Chapter 18

Carboxylic Acid Derivatives

Lecture 24
Chem 30B
 Carboxyl Derivatives
• In this chapter, we study five classes of
organic compounds.
– Under the structural formula of each is a drawing
to help you see its relationship to the carboxyl
group.
O O O O O
RCCl RCOCR' RCOR' RCNH2 RC N
A n acid An acid An ester An amide A nitrile
chloride anhydride
-H2 O
-H2 O -H2 O -H2 O -H2 O
O O O O O HO H
RC-OH H-Cl RC-OH H-OCR' RC-OH H-OR' RC-OH H-NH2 RC=N
Th e enol of
an amide
 Structure: Acid Chlorides
• The functional group of an acid halide is an acyl
group bonded to a halogen.
– The most common are the acid chlorides.
– To name, change the suffix -ic acid to -yl halide.

O O
O O Cl Cl
Cl
RC- CH3 CCl
O
An acyl Ethan oyl ch loride Benzoyl chloride Hexan edioyl ch loride
group (Acetyl ch loride) (Adip oyl chloride)
 Sulfonyl Chlorides
– Replacement of -OH in a sulfonic acid by
-Cl gives a sulfonyl chloride.
O O
CH 3 SOH CH3 SCl
O O
Methanes ulfon ic Methanes ulfonyl ch loride
acid (Mesyl ch loride, MsCl)
O O
H3 C SOH H3 C SCl
O O
p-Toluen esulfon ic p-Toluen esulfon yl chloride
acid (Tosyl chlorid e, TsCl)
 Acid Anhydrides
• The functional group of an acid anhydride is
two acyl groups bonded to an oxygen atom.
– The anhydride may be symmetrical (two
identical acyl groups) or mixed (two different
acyl groups).
– To name, replace acid of the parent acid by
anhydride.
O O O O
CH3 COCCH3 COC

A cetic an h ydrid e Ben zoic anh ydrid e

 Acid Anhydrides

• Cyclic anhydrides are named from the

dicarboxylic acids from which they are
derived.
O O O

O O O

O O O
Succinic Maleic Phthalic
anhydride anhydride anhydride
 Phosphoric Anhydrides
• A phosphoric anhydride contains two
phosphoryl groups bonded to an oxygen
atom.
O O O O
- -
HO- P-O- P-OH O- P-O-P- O
OH OH O- O-
Diphosphoric acid Diphosphate ion
(Pyrophosphoric acid) (Pyrophosphate ion)

O O O O O O
- -
HO- P-O- P-O-P- OH O- P-O-P- O-P- O
O- O- O- O- O- O-
Triphosphoric acid Triphosphate ion
 Esters
• The functional group of an ester is an acyl
group bonded to -OR or -OAr.
– Name the alkyl or aryl group bonded to oxygen
followed by the name of the acid.
– Change the suffix -ic acid to -ate.
O O
O
O OEt
EtO
O
O
Ethyl ethan oate Is op ropyl D iethyl butaned ioate
(Ethyl acetate) ben zoate (D ieth yl s uccin ate)
 Esters
• Lactone: A cyclic ester.
– name the parent carboxylic acid, drop the
suffix -ic acid and add -olactone.

O  O
 O  2
2
3
1  1
O
3 1
O 2
3 4
 4 O
H3 C 5 6
   
3-Bu tanolactone 4-Bu tanolactone 6-Hexan olacton e
-Butyrolactone) -Bu tyrolacton e) -Cap rolactone)
 Esters of Phosphoric Acid
• Phosphoric acid forms mono-, di-, and triesters.
• Name by giving the name of the alkyl or aryl
group(s) bonded to oxygen followed by the word
phosphate.
• In more complex phosphoric esters, it is common
to name the organic molecule and then indicate the
presence of the phosphoric ester by the word
phosphate or the prefix phospho-.
CHO CHO O O
O
HO C-H O HO CH2 O-P-O- CO- O
CH3 OPOH
CH2 -O-P-O- O- C O P O-
OCH3 O- H3 C N CH2 O-
D imethyl Glyceraldeh yd e Pyridoxal phosp hate Phosphoenol-
phosp hate 3-phosph ate pyruvate
 Amides
• IUPAC: drop -oic acid from the name of the parent
acid and add -amide. For the common name, drop
-ic of the parent name and add -amide.
• if the amide nitrogen is bonded to an alkyl or aryl
group, name the group and show its location on
nitrogen by N-.
O O H O CH3
CH3 CNH2 CH3 C-N H-C-N
CH3 CH3
A cetamide N-Methylacetamide N ,N-D imethyl-
(a 1° amide) (a 2° amid e) formamid e (DMF)
(a 3° amide)
 Amides
• Lactams: A cyclic amides are called lactams.
– Name the parent carboxylic acid, drop the
suffix -ic acid and add -lactam.

