2.

ALDEHYDES, KETONES AND DERIVATIVES

O O O
C C C
R R R H
carbonyl group ketone (RH) aldehyde

C O 2 + −
C O lone pairs in sp orbitals C O C O C O

the unhybridized the  bond polarized bond resonance structures

p orbitals

O - O O
Nu O base
C + Nu- C C - C
R R R R RCH2 R RCH R

➢ Electrophylic carbon may be attacked by a nucleophile: nucleophilic addition.

➢  hydrogens are slighlty acidic  the carbon can behave as a nucleophile

1
 2.1. Synthetic Routes to Aldehydes and Ketones

2.1.1 Oxidation reactions

O
R' O
[O]
RCH2OH [O]
RCHOH
R H
R R'
a) Aldehydes

Me Me O
PCC
CHCH2CH2CH2OH CHCH2CH2C
CH2Cl2
Me Me H

PCC: Pyridinium Chlorochromate

N
- 2
H ClCrO3
b) Aldehydes and Ketones: ozonolysis

O O
O3, CH2Cl2 Zn
+
-78 oC AcOH H H
62%
[O]
c) Ketones: Jones oxidation H2O2

Na2Cr2O7
H2O, H2SO4
OH O

menthol menthone

O OH O
1. CH3MgBr Na2Cr2O7
Ph CH CH3 C
+ H2O, H2SO4
Ph H 2. H3O Ph CH3
racemic

Grignard reaction (on aldehyde) followed by oxidation

3
2.1.2 Electrophilic aromatic substitution

Friedel Craft Acylations

OMe
O O
O
1. O , AlCl3
MeO
2. HCl, H2O

93%

2.1.3 Nucleophilic acyl substitution with organo cuprate

Cl
-78 oC
+ Et2CuLi
O Et2O O

4
 2.3. Acidity and Enolization of Aldehydes and Ketones

C O
H

➢ Geometric requirement for proton removal: C-H bond must be H

aligned with the p-orbitals of the C=O p-bond. all aligned, so H is
➢ Conformation easily achieved in a freely rotating system, ideal for removal
➢ In cyclic or constrained molecules without the proper orbital overlap
the p-resonance stabilization of the anion is not possible  the
acidity of the  hydrogen is greatly reduced. 5
2.3.1 Keto-enol tautomerism (tautomers)
- H O
O O
+
H

O H+
H+
C C Keq (keto-enol)
for acetone in water
R 1.5 X 10-7

Enolate
HO O H
C C C
R [enol] R
Keq = [keto]
Enol form Keto form

➢ fully reversible acid/base equilibria

➢ carbonyl compound can be regenerated from an enolate by simply adding acid
➢ isolation of an enol from an acid solution is no possible
6
 Keto and Enol Tautomers
➢ Constitutional isomers
➢ Easily interconverted by a trace of acid or base
➢ Most aldehydes and ketones exist primarily in the keto form: greater strength of the carbon-oxygen
double bond relative to the carbon-carbon double bond

7
-Dicarbonyl compounds
➢ exist primarily in the enol form
➢ enol more stable:
1. conjugated π systems
2. stabilization of the enol through hydrogen bonding

8
2.3.2 Generation of enols through acid catalysis

+ H H H
O O O O
+
H
+
H H H +
+ H3O
base (= H2O)
H is much more acidic
since the protonated
carbonyl is a much better
electron sink

9
2.3.3. Keto-enol tautomerism: Deuterium exchanges

Acidity of  hydrogens allow for hydrogen to deuterium exchange:

1. Dissolution of the carbonyl compound into D2O
2. Addition of a trace amount of acid or base.

-hydrogens that can adopt the required conformation for enol or enolate formation will be
exchanged for deuterium atoms

O O
-
CH3 D2O, OD CH3
CH3 CD3
H H D D

O + O
D2O, D3O
(Me)2CH H (Me)2CD H

10
2.3.4 Keto-enol tautomerism: Racemizations

O - O
- Ph O -
Ph EtO /EtOH EtO /EtOH Ph
CH3 CH3
H CH3 H3C CH3 H3C H

(S)-3-Phenyl- Achiral, planar

(R)-3-Phenyl-
2-butanone 2-butanone
isolation

racemic ketone
Anionic form: -carbon is planar  can be protonated from either face

11
 - +
O OK O
 CH2CH=CH2 10% KOH CH2CH=CH2  CH2CH=CH2
EtOH
 CH CH3  CH
3 3

• Anionic form: -carbon is planar  can be protonated from either face

• Configuration of the -carbon creates a bias in the reprotonation reaction

• Allyl and methyl substituents favor trans for steric reasons

 the trans isomer is produced in >95% yield under thermodynamic conditions.

