Reactions of Carbonyl Compounds

Outline 1. Addition to the carbonyl group of aldehydes and ketones 2. Reduction of aldehydes and ketones 3. Reaction of aldehydes and ketones with the Gringard Reagent 4. Reactions of aldehydes and ketones with ammonia and its derivatives 5. The Wittig Reaction 6. Oxidation of aldehydes and ketones 7. Aldehydes and ketones as electrophiles 8. Acidity and basicity of carboxylic acids 9. Conversion of carboxylic acids to esters 10. Conversion of carboxylic acids to acid chlorides and anhydrides 11. Decarboxylation

12. Reactions of carboxylic acid derivatives with nucleophiles 13. Hydrolysis of carboxylic acid derivatives 14. Reduction of carboxylic acid derivatives 15. Formation of enoles and enolates 16. Reactions of aldehydes and ketones, involving enolates 17. Reactions of esters and acids, involving enolates 18. Reactions of a,b-unsaturated carbonyl compounds 19. Reactions of a-halocarbonyl compounds

1. Addition to the carbonyl group of aldehydes and ketones

CH2 1.34 A H3C H H3C O 1.21 A H

The carbonyl group (C=O bond) is shorter, stronger, and more polar, than the C=C bond CH2 H3C CH3 H3C O O CH3 R CH2 H Aldehydes (R is H) or ketones (R is not H) Reacts with bases Reacts with nucleophiles Reacts with acids

b.p. = -6.9 oC = 0.5D Unsoluble in water

b.p. = 56.5 oC = 2.7D Soluble in water

NuR1 R

OH Nu R1 H
+

Nu R R1 NuO C
+

H R R1

R1

R1

Activation of the carbonyl group

Aldehydes are more reactive, than ketones due to the steric reasons and a larger positive charge on the carbonyl carbon in aldehydes.

Addition to C=O bonds is faster, than addition to C=C bonds due to the higher polarity of the C=O bond, but less favorable thermodynamically due to the stronger C=O bond vs. the C=C bond. Example: Cyanohydrin synthesis

Acetals and their use in synthesis

O R2OH, H or OH R R1
+ -

OH OR2 R R2OH, H+

OR2 OR2

R1 R R acetal 1 hemiacetal Stable at neutral conditions Stable at neutral and alkaline conditions

OH

HO

R2

OH O

H
+

R O H
+

R1

R1

R2 OH

H R R1 O
-

OR2 O R2 R R1 hemiacetal

O R2 R

OR2 R1

H OR2 OR2 OR2 R acetal R1 OR2 H O OR2 C R

+ +

OH OR2 R R1 hemiacetal

R1

R2

H O R2

R1

R1

Examples:

O CH3 CH3OH, H+

OCH3 OCH3 CH3 Methyl phenyl ketone dimethylacetal

O HOCH2CH2OH, H+ O

Cyclohexanone ethyleneacetal

2. Reduction of aldehydes and ketones

O NaBH 4 R CH3OH R1 CH3 H O H R R1 H B H H
-

OH H R R1

O OH H R R1 CH3

O H B H
-

H This anion can reduce three more carbonyl groups

The carbonyl group can be reduced by catalytic hydrogenation, but it is less reactive, than the C=C bond
OH H2, Ni Heat, pressure H O H2, Pd/C H O

Cannizzaro Reaction

Crossed Cannizzaro Reaction

O H O OH-, H2O H OH O

3. Reaction of aldehydes and ketones with the Gringard Reagent (ORA 737) Synthesis of Grignard reagents
Most hydrocarbons are so weak acids, that it is practical to substitute hydrogens with metals indirectly (ORA 737)
Solvent CH 2 H3C Li (C2H5)2O Mg Heat H3C CH 2 MgBr

+
Br

Grignard's reagent (C2H5)2O CH 2 H3C Li Ethyl magnesium bromide

H3C

CH 2

+
MgBr

H2O

H3C

CH3

+ Mg(OH)Br

Nucleophilic addition of Grignard reagents to the carbonyl group

Depending on R, R1, and R2, the reaction can produce primary, secondary or tertiary alcohols. R-Li is often used instead of R-MgBr. Example:
O 1. CH3(CH2)3Li H3C CH3 2. H+, H2O H3C 80% OH

(CH2)3CH3 CH3

If the ketyl radical is stabilized, the reaction switches to the redox-path

4. Reactions of aldehydes and ketones with ammonia and its derivatives

. . H C . R3 H if R1 = H . . H C N R3 . . if R2 = H . -H2O H C . carbinolamine OH R2 N R3 . enamine -H2O . . C R2 N R3 .

