.71 g, 24%) as the first fraction. Changing the eluent to petrol/CH2Cl2 (1:1) afforded a second fraction. The latter was further purified by column chromatography over silica (eluent: petrol/CH2Cl2 19:1) to afford 1,4-dibutoxy- 2,3-dibromo-8,ll,15,18,22,25-hexakis(decyl)phthalocyaninato nickel(II) (45.7mg, 3.8%>) after recrystallisation from THF-methanol [m.p. 72°C (K-I), 67°C (I-D), 57°C (D-K). Found C, 70.40; H, 8.90; N, 6.30. Cιo0H,50N8O2Br2Niι (1715.84) requires C, 70.04; H, 8.82; N, 6.53. 1H NMR (300 MHz, C6D6) δ 7.82 (s, 4H), 7.81 (s, 2H), 4.75 (t, 4H, J = 7.5 Hz), 4.66-4.57 (3 overlapping t, 12H), 2.34-2.17 (m, 16H), 1.92-1.11 (m, 88H), 0.95 (t, 6H, J = 7.4 Hz), 0.87-0.80 (m, 18H) ppm. UV/Vis (3.68 x 10"6M in toluene, log ε) λ 716 (5.10), 698 (5.03), 636 (4.39) nm. MS (FAB): m/z : isotopic cluster at 1716 [M+ + H].].
Preparation of l,4-dibutoxy-2,3-(2'-trimethylsilylethynyl)-8,l 1,15,18,22,25- hexakis(decyl)-phthalocyaninato nickel(II) :
To a stirred solution of l,4-dibutoxy-2,3-dibromo-8,l l,15,18,22,25-hexakis(decyl)- phthalocyaninato nickel(II) (40 mg, 23.3 μmol) in dry degassed triethylamine (3.5 ml) under argon in a dry screw-cap pressure tube, was added bis(triphenylphosphine)palladium (II) chloride (7 mg, 10 μmol), copper (I) iodide (2.2 mg, 11.6 μmol) and TMSA (25 mg, 255 μmol) in that order and at 10 minute intervals. Under a fast stream of argon the rubber septum was removed and the screw-cap sealed and heated with stirring in an oil bath at 100°C for 16 hours. The tube was cooled, and further bis(triphenylphosphine)palladium (II) chloride (4.1 mg), copper iodide (1.7 mg) and TMSA (25 mg) were added under argon. The reaction was heated at 100°C for a further 12 hours. The mixture was cooled, filtered and concentrated under reduced pressure. The residue was dried at 0.5 mmHg for 12 hours to remove excess TMSA and triethylamine traces, and further purified by column chromatography over silica (eluent: petrol/CH2Cl2 97:3). The first fraction was unreacted starting material (3.4 mg). The second fraction contained a mixture; subsequent green fractions containing minor amounts of material were discarded. The second fraction was further purified by column chromatography over silica (eluent: petrol/CH2Cl2 98.5:1.5 then 97:3) to afford l,4-dibutoxy-2,3-(2 '-trimethylsilylethynyl)-8,l 1,15, 18,22,25- hexakis(decyl)phthalocyaninato nickel (II) as second fraction (13.2 mg, 35 %>) after recrystallisation from THF-methanol [m.p. 69°C 1H NMR (270 MHz, CDC13) δ 7.78 (br s, 4H), 7.75 (s, 2H), 4.60 (t, 4H, J = 7.2 Hz), 4.47 (t, 4H, J = 6.9 Hz), 4.35-4.26 (m, 8H), 2.10-1.90 (m, 16 H), 1.60-1.08 (m, 88H), 0.95 (t, 6H, J = 7.4 Hz), 0.80 (t, 12H, J = 6.6 Hz), 0.79 (t, 6H, J = 6.6 Hz), 0.43 (s, 18H) ppm. 13C NMR (67.5 MHz, CDC13) δ 154.18 (ArCO), 147.99, 139.19, 138.13, 137.77, 134.75, 134.66, 134.43, 130.83, 130.47, 130.29, 130.19, 129.16, 128.17, 127.81, 127.47, 104.74 (C≡CSi), 100.97 (C≡CSi), 75.43 (OCH2), 32.66, 32.56, 32.18, 31.88, 31.50, 30.53, 29.90, 29.85, 29.72, 29.67, 29.61, 29.45, 29.31, 22.64, 22.55, 19.37, 14.20, 14.07, 0.20 ppm. vmax (KBR) 2929 (s), 2861 (m), 2155 (w), 1598 (w), 1457 (w), 1200 (w), 1092 (m) cm'1. UV/Vis (2.80 x 10"6M in toluene, log ε) λ 732 (4.99), 702 (4.95) nm. MS (FAB): m/z: isotopic cluster at 1747 [M+ + H].].
Preparation of l,4-dibutoxy-2,3-di(ethynyl)-8,l l,15,18,22,25-hexakis(decyl)- phthalocyaninato nickel(II):
To a solution of l,4-dibutoxy-2,3-dibromo-8,l l,15,18,22,25-hexakis(decyl)- phthalocyaninato nickel(II) (48.6 mg, 28.3 μmol), anhydrous lithium chloride (10 mg, 233 μmol) and triphenylphosphine (9.5 mg, 36 μmol) in dry degassed toluene (6 ml) under argon was added tetrakis(triphenylphosphine)-palladium(0) (10.5 mg, 9.0 μmol). After stirring for 10 minutes, tributyl(ethynyl)tin (60 mg, 190 μmol) was added, and the reaction heated at 100°C for 16 hours. The reaction was cooled and the toluene removed under reduced pressure. The residue was triturated with acetone to remove excess tributyl(ethynyl)tin, and the residue was washed from the filter paper with THF. The THF was removed under reduced pressure and the residue was purified by column chromatography (eluent: petrol/CH2Cl2 19:1), and recrystallised from THF/methanol to afford 1 ,4-dibutoxy-2,3-di(ethynyl)-8, 11 , 15, 18,22,25-hexakis(decyl)phthalocyaninato nickel(II) (27.2 mg, 60%) [m.p. 83°C (K-D), 91°C (D-I). Found C, 76.99; H, 9.56; N, 6.98. Cιo4Hι52N8O2Niι . CH3OH (1637.14) requires C, 77.03; H, 9.60; N, 6.84. Η NMR (270 MHz, C6D6) δ 7.81-7.78 (m, 6H), 4.83-4.76 (m, 8H), 4.61-4.56 (m, 8H), 3.53 (s, 2H), 2.33-2.21 (m, 16H), 1.93-1.1 1 (m, 88H), 0.96 (t, 6H, J= 7.4 Hz), 0.92-0.81 (m, 18H) ppm. 13C NMR (67.5 MHz, C6D6) δ 154.86, 148.47, 148.40, 142.86, 139.57, 138.37, 138.01, 135.40, 135.31, 131.45, 130.93, 130.89, 130.00, 121.68, 87.63, 80.13, 75.87, 33.23, 32.93, 32.20, 31.16, 31.09, 30.57-29.6, 23.04, 23.01, 19.70, 14.33, 14.26 ppm. UV/Vis (2.51 x 10"6M in toluene, log ε) λ 729 (4.99), 698 (4.88), 666 (4.44), 628 (4.23) nm. MS (FAB): m/z: isotopic cluster at 1606 [M+ + H].].
Preparartion of 1 ,4-dibutoxy-2,3-di(ethynyl)-8, 11,15,18,22,25-hexakis(decyl)- phthalocyaninato nickel(II): To a solution of l,4-dibutoxy-2,3-(2'-trimethylsilylethynyl)-8,l 1,15,18,22,25- hexakis(decyl)-phthalocyaninato nickel(II) (9.2 mg, 5.3 μmol) in THF (5 ml) and methanol (1 ml) was added potassium hydroxide solution (0.1 ml of a solution containing 1 flake in 0.5 ml of H O) and the reaction was stirred under argon in the dark for 12 hours. One drop of 5%> HCl was added, and the solvents were removed under reduced pressure. The residue was triturated with methanol and further purified by column chromatography over silica (eluent: petrol/CH2Cl2 10:1) to afford l,4-dibutoxy-2,3-di(ethynyl)-8,l 1,15, 18,22,25- hexakis(decyl)phthalocyaninato nickel(II) as a green solid (6.7mg, 79%>) identical to the sample obtained above.
Preparation of l,4-dibutoxy-2-bromo-8,l l,15,18,22,25-hexakis(decyl)phthalocyaninato nickel(II):
1, 4-Dibutoxy-2-bromo-8, 11,15,18,22, 25-hexakis(decyl)phthalocyaninato nickel (II) was prepared from a mixed cyclotetramerisation of 4-bromo-3,6-dibutoxyphthalonitrile and 3,6-didecylphthalonitrile using the method which afforded l,4-dibutoxy-2,3-dibromo- 8,l l,15,18,22,25-hexakis(decyl)phthalocyaninato nickel(II) above (yield 4%) [m.p. 30°C (K-D), 106°C (D-I). Found C, 74.08; H, 9.52; N, 6.19. C10oH151N8O2BrιNiι (1635.95) requires C, 73.42; H, 9.30; N, 6.85. 1H NMR (300 MHz, C6D6) δ 7.82 (br s, 4H), 7.77 (s, 2H), 7.68 (s, IH), 4.83-4.78 (br t, 4H), 4.66 (t, 2H, J= 7.0 Hz), 4.63-4.57 (2 x t, 8H), 4.22 (t, 2H, J= 6.8 Hz), 2.34-2.22 (m, 14 H), 2.13 (quint, 2H, J = 7.2 Hz), 1.93-1.10 (m, 88H), 0.99 (t, 3H, J= 7.4 Hz), 0.91-0.76 (m, 21H) ppm. 13C NMR (67.5 MHz, CDC13) δ 151.54, 147.74, 147.67, 147.46, 147.13, 146.70, 146.52, 143.68, 142.61, 139.03, 138.94, 137.93, 137.70, 137.66, 134.84, 134.77, 134.70, 134.65, 134.47, 134.38, 130.87, 130.28, 130.17, 130.10, 125.19, 119.52, 116.37, 75.10 (OCH2), 69.76 (OCH2), 32.74, 32.62, 32.31, 32.15, 31.86, 31.81, 31.65, 31.48, 31.16, 30.46, 30.26, 29.90, 29.80, 29.71, 29.65, 29.62, 29.45, 29.36, 29.29, 29.24, 22.63, 22.57, 19.45, 19.36, 14.05 ppm. UV/Vis (3.37 x 10"6M in toluene, log ε) λ 714 (5.10), 700 (sh), 635 (4.47) nm.].
Preparation of l,4-dibutoxy-2-(2'-trimethylsilylethynyl)-8,l l,15,18,22,25-hexakis(decyl)- phthalocyaninato nickel(II):
1, 4-Dϊbutoxy-2-(2 '-trimethylsilylethynyl)-8, 11,15,18, 22, 25-hexakis(decyl)- phthalocyaninato nickel(II) was prepared from l,4-dibutoxy-2-bromo-8,l 1,15, 18,22,25- hexakis(decyl)-phthalocyaninato nickel(II) following the procedure for l,4-dibutoxy-2,3- (2'-trimethylsilylethynyl)-8,l l,15,18,22,25-hexakis(decyl)phthalocyaninato nickel(II) above using dry THF/Et3N (5:1) as solvent (yield 62%) [m.p. 46°C (K-D), 113°C (D-I). Found C, 76.95; H, 9.67; N, 6.84. Cιo5Hι60N8O2Si1Ni1 (1653.25) requires C, 76.28; H, 9.75; N, 6.78. 1H NMR (270 MHz, toluene-d8) δ 7.81 (s, 6H), 7.65 (s, IH), 4.86-4.78 (br t, 6H), 4.68-4.58 (2 x t, 8H), 4.26 (br t, 2H), 2.38-2.20 (m, 16H), 1.90-1.10 (m, 88H), 0.99- 0.76 (m, 24H), 0.49 (s, 9H) ppm. UV/Vis (3.44 x 10"6M in toluene, log ε) λ 722 (5.09), 700 (5.02), 640 (4.43), 346 (4.59) nm. MS (FAB): m/z: isotopic cluster at 1653 [M+ + H].].
Preparation of l,4-dibutoxy-2-(ethynyl)-8,l l,15,18,22,25-hexakis(decyl)phthalocyaninato nickel(II):
1 ,4-Dibutoxy-2-(ethynyl)-8, 11 , 15, 18,22,25-hexakis(decyl)phthalocyaninato nickel(Il) was prepared from l,4-dibutoxy-2-bromo-8,l l,15,18,22,25-hexakis(decyl)- phthalocyaninato nickel(II) following the procedure used to prepare l,4-dibutoxy-2,3- di(ethynyl)-8,l l,15,18,22,25-hexakis(decyl)phthalocyaninato nickel(II) above (yield 48%>) [m.p. 36°C (K-D), 131°C (D-I). Found C, 77.80; H, 9.68; N, 7.09. C1o2H152N8O2Niι (1518.07) requires C, 77.49; H, 9.69; N, 7.09. 1H NMR (270 MHz, C6D6) δ 7.81-7.78 (m, 6H), 7.75 (s, IH), 4.87-4.82 (m, 6H), 4.66-4.55 (m, 8H), 4.27 (t, 2H, J = 7.0 Hz), 3.28 (s, IH), 2.31-2.23 (m, 16H), 1.98-1.06 (m, 88H), 0.99 (2 x t, 6H), 0.94-0.77 (m, 18H) ppm. vmax (KBR) 3304 (m), 2965 (sh), 2927 (s), 2853 (s), 1468 (m), 1318 (m), 1187 (m), 1102 (m) cm"1. UV Vis (5.20 x 10"6M in toluene, log ε) λ 721 (5.07), 701 (5.01), 641 (4.39), 347 (4.54) nm.].
Preparation of l,4-dibutoxy-2,3-di(4'-ethynylpyridine)-8,l l,15,18,22,25-hexakis(decyl)- phthalocyaninato nickel (II):
To a solution of l,4-dibutoxy-2,3-di(ethynyl)-8,l l,15,18,22,25-hexakis(decyl)- phthalocyaninato nickel (II) (40 mg, 25.0 μmol) and 4-iodopyridine (31mg, 150 μmol) in dry degassed toluene/triethylamine (5:1, 6 ml) under argon, was added tris(dibenzylideneacetone)-dipalladium (0) [Pd2(dba)3] (10 mol%>, 2.3 mg) and triphenylarsine (40 mol%>, 3.0 mg). The reaction was heated at 80°C for 24 hours, cooled and the solvents removed under reduced pressure. The residue was triturated with acetone, and purified by column chromatography (eluent: petrol/DCM/Et3N 25:2:0.25) to remove unreacted starting material. Changing the eluent to THF/petrol (1 :1) afforded 1,4- dibutoxy-2, 3-di(4 '-ethynylpyridine)-8, 11,15,18, 22, 25-hexakis(decyl)phthalocyaninato nickel (II) (31.2 mg, 71%.) after recrystallisation from THF/methanol [Found C, 77.80; H, 8.90; N, 7.83. Cn4H158NιoO2Ni1 requires C, 77.83; H, 9.05; N, 7.96. 1H NMR (270 MHz, C6D6, 50°C) δ 8.57 (dd, 4H, J= 4.5 & 1.5 Hz), 7.87-7.81 (m, 6H), 7.42 (dd, 4H, J- 4.3 & 1.5 Hz), 4.89 (t, 4H, J= 6.9 Hz), 4.81 (t, 4H, J= 7.4 Hz), 4.64-4.57 (m, 8H), 2.33-2.22 (m, 16H), 1.95-1.09 (m, 88H), 0.94 (t, 6H, J= 7.4 Hz), 0.87-0.76 (m, 18H) ppm].
Preparation of l,4-dibutoxy-2-bromo-8,l l,15,18,22,25-hexakis(decyl)phthalocyanine:
To dry /.-butanol (10ml) was added lithium metal (60mg, 8.5mmol) and the mixture was heated until the lithium had reacted. The solution was cooled to room temperature. 3,6-Didecylphthalonitrile (350mg, 0.85mmol), 4-bromo-3,6-dibutoxyphthalonitrile (300mg, 0.85mmol), and tetrakis(triphenylphosphine)palladium(0) (49mg, 0.0425mmol, 5%>mol) were added under N2 and heated at 60°C for 12 hours in the dark. After cooling to room temperature, glacial acetic acid (2ml) was added and stirring was continued for 30 minutes. The solvent was removed under reduced pressure and the residue washed with methanol (3x50ml). The crude phthalocyanine mixture was separated by column chromatography over silica (eluent: petrol ether). The first fraction is 1,4,8,11, 15, 18,22,25-octakis(decyl)phthalocyanine (50mg) identical with an authentic sample. The eluent was then changed to petrol/CH2Cl2 (10:1) and a second fraction collected. This fraction was further purified by preparative scale TLC (eluent: petrol/CH2Cl2 (3:1)) and recrystallised from THF/methanol to afford l,4-dibutoxy-2- bromo-8, 11 , 15,22,25-hexakis(decyl)phthalocyanine (150mg) as a dark green solid. [1H NMR (300Mz, C6D6) δ 7.93 (s,lH), 7.91 (br s, 3H), 7.81 (s,2H), 7.75 (s,lH), 4.95-4.88 (m, 8H), 4.26 (t, 2H), 2.40-2.22 (m,14H), 2.15 (quint, 2H), 1.96 (br quint, 2H), 1.78-1.08 (m, 86H), 1.01 (t, 3H) ,1.00 (t, 3H), 0.91-0.75 (m, 18H), -0.35 (s, 2H). MALDI-MS: cluster centred at 1579. λmax (abs.) 720, 648 nm (THF)].
