Carboxylic acids and Derivatives

OH

Carboxylic
Acid

Ester

R
R

Carboxylic
Acid
Anhydride

Cl

Acid Chloride

NH2

Amide

Preparation: Oxidation (Which of the follow reactions will produce carboxylic acids?
O

HO

KMnO4/NaOH

O
CH3

KMnO4/NaOH

KMnO4/NaOH

H3C

Carbonyl compounds

KMnO4/NaOH

Nucleophilic Addition-Elimination at the Acyl Carbon

Recall that aldehydes and ketones undergo nucleophilic addition to
the carbon-oxygen double bond

The nucleophile reacts at the carbonyl group to form a tetrahedral

intermediate
The tetrahedral intermediate eliminates a leaving group (L)
The carbonyl group is regenerated; the net effect is an acyl substitution

Carbonyl compounds

To undergo nucleophilic addition-elimination the acyl compound must have a

good leaving group or a group that can be converted into a good leaving group
Acid chlorides react with loss of chloride ion
Anhydrides react with loss of a carboxylate ion
Esters, carboxylic acids and amides generally react with loss of the
leaving groups alcohol, water and amine, respectively (These leaving
groups are generated by protonation of the acyl compound)
Aldehydes and ketones cannot react by this mechanism because they
lack a good leaving group

Carbonyl compounds

Relative Reactivity of Acyl Compounds

The relative reactivity of carboxylic acids and their derivatives is as follows:

In general, reactivity can be related to the ability of the leaving group to depart
Leaving group ability is inversely related to basicity
Chloride is the weakest base and the best leaving group
Amines are the strongest bases and the worst leaving groups
As a general rule, less reactive acyl compounds can be synthesized from more
reactive ones
Synthesis of more reactive acyl derivatives from less reactive ones
is difficult and requires special reagents (if at all possible)

Carbonyl compounds

Acid Chlorides
Synthesis of Acid Chlorides
Acid chlorides are made from carboxylic acids by reaction with thionyl chloride,
phosphorus trichloride or phosphorus pentachloride
These reagents work because they turn the hydroxyl group of the carboxylic acid
into an excellent leaving group

Carbonyl compounds

Mechanism 1

Mechanism with Thionyl Chloride

(Nucleophilic addition-elimination reaction)

Carbonyl compounds

Mechanism with Phosphorous Trichloride

(Nucleophilic addition-elimination reaction)
O
+

C
R

OH

Cl

Cl
+
P

O
+

C
R

Cl

Cl
HO

O
C
Cl

O
Cl

+ Cl

Cl

Cl

Cl

P
Cl

reacts two more times

Cl

Reactions of Acyl Chlorides

Acyl chlorides are the most reactive acyl compounds and can be used to make any of
the other derivatives
Since acyl chlorides are easily made from carboxylic acids they provide a way to
synthesize any acyl compound from a carboxylic acid
Acyl chlorides react readily with water, but this is not a synthetically useful reaction

Carbonyl compounds

Carbonyl compounds

Mechanism 2

Mechanism 3

Carbonyl compounds

All the Mechanisms are similar.

The main difference is the nucleophile

O
R

O
+ C

H3 C

R
R

OH
NH2

O
+

Cl

H-Nu

H3C

Nu H

H3C

Cl
sp3 tetrahedral
intermediate

Nu H + Cl

H-Nu
or solvent
O
+

H3C

Carbonyl compounds

Nu

+ NuH2

10

Carboxylic Acid Anhydrides

Acid chlorides react with carboxylic acids to form mixed or symmetrical anhydrides
It is necessary to use a base such as pyridine to remove the proton on the OH group
This is not a mechanism
It is a thought process

forms tetrahedral intermediate

chloride leaves
Sodium carboxylates react readily with acid chlorides to form anhydrides

Carbonyl compounds

11

Cyclic anhydrides with 5- and 6-membered rings can be synthesized

by heating the appropriate diacid

Reactions of Carboxylic Acid Anhydrides

Carboxylic acid anhydrides are very reactive and can be used to
synthesize esters and amides
Hydrolysis of an anhydride yields the corresponding carboxylic acids

Carbonyl compounds

12

Carbonyl compounds

13

Mechanism 4

Carbonyl compounds

14

Esterification
Mechanism (acid catalyzed)
O
C

R1

O
R1

OH

R1

H2SO4 or HCl
OH

R2

OH
H

O
OH

R2
H

H
C

R1

R1

C
+

R2

OH

R1

C
+

OH

OH
R2

H
Proton
Transfer

O
+

R1

C
O

OH2

R1

R2

+ H2O + H+
(regenerates catalyst)

R2

Esterification is an equilibrium reaction. To make the reaction favor the ester

side use excess of either reagent (the alcohol or acid) and remove water. To
push the reaction to the hydrolysis side of the equilibrium use a large excess of
water by refluxing with a dilute acid.