 O
 O  2
1
3
2
3
1
 4 NH
NH 5 6
H3 C  
3-Butanolactam 6-Hexanolactam
-Butyrolactam) -Caprolactam)
 Penicillins

– The penicillins are a family of -lactam

antibiotics.
HO O
The penicillin s H H
differ in the NH S
grou p bond ed H2 N
to the acyl carb on N
O
-lactam
COOH
Amoxicillin
(a -lactam an tib iotic)
 Cephalosporins
– The cephalosporins are also -lactam antibiotics.

The cephalosporins d iffer in the

group bonded to the acyl carbon an d
the s ide chain of the thiazin e rin g

O
H H
S
N
NH2 H N
O Me
-lactam COOH
Cep halexin
(Keflex)
 Imides

• The functional group of an imide is two

acyl groups bonded to nitrogen.
– Both succinimide and phthalimide are
cyclic imides.

O O

NH NH

O O
Succinimide Phthalimide
 Nitriles
• The functional group of a nitrile is a cyano
group
– IUPAC names: name as an alkanenitrile.
– common names: drop the -ic acid and add
-onitrile.

CH3 C N C N CH2 C N

Ethanen itrile Benzon itrile Phenylethan enitrile

(A cetonitrile) (Phenylacetonitrile)
 Acidity of N-H bonds
• Amides are comparable in acidity to alcohols.
– Water-insoluble amides do not react with NaOH or
other alkali metal hydroxides to form water-soluble
salts.
• Sulfonamides and imides are more acidic than
amides.
O O
O
O
SNH2 NH NH
CH3 CNH2
O
O O
Acetamide Ben zenesu lfonamide Succinimide Phth alimide
pKa 15-17 pK a 10 p Ka 9.7 p Ka 8.3
 Acidity of N-H bonds
• Imides are more acidic than amides because
1. the electron-withdrawing inductive of the two
adjacent C=O groups weakens the N-H bond

2. the imide anion is stabilized by resonance

delocalization of the negative charge.
O O O

N N N

O O O
A resonance-stabilized an ion
 Acidity of N-H
– Imides such as phthalimide readily dissolve
in aqueous NaOH as water-soluble salts.

O O
- +
NH + N aOH N Na + H2 O

O O
pK a 8.3 pK a 15.7
(stronger (stronger (weaker (weaker
acid) base) base) acid)
 Acidity of N-H
• Saccharin, an artificial sweetener, is an
imide.
The imide is sufficiently acidic that it reacts with
NaOH and aqueous NH3 to form water-soluble
salts. The ammonium salt is used to make liquid
Saccharin. Saccharin in solid form is the Ca2+ salt.
O O

NH + NH3 N- NH4+
S H2 O S
O O O O
Saccharin Saccharin
A water-soluble
ammonium salt
 Characteristic Reactions
• Nucleophilic acyl substitution: An addition-
elimination sequence resulting in
substitution of one nucleophile for another.

O
O O

C + :Nu C C + :Y
R Y R Nu R Nu
Y
Tetrahedral carbonyl Substitution
addition intermediate product
 Characteristic Reactions

– In the general reaction, we showed the

leaving group as an anion to illustrate an
important point about them: the weaker the
base, the better the leaving group.
O
R2 N- RO- RCO- X-
Increasin g leaving ability
Increasin g b asicity
 Characteristic Reactions
– Halide ion is the weakest base and the best
leaving group; acid halides are the most reactive
toward nucleophilic acyl substitution.
– Amide ion is the strongest base and the poorest
leaving group; amides are the least reactive
toward nucleophilic acyl substitution.
Reaction with H2O - Acid Chlorides

– Low-molecular-weight acid chlorides react

rapidly with water.
– Higher molecular-weight acid chlorides are
less soluble in water and react less readily.