Preparation of [l,4-dibutoxy-2-bromo-8,l l,15,18,22,25-hexakis(decyl)phthalocyaninato] zinc(II): Method 1
3,6-Didecylphthalonitrile (l.OOg, 2.45mmol), 4-bromo-3,6-dibutoxyphthalonitrile (0.30g, 0.82mmol), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1.18g, 8.2mmol) and zinc acetate dihydrate (99.999%), 0.27g, 1.23mmol) were refluxed under N2 in dry butan-1-ol (20ml) for 3 days in the dark. After cooling to room temperature, the solvent was removed under reduced pressure and the residue washed with methanol (3x50ml). The crude material was separated by column chromatography over silica (eluent: petroleum ether (bp. 40-60°C) /dichloromethane 4:1). The first fraction contains [1,4,8,11,15,18,22,25- octakis(decyl)phthalocyaninato] zinc(II) (240mg, 5.8%>). The eluent was then changed to petroleum ether (bp. 40-60°C)/dichloromethane 1 : 1 and a second fraction was collected. This fraction was further purified by preparative tic on silica (eluent: petroleum ether (bp. 40-60°C)/dichloromethane 3:2). The second green fraction was collected, the solvent evaporated and the residue recrystallised from THF/methanol to afford the product as a dark green solid, 50mg (0.03mmol, 3.7%). [1H NMR (300 MHz, C6D6) δ 7.85-8.0 (m, 7H), 5.08 (t, 2H), 4.96 (t, 4H), 4.79 (m, 8H), 4.35 (t, 2H), 1.1-2.5 (m, 104H), 0.84 (m, 24H) ppm. λmax (abs.) 716.5 nm (THF)].
Preparation of [l,4-dibutoxy-2-bromo-8,l l,15,18,22,25-hexakis(decyl)phthalocyaninato] zinc(II): Method 2 In dry rc-butanol (20ml) was added Li metal (0.2g, 30mmol) and the mixture was heated under N2 until the lithium was consumed. The solution was cooled to room temperature and 3,6-didecylphthalonitrile (3.49g, 8.4mmol), 4-bromo-3,6- dibutoxyphthalonitrile (l .Og, 2.8mmol) and zinc acetate dihydrate (99.999%), 0.9g, 4.25mmol) were added under N2. The mixture was refluxed for 20 hours in the dark. The solvent was removed under reduced pressure and the residue washed with methanol (3x50ml). The crude product was separated by column chromatography over silica (eluent: petroleum ether (bp. 40-60°C): CH2CI2 4:1). The first fraction contains symmetrical 1,4,8,11,15, 18,22,25-octakis(decyl)phthalocyaninato zinc(II) (300mg). The eluent was changed to petroleum ether (bp. 40-60°C): CH2CI2 (1:1) and a second fraction collected. This fraction was further purified by preparation TLC silica plates (eluent: petroleum ether (bp. 40-60°C): CH2C12 3:2). [l,4-Dibutoxy-2-bromo-8,ll, 15, 18,22,25- hexakis(decyl)phthalocyaninato] zinc(II) (126mg, 2.7%>) was obtained as a dark green solid which was identical to the known sample obtained above.
Preparation of [l,4-dibutoxy-2-bromo-8,l l,15,18,22,25-hexakis(decyl)phthalocyaninato] zinc(II): Method 3
1 ,4-Dibutoxy-2-bromo-8, 11,15,18,22,25-hexakis(decyl)phthalocyanine (40mg, 0.025mmol) was dissolved in dry H-butanol (10ml) under reflux. Anhydrous zinc(II) bromide (17mg, 0.076mmol) was added and reflux continued for 45 minutes. The solvent was removed under reduced pressure and the residue purified using silica TLC plates (eluent: petroleum ether (bp. 40-60°C): CH2CI2 3:1). The product was recrystallised from THF/methanol. A dark green powder was obtained (20mg, 49%>) which was identical to the known sample.
Preparation of [l,4-dibutoxy-2-[l-(3-hydroxy-3-methyl)butynyl]-8,l 1,15,18,22,25- hexakis(decyl)phthalocyaninato] zinc(II) :
To a solution of l,4-dibutoxy-2-bromo-8,l l,15,18,22,25-hexakis(decyl)- phthalocyaninato zinc(II) (30mg, 0.018mmol) in dry triethylamine (5ml) under Ar in a dry screw-cap pressure tube, was added bis(triphenylphosphine)palladium(II) chloride (3.84mg, 30%mol), copper(I) iodide (1.56mg, 45%mol) and 2-methyl-3-butyn-2-ol (15mg, lOeq) in that order and at 10 minute intervals. The solution was degassed 3 times with Ar, then stirred in the dark in an oil bath at 80°C for 24 hours. The reaction was cooled and again, under an Ar atmosphere, was added bis(triphenylphosphine)- palladium(II) chloride (3.84mg), copper(I) iodide (1.56mg) and 2-methyl-3-butyn-2-ol (15mg, lOeq). The tube was resealed and heated at 80°C for a further 24 hours. The reaction was monitored by TLC. After the starting material was consumed, the reaction was cooled, filtered and washed with diethyl ether until the washings were clear. The organics were combined and concentrated under reduced pressure. The crude product was further purified by preparative TLC silica plates (eluent: CH2CI2) and recrystallised from THF/MeOH to afford [l,4-dibutoxy-2-[l-(3-hydroxy-3-methyl)butynyl]-8,ll, 15, 18,22,25- hexakis(decyl)phthalocyaninato] zinc(ll) (20mg, 0.012mmol, 67.5%). [Η NMR (300MHz, C6D6) δ 7.94-8.02 (m, 6H), 7.82 (s, IH), 5.09 (br t, 6H), 4.85 (m, 8H), 4.46 (t, 2H), 2.42 (m, 12H), 1.0-2.0 (m, 104H), 0.88 (m, 18H) ppm. λmax (abs.) 721, 702 nm (THF). MALDI-MS: cluster at 1645].
Preparation of 2-(4-pyridyl)-4,4,5,5-tetramethyl- 1 ,3-dioxaborolane
To a cold slurry at -78°C of 4-iodopyridine (5g, 24mmol) in dry diethylether (250ml) was added «-butyllithium (2.5M in hexanes, 12ml, 30.1mmol) slowly. After 20 minutes, tributoxyboron (6.9g, 30.1mmol) was added and the temperature was allowed to rise to room temperature over 2 hours. Pinacol (3.8g, 32.3mmol) was added followed, 10 minutes later, by glacial acetic acid (1.47g, 24.6mmol). The mixture was filtered through celite, the filter washed with diethylether (100ml) and the combined organics were reduced under vacuum. The crude product was recrystallised from cyclohexane yielding a white solid, 3.14g (15.4mmol, 64%). [mp. 150-152°C (Lit. (C Coudret, Synthetic Commun., 1996, vol. 26, page 3543) 151°C). 1H NMR (300 MHz, CDC13) δ 8.65 (d, 2H, J=6Hz), 7.65 (d, 2H, J=6Hz), 1.38 (s, 12H) ppm].
Preparation of 4-pyridyl-3,6-dibutoxyphthalonitrile
Cesium fluoride (0.66g, 4.4mmol), tetrakis(triphenylphosphine)palladium(0) (0.25g, 10mol%) and 2-(4-pyridyl)-4,4,5,5-tetramethyl-l,3-dioxaborolane (0.45g, 2.2mmol) were placed under nitrogen for 10 minutes. 4-Bromo-3,6-dibutoxyphthalonitrile (0.38g, l.lmmol) in 1 ,2-dimethoxyethane (DME) (20ml) was added and the mixture was refluxed for 48 hours, adding fresh tetrakis(triphenylphosphine)palladium(0) catalyst (0.25g, 10mol%) every 24 hours. After cooling, water (50ml) was added and the organics were extracted with diethylether (100ml), washed with brine and dried (MgSO4). The drying agent was filtered off and the solvent was removed under reduced pressure to leave a solid which was recrystallised from cyclohexane as white needles, 0.2g (0.6mmol, 53%). [mp. 150-151°C. Η NMR (300 MHz, CDC13) δ 8.76 (d, 2H), 7.46 (d, 2H), 7.13 (s, IH), 4.12 (t, 2H), 3.71 (t, 2H), 1.85 (qn, 2H), 1.48-1.6 (m, 4H), 1.39 (m, 2H), 1.02 (t, 3H), 0.83 (t, 3H) ppm. 13C NMR (300 MHz, CDC13) δ 157.79 (ar.C-O), 153.4 (ar.C-O), 150.58 (2xpyr.C), 143.49 (ar.C-pyr), 139.63 (2xpyr.C), 123.55 (2x CN), 118.88 (ar.CH), 113.23 (ar.C-CN), 112.76 (ar.C-CN), 112.23 (pyr.C-ar), 76.28, 70.30, 31.86, 30.9, 19.08, 18.81, 13.73, 13.58 ppm]
Preparation of 4-(2-thienyl)-3,6-dibutoxyphthalonitrile
4-Bromo-3,6-dibutoxyphthalonitrile (0.5g, 1.42mmol) and tetrakis(triphenylphosphine)palladium(0) (0.16g, 10mol%>) were stirred in DME (20ml) under N2 for 10 minutes. 2-Thiopheneboronic acid (0.27g, 2.1mmol) was added, followed by a 2M aqueous solution of Na2CO3 (2ml). The mixture was brought to reflux for 12 hours. After cooling, a saturated solution of K2CO3 (100ml) was added and the organics were extracted with diethylether (2x100ml), washed with aq. 5%> HCl (100ml), water (100ml), brine and dried (MgSO ). The drying agent was filtered off and the solvent was removed under reduced pressure to leave an orange solid. This was recrystallised from cyclohexane as pale yellow crystals, 0.31g (0.88mmol, 62%.). [1H NMR (300 MHz, CDC13) δ 7.59 (d, IH), 7.45 (d, IH), 7.34 (s, IH), 7.16 (qn, IH), 4.13 (t, 2H), 3.96 (t, 2H), 1.77-1.9 (m, 4H), 1.43-1.61 (m, 4H), 1.0 (t, 3H), 0.94 (t, 3H) ppm].
Preparation of 4-phenyl-3 ,6-dibutoxyphthalonitrile 4-Bromo-3,6-dibutoxyphthalonitrile (0.6g, 1.7mmol) and tetrakis(triphenylphosphine)palladium(0) (0.19g, 10mol%>) were stirred in DME (50ml) under N2 for 10 minutes. Phenylboronic acid (0.23g, 1.87mmol) was added, followed by a 2M aqueous solution of Na2CO3 (2ml). The mixture was brought to reflux for 12 hours. After cooling, a saturated solution of K2CO3 (100ml) was added and the organics were extracted with dithylether (2x100ml), washed with aq. 5% HCl (100ml), water (100ml), brine and dried (MgSO4). The drying agent was filtered off and the solvent was removed under reduced pressure to leave an orange solid. This was recrystallised from cyclohexane as pale orange crystals, 0.38g (1.09mmol, 64%). [Η NMR (300 MHz, CDC13) δ 7.45-7.54 (m, 6H), 7.13 (s, IH), 4.11 (t, 2H), 1.84 (qn, 4H), 1.49-1.6 (m, 4H), 1.29 (m, 2H), 1.01 (t, 3H), 0.78 (t, 3H) ppm]
Preparation of 4,5-diphenyl-3,6-dibutoxyρhthalonitrile 4,5-Dibromo-3,6-dibutoxyphthalonitrile (0.5g, 0.16mmol) and tetrakis(triphenylphosphine)palladium(0) (0.13g, 10mol%o) were stirred under N2 for 10 minutes in DME (20ml). Phenylboronic acid (0.3 lg, 2.55mmol) followed by a 2M aqueous solution of Na2CO3 (2ml) were added and the mixture brought to reflux. The reaction was followed by tic (eluent: ethylacetate-hexane 1 :3). One more eq. of tetrakis(triphenylphosphine)palladium(0) (0.13g, 10mol%>) was added after 24 hours and reflux continued for a further 12 hours. After cooling, water (100ml) was added and the product was extracted with diethylether (3x100ml). The organic phase was washed with brine and dried (MgSO4). The drying agent was removed by filtration and the solvent was removed under reduced pressure. The product was recrystallised from cyclohexane as yellow crystals, 130mg (0.4mmol, 34%). [1H NMR (300 MHz, CDC13) δ 7.17-7.23 (m, 6H), 6.97-7.03 (m, 4H), 3.56 (t, 4H), 1.44 (qn, 4H), 1.14 (m, 4H), 0.72 (t, 6H) ppm]
Preparation of 4-(p-N,N-dimethylaminophenyl)-3 ,6-dibutoxyphthalonitrile: 4-Bromo-3,6-dibutoxyphthalonitrile (0.5g, 1.42mmol) and tetrakis(triphenyl)phosphine palladium(O) (0.2g, 10mol%>) was dissolved in dry DME
(20ml) and left to stir under N2 for 30 minutes. 4-(N,N-Dimethylaminophenyl)boronic acid (0.4g 2.84mmol) was added followed by 2M Na2CO3 (2ml) solution. The reaction was brought to reflux for 16 hours and then allowed to cool to room temperature. The product was partitioned between water (100ml) and ether (100ml). The ether layer was washed with brine (2x100ml) and dried over MgSO4. The ether was filtered and reduced yielding a yellow solid which was purified by column chromatography (ethyl acetate: hexane, 3:1) and recrystallised from cyclohexane to afford 4-(p-N,N- dimethylaminophenyl)-3,6-dibutoxyphthalonitrile (0.3g, 0.76mmol, 53.9%.) as yellow fluffy crystals [1H NMR (300 MHz, CDC13) δ 7.85 (d, 2H), 7.09 (s, IH), 6.78 (d, 2H), 4.09
(t, 2H), 3.65 (t, 2H), 3.04 (s, 6H), 1.83 (pent, 2H), 1.15 (pent, 4H), 1.34 (sex, 2H), 0.98 (t,
3H), 0.84 (t, 3H) ppm].
Preparation of 3,6-dibutoxy-4-j_ -methoxyphenylphthalonitrile: 4-Bromo-3,6-dibutoxyphthalonitrile (0.5g, 1.42mmol) and tetrakis(triphenyl)phosphine palladium(O) (0.2g, 10mol%>) was dissolved in dry DME (20ml) and left to stir under N2 for 30 minutes. 4-p-Methoxyphenylboronic acid (0.43g, 2.84mmol) was added followed by 2M Na2CO3 (2ml) solution. The reaction was brought to reflux for 16 hours and then allowed to cool to room temperature. The product was partitioned between water (100ml) and ether (100ml). The ether layer was washed with brine (2x100ml) and dried over (MgSO4). The ether was filtered and reduced yielding a brown solid, crude yield 0.3 lg, which was purified by column chromatography (ethyl acetate) and recrystallised from cyclohexane to afford 3,6-dibutoxy-4-p- methoxyphenylphthalonitrile. [Η NMR (300MHz, CDC13) δ 7.67 (d, 2H), 7.17 (s, IH), 7.04 (d, 2H), 4.11 (t, 2H), 3.63 (t, 2H), 3.03 (s, 6H), 1.81 (p, 2H), 1.13 (p, 4H), 1.31 (sex, 2H), 0.96 (t, 3H), 0.83 (t, 3H) ppm].
Preparation of 3 ,6-dibutoxy-4-carboxyphenylphthalonitrile :
4-Bromo-3,6-dibutoxyphthalonitrile (0.25g, 0.7mmol), tetrakis(triphenyl)phosphine palladium(O) (O.lg, 10moP/o), cesium carbonate (0.92g, 5.69mmol) and para-caroxylic acid-boronic acid (0.23g, 1.42mmol) were placed under N2 for 1 hour. Toluene:ethanol:water 3:3:1 (21ml) was added and the reaction brought to reflux for 12 hours. On cooling the mixture was acidified with cone. HCl (20ml) and extracted with DCM (2x100ml). The combined organic layers were dried over MgSO4, filtered and reduced yielding a yellow solid which was recrystallised from ethanol to afford 3,6- dibutoxy-4-carboxyphenylphthalonitrile (0.06g, 0.168mmol, 24%). [1H NMR (300MHz, CDC13) δ 8.23 (d, 2H), 7.67 (d, 2H), 7.16 (s, IH), 4.08 (t, 2H), 3.64 (t, 2H), 3.05 (s, 6H), 1.84 (p, 2H), 1.15 (p, 4H), 1.33 (sex, 2H), 0.94 (t, 3H), 0.85 (t, 3H) ppm].
Preparation of 4-p-aminophenyl-3,6-dibutoxyphthalonitrile:
4-Bromo-3,6-dibutoxyphthalonitrile (0.05g, 0.142mmol), tetrakis(triphenyl)- phosphine palladium(O) (0.02g, 10 mol %>), caesium carbonate (0.09g, 0.569mmol) and p- aminophenyl boronic acid (0.06g 0.284mmol) were placed under N2 for 1 hour. Dry DME (10ml) was added and the reaction brought to reflux for 12 hours. The product was partitioned between ether (20ml) and water (20ml). The organics were dried over MgSO4, filtered and reduced yielding a yellow solid, crude yield 0.021 g which was recrystallised from ethanol to afford 4-p-aminophenyl-3,6-dibutoxyphthalonitrile. [1H NMR (300MHz, CDC13) δ 7.38 (d, 2H), 7.17 (s, IH), 6.75 (d, 2H), 4.07 (t, 2H), 3.62 (t, 2H), 3.07 (s, 6H), 1.85 (p, 2H), 1.16 (p, 4H), 1.32 (sex, 2H), 0.93 (t, 3H), 0.84 (t, 3H) ppm].
