1

Chapter 21

Carboxylic Acid Derivatives

and Nucleophilic Acyl Substitution

Reactions

- many carboxylic acid derivatives are known:

RC

OH

O

RC

X

O

RC

O

O

CR'

O

RC

OR'

O

RC

NH2

O

R C N

carboxylic acid acid halide(X = F, Cl, Br, I)

acid anhydride

ester amide nitrile

- chemistry of carboxylic acid derivatives is dominated by a single reaction - nucleophilic acyl substitution reaction:

RC

Y

O

RC

Nu

O+ :Nu-

2

Naming Carboxylic Acid Derivativesand Nitriles

Acid Halides

- first identify the acyl group, then identify the halide

- acyl group name is derived from the carboxylic acid name by replacing the -ic acid ending with -yl or the -carboxylic acid ending with -carbonyl

H3CC

Cl

O CBr

O

CCl

O

acetyl chloride(from acetic acid)

benzoyl bromide(from benzoic acid)

cyclohexanecarbonyl chloride(from cyclohexanecarboxylic acid)

Acid Anhydrides

- anhydrides are named by replacing the word acid with anhydride

H3CC

O

O

CCH3

O CO

O

C

OOO O

H3CC

O

O

C

O

acetic anhydride benzoic anhydride succinic anhydride

bis(chloroacetic) anhydride acetic benzoic anhydride

ClCH2C

O

O

CCH2Cl

O

Amides- amides with an unsubstituted -NH2 group are named by replacing the -oic acid or -ic acid ending with -amide, or by replacing the -carboxylic acid ending with -carboxamide

- compound is also named by identifying substituents and parent amide

H3CC

NH2

O

CH3(CH2)4C

NH2

OC

NH2

O

acetamide(from acetic acid)

hexanamide(from hexanoic acid)

cyclopentanecarboxamide(from cyclopentanecarboxylic acid)

CN(CH2CH3)2

O

N-methylpropanamide N,N-cyclohexanecarboxamide

CH3CH2C

NHCH3

O

3

Esters

- first identify the alkyl group attached to the oxygen and then the carboxylic acid, with the -ic acid ending being replaced by -ate

H3CC

OCH2CH3

O

CH3OC

CH2

O

COCH3

O

CO

O

C(CH3)3

ethyl acetate(ethyl ester of acetic acid)

dimethyl malonate(dimethyl ester of malonic acid)

tert-butylcyclohexanecarboxylate(tert-butyl ester of cyclohexanecarboxylic acid)

Nitriles- open-chain nitriles are named by adding -nitrile as a suffix to the alkane name, with the -C≡N carbon being C1

- more complex nitriles are named as derivatives of carboxylic acids by using the ending -onitrile or -carbonitrile where the -C≡N carbon is not part of the numbering system

C

CH3

CH2CH2CNH3C

H

4-methylpentanenitrile

C NH3C

acetonitrile(from acetic acid)

C N

benzonitrile(from benzoic acid)

CN

CH3

CH3

2,2-dimethylcyclohexanecarbonitrile(from 2,2-dimethylcyclohexane

carboxylic acid)

Nucleophilic Acyl Substitution Reactions

- carboxylic acid derivatives have an acyl carbon bonded to a potential leaving group -Y

- as soon as the tetrahedral intermediate is formed, the leaving group is expelled

- such a leaving group is not present in aldehydes and ketones

RC

Y

O

RC

H

O

RC

R'

O

carboxylic acidderivative

aldehyde ketone

not a good leaving groupgood leaving group

4

Relative Reactivity of Carboxylic Acid Derivatives

- of the addition and elimination steps of a nucleophilic acyl substitution reaction, the first-step is generally rate-limiting

- factors that can effect the first-step arise from steric and electronic considerations

- sterically, unhindered carbonyl groups react with nucleophiles more readily that do hindered groups

- electronically, strongly polarized acid derivatives react more readily that less polar ones

C

O

CR

RR

C

O

CR

HH

C

O

CR

HR

C

O

CH

HH

RC

O

O

CR'

O

RC

OR'

O

RC

NH2

O

< < <

< < <

Less reactive More reactive

Less reactive More reactive

C

O

R Cl

5

Consequences of Observed Reactivity

1) It is usually possible to transform a more reactive acid derivative into a less reactive one (downhill process in terms of energy)

2) Only esters and amides are commonly found in nature. Acid halides and acid anhydrides undergo nucleophilic attack by water such that they cannot exist in living organisms.