O O
CH3 CCl + H2 O CH3 COH + HCl
Acetyl chlorid e
 Reaction with H2O - Anhydrides

– Low-molecular-weight anhydrides react

readily with water to give two molecules of
carboxylic acid.
– Higher-molecular-weight anhydrides also
react with water, but less readily.

O O O O
CH3 COCCH3 + H2 O CH3 COH + HOCCH3
Acetic an hydrid e
 Reaction with H2O - Anhydrides
– Step 1: Addition of H2O to give a TCAI.
H + H
O O O H
O O +
CH3 -C- O-C- CH 3 CH3 -C- O-C- CH 3 CH3 -C- O-C- CH 3 + H- O-H
+ O H
O H H
O-H H
O-H Tetrahedral carbonyl
H H addition intermediate
 Reaction with H2O - Anhydrides
–Step 2: Protonation followed
collapse of the TCAI.

H H H H H H
+O O +O
H H H H
H + H
O O O O O O
CH3 -C-O-C-CH3 CH3 C O C CH3 CH3 C + O C CH3
O O O
H H H
 Reaction with H2O - Esters
• Esters are hydrolyzed only slowly, even in boiling
water.
– Hydrolysis becomes more rapid if they are heated with
either aqueous acid or base.
• Hydrolysis in aqueous acid is the reverse of
Fischer esterification.
– The role of the acid catalyst is to protonate the carbonyl
oxygen and increase its electrophilic character toward
attack by water (a weak nucleophile) to form a
tetrahedral carbonyl addition intermediate.
– Collapse of this intermediate gives the carboxylic acid
and alcohol.
 Reaction with H2O - Esters

• Acid-catalyzed ester hydrolysis

O +
OH + O
C H C H C
+ H2 O + CH3 OH
R OCH3 R OH R OH
OCH3
Tetrahed ral carbonyl
ad dition intermediate
 Reaction with H2O - Esters
• Saponification: The hydrolysis of an esters in
aqueous base.
– Each mole of ester hydrolyzed requires 1 mole of base
– For this reason, ester hydrolysis in aqueous base is said
to be base promoted.
O O
H2 O - +
RCOCH3 + NaOH RCO Na + CH3 OH

– Hydrolysis of an ester in aqueous base involves formation

of a tetrahedral carbonyl addition intermediate followed by
its collapse and proton transfer.
 Reaction with H2O - Esters
– Step 1: Attack of hydroxide ion (a nucleophile) on
the carbonyl carbon (an electrophile).
– Step 2: Collapse of the TCAI.
– Step 3: Proton transfer to the alkoxide ion; this
step is irreversible and drives saponification to
completion.

O
O O O
(1) (2)
R- C-OCH3+ OH R- C OCH3 R- C + OCH3 (3) R- C + HOCH3
OH O O
H
 Reaction with H2O - Amides
• Hydrolysis of an amide in aqueous acid
requires one mole of acid per mole of amide.
– Reaction is driven to completion by the acid-
base reaction between the amine or ammonia
and the acid.
O O
H2 O + -
NH2 + H2 O + HCl heat
OH + NH4 Cl
Ph Ph
2-Phenylbutanamide 2-Phenylbutanoic acid
 Reaction with H2O - Amides
• Hydrolysis of an amide in aqueous base requires
one mole of base per mole of amide.
– Reaction is driven to completion by the
irreversible formation of the carboxylate salt.

O O
H2 O
CH3 CNH + NaOH CH3 CO- Na+ + H2 N
heat
N-Phen yleth anamide Sodiu m A niline
(N-Phen ylacetamid e, acetate
Acetan ilide)
 Reaction with H2O - Amides

– Step1: Protonation of the carbonyl oxygen gives a

resonance-stabilized cation intermediate.