Carbonyl compounds

15

Mechanism 5

OH

O
O

H+

This is not a mechanism

It is a thought process

Carbonyl compounds

16

Examples
O

O CH3OH O
4

1
2

O
H

H2SO4

1
2

This is not a mechanism

It is a thought process

H
+

H3C

O
CH2OH

C OCH2CH3 +
Excess

O
H3C

Br

sp2

H2SO4

Trans-Esterification

Br

acetone

ONa

Carbonyl compounds

17

Lactones
- or -Hydroxyacids undergo acid catalyzed reaction to give cyclic esters
known as - or -lactones, respectively

Carbonyl compounds

18

Amides
Amides can be prepared from acyl chlorides, acid anhydrides, esters,
carboxylic acids and carboxylic salts

NH3

NH2

NH

Leaving Group

O
+ H-Leaving Group

C
R

NR2

Carbonyl compounds

19

nucleophile
(base)

O
CH3CCl +
+

HN

Examples

CH3

H3C

CH3

H3C

CH3 + Cl

Cl

electrophile
(acid)

NH
Excess

NH2

CH3

H3C

CH3

CH3
O

O
NHCH3

O + H2N CH3
O

NHCH3

H 3 O+

OH

NH3CH3

Carbonyl compounds

20

Examples

O
+

O
+ NH3

O
CH3COH + NH3

O
HOCH2CH2CH2CNH2

O
+

+ NH4
CH3CO
solid salt

heat

O
CH3CNH2 + H2O

dehydration of the salt produces the amide

but generally in poor yield
A good way to synthesize an amide is to convert a carboxylic acid to an acid
chloride and to then to react the acid chloride with ammonia or an amine
Dicylohexylcarbodiimide (DCC) is a reagent used to form amides from carboxylic
acids and amines

Carbonyl compounds

21

DCC activates the carbonyl group of a carboxylic acid toward

nucleophilic addition-elimination

Carbonyl compounds

22

Hydrolysis (acid or base) of Carboxylic Acid Derivatives

-O
C
+
H3C

O
Dilute acid or base
Derivative

H
O

H3C

Heat

C
OH + H

Derivative

H
When using acid conditions it is called a hydrolysis reaction.
When using basic conditions it is called saponification
O
H3C

O
H2SO4/H2O

C
OCH3

H3C

O
H3C

OH + H

OCH3

C
NH2

NaOH/H2O

H3C

OH + H

Carbonyl compounds

NH2

23

Mechanism 6

Mechanism for the acid catalyzed Hydrolysis of an Ester:

Carbonyl compounds

24

Mechanism 7

Mechanism for the Saponification of an Ester:

Carbonyl compounds

25

Mechanism for the hydrolysis of the Nitrile

R

H+

H2O

OH2

Proton
Transfer

R
H

O
C

H
R

H
-H

H2O

H
N

O
R

C
OH2

H+

amide

- H+

H Proton

Transfer

N
H

H
+

C
OH

H
H
H

O
R

OH + NH3

H+

NH4

Carbonyl compounds

26

What are the products of the following reactions:

+
C -N
C

NaOH/H2O

H2SO4/H2O R

NH2

NaOH/H2O

H2SO4/H2O

C
NH2

Cl

NH2

NH2

RCO2H + NH4

OH

RCO2H + NH4
NH2
O

RCO2 + Cl

C
OH

Cl

H2SO4/H2O

C
Cl

RCO2 + NH3

NaOH/H2O

R
+

O
R

H2SO4/H2O

O
R

RCO2 + NH3 + HO

O
R

NaOH/H2O

NH2

NH

O
R

(not balanced)

H
RCO2H + Cl

Cl
Carbonyl compounds

27

Mechanism 8

Urethane

Carbonyl compounds

28

Mechanism 9

Urea

Carbonyl compounds

29

Summary
R

Cl
O

NaCl
R
O

ROH

R
HCl

ONa

HCl

RR'NH

O
R

ROH

OH

RR'NH

O
R

OH

O
R

All downward arrows

indicates that this
conversion is possible in
one step

ROH

RR'NH

O
R

R
R'

R' could be a hydrogen

Carbonyl compounds

30

Aldehydes and Ketones

The carbonyl group is susceptible to
nucleophilic attack.
Electrophile
(acid)

Nucleophile
(base)

Addition of a Strong Nucleophile

Carbonyl compounds

31

Reactivity of Aldehydes and Ketones

Aldehydes are generally more reactive than ketones
Two factors:

1) the amount of positive charge on the carbonyl carbon and

2) steric interaction.