Preparation of 4-(p-hydroxymethylphenyl)-3 ,6-dibutoxyphthalonitrile A mixture of 4-(hydroxymethyl)benzeneboronic acid (500 mg, 3.311 mmol), 4- bromo-3,6-dibutoxyphthalonitrile (764 mg, 2.17 mmol), triphenylphosphine (85.7 mg, 0.327 mmol), palladium chloride (42.8 mg, 0.241 mmol), and Na2CO3 (50 mg) was placed under nitrogen for 30 minutes. The solvent (35 ml), consisting of toluene, ethanol and water, 3:3:1 respectively was then added. The mixture was refluxed for 24 hours under N . The solvent was then removed under reduced pressure and the mixture redissolved in dichloromethane (50ml) and filtered through celite to remove palladium residues. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica (eluent: dichloromethane :ethylacetate, 9:1) to give 4-(p- hydroxymethylphenyl)-3,6-dibutoxyphthalonitrile (700mg, 1.85mmol, 85%>). [Η NMR (300 MHz, CDC13) δ 7.54 (d, 2H, J= 8.4Hz), 7.48 (d, 2H, J= 8.4Hz), 7.12(s, IH), 4.80 (s, 2H), 4.11 (t, 2H, J= 6.5Hz), 3.64 (t, 2H, J= 6.4Hz), 1.84(qn, 2H, J= 6.6Hz), 1.47-1.58 (m, 4H),1.26 (qn, 2H, J= 7.3Hz), 0.98 (t, 3H, J= 7.4Hz), 0.80 (t, 3H, J= 7.4Hz) ppm. Found: C, 72.82; H, 6.93; N, 7.22%. C23H26N2O3 requires: C, 73.01; H, 6.88; N; 7.41%]
Preparation of 4-(p-methanesulfonyloxymethylphenyl)-3,6-dibutoxyphthalonitrile:
4-(p-Hydroxymethylphenyl)-3,6-dibutoxyphthalonitrile (lOOmg, 0.26mmol) was dissolved in DCM (30ml) containing triethylamine (30mg, 0.29mmol). The reaction mixture was cooled to 0°C and stirred. Methanesulfonylchloride (33mg, 0.29mmol) was added dropwise. The resulting mixture was allowed to warm to room temperature and stirred for 2 hours, and then washed with 10%. HCl (2x25 ml) and brine (25ml), and dried (MgSO4). The mixture was filtered and the solvent removed under vacuum to yield a yellow oil. The oil was chromatographed (silica gel; eluent: DCM) to obtain 4-(p- methanesulfonyloxymethylphenyl)-3,6-dibutoxyphthalonitrile (85 mg, 70%>) [Found: C, 62.97; H, 6.13; N, 6.10. C24 H 8 N2 O5S requires C, 63.15; H, 6.14; N, 6.14%. Η-NMR (CDC13) δ 7.59 (2H, d, J 8.2), 7.54 (2H, d, J 8.2), 7.14 (IH, s), 5.31 (2H, s), 4.12 (2H, t, J 6.3), 3.65 (2H, t, J 6.4), 3.04 (3H, S), 1.85 (2H, quint, J 6.6), 1.48-1.60 (4H, m),1.27 (2H, quint, J 7.2), 0.99 (3H, t, J 7.3), 0.79 (3H, t, J 7.4)].
Preparation of 4-/?-[(O-tyrosinyl methyl ester)oxymethylphenyl]-3,6-dibutoxy- phthalonitrile:
A mixture of 4-(p-methanesulfonyloxymethylphenyl)-3,6-dibutoxyphthalonitrile (500mg, 1.08mmol), Dl-p-Tyrosine (318mg, 1.63mmol), K2CO3 (600mg, excess) and tris(3,6-dioxaheptyl)amine (TDA-1, Aldrich) (50mg, 0.154mmol) in MEK (30ml) as solvent was stirred under Ar at reflux for 48 hours. After cooling the solid was filtered off and washed with DCM. The solution was evaporated off under reduced pressure to leave a yellow oil which was purified by column chromatography (silica gel, eluent: DCM:ethylacetate, 2:3) to yield 4-p[(0-tyrosinyl methyl ester) oxymethylphenyl] -3,6- dibutoxyphthalonitrile (210 mg, 34%) [1H-NMR (CDC13) δ 7.55 (4H, s), 7.11-7.14 (3H, m), 6.93 (2H, d, J 8.7), 5.12 (2H, s), 4.11 (2H, t, J 6.4), 3.65 (2H, t, J 6.3), 3.68-3.75 (4H, m), 3.06 (IH, dd, J4.1 and 13.5), 2.84 (IH, dd, J7.7 and 13.5), 1.21-1.86(10H, bm), 0.98 (3H, t, J 7.4), 0.79 (3H, t, J 7.4)].
Preparation of 3 ,6-di(butyloxy)-4-(4 ' -ethoxy-4 ' -oxobutyl)phthalonitrile:
A mixture of triphenylphosphine (250mg, 0.95mmol), lithium chloride (0.6g, 14mmol) and bis(triphenylphosphine)nickel (II) chloride (313mg, 0.5mmol) was stirred in dry THF (10ml) under nitrogen for 10 minutes. H-BuLi (2.5M in hexanes, 0.4ml) was added to the blue solution at room temperature. The solution turns deep red. Solid 3,6- bis(butyloxy)-4-bromophthalonitrile (3.5g, lOmmol) was added at once under a fast stream of nitrogen and the pale brown solution was cooled to -78°C 4-Ethoxy-4-oxobutylzinc bromide (0.5M in THF purchased from Aldrich, (20ml, lOmmol)) was added via a syringe. The solution was allowed to warm to room temperature and stirring continued for 12 hours under nitrogen. 5%> HCl (50ml) was added and the mixture extracted with ethyl acetate (3x20ml). The combined organics were washed with 5% HCl (10ml), 5% NaOH (10ml), brine (10ml), and dried (MgSO4). The drying agent was removed by filtration and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica [eluent: petroleum ether (bp. 40-60°C): dichloromethane 1 :1] to remove triphenylphosphine. The eluent was changed to dichloromethane. A fluorescent fraction eluted. This proved to be 3,6-dibutyloxyphthalonitrile by 1H-NMR spectroscopy (570mg, white powder). Another fluorescent fraction eluted which was not identified. Finally, 3, 6-di(butyloxy)-4-(4 '-ethoxy-4 '-oxobutyl)phthalonitrile (1.9g, 4.9mmol, 49%>) was obtained in the last eluting fraction as a pale yellow oil which solidifies on standing [mp 43-48°C Η NMR (270 MHz, CDC13) δ 7.0 (s, IH), 4.1 (q, 2H), 4.04 (m, 4H), 2.69 (t, 2H), 2.31 (t, 2H), 1.9 (m, 2H), 1.78 (m, 4H), 1.5 (m, 4H), 1.24 (t, 3H), 0.95 (m, 6H) ppm. m/z. 386 (M, 14.9%)]. Preparation of 3,6-bis(butyloxy)-4-(4'-chlorobutyl)phthalonitrile:
A mixture of triphenylphosphine (125mg, 0.5mmol), lithium chloride (0.3g, 7mmol) and bis(triphenylphosphine)nickel (II) chloride (156mg, 0.24mmol) was stirred in dry THF (5ml) under nitrogen for 10 minutes. rø-BuLi (2.5M in hexanes, 0.2ml) was added to the blue solution at room temperature. The solution turns deep red. Solid 3,6- bis(butyloxy)-4-bromophthalonitrile (1.4g, 4mmol) was added at once under a fast stream of nitrogen and the pale brown solution was cooled to -78°C 4-Chlorobutylzinc bromide (0.5M in THF purchased from Aldrich, (10ml, 5mmol)) was added via a syringe. The solution was allowed to warm to room temperature and stirring continued for 12 hours under nitrogen. 5% HCl (20ml) was added and the mixture extracted with ethyl acetate (3x10ml). The combined organics were washed with 5% HCl (10ml), 5% NaOH (10ml), brine (10ml), and dried (MgSO4). The drying agent was removed by filtration and the solvent removed under reduced pressure. The residue was purified by column chromatography over silica [eluent: petroleum ether (bp. 40-60°C): dichloromethane, 1:1] to remove triphenylphosphine. A second fraction was collected which proved to be unreacted starting material (0.9g). The eluent was changed to dichloromethane to obtain 3,6-bis(butyloxy)-4-(4 '-chlorobutyl)phthalonitrile (200mg, 0.55mmol, 14%> or 39%> based on recovered starting material) as a pale yellow oil which solidifies on standing [1H NMR (270 MHz, CDC13) δ 7.19 (s, IH), 4.8 (t, 2H), 4.6 (t, 2H), 3.59 (t, 2H), 2.7 (t, 2H), 1.82 (m, 8H), 1.45-1.6 (m, 4H), 0.95-1.03 (m, 6H) ppm. m/z. 362 (M, 1.6%), 364 (M+2, 0.53%)].
Preparation of 3 ,6-dibutoxy-4,5-(tris(isopropyl)silylethynyl)phthalonitrile:
A solution of 4,5-dibromo-3,6-dibutoxyphthalonitrile (l.OOg, 2.33mmol) was dissolved in freshly distilled triethylamine (6ml). The solution was degassed by heating it briefly under argon. PdCl2(PPh3)2 (0.164g, 10mol%) was added, followed by TIPS- acetylene (1.06g, 5.82mmol) and finally Cul (0.06g, 13mol%) at 10 minute intervals. The reaction was refluxed for 16 hours, cooled, filtered to remove palladium salts, washed with ethyl acetate and concentrated under reduced pressure. The crude product was purified by column chromatography over silica (eluent: petrol/DCM, 1 :2) to afford 3,6-dibutoxy-4,5- (tris(isopropyl)silylethynyl)phthalonitrile (0.82 g, 56%>) after recrystallisation from ethanol [Found: C, 72.11; H, 9.37; N, 4.28. C38H60O2N2Si2 requires C, 72.10; H, 9.55; N, 4.42. 1H NMR (300 MHz, CDC13) δ 4.26 (t, 4H, J - 6.8 Hz), 1.83 (quint, 4H, J = 7.2 Hz), 1.56-1.45 (m, 4H), 1.2-1.08 (br s, 42H), 0.97 (t, 6H, J = 7.4 Hz) ppm. 13C NMR (300 MHz, CDC13) δ 160.03, 127.13, 112.94, 109.05, 108.60, 98.43, 75.98, 31.94, 18.80, 15.58, 13.73, 11.28 ppm].
Preparation of l,4-dibutoxy-2-pyridyl-8,l l,15,18,22,25-hexakis(decyl)phthalocyanine 3,6-Didecylphthalonitrile (2.2g, 7.65mmol) and 4-pyridyl-3,6- dibutoxyphthalonitrile (0.3g, 0.85mmol) were refluxed in butan-1-ol (10ml). Lithium metal (0.12g, 17mmol) was added slowly in portions and refluxed was carried on for 12 hours in the dark. After cooling, glacial acetic acid (10ml) was added and the mixture stirred for 30 minutes. The solvents were removed under reduced pressure and methanol was added to the resulting green slurry. The solid was filtered and washed with methanol. The product was separated by column chromatography on silica (eluent: petroleum ether (bp. 40-60°C) to remove 1,4,8,1 l,15,18,22,25-octakis(decyl)phthalocyanine). The eluent was changed (petroleum ether (bp.40-60°C)-dichloromethane 9:1) and a second green fraction was collected. This was purified through a second silica column (eluents: petroleum ether (bp. 40-60°C) followed by petroleum ether (bp. 40-60°C)-dichloromethane 19:1). The product was recrystallised from THF/methanol to afford a green powder, 43mg (0.03mmol, 3.2%). [Η NMR (300 MHz, benzene-d6) δ 8.99 (d, 2H), 7.89-7.96 (m, 8H), 7.79 (s, IH), 4.99 (t, 2H), 4.92 (t, 2H), 4.97 (qn, 8H), 4.49 (qn, 2H), 2.24-2.42 (m, 14H), 2.05 (qn, 2H), 0.99-1.89 (m, 93H), 0.65-0.86 (m, 21H), -0.48 (s, 2H) ppm. Found: C, 79.74; H, 9.88; N, 7.73%. C105H157N9O2 requires: C, 79.95; H, 10.03; N, 7.99%. λmax (THF): Abs. 723 (ε=1.4xl04) nm. MALDI-MS: isotopic cluster at 1577 [M+]]
Preparation of l,4-dibutoxy-2-thienyl-8,l l,15,18,22,25-hexakis(decyl)phthalocyanine
4-Thienyl-3,6-dibutoxyphthalonitrile (0.37g, l .Oόmmol) and 3,6- didecylphthalonitrile (3.9g, 9.55mmol) were dissolved in butan-1-ol (15ml) and the mixture brought to reflux. Lithium metal (0.4g, 57mmol) was added slowly in portions. Reflux was carried on for 12 hours and the mixture was left to cool. Glacial acetic acid (10ml) was added and the mixture stirred for 30 minutes. The solvents were removed under reduced pressure and the residue was washed with methanol (3x100ml). The product was separated by column chromatography on silica (eluent: petroleum ether (bp. 40-60°C) to remove 1,4,8,11,15, 18,22,25-octakis(decyl)phthalocyanine). The eluent was changed to dichloromethane/petroleum ether (bp. 40-60°C), increasing progressively the amount of dichloromethane from 5 to 25%. The second fraction collected was further purified by column chromatography on silica (same solvent systems used as previously described). A third purification by column chromatography was deemed necessary (eluent: 25%. dichloromethane in petroleum ether (bp. 40-60°C)) to obtain a pure product which was recrystallised from THF/methanol as a green powder, 32mg (20μmol, 1.9%). [1H NMR (300 MHz, C6D6) δ 8.29 (dd, IH), 7.91 (q, IH), 7.88 (s, IH), 7.82 (s, 4H), 7.69 (s, 2H), 7.27 (dd, IH), 4.98 (t, 2H), 4.85 (t, 2H), 4.78 (t, 2H), 4.46-4.64 (m, 10H), 2.07-2.4 (m, 16H), 1.6-1.83 (m, 12H), 0.97-1.58 (m, 79H), 0.68-0.96 (m, 21H), -0.35 (s, 2H) ppm. Found: C, 79.18; H, 9.87; N, 6.86%. C104H156N8O2S requires: C, 78.94; H, 9.94; N, 7.08%. MALDI-MS: isotopic cluster at 1582 [M+]. λmax (THF): Abs. 727 (ε=1.85xl04) nm]
Preparation of l,4-dibutoxy-2-phenyl-8,l l,15,18,22,25-hexakis(decyl)phthalocyanine
4-Phenyl-3,6-dibutoxyphthalonitrile (0.37g, l.Oόmmol) and 3,6- didecylphthalonitrile (3.9g, 9.55mmol) were dissolved in butan-1-ol (15ml) and the mixture brought to reflux. Lithium metal (0.4g, 57mmol) was added slowly in portions. Reflux was carried on for 12 hours and the mixture was left to cool. Glacial acetic acid (10ml) was added and the mixture stirred for 30 minutes. The solvents were removed under reduced pressure and the residue was washed with methanol (3x100ml). The product was separated by column chromatography on silica (eluent: petroleum ether (bp. 40-60°C) to remove 1,4,8,11, 15, 18,22,25-octakis(decyl)phthalocyanine). The eluent was changed to dichloromethane/petroleum ether (bp. 40-60°C), increasing progressively the amount of dichloromethane from 5 to 25%). The second fraction collected was further purified by column chromatography on silica (same solvent systems used as previously described). A third purification by column chromatography was deemed necessary (eluent: 25%) dichloromethane in petroleum ether (bp. 40-60°C)) to obtain a pure product which was recrystallised from THF/methanol as a green powder, 22mg (14μmol, 1.3%). [1H NMR (300 MHz, C6D6) δ 8.18 (d, 2H), 7.89-8.0 (m, 3H), 7.83 (s, 2H), 7.62 (s, IH), 7.55 (t, 2H), 7.3-7.41 (m, 2H), 4.92-5.09 (m, 4H), 4.63-4.81 (m, 8H), 4.48 (t, 4H), 1.95-2.48 (m, 18H), 1.55-1.94 (m, 16H), 0.15-1.54 (m, 94H), -0.27 (s, 2H) ppm]
Preparation of 1 ,4-dibutoxy-2,3-diphenyl-8, 11,15,18,22,25-hexakis(decyl)phthalocyanine 4,5-Diphenyl-3,6-dibutoxyphthalonitrile (0.2g, 0.47mmol) and 3,6- didecylphthalonitrile (0.7g, 1.88mmol) were brought to reflux in butan-1-ol (10ml). Lithium metal (0.12g, 17mmol) was added slowly in portions and reflux was continued for 12 hours in the dark. The reaction mixture was allowed to cool and glacial acetic acid (10ml) was added and the solution stirred for 30 minutes. The solvents were removed under reduced pressure and the residue was chromatographed on silica (eluent: petroleum ether (bp. 40-60°C) to remove 1,4,8,11,15, 18,22,25-octakis(decyl)phthalocyanine). The eluent was changed to dichloromethane/petroleum ether (bp. 40-60°C) 1:19. The isolated product was recrystallised from THF/methanol as a green powder, 50mg (0.03mmol, 6.5%). [Η NMR (300 MHz, C6D6) δ 7.96 (s, 4H), 7.88 (s, 2H), 7.72 (d, 4H), 7.3 (t, 4H), 4.96 (t, 4H), 4.76 (t, 8H), 4.48 (t, 4H), 2.4 (m, 10H), 2.09 (qn, 4H), 1.69-1.87 (m, 12H), 1.57-1.67 (m, 4H), 1.4-1.57 (m, 12H), 0.89-1.39 (m, 74H), 0.74-0.87 (m, 14H), -0.17 (s, 2H) ppm. Found: C, 81.58; H, 9.94; N, 6.34%. Cι12Hι62N8O2 requires: C, 81.4; H, 9.88; N,
6.78%. λmax (THF): Abs. 725 (ε=9.19xl04), 711 (ε=9.12xl04) nm. MALDI-MS: isotopic cluster at 1652 [M+]]
Preparation of 1 ,4-dibutoxy-2-(p-hydroxymethylphenyl)-8, 11,15,18,22,25- hexakis(decyl)phthalocyanine
To a rapidly stirring solution of 3,6-didecylphthalonitrile (1.01 g, 2.4 mmol) and 4- (p-hydroxymethylphenyl)-3,6-dibutoxyphthalonitrile (0.233 g, 0.6 mmol) in butan-1-ol (25 ml) at 120°C under nitrogen was added an excess of lithium metal (0.1 g, 14mmol). Heating and stirring were continued for 12 hours. After cooling to room temperature, glacial acetic acid (30 ml) was added and the resulting mixture was stirred for 20 minutes. This was poured onto methanol (100ml) and stirred for 5 minutes. The resulting precipitate was collected by filtration and air dried for 10 minutes. The green product was separated by column chromatography on silica (eluent: toluene). The first fraction contained symmetrical 1,4,8,11,15, 18,22,25-octakis(decyl)phthalocyanine. The second fraction, which contained the required product, was collected and was precipitated from toluene by addition of methanol to afford l,4-dibutoxy-2-(p-hydroxymethylphenyl)- 8, 11 , 15, 18,22,25-hexakis(decyl)phthalocyanine as a dark green solid, 100 mg (0.062mmol, 10%). [1H NMR (300 MHz, CDC13) δ 8.01 (d, 2H, J= 8.1Hz), 7.94 (d, 4H, J=8.7Hz), 7.80 (s, 2H), 7.63 (d, 2H, J= 8.3Hz ), 7.59 (s, IH), 4.9 (d, 2H, J= 5.6Hz), 4.61-4.72 (m, 6H), 4.40-4.47 (m, 8H), 4.25 (t, 2H, J= 7.1Hz), 2.31 (qn, 2H, J=6.6Hz), 0.71-2.17 (m, 126H), 0.61 (t, 3H, J= 7.4Hz) ppm. Found: C, 80.00; H, 10.03; N, 6.86%. C107H160N8O3 requires: C, 80.00; H, 10.04; N; 6.98%; MALDI-MS: isotopic cluster at 1606 [M+]. λmax (THF): Abs. 728, 718 nm]
Preparation of [l,4-dibutoxy-2-pyridyl-8,l l,15,18,22,25-hexakis(decyl)phthalocyaninato] zinc(II)
1 ,4-Dibutoxy-2-pyridyl-8, 11,15,18,22,25-hexakis(decyl)phthalocyanine (0.4g,
0.25mmol) and zinc acetate dihydrate 99.999%) (0.2g, 1.09mmol) were added to butan-1-ol (10ml). The mixture was refluxed for 4 hours. After cooling, the solvent was removed under reduced pressure. The green residue was recrystallised from THF/methanol to afford a green powder, 0.2g (0.12mmol, 48%). [!H NMR (300 MHz, benzene-d6 containing 1 drop of pyridine-d5) δ 8.96 (d, 2H), 8.5 (s, 2H), 7.92-7.99 (m, 8H), 7.55 (s, IH), 5.19 (t, 2H), 5.07 (t, 2H), 4.88 (m, 8H), 4.57-4.62 (t, 2H), 2.47-2.52 (m, 14H), 2.07 (qn, 2H), 1.81 (m, 12H), 0.99-1.79 (m, 100H) ppm. λmax (THF): Abs. 718 (ε=1.44xl05) Em. 725 nm Found: C, 76.56; H, 9.49; N, 7.39%. C1o5H155N9O2Zn requires: C, 76.86; H, 9.52; N, 7.68%. MALDI-MS: isotopic cluster at 1640 [M+]]
Preparation of [l,4-dibutoxy-2-thienyl-8,l l,15,18,22,25-hexakis(decyl)phthalocyaninato] zinc(II) l,4-Dibutoxy-2-thienyl-8,l 1,15,18,22,25-hexakis(decyl)phthalocyanine (50mg, 0.03mmol) and zinc acetate dihydrate 99.999%) (200mg, lmmol) were added to butan-1-ol (12ml). The mixture was refluxed for 4 hours. After cooling, the solvent was removed under reduced pressure. The green residue was recrystallised from THF/methanol to afford a green powder, 20mg (12.1μmol, 41%). [Η NMR (300 MHz, benzene-d6) δ 8.09 (dd, IH), 8.0 (q, IH), 7.99 (s,lH), 7.91 (s, 4H), 7.87 (s, 2H), 7.29 (dd, IH), 5.13 (t, 2H), 5.03 (t, 2H), 4.91 (t, 2H), 4.81 (m, 8H), 4.64 (t, 2H), 2.5 (m, 12H), 2.19-2.37 (m, 8H), 1.85 (m, 8H), 1.72 (m, 4H), 0.72-1.6 (m, 96H) ppm]
Preparation of [1 ,4-dibutoxy-2,3-diphenyl-8, 11,15, 18,22,25-hexakis(decyl)- phthalocyaninato] zinc(II): 1 ,4-Dibutoxy-2,3-diphenyl-8, 11,15,18,22,25-hexakis(decyl)phthalocyanine (0.04g,
0.0242mmol) and zinc acetate dihydrate (0.02g, excess) were dissolved in dry butanol (10ml) and the solution brought to reflux for 4 hours. All solvents were removed and the product purified by column chromatography (petrohTHF, 15:1) and recrystallised (THF:methanol) to afford fl,4-dibutoxy-2,3-diphenyl-8,ll,15,18,22,25-hexakis(decyl)- phthalocyaninato] zinc(II) (O.Olg, 0.005.8mmol, 24%>) as a waxy green solid [1H NMR (300 MHz, C6D6) δ 8.00 (q, 4H), 7.81 (s, 4H), 7.78 (s, 2H), 7.32 (t, 4H), 5.11 (t, 4H), 4.83- 4.77 (m, 8H), 4.66 (t, 4H), 2.56-2.46 (m, 14H), 2.43-2.21 (m, 6H), 1.85-1.81 (m, 10H), 1.50-1.19 (m, 68H), 0.91-0.72 (m, 16H) ppm. λmax (abs.) 712 nm (THF); λmax (em.) 720 nm (THF)].
