1

R CO

ClR C

O

OC

OR

R CO

OR'

R CO

NR'

R"

acid halide acid anhydride an ester an amide

Carboxylic Acid Derivatives

The most important derivatives of carboxylic acids are —

Although not direct derivatives, nitriles, R-CN, are relatedto carboxylic acids. They can be hydrolyzed to carboxylicacids and they can be prepared from carboxylic acids viadehydration of the amide.

2

R CO

Y

:Nu-

R CO-

YNuR C

O

Nu

trigonal tetrahedral trigonal

less crowded more crowded+ Y-

slowstep

The typical reaction type of carboxylic acid derivatives isnucleophilic substitution at the carbonyl carbon.[Aldehydes and ketones usually undergo nucleophilicaddition because they do not contain reasonable leavinggroups: R- and H- are poor leaving groups.] Ageneralized reaction mechanism under basic conditions,BAC2 (basic, acyl, bimolecular) looks like this, where Y is aleaving group – one of the boxed groups above:

[If :Nu is neutral, the intermediate will be a neutral betaine(-O-, -Nu+), and the product will carry a + charge unlessthe -Nu+ expels an H+.]

3

R CO

Y

H

:Nu-H

R CO

YNu-H

H

R CO

Nu

H

trigonal tetrahedral

trigonal

less crowded more crowded

+ Y-H

R CO

Y

H+

R CO

Y-HNu

H

tetrahedralR C

O

Nu+ H+

slowstep

A generalized reaction mechanism under acidicconditions, AAC2 (acidic, acyl, bimolecular) looks like this:

Since the intermediate is more crowded than the reactant,bulky R-groups slow down the reaction: for a given Nuand Y, the rate of reaction is usually in the order: 1o > 2o >3o.

4

The more electronegative Y the faster the reaction: for agiven R and Nu, the rate of reaction is usually in theorder: Cl > OCOR > OR' > NR'R". The reason for thisdepends on the reaction type.

+ If it is BAC2 with Nu-, the intermediate carries a negative charge and it(and the transition state leading to it) are stabilized by an electronegativegroup. The reacting molecule, on the other hand, is destabilized byelectronegative groups because of the δ+ charge on the carbonyl carbon. These effects work together causing electronegative groups to reduce∆G‡.

+ If it is BAC2 with Nu, the intermediate is neutral, but the startingmaterial is destabilized by electronegative groups because of the δ+charge on the carbonyl carbon, thus reducing ∆G‡.

+ If it is AAC2 (with Nu), the intermediate and reactant (the protonatedstarting material) are both positively charged. Electronegative groupswould destabilize both. However, the effect may be greater on thereactant because the positive charge is transferred to the carbonyl carbonby both an inductive and resonance effect, while in the intermediate thereis only an inductive effect. If the reactant is more destabilized than theintermediate, ∆G‡ is reduced.

A consequence of this reactivity order is that acidchlorides can be directly converted into the otherderivates and anhydrides can be directly converted intoesters and amides, but directly converting the lessreactive derivatives into the more reactive ones is difficult.

5

R CO

OH

SOCl2

PCl5

ClCOCOCl

R CO

Cl

RCCl

O

+ R'OHor Ar or Ar'

RCOR'

O

+ HCl

R, R' = 1o, 2o, 3o

To convert acarboxylic acid intoan ester or amide, itis usually convertedto a chloride first.

Esters: Preparation

Reaction of an Acid Chloride with an Alcohol or Phenol –

6

R CO

OH+ HOR' R C

O

OR'+ H2O

H+

Dean-Stark Apparatus

Fisher Esterification —

The equilibrium constant fora Fisher Esterification istypically about 1. However,when phenols are employedKeq is usually much less than1; phenols are not usuallyacylated by the Fisheresterification.

This reaction can be driven inthe forward direction by usingthe alcohol as the solvent orby removal of water. Removal of water is oftenaccomplished by use of aDean-Stark trap.

This reaction can be driven inthe reverse direction(hydrolysis of an ester) byuse of an excess of water.

7

C

O

OH

H18OCH3

+ H3O+ C

OH

OH C

OH

OH

C

OH

OH

H18OCH3

C

OH2

OH18OCH3

2 steps

H2O - H2O

C OH18OCH3

C OH18OCH3

C O18OCH3

+ H+

Mechanism of the Fisher Esterification (and AcidCatalyzed Hydrolysis of an Ester), AAC2 —

8

C

O

OCH3

+ OH-

C

O

OCH3

OH

C

O

OH+ OCH3 C

O

O+ HOCH3

Esters: Reactions

Hydrolysis: Conversion to Carboxylic Acids —

+ Acidic: see Fisher Esterification.