12
2.3.5 General base induced formation of enolate ions

• pKa values for the hydrogens of simple aldehydes or ketones: 19-20 (more acidic than
ethyne, pKa = 25 , far more acidic than ethene pKa = 44 or of ethane pKa = 50 )

• Base must be strong enough to remove the hydrogen:

the conjugate acid of the base considered must be a weaker acid (pKa larger) than
the Aldehyde or ketone α hydrogen. Good bases have conjugate acids of pKa > 20
• A weaker base may work → the reaction will proceed under equilibrium deprotonation
• Base must not behave as a nucleophile that would attack the carbonyl group
Sterically hindered strong base

pKa of about 35

13
 Equilibrium that lies to the left
Keq < 1

Weaker Acid
Equilibrium that lies to the left

Keq ≈ 1

Reaction lies to the right

Keq >>> 1

Weaker Acid

Reaction lies to the right

Keq ≈ 106

14
Weaker Acid
pKa values and enolate structures for a few ketones/aldehydes

Structure Enolate Structure Enolate

15
2.3.6. Kinetic and thermodynamic enolates

➢ Thermodynamic enolate: most stable enolate i.e. the one with the more highly substituted double bond
electronic effects (Zaitsev type)
➢ Weak bases favor the thermodynamic enolates because an equilibrium between the enolates is
established

➢ Kinetic enolate: enolate formed fastest - usually enolate with the least substituted double bond
➢ A strong, sterically hindered bases such as LDA favor formation of kinetic enolates

16
 2.4. Halogenation of Ketones and Aldehydes

O O
acid or
H + X2 X
base
➢ Halogenation may proceed under acidic or basic conditions
➢ General formation of the enol or enolate
➢ The reactive enol or enolate then attacks the halogen rather than any other electrophile such as a proton.
❖ Initial rates of halogenation independent of halogen concentration [X2]
 Introduction of halogen not rate determining
❖ Rate dependent on concentration of [C=O] and acid (or base)
 enol or enolate formation is rate determining.

via enolate O- O

X X X

+
-H

H +O H
via enol O

X X 17
X
2.4.1 Acid catalyzed halogenation

Examples

O O
+
Cl2, H
70 °C Cl
85%

Auto-catalytic reaction

• very slow until some halogenation occurs producing acid as a byproduct.

• rate of halogenation then accelerates in the presence of acid
AUTOCATALYTIC: the reaction provides the means to promote itself

O O
Br2
+ HBr

MeOH

Br
18
Mechanism

Under Acidic Conditions Mono-halogenation is favored

In the halogenated form, the electron

+ +
O H O H withdrawing nature of the halogen
H X retards the initial step of enol formation
and hence slows the introduction of
more halogens.

halogen pulls electron

density away from the
carbonyl group 19
 2.4.2 Base catalysed halogenation and iodoform reaction

Mechanism

20
 O
Monohalogenation is NOT observed X

H
B

The HALOFORM reaction:

• Iodine: I2 is the more common halogen employed: Iodoform reaction.

• Iodoform is CHI3: bright yellow precipitate confirms the presence of a methyl ketone
• Synthetically use: overall conversion of a methyl ketone to a carboxylic acid.
21
Mechanism O -
O O
H -
R OH H I I H -
R R OH
H H
H H I

-
O O O
-

H I I H - I I
R R OH I
R
I I I
I

O -
O OH O I -
-
I HO I + I C
R R
I I R OH I
I I
-
HO H2O
-no  H's remain;
-carbonyl is most electrophilic
O I
I C H
-
R O I
yellow 22
precipitate
Synthetic examples:

