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WO2000063140A1 - Template directed solid-state organic synthesis - Google Patents

Template directed solid-state organic synthesis Download PDF

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Publication number
WO2000063140A1
WO2000063140A1 PCT/CA2000/000387 CA0000387W WO0063140A1 WO 2000063140 A1 WO2000063140 A1 WO 2000063140A1 CA 0000387 W CA0000387 W CA 0000387W WO 0063140 A1 WO0063140 A1 WO 0063140A1
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WIPO (PCT)
Prior art keywords
substrate
template molecule
template
donor
hydrogen
Prior art date
Application number
PCT/CA2000/000387
Other languages
French (fr)
Inventor
Leonard R. Macgillivray
Jennifer L. Reid
John A. Ripmeester
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National Research Council Of Canada
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Publication date
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Priority to AU37995/00A priority Critical patent/AU3799500A/en
Publication of WO2000063140A1 publication Critical patent/WO2000063140A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B37/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving either the formation of a carbon-to-carbon bond between two carbon atoms not directly linked already or the disconnection of two directly linked carbon atoms
    • C07B37/10—Cyclisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/68—One oxygen atom attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention relates to methods of organic syntheses in the solid state.
  • the invention provides a method for reacting a substrate to produce a desired product, the method comprising the steps of: mixing the substrate with a template molecule to produce a solid-state mixture, the template molecule being capable of reversibly binding the substrate into a desired orientation or desired conformation; initiating a reaction involving the substrate to produce the desired product; and releasing the desired product from the template molecule.
  • Figure 1 shows an X-ray crystallographic structure for a 2:2 complex of tr ⁇ s-l,2-bis(4-pyridyl)ethylene and 1,3-dihydroxybenzene.
  • Figure 2 shows the structure of compound 3d, the photodimerization product of l,4-_.zs-[2-(4-pyridyl)ethenyl]benzene, complexed with two molecules of 1,3-dihydroxybenzene.
  • Figure 3 shows the X-ray crystallographic structure for a 2:2 complex of l,4--..s-[2-(4-pyridyl)ethenyl]benzene and 5-methoxyresorcinol
  • Figure 4 shows the ⁇ NMR spectrum of the product (3d)of photodimerisation of l,4-bzs-[2-(4-pyridyl)ethenyl]benzene (lc) in the presence of 5-methoxyresorcinol (2b).
  • the invention provides a method, using a template molecule, for placing a molecule or molecules in a desired orientation with respect to one another, or a desired conformation, in order to favour one product over another, to cause
  • reaction to occur when it would not otherwise occur, or to achieve regio- and/or stereo-specificity in the product.
  • the template molecule may be any molecule capable of binding the substrate or substrates reversibly in order to bring about the correct reaction geometry.
  • the template molecule may bind the substrate through complementary hydrogen bonding groups. If the substrate has aromatic groups which are capable of ⁇ - ⁇ -interactions, the template molecule may have complementary groups capable of ⁇ - ⁇ -interactions. It is preferred that the template molecule be such that groups which bind or interact with the substrate ("binding groups") are held in a fairly rigid relationship, however, it is possible that the preferred relative arrangement of binding groups may be brought about as a result of binding with the substrate ("conformed fit").
  • the method of the invention is particularly suited to the use of substrates having hydrogen bonding groups.
  • a template and substrate may interact by way of a single hydrogen bonding group. It is preferred that the substrate have at least two hydrogen bonding groups, complemented by two hydrogen bonding groups on the template molecule.
  • the template have a certain degree of conformational rigidity, so that hydrogen bonding groups are held in a relatively rigid spatial relationship to each other. It is particularly preferred to use a template containing an aromatic group, as the direction and planarity of hydrogen bonds can be more readily engineered. It is even more preferred if the hydrogen bonding group or groups is/ are attached directly to the aromatic group, or form part of it.
  • the substrate have a certain degree of conformational rigidity, so that hydrogen bonding groups are held in a relatively rigid spatial relationship to each other. It is particularly preferred that the substrate have an aromatic group, and even more preferred if the hydrogen bonding group or groups is/ are attached directly to the aromatic group, or form part of it. If the substrate has a hydrogen bond donating group, the template molecule should have a complementary hydrogen bond accepting group. If the substrate has a hydrogen bond accepting group, the template molecule should have a complementary hydrogen bond donating group. Hydrogen bonding occurs in groups in which hydrogen is covalently bonded to highly electronegative elements of small atomic size. Examples of good hydrogen bond donating groups include groups in which hydrogen is bonded directly to O, N and S.