The tetrahedral carbon resulting from addition to an aldehyde is less sterically

hindered than the tetrahedral carbon resulting from addition to a ketone
Aldehyde carbonyl groups are more electron deficient because they have only
one electron-donating group attached to the carbonyl carbon

R + R

R + H

H + H

alkyl groups are electron donating

increasing reactivity
O

O
H

decreasing steric interaction increasing reactivity

Carbonyl compounds

32

Acid catalyzed Nucleophilic Addition of a Nucleophile

Carbonyl compounds

33

Reaction with Water

O

R
+
R
acid
electrophile
O

base
nucleophile
+ H2O

Cl3C H
chloral
+

OH

OH

H+
+ H2O

OH

Cl3C

H
OH

hydrate (generally
not stable)

chloral hydrate chief

ingredient in knock out drops

electron withdrawing makes carbonyl carbon

more reactive (more positive)
Formalin is a 10% solution of formaldehyde
in water; used as a disinfectant or to
OH
O
preserve biological specimens.
H+
methylene hydrate HOCH2OH reacts
+ H2O
H
H
with various parts of proteins to form
H
H
OH
methylene cross-links to fix and stabilize
formaldehyde
the proteins and stop decomposition.
no alkyl groups

Carbonyl compounds

34

Oxygen Nucleophiles
Reaction with alcohols: Acetal and Ketal formation
OR2
OH

O
R

R2OH

R1

H 3 O+

R1 = alkyl or H

H 3 O+

R1

R1 + H 2 O + H+

OR2

OR2
hemi-ketal
R1 = alkyl
memi-acetal R1 = H

ketal R1 = alkyl
acetal R1 = H

acid catalyst

Example
O
H3C

CH3CH2OH, H

OCH2CH3

OH
+

H3 C

OCH2CH3

H 3 O+
-H2O

H3 C

memi-acetal

Carbonyl compounds

+ H2O + H+

OCH2CH3
acetal R1 = H

35

Mechanism

base
acid

- O
H3 C

C
+

H3 C

O
C

electrophile

H3 C

nucleophile
CH3CH2OH

H3 C

CH2CH3

resonance structures
both are occurring at the same time
base

- H+

H3 C

acid/base
not shown

acid

CH2CH3

H3 C

CH2CH3

H3 C

-H

H3 C

acid/base
CH2CH3 not shown
acetal

H2O great leaving group

- H2O

CH2CH3

H3 C

CH2CH3
electrophile

H+

hemi-acetal
O

CH2CH3

CH3CH2OH
nucleophile

CH2CH3

Carbonyl compounds

H3 C

CH2CH3

resonance stabilized
carbocation

36

OR2

OH

R2OH

R1

H 3 O+

R1 = alkyl or H

R1

H 3 O+

OR2
hemi-ketal
R1 = alkyl
memi-acetal R1 = H

R 1 + H2 O + H +

OR2
ketal R1 = alkyl
acetal R1 = H

acid catalyst
This is a reversible reaction and usually the reverse reaction is favored (aldehyde).
The reaction can be made to go forward by dissolving the aldehyde in an excess of
anhydrous alcohol and add an anhydrous acid or by removing the water that is
formed in the reaction. This can be done by azeotropic distillation with benzene, or
adding molecular sieves that absorb water or by using a quenching agent like AlCl2

Carbonyl compounds

37

Acetal formation from ketones and simple alcohols is less

favorable than formation from aldehydes
Formation of cyclic 5- and 6- membered ring acetals from ketones is,
however, favorable
Such cyclic acetals are often used as protecting groups for aldehydes
and ketones
These protecting groups can be removed using dilute aqueous acid

Carbonyl compounds

38

Mechanism 10

Carbonyl compounds

39

Nitrogen Nucleophiles
The Addition of Primary and Secondary Amines
Aldehydes and ketones react with primary amines (and ammonia)
to yield imines
They react with secondary amines to yield enamines

Carbonyl compounds

40

Mechanism 11

The reaction is pH dependant. If it is too acidic RNH 2 will protonate (RNH2 + H+ RNH3+) and will
no longer be a nucleophile. Elimination of water increases with increasing pH but will slow
down the first step of the reaction. The optimal pH is 3-4. Some of the amine will be protonated
but there will be enough free base for a reaction to occur.