O O
1. Cl2/NaOH
2. HCl/H2O OH + CHCl3

5-methyl-3-hexen-2-one 5-methyl-2-pentenoic acid chloroform

23
 2.5. Alkylations of Ketones and Aldehydes

➢ Enolates from a ketone or aldehyde react with an alkylating agents

➢  carbon is ‘nucleophilic” → SN2 displacing a leaving group (or Nucleophilic Acyl Substitution)

O O
1. NaH, C6H6
2. Me2C=CHCH2Br
CH2CH=CMe2

88%
-
O
via
Br

O - + O
O Li
LDA MeI Me
cold warm
EtO to r.t. EtO
EtO
93%
+ HN(iPr)2
24
Potential Problems:
➢ If the ketone bears -hydrogens on either side of the carbonyl group  two sites for alkylation
➢ multiple alkylations, depending on the substrate and reaction conditions
➢ the base can affect other functional groups in the molecule

25
2.5.1 Direct alkylation using lithium enolates: i.e. kinetic enolates

LDA is a very hindered strong base,

 the kinetic enolate is formed preferentially and non-reversibly
 least substituted alkene

Regioselective alkylations at the least substituted -carbon:

26
 2.5.2 Alkylation and acylation reactions using Enamines

Enamines contain a double bond (ene) and an amine conjugated

N - N
+

a. Enamine formation:

➢ Prepared by condensing a secondary amine with a ketone or an aldehyde

➢ Primary amines will give imines: more thermodynamically stable form of an imine/enamine tautomeric
equilibrium. O
R R' R
+ N (R' = H)
+ H N
R -H2O
NH
R' enamine imine

➢ Enol properties: enhace nucleophilic character of α carbon

27
Mechanism
+ H H
O O +
+
H /toluene HO N O
NH
+
NH
O
O
NH
O

O
O O
H H
H2 O + N+ HO+ N HO N N
+ + H
H O

iminium ion
NH note with 1re amines
O
O N
O EtNH2 + -H2O

N
via deprotonation of the N at the
iminium ion stage
enamine
28
 Removal of water shifts the equilibrium to the formation of the enamine

This is usually achieved through the use of a Dean Stark apparatus:

evaporated compounds condense,

fall into graduated tube and
separate. Water stays on lower
layer and never return to the flask
while the benzene (or toluene) rises
to the level where it runs back into
the reaction vessel. reaction mixture of benzene or
toluene and maybe water, which
also is created by the reaction

29
b. Reactions and synthetic use of enamines

➢ -carbon of the enamine (-carbon of the ketone) bears the new substituent
➢ Removal the nitrogen auxiliary and recover the new ketone is done through hydrolysis of the
iminium salt under aqueous acid conditions
➢ Amine can be recycled

X X
N N+ I-
SN2 CH3

CH3 I

+
H3O
usually X = -CH2CH2- (pyrrolidine)
-CH2CH2CH2- (piperidine)
-CH2OCH2- (morpholine) O
CH3

30
➢ Method minimizes double or multiple alkylations.
➢ Occurs best with reactive halo compounds such as methyl iodide, benzyl halides, allyl
halides, -halocarbonyl
➢ Used as an acylation method using acyl halides as well and with other electophilic reagents
(Pay attention to stereochemistry!)

Themodynamic
enamine

31
Examples alkylation using enamines as intermediates

O + O
1. pyrrolidine, H
H 2. BrCH2CH3 H 67%
+
3. H , H2O CH2CH3

1.
O O
N Br
O
O

2. H3O
+ O

N 1. O O O
Cl
+
2. H3O
32
2.6. The Aldol Condensation

Nucleophilic addition on an enolate onto carbonyl group gives the aldol adduct

• One aldehyde (or ketone) forms and enolate that acts a nucleophile
• One aldehyde (or ketone) undergoes nucleophilic attack: nucleophilic addition

Elimination of water gives the condensation product

33
2.6.1. Aldol addition and condensations in basic conditions

Aldehydes H
KOH, H2O OH O
6-8 oC CH3CH2CH2 CH CH

75 % CH2CH3
O Aldol Addition

2 CH3CH2CH2 H H H
OH O O
KOH, H2O
CH3CH2CH2 CH CH CH3CH2CH2 CH
80-100 oC
CH2CH3 86 % CH2CH3

Aldol Addition Aldol Condensation

Ketones
H3C
H3C O
O KOH, H2O OH O CH3 CH
2
CH3 CH3 heat CH3 CH CH2 H

Aldol Condensation
Aldol Addition
34
Mechanism of the base promoted aldol additon

Aldol adduct 35
 Step 4:
Base catalyzed dehydration

➢ Some aldol are rapidly dehydrated to the ,-unsaturated compound and cannot be isolated

➢ In contrast, some aldol may not dehydrate efficiently in basic conditions.