  • good hydrogen bond accepting groups are groups containing the electronegative elements F, O, and N.
  • Some donor/ acceptor pairs are OH/O, NH/O, OH/N, OH/ OH, FH/O, OH/F, FH/N, NH/F, and NHCO/ NHCO, CH/F, CH/O, CH/N, CH/C1, CH/S, CH/Br, CH/I, OH/C1, OH/Br, OH/ 1, NH/C1, NH/Br, NH/I, SH/O, SH/N, SH/F (wherein non-indicated valences are not hydrogen).
  • Preferred donor/ acceptor pairs are: OH/O, NH/O, OH/N, OH/ OH, FH/O, OH/F, FH/N, NH/F, and NHCO/ NHCO.
  • the hydrogen bond donor groups (either on the substrate or the template molecule) be single hydrogen donors, such as OH and NHCO. It is preferred that all hydrogens which are capable of forming hydrogen bonds in either the substrate or the template participate in the specific interaction of the substrate and the template. If not, they may form hydrogen bonds with other groups, which may detract from the specificity of the interaction between substrate and template. It is preferred that all H-bonds be formed within the substrate-template pair.
  • hydrogen bond donors having multiple hydrogens for example NH 2 or NH 3
  • the directionality of the hydrogen bond in the interaction of the template and the substrate may be difficult to predict and control.
  • Donor groups having more than one hydrogen may form hydrogen bonds with other components in the solid-state mixture, making the prediction of the interaction between substrate and template difficult.
  • the hydrogen bonding groups be neutral. Ionic groups will tend to form ionic bonds rather than hydrogen bonds. Ionic bonds are not directional, making the interaction of the substrate and the template less predictable and specific.
  • Particularly preferred hydrogen bond acceptors are aromatic nitrogens, such as in pyridine and pyridine derivatives.
  • ⁇ - ⁇ -interactions can be used to cause the substrate to assemble with a template molecule, with the desired geometry for reaction.
  • Molecules capable of ⁇ - ⁇ -interactions are those having aromatic rings.
  • a substrate:template pair interact by a combination of more than one type of interaction, i.e. hydrogen bonding and ⁇ - ⁇ -interactions.
  • Mixing of the substrate and the template molecule is done to produce a solid-state mixture. This can be accomplished by dissolving the substrate and the template molecule in a solvent and allowing crystals to form either naturally, or, for example, through precipitation by adding a precipitating co- solvent, adjusting the pH, or evaporating the solvent.
  • Mixing can also be accomplished by comminuting the substrate and the template molecule by grinding, or sonicating, or by melting the substrates together and then solidifying them.
  • the mixture may be made by dispersing the solid component in the liquid component.
  • Solid-state mixture is meant, in the context of this specification, to encompass such dispersions.
  • the molecules of the substrate and the template molecule have a mobility of less than about 10" 10 m 2 /s, more preferably less than about 10" 13 m 2 /s in the solid-state mixture.
  • the expression "solid-state mixture” further encompasses the liquid crystalline state.
  • Some substrate/ template molecule pairs will form complexes having sufficient stability to form crystals, which may be isolated. It is possible that one or both of the substrate and the template molecule will be a liquid in the pure state but a complex formed between the two will be solid. It is possible for not only 2:2 substrate:template complexes to assemble, but also complexes comprising multiple substrate molecules assembled with one template molecule, and multiple substrate molecules to assemble with multiple template molecules, preferably the complex is of the following formula: n(substrate):m(template), wherein n is an integer of 2 to 4, and m is an integer of 1 to 12. It is also possible for the complex to have an infinite number of members, which would result in a polymeric product.
  • the solid-state mixture can also be produced by co-sublimating the substrate and the template molecule, such that a complex assembles in the gas phase. Solidification yields a solid-state mixture, preferably in the form of a crystalline complex.
  • reaction may be initiated between substrate molecules aligned by template molecules. If a single substrate is used, the substrate must be a molecule capable of self- reacting. If more than one substrate is used, the multiple substrates must have complementary reacting groups. For substrates having double bonds, carbonyl, alkynyl or aromatic groups, a photochemical reaction can be induced. Reaction can be caused to occur by such means as ⁇ , ⁇ , ⁇ , UV, IR or visible radiation, heat and microwaves. It is particularly preferred to use UV or visible radiation.