R1

. . C

R2

R1 N
+

R2 R3

imine, if R 3 starts from H or C oxime, if R 3 = OH hydrazone, if R 3 = NH2

Examples:

H NH2 Heat

H N

+
HN O O2N

-H2O NH2 H3C NO2 Heat -H2O NO2 H3C N O2N NH O2N NO2

+
H3C CH3

H3C

H3C NH CH3

+
H3C H

H+ -H2O

H3C

H3C O KOH H2N NH2 H2N N Heat -N2

82%

Imine formation (ORA 726)

HN H3C H3C O H

CH3 H3C

H+ - H2 O

H3C H3C

N H

Enamine
NH2 CH3 N

KOH
H2N NH2

CH3

+
NH2 N CH3

Hydrazone

KOH - H2O 82% OH- H2 O

N CH3 H O H

CH3

Wolff-Kishner reaction
NH
-

- OHNH N CH3
-

- N2 OH- H2 O

N N

CH3 H O

- OH

5. The Wittig Reaction (ORA 745)

O P Ph O Ph CH2 Ph Ph Ph NaH Ph H3C P Br
+

Ph Ph

H2C

P Ph

Ph

Ph Br Ph S N2 CH3 P Ph Ph

Ph

This reaction is a common method for conversion of carbonyl compounds to alkenes

6. Oxidation of aldehydes and ketones

O R H KMnO4, H2O, H+ or K2Cr2O7, H2O, H
+

O R OH

O Ag2O, H2O, NH3 R H R

O
-

Ag

Tollens Reagent

Silver mirror test

O O

R R O R1 Heat R1

KMnO4, H2O, H

+
OH

R1 OH

+
OH

R OH

Bayer-Villiger oxidation (ORA 989)

8. Acidity and basicity of carboxylic acids

O R OH H
+

O R O
-

Carboxylic acids are stronger acids, than phenol, because the conjugate base (carboxylate) is stabilized by the delocalization of the negative charge between two electronegative oxygens.
Acidity trend:

OH

HO 3S

OH pKa = 16

<
pKa = 10

<

R OH pKa = 5

<
pKa = -1

O R O
+

H H

O R OH

O R

H R C
+

OH O R O
+

H O H

9. Conversion of carboxylic acids to esters Fischer esterification (ORA 896)

O R
+

+
OH H

H CH3OH

R O OCH3 H R O O ~H+ R
+

O R

H R

CH3

OH CH3OH H

OH CH3

O CH3

OH

Alkylation of salts
O R O Na
+

H3C

I R

OCH3

Alkylation of acids by diazomethane

solvent O R OH diazomethane (yellow gas) O (C2H5)2O CH2N2 R

+
OCH3

N2

Mild formation of esters

DCC (dicyclohexylcarbodiimide)

O R N C N O

+
H

DCC CH3OH

R OCH3 H N C O H N

H N
-

H N C N C O CH3OH O R O O
+

N C O ~H+ R O
+

H CH3

R H

10. Conversion of carboxylic acids to acid chlorides and anhydrides

O R O O

+
H

SOCl2 thionyl chloride

R Cl

HCl

SO2

O R O O H3C O

+
H

PCl5

R Cl

+
O

HCl

POCl3

O P 2O5

H3C O

+
H

H3C O H H3C O COOH P 2O5 COOH O O

acetic anhydride O

phthalic anhydride

11. Decarboxylation (ORA 983)

O NaOH, melting R O NaOH H2O O R O
-

R H

Na2CO3

NaOH

R-

CO2

O slight heating R O O slight heating HO O O H CO2 ~H+ HO OH O O H CO2 ~H+ R OH O