Acidifying the reaction conditions will promote dehydration

36
2.6.2. Aldol condensations in acidic conditions:

• The enol is formed under acidic conditions

• The second carbonyl group is FIRST protonated then attacked by the nucleophilic enol
• The aldol is usually not isolated but undergo acid catalyzed dehydration right away

37
 2.6.3. Crossed-aldol and Claisen-Schmidt reactions

a. Crossed aldol products:

If two 2 aldehydes or two ketones that both carry α-hydrogens are reacted together:
 we will get 4 possible products
 two self adducts
 two crossed aldol products

Crossed Aldol

Solving the problem: one reagent does not carry -hydrogens

38
b. Crossed Aldol Reactions (Condensations)

CHO
+ CH3CH2CHO NaOH, H2O
C
O CHO O CH CH3

72%

39
c. Claisen Schmidt Condensations: Aromatic aldehyde with ketone

O CHO O OH
+ NaOH, H2O
25 °C, 4 hr.

100 %

40
 d. Selective Formation of Enolates

- Conformationally restricted

O O
+ (CH3)3C CHO NaOH, H2O CHC(CH3)3
CH3 CH

81%
Formation of a kinetic enolate using LDA

- +
O LDA, THF O Li

CH3 CH2CH3 -78 °C CH2 CH2CH3

CH3CHO

- +
OH O O Li O
H2O
CH3 CH2 CH2CH3 CH3 CH2 CH2CH3

41
42
43
e. Intramolacular: Cyclic aldol Condensations

O O O
NaOH, H2O
not
100 °C
O

44
e. Intramolacular: Planning for Cyclic aldol Condensations

Step 1. identify acidic hydrogens

Step 2: Thermo vs. kinetic control
Step 3 identify if cyclization is possible
(5/6 member rings: no 4 membered rings). This does not
Mean that enols/enolates are not forming. They are just NOT
productive
Step 4: number atoms
Step5: draw mechanism (partial / full), do not eliminate at a bridgehead
• aldehydes are more electrophilic than ketones
• Themodynamic conditions: favors MOST stable enol
• Favors formation of stable cycles (5/6 membered
rings)
• Favors alpha beta unsaturation

Without heat, the aldol product is reversible,

45
 4 Possible Enolates

These Aldol Product DO NOT FORM

Energetic barrier TOO high

46
 O

O ONa HO
C
Thermodynamic C
H
RETRO ALDOL
4-membered ring!

O O

O O

O ONa HO
C - H 2O
CH 2

47
6. Condensations of Esters: Claisen Condensations (SF 19.2)
Reaction of an enolate of an ester and a carboxylic acid derivative following a Nucleophilic acyl subsitution
Enols of esters are less acidic than enols of ketones or aldehydes (pKa ~22)
 Need for a stronger base to form the enoate (need to “match” the ester) but Ester enolates are more reactive
-keto ester enols are much more acidic (pKa ~ 9-11)  will be easily deprotonated  driving equilibrium

48
Quenching

49
Esters with only one a hydrogen do not undergo Claisen condensation

A second hydrogen on the a carbon is necessary so that it can be deprotonated in

Step 3
This deprotonation drives the reaction to completion

50
6.1. Crossed Claisen condensations

Crossed Claisen condensations are possible when one of the esters does not possess -hydrogens, much
like the ideal situation for crossed aldol reactions.