  • reactions which can be caused to occur include Michael addition, Aldol addition, [4 + 2] cycloaddition, [6 + 2] cycloaddition, aldol condensation, Dieckmann condensation, Grignard reactions, Reformatsky reactions, Luche reactions, Wittig reactions, Ylid reactions, pinacol coupling, phenol coupling, oxidative coupling of acetylenes, substitution (for example aromatic substitution), aminolysis, hydrolysis, transesterification, pinacol rearrangement, benzilic acid rearrangement, Beckmann rearrangement, Meyer-Schuster rearrangement, Chapman rearrangement, and Diels- Alder reactions.
  • the template should cause the substrate molecules to assemble such that the olefinic double bonds intended to react are parallel and separated by a distance of less than about 5 A (centre-to-centre), more preferably about 3.5 to 4.2 A (centre-to-centre).
  • a molecule into the solid-state mixture that does not participate or interfere with substrate-template binding.
  • a molecule may serve to catalyse a reaction between substrate molecules, or to react with the substrate molecules.
  • the product may be separated from the template molecule by methods known to organic chemists, these include re-crystallization, sublimation, distillation, and chromatography.
  • organic chemists these include re-crystallization, sublimation, distillation, and chromatography.
  • the template molecule if recovered in sufficient purity, may be re-used.
  • the method of the invention is not limited to dimerizations, but also extends to polymerizations.
  • the method of the invention permits not only chemio- stereo- and regio- specific reactions, it permits reaction in the absence of solvent. Solvent-free reactions are more economical. Furthermore, the removal or recycling of solvent is often a considerable hazard to the environment.
  • the invention is illustrated by the reaction of two molecules of -r ⁇ ns-l,2-bis(4-pyridyl)ethylene (la) to form rctt-tetrakis(4-pyridyl)cyclobutane (3a) in the presence of 1,3- dihydroxybenzene (2a) as template molecule 6 .
  • the compound fr ⁇ s-l,2-bis(4-pyridyl)ethylene (la) is a solid at ambient temperatures.
  • the crystal structure of la does not satisfy topochemical requirements, with the result that pure la in the solid-state is not photochemically active 7 .
  • the complex 2(la):2(2a) was spread as a thin film between glass plates and irradiated with an Hg lamp for 42 hours to produce rctf-tetrakis(4- pyridyl)cyclobutane (3a) in 96% yield.
  • the product was separated from the template using column chromatography (silica support; eluent was a CHC1 3 to MeOH gradient; template recovered first, followed by the product).
  • rr ⁇ ns-l,2-bis(2-pyridyl)ethylene (lb) as substrate was assembled with 2a to yield the complex 2(lb):2(2a), as described in Example 1.
  • Irradiation yielded quantitatively rctt-tetrakis(2-pyridyl)cyclobutane.
  • the product was separated from the template using column chromatography (silica support; eluent was a CHC1 3 to MeOH gradient; template recovered first, followed by the product).
  • the olefins of lc are aligned such that the olefin of the major site is separated from the ordered olefin by 3.70 A.
  • Two ordered olefins of neighbouring complexes lie parallel and within 3.95 A of each other.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyridine Compounds (AREA)

Abstract

The invention provides a method for reacting a substrate to produce a desired product, the method comprising the steps of: mixing the substrate with a template molecule to produce a solid-state mixture, the template molecule being capable of reversibly binding the substrate into a desired orientation or desired conformation; initiating a reaction involving the substrate to produce the desired product; and releasing the desired product from the template molecule, characterised in that the substrate and the template molecule interact through one or more hydrogen bonds formed between donor/acceptor pairs, wherein the donor and the acceptor are neutral in charge.

Description

Template directed solid-state organic synthesis
Technical field of the invention
The invention relates to methods of organic syntheses in the solid state.
Background art
Conventional reactions in solution or in the solid-phase suffer some limitations and disadvantages. For example, in many cases it is necessary to align reacting molecules correctly and in the correct proximity in order for reaction to occur. Because of the relatively high translational and rotational freedom of molecules in solution, often solution reactions will produce multiple products: mixtures of different compounds, regio-isomers, and/ or stereoisomers.
Reactions in solution also require the use of solvents, often in huge excess to the substrate and/ or product. The removal of and/ or recycling of solvents can often pose serious environmental problems, and entail significant costs.