Preparation of [l,4-dibutoxy-2-p-N,N-dimethylaminophenyl-8,l 1,15, 18,22,25- hexakis(decyl)phthalocyaninato] zinc(II):
3,6-Didecylphthalonitrile (0.61 g, 1.5mmol), 4-(p-N,N-dimethylaminophenyl)-3,6- dibutoxy phthalonitrile (0.196g, 0.5mmol) and zinc acetate (0.02g, excess) were brought to reflux under N2 in dry butanol (10ml). At reflux DBU (2.3ml, excess) was added and the reaction left to reflux in the absence of light for 9 hours. The reaction was allowed to cool and the solvent was removed. The resulting oil was purified by column chromatography (petro DCM, 8:2) firstly removing the symmetrical product. The solvent system was slowly changed in favour of DCM (petro DCM, 6:4, 1:1, 4:6, 2:8, and to 100%> DCM) this yielded a green fraction which was again purified by column chromatography (petrohDCM, 8:2) removing any further trace of the symmetrical product. Petro DCM 2:8 removed a light green fraction, then THF:petrol, 5:100 gave the desired fraction. The solvents were removed and the solid recrystallised from THF:methanol yielding [1,4- dibutoxy-2-p-N, N-dimethylaminophenyl-8, 11,15,18,22, 25-hexakis(decyl)phthalocyaninato] zinc(II) (0.03g, 0.017mmol, 3.5%) [1H NMR (300 MHz, C6D6) δ 8.29 (d, 2H), 8.01 (s, 4H), 7.97 (s, 2H), 7.87 (s, IH), 6.97 (d, 2H), 5.20 (m, 4H), 4.92-4.90 (ot, 8H), 4.71-4.66 (ot, 4H), 2.98 (m, 4H), 2.64 (s, 6H), 2.51 (m, 10H), 1.87 (m, 8H), 1.50 (t, 8H), 1.40-1.00 (m, 74H), 0.86-0.70 (m, 24H) ppm].
Preparation of [l,4-dibutoxy-2-(p-hydroxymethylphenyl)-8,l 1,15, 18,22,25- hexakis(decyl)phthalocyaninato] zinc(II) To a refluxed and stirred solution of l,4-dibutoxy-2-(p-hydroxymethylphenyl)-
8,l l,15,18,22,25-hexakis(decyl)phthalocyanine (40 mg, 0.025 mmol) in butan-1-ol (10 ml), zinc acetate dihydrate 99.999%) (22 mg, 0.1 mmol) was added. The reaction mixture was heated under reflux until reaction was complete (as shown by tic). The solvent was removed under reduced pressure and the product was purified by column chromatography on silica (eluent: toluene). The second blue fraction contained [l,4-dibutoxy-2-(p- hydroxymethylphenyl)-8,ll, 15, 18,22, 25-hexakis(decyl)phthalocyaninato] zincfllj, 37 mg (0.022mmol, 90%). [Η NMR (300 MHz, CDC13) δ 8.03 (d, 2H, J= 7.8Hz), 7.82-7.89 (m, 2H), 7.55-7.61 (m, 7H), 4.65-4.76 (m, 6H), 4.23-4.41 (m, 10H), 4.03 (t, 2H, J= 6.2Hz), 2.25 (qn, 2H, J= 7.4Hz), 0.70-2.17 (m, 120H), 0.61 (t, 3H, J= 7.4Hz) ppm. Found: C, 76.85; H, 9.45; N, 6.55%. C107H158N8O3Zn requires: C, 76.96; H, 9.54; N; 6.71%; MALDI- MS: isotopic cluster at 1669 [M+]. λmax (abs.) 715.5 nm (THF)]
Preparation of [l,4-dibutoxy-2-p-[(O-tyrosinyl butyl ester)oxymethylphenyl]- 8,11,15, 18,22,25-hexakis(decyl)phthalocyaninato] zinc(II):
3,6-Didecylphthalonitrile (1.442 g, 3.528 mmol), 4-p-[(O-tyrosinyl methyl ester)oxymethylphenyl]-3,6-dibutoxyphthalonitrile (0.218g, 0.3927mmol) and zinc acetate dihydrate (0.128g) were brought to reflux under N in dry butanol (30ml) for 1 hour. DBU (0.592 mg, excess) was added and the reaction heated to reflux in the absence of light for a further 36 hours. The reaction was allowed to cool and the solvent removed by evaporation under reduced pressure. The residue was washed with MeOH and purified by column chromatography (toluene) which first separated the symmetrical octadecyl zinc phthalocyanine. The solvent system was changed to petro THF (10:1) which yielded a greenish-yellow fraction. The solvents were removed and the greenish-yellow solid recrystallised from THF:MeOH to yield [l,4-dibutoxy-2-p-[(0-tyrosinyl butyl ester)oxymethylphenyl]-8,ll,15,18,22,25-hexakis(decyl)phthalocyaninato] zinc(II) as a blue/green solid (6mg). [MALDI-MS: isotopic cluster centred at 1886 (indicating trans- esterification of the methoxy group of the starting material for the butoxy group from the solvent). λmax (abs.) 716 nm (THF)] .
Preparation of [l,4-di(butyloxy)-2-(4'-butoxy-4'-oxobutyl)-8,l 1,15,18,22,25- hexakis(decyl)phthalocyaninato] zinc(II) :
A mixture of 3,6-didecylphthalonitrile (1.6g, 3.9mmol), 3,6-bis(butyloxy)-4-(4'- ethyl-4'-oxobutyl)phthalonitrile (500mg, 1.3mmol) and zinc acetate dihydrate 99.999%
(370mg, 1.73mmol) was refluxed in butan-1-ol (20ml). DBU (large excess) was added and reflux continued for 6 hours. The solvent was removed under reduced pressure and the residue was chromatographed over silica (eluent: petroleum ether (bp. 40-60°C): THF 10:1). The first blue fraction contained 1,4,8,11,15,18,22,25- octakis(decyl)phthalocyaninato zinc(II). The second green fraction was collected. This was further purified by column chromatography on silica (eluent: same as above). The product was precipitated as an oil from THF/methanol. This was decanted and the green residue dried under high vacuum to afford fl,4-di(butyloxy)-2-(4 '-butoxy-4'-oxobutyl)- 8,ll,15,18,22,25-hexakis(decyl)phthalocyaninatoJ zinc(II) (18mg, O.Olmmol, 0.8%>) [Η NMR (270 MHz, C6D6 ) δ 8.0 (m, 4H), 7.92 (s, 2H), 7.6 (s, IH), 4.6-5.4 (m, 18H), 4.15 (t, 2H), 3.42 (t, 2H), 1.0-2.6 (m, 110H), 0.81 (m, 27H) ppm. MALDI ms cluster at 1704. λmax (abs.) 711 nm; λmax(em.) 719 nm (THF)].
Preparation of [l,4-diphenyl-8,l l,15,18,22,25-hexakis(decyl)phthalocyaninato] zinc(II)
To a solution of 3,6-diphenylphthalonitrile (0.28g, lmmol) and 3,6- didecylphthalonitrile (0.408g, lmmol) in refluxing pentan-1-ol (8ml) was added DBU (106mg, 0.7eq.). The solution was refluxed for 1 hour, then zinc acetate dihydrate (99.999%), 70mg, 0.3eq.) was added. The solution turned green. Reflux was continued for a further 24 hours. After cooling, methanol (10ml) was added and the precipitate was filtered and washed with methanol (3x10ml). The product was purified by column chromatography on silica (eluent: petroleum ether (bp. 40-60°C)/dichloromethane 4:1 to remove [1,4,8,11,15, 18,22,25-octakis(decyl)phthalocyaninato] zinc(II) (O.lg, 6.3%)). The eluent was changed to petroleum ether (bp. 40-60°C)/dichloromethane 7:3 and the desired compound was isolated and recrystallised from THF/methanol, 60mg (0.04mmol, 4%>). [Η NMR (270 MHz, CDC13) δ 8.02-8.08 (m, 4H), 8.01 (s, 2H), 7.75 (d, 2H), 7.6-7.68 (m, 8H), 7.26 (br s, 2H), 4.32 (t, 4H), 4.08 (t, 4H), 3.11 (t, 4H), 2.07 (qn, 4H), 1.88 (qn, 4H), 1.0-1.6 (m, 88H), 0.7-0.9 (m, 18H) ppm. λmax (THF): Abs. 710 nm. MALDI-MS: isotopic cluster at 1571 [M+]]
Preparation of [l,4-bis(4-methoxyphenyl)-8,l l, 15,18,22,25- hexakis(decyl)phthalocyaninato] zinc(II)
To a solution of 3,6-bis(4-methoxyphenyl)phthalonitrile (342mg, lmmol) and 3,6- didecylphthalonitrile (0.816g, 2mmol) in refluxing pentan-1-ol (10ml) was added DBU
(0.32g, 0.7eq.). The solution was refluxed for 1 hour, then zinc acetate dihydrate 99.999%)
(0.2g, 0.3eq.) was added. The solution turned green. Reflux was continued for a further 24 hours. After cooling, methanol (10ml) was added and the precipitate was filtered and washed with methanol (3x10ml). The product was purified by column chromatography on silica (eluent: petroleum ether (bp. 40-60°C)/dichloromethane 4:1 to remove [1,4,8,1 l,15,18,22,25-octakis(decyl)phthalocyaninato] zinc(II) (0.21g, 12.3%))). The eluent was changed to petroleum ether (bp. 40-60°C)/dichloromethane 1 :1 and the desired compound was isolated and recrystallised from THF/methanol, 0.2 lg (0.13mmol, 13%>). [Η NMR (300 MHz, CDC13) δ 7.94 (m, 6H), 7.74 (d, 2H), 7.62 (d, 2H), 7.44 (s, 2H), 7.12 (d, 4H), 4.35 (t, 4H), 4.2 (t, 4H), 3.96 (s, 6H), 3.2 (t, 4H), 2.08 (qn, 4H), 1.95 (qn, 4H), 1.0- 1.6 (m, 88H), 0.81 (t, 12H), 0.74 (t, 6H) ppm. λmax (THF): Abs. 713.5 nm].
Preparation of [1,4,8,1 l-tetrakis(decyl)-15,18,22,25-tetrakis(phenyl)phthalocyaninato] zinc(II) and [1,4,15, 18-tetrakis(decyl)-8,l l,22,25-tetrakis(phenyl)phthalocyaninato] zinc(II):
To a refluxing solution of 3,6-diphenylphthalonitrile (0.30g, 1.07mmol) and 3,6- didecylphthalonitrile (1.31g, 3.2 lmmol, 3eq) in dry pentanol (15ml), was added DBU (0.46g, 3mmol, 0.7eq) under a nitrogen atmosphere. The solution was refluxed for 1 hour and zinc acetate dihydrate (0.28g, 1.29mmol, 0.3eq) added. Reflux was carried on for a 20 hours. The solution was cooled to room temperature, and the residue dissolved in THF. The solvents were removed under reduced pressure and the mixture washed with cold methanol. The products were purified by column chromatography on silica (eluent: petroleum ether (bp. 40-60°C)/dichloromethane 9:1 containing triethylamine (1%))). 1,4,8,11,15, 18,22,25-Octakis(decyl)phthalocyaninato zinc(II) was isolated first (90mg, 4.3%>). The eluent was changed to petroleum ether (bp. 40-60°C)/dichloromethane 3:1. 1,4,8,11, 15, 18-Hexakis(decyl)-22,25-diphenylphthalocyaninato zinc(II) was isolated. Finally, [1, 4,8,11 -tetrakis(decyl)-15, 18, 22, 25-tetrakis(phenyl)phthalocyaninato] zinc(II) and [l,4,15,18-tetrakis(decyl)-8,ll,22,25-tetrakis(phenyl)phthalocyaninato] zinc(II) were obtained as a mixture using petroleum ether (bp. 40-60°C)/dichloromethane (1 :3) as the eluent (40mg, 0.03mmol, 2.6%). [MALDI-MS: cluster at 1443. λmax (abs.) 723 nm (THF)].
Preparation of [l,4-bis(3-methoxyphenyl)-8,l l,15,18,22,25-hexakis(decyl)- phthalocyaninato] zinc(II):
To a solution of 3,6-bis(3-methoxyphenyl)phthalonitrile (0.13g, 0.38mmol) and 3,6-didecylphthalonitrile (0.94g, 2.29mmol, 6eq.) in refluxing pentan-1-ol (10ml) was added DBU (0.30g, 0.7eq.). The solution was refluxed for 1 hour, then zinc acetate dihydrate (99.999%), 0.18g, 0.3eq.) was added. The solution turned green. Reflux was continued for a further 24 hours. After cooling, methanol (10ml) was added and the precipitate was filtered and washed with methanol (3x10ml). The product was purified by column chromatography over silica (eluent: petroleum ether (bp. 40-60°C): dichloromethane 4:1) to remove [1,4,8,11, 15, 18,22,25-octakis(decyl)phthalocyaninato] zinc(II). The eluent was changed to petroleum ether (bp. 40-60°C): dichloromethane 1 :1) and [1, 4-bis(3-methoxyphenyl)-8, 11,15,18,22, 25-hexakis(decyl)phthalocyaninato] zinc(II) was isolated as a green solid and recrystallised from THF/acetone [MALDI ms shows cluster at 1632. λmax (abs.) 710 nm (THF); λmax (em.) 722.4 nm (THF)].