O +
R C NH2 + H O H
H
+H H H
O O O
+
R C NH2 R C NH2 R C NH2 + H2 O
+
Reso nance-stabil ized catio n i ntermed iate
 Reaction with H2O - Amides
– Step 2: Addition of water to the carbonyl carbon followed
by proton transfer gives a TCAI.
proton
OH OH trans fer from OH
+ O to N
R C N H2 + O H R C N H2 R C NH3 +
H O+ O
H H H

– Step 3: Collapse of the TCAI and proton transfer.

H
O + H
O O
R C NH3 + R C + NH3 R C OH + NH4 +
OH OH
 Reaction with H2O - Nitriles
• The cyano group is hydrolyzed in aqueous acid to
a carboxyl group and ammonium ion.
O
H2 O + -
Ph CH2 C N + 2H2 O + H2 SO4 Ph CH2 COH + NH4 HSO4
heat
Phenylacetonitrile Phenylacetic Ammonium
acid hydrogen s ulfate

– Protonation of the cyano nitrogen gives a cation

that reacts with water to give an imidic acid.
– Keto-enol tautomerism gives the amide.
+
OH O
R-C N + H2 O H R-C NH R-C-NH2
A n imidic acid An amide
(en ol of an amide)
 Reaction with H2O - Nitriles
– Hydrolysis of a cyano group in aqueous base
gives a carboxylic anion and ammonia;
acidification converts the carboxylic anion to the
carboxylic acid.
O
NaOH, H2 O - +
CH3 ( CH2 ) 9 C N CH3 ( CH2 ) 9 CO Na + NH3
h eat
Un decan enitrile S od ium und ecanoate

HCl H2 O

O
CH3 ( CH2 ) 9 COH + NaCl + NH4 Cl
Und ecanoic acid
 Reaction with H2O - Nitriles
Hydrolysis of nitriles is a valuable route to
carboxylic acids.
O
KCN H2 SO 4 , H2 O
CH 3 ( CH2 ) 8 CH2 Cl CH3 ( CH2 ) 9 C N CH3 ( CH2 ) 9 COH
ethanol, heat
1-Chlorodecane Undecanenitrile Undecanoic acid
water

OH OH
CHO HCN , KCN
CN H2 SO 4 , H2 O COOH
ethanol, heat
water
Benzaldehyde Benzaldehyde cyanohydrin 2-Hydroxyphenylacetic acid
(Mandelonitrile) (Mandelic acid)
(racemic) (racemic)
 Chapter 18
Carboxylic Acid Derivatives
Lecture 25
Chem 30B
 Reaction with Alcohols
• Acid halides react with alcohols to give esters.
– Acid halides are so reactive toward even weak
nucleophiles such as alcohols that no catalyst is
necessary.
– If the alcohol or resulting ester is sensitive to
HCl, the reaction is carried out in the presence
of a 3° amine to neutralize the acid.
O O
Cl + HO O + HCl
Butanoyl Cyclohexan ol Cyclohexyl butan oate
chloride
 Reaction with Alcohols
– Sulfonic acid esters are prepared by the reaction
of an alkane- or arenesulfonyl chloride with an
alcohol or phenol.
– The key point here is that OH- is transformed
into a sulfonic ester (a good leaving group) with
retention of configuration at the chiral center.

OH OT s
+ T sCl pyridine
(R)-2-Octanol p-Toluenesulfonyl (R)-2-Octyl p-t oluenesulfonate
chloride [(R)-2-Octyl tosylate]
(Tosyl chloride)
 Reaction with Alcohols
• Acid anhydrides react with alcohols to give one
mole of ester and one mole of a carboxylic acid.
O O O O
CH3 COCCH3 + HOCH2 CH 3 CH3 COCH2 CH3 + CH3 COH
Acetic anhydride Ethanol Ethyl acetate Acetic acid