Organic and inorganic reactions are known to proceed in the solid-state1. Schmidt has demonstrated2 the solid-state photodimerization of trans cinnamic acid to produce l,2-dicarboxy-3,4-diphenyl-cyclobutane.
Ito et al. has reviewed reactions in the solid state between substrates that co- crystallise3, and demonstrated the solid state photodimerisation of trans- cinnamic acid and derivatives by double salt formation with diamines4-5. Disclosure of the invention
Summary of the invention
In a first aspect, the invention provides a method for reacting a substrate to produce a desired product, the method comprising the steps of: mixing the substrate with a template molecule to produce a solid-state mixture, the template molecule being capable of reversibly binding the substrate into a desired orientation or desired conformation; initiating a reaction involving the substrate to produce the desired product; and releasing the desired product from the template molecule.
Detailed description of the invention
Brief description of the drawings
Figure 1 shows an X-ray crystallographic structure for a 2:2 complex of trαπs-l,2-bis(4-pyridyl)ethylene and 1,3-dihydroxybenzene.
Figure 2 shows the structure of compound 3d, the photodimerization product of l,4-_.zs-[2-(4-pyridyl)ethenyl]benzene, complexed with two molecules of 1,3-dihydroxybenzene.
Figure 3 shows the X-ray crystallographic structure for a 2:2 complex of l,4--..s-[2-(4-pyridyl)ethenyl]benzene and 5-methoxyresorcinol Figure 4 shows the Η NMR spectrum of the product (3d)of photodimerisation of l,4-bzs-[2-(4-pyridyl)ethenyl]benzene (lc) in the presence of 5-methoxyresorcinol (2b). The invention provides a method, using a template molecule, for placing a molecule or molecules in a desired orientation with respect to one another, or a desired conformation, in order to favour one product over another, to cause
reaction to occur when it would not otherwise occur, or to achieve regio- and/or stereo-specificity in the product.
The template molecule may be any molecule capable of binding the substrate or substrates reversibly in order to bring about the correct reaction geometry.
If the substrate has groups which are capable of forming hydrogen bonds, the template molecule may bind the substrate through complementary hydrogen bonding groups. If the substrate has aromatic groups which are capable of π-π-interactions, the template molecule may have complementary groups capable of π-π-interactions. It is preferred that the template molecule be such that groups which bind or interact with the substrate ("binding groups") are held in a fairly rigid relationship, however, it is possible that the preferred relative arrangement of binding groups may be brought about as a result of binding with the substrate ("conformed fit").
The method of the invention is particularly suited to the use of substrates having hydrogen bonding groups. A template and substrate may interact by way of a single hydrogen bonding group. It is preferred that the substrate have at least two hydrogen bonding groups, complemented by two hydrogen bonding groups on the template molecule.
It is further preferred that the template have a certain degree of conformational rigidity, so that hydrogen bonding groups are held in a relatively rigid spatial relationship to each other. It is particularly preferred to use a template containing an aromatic group, as the direction and planarity of hydrogen bonds can be more readily engineered. It is even more preferred if the hydrogen bonding group or groups is/ are attached directly to the aromatic group, or form part of it.