Preparation of [l,4-bis[6'-(imidazol-l-yl)hexyl]-8,l l,15,18,22,25-hexakis(decyl phthalocyaninato] zinc(II):
3,6-Bis(6'-(imidazol-l-yl)hexyl)phthalonitrile (550mg, 1.3mmol) and 3,6- didecylphthalonitrile (3.14g, 7.7 lmmol, 9eq.) were refluxed in pentan-1-ol (25ml) in the presence of zinc acetate dihydrate (99.999%), 500mg, 2.3mmol). DBU (lOeq.) was added and reflux continued for 24 hours. The solvent was removed under reduced pressure. Methanol (50ml) was added to the residue and the solution decanted. The dark green oil at the bottom of the flask was chromatographed on silica (eluent: petroleum ether (bp. 40- 60°C)/THF 2:1) to afford 1,4,8,1 l,15,18,22,25-octakis(decyl)phthalocyaninato zinc(II) (2.08g, 64%). The eluent was changed to petroleum ether (bp. 40-60°C)/THF (1 :1) and a green fraction eluted. The column was then eluted with THF and a second green fraction collected. The last two fractions appeared identical by TLC and NMR and were combined. The solvent was evaporated. The green residue was dissolved in hot THF/MeOH. [1,4- bis[6 '-(imidazol-1 -yl)hexyl]-8, 11 , 15, 18,22,25-hexakis(decyl)-phthalocyaninato] zinc(II) separated as a green oil upon cooling and was recovered (270mg, O.lόmmol, 12%) and dried under high vacuum. [Η NMR (270MHz, C6D6 with pyridine-d5 added) δ 7.95 (s, 2H), 7.91 (s, 4H), 7.82 (s, 2H), 5.65-5.81 (m, 6H), 4.7-4.92 (m, 16H), 2.65 (t, 4H), 2.37 (m, 12H), 2.18 (m, 4H), 1.78 (m, 12H), 1.4 (m, 12H), 1.1-1.34 (m, 72H), 0.79 (m, 18H) ppm. λmax (abs.) 705.0 nm (THF). MALDI-MS: cluster at 1719].
Further phthalocyanines with the same substituents on each ring: Preparation of [2,3,9,10,16,17,23,24-octabromo-l,4,8,l 1,15,18,22,25-octabutoxy- phthalocyaninato] nickel(II):
4,5-Dibromo-3,6-dibutoxyphthalonitrile (0.5g, l.lόmmol) was heated in dry butanol (6ml) under nitrogen. DBU (0.18g, 1.2mmol) was added and reflux continued for 1 hour. Nickel acetate tetrahydrate (0.09g, 0.3mmol) was added and reflux continued for 24 hours. The reaction was cooled and the solvent evaporated under reduced pressure. The residue was purified by column chromatography over silicia (eluent: DCM/Et3N 99:1) to afford [2, 3, 9,10,16,17, 23, 24-octabromo-l, 4,8,11,15,18, 22, 25-octabutoxy- phthalocyaninato] nickel(II) which was recrystallised from THF/methanol (0.2 lg, 40.6%) [mp >250°C. Found: C, 43.45; H, 4.00; N, 6.23. C64H72N8O8Br8Ni requires C, 43.20; H, 4.08; N, 6.30. Η NMR (270 MHz, CDC13, 3.4 mg in 0.7 ml) δ 4.78 (t, 16H, J = 6.9 Hz), 2.22 (quint, 16H, J = 7.3Hz), 1.70-1.56 (m, 16H), 1.04 (t, 24H, J = 7.3 Hz) ppm].
Preparation of [1,4,8,11, 15,18,22,25-octabutoxy-2,3,9,10,16,17,23,24- octa(tris(isopropyl)silylethynyl)phthalocyaninato] nickel(II):
According to the method above, 4,5-(tris(isopropyl)silylethynyl)-3,6- dibutoxyphthalonitrile (0.51g, 0.81mmol) was reacted with DBU (0.7g, 0.48mmol) and nickel acetate tetrahydrate (0.07g, 0.24mmol) in dry butanol (6ml) for 20 hours. Purification by column chromatography (DCM/petrol 1 :2) afforded [1,4,8,11,15,18,22,25- octabutoxy-2,3 ,9,10,16,17,23 ,24-octa(tris(isopropyl)silylethynyl)phthalocyaninato] nickel(II) (0.25 g, 48%) [Found: C, 70.37; H, 9.26; N, 4.28. C,52H24oN8O8Si8Ni requires C, 70.46; H, 9.34; N, 4.32. MS (MALDI) isotopic cluster at 2591 (M+). 1H NMR (270 MHz, CDC13, 3.0mg in 0.7ml) δ 4.80 (t, 16H, J = 7.7 Hz), 2.13 (quint, 16H, J = 7.6Hz), 1.36- 1.25 (br s, 168H), 0.83 (t, 24H, J = 7.4 Hz) ppm].
Preparation of [1,4,8,1 l,15,18,22,25-octakis(butoxy)-2,3,9,10,16,17,23,24- octakis(ethynyl)phthalocyaninato] nickel(II) :
The above sample (130mg, 0.05mmol) was stirred in dry THF (5ml) under argon at -78°C TBAF (1.1M in THF, 1ml, excess) was added dropwise. The reaction mixture was allowed to warm up to room temperature and stirred for 12 hours. This was then poured into 5%> HCl (20ml). The solution was extracted with diethyl ether (2x20ml). The combined organics were washed with a saturated solution of NaHCO , water, brine, dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue was chromatographed on silica (eluent: petroleum ether (bp. 40-60°C)/DCM 2:1 to 1 :1). [1,4,8, 11,15,18, 22, 25-octakis(butoxy)-2, 3, 9,10,16,17, 23, 24-octakis(ethynyl)- phthalocyaninato] nickel(Il) was obtained as a green solid (42mg, 0.03mmol, 60%). [1H NMR (270MHz, C6D6) δ 5.11 (t, 16H), 3.5 (s, 8H), 2.35 (p, 16H), 1.75 (m, 16H), 1.1 (t, 24H) ppm. 13C (270MHz, C6D6) δ 155.24, 145.41, 129.62, 123.42, 88.04, 79.73, 77.31, 33.09, 19.89, 14.39 ppm. λmax (abs.) 762.0 nm (THF)].
Preparation of [1,4,8,1 l,15,18,22,25-octa(butoxy)-2,9/10,16/17,23/24-tetrabromo- phthalocyaninato] zinc(II): 4-Bromo-3,6-dibutoxyphthalonitrile (0.5g, 1.42 mmol), 1 ,8-diazabicyclo [5,4,0] undec-7-ene (DBU) (0.5g, 3.28mmol) and zinc acetate (71mg, 0.39mmol) in dry butanol (20ml) were heated under reflux under an atmosphere of nitrogen in the dark for 2 days. The solution was cooled and the solvent evaporated under reduced pressure. The crude product was washed with methanol (3x50ml). The remaining green solid was chromatographed over silica (preparative plate TLC). The four possible structural isomers were not fully separated, and were contained within two green fractions. Separation of these fractions was achieved. On the basis of 1H NMR spectroscopy the first (30mg) was assigned to a mixture containing predominantly (>70%) 1,4, 8,11,15, 18,22, 25-octa(butoxy)- 2,9,16,23,-tetrabromophthalocyaninato zinc(II). [1H NMR (300MHz, C6D6) δ 7.95 (s,2H), 7.85 (s, 2H), 5.43-5.20 (m, 8H), 4.64 (br s, 4H), 4.45 (br s, 4H), 2.46 (m, 4H), 2.30 (m, 8H), 2.03 (m, 4H), 1.8-1.5 (m, 16H), 1.3-1.2 (m, 12H), 1.2-0.8 (m, 12H). λmax (abs.) 733 nm (THF)].
Biological Experimental Details
Use of cell inactivation studies
In order to demonstrate that the compounds being studied also possess the ability to act as efficient photosensitizer of biological systems, cells were incubated with the compound of interest, formulated in a liposome suspension, and then exposed to light of a suitable wavelength and energy. The number of viable cells surviving this treatment was registered. The cell line chosen is the HT 1080 fibrosarcoma cell line [ATCC number: CCL-
1212. (Reference: S. Rasheed, W.A. Nelson-Rees, E.M. Toth, P. Arnstein, M.B. Gardner,
"Characterisation of a newly derived human sarcoma cell line (HT-1080)", Cancer, vol.
33, pages 1027-1033, 1974)]. This cell line represents hypeφroliferating cells and is thus a useful model for the rapid cell cycle occurring in psoriasis.
Preparation of liposomes
Reference: G. Valduga, G. Bianco, G. Csik, E. Reddi, L. Masiero, S. Garbisa, G. Jori "Interaction of hydro- or lipophilic phthalocyanines with cells of different metastatic potential" Biochem. Pharmacol, vol. 51, pages 585-590, 1996.
Formulation of compounds in unilamellar liposomes of L-α-dioleoyl- phosphatidylcholine (DOPC). The procedure developed can be schematised as follows: 1. A stock solution of DOPC in chloroform is prepared at a concentration of 20 mg/ml.
2. 4ml from such solution are introduced into a 250ml glass flask connected to a Rotavapor, and mixed with a suitable volume of the compound in solution in tetrahydrofuran (THF) to reach a final molar ratio 1:200 between the phthalocyanine and the phospholipid. The flask is wrapped with aluminium foil.
3. The flask is saturated with nitrogen and kept at room temperature for 5 minutes.
4. The Rotavapor is then connected to a water pump in order to generate reduced pressure and the solvent is evaporated at room temperature.
5. The flask is saturated with nitrogen and 4ml of nitrogen-saturated phosphate buffered saline (PBS) are added. The lipid film containing the phthalocyanine is resuspended by gently shaking in the presence of glass beads.
6. The aqueous suspension is sonicated (10 Hz) for about 30 minutes. The vial is saturated with nitrogen and kept in an ice bath. At the end the liposomes are kept at room temperature overnight. The liposomes have a shelf-life at 4°C of at least three months. Before use, they are filtered through a 0.2 μm filter and the phthalocyanine concentration is measured by diluting a small aliquot of the suspension into a known excess of THF and determining the absorbance of such solution. Cell studies
The cells were routinely cultured with DMEM (Eagle's modified Dulbecco medium added with 100 units/ml penicillin, 100 μg/ml streptomicin, 0.25 μm/ml anfotericin, 2mM glutamine) containing 10%> FCS (foetal calf serum) and maintained in a humid atmosphere containing 5%. CO2 at a temperature of 37°C Normally, the cells were detached by using a solution of 0.05%> trypsin - 0.02% EDTA in phosphate-buffered saline. The action of trypsin was blocked by addition of FCS. The cell pellet, obtained by centrifugation at 1,000 φm for 8 minutes was resuspended with DMEM and 10%> FCS and then seeded in 75 cm2 tissue cultured flasks.
Cell uptake of phthalocyanine
In a typical experiment, 6x10 cells were suspended in DMEM (Eagle's modified
Dulbecco medium) containing 10%. FCS (foetal calf serum) and incubated in 25 cm tissue culture flasks. After 24 hours the culture medium was removed and replaced by 5ml DMEM (enriched with 3%> FCS) containing either 5 μM or 10 μMof the phthalocyanine. The phthalocyanine was added in an aqueous suspension of DOPC liposomes. After 1 hour incubation, the medium was removed, the cells were washed twice with 4ml of
2+ 2+
PBS devoid of Ca and Mg ions.
The cell pellet was homogenised with 2% aqueous sodium dodecylsulphate (SDS) (2ml). The suspension thus obtained was divided into two portions: a) 1ml was diluted with a known volume of THF for the determination of the phthalocyanine concentration by spectrophotofluorimetric analysis (excitation at 650 nm, emission collected in the 660-780 nm interval)using a Perkin-Elmer LS50B spectrophotofluorimeter. b) 0.5ml was used for the determination of the protein content by the standard assay with bicinchoninic acid.
Reference: P.K. Smith, "Measurement of protein using bicinchoninic acid, Anal Biochem., vol. 150, pages 76-85, 1985. The amount of phthalocyanine recovered was calculated by inteφolation with a calibration plot and the uptake was expressed as nmoles of phthalocyanine/mg of cell protein.
Cell irradiation studies
For irradiation studies, 1.8x10 cells were seeded in Petri dishes of 7cm diameter, incubated for 24 hours in DMEM containing 10%. FCS in a humid atmosphere containing 5%. CO2 and at a temperature of 37°C The medium was removed and replaced by 1ml DMEM containing 2.5 μM to 10 μM phthalocyanine which was added in DOPC liposomes. After 1 hour incubation, the cells were washed twice with PBS containing Ca2+ (0.9 mM CaCl2 • 2 H2O) ions and Mg2+ (0.5 mM MgCl2 • 2 H2O) ions.
Light source
The light source - Waldmann PDT 1200 (Waldmann Medical Division, Villingen- Schwenningen, Germany) - is a non-coherent light source with a filter allowing light between 600 and 730 nm to pass. A built-in output meter is used to monitor the doses given. The lamp was operated at a fluence rate of 100 mW/cm .
2
The cells in the Petri dish were irradiated (100 mW/cm ) for 1, 5, 10, 15 minutes (6 up to 90 J/cm2) with 1ml PBS containing Ca2+ and Mg2+ ions.
The irradiated cells were mixed with 2ml DMEM containing 10%. FCS and incubated overnight. The photosensitised cells were assayed by the trypan blue test (Reference: C. Milanesi, F. Sorgato, G. Jori, "Photokinetic and ultrastructural studies on poφhyrin photosensitization of HeLa cells", Int. J. Radiat. Biol, vol. 55, pages 59-69, 1989) and the survival was expressed as the percentage of the survival typical of cells which had been treated by an identical procedure but were not exposed to light. Preliminary studies showed that irradiation of the cells in the absence of the photosensitizer and dark incubation of the cells with phthalocyanines has no effect on cell survival. Photosensitised inactivation of human fibroblasts by phthalocyanines
Table 3 summarises the results obtained in the above described experiments. Substituents e, f, g and h are defined as shown in formula (VIII) below.
Figure imgf000106_0001
Figure imgf000106_0002
Table 3. Photophvsical Experimental Details
UV-Vis Spectral Measurement
UV-Vis spectra were recorded using a Hitachi U-3000 Spectrophotometer. The phthalocyanines samples were dissolved in THF, unless otherwise stated, and held in a lcm x 1cm quartz cuvette. The data were recorded at ambient temperature, 20-23°C
Fluorescence Spectral Measurements
Fluorescence spectra were recorded using a Hitachi U-4500 Fluorescence Spectrophotometer. The phthalocyanines samples were dissolved in THF and held in a lcm x lcm quartz cuvette. The data were recorded at ambient temperature, 20-23 °C
Singlet Oxygen Quantum Yields, ΦΔ
The singlet oxygen quantum yields were determined by the direct measurement of singlet oxygen phosphorescence at 1270nm using the method described by Nonell (S. Nonell and S. Braslavzky, "Time Resolved Singlet Oxygen Detection", in Singlet Oxygen, UV-A and Ozone, Methods in Enzymology, vol. 319, Academic Press, 2000). Samples were excited using the third harmonic of a Q-switched NdNAG laser, λex = 355nm, (Spectra Physics GCR-150-10). A small fraction of the laser output was passed through a solution state filter containing aqueous CoSO4 to remove residual 532 and 1064nm radiation and then into the sample holder. The samples were held in a lcm x lcm fluorescence cuvette (Hellma). During the course of the experiments the incident laser energy for each measurement was determined using a pyroelectric detector held behind the sample. The laser energy was adjusted by placing cells containing aqueous sodium nitrite between the CoSO4 filter and the light guide. Typical pulse energies used here were in the range 25-500μJ per pulse, as measured using a second, calibrated pyroelectric detector, (Gentec ED-100). Shot to shot noise was estimated to be <10% and sets of 20 shots gave an average value within <3%>.
Phosphorescence from the sample was collected and passed through an interference filter centred at 1270nm (Infra Red Engineering Ltd) and then focussed onto the active area of a liquid nitrogen cooled germanium photodiode (North Coast EO-817P). The signal form the detector was AC coupled to a digital oscilloscope (Tektronix TDS-320) which digitised and averaged the transients. Typically 32 laser shots were used for each sample. The averaged data was transferred to a PC where it was stored and analysed.
Stock solutions of the materials were prepared by taking a small sample of the materials supplied and dissolving them in toluene (Fischer Scientific, Analytical grade) containing l%(v/v) pyridine. The pyridine was added to ensure that the samples did not aggregate. Exact concentrations of these solutions were not determined. Working solutions were prepared by dilution of the stock with toluene to give absorbances of 0.01- 0.100 at 355nm when placed in a UV-Vis spectrometer (ATI-Unicam UV-2) compared to a reference cell containing the pure solvent. UV-Vis spectra were recorded in long pathlength cells (2cm) to ensure a more accurate measure of absorbance. Care was taken to avoid high absorbances in the region of the Q-bands (600-750nm) where re-absoφtion of the fluorescence from the sample can lead to error.
The data were recorded at ambient temperature, 20-23 °C, and the solutions were aerated. The singlet oxygen emission decay was recorded for each sample using 5 laser energies and the data for each measurement were fitted to an exponential decay of the form I(t) = A.exp(-t/τ) using a fitting function which optimised both A and τ. A typical decay is shown below. A plot of A v's incident laser energy was drawn for each solution and the slope determined. The slope is proportional to the singlet oxygen quantum yield and the amount of light absorbed by the sample. The slope of the graph for each sample was taken and plotted against (1-10"A), where A is the absorbance of the samples at the excitation wavelength. The slope of this graph is then proportional to the singlet oxygen quantum yield.