+ Basic: typical nucleophilic acyl substitution via atetrahedral intermediate, BAC2 —

9

Saponification —

Hydrolysis of esters under basic conditions is known assaponification.

Soap is made by saponification of oil or fat. Most soap ismade from fat; Castile soap is made from olive oil.

Oils and fats are triglycerides, ie triesters of glycerol andfatty acids. Fatty acids are straight chain carboxylicacids, having an even number of carbons ranging from~10 to ~20. The alkyl portion may be saturated orunsaturated; if unsaturated the double bond(s) areusually cis and there are usually not more than 3.

10

O C

O

RCH2

CH

CH2

O C

O C

O

R'O

R"

H2Oheat

O C

O

RCH2OH

CHOH

CH2OH

O C

O

R'

O C

O

R"

+ 3 NaOH

Na

Na

Na

a triglyceride glycerol sodium soap

S

O

O

O- Na+

a branched alkyl sulfonate, not biodegradable

When triglycerides are saponified, soap and glycerol areproduced —

Sodium soap is a surfactant; it disperses into water in theform of micelles and is able to emulsify grease.

Hard water contains Ca+2, Mg+2 or iron ions. Sodium soapreacts with these ions forming an insoluble magnesium orcalcium soap, soap scum. This problem can be remediedby replacing soap by a synthetic detergent which doesnot precipitate in the presence of the "hard water" ions.

Sodium sulfonates,having long alkylchains, are sometimesused as detergents andare effective in hardwater. Often thesulfonic acid group is on an aromatic ring which alsoholds the long alkyl group.

11

C

O

OCH3 OCH3

O

C 1. LiAlH 4, ether

2. H 3O+

CH2OHHOCH2

R C

O

Cl + HNR'R":B R C

O

NR'R" HB+ Cl-+

Reduction to Primary Alcohols —

Amides: Preparation

Amides can be prepared from acid chlorides by reactionwith ammonia, NH3, primary amines, NH2R', andsecondary amines, NHR'R" –

When a base, such as pyridine, is added to promote thisreaction, it is known as the Schotten-Baumann reaction.

Nylon 6.10 can be made by interfacial (water andpetroleum ether are insoluble in each other)polymerization of decanedioyl dichloride in petroleumether and hexamethylenediamine and NaOH in water –

12

HN

H

O

NO

n

Cl ClO

OH N N

HH

H+

+ HCl

base

R C

O

OH + HNR'R"

R C

O

NR'R"

R C

O

O- + H2NR'R"

+ H2Oheat

Sometimes, amides can be formed by reacting acarboxylic acid with a primary or secondary amine to formthe salt and then heating this salt to expel water –

13

R C

O

OH

+ HNR'R"

R C

O

NR'R"

R C

O

O-

+ H2NR'R"

+ H2OheatH3O

+

OH-

heat

H2NN

NN

NN

OH

R8

O R15

O R3

O R20

O R3

O R17

OH

H

H

H

H

H2NN

NN

NN

OH

R8

O R15

O R3

O R20

O R3

O R17

OH

H

H

H

H

H2N

R8

O

OH

N

R15

OH

H OH

N

R3

OH

OHH

N

R20

OH

OHH

N

R3

OH

OHH

NOH

R17

OH

H

HCl,H2O heat

Polypeptide...

...showing cleavagesites at peptide (amide)bonds between aminoacid residues.

Soup of amino acids afterhydrolysis; can be analyzedby chromatography.

Reactions of Amides

Hydrolysis —

Acid hydrolysis is used to determine which amino acidresidues are present in a polypeptide or protein.

14

R C

O

NR'R" 1. LiAlH 4

2. H2OR CH2 NR'R"

R X + C N R C N + X

C O

R'

R

+ K+ -C N H3O

+

R' C

OH

CN

R

Reduction to Amines —

Nitriles

Preparation —

Reaction of cyanide ion with alkyl halides (usually SN2):

Works best for 1o R.

Cyanohydrin synthesis from aldehydes and unhinderedketones:

15

R C N1. R'MgX

2. H2OR C

O

R'

R C N 1. LiAlH42. H2O

R CH2 NH2 a primary amine

Reactions —

Acidic or basic hydrolysis to give carboxylic acids — discussed earlier.

Reduction —

Reaction with Grignard reagents to give ketones —