Aldehyde & KetoneAldehyde & Ketone

Nucleophilic Addition Nucleophilic Addition to to the Carbonyl Groupthe Carbonyl Group

Oxygen NucleophilesOxygen Nucleophiles

Sulfur Sulfur NucleophilesNucleophiles

Carbon Carbon NucleophilesNucleophiles

Nitrogen Nitrogen NucleophilesNucleophiles

Reactions at the Reactions at the -Carbon of Aldeh-Carbon of Aldeh

yde & Ketoneyde & Ketone

Reactions at the Reactions at the -Carbon of Carbonyl Compounds-Carbon of Carbonyl Compounds

Acidity of the Acidity of the -hydrogens-hydrogens

Keto-Enol tautomerizationKeto-Enol tautomerization

ApplicationsApplications

Acidity of the -hydrogens

O C

C

O C

C

R C C C

H H

O

Hydrogens are unusually acidic

(pKa=19-20)

Hydrogens are not acidic(pKa=40-50)

pKpKaa

CC22HH66 5050

CC22HH44 4444

NHNH33 3434

CC22HH22 2525

CHCH33COCHCOCH33 2020

CC22HH55OHOH 15.915.9

HH22OO 15.7415.74

Ph-OHPh-OH 1010

HH22COCO33 6.56.5

Keto-Enol Tautomerization

KetoKeto EnolEnol

Which makes a greater contribution to the hybrid?

A. InterconversionA. Interconversion ：：

B. Keto-enol tautomers B. Keto-enol tautomers

in equilibriumin equilibrium KK ＝＝[enol[enol]]

[keto][keto]

Monocarbonyl compounds

C

O

H3C CH3

C

OH

H2C CH3

((99%) (1.5×1099%) (1.5×10-4-4%)%)

C

O

H3C HC

OH

H2C H

((100%) (extremely small)100%) (extremely small)

O OH

(98.8%) (1.2%)(98.8%) (1.2%)

-dicarbonyl compounds-dicarbonyl compounds

H3C

C

CH2

C

CH3

O O

H3C

C

CH

C

CH3

OH O

O

CC

C

OH

CH3H3C

H

O

CC

C

OH

CH3H3C

H

24%24% 76%76%

PhenolPhenol O OH

K K 10 101414

C. C. Detection:Detection:

H3C

C

CH

C

CH3

OH O

+ FeCl+ FeCl33

H3C

C

CH

C

CH3

O O

6

Fe

Purple or bluePurple or blue

D. Formation of enolate:D. Formation of enolate:

Which “Base”?Which “Base”?

C OH3C

H3C+ K+H-

H2C C

CH3

O-K+ + H2

enolateenolate

E. Regioselective Formation of Enolate Anions E. Regioselective Formation of Enolate Anions

?? ??Kinetic enolate

Thermodynamic enolate

Generally:Generally:

1. Low temperature gives the kinetic enolate.1. Low temperature gives the kinetic enolate.

2. High temperature, relatively weak base in a protic so2. High temperature, relatively weak base in a protic solvent gives the thermodynamic enolate.lvent gives the thermodynamic enolate.

LDA

Two special examples:Two special examples:

1. The kinetically favored enolate can be formed cl1. The kinetically favored enolate can be formed cleanly through the use of diisopropylamide (LDeanly through the use of diisopropylamide (LDA).A).

2. In acid condition, the thermodynamic 2. In acid condition, the thermodynamic enolenol is for is formed predominantly.med predominantly.

enolenolenolateenolate

F. Racemization:F. Racemization:

C CH

CH3

C2H5C C

CH3

C2H5BaseO O

a

b

b

C C CH3

C2H5O

H

(R-)

(S-)a

Application

Nucleophilic center

Nucleophilic center

Ambident nucleophileAmbident nucleophile

carbanion

alkoxide anions

React as an alkoxide anionsReact as an alkoxide anions

OH

NaOH

O

RI

O R

C

O

H3C CH2-

C

O

H3C CH2

(CH3)3Si-Cl

THFC

OSi(CH3)3

H3C CH2

trapped trapped

React as a carbanionReact as a carbanion

React as a carbanion 1: HalogenationReact as a carbanion 1: Halogenation

Haloform reactionHaloform reaction

iodoform reactioniodoform reaction

CH

OH

R CH3

C

O

R CH3

React as a carbanion 2: AlkylationReact as a carbanion 2: Alkylation

side reaction:side reaction:

solution:solution:

React as a carbanion 3: Aldol ReactionReact as a carbanion 3: Aldol Reaction

Reversible

easyeasy

difficultdifficult

Soxhlet ExtractorSoxhlet Extractorcatalyst

acetone

How does it work?How does it work?

Crossed Aldol ReactionCrossed Aldol Reaction

Practical Crossed Aldol Reaction

React as a carbanion 4: React as a carbanion 4:

Glucose

2 ATP

2 ADT

H

C OHH

C

C

O

OPO32-H

H

H

C OHH

C

C OPO32-H

H

OHH

DHAP GAP

C

C

H OH

2-O3POCH2 OH

Enediol Intermediate

glycolysisglycolysis