O O
O + O
O O
O O
diethyl succinate diethyl oxalate

- + O
CH3CH3O Na
O
toluene O
O O
O
O
90%

O - + O O
O 1. CH3CH3O Na
O + ethanol O
O +
2. H

ethyl benzoate 71%

O O - + O O
+ 1. CH3CH3O Na
H O CH3 O ethanol H O
+
ethyl formate 2. H 80%
51
6.2. Crossed Claisen condensations on aldehydes and ketones: Reformatsky reaction (SF 16.11)
➢ Enolate is generated from an a-halo ester via the synthesis of an organometallic intermediate
➢ Chemistry similar to a Grignard reagent that adds on a aldehyde or ketone
➢ Organo zinc reagent does NOT react with the carbonyl group of the ester itself
O O - +
O (ZnBr)
Zn
O
- + O O
Br (ZnBr)
O 1. Zn, toluene OH O
Br O
O 2.
CHO O
70%
+
3. H

OH O
➢ - hydroxy ester can then be dehydrated
O
60%

Generation of an -halo ester: Hell-Volhard-Zellinsky

O O
O Br2
R 1) SOCl2
R PCl3 CH R
OH CH OEt
C OH 2) EtOH
H2
Br Br
SOCl2
O 1) NBS
R
C Cl 2) EtOH 52
H2
6.3. Intramolecular Claisen condensations: Dieckmann condensation (SF 883)

➢ 2 ester groups in the same molecule separated by 4 or 5 carbon atoms

 intramolecular Claisen condensation
 Only 5- and 6-membered rings may be prepared in this way.

O
H
CO2Et CO2Et
- +
CO2Et EtO H
O O O O
53
6.4. Biologically relevant Claisen condensations: Fatty acid Synthase

NaDPH, H+
-
CO2
NaDP-

NaDPH, H+
-H2O

NaDP-

54
55
7. Synthetic Applications of Condensation Reactions

7.1 Acetoacetic Ester Synthesis (SF 19.3)

O O O O O
H
O O
R R' R R'

substituted acetone

alkylation Hydrolysis/decarboxylation

Step 1: Alkylation

O O O O
- +
RO M
O O
-
H H +
H M
pKa = 10.7

- +
OM O O O
RX
O O
H H R'

- +
O OM

O
56
H
Step 2: Saponification hydrogen bond

O O O O H
1. NaOH, H2O O O O O
O 2. HCl, H2O OH
H R' H R' OH O
H R' H R'

Step 3: Decarboxylation

HO
H
O O O
heat O O
R' H
OH -CO2
H R' H H R' O
H R'

Two alkylations may be achieved before the saponification and decarboxylation steps

O O O
1) RO- O O
1) RO- O O OH
1) NaOH, H2O R
OEt 2) RX R
OEt 2) R'X OEt 2) H , Heat
+
H H H R R' R R' R'
racemic mixture

57
 O O
Examples: O O 1. NaOH, H2O O
1. NaOEt, EtOH
OEt 2. H
+
OEt 2. (Me)2CHCH2Br
3. heat, -CO2

O O O O
1. NaOEt, EtOH
O O
2. O
Cl O
Ph
Ph
+
1. NaOH, H2O, then H
2. heat, -CO2

O
Ph

O O
H 1. NaOEt, EtOH CH2CH2CH2Br
CO2Et CO2Et
2. excess Br(CH2)3Br
1. saponification
+
2. H 3. heat

O
H
CH2CH2CH2Br
60%
58
Sometimes the acid and thermolysis treatments can be addressed simultaneously:

O O O O
1. NaOEt, EtOH
O O
2. CH3CH2CH2CH2Br

1. NaOH, H2O
2. H2O, H2SO4, heat

O O 1. NaOEt 1. NaOEt O O
EtOH EtOH
O O
2. MeI 2. Br

+
1. NaOH, H2O, then H
2. heat, -CO2

H 59
7.2 Malonic Ester Synthesis (SF 19.4)

Acetoacetic acid synthesis Malonic Ester Synthesis

O O O O

Starting material: O
vs O O

O O
vs H
Final product: O
R R

Overall reaction of malonate synthesis

O O O O O
H
EtO OEt EtO OEt HO
R R' R R'

substituted
acetic acid
60
*
 CO2Et
1. NaOEt, EtOH 1. NaOH, H2O
CH2(CO2Et)2 C CO Et +
CO2H
2. allyl bromide 2 2. H3O
H
3. heat

61
62
7.3 “Other Active Hydrogen” compounds (SF 19.5)

Me Me Me
O O 1 eq. NaOH O O O O
MeI, H2O
70%
2 eq. NaOMe, MeI, MeOH
80%

63
7.4 Robinson Annulation (SF 798): Michael Addition / intramolecular aldol condensation
7.4.1 Michael Addition:
Examples pKa