HO

12. Reactions of carboxylic acid derivatives with nucleophiles

O O Nu X R Nu X R
-

+
Nu

Reactions of acid chlorides (ORA 949)

O PhCH2CH2NH2 Cl Pyridine

NH

H2N

Py O Cl
+

NH2

NH2

O O CH3C(O)Cl H3C H3C H3C CH3 CH3 Pyridine O OH H3C 75% O Cl O Cl S O Py O S O TsCl H3C O O 60% O 90% Py O CH3 CH3 CH3 CH3 CH3

HO

+
OH O Cl H3C O

Na O

Reactions of anhydrides
NH2 HN

O CH3

+
OH

O O O

H2O Paracetamol OH O

OH COOH

CH3 COOH

O O O

H2O

Aspirin O O O CH3OH, reflux O CH3 O O O O NH2 Heat NH OH O Acetic anhydride heat O N O O COOH

Reactions of esters
O NH3 O

+
NH2

OH

O NH2OH O

O OH NH

OH

A hydroxamic acid (forms a red complex with Fe(III))

Alkaline hydrolysis of esters (ORA 955)

Reaction of esters with Grignard reagent

O 1. 2CH3MgBr R OR1 2. H+, H2O R OH CH3 CH3

H H3C MgBr

OR1

O Mg

Br

CH3 R O Mg Br CH3 R OR1 R CH3

+

O H3C

CH3

MgBr

13. Hydrolysis of carboxylic acid derivatives

O O O R1

+
R OH OR1 R OH

R R O

+
-

Acid-catalyzed hydrolysis of esters is the reaction of esterification, going backwards.

H COOH

H2O 25 oC

COOH 94%

H2O, 0 oC 5 min CH3COOH

HCl

Cl

O NH2 55% H2SO4 heat 90%

OH

NH4HSO 4

O HN NO2 30% KOH CH3OH, H2O, heat O O

NH2 NO2

CH3COOK

97%

Nitriles are less active for hydrolysis

CN

57% H2SO4 heat O

COOH

NH4HSO 4 O

CN

KOH, H2O heat

H+

OH

Hydrolysis of sulfonic esters

O S O R R1 O R2 O H R1 S O R O
-

R2

OH-

S N2

OH

Alkaline and acidic hydrolysis of nitriles

R R C N C HO N
-

~ H+

R C O
-

R NH H O H

- OH

C O

NH2

OH-

H O

H H NH
+

- H+ ~ H+
C NH R H O C NH2
+

H
R C N

14. Reduction of carboxylic acid derivatives

O 1. LiAlH4 R OC2H5 H
-

a source of H R CH2OH
+

2. H , H2O

H O
-

O R

O R

R H OC2H5

O 1. LiAlH4 R NH2 2. H2O R NH2

CN

1. LiAlH4 2. H2O 74%

NH2

H2 / Ni O R Cl -78% H Li
+

O Pd / C, H2, quinoline R H

Al O O

O 1. (CH3)2CuLi, -78 C Cl 2. H2O 81%

o

15. Formation of enoles and enolates

O a strong and polar bond O . . H . R . enolate (a common conjugate base) R O
-

. base

C .

R acid .

OH

R . enol

The equilibrium is strongly shifted toward the carbonyl form, especially in polar solvents
O K = 6.10-7 H3C H H2C H OH

In esters, enolization is even less favorable due to stabilization of the carbonyl group.
O OH H3C O
-

OC2H5

K = 10-20 H2C OC2H5

H3C

OC2H5

Stabilization of the carbonyl form decreases acidity of the compound

CH2 O O

H2C H pKa = 42

H2C H pKa = 25

OC2H5

H2C H pKa = 17

Stabilization of the double bond (by conjugation) shifts the equilibrium toward the enol.
H O O O O

H3C

CH2

CH3

H3C

CH 92% in hexane HO

CH3

O K = 1014

Enolization, catalyzed by acids

O . . H R . H H
+

H OH H2O . R . enol

. R

16. Reactions of aldehydes and ketones, involving enoles and enolates

a-Monohalogenation (ORA 830)