Experimental errors
The dominant sources of error in the experiment include the shot-to-shot fluctuations in the laser and errors in the measured sample absorbances. For these reasons we are reporting values to have an error of ± 10%>. Standards/ Reference Materials
The values reported here (see Figures 1 to 3) have been recorded relative to perinaphthenone, which has been reported to have a quantum yield of 0.97 (S. Nonell and S. Braslavzky, "Time Resolved Singlet Oxygen Detection", in Singlet Oxygen, UV-A and Ozone, Methods in Enzymology, vol. 319, Academic Press, 2000; F. Wilkinson, W.P. Helman and A.B. Ross, "Quantum yields for the photosensitised production of the lowest excited singlet state of molecular oxygen in solution", J. Phys. Chem. Ref Data., vol. 22, pages 113-262, 1993). Wilkinson et al.'s review of singlet oxygen quantum yields contains a number of values for this material, ranging from 0.95-0.97. For this reason there may be a small error in the absolute value, but the trends in the reported yields are significant.
Singlet Oxygen Quantum Yields: Results
Values are reported relative to the standard perinaphthenone, ΦΛ = 0.97 (S. Nonell and S. Braslavzky, "Time Resolved Singlet Oxygen Detection", in Singlet Oxygen, UV-A and Ozone, Methods in Enzymology, vol. 319, Academic Press, 2000). As discussed above the recorded values have an error of ± 10%>.
Fluorescence Lifetimes
Fluorescence lifetimes were determined using the method of time-correlated single photon counting (Principles of Fluorescence Spectroscopy 2nd Ed, J. Lakowicz, Kluwer Academic/ Plenum Press). Samples were excited using the output from a 635nm pulsed diode laser (IBH NanoLed). This produced a 1MHz train of pulses with a FWHM of 200ps. Fluorescence was collected at 90° to the excitation source and the emission wavelength selected by a monochromator (Jobin-Yvon Triax 190) and detected using a cooled red-sensitive photomultiplier/discriminator (IBH TXB-04). The output from the detector was used as the start signal for a time to amplitude converter (Ortec 567) and the stop signal was derived from the laser power supply/driver. The TAC output was processed by a pulse height analyser (Ortec Trump 8K). Typically decays were obtained using a record length of 1024 channels with a time-window of 55ps/channel. Instrument response functions were obtained using a scattering suspension and were typically 45 Ops FWHM. Decays were analysed by the method of iterative reconvolution of the response function with a sum-of-exponentials and the fit optimised by the method of non-linear least-squares analysis. The quality of fit was judged by the reduced chi-squared, randomness of residuals and auto-correlation function (Principles of Fluorescence Spectroscopy 2nd Ed, J. Lakowicz, Kluwer Academic/ Plenum Press).
Fluorescence Quantum Yields
Florescence quantum yields were determined using the relative method. Spectra were recorded using a Jobin-Yvon Fluoromax-2 spectrofluorimeter and were corrected for background and the spectral response of the instrument. Samples were compared to the following standard materials: quinine sulfate in IM sulfuric acid, Φf = 0.55 and
Rhodamine 101 in acidified ethanol Φf = 1.00.
Photophysical data for examples of octa-, nona- and deca-substituted phthalocyanines
Table 4 summarises the results obtained in the above described experiments. Substituents e, f, g and h are defined as shown in formula (VIII) below.
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Table 4. (a = value not measured)

Claims

Claims:
1. A process for the preparation of a substituted phthalocyanine of formula (I)
Figure imgf000113_0001
wherein m are the same or different and each m is 0, 1, 2, 3 or 4, provided that not all four m are 0 simultaneously;
R1 are the same or different and each R1 is Cι-C20 alkyl optionally substituted;
C2-C20 alkenyl optionally substituted; C2-C20 alkynyl optionally substituted;
-R4-O-R5; -R4-S-R5; -R4-SO3H; -R4-SO2R5; -R4-SO2N(R5)2; -R4-N-(R5)2;
-R4-P-(R5)2; -R4-P(O)(OR5)2; -R4-aryl optionally substituted; -R4-heteroaryl optionally substituted; -R4-COR5; -R4-COOR5 or -R4-CON(R5)2; where
-R4- are the same or different and each -R4- is a chemical bond, -(CH2)q- with q being an integer from 1 to 20, or -(CH2)aCH=CH(CH2)b- with a and b being integers from 0 to 20 and the sum of a and b being from 0 to 20; and -R5 are the same or different and each -R5 is Cι-C20 alkyl, C2-C20 alkenyl, aryl optionally substituted, heteroaryl optionally substituted or H, or two -R5 together form a saturated or unsaturated ring;
R are the same or different and each R is
Figure imgf000113_0002
p are the same or different and each p is 0, 1, 2 or 3;
R are the same or different and each R is -F, -Cl, -Br or -I; and
M is a metal atom in the M(II) oxidation state, a metal chloride, a metal bromide, a metal oxide, silicon with two axial substituents or two hydrogen atoms, one hydrogen being bonded to each of the two bonding nitrogen atoms;
comprising the steps of
(a) converting a phthalonitrile alcohol of formula (II)
Figure imgf000114_0001
into a sulfonate ester of formula (III)
Figure imgf000114_0002
wherein R6 is either C1-C12 alkyl, optionally substituted with one or more of -F and/or -Cl, or aryl, optionally substituted with one or more of -CH3, -NO2, -OCH3, -F, -Cl and/or -Br; and when m is 2, 3 or 4, R6 are the same or different;
(b) converting the sulfonate ester of formula (III) into the substituted phthalonitrile of formula (IV)
Figure imgf000114_0003
(c) cyclising the substituted phthalonitrile of formula (IV) either by itself or together with any other phthalonitrile of formula (IV).
2. The process of claim 1, wherein the substituted phthalocyanine is a non-mixed or a mixed phthalocyanine.
3. The process of claim 1 or claim 2, wherein M is an isotope of Cu, Ni, Pb, V, Pd, Pt, Co, Nb, Al, Sn, Zn, Mg, Ca, In, Ga, Fe, Ge, a lanthanide, Si with two axial substituents or 2H.
4. The process of claim 3, wherein M is an isotope of a diamagnetic metal, Si with two axial substituents or 2H.
5. The process of claim 4, wherein M is an isotope of Zn, Al, Mg, Pd, Pt, Si with two axial substituents or 2H.
6. The process of any one of claims 1 to 5, wherein if the phthalocyanine is a non-mixed phthalocyanine or if the phthalocyanine is substituted with -S-R5, the sum of m and p is not 4 or 8.
7. The process of any one of claims 1 to 6, wherein the compound of formula (I) forms a sandwich complex or multimer.
8. A process for the preparation of a substituted phthalonitrile of formula (IV)
Figure imgf000115_0001
1 7 ^ wherein R , R , R and p are defined as in claim 1, and m is 1, 2, 3 or 4,
comprising the steps of
(a) converting a phthalonitrile alcohol of formula (II)
Figure imgf000116_0001
into a sulfonate ester of formula (III)
Figure imgf000116_0002
wherein R6 is defined as in claim 1 , and
(b) converting the sulfonate ester of formula (III) into the substituted phthalonitrile of formula (IV).
9. The process of any one of claims 1 to 8, wherein the conversion of the sulfonate ester of formula (III) into the substituted phthalonitrile of formula (IV) comprises a cross- coupling of the sulfonate ester of formula (III) with an organozinc reagent R'ZnX or an organocopper reagent R!CuX catalysed by palladium, wherein R1 is defined as in claim 1 and X is a halogen.
10. The process of any one of claims 1 to 8, wherein the conversion of the sulfonate ester of formula (III) into the substituted phthalonitrile of formula (IV) comprises a cross- coupling of the sulfonate ester of formula (III) with an organozinc reagent R]ZnX or an organocopper reagent R'CuX catalysed by nickel, wherein R1 is defined as in claim 1 and X is a halogen.
11. The process of claim 9 or claim 10, wherein the halogen is Cl, Br or I.
12. The process of any one of claims 1 to 8, wherein the conversion of the sulfonate ester of formula (III) into the substituted phthalonitrile of formula (IV) comprises a cross- coupling of the sulfonate ester of formula (III) with a trialkylborane B(R!)3 catalysed by palladium, wherein R1 are the same or different and each R1 is Cι-C20 alkyl optionally substituted; -R4-O-R5; -R4-S-R5; -R4-N_(R5)2; _RAP_(R 5)2; _RXaτyι optionally substituted; -R -heteroaryl optionally substituted; -R4-COR5; -R4-COOR5 or -R4-CONR5 2; where -R4- are the same or different and each -R4- is -(CH2)q- with q being an integer from 1 to 20, or -(CH2)aCH=CH(CH2)b- with a and b being integers from 0 to 20 and the sum of a and b being from 0 to 20; and -R5 are the same or different and each -R5 is Cι-C20 alkyl, C2-C20 alkenyl, aryl, heteroaryl or H, or two -R5 together form a saturated or unsaturated ring.
13. The process of claim 12, wherein B(R!)3 is R*B(C8Hi4).
14. The process of any one of claims 1 to 8, wherein the conversion of the sulfonate ester of formula (III) into the substituted phthalonitrile of formula (IV) comprises a cross- coupling of the sulfonate ester of formula (III) with a boronic acid R1B(OH)2 or a
1 7 boronic ester R B(OR )2 catalysed by palladium or nickel, wherein
R1 is C2-C20 alkenyl, -aryl optionally substituted or -heteroaryl optionally substituted; and R7 are the same or different and each R7 is C-Cio alkyl optionally substituted and both R7 together with -O-B-O- may form a ring.
15. The process of claim 14, wherein R1B(OR7) is R1B(-OCH2CH2CH2O-), R B -OCHzCHzO-) or R'B(-0C(CH3)2C(CH3)20-).
16. The process of any one of claims 1 to 8, wherein the conversion of the sulfonate ester of formula (III) into the substituted phthalonitrile of formula (IV) comprises an SNAT reaction of the sulfonate ester of formula (III) with a nucleophile HO-R5, HS-R5 or
HN(R5)2, HP(R5)2 or I , wherein -R5 are the same or different and each R5 is C1-C20 alkyl, C2-C20 alkenyl, aryl, heteroaryl or H, or two -R5 together form a saturated or unsaturated ring.
17. The process of any one of claims 1 to 8, wherein the conversion of the sulfonate ester of formula (III) into the substituted phthalonitrile of formula (IV) comprises a coupling of the sulfonate ester of formula (III) with a coupling partner R1H catalysed by palladium, wherein R1 is C2-C20 terminally alkenyl optionally substituted or C2-C20 terminally alkynyl optionally substituted.
18. The process of any one of claims 1 to 17, wherein R1 are the same or different and each R1 is Ci-C20 alkyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -R4-O-R5, -R4-S-R5, -NH2, -NHR5, -N(R5)2, -N(R5)3 + and or -R4-N-(R5)2; C2-C20 alkenyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -R4-O-R5,
-R4-S-R5, -NH2, -NHR5, -N(R5)2, -N(R5)3 + and/or -R4-N-(R5)2; C2-C20 alkynyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -R4-O-R5, -R4-S-R5, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -R4-N-(R5)2, -Si(R5)3, -C5H4N, -C4H3S or -C6H5; -R4-O-R5; -R4-S-R5; -R4-SO3H; -R4-SO2R5; -R4-SO2N(R5)2; -R4-N-(R5)2; -R4-P-(R5)2; -R4-P(O)(OR5)2; -R4-aryl, optionally substituted with one or more of CrC10 alkyl, C2-Cι0 alkenyl, -NO2, -OCH3, -CH2OH, -F, -Cl, -Br, -OH, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -NHCOR5, -COR5, -COOR5 and/or -CON(R5)2; -R4-heteroaryl, optionally substituted with one or more of Cj-Cio alkyl, C2-C10 alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -NHCOR5, -COR5, -COOR5 and/or -CON(R5)2; -R4-COR5; -R4-COOR5 or
-R4-CON(R5)2; where R4 and R5 are defined as in claim 1.
19. The process of claim 18, wherein R1 are the same or different and each R1 is Cι-C20 alkyl, optionally substituted with one or more of-F, -Cl, -Br, -I, -OH, -NH2, -NHR5, -N(R5)2 and/or -N(R5)3 +; C2-C20 alkenyl; C2-C20 alkynyl; -S-R5; -N-(R5)2; -R4-aryl, optionally substituted with one or more of C]-C10 alkyl, C2-Cι0 alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -NHCOR5, -COR5, -COOR5 and/or -CON(R5)2; where R4 and R5 are defined as in claim 1.
20. The process of any one of claims 1 to 19, wherein at least one R1 is not C]-C20 alkyl non-substituted.
21. The process of any one of claims 1 to 20, wherein at least one R1 is a non-peripheral substituent.
22. The process of any one of claims 1 to 21, wherein the substituted phthalocyanine of formula (I) and/or the substituted phthalonitrile of formula (IV) is substituted with or conjugated to an amino acid, a fatty acid, a nucleic acid, a di-, tri- or up to decapeptide, a polypeptide, a protein, a saccharide, a polysaccharide or a polymer.
23. The process of claim 22, wherein the substituted phthalocyanine of formula (I) and/or the substituted phthalonitrile of formula (IV) is substituted with or conjugated to an amino acid, a fatty acid, a nucleic acid, a di-, tri- or up to decapeptide, a polypeptide, a protein, a saccharide, a polysaccharide or a polymer via R1.
24. A process for the preparation of a phthalonitrile sulfonate ester of formula (III)
Figure imgf000119_0001
wherein R , R , R and p are defined as in claim 1 , and m is 1 , 2, 3 or 4,
comprising the step of
(a) converting a phthalonitrile alcohol of formula (II)
Figure imgf000119_0002
into a sulfonate ester of formula (III).
25. The process of any one of claims 1 to 24, wherein R2 is
26. The process of any one of claims 1 to 25, wherein R6 are the same or different and each R6 is -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -C8H17, -CHC12, -CF3, -C4F9, -C6H5, -(C6H4)-4-CH3, -(C6H4)-2-NO2, -(C6H4)-3-NO2, -(C6H4)-4-NO2, -(C6H4)-2-Br, -(C6H4)-4-Br, _(C6H4)-4-Cl, -(C6H4)-4-F, -(C6H3)-2,5-Cl2, -(C6H3)-3,4-Cl2, -(C6H3)-3,4-(OCH3)2 or -(C6H3)-2,4-(NO2) .
27. The process of claim 26, wherein R are the same or different and each R6 is -CH3, -CF3 or -C4F9.
28. The process of any one of claims 1 to 27, wherein p = 0.
29. A process for the preparation of a substituted phthalocyanine of formula (V)
Figure imgf000120_0001
wherein m are the same or different and each m is 0, 1, 2, 3 or 4;
R1 are the same or different and each R1 is C1-C20 alkyl optionally substituted;
C2-C20 alkenyl optionally substituted; C2-C20 alkynyl optionally substituted;
-R4-O-R5; -R4-S-R5; -R4-SO3H; -R4-SO2R5; -R4-SO2N(R5)2; -R4-N-(R5)2;
-R4-P-(R5)2; -R4-P(O)(OR5)2; -R4-aryl optionally substituted; -R4-heteroaryl optionally substituted; -R4-COR5; -R4-COOR5 or -R4-CON(R5)2; where
-R4- are the same or different and each -R4- is a chemical bond, -(CH2)q- with q being an integer from 1 to 20, or -(CH2)aCH=CH(CH2)b- with a and b being integers from 0 to 20 and the sum of a and b being from 0 to 20; and -R5 are the same or different and each -R5 is Cι-C20 alkyl, C2-C20 alkenyl, aryl optionally substituted, heteroaryl optionally substituted or H, or two -R5 together form a saturated or unsaturated ring;
R are the same or different and each R is
Figure imgf000121_0001
p are the same or different and each p is 0, 1, 2 or 3;
R3 are the same or different and each R3 is -F, -Cl, -Br or -I;
R8 are the same or different and each R8 is C1-C20 alkyl optionally substituted;
q is 1 or 2;
R9 are the same or different and each R9 is -Cl, -Br, -I, -alkyl optionally substituted, -alkenyl optionally substituted, -alkynyl optionally substituted, -aryl optionally substituted or -heteroaryl optionally substituted; and
M is a metal atom in the M(II) oxidation state, a metal chloride, a metal bromide, a metal oxide, silicon with two axial substituents or two hydrogen atoms, one hydrogen being bonded to each of the two bonding nitrogen atoms;
comprising either the steps of (a) converting a phthalonitrile halide of formula (VI)
Figure imgf000121_0002
wherein R10 are the same or different and each R10 is -Cl, -Br or -I, into a substituted phthalonitrile of formula (VII)
Figure imgf000122_0001
wherein R ' are the same or different and each R1 ' is -alkyl optionally substituted, -alkenyl optionally substituted, -alkynyl optionally substituted, -aryl optionally substituted or -heteroaryl optionally substituted; and
(b) cyclising the substituted phthalonitrile of formula (VII) either by itself or together with any other phthalonitrile of formula (IV)
Figure imgf000122_0002
to yield a substituted phthalocyanine of formula (V);
or alternatively comprising the steps of
(a) cyclising the phthalonitrile halide of formula (VI) either by itself or together with any other phthalonitrile of formula (IV) to yield a substituted phthalocyanine of formula (V); and
(b) optionally converting the R9 being -Cl, -Br or -I into an R9 being -alkyl optionally substituted, -alkenyl optionally substituted, -alkynyl optionally substituted, -aryl optionally substituted, or -heteroaryl optionally substituted.
30. The process of claim 29, wherein the substituted phthalocyanine is a non-mixed or a mixed phthalocyanine.
31. The process of claim 29 or claim 30, wherein M is an isotope of Cu, Ni, Pb, V, Pd, Pt, Co, Nb, Al, Sn, Zn, Mg, Ca, In, Ga, Fe, Ge, a lanthanide, Si with two axial substituents or 2H.
