11.

Chemical reactions of aldehydes and ketones:

The reactivity of aldehydes or ketones arises from the polarization of the carbonoxygen double bond of the carbonyl group. This leads to 2 main types of reactions: 1. Nucleophilic addition reactions: The carbonyl carbon acts as electrophile. 2. Reactions at an -carbon 11.1. Nucleophilic addition reactions: It is the most common reactions of aldehydes and ketones. According to the nature and strength of the nucleophile (charged or uncharged), there are two main mechanisms for nucleophilic addition. 1. Nucleophilic addition with charged (Strong) nucleophiles. - The reaction starts by addition of the nucleophile at the carbonyl carbon followed by protonation of the resulting tetrahedral alkoxide intermediate to give the addition product.
Nu Chyarged nucleophile Nu = H
+ C

Nu C O

Trigonal ,R , CN Tetrahedral alkoxide structure

H2O Protonation

Nu C OH

2. Acid catalyzed nucleophilic addition with uncharged (neutral) weak nucleophiles The reaction involves protonation of the carbonyl oxygen to increase the electrophilicity of the carbonyl carbon. It gives a resonance stabilized carbocation which is readily attacked by a weak nucleophile to give the addition product . It is always an reversible reaction.
1

H+

Nu
C O H C O H

Nu C O H

H+

Nucleophiles = H2O, R-OH, R-SH, NH3, R-NH2 or R2-NH

Nu-H
11.1.1. Relative reactivity of aldehydes and ketones towards nucleophilic additions. Aldehydes are generally more reactive than ketones for two reasons. 1- Aldehydes have more electrophilic carbonyl carbon atom because there is only one (rather than two) alkyl or aryl group that donates electrons to the carbonyl carbon and reduces its electrophilicity by +I or +M respectively.
H H R O C H O C

R R

One +I alkyl group

Two +I alkyl +M Effect of aryl group

2- While the nucleophilic attack at the carbonyl carbon of ketones is hindered by two alkyl or aryl groups, only one alkyl or aryl group hinders the nucleophilic attack at the carbonyl carbon of aldehydes.

The order of increasing reactivity of the following aldehydes and ketones towards nucleophiles is:

H C H O

>

R C H O

>

R C `R O

Ar

Ar C O

Ar C O

>

>

> Ar C

R= Alkyl group and Ar= Aryl group

11.1.2. Nucleophilic addition of hydride ion: Reduction

Nucleophilic addition of hydride ion (strong nucleophile) to aldehydes or ketones leads to their reduction and formation of alkoxide intermediate which upon protonation gives alcohols. The hydride ion can be derived from a number of reagents such as metal hydrides or aldehydes lacking -hydrogens in the presence of a strong base (Cannizzaro reaction).

11.1.2.1. Complex metal hydrides: Lithium aluminium hydride (LiAlH4) or sodium borohydride (NaBH4) acts as hydride donor. Nucleophilic addition of the hydride ion to the carbonyl carbon atom of an aldehyde or ketone gives alkoxide intermediate which upon protonation gives 1o or 2o alcohol respectively. For examples:
O C H O R Li or Na H+/H2O C H H OH C H + LiOH or NaOH H 1o alcohol OH R C R + LiOH or NaOH H 2o alcohol R

i. R

LiAlH4 or NaBH4

An aldehyde O C R

ii. R

A ketone

LiAlH4 or NaBH4

Li or Na H+/H2O C H R O

LiAlH4 is a stronger reducing agent than NaBH4 because aluminium-hydrogen bond is more polar than boron-hydrogen bond.
i. LiAlH4 Li
+

ii. NaBH 4

Na+ + H

H Al H H H B H H

LiH

NaH

H H H H B H H Al

LiAlH4 reduction must be carried in anhydrous aprotic solvent such as anhydrous ether ( ). In contrast, NaBH4 can be carried in protic solvents such as water.
3

Metal hydride reductions are highly regioselective and can reduce the carbonyl group without affecting the carbon-carbon double bond. For example, while the catalytic reduction of 4-penten-2-one with H2/Pd gives 2-pentanol , the metal hydride reduction affords 4-penten-2-ol
OH H2/Pd 2-Pentanol 4-Penten-2-one O LiAlH4 or NaBH4 4-Penten-2-ol OH H

11.1.2.2. Cannizzaro reaction Heating of an aldehyde lacking - hydrogens such as formaldehyde, benzaldehyde or 2,2-dimethylpropanal with strong base such as sodium or potassium hydroxide gives a pair of an alcohol and a carboxylic acid salt. This reaction is called Cannizzaro reaction. It involves base initiated mutual oxidation and reduction of two molecules of an aldehyde lacking -hydrogens. A carbon atom adjacent to a carbonyl group is called -carbon and any hydrogen bonded to it are called -hydrogen. Aldehydes that possess -Hydrogen do not undergo Cannizzaro with base. They Undergo the Aldol reaction.