– Cyclic anhydrides react with alcohols to give one

ester group and one carboxyl group.
O
O
O
O +
HO OH
O O
Phth alic 2-Butan ol
anh yd rid e (sec-Butyl alcohol) (s ec-Bu tyl h yd rogen
phth alate
 Reaction with Alcohols
– Aspirin is synthesized by treating salicylic acid
with acetic anhydride.
COOH
OH O O
+ CH COCCH
3 3
Acetic
2-Hydroxybenzoic anhydride
acid
(Salicylic acid) COOH
O CH3 O
+ CH3 COH
O
Acetyls alicylic acid Acetic acid
(Aspirin)
 Reaction with Alcohols
• Esters react with alcohols in the presence of an
acid catalyst in an equilibrium reaction called
transesterification.
O
+ HCl
OCH3 HO
Methyl propenoate 1-Butanol
(Methyl acrylate) (bp 117°C)
(bp 81°C)
O
O + CH3 OH
Butyl propenoate Methanol
(Butyl acrylate) (bp 65°C)
(bp 147°C)
 Reaction with Ammonia, etc.

• Acid halides react with ammonia, 1° amines, and

2° amines to form amides.
– Two moles of the amine are required per mole of
acid chloride.

O O
+ -
Cl+ 2 NH3 NH2 + NH4 Cl
Hexanoyl Ammon ia Hexan amid e Ammon ium
chloride chloride
 Reaction with Ammonia, etc.
• Acid anhydrides react with ammonia, and 1° and
2° amines to form amides.
– Two moles of ammonia or amine are required.

O O O O
- +
CH3 COCCH3 + 2 NH3 CH3 CNH2 + CH3 CO NH 4

Acetic Ammon ia Acetamid e Ammon ium

anh yd rid e acetate
 Reaction with Ammonia, etc.
• Esters react with ammonia and with 1° and
2° amines to form amides.
– Esters are less reactive than either acid halides or
acid anhydrides.
O O
Ph Ph
OEt + NH3 NH2 + Et OH
Ethyl phenylacetate Phenylacetamide Ethanol

• Amides do not react with ammonia or with

1° or 2° amines.
 Acid Chlorides with Salts

• Acid chlorides react with salts of carboxylic acids

to give anhydrides.
– Most commonly used are sodium or potassium
salts.
O O O O
CH3 CCl + N a+ - OC CH3 COC + N a+ Cl -

Acetyl Sodium Acetic benzoic

chloride benzoate anhydride
 Chapter 18
Carboxylic Acid Derivatives
Lecture 26
Chem 30B
Interconversions of Acid
Derivatives
 Reaction with Grignard Reagents
1. Addition of 1 mole of RMgX to the carbonyl
carbon of an ester gives a TCAI.
2. Collapse of the TCAI gives a ketone (an
aldehyde from a formic ester).

- +
1 O 2
O [MgX] O
- +
CH3 -C-OCH3 + R MgX CH3 -C OCH3 CH3 -C + CH3 O [ MgX]
R 2 R
1
A magnesiu m s alt A ketone
(a tetrahed ral carbonyl
addition intermediate)
 Reaction with Grignard Reagents

– Treating a formic ester with two moles of

Grignard reagent followed by hydrolysis in
aqueous acid gives a 2° alcohol.

O magn esium H O, HCl OH

alkoxide 2
HCOCH3 + 2 RMgX HC-R + CH3 OH
salt R
An ester of A 2° alcohol
formic acid
 Reaction with Grignard Reagents

– Treating an ester other than formic with a

Grignard reagent followed by hydrolysis in
aqueous acid gives a 3° alcohol.

O magnesiu m H O, HCl OH
2 CH3 C-R + CH3 OH
CH3 COCH3 + 2 RMgX alk oxid e
salt R
An ester of an y acid A 3° alcohol
other than formic acid
 Reaction with Grignard Reagents
3. Reaction of the ketone with a second mole
of RMgX gives a second TCAI.
4. Treatment with aqueous acid gives the
alcohol.
- +
3 O 3 O [MgX] OH
CH3 -C + R MgX CH3 -C-R H2 O, HCl
CH3 -C-R
R R (4)
R
A k eton e Magnesium salt A 3° alcohol
 Reactions with RLi
• Organolithium compounds are even more
powerful nucleophiles than Grignard
reagents.
– They react with esters to give the same types of
2° and 3° alcohols as do Grignard reagents
– and often in higher yields.

O OH
1 . 2 R' Li
RCOCH3 R- C-R' + CH3 OH
2 . H2 O, HCl
R'
 Gilman Reagents
• Acid chlorides at -78°C react with Gilman
reagents to give ketones.
– Under these conditions, the TCAI is stable, and it
is not until acid hydrolysis that the ketone is
liberated.