32. The process of claim 31, wherein M is an isotope of a diamagnetic metal, Si with two axial substituents or 2H.
33. The process of claim 32, wherein M is an isotope of Zn, Al, Mg, Pd, Pt, Si with two axial substituents or 2H.
34. The process of any one of claims 29 to 33, wherein R1 are the same or different and each R1 is Cι-C20 alkyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -R4-O-R5, -R4-S-R5, -NH2, -NHR5, -N(R5)2, -N(R5)3 + and or -R4-N-(R5)2; C2-C20 alkenyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -R4-O-R5, -R4-S-R5, -NH2, -NHR5, -N(R5)2, -N(R5)3 + and/or -R4-N-(R5)2; C2-C20 alkynyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -R4-O-R5, -R4-S-R5, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -R4-NAR5)2, -Si(R5)3, -CsHjN, -C4H3S and or -C6H5; -R4-O-R5; -R4-S-R5; -R4-SO3H; -R4-SO2R5; -R4-SO2N(R5)2; -R4-N-(R5)2; -R4-P-(R5)2; -R4-P(O)(OR5)2; -R4-aryl, optionally substituted with one or more of Cι-C10 alkyl, C2-C10 alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -NH2,
-NHR5, -N(R5)2, -N(R5)3 +, -NHCOR5, -COR5, -COOR5 and/or -CON(R5)2; -R4-heteroaryl, optionally substituted with one or more of C1-C10 alkyl, C2-Cι0 alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -NHCOR5, -COR5, -COOR5 and/or -CON(R5)2; -R4-COR5; -R4-COOR5 or -R4-CON(R5)2; where R4 and R5 are defined as in claim 1.
35. The process of claim 34, wherein R1 are the same or different and each R1 is C1-C20 alkyl, optionally substituted with one or more of-F, -Cl, -Br, -I, -OH, -NH2, -NHR5, -N(R5)2 and/or -N(R5)3 +; C2-C2o alkenyl; C2-C20 alkynyl; -S-R5; -N-(R5)2; -R4-aryl, optionally substituted with one or more of Cι-Cι0 alkyl, C2-C10 alkenyl, -NO2, -OCH3,
-F, -Cl, -Br, -OH, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -NHCOR5, -COR5, -COOR5 and/or -CON(R5)2; where R4 and R5 are defined as in claim 1.
36. The process of any one of claims 29 to 35, wherein at least one R1 is not C-C20 alkyl non-substituted.
37. The process of any one of claims 29 to 36, wherein at least one R1 is a non-peripheral substituent.
38. The process of any one of claims 29 to 37, wherein the substituted phthalocyanine of formula (V) is substituted with or conjugated to an amino acid, a fatty acid, a nucleic acid, a di-, tri- or up to decapeptide, a polypeptide, a protein, a saccharide, a polysaccharide or a polymer.
39. The process of claim 38, wherein the substituted phthalocyanine of formula (V) is substituted with or conjugated to an amino acid, a fatty acid, a nucleic acid, a di-, tri- or up to decapeptide, a polypeptide, a protein, a saccharide, a polysaccharide or a polymer via R1.
40. The process of any one of claims 29 to 39, wherein if the phthalocyanine is a non- mixed phthalocyanine or if the phthalocyanine is substituted with -S-R5, the sum of m and p is not 4 or 8.
,A
41. The process of any one of claims 29 to 40, wherein R2 is A .
42. The process of any one of claims 29 to 41, wherein p = 0.
43. The process of any one of claims 29 to 42, wherein R9 are the same or different and each R9 is -Br, -I, -alkenyl optionally substituted, -alkynyl optionally substituted, -aryl optionally substituted or -heteroaryl optionally substituted;
44. The process of claim 43, wherein R9 is -Br, -I, -CH=CH2, -C≡CH, -C≡C-Si(R5)3, -C≡C-C5H4N, -C≡C-C4H3S, -C≡C-C6H5, -C5H5N, -C4H3S or -C6H5 optionally substituted.
45. The process of claim 44, wherein R9 is -Br, -I, -CH=CH2, -C≡CH, -C≡C-SiMe3, -C≡C-Si'Pr3, -C≡C-CsI tN, -C≡C-C4H3S, -C≡C-C6H5, -C5H5N, -C4H3S, -C6H5, -C6H5-CH2OH or -C6H5-OCH3.
46. The process of any one of claims 29 to 45, wherein the compound of formula (I) forms a sandwich complex or multimer.
47. A process for the preparation of a phthalonitrile halide of formula (VI)
Figure imgf000125_0001
wherein R are the same or different and each R is Cι-20 alkyl optionaly substituted; q is 1 or 2; and R10 are the same or different and each R10 is -Cl, -Br or -I; comprising the steps of
(c) halogenating 2,3-dicyanohydroquinone to afford the dihalogenated product,
(d) alkylating the dihalogenated product to yield the alkylated mono- or dihalogenated product.
48. The process of any one of claims 29 to 47, wherem R are the same or different and each R8 is Cι-C20 alkyl optionally substituted with -OH.
49. The process of claim 48, wherein R8 are the same or different and each R8 is Cj-C20 alkyl.
50. The process of claim 49, wherein R are the same or different and each R is Cι-C10 alkyl.
51. A phthalonitrile sulfonate ester of formula (III)
Figure imgf000126_0001
wherein R^ is
Figure imgf000126_0002
m is 1, 2, 3 or 4;
R6 is either Cι-C12 alkyl, optionally substituted with one or more of -F and/or -Cl, or aryl, optionally substituted with -CH3, -NO2, -OCH3, -F, -Cl and/or -Br; and when m is 2, 3 or 4, R6 are the same or different;
10 p is 0, 1, 2 or 3; and
R >3" ; is either -F, -Cl, -Br or -I; and when p is 2 or 3, R are the same or different.
15 52. The phthalonitrile sulfonate ester of claim 51 , wherein R2 is
53. The phthalonitrile sulfonate ester of claim 51 or claim 52, wherein R° are the same or different and each R6 is -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -C8H,7, -CHC12,
-CF3, -C4F9, -C6H5, -(C6H4)-4-CH3, -(C6H4)-2-NO2, -(C6H4)-3-NO2, -(C6H4)-4-NO2, 0 -(C6H4)-2-Br, -(C6H4)-4-Br, -(C6H4)-4-Cl, -(C6H4)-4-F, -(C6H3)-2,5-Cl2,
-(C6H3)-3,4-Cl2, -(C6H3)-3,4-(OCH3)2 or -(C6H3)-2,4-(NO2)2.
54. The phthalonitrile sulfonate ester of claim 53, wherein R6 are the same or different and each R6 is -CH3, -CF3 or -C4F9. 5
55. The phthalonitrile sulfonate ester of any one of claims 51 to 54, wherein p = 0.
6. A substituted phthalonitrile of formula (IV)
Figure imgf000127_0001
wherein m is 1, 2, 3 or 4;
R is Cι-C20 alkyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -R4-O-R5, -R4-S-R5, -NH2, -NHR5, -N(R5)2, -N(R5)3 + and/or -R4-N-(R5)2; C2-C20 alkenyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -R4-O-R5, -R4-S-R5, -NH2, -NHR5, -N(R5)2, -N(R5)3 + and/or -R4-N-(R5)2; C2-C20 alkynyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -R4-O-R5, -R4-S-RD, -NH2, -NHR\ -N(R3)2, -N(R 55\)3 + -R4-N-(R5)2, -Si(R5)3, -C5H4N, -C4H3S and/or -C6H5; -R4-O-R5; -R4-S-R5;
-R4-SO3H; -R4-SO2R5; -R4-SO2N(R5)2; - -N-(R5)2; -R4-P-(R5)2;
-R4-P(O)(OR5)2; -R4-aryl, optionally substituted with one or more of Cι-C10 alkyl, C2-C10 alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -NH2, -NHR5, -N(R )2, -N(R5)3 +, -NHCOR5, -COR5, -COOR5 and/or -CON(R5)2; -R4-heteroaryl, optionally substituted with one or more of Ci-Cio alkyl, C2-C10 alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -NHCOR5, -COR5, -COOR5 and/or -CON(R5)2; -R4-COR5; -R4-COOR5 or -R4-CON(R5)2; where
-R4- is a chemical bond, -(CH2)q- with q being an integer from 1 to 20, or
-(CH2)aCH=CH(CH2)b- with a and b being integers from 0 to 20 and the sum of a and b being from 0 to 20;
-R5 is Cι-C20 alkyl, C2-C20 alkenyl, aryl, heteroaryl or H, or two -R5 together form a saturated or unsaturated ring; and when m is 2, 3 or 4, R1, -R4- and -R5 are the same or different;
RAs
Figure imgf000127_0002
p is 0, 1, 2 or 3; and
R3 is either -F, -Cl, -Br or -I; and when p is 2 or 3, R3 are the same or different;
provided that when R1 is Cι-C20 alkyl non-substituted, -CF3, -OR5, -CH2OR5 or -S-aryl, m is 3 or 4 or p is 1 , 2 or 3.
57. The substituted phthalonitrile of claim 56, wherein at least one R1 is not Cι-C20 alkyl non-substituted.
58. The substituted phthalonitrile claim 56 or claim 57, wherein R1 are the same or different and each R1 is Cι-C20 alkyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR5, -SR5, -NH2, -NHR5, -N(R5)2 and/or -N(R5)3 +; C2-C20 alkenyl, optionally substituted with one or more of-F, -Cl, -Br, -I, -OH, -OR5, -SR5,
-NH2, -NHR5, -N(R5)2 and/or -N(R5)3 +; C2-C20 alkynyl, optionally substituted with one or more of-F, -Cl, -Br, -I, -OH, -OR5, -SR5, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -Si(R5)3, -C5H4N, -C4H3S and/or -C6H5; -OR5; -SR5; -SO2R5; -N-(R5)2; -P-(R5)2; -P(O)(OR5)2; -aryl, optionally substituted with one or more of Cι-C10 alkyl, C2-Cι0 alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -OR5, -SO3H, -NH2, -NHR5, -N(R5)2,
-N(R5)3 +, -NHCOR5, -COR5, -COOR5 and/or -CON(R5)2; -heteroaryl, optionally substituted with one or more of Cι-C10 alkyl, C2-C10 alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -NHCOR5, -COR5, -COOR5 and/or -CON(R5)2; -COR5; -COOR5 or -CON(R5)2; where -R5 are the same or different and each -R5 is C1-C20 alkyl, C2-C20 alkenyl, aryl, hetereoaryl or H, or two -R5 together form a saturated or unsaturated ring.
59. The substituted phthalonitrile of claim 58, wherein R1 are the same or different and each R1 is C1-C20 alkyl, optionally substituted with one or more of -F, -Cl, -Br, -I, - OH, -OR5, -SR5, -NH2 and/or -NHR5; C2-C2o alkenyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR5, -SR5, -NH2 and or -NHR5; C2-C20 alkynyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR5, -SR5, -NH2 and/or -NHR5; -OR5; -SR5; -SO2R5; -N-(R5)2; -P-(R5)2; -aryl, optionally substituted with one or more of C Cιo alkyl, C2-C10 alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -OR5, -SO3H, -NH2 and/or -NHR5; -heteroaryl, optionally substituted with one or more of C1-C.0 alkyl, C2-C10 alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -NH2 and/or -NHR5; -COR5; -COOR5 or -CON(R5)2; where -R5 are the same or different and each -R5 is Cι-C20 alkyl, C2-C20 alkenyl, aryl, hetereoaryl or H, or two -R5 together form a saturated or unsaturated ring.
60. The substituted phthalonitrile of claim 56 or claim 57, wherein R are the same or different and each R is Cι-C20 alkyl substituted with at least one or more of -F, -Cl, -Br, -I, -OH, -NH2, -NHR5, -N(R5)2 and/or -N(R5)3 +; C2-C20 alkenyl; C2-C20 alkynyl;
-S-R5; -N-(R5)2; -aryl, optionally substituted with one or more of Cι-C10 alkyl, C2-C10 alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -NHCOR5, -COR5, -COOR5 and/or -CON(R5)2; where -R5 are the same or different and each -R5 is Cι-C20 alkyl, C -C20 alkenyl, aryl, heteroaryl or H, or two -R5 together form a saturated or unsaturated ring.
61. The substituted phthalonitrile of claim 60, wherein R1 are the same or different and each R1 is Cι-C20 alkyl fully substituted with -F, -Cl and/or -Br; C2-C20 alkenyl; C2-C20 alkynyl; -S-R5; or -aryl, optionally substituted with one or more of -CH3, -NO2, -OCH3, -F, -Cl, -Br, -OH and/or -NH2; where -R5 are the same or different and each -R5 is C1-C20 alkyl, C2-C20 alkenyl, aryl, heteroaryl or H, or two -R5 together form a saturated or unsaturated ring.
62. The substituted phthalonitrile of any one of claims 56 to 61, wherein at least one R1 is a non-peripheral substituent.
63. The substituted phthalonitrile of any one of claims 56 to 62, wherein the substituted phthalonitrile of formula (IV) is substituted with or conjugated to an amino acid, a fatty acid, a nucleic acid, a di-, tri- or up to decapeptide, a polypeptide, a protein, a saccharide, a polysaccharide or a polymer.
64. The substituted phthalonitrile of claim 63, wherein the substituted phthalonitrile of formula (IV) is substituted with or conjugated to an amino acid, a fatty acid, a nucleic acid, a di-, tri- or up to decapeptide, a polypeptide, a protein, a saccharide, polysaccharide or a polymer via R1.
65. The substituted phthalonitrile of any one of claims 56 to 64, wherein R is
66. The substituted phthalonitrile of any one of claims 56 to 65, wherein p = 0.
67. A substituted phthalocyanine of formula (I)
Figure imgf000130_0001
wherein m are the same or different and each m is 0, 1, 2, 3 or 4;
R1 are the same or different and each R1 is Cι-C-20 alkyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -R4-O-R5, -R4-S-R5, -NH2, -NHR5, -N(R5)2, -N(R5)3 + and/or -R4-N-(R5)2; C2-C20 alkenyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -R4-O-R5, -R4-S-R5, -NH2, -NHR5, -N(R5)2, -N(R5)3 + and/or -R4-N-(R5)2; C2-C20 alkynyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -R4-O-R5, -R4-S-R5, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -R4-N-(R5)2, -Si(R5)3, -C5H4N, -C4H3S and/or -C6H5; -R4-O-R5; -R4-S-R5; -R4-SO3H; -R4-SO2R5; -R4-SO2N(R5)2; -R4-N-(R5)2; -R4-P-(R5)2; -R4-P(O)(OR5)2; -R4-aryl, optionally substituted with one or more of C1-C10 alkyl, C2-C,0 alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -OR5, -SO3H, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -NHCOR5, -COR5, -COOR5 and/or -CON(R5)2; -R4-heteroaryl, optionally substituted with one or more of Cι-C10 alkyl, C2-Cι0 alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -NHCOR5, -COR5, -COOR5 and/or -CON(R5)2; -R4-COR5; -R4-COOR5 or -R4-CON(R5)2; where
-R4- are the same or different and each -R4- is a chemical bond, -(CH2)q- > with q being an integer from 1 to 20, or -(CH2)aCH=CH(CH2)b- with a and b being integers from 0 to 20 and the sum of a and b being from 0 to 20; and -R5 are the same or different and each -R5 is Cι-C20 alkyl, C2-C20 alkenyl, aryl optionally substituted, hetereoaryl optionally substituted or H, or two -R5 together form a saturated or unsaturated ring;
R2 are the same or different and each R2 is
Figure imgf000131_0001
p are the same or different and each p is 0, 1, 2 or 3; provided that not all four m and all four p are 0 simultaneously;
R are the same or different and each R is either -F, -Cl, -Br or -I; and
M is a metal atom in the M(II) oxidation state, a metal chloride, a metal bromide, a metal oxide, silicon with two axial substituents or two hydrogen atoms, one hydrogen being bonded to each of the two bonding nitrogen atoms;
provided that when all R1 are the same and are C1-C20 alkyl non-substituted, -CF3, -OR5, -CH2OR5 or -S-aryl, m is 3 or 4 or p is 1, 2 or 3.
68. The substituted phthalocyanine of claim 67, wherein the substituted phthalocyanine is a non-mixed or a mixed phthalocyanine.
69. The substituted phthalocyanine of claim 67 or claim 68, wherein at least one R1 is not C1-C20 alkyl non-substituted.
70. The substituted phthalocyanine of any one of claims 67 to 69, wherein R1 are the same or different and each R1 is C1-C20 alkyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR5, -SR5, -NH2, -NHR5, -N(R5)2 and/or -N(R5)3 +; C2-C20 alkenyl, optionally substituted with one or more of-F, -Cl, -Br, -I, -OH, -OR5, -SR5, -NH2, -NHR5, -N(R5)2 and/or -N(R5)3 +; C2-C2o alkynyl, optionally substituted with one or more of-F, -Cl, -Br, -I, -OH, -OR5, -SR5, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -Si(R5)3, -C5H4N, -C4H3S and or -C6H5; -OR5; -SR5; -SO2R5; -N-(R5)2; -P-(R5)2; -P(O)(OR5)2; -aryl, optionally substituted with one or more of Cι-Cι0 alkyl, C2-C0 alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -OR5, -SO3H, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -NHCOR5, -COR5, -COOR5 and/or -CON(R5)2; -heteroaryl, optionally substituted with one or more of C-C10 alkyl, C2-C10 alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -NHCOR5, -COR5, -COOR5 and/or -CON(R5)2; -COR5; -COOR5 or -CON(R5)2; where -R5 are the same or different and each -R5 is Cι-C2o alkyl, C2-C20 alkenyl, aryl, hetereoaryl or H, or two -R5 together form a saturated or unsaturated ring.