O CH3

CH3COOH Br 2 25 oC

Br 70%

H OH Br CH2 Br O C
+

-H

Br CH2

The haloform reaction

CHCl3 - chloroform
O CH3 1. OH-

CHBr3 - bromoform
O

CHI3 - iodoform

Br 2

OH H
+

2. H+

+
O

CHBr 3

HO

O O
CH2

OH Br

O Br Br Br O Br CH2 Two more times Br The reaction also works with Cl2 and I2 HO
-

OH O Br Br

Br

CBr3

Aldol reaction (acid catalyzed)

R1 O R2 R3 H R1 O R2
+ +

R4

H O H R4
+

R1 R2 R3

R4

-H2O OH

+
OH R3

R1 R2

R4

O R3

R1 R2

OH R 4 H C R3
+

-H O

Aldol reaction (base catalyzed, ORA 840, 852)

R4 HO R4 HC
-

R1 R2 R3

R4

HO O

O R3

R3 R1 O R2 R2 R3 O R1 O
-

-H2O OH

R4

R1 H2O R2

R4

O R3

Examples:

O O H O

H2SO4 95%

OH

O Ba(OH)2 heat KOH heat

17. Reactions of esters and acids, involving enolates

Br Br2, PBr3

a-Bromination of carboxylic acids

COOH PBr 3 Br H or PBr3 O OH Br

+

COOH Br COOH Br O -HBr

Br 2

At least two hydrogens must be there! R2 H H R2 HC

-

O 2. H+

R2

1. R3COOR4, base O R3 R1 O H R1 Ketone or aldehyde or ester

+

base O

O C R3
-

R2

R1 R3 O O R4 O R4 R1 O R3 O
-

O R1

Highly acidic hydrogen R2 O R2 Base

R3

R1 b-Ketoester or b-diketone

Claisen condensation
O 1. NaOC2H5 O 2. H+ 75% H O H2C
+

O O

O O CH Base
-

O O

O O O O O
-

O O

Crossed Claisen condensation

O O

+
O

1. NaOC2H5 O O 2. H+
+

O O

O O 86%

H O CH O O O Base O O O
-

O O O C
-

O O

O O O O O O

Dieckmann condensation
O O 1. NaOC2H5 O O 2. H
+

O O 80%

Synthesis of carboxylic acids from the malonic ester

COOEt R COOEt Base COOEt HC
-

R1

H2O, H -CO2

R R1

COOEt

COOH

COOEt

R1 COOEt

Br

R COOEt

Br

R COOEt

Base R

COOEt C
-

COOEt

Synthesis of ketones from the b-ketoesters

R O R1 COOEt Base R O HC
-

R O -CO2 R2 H2O, H
+

R R1 R2 O

COOEt

R2 R R O Base R1 COOEt R1 C
-

Br

R1 COOEt

Br

COOEt

18. Reactions of a,b-unsaturated carbonyl compounds

Electrophilic addition
O O
+

HBr

Br

O O 84%

~H+ O Br O
+ -

Br

O O

Nucleophilic (Michael) addition (ORA 858)

Nu R O Nu1,4-addition Nu
-

R OH

H2O R Nu O R

1,2-addition

Nu

O Irreversible and especially preferred by very strong nucleophiles

R Nu O
-

In most cases reversible

O HCN KCN

CN

OH O 1. (CH3)2CuLi

90% OH 1. PhLi 2. H2O O 2. H2O

Selective reduction of a,b-unsaturated compounds

O H2 Pt, 3 atm 90% O 1. LiAlH4 2. H2O 98% O

HO

19. Reactions of halocarbonyl compounds

O Hal R . Slower, than for alkyl halidesSN1 . NuNu SN2 Faster, than for alkyl halides . NuO . .
+ +

R .

O . R .

This structure has a little contribution to resonance

1. NaCN Cl COOH 2. H+ NC 80% COOH Cl COOH

OH Cl 1. OH-

+
Cl

Cl

COOH

2. H+ Cl 87%

(2,4-dichlorophenoxy)acetic acid

(a selective herbicide)

Decarboxylation-elimination
1. OH-, heat 2. H+ HO HO
-

Br

H2C

CH2

CO2

Br

Br
-

O O