Topic: IV

Chemistry of Carbonyl Compounds

Lecture slides are courtesy of:

Prof. Pradeepkumar P. I., IIT Bombay
Prof. Peter Volhardt, UC Berkeley
Prof. J. M McBride, Yale University
Oxford University Press
 Nucleophilic Addition to C=O
Curly arrow representation:

The C-O bond is polarized towards the more electronegative

oxygen
Nucleophilic Addition Reactions of carbonyls

Nucleophile Product
Water hydration
Alcohols acetal formation
HCN cyanohydrin formation
Ammonia derivatives Schiff bases
Grignard reagents alcohols
Ylides olefins
Hydrides reduction
Oxygen oxidation
1. Addition of HCN
Strong nucleophiles add to carbonyl as,

Tetrahedral intermediate (TI)

Achiral substrate to chiral products

prochiral faces
2a. Addition of alcohol
Weak nucleophiles add to carbonyl group of aldehyde
under acid catalysis,
acid-catalysed hemiacetal formation

acid-catalysed acetal formation from hemiacetal

2b. Addition of alcohol-intramolecular
Alcohols add to ketones to yield acetal.
Acyclic hemiacetals are not quite stable enough to be
isolated.
But cyclic hemiacetals as well as acetals are stable

acetal
2c. Importance of cyclic acetals
Cyclic acetals are stable to water, bases and nucleophiles
but labile to acids
These features are useful as a means to ‘protect’ aldehydes
and ketones
Example for protection and deprotection,

protection
deprotection
2d. Importance of cyclic acetals
Nature uses the stability of cyclic hemiacetals
E.g., glucose has a cyclic hemiacetal structure than the
corresponding open-chair structure

Favored by entropy relative to intermolecular addition;

ΔG ° = ΔH ° - TΔS °
ΔS ° is less negative for intramolecular reaction.
Chemistry of Carbonyl Compounds
Part-II: Enols & Enolates
 Enols
Keto-Enol tautomeric equilibrium leads to enol formation

K = 10-6

For a normal ketone under ordinary conditions only one in

106 exist as enol
 Catalyzed enol formation

(i) Acid catalyzed enol formation

(ii) Base catalyzed enol formation

 Enloates are conjugate bases of enols

Enol Resonance stabilized enolate anion

Alternatively, the acidity of a-hydrogen (next to carbonyl

carbon) helps to generate enolate anion

Enolates are powerful carbon nucleophiles!

 A general idea of pKa values

O
H + B + BH

One can use iPr2N- (pKa of conjugate acid ~ 36) for deprotonation of CH3COCH3
(pKa = 26.5) in such a way that equilibrium will be almost exclusively towards
enolate.
 Reactivity

One has to look at C=O as well. Due to the polarization of C=O bond,
it can act as an electrophile at carbon centre or as a nucleophile (or
base) through oxygen or α-carbon centre (of the enol from)

δ+ δ- δ+ δ- OH
O O E or
Nu
E
electrophile nucleophile
 Direction of enolization
With the help of suitable experimental conditions good regio
control can be obtained in enolization

Excess ketone, Ph3CLi (base)

Kinetic Thermodynamic
 Kinetic and Thermodynamic Control
General Features
Kinetic Thermodynamic
•Thermodynamic refers to
•Kinetic refers to SPEED feasibility (stability)
•Governed by activation energy •Governed by heat of reaction
•Shows propensity to be reversible •Products are usually not quite
reversible

Kinetic Thermodynamic
 The aldol reaction

Aldehyde (as well as ketones) can undergo self-

condensation upon treatment with suitable bases
O O
OH O
+ Base
H3C H H3C H H3C H

The product contains both aldehyde and alcohol functional

groups, hence the reaction is known as aldol reaction

O OH

H CH3

aldehyde alcohol

Remember: aldol is not ‘named’ after anyone!

 The aldol reaction
Basic condition
H H
O
O O O
+ O O OH O
OH + H
H H CH 2 H CH3
H 3C - OH H 3C H
H
aldol product

OH O OH O O
H 3C H H 3C H H 3C H
H
aldol condensation
OH product

Acidic condition

O HO OH O OH O
+ H OH 2 + H 2O +
H 3C H H 2C H H 3C CH 2 H CH3 H 3C CH3
- H 3O
H
- H 3O H 3O

O O OH 2 H 3O O OH

H 3C CH3 H 3C CH3 H 3C CH
- H 3O 3
 The aldol reaction

How to ensure that the aldol product rather than aldol condensation
product?
O
O LDA O OH
O H
Ph CH3 Ph
-78 oC, THF Ph CH 2
then H 3O+
 The Claisen Condensation
Base catalyzed condensation between two esters.
Only one of the esters can undergo enolization while the other serves as
an electrophile (acceptor)

In other words, one ester has acidic a-hydrogen and the electrophile(or
acceptor molecule) do not have a-hydrogens

electrophile
 Mechanism of Claisen Condensation

TI Claisen Product

What about the situation where both esters have acidic a-

hydrogens?
OR
What if both esters can undergo enolization?
 Crossed-Claisen Condensation
If both esters can undergo enolization, a mixture of products are
formed,
R1 R2

E1 E2

(i) Self condensation (ii) Crossed condensation

E1R1 E1R2

E2R2 E2R1
 Intramolecular Claisen (Dieckmann) Condensation
In the case of acylic diesters, where the ester groups are at suitable
positions, an intramolecular Claisen condensation would lead to a
cyclic ester as the product.
Intramolecular Claisen condensation where the ester enolate as well as
the acceptor electrophile are part of the same molecule is known as
Dieckmann condensation
 Conjugate addition
Activated double bonds are the ones which are connected to electron
withdrawing groups such as CO, CHO, COOH, CN, NO2 etc.,

1,2-additions* are also known as direct addition

1,4-additions are known as conjugate addition

* Addition of Nu and H+
 Additions to a,b-unsaturated carbonyl compounds

Key factors that control conjugate addition are,

(i) Reaction conditions
(ii) Nature of the a,b-unsaturated carbonyl compound
(iii) Type of nucleophile
Kinetic versus thermodynamic products

DG‡(reaction) DG(reaction)

speed product stability

reversible irreversible
lower temp higher temp
 Direct versus Conjugate additions
Strong nucleophiles generally exhibit direct addition

85%

‘Me2Cu’ generated by mixing MeMgBr and CuCl

Copper is less electropositive than Mg [Cu(1.9), Mg(1.3)]. Hence the C-Cu bond is
less polarized and gives less partial negative charge as compared to that with Mg
 Michael Additions
Nucleophilic addition of stabilized carbanion (carbon
nucleophiles) a,b-unsaturated carbonyl compounds
Michael addition

aldol
Application to steroid synthesis:

Acidic -H