CH2(CO2Et)2 13.3 O
O
O R
O catalytic R
ca. 9
O OR RO- in ROH CH(CO2Et)2
O O
and others
ca. 11 CN
O

Nucleophiles: Michael Acceptors:

-diketones, -keto esters, conjugated aldehydes, conjugated ketones,
dialkyl cuprates, enamines, conjugated esters, conjugated amides, conjugated
-keto nitriles, -nitro ketones nitriles, conjugated nitro compounds
amines, alcohols, thiols

64
65
❖ Other examples of Michael additions
O
MeOOC 1. NaOMe, MeOH
(1) MeOOC
O OEt
MeOOC
2. COOMe
OEt

O O O O
1. NaOMe, MeOH
(2)
OMe 2. COOMe OMe

COOMe
66
7.4.2 Robinson annulation

1. Michael Addition

O
O O O
RO-
+ O

MVK
O

2. Annulation: intra molecular aldol condensation

O
O O O

O Base O
O
-BH O
O O O O

O O
O

BH -H2O

O HO
O H H O
O
-
B

67
 Michael addition

O C H2 O O

cyclohexenone
aldol condensation

O O O
NaOH
+
EtOH
CO2Et
methyl vinyl ketone CO2Et
(MVK)

O
O
O
NaOMe
+ O
MeO MeOH
ethyl vinyl ketone
MeO

Michael addition product

MeO
68
Robinson annulation product
More, general examples of the annulation.

O
O O O O
+ Michael
OEt OEt

Aldol

C(O)OEt

O O O O

+ Michael

Aldol

69
 7.4.3 Other Conjugate Additions (S/SF 17.9)

Carbon Nucleophiles: organometallic reagents

➢ Grignards will still attack at the C=O group.
➢ Organolithium reagents attack at either electrophilic site thus not synthetically useful
➢ Organocuprate reagents attack in a conjugate fashion: easily generated in situ using Grignard reagents
in the presence of CuI.

1. EtMgBr 1. EtMgBr
HO Et2O CuI, Et2O
+
2. H /H2O O +
2. H /H2O O
Et H H Et

Other Nucelophiles and CN

➢ RNH2, RR’NH (needs to be able to loose H+, thus no tertiary amines)
➢ ROH
➢ RSH
➢ HCN (CN-)
All Add in a conjugate manner

O HNMe O
MeNH2

70
 A significant example of a Michael addition: Death of a Cancer Cell

O -
NHCOOMe O O NHCOOMe
NHCOOMe
SSSMe - S
S
OR OR OR
HO HO HO

2
1
Calicheamicin

-
-
O O NHCOOMe
NHCOOMe
S S
DNA OR
OR HO
dead + HO
cancer
cells H H

R = series of sugar moieties 71

8. The Wittig Olefination of Aldehydes and Ketones (SF 16.10)

72
8.1 Making a Phosphorus ylide

React a primary or secondary alkyl halide of choice with triphenyl phosphine and then nBuLi to get
the corresponding phosphonium ylide

73
8.2 Reaction of the ylide with a carbonyl group:

74
 EXAMPLES OF WITTIG REACTIONS

O _
+ +
Ph3P CH(CH2)3CH3 CH(CH2)3CH3 + Ph3P=O

O _ CHCH3
+
+ Ph P CHCH + Ph3P=O
3 3
PhCH2 H PhCH2 H

87:13 = Z:E

O O O
_
+ + + Ph3P=O
PhCH2 H Ph3P CH O PhCH2CH CH O
E isomer only

75
SYNTHESIS OF VITAMIN A1 : a final Wittig reaction

+ - NaOMe
PPh3X PPh3
MeOH

O
OC(O)Me
H

OC(O)Me

-
HO , H2O (saponification)

