sp2, planar, bond angle 120

sp3, tetrahedral, 109.5.

Acetal formation

Acetal is a protecting group for carbonyl; hydrolyzes in acid but stable in base
Hemiacetal can be by hydrolyzed by acid and base

Imine formation with Primary Amines

Two key steps

1. Nucleophilic attack of amine to
carbonyl carbon
2. Dehydration of hemiaminal

2
2

mine is more nucleophilic than alcohol

t very low pH values, the amine will mostly be in protonated form and the rate

his step will be significantly slower

The protonation of OH group is required to make it a good leaving group

3

Imine formation works better with aromatic amines:

1. The pKa value of is much lower than alkyl amines

2. The imine product, which is prone to hydrolysis is more stable for aromatic

amines
pKa
4.6

10.7
Henderson Hasselbalch equation

Other derivatives likes Imine

Hydroxyl amine: NH2OH

Oxime

Hydrazine: NH2NH2

Hydrazone

Semicarbazide: NH2NH2CONH2

Semicarbazone

More stable than imine towards hydrolysis

Enamine with Secondary Amines

We will come back to enamines shortly

Cyanohydrin Formation

HCN is a weak acid

Does not provide enough CN- ion
proceed at a
reasonable rate

for the reaction to

ecker synthesis of amino acids

Diverse reactivity of Carbonyl groups

Electrophilic un-enolized molecules of carbonyl compounds are always there.

9

Reactions of Enolates

Alkylation of enolates

Enolates

Enol/Enolate equivalent : enamine and silyl enol ether

Thermodynamic and kinetic control, choice of base

ensation reactions with other carbonyl compounds (aldehyde, ketone, es

ol, Cannizaro, Michael addition, Mannich, Claisen, Knoevenagel, Dickmann,

binson annulation, Benzoin, etc.

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Enols and Enolates

(1)

Keq = 10-7

pKa
13.5

Keq = 10-20
(2)

25
Keq = 10

(3)

8.9

1. Simple aldehydes and ketones: very small equilibrium constants

for enol formation
2. Esters are even worse
3. 1,3 dicarbonyl compounds: resonance stabilized enol form with
intramolecular H-bonding; higher proportion of enol in the

11

Thermodynamically stable enolates from 1,3 dicarbonyl compounds

12

Enolates exist under basic conditions

A strong base deprotonates the carbonyl compound completely. The electrophile

is then added to the enolate in a subsequent step
A weaker base is used in the presence of electrophile: a small amount of anion is
produced. Practically easier: starting material, base and electrophile are all added
together.

13

Regioselectivity of Enolate formation

Unsymmetrical carbonyl compounds

Thermodynamic and kinetic enolates

On what factors does the enolate formation depend on?

1. Structure of the carbonyl compound
2. Strength of the base
3. Size of the base
4. Temperature

14

Thermodynamic
Enolate
(high temperature,
small
base size)

Kinetic Enolate
(low temperature,
bulky
base)

15

LDA: Lithium Di-isopropyl Amide

pKa of diisopropylamine is 36
How to determine pKa in this range?
Check Evans pKa table (H2O, DMSO, THF)
LDA is bulky and hence does not attack the carbonyl group directly
The reaction is done typically at -78 C in order to slow down the selfcondensation
The alkyl halide is added at this temperature and then warmed up
to room temperature
16