Cannizzaro reaction involves nucleophilic addition of the hydroxide ion to the carbonyl carbon of the aldehyde to give a potential hydride donor (Oxidation product). Hydride transfer from the oxidation product to a second molecule of either the same aldehyde (or to a different aldehyde molecule (crossed Cannizzaro) leads to an oxidation product (sodium salt of carboylic acid) and a reduction product (alcohol). The reaction mechanism is illustrated in the following equations:

11.1.2.3. Intramolecular Cannizzaro reaction.

Intramolecular Hydride transfer can take place in Cannizzaro reactions. For examples.

11.1.3. Nucleophilic addition of carbon nucleophiles: Formation of C-C bond. 11.1.3.1. Reaction with cyanide Reaction of aldehydes and ketones with hydrogen cyanide (HCN) in the presence of catalytic amount sodium or potassium cyanide KCN produce cyanohydrins (-hydroxynitrile).
O C OH C H

i. H3C CH2

+ H C N / Na CN

H3C CH2

Propanal

C N Propanal cyanohydrin OH C CH3

ii. H3C CH2

O C

Butanone

+ H C N / Na CN CH3

H3C CH2

C N 2-Butanone cyanohydrin

The reaction mechanism involves nucleophilic addition of cyanide ion (carbon nucleophile) to the electrophilic carbonyl carbon. The produced alkoxide intermediate reacts with the acidic hydrogen of HCN to give cyanohydrins. This reaction is reversible.
O C R` N R C R` H CN R OH C CN Cyanohydrin R`

O C R

+ C N

An aldehyde or ketone

CN Tetrahedral alkoxide intermediate

Sterically hindered ketones react slowly with HCN and give poor yield.

Cyanohydrins are useful intermediates for preparation of -hydroxy carboxylic acids via acid catalyzed hydrolysis of the cyanohydrin.

H3C CH2

OH C CH3

H /H2O

H3C CH2

OH C CH3 COOH

C N 2-Butanone cyanohydrin
11.1.3.2. Reaction with organometallics.

2-Hydroxy-2-methylbutanoic acid

The nucleophilic alkyl or aryl group of organometallic compounds ( as organolithium reagents (R) and Grignard reagent (

-Metal) such

-MgX) adds to the

carbonyl carbon of aldehydes and ketones in dry ether to form alkoxide intermediates. Subsequent protonation gives 1o, 2o or 3o alcohol.

O C + R R1 An aldehyde or ketone

R Metal
2

O R C R1 R2

OH H /H2O R C R1 R2

Organometallic compound

Alcohol

Metal = Li or MgX
By choosing the correct organometallic compound and the suitable aldehyde or ketone the appropriate 1o, 2o or 3o alcohol can be produced. For examples:

O 1) H C 1. Rmetal H
+

H R C OH Primary alcohol H

2. H /H2O Formaldehyde
O H

2. H+/H2O Any other aldehyde O 3) R C R

1

2)

1. R1Metal H

R C OH Secondary alcohol R1 R1

1. R2Metal 2. H+/H2O

R C OH R
2

Tertiary alcohol

A ketone

11.1.3.3. Reaction with phosphorus ylides: Wittig reaction. The carbanion of a phosphorus ylide adds to the carbonyl carbon of aldehydes and ketones to form alkenes in a very good yield. The reaction is called Wittig reaction.
O C P(Ph)3
+

O R C

P(Ph)3 C R2

R R1 C An aldehyde R3 or ketone

R1 R3

P(Ph)3 C R R Phosphorus ylide

3 2

O + R C R1

P(Ph)3 R2 C R3

Alkene

An ylide is a neutral molecule that has an electronegative carbon attached to the electropositive heteroatom. Phosphorus ylides are prepared from a nucleophilic substitution reaction between 1o or 2o (but not 3o) alkyl halide and triphenyl phosphine (Ph3P). The resulting alkyltriphenylphosphonium salts is then deprotonated by the reaction with a strong base such as alkyl or phenyl lithium (
R (Ph)3P Triphenyl phosphine
+

or
X + (Ph)3P

) to form the ylide.