Vitamin A1 OH

76
 + H
H +PPh3 PPh3 CHO
- +
Bu Li -

O
O
+ Ph3P CH
O O CH
O

77
How to Plan a Witting Synthesis

❖ Synthesis of

using a Wittig reaction

78
❖ Retrosynthetic analysis
O
route 1
+ Ph3P
disconnection

route 2 Ph3P: + Br

PPh3
+ O

Br
+ :PPh3

79
❖ Synthesis – Route 1

:PPh3
Br Ph3P Br

n
BuLi
O

Ph3P

80
❖ Synthesis – Route 2

Br PPh3 Br
:PPh3

n
BuLi

PPh3
O

81
 9. Reductive Conversion of C=O to CH2

9.1 Wolff-Kishner approach (SF 16.8B)

H2NNH2, NaOH H
O 47%
(HOCH2CH2)2O H
heat

O
Me Me
H2NNH2, NaOH
(HOCH2CH2)2O 69%
O H2O, heat

82
Mechanism of the Wolff Kishner reduction

83
9.2 Clemmensen Reduction (SF 15.9)

Possible Mechanism for Clemmensen reduction

84
8. The Mannich Reaction

O O
+ + Et2NH
H H
HCl

O
H2O +
NEt2

85
❖ Mechanism of the Mannich Reaction
H OH
O OH
HCl
+ Et2NH
H H H H
H H N
N
Et Et Et Et

(-HOH)

H H H
O O O H H
N
HCl Et Et NEt2

86
 ❖ Other examples of the Mannich Reaction

O O O
HCl
(1) + + Et2NH
H H NEt2

O O
HCl N
(2) + +
H H
N
H

87
9. Summary of Important
Reactions
❖ Claisen Condensations
❖ Crossed Claisen Condensations
❖ Aldol Reaction
❖ Directed Aldol Reaction via Lithium
Enolates
❖ Conjugate Addition
❖ Mannich Reaction

88
❖ Claisen Condensations

O
R
OEt

89
 ❖ Aldol Condensations
O
O OH O
R
R H R
H NaOH, H2O H
R
1. LDA, THF, -78oC
O
2. (-H2O)
R' R'
3. NH4Cl
O
O
R
R H
H
R
R' OH
R' 90
❖ Simple & Conjugate (Michael) Additions
OH
O O
R'
R (simple addition: R
O major product)

1. R'MgBr, Et2O
MeOH, NaOMe
O 2. H3O+

R NaCN
EtOH, AcOH
R'
NH O R'NH2 CN O

R R
H H 91
❖ Mannich Reaction
O O R'
+ + H N
R H H R''

H+

O H H
R'
R N
R''
92
12. Chemical Analyses for
Aldehydes and Ketones
12A. Derivatives of Aldehydes & Ketones
R H
O + H2N N NO2
R' hydrazine
O2N
R
+ N
H
R' N NO2
H
hydrazone
(orange ppt.) O2N
93
12B. Tollens’ Test
(Silver Mirror Test)

O Ag(NH3)2+ O
+ Ag
R H H2O R O−
silver
mirror

94
Review question

95
Review question

❖ Intramolecular Aldol condensation

● Useful for the synthesis of five- and
six-membered rings
● Using a dialdehyde, a keto
aldehyde, or a diketone

96
Review of useful synthetic
transformations

97
2F. Reduction of Acyl Chlorides,
Esters, and Nitriles

98
❖ LiAlH4 is a very powerful reducing
agent and aldehydes are easily
reduced
● Usually reduced all the way to the
o
corresponding 1 alcohol
● Difficult to stop at the aldehyde
stage
⧫ Not a good method to
synthesize aldehydes using
LiAlH4

99
❖ Two derivatives of aluminum hydride
that are less reactive than LAH

100
 O
1. LiAlH(OtBu)3, -78oC

R Cl 2. H2O
Acyl chloride

O o O
1. DIBAL-H, hexane, -78 C

R OR' 2. H2O R H
Ester

1. DIBAL-H, hexane
R C N
2. H2O
Nitrile 101
2G. Reaction of Nitriles with
Grignard Reagents
O
1. R'−M, Et2O
R C N +
2. H3O R R'

N M

R R'

102
❖ Examples

103
❖ Suggest synthesis of
O

Br
from and HO

104
❖ Retrosynthetic analysis
O

HO

5 carbons here 4 carbons here

 need to add
one carbon

105
❖ Retrosynthetic analysis
O
disconnection

disconnection

NC +
Br

HO

106
❖ Synthesis

PBr3
HO Br

NaCN
MgBr DMSO

1.
O
Et2O
N C
2. H3O+

107
3A. Review from CHEM*2700

108