Carbonyl compounds

41

Reactions
reagent

(R) NH2

hydroxylamine

(HO) - NH2

Product
OH

R1

hydrazine

R2
NH2

(H2N)-NH2

a hydrazone

N
R1

arylhydrazine

an oxime

(Ar-NH)-NH2

R2

R1
N

H
N

R2

an
arylhydrazone

Ar

semicarbazide

H
N

O
H2N

NH

O
C

NH2

NH2

R1

a semicarbazone

R2

Carbonyl compounds

42

Common aromatic compounds used:

NH NH2

phenylhydrazine

Note: When R = H (i.e. a

reaction with NH3) the
unsubstituted imine results
is unstable and will
polymerize.

O
CH3

S NH NH2

tosylhydrazine

O2N

NO2

Example
H3C

2,4-dinitrophenylhydrazine (2,4-DNPH)

NH NH2

O
+
C

leaves as H2O

NH2

electrophile
(acid)

H3C

nucleophile
(base)

C6H5-NH-NH2 + CH3CH2COH

C6H5-NH-N=CHCH2CH3

nucleophile
(base)

CH

O
CH3CH2CH

electrophile
(acid)

Carbonyl compounds

43

Enamines
Secondary amines cannot form a neutral imine by loss of a second proton on nitrogen
An enamine is formed instead
Mechanism 12

Carbonyl compounds

44

Carbon Nucleophiles
OH

Grignard Reactions (previously looked at)

Cyanohydrin Formation

O
+

NaCN-HCN
buffer

Slightly
alkaline

CH2NH2

H-CN

O
C

H
C

1) LiAlH4/Et2O
2) H2O
OH
C

H
C

N
95% H2SO4
heat

CH3CH2CH=CH-COOH
unsaturated
carboxylic acid

+ NaCN
N

HCl
H2O
heat
OH

CH

COH

-hydroxy acid

Carbonyl compounds

45

Aldol Condensations
The Acidity of the a Hydrogens of Carbonyl Compounds: Enolate Anions
Hydrogens on carbons a to carbonyls are unusually acidic
The resulting anion is stabilized by resonance to the carbonyl

Carbonyl compounds

46

The enolate anion can be protonated at the carbon or the oxygen

The resultant enol and keto forms of the carbonyl are formed
reversibly and are interconvertible

Carbonyl compounds

47

Keto and Enol Tautomers

Enol-keto tautomers are constitutional isomers that are easily interconverted
by a trace of acid or base
Most aldehydes and ketones exist primarily in the keto form because of the
greater strength of the carbon-oxygen double bond relative to the carboncarbon double bond

Carbonyl compounds

48

Aldol Condensations
aldol aldehyde and alcohol
A condensation reaction is one in which two or more smaller
molecules combine to form a larger molecule often with the loss
of a small molecule
O
O
HO
OH
2 CH3CH
CH3CH CH2CH
acetaldehyde

HO

3-hydroxybutanol (50%)
(acetaldol or aldol)

O
CH2CH

CH3CH

O
H2C

stronger base than OH

CH3CH CH2 C H

H2O

OH

CH3CH CH2 C H

Carbonyl compounds

CH3CH
+

aldehyde more
reactive than ketones
- more positive carbonyl
carbon less steric
interaction

49

The reaction between 2 moles of an Aldehyde is called

a self condensation reaction
Mechanism 13

Carbonyl compounds

50

Dehydration of the Aldol Product

If the aldol reaction mixture is heated, dehydration to an ,unsaturated carbonyl compound takes place
Dehydration is favorable because the product is stabilized by
conjugation of the alkene with the carbonyl group

In some aldol reactions, the aldol product cannot be isolated

because it is rapidly dehydrated to the ,-unsaturated compound

Carbonyl compounds

51

Acid-Catalyzed Aldol Condensation

This reaction generally leads directly to the dehydration product

Carbonyl compounds

52

What is the product of the following reaction?

Crossed Aldol condensation
Mechanism 14

Readily dehydrates to an unsaturated aldehyde. Forms a

stable conjugated product. Helps
drive the reaction to products

Carbonyl compounds

hydroxide is considered a
poor leaving group but because
this step is intermolecular and
the product is stabilized by
conjugation even a poor leaving
group such as a hydroxide can
leave
53

Practical Crossed Aldol Reactions

Crossed aldol reactions give one predictable product when one of the reaction
partners has no hydrogens
The carbonyl compound without any hydrogens is put in basic solution, and
the carbonyl with one or two hydrogens is added slowly
Dehydration usually occurs immediately, especially if an extended conjugated
system results

Carbonyl compounds

54

Claisen-Schmidt Reactions
Crossed-aldol reactions in which one partner is a ketone are called ClaisenSchmidt reactions
The product of ketone self-condensation is not obtained because the
equilibrium is not favorable

Carbonyl compounds

55

What is the product of the following reaction?