Acid Derivative

6

Nucleophilic Acyl Substitution Reactionsof Carboxylic Acids

Carboxylic Acids →→→→ Acid Chlorides

- carboxylic acids are converted into acid chlorides using thionyl chloride (SOCl2)

C

H3C CH3

CH3

O OHC

H3C CH3

CH3

O Cl

SOCl2

CHCl3

+ HCl + SO2

2,4,6-trimethylbenzoicacid

2,4,6-trimethylbenzoylchloride (90%)

Mechanism

C

O

R OH

S

O

Cl ClC

O

R OS

Cl

O

HCl

Base

C

O

R OS

Cl

O

Cl R OS

Cl

OOC

O

R OS

Cl

OC

O

R Cl

carboxylic acid chlorosulfite

acid chloride

Carboxylic Acids →→→→ Acid Anhydrides- acid anhydrides are derived from two carboxylic functionalities by heating to remove 1 equivalent of water

- reaction typically requires very harsh conditions

H2C

H2C

COOH

COOH

H2C

H2C CO

C

O

O

200o C

succinic acidsuccinic anhydride

+ H2O

7

COOH

COOH

C

CO

O

O

Proximity Effects

40o C+ H2O

1,8-naphthalenedicarboxylic acid 1,8-naphthalene anhydride

EtOH

Carboxylic Acids →→→→ Esters

1) SN2 reaction of a carboxylate anion with a primary alkyl halide

2) Fischer esterification reaction

- commerical constraints limit reaction to methyl, ethyl, propyl esters

C

O

CH3CH2CH2 O H3C I C

O

CH3CH2CH2 OCH3

SN2

reaction+ NaI+

Na+

sodium butanoate methyl butanoate (ester)(97%)

CH

HOCOH

O

CH

HO

COCH2CH3

O

+ CH3CH2OHethanol

HCl

mandelic acid ethyl mandelate (86%)

+ H2O

Mechanism

8

Evidence Comes from 18O-Labeling Experiments

C

O

OHC

O

OCH3CH3O H+HCl

catalyst

* * + HOH

Carboxylic Acids →→→→ Amides

- acid-base reaction occurs and reaction to form an an amide does not occur readily

RC

O

OH RC

O

O+ :NH3 NH4

+

carboxylic acid ammonium salt

Chemistry of Acid Halides

- there are two general methods to prepare acid halides:

C

O

R OHC

O

R Cl

C

O

R BrC

O

R OH

SOCl2

PBr3

ether

9

Acid Chloride

Hydrolysis: Conversion of Acid Halides into Acids

- since HCl is generated during hydrolysis, the reaction is often carried out in the presence of a base (e.g. pyridine, NaOH)

C

O

R ClC

O

R OH

HCl

C

O

R OH

H

C

O

R OH

BaseOH2+

acid chloride carboxylicacid

Alcoholysis: Conversion of Acid Halides into Esters

- reaction is analogous to hydrolysis and is strongly affected by steric hindrance

- reactivity order among alcohols:

primary > secondary > tertiary

CCl

OOH

CO

O

pyridine

cyclohexanolbenzoyl chloridecyclohexyl benzoate (97%)

+

10

Illustration of Alcohol Reactivity

CH2OH

HOC

O

H3C Cl HO

OC

O

CH3pyridine+

secondary alcohol(more hindered and

less reactive)

primary alcohol(less hindered and

more reactive)

Aminolysis: Conversion of Acid Halides into Amides- reaction is analogous to hydrolysis and alcoholysis; in a similar way to alcoholysis, the reaction is sensitive to steric hindrance such that primary and secondary amine react, while tertiary amines do not

C

O

(CH3)2CH ClNH3 C

O

(CH3)2CH NH2

CCl

O

NH(CH3)2C

N(CH3)2

O

CH3O

CH3O

CH3O

C

O

Cl ONH

CH3O

CH3O

CH3O

C

O

N O

+ 2

+ 2

NaOH

H2O+

2-methylpropanoyl chloride 2-methylpropanamide (83%)

benzoyl chloride N,N-dimethylbenzamide

3,4,5-trimethoxybenzoyl chloride

morpholinetrimetozine

Reduction: Conversion of Acid Halides into Alcohols

- acid chlorides are reduced by LiAlH4, by way of an aldehyde intermediate which can be trapped using lithium tri-tert- butoxyaluminum hydride as the reducing agent

CCl

OCH2OH

C

O

R ClH C

O

R HCl

C

O

R HC

OH

R HH

+

1) LiAlH4, ether

2) H3O+

LiAlH4

ether

1) LiAlH4

2) H3O+

benzoyl chloride benzyl alcohol (96%)

acid chloride aldehyde(not isolated)

primaryalcohol

11

- lithium tri-tert-butoxyaluminum hydride is effective for achieving partial reduction of acid chlorides to aldehydes