71. The substituted phthalocyanine of claim 70, wherein R1 are the same or different and each R1 is Cι-C20 alkyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR5, -SR5, -NH2 and/or -NHR5; C2-C2o alkenyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -OH, -OR5, -SR5, -NH2 and/or -NHR5; C2-C20 alkynyl, optionally substituted with one or more of-F, -Cl, -Br, -I, -OH, -OR5, -SR5, -NH2 and/or -NHR5; -OR5; -SR5; -SO2R5; -N-(R5)2; -P-(R5)2; -aryl, optionally substituted with one or more of C1-C10 alkyl, C2-C0 alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -OR5, -SO3H, -NH2 and/or -NHR5; -heteroaryl, optionally substituted with one or more of C C10 alkyl, C2-Cι0 alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -NH2 and/or -NHR5; -COR5; -COOR5 or -CON(R5)2; where -R5 are the same or different and each -R5 is C1-C20 alkyl, C2-C20 alkenyl, aryl, hetereoaryl or H, or two -R5 together form a saturated or unsaturated ring.
72. The substituted phthalocyanine of any one of claims 67 to 69, wherein R1 are the same or different and each R1 is Cι-C20 alkyl substituted with at least one or more of-F, -Cl, -Br, -I, -OH, -NH2, -NHR5, -N(R5)2 and/or -N(R5)3 +; C2-C2o alkenyl; C2-C20 alkynyl; -S-R5; -N-(R5)2; -aryl, optionally substituted with one or more of Cι-C10 alkyl, C2-C10 alkenyl, -NO2, -OCH3, -F, -Cl, -Br, -OH, -NH2, -NHR5, -N(R5)2, -N(R5)3 +, -NHCOR5, -COR5, -COOR5 and/or -CON(R5)2; where -R5 are the same or different and each -R5 is Cι-C20 alkyl, C2-C20 alkenyl, aryl, heteroaryl or H, or two -R5 together form a saturated or unsaturated ring.
73. The substituted phthalocyanine of claim 72, wherein R1 are the same or different and each R1 is C1-C20 alkyl fully substituted with -F, -Cl and/or -Br; C2-C20 alkenyl; C2-C20 alkynyl; -S-R5; or -aryl, optionally substituted with one or more of -CH3, -NO2, -OCH3, -F, -Cl, -Br, -OH and/or -NH2; where -R5 are the same or different and each -R5 is CrC20 alkyl, C2-C2o alkenyl, aryl, heteroaryl or H, or two -R5 together form a saturated or unsaturated ring.
74. The substituted phthalocyanine of any one of claims 67 to 73, wherein at least one R1 is a non-peripheral substituent.
75. The substituted phthalocyanine of any one of claims 67 to 74, wherein the substituted phthalocyanine of formula (I) is substituted with or conjugated to an amino acid, a fatty acid, a nucleic acid, a di-, tri- or up to decapeptide, a polypeptide, a protein, a saccharide, a polysaccharide or a polymer.
76. The substituted phthalocyanine of claim 75, wherein the substituted phthalocyanine of formula (I) is substituted with or conjugated to an amino acid, a fatty acid, a nucleic acid, a di-, tri- or up to decapeptide, a polypeptide, a protein, a saccharide, a polysaccharide or a polymer via R1.
77. The substituted phthalocyanine of any one of claims 67 to 76, wherein if the phthalocyanine is a non-mixed phthalocyanine or if the phthalocyanine is substituted with -S-R5, the sum of m and p is not 4 or 8.
78. The substituted phthalocyanine of any one of claims 67 to 77, wherein R 1 is I
79. The substituted phthalocyanine of any one of claims 67 to 78, wherein p = 0.
80. The substituted phthalocyanine of any one of claims 67 to 79, wherein M is an isotope of Cu, Ni, Pb, V, Pd, Pt, Co, Nb, Al, Sn, Zn, Mg, Ca, In, Ga, Fe, Ge, a lanthanide, Si with two axial substituents or 2H.
81. The substituted phthalocyanine of claim 80, wherein M is an isotope of a diamagnetic metal, Si with two axial substituents or 2H.
82. The substituted phthalocyanine of claim 81, wherein M is an isotope of Zn, Al, Mg, Pd, Pt, Si with two axial substituents or 2H.
83. The substituted phthalocyanine of any one of claims 67 to 82, wherein p = 0;
R1 are the same or different and each R1 is C2-C20 alkyl fully substituted with -F, -Cl and or -Br; C2-C 0 alkenyl; C2-C20 alkynyl; -S-R5; or -aryl, optionally substituted with one or more of -CH3, -NO2, -OCH3, -F, -Cl, -Br, -OH and/or
-NH2; where -R5 are the same or different and each -R5 is C1-C20 alkyl, C2-C20 alkenyl, aryl, hetereoaryl or H, or two -R5 together form a saturated or unsaturated ring;
A R2 is ^ ; and M is an isotope of Zn, Al, Mg, Pd, Pt, Si with two axial substituents or 2H.
84. The substituted phthalocyanine of any one of claims 67 to 83, wherein the substituted phthalocyanine forms a sandwich complex.
85. The substituted phthalocyanine of any one of claims 67 to 83, wherein the substituted phthalocyanine forms a multimer.
86. The substituted phthalocyanine of claim 85, wherein the multimer comprises at least two phthalocyanines.
87. The substituted phthalocyanine of claim 86, wherein the at least two phthalocyanines forming the multimer are covalently linked.
88. The substituted phthalocyanine of claim 87, wherein the covalently linked phthalocyanines are covalently linked via substituents R1, R8 and/or R9.
89. The substituted phthalocyanine of any one of claims 67 to 88, wherein the substituted phthalocyanine is conjugated to a carrier or entrapped or embedded in a macromolecular carrier.
90. The substituted phthalocyanine of claim 89, wherein the carrier is an amino acid, a fatty acid, a nucleic acid, a di-, tri- or up to decapeptide, a polypeptide, a protein, a saccharide, a polysaccharide or a polymer.
91. The substituted phthalocyanine of claim 89 or claim 90, wherein the substituted phthalocyanine is conjugated to the carrier via substituent R1, R8 or R9.
92. The substituted phthalocyanine of claim 90, wherein the polypeptide is an antibody.
93. The substituted phthalocyanine of claim 90, wherein the substituted phthalocyanine is entrapped or embedded in a solid polymer, or wherein the substituted phthalocyanine is conjugated to a soluble polymer.
94. The substituted phthalocyanine of claim 93, wherein the solid polymer is selected from polyesters, poly(orthoesters), polyanhydrides, tyrosine derived pseudo-poly(amino acids) or polyphosphazenes, or wherein the soluble polymer is selected from N-(2- hydroxypropyl)methacrylamide (HMPA) copolymers, polyvinylpyrrolidone (PVP), poly(ethylene glycol) (PEG) polymers, copolymers or block copolymers, amino acid derived polymers or polyesters.
95. The substituted phthalocyanine of claim 93 or claim 94, wherein the solid or soluble polymer is a biodegradable polymer.
96. The substituted phthalocyanine of any one of claims 67 to 95 for use as a medicament.
97. The substituted phthalocyanine of claim 96, wherein the medicament is for use in the photodynamic therapy of a human or animal disease.
98. A pharmaceutical composition comprising a substituted phthalocyanine according to any one of claims 67 to 97 or a pharmaceutically acceptable salt thereof in a mixture or in association with a pharmaceutically acceptable carrier, diluent or excipient.
99. The pharmaceutical composition of claim 98, wherein the pharmaceutical composition is in a form suitable for topical, subcutaneous, mucosal, parenteral, systemic, intra- articular, intra-venous, intra-muscular, intra-cranial, rectal or oral application.
100. The pharmaceutical composition of claim 98 or claim 99, for use in the photodynamic therapy of a human or animal disease.
101. The pharmaceutical composition of claim 100, wherein the human or animal disease is characterised by benign or malignant cellular hypeφroliferation or by areas of neovascularisation.
102. The pharmaceutical composition of claim 100, wherein the human or animal disease is a viral, fungal or bacterial disease or a disease caused by prions.
103. The pharmaceutical composition of claim 100, wherein the human or animal disease is a tumour, rheumatoid arthritis, inflammatory arthritis, hemophilia, osteoarthritis, vascular stenosis, vascular restenosis, atheromas, hypeφlasia, intimal hypeφlasia, benign prostate hypeφlasia, psoriasis, mycosis fungoides, eczema, actinic keratosis or lichen planus.
104. The pharmaceutical composition of any one of claims 100 to 103, wherein the source of illumination is a laser or a non-coherent light source emitting light of optimal wavelength.
105. Use of a substituted phthalocyanine of any one of claims 67 to 97 for the manufacture of a phototherapeutic agent for the use in photodynamic therapy.
106. The use of claim 105, wherein the phototherapeutic agent is used for the treatment of a disease characterised by benign or malignant cellular hypeφroliferation.
107. The use of claim 105, wherein the phototherapeutic agent is used for the treatment of a viral, fungal or bacterial disease or a disease caused by prions.
108. The use of claim 105, wherein the phototherapeutic agent is used for the treatment of a disease such as a tumour, rheumatoid arthritis, inflammatory arthritis, hemophilia, osteoarthritis, vascular stenosis, vascular restenosis, atheromas, hypeφlasia, intimal hypeφlasia, benign prostate hypeφlasia, psoriasis, mycosis fungoides, eczema, actinic keratosis and lichen planus.
109. Use of a substituted phthalocyanine of any one of claim 67 to 97 for the manufacture of a photodiagnostic agent for the identification of areas that are pathologically affected by cellular hypeφroliferation.
110. A material comprising a substituted phthalocyanine of any one of claims 67 to 97, wherein the optical or physical properties of the material may be altered by incident radiation.
111. The material of claim 110, wherein the incident radiation is electromagnetic radiation.
1 12. The material of claim 111, wherein the incident radiation is electromagnetic radiation with a wavelength in the range of from 200nm to lOOOnm.
PCT/GB2000/004708 1999-12-08 2000-12-08 Substituted phthalocyanines and their precursors WO2001042368A1 (en)

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004101516A3 (en) * 2003-05-14 2005-09-15 Univ Sherbrooke Amphiphilic trisulfonated porphyrazines for photodynamic applications in medicine
US7091373B2 (en) 2002-03-18 2006-08-15 Sumitomo Chemical Company, Limited Production method for biarylalanine
CN100415715C (en) * 2003-02-11 2008-09-03 杜锡光 Superphthalocyanine compound with six isoindole structural subunits in porphyrazine ring, synthesis method and application
CZ303612B6 (en) * 2010-08-19 2013-01-09 Výzkumný ústav organických syntéz a.s. Compound based on phthalocyanine derivative for photodynamic inactivation of both gram-positive and gram-negative bacteria as well as pathogenic yeast, and use of this compound
CN103864645A (en) * 2013-12-30 2014-06-18 常州大学 Disubstituted perfluoroalkyl phthalonitrile compound and preparation method thereof
CN104016995A (en) * 2014-06-26 2014-09-03 常州大学 Octa-substituted perfluoroalkyl cobalt phthalocyanine compound and preparation method thereof
CN108017650A (en) * 2017-03-08 2018-05-11 先尼科化工（上海）有限公司 A kind of phthalocyanine compound for optical filter and its preparation method and application method
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US11015061B2 (en) 2017-04-07 2021-05-25 Yamamoto Chemicals, Inc. Phthalocyanine-based compound and uses of same
US11174274B2 (en) * 2017-04-07 2021-11-16 Yamamoto Chemicals, Inc. Naphthalocyanine compound, method for producing same, and use thereof
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7153841B2 (en) * 2001-03-21 2006-12-26 L. Molteni & C. Dei Fratelli Alitti Societa Di Esercizio S.P.A. Metal substituted non-centrosimmetrical phthalocyanine analogues, their preparation and use in photodynamic therapy and in vivo diagnostic
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Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0155780A2 (en) * 1984-03-21 1985-09-25 Imperial Chemical Industries Plc Infra-red absorber
GB2168372A (en) * 1984-12-13 1986-06-18 Secr Defence Alkoxyphthalocyanines
EP0262761A1 (en) * 1986-08-06 1988-04-06 Imperial Chemical Industries Plc Organic photoconductor
WO1988006175A1 (en) * 1987-02-13 1988-08-25 The Secretary Of State For Defence In Her Britanni Substituted phthalocyanines
EP0337209A2 (en) * 1988-04-01 1989-10-18 MITSUI TOATSU CHEMICALS, Inc. Alkylphthalocyanine near-infrared absorbers and recording/display materials using the same
EP0373643A2 (en) * 1988-12-15 1990-06-20 MITSUI TOATSU CHEMICALS, Inc. Near infrared absorbers and display/recording materials prepared by using same
JPH02184665A (en) * 1989-01-12 1990-07-19 Mitsui Toatsu Chem Inc Phthalonitrile compounds and their manufacturing method
EP0519423A2 (en) * 1991-06-19 1992-12-23 MITSUI TOATSU CHEMICALS, Inc. Phthalocyanine compounds and usage thereof
US5456998A (en) * 1994-04-26 1995-10-10 Xerox Corporation Photoconductive imaging members containing alkoxy-bridged metallophthalocyanine dimers
JPH0892190A (en) * 1994-09-26 1996-04-09 Kanto Chem Co Inc Cyanobiphenyl derivative and liquid crystal composition containing the derivative
GB2295547A (en) * 1993-08-27 1996-06-05 Secr Defence Photosensitizers
GB2314844A (en) * 1996-06-27 1998-01-14 British Polythene Ltd Improvements in or relating to film and/or coatings
EP0875505A2 (en) * 1991-11-08 1998-11-04 Eastman Chemical Company Near-infrared fluorescing compounds
EP0906758A1 (en) * 1997-08-14 1999-04-07 MOLTENI L. &amp; C. dei Fratelli Alitti Società di Esercizio S.P.A. Zinc-phthalocyanines and corresponding conjugates, their preparation and use in photodynamic therapy and as diagnostic agents
WO2000021965A1 (en) * 1998-10-13 2000-04-20 Brown University Research Foundation Substituted perhalogenated phthalocyanines

Patent Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0155780A2 (en) * 1984-03-21 1985-09-25 Imperial Chemical Industries Plc Infra-red absorber
GB2168372A (en) * 1984-12-13 1986-06-18 Secr Defence Alkoxyphthalocyanines
EP0262761A1 (en) * 1986-08-06 1988-04-06 Imperial Chemical Industries Plc Organic photoconductor
WO1988006175A1 (en) * 1987-02-13 1988-08-25 The Secretary Of State For Defence In Her Britanni Substituted phthalocyanines
GB2229190A (en) * 1987-02-13 1990-09-19 Nat Res Dev Substituted phthalocyanines
EP0337209A2 (en) * 1988-04-01 1989-10-18 MITSUI TOATSU CHEMICALS, Inc. Alkylphthalocyanine near-infrared absorbers and recording/display materials using the same
EP0373643A2 (en) * 1988-12-15 1990-06-20 MITSUI TOATSU CHEMICALS, Inc. Near infrared absorbers and display/recording materials prepared by using same
JPH02184665A (en) * 1989-01-12 1990-07-19 Mitsui Toatsu Chem Inc Phthalonitrile compounds and their manufacturing method
EP0519423A2 (en) * 1991-06-19 1992-12-23 MITSUI TOATSU CHEMICALS, Inc. Phthalocyanine compounds and usage thereof
EP0875505A2 (en) * 1991-11-08 1998-11-04 Eastman Chemical Company Near-infrared fluorescing compounds
GB2295547A (en) * 1993-08-27 1996-06-05 Secr Defence Photosensitizers
US5834455A (en) * 1993-08-27 1998-11-10 The Secretary Of State For Defence In Her Britannic Majesty's Government Of The United Kingdom Of Great Britain And Northern Ireland Of Defence & Evaluation Research Agency, Dra Photosensitizers for sensitizing cells
US5456998A (en) * 1994-04-26 1995-10-10 Xerox Corporation Photoconductive imaging members containing alkoxy-bridged metallophthalocyanine dimers
JPH0892190A (en) * 1994-09-26 1996-04-09 Kanto Chem Co Inc Cyanobiphenyl derivative and liquid crystal composition containing the derivative
GB2314844A (en) * 1996-06-27 1998-01-14 British Polythene Ltd Improvements in or relating to film and/or coatings
EP0906758A1 (en) * 1997-08-14 1999-04-07 MOLTENI L. &amp; C. dei Fratelli Alitti Società di Esercizio S.P.A. Zinc-phthalocyanines and corresponding conjugates, their preparation and use in photodynamic therapy and as diagnostic agents
WO2000021965A1 (en) * 1998-10-13 2000-04-20 Brown University Research Foundation Substituted perhalogenated phthalocyanines

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
AGAR E ET AL: "Synthesis and Properties of 1,5-Dithio-3-oxa-pentanediyl Bridged Polymeric Phthalocyanines", DYES AND PIGMENTS,GB,ELSEVIER APPLIED SCIENCE PUBLISHERS. BARKING, vol. 35, no. 3, 1 November 1997 (1997-11-01), pages 269 - 278, XP004097409, ISSN: 0143-7208 *
CHEMICAL ABSTRACTS, vol. 114, no. 2, 1991, Columbus, Ohio, US; abstract no. 8269n, XP002163076 *
CHEMICAL ABSTRACTS, vol. 125, no. 6, 1996, Columbus, Ohio, US; abstract no. 72570h, XP002163075 *

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7091373B2 (en) 2002-03-18 2006-08-15 Sumitomo Chemical Company, Limited Production method for biarylalanine
CN100415715C (en) * 2003-02-11 2008-09-03 杜锡光 Superphthalocyanine compound with six isoindole structural subunits in porphyrazine ring, synthesis method and application
WO2004101516A3 (en) * 2003-05-14 2005-09-15 Univ Sherbrooke Amphiphilic trisulfonated porphyrazines for photodynamic applications in medicine
US7541457B2 (en) 2003-05-14 2009-06-02 Universite De Sherbrooke Amphiphilic trisulfonated porphyrazines for photodynamic applications in medicine
AU2004238410B2 (en) * 2003-05-14 2010-07-29 Rsem, Societe En Commandite Amphiphilic trisulfonated porphyrazines for photodynamic applications in medicine
CZ303612B6 (en) * 2010-08-19 2013-01-09 Výzkumný ústav organických syntéz a.s. Compound based on phthalocyanine derivative for photodynamic inactivation of both gram-positive and gram-negative bacteria as well as pathogenic yeast, and use of this compound
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