O O
1 . ( CH3 ) 2 CuLi, eth er, -78°C
Cl 2 . H O
2
Pentanoyl chloride 2-Hexanone
 Gilman Reagents

– Gilman reagents react only with acid

chlorides.
– They do not react with acid anhydrides,
esters, amides or nitriles under the conditions
described.
O
1 . ( CH3 ) 2 CuLi, eth er, -78°C
H 3 CO
Cl 2 . H O
2
O O
H 3 CO
O
 Reduction - Esters by LiAlH4
• Most reductions of carbonyl compounds now
use hydride reducing agents.
– Esters are reduced by LiAlH4 to two alcohols.
– The alcohol derived from the carbonyl group is
primary.
O Ph
Ph 1 . LiA lH4 , e t he r OH + CH3 OH
OCH3
2 . H2 O, HCl
2-Phenyl-1- Methanol
Methyl 2-phenyl- propanol
propanoate (racemic)
(racemic)
 Reduction - Esters by LiAlH4
• Reduction occurs in three steps plus workup:
– Steps 1 and 2 reduce the ester to an aldehyde.
O O O
(1) (2)
R C OR' + H R C OR' R C + OR'
H H
A tetrahedral carbonyl
addition intermediate
– Step 3: Reduction of the aldehyde followed by work-up
gives a 1° alcohol derived from the carbonyl group.

O O OH
(3) (4)
R C + H R C H R C H
H H H
A 1° alcohol
 Reduction - Esters by NaBH4
• NaBH4 does not normally reduce esters, but
it does reduce aldehydes and ketones.
• Selective reduction is often possible by the
proper choice of reducing agents and
experimental conditions.

O O NaBH4 OH O

OEt EtOH OEt

(racemic)
 Reduction - Esters by DIBALH

• Diisobutylaluminum hydride at -78°C

selectively reduces an ester to an aldehyde.
– At -78°C, the TCAI does not collapse and it is
not until hydrolysis in aqueous acid that the
carbonyl group of the aldehyde is liberated.
O
1 . DIBALH , toluen e, -78°C
OCH3
2 . H2 O, HCl
Methyl hexanoate
O
H + CH3 OH
Hexanal
 Reduction - Amides by LiAlH4
• LiAlH4 reduction of an amide gives a 1°,
2°, or 3° amine, depending on the degree
of substitution of the amide.
O
1 . LiAlH4
NH2 NH2
2 . H2 O
Octanamide 1-Octanamine

O
NMe2 1 . LiAlH4 NMe2
2 . H2 O
N,N -D imethylben zamide N ,N-D imeth ylb enzylamine
 Reduction - Amides by LiAlH4

• The mechanism is divided into 4 steps:

– Step 1: Transfer of a hydride ion to the
carbonyl carbon.
– Step 2: A Lewis acid-base reaction and
formation of an oxygen-aluminum bond.

O O AlH3
O
R C NH2 + H AlH3 (1) R C NH2 + AlH3
(2)
R C NH2
H H
 Reduction - Amides by LiAlH4
– Step 3: Redistribution of electrons and ejection
of H3AlO- gives an iminium ion.
– Step 4: Transfer of a second hydride ion to the
iminium ion completes the reduction to the
amine.

AlH3 H
O
(3) (4)
R C N H R C N H R-CH2 -NH2
H H H H
An iminium ion A 1° amine
 Reduction - Nitriles by LiAlH4
The cyano group of a nitrile is reduced by LiAlH4 to
a 1° amine.

1 . LiA lH4
CH3 CH= CH( CH 2 ) 4 C N
2 . H2 O
6-Octenenitrile

CH3 CH= CH ( CH2 ) 4 CH2 N H2

6-Octen-1-amine
 Interconversions
Problem: Show reagents and experimental
conditions to bring about each reaction.
O
Ph
Cl

(a) (b ) (c)

O O
O (e)
Ph (d ) Ph
OH Ph NH2
OMe
Ph enylacetic
acid (g) (h )

(f) Ph
Ph NH2
OH