R C H + Base

H C

R 1o or 2o alkyl halide

R Alkyl triphenyl phosphonium ylide + (Ph)3P R C R (Ph)3P C R

R Phosphorous ylide ( A hybrid of two resonance structure )

The following are examples for the preparation of phosphorous ylides. i.

(Ph)3P + H3C Br Triphenyl phosphine Methyl bromide

Br + (Ph)3P

H C H Bu-Li

H Alkyl triphenyl Phosphonium Ylide H C H (Ph)3P C

+ LiBr + Butane + (Ph)3P

H H Phosphorous ylide ( A hybrid of two resonance structure )

ii.
CH3 (Ph)3P + H C Ph Br (Ph)3P CH3 C Ph H

Bu-Li

Triphenyl phosphine

1-Bromo-1phenylethane (2o alkyl halide)

LiBr + Butane +

Alkyl triphenyl phosphonium ylide

(Ph)3P

C Ph

CH3

CH3 (Ph)3P C Ph

Phosphorous ylide ( A hybrid of two resonance structure )

Wittig received the Noble prize in 1979 because Wittig reaction is one of the best method for preparation of alkenes of any structure in quantitative yield. For example.
O H C + P(Ph)3 C CH3 O H C P(Ph)3 C CH3 H3C H C C + C H3C C H

Benzaldehyde

Z-1,2-Diphenylpropene E-1,2-Diphenyl propene

+

P(Ph)3

Mixture of cis and Trans isomers of an alkene often result from Wittig reactions when geometrical isomerism is possible.

11.1.4. Formation of acetals and ketals: Nucleophilic addition of alcohols as oxygen nucleophiles
9

The reaction of aldehydes and ketones with two molecules of an alcohol in the presence of anhydrous acid as a catalyst results in the formation of acetals and ketals respectively.
O C R' R
Aldehyde or Ketone HO-R'' / HCl Alcohol

HO C R'

OR''
HO-R'' / HCl

R''-O C R'

O-R'' R
Acetal

R
Hemiacetal

Alcohol

The reaction involves nucleophilic addition of one molecule of alcohol to the

carbonyl carbon of an aldehyde or a ketone followed by elimination of water to form hemiacetal or hemiketal which reacts further with a second molecule of alcohol to form acetal or ketal respectively.

H R C R1 -H +H
+

+ H

- Cl / - Cl -H
+

R C R
'

O H

R1

+ C R

OH

.. H O R2 - H O R
2

+ OR2 R1 C OH OR2 R1 C H O + R R2 + H+ OR R

OR R1 C

OR O H+ -H
+

OR2 C

..

H O R2 - H O R
2

R1

C O +

R H Hemiacetal

R - H2O H + H2O H

R1

R Resonance stabilised carbocation

- H+

OR R
1

R1

C OR

C R

Acetal

Hemiacetal and hemiketal are derivatives of an aldehyde and ketone having an OH and OR (alkoxy) groups bonded to the carbonyl carbon. Both acetal and ketals have two alkoxy groups attached to the carbonyl carbon of aldehydes and ketones respectively. Most hemiacetals and hemiketals cannot be isolated since they break back down to the original carbonyl compounds when the solvent is removed.

The reaction is reversible and as a result acetals and ketals are good protecting
groups for aldehydes and ketones from reaction with nucleophiles and bases. The
10

synthesis of the acetal or ketal is carried out under anhydrous acid conditions while the reverse reaction is carried out using aqueous acid.

Cyclic acetals and ketals are better protecting groups than acyclic ones. Formation
of an acetal using 1,2-alkanediol as the alcohol (e.g. 1,2-ethanediol) gives a cyclic acetal. For example:
O H O C HO H
+

C O

+
HO Ethanediol

Benzaldehyde

Benzaldehyde ethylene acetal

11.1.5. Formation of thioacetal and thioketals: Nucleophilic addition of thioalcohols as sulfur nucleophiles

Aldehydes or ketones react with two molecules of thioalcohols (R-SH) in the

presence of anhydrous acid as catalyst to yield thioacetal or thioketal respectively. The reaction mechanism is analogues to the formation of acetals and ketals.
O R C + 2 R-SH Thioalcohol H+ R RS C R' Thioacetal SR + H2O

R' Aldehyde or Ketones

Thioacetals are useful because they undergo desulfurization when treated with

raney nickel in the Mozingo reduction. This is an excellent method for reducing aldehydes or ketones to alkanes.
O H+ S + HS SH S Raney Ni /H2 H H

Cyclic thioacetal

11