It is further preferred that the substrate have a certain degree of conformational rigidity, so that hydrogen bonding groups are held in a relatively rigid spatial relationship to each other. It is particularly preferred that the substrate have an aromatic group, and even more preferred if the hydrogen bonding group or groups is/ are attached directly to the aromatic group, or form part of it. If the substrate has a hydrogen bond donating group, the template molecule should have a complementary hydrogen bond accepting group. If the substrate has a hydrogen bond accepting group, the template molecule should have a complementary hydrogen bond donating group. Hydrogen bonding occurs in groups in which hydrogen is covalently bonded to highly electronegative elements of small atomic size. Examples of good hydrogen bond donating groups include groups in which hydrogen is bonded directly to O, N and S. For example COOH, OH, NH2, NH-alkyl, NH-CO, NH-NH2 and SH. Examples of good hydrogen bond accepting groups are groups containing the electronegative elements F, O, and N. For example OH, COOH, ketones, aldehydes, NH2, NH-alkyl, NHCO, NH-NH2. Some donor/ acceptor pairs are OH/O, NH/O, OH/N, OH/ OH, FH/O, OH/F, FH/N, NH/F, and NHCO/ NHCO, CH/F, CH/O, CH/N, CH/C1, CH/S, CH/Br, CH/I, OH/C1, OH/Br, OH/ 1, NH/C1, NH/Br, NH/I, SH/O, SH/N, SH/F (wherein non-indicated valences are not hydrogen). Preferred donor/ acceptor pairs are: OH/O, NH/O, OH/N, OH/ OH, FH/O, OH/F, FH/N, NH/F, and NHCO/ NHCO. It is particularly preferred that the hydrogen bond donor groups (either on the substrate or the template molecule) be single hydrogen donors, such as OH and NHCO. It is preferred that all hydrogens which are capable of forming hydrogen bonds in either the substrate or the template participate in the specific interaction of the substrate and the template. If not, they may form hydrogen bonds with other groups, which may detract from the specificity of the interaction between substrate and template. It is preferred that all H-bonds be formed within the substrate-template pair. With hydrogen bond donors having multiple hydrogens, for example NH2 or NH3, the directionality of the hydrogen bond in the interaction of the template and the substrate may be difficult to predict and control. Donor groups having more than one hydrogen may form hydrogen bonds with other components in the solid-state mixture, making the prediction of the interaction between substrate and template difficult.
It is preferred that the hydrogen bonding groups be neutral. Ionic groups will tend to form ionic bonds rather than hydrogen bonds. Ionic bonds are not directional, making the interaction of the substrate and the template less predictable and specific.
Particularly preferred hydrogen bond acceptors are aromatic nitrogens, such as in pyridine and pyridine derivatives.
In a further embodiment of the method of the invention, π-π-interactions can be used to cause the substrate to assemble with a template molecule, with the desired geometry for reaction. Molecules capable of π-π-interactions are those having aromatic rings.
It is possible that a substrate:template pair interact by a combination of more than one type of interaction, i.e. hydrogen bonding and π-π-interactions. Mixing of the substrate and the template molecule is done to produce a solid-state mixture. This can be accomplished by dissolving the substrate and the template molecule in a solvent and allowing crystals to form either naturally, or, for example, through precipitation by adding a precipitating co- solvent, adjusting the pH, or evaporating the solvent.
Mixing can also be accomplished by comminuting the substrate and the template molecule by grinding, or sonicating, or by melting the substrates together and then solidifying them. In cases in which either of the substrate or the template molecule is a liquid at ambient temperature, the mixture may be made by dispersing the solid component in the liquid component. Solid-state mixture is meant, in the context of this specification, to encompass such dispersions. For better binding between the substrate and the template molecule, and greater control of the reaction, it is preferred that the molecules of the substrate and the template molecule have a mobility of less than about 10"10 m2/s, more preferably less than about 10"13 m2/s in the solid-state mixture. The expression "solid-state mixture" further encompasses the liquid crystalline state.
Some substrate/ template molecule pairs will form complexes having sufficient stability to form crystals, which may be isolated. It is possible that one or both of the substrate and the template molecule will be a liquid in the pure state but a complex formed between the two will be solid. It is possible for not only 2:2 substrate:template complexes to assemble, but also complexes comprising multiple substrate molecules assembled with one template molecule, and multiple substrate molecules to assemble with multiple template molecules, preferably the complex is of the following formula: n(substrate):m(template), wherein n is an integer of 2 to 4, and m is an integer of 1 to 12. It is also possible for the complex to have an infinite number of members, which would result in a polymeric product. The solid-state mixture can also be produced by co-sublimating the substrate and the template molecule, such that a complex assembles in the gas phase. Solidification yields a solid-state mixture, preferably in the form of a crystalline complex.
The means by which reaction may be initiated between substrate molecules aligned by template molecules will depend on the nature of the substrate. If a single substrate is used, the substrate must be a molecule capable of self- reacting. If more than one substrate is used, the multiple substrates must have complementary reacting groups. For substrates having double bonds, carbonyl, alkynyl or aromatic groups, a photochemical reaction can be induced. Reaction can be caused to occur by such means as α, β, γ, UV, IR or visible radiation, heat and microwaves. It is particularly preferred to use UV or visible radiation.
It is possible to use a combination of reactive groups on the substrate, such that one group reacts, for example, on exposure to UV-vis radiation, and a second group reacts, for example, on exposure to heat.
It is also possible to use multiple photo-chemically reactive groups which undergo reaction when irradiated with different wavelengths. Selective irradiation can then cause one group to react, while the other groups remain unchanged.