O

NaOH

H+

Heat

Ph

O
b

no hydrogens

Heat

+ H2O + HO

Ph

Ph

hydrogens

94%

Ph

Ph

OH

O
Ph

Ph
85%

NaOH

1 Ph

hydrogens

no hydrogens

Ph

OH

Ph
a

c
a
hydrogens

OH

Ph

Carbonyl compounds

Ph

56

Cyclization via Aldol Condensations

Intramolecular reaction of dicarbonyl compounds proceeds to form fiveand six-membered rings preferentially
In the following reaction the aldehyde carbonyl carbon is attacked
preferentially because an aldehyde is less sterically hindered and
more electrophilic than a ketone

Carbonyl compounds

57

Lithium Enolates
In the presence of a very strong base such as lithium diisopropyl amide
(LDA), enolate formation is greatly favored
Weak bases such as sodium hydroxide produce only a small amount of
the enolate

Carbonyl compounds

58

Regioselective Formation of Enolate Anions

Unsymmetrical ketones can form two different enolates
The thermodynamic enolate is the most stable enolate i.e. the one with
the more highly substituted double bond
A weak base favors the thermodynamic enolate because an
equilibrium between the enolates is estabilished

The kinetic enolate is the enolate formed fastest and it usually is the
enolate with the least substituted double bond
A strong, sterically hindered base such as lithium diisopropyl
amide favors formation of the kinetic enolate

Carbonyl compounds

59

Lithium Enolates in Directed Aldol Reactions

Crossed aldol reactions proceed effectively when a ketone is first
deprotonated with a strong base such as LDA and the aldehyde is
added slowly to the enolate

Carbonyl compounds

60

Direct Alkylation of Ketones via Lithium Enolates

Enolates can also be alkylated with primary alkyl halides via an SN2
reaction
Unsymmetrical ketones can be alkylated at the least substituted
position if LDA is used to form the kinetic enolate

Carbonyl compounds

61

Enolates and Carbanions:

Building blocks for organic synthesis
Acidity of the Alpha Hydrogen

B:

resonance stabilized
enolate ion

ketone

ester

OH
R

enol
alcohol and
alkene

Minor resonance structure but

oxygen caries a partial
R C C O R
negative charge on the
H
carbonyl carbon. Thus the
B:
carbonyl group is less able to
help stabilize the negative
O
charge of the enolate ion.
R C C O R
Carbonyl compounds
62
H

Acidity of the hydrogen next to the carbonyl carbon

O

CH3CCHCCH3 acetoacetone

CH3CCHCCH3

acetone

pKa = 20

H
O

CH3CCHCOCH2CH3

CH2COCH3

ethyl acetoacetate

ethyl acetate

pKa = 25

pKa = 11

CH2CCH3

pKb =14 9 = 5

H pKa = 9
O

O O
CH3CCCOCH2CH3
R
O

an alkylacetoacetic acid

CH3CH2OH

pKa = 16

CH3OH

pKa = 15.5

pKa = 13

diethyl malonate
H pKa = 13 (malonic ester)

Compounds that are separated by

two carbonyl compounds are called
-dicarbonyl compounds

NH2
pKb =14 35 = -21

HNH2
pKa = 35

CH3CH2OCCHCOCH2CH3

C C

O
R

O
C

OR

a-keto ester

Carbonyl compounds

RO

O
C

OR

a malonic ester

63

Synthesis
O

CH3CH2OC-C-COCH2CH3
H H

or NaNH2
or NaH in a
aprotic solvent

diethyl malonate

O
NaH

EtOC-C-COEt
Et

H+, H2O
heat
or base
hydrolysis

Me

Et

a -diacid

CH3CH2- Br
SN2

enolate
Et -CH2CH3

O
CH3-Br

EtOC-C-COEt

SN2

Et

Me

Et

HOC-C-COH

EtOCCHCOEt

EtOC-C-COEt
enolate

H
O

CH3CH2ONa
CH3CH2OH

heat

HOC-CH

-CO2

Me

Et

or

HOC-CHCH2CH3
CH3

2-methylbutanoic acid
Carbonyl compounds

64

Mechanism for decarboxylation

H
H
O

O
C
R

C
C
R

O
C
O

HO

H
C R
R

+ CO2

tautomers

enol

HO

C
R

O
C
C

Carbonyl compounds

C
HO

H + CO2
C R
R

65

Mechanism 15

Li N[CH(CH3)2]2, cold

CH3Br

LDA lithum diisopropylamide

warm

Carbonyl
compounds
enolate

66