Examples of reactions which can be caused to occur include Michael addition, Aldol addition, [4 + 2] cycloaddition, [6 + 2] cycloaddition, aldol condensation, Dieckmann condensation, Grignard reactions, Reformatsky reactions, Luche reactions, Wittig reactions, Ylid reactions, pinacol coupling, phenol coupling, oxidative coupling of acetylenes, substitution (for example aromatic substitution), aminolysis, hydrolysis, transesterification, pinacol rearrangement, benzilic acid rearrangement, Beckmann rearrangement, Meyer-Schuster rearrangement, Chapman rearrangement, and Diels- Alder reactions.
For photochemical reactions involving olefinic double bonds, preferably the template should cause the substrate molecules to assemble such that the olefinic double bonds intended to react are parallel and separated by a distance of less than about 5 A (centre-to-centre), more preferably about 3.5 to 4.2 A (centre-to-centre).
It is also possible to incorporate a molecule into the solid-state mixture that does not participate or interfere with substrate-template binding. Such a molecule may serve to catalyse a reaction between substrate molecules, or to react with the substrate molecules.
After reaction has taken place to produce the desired product, the product may be separated from the template molecule by methods known to organic chemists, these include re-crystallization, sublimation, distillation, and chromatography. The template molecule, if recovered in sufficient purity, may be re-used.
It is possible to use more than one substrate and more than one template molecule.
The method of the invention is not limited to dimerizations, but also extends to polymerizations.
The method of the invention permits not only chemio- stereo- and regio- specific reactions, it permits reaction in the absence of solvent. Solvent-free reactions are more economical. Furthermore, the removal or recycling of solvent is often a considerable hazard to the environment.
Best mode for carrying out the invention
The invention is illustrated by the reaction of two molecules of -rαns-l,2-bis(4-pyridyl)ethylene (la) to form rctt-tetrakis(4-pyridyl)cyclobutane (3a) in the presence of 1,3- dihydroxybenzene (2a) as template molecule6.
The compound frαπs-l,2-bis(4-pyridyl)ethylene (la) is a solid at ambient temperatures. The bipyridine crystallises to form a layered structure, π-π interactions cause the molecules of adjacent layers to lie orthogonal to each other, with the olefinic double bonds separated by a distance of 6.52 A. The crystal structure of la does not satisfy topochemical requirements, with the result that pure la in the solid-state is not photochemically active7.
However, when la is co-crystallised with 1,3-dihydroxybenzene (2a), the result is a four-component hydrogen bonded molecular assembly 2(la) »2(2a), in which the pyridine units of la lie approximately orthogonal to 2a and interact by π-π interactions. The olefinic double bonds of adjacent molecules of la are arranged in parallel fashion, separated by a distance of approximately 4 A. Radiation of the complex 2(la) »2(2a) causes [2+2] cycloaddition to occur, producing a single product: rcft-tetrakis(4-pyridyl)cyclobutane (3a), in marked contrast to the reaction of la in solution, which produces a mixture of 2 isomers7. Examples
The examples which follow are intended to illustrate the invention and do not limit its scope.
Example 1: synthesis of rctt-tetrakis(4-pyrid l)cyclobutane
trøns-l,2-bis(4-pyridyl)ethylene (la, 0.020 g, 0.11 mmol) was added to a hot solution of 1,3-dihydroxybenzene (2a, 0.012 g, 0.11 mmol) in EtOH/MeCN (1:1) (5 ml). The solution was cooled and evaporated under ambient conditions to near dryness, resulting in crystals of the complex 2(la):2(2a). The X-ray structure of the substrate:template complex is shown in Figure 1. The complex assembles such that a four-component cyclic array is formed, held together by four O-H N hydrogen bonds [Ol Nl = 2.734(2) A; 02 N2
= 2.753(2) A], in which the pyridine units of la lie approximately orthogonal to 2a [dihedral angles: 84.9° Nl, 84.7° N2]. The olefinic double bonds within the complex are in a parallel arrangement, and are separated by a distance of 3.65 A. Olefinic double bonds of adjacent complexes are offset and are separated by a distance of 4.71 A.
The complex 2(la):2(2a) was spread as a thin film between glass plates and irradiated with an Hg lamp for 42 hours to produce rctf-tetrakis(4- pyridyl)cyclobutane (3a) in 96% yield. The product was separated from the template using column chromatography (silica support; eluent was a CHC13 to MeOH gradient; template recovered first, followed by the product). The product was confirmed by mass spectrometry (m/z 365.2, [M+H]+), and by :H NMR in DMSO-dό which shows resonances at 8.35, 7.23 and 4.66 ppm, which are assigned to the pyridyl and methine protons of 3a, respectively. The position of the methine signals distinguishes the rctt and rtct isomers7. The same product can also be made using 5-methoxyresorcinol (2b) as template molecule.
Example 2: synthesis of rctt-tetrakis(2-pyrid l)cyclobιιtane
rrαns-l,2-bis(2-pyridyl)ethylene (lb) as substrate was assembled with 2a to yield the complex 2(lb):2(2a), as described in Example 1. Irradiation yielded quantitatively rctt-tetrakis(2-pyridyl)cyclobutane. The product was separated from the template using column chromatography (silica support; eluent was a CHC13 to MeOH gradient; template recovered first, followed by the product).
Example 3: synthesis of [2.2]paracyclophane derivative (3d) (Figure 2)
The starting material l,4-_.z's-[2-(4-pyridyl)ethenyl]benzene (lc) (0.050 g, 0.18 mmol), obtained by the Heck reaction8, was co-crystallised with
5-methoxyresorcinol (2b) (0.025 g, 0.18 mmol) from EtOH:MeCN (8:1) (5 ml). Evaporation to dryness yielded yellow crystals of the complex 2(lc):2(2b). The X-ray crystal structure of the complex 2(lc):2(2b) is shown in Figure 3. The components of the complex assemble to form a four-component complex, held together by four O-H-N hydrogen bonds [Ol -Nl = 2.731(4) A; 02-N2 = 2.736(4) A; dihedral angles: 62.8° Nl; 82.3° N2]. The olefins of lc, one of which lies disordered across two positions (relative occupancies of 70:30), are aligned such that the olefin of the major site is separated from the ordered olefin by 3.70 A. Two ordered olefins of neighbouring complexes lie parallel and within 3.95 A of each other.
UV irradiation of complex 2(lc):2(2b) produced [2.2]paracyclophane derivative (3d) (Figure 2) in 60% yield, after 49 hours. The product was separated from the template using column chromatography (silica support; eluent was a CHCI3 to MeOH gradient; template recovered first, followed by the product). The product was characterised by Η NMR, which revealed three pairs of doublets at 8.35 and 7.25 ppm, 7.07 and 6.78 ppm, and 4.74 and 4.61 ppm, which correspond to the pyridyl, phenylene and cyclobutane protons of 3d, respectively (Figure 4).
Example 4: other substrate template pairs
Additional examples of substrates and template molecules suitable for use in the method of the invention are listed in Table 1.
Table 1: illustrative substrateitemplate pairs
Figure imgf000015_0001
Example 5: other templates
R = (CH2)nCH3,n = 0-12; orAr
Figure imgf000016_0002
Figure imgf000016_0001
Figure imgf000016_0003
951, 73, 2981
Figure imgf000016_0004
by reference
Figure imgf000017_0001
oιc acid
Figure imgf000017_0002
Example 6: other substrates
Figure imgf000017_0003
References (all of which are incorporated herein by reference)
1 Ramamurthy, V ; Venkatesan, K , Chem Rev 1987, 87, 433 2 Schmidt, G M , Pw re Appl Chem 1971, 27, 647 Ito, Y , Synthesis 1998, 1
4 Ito, Y , Borecka, B., Trotter, J.; Scheffer, J.R., Tetrahedron Lett 1995, 36, 6083
5 Ito, Y., Borecka, B ; Olovsson, G., Trotter, J.; Scheffer, J.R., Tetrahedron Lett 1995, 36, 6087
6 the structure of the cyclobutanes is designated according to IUPAC rules (Pure Appl. Chem., 1976, 45, 13), which stipulate that when alternative numbeπngs of the ring are permissible, numbering is chosen which gives a as attachment at the first point of difference When one substituent and one hydrogen atom are attached at each of more than two positions of a monocycle, the steπc relations of the substituents are expressed by adding r (for reference substituent), followed by a hyphen, before the locant of the lowest numbered of these substituents and c or t (as appropriate), followed by a hyphen, before the locants of the other substituents to express their relation to the reference substituent.
7 Vansant, J.; Smets, G.; Declercq, J.P , Germain, G ; Van Meerssche, M., / Org. Chem. 1980, 45, 1565
8 Amoroso, A J.; Thompson, A.M W.C; Maher, J.P.; McCleverty, J.A.; Ward, M.D.; Inorg Chem 1995, 34, 4828

Claims

What is claimed is:
1. A method for reacting a substrate to produce a desired product, the method comprising the steps of: mixing the substrate with a template molecule to produce a solid-state mixture, the template molecule being capable of reversibly binding the substrate into a desired orientation or desired conformation; initiating a reaction involving the substrate to produce the desired product; and releasing the desired product from the template molecule, characterised in that the substrate and the template molecule interact through one or more hydrogen bonds formed between donor/ acceptor pairs, wherein the donor and the acceptor are neutral in charge.
2. A method according to claim 1, characterised in that the substrate binds reversibly with the template molecule via π-π-interactions.
3. A method according to claim 1 or 2, characterised in that the substrate forms a hydrogen bond involving an OH group with the template molecule.
4. A method according to claim 1, 2 or 3, characterised in that the substrate forms a hydrogen bond involving a nitrogen containing group with the template molecule.
5. A method according to any one of claims 1 to 4, characterised in that the solid-state mixture is produced by dissolving the substrate and the template molecule in a solvent and removing the solvent.
6. A method according to any one of claims 1 to 5, characterised in that the solid state mixture comprises a complex of n(substrate):m(template), wherein n is an integer of 2 to 4, and m is an integer of 1 to 4.
7. A method according to any one of claims 1 to 6, characterised in that the reaction involving the substrate is a photochemical reaction.
8. A method according to any one of claims 1 to 7, characterised in that the reaction involving the substrate is a photo-dimerization.
9. A method according to any one of claims 1 to 8, characterised in that the reaction involving the substrate is initiated with UV light.
10. A method according to any one of claims 1 to 9, characterised in that the substrate contains olefinic double bonds.
11. A method according to any one of claims 1 to 10, characterised in that the desired product is released from the template molecule by re- crystallisation, sublimation, distillation, chromatography or a combination of these.
12. A method according to any one of claims 1 to 11, characterised in that the substrate forms a 2:2 complex with the template.
13. A method according to any one of claims 1 to 12, characterised in that the complex can be isolated as crystals.
14. A method according to any one of claims 1 to 13, characterised in that the substrate and the template molecule interact by one or more hydrogen bonds formed between the pairs OH/O, NH/O, OH/N, wherein non- indicated valences are not hydrogen.
15. A method according to any one of claims 1 to 14, characterised in that the substrate and the template molecule interact by one or more hydrogen bonds formed between donor/ acceptor pairs wherein at least one of the donor and acceptor is attached directly to or forms part of an aromatic group.
16. A method according to any one of claims 1 to 15, characterised in that the substrate and the template molecule interact by hydrogen bonds between donor and acceptor pairs, and wherein each donor is a single hydrogen donor, and each acceptor is a single hydrogen acceptor.
17. A product produced by the method of any one of claims 1 to 16.
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Y. ITO: "Control of solid-state photodimerization of some derivatives and analogs of trans-cinnamic acid by ethylenediamine", TETRAHEDRON LETTERS, vol. 36, no. 34, 1995, OXFORD GB, pages 6087 - 6090, XP004027456 *
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005035473A3 (en) * 2003-10-08 2005-06-16 Univ Iowa Res Found Method for preparing ladderanes from pre-oriented polyenes
US7524966B2 (en) 2003-10-08 2009-04-28 University Of Iowa Research Foundation Method for preparing ladderanes
WO2005124754A3 (en) * 2004-06-10 2006-02-16 Univ Iowa Res Found Data storage materials
US7772416B2 (en) 2004-06-10 2010-08-10 University Of Iowa Research Foundation Data storage materials
CN101503388A (en) * 2009-03-20 2009-08-12 苏州大学 Preparation of 1,2,4-tetra (4-pyridinyl) cyclobutane
CN101503388B (en) * 2009-03-20 2013-01-30 苏州大学 Preparation method of 1,2,3,4-tetrakis(4-pyridyl)cyclobutane
CN116178247A (en) * 2021-11-26 2023-05-30 中国科学院化学研究所 A kind of method of synthesizing tetrapyridyl cyclobutane

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