3 (CH3)3COH + LiAlH4 Li+ -AlH[OC(CH3)3]3 + 3 H2

C

O

ClO2N

lithium tri-tert-butoxyaluminum

C

O

HO2N1) LiAlH[OC(CH3)3]3, ether

2) H3O+

p-nitrobenzoyl chloride p-nitrobenzaldehyde(81%)

Reaction of Acid Halides with Organometallic Reagents

- Grignard reagents react with acid chlorides to give tertiary alcohols with two identical substituents that originate from the organometallic reagent

- reaction proceeds through a ketone intermediate

C

O

R Cl+ 2R’MgX

1) Ether

2) H3O+ R OH

R'R'

CCl

O

COH

CH3H3CC

CH3

O1) CH3MgBr

2) Ether

1) CH3MgBr

2) Ether

benzoyl chloride acetophenone 2-phenyl-2-propanol

acid chloride 3o alcohol

- ketone intermediate can be isolated using a Gilman reagent

C

O

R Cl

acid chloride

+ R’2Cu- Li+ether

solvent C

O

R R'

ketone

C CCH3

CO

Cl

CH

H

CH3

CH3CH2C C

CH3

CO

CH2CH3

CH

H

CH3

CH3CH2

(CH3CH2)2CuLi

ether, -78oC

2,4-dimethyl-2-hexenoylchloride

manicone (92%)

12

Chemistry of Acid Anhydrides

Preparation of Acid Anhydrides

- most general method is nucleophilic acyl substitution involving a carboxylate anion

C

O

Cl CH3C

O

H OC

CH3

Oether

25oC

+C

O

H O Na+

sodium formate acetyl chloride acetyl formicanhydride (64%)

Acid Anhydride

- acid anhydrides and acid chlorides undergo the same reactions

Reactions of Acid Anhydrides

COH

O

OH

C

O

H3C OC

CH3

O

C

O

H3C OC

CH3

O

COH

O

O

CCH3O

NH2

HO

N

HO

H

CO

CH3

NaOH

H2O+

+NaOH

H2O

salicyclic acid acetic anhydrideaspirin

p-hydroxyaniline acetominophenacetic anhydride

+ C

O

H 3C O

C

O

H3C O+

13

Chemistry of Esters

- esters are among the most widespread of all types of molecules

C

O

OCH3CH3CH2CH2 C

O

OCH2CH2CH3 CH

CH3

CH3

COCH2CH2CH3

COCH2CH2CH3

O

O

methyl butanoate(from pineapples)

isopentyl acetate(from bananas)

dibutyl phthalate(a plasticizer)

Preparation of Esters

- methods that we have previously discussed:

C

O

R OHC

O

R Cl

C

O

R OR'C

O

R OR'C

O

R OR'

1) NaOH2) R’X R’OH

HClR’OHpyridine

SOCl2

limited to primaryalkyl halides

limited to simplealcohols

very general

Reactions of Esters- reactions similar to acid chlorides and acid anhydrides, yet are less reactive since the alkoxide ion is a relatively poor leaving group

Ester

14

Hydrolysis of Esters

- hydrolysis of an ester can be achieved in two ways:

1) base-catalyzed mechanism (saponification)

2) acid-catalyzed mechanism

C

O

R OHC

O

R OR'

H2O, NaOH

or H3O+

Base-Induced Ester Hydrolysis

Acid-Induced Ester Hydrolysis

Mechanism

15

Support for Mechanism of Base-Catalysis

C

O

CH3CH2 OCH2CH3C

O

CH3CH2 OH

1) NaOH, H2O

2) H3O+CH3CH2OH+*

*

bond broken

- 18O-labeling experiments

Aminolysis and Reduction

COCH3

O

CNH2

O

NH3

ether+ CH3OH

C

O

OCH2CH3CHCH3CH2CH CHCH2OHCH3CH2CH CH3CH2OH1) LiAlH4, ether

2) H3O++

O

O

CH3

CHOH

CH3HOCH2CH2CH21) LiAlH4, ether

2) H3O+

methyl benzoate benzamide

ethyl 2-pentenoate 2-penten-1-ol (91%)

lactone

1,4-pentanediol (86%)

- the intermediate aldehyde involved in the reduction reaction can be isolated using diisobutylaluminum hydride (DIBAH)

C

O

R OR'H C

O

R HR'O

C

O

R HC

OH

R HH

LiAlH4

ether

1) LiAlH4

2) H3O++

- mechanism of reduction is similar to that of acid chloride:

C

O

OCH2CH3CH3(CH2)10 CH

O

CH3(CH2)101) DIBAH in toluene

2) H3O+

ethyl dodecanoate dodecanal (88%)

- where DIBAH = [(CH3)2CHCH2]2AlH

16

Reaction of Esters with Grignard Reagents

- esters react with two equivalents of Grignard reagent to yield a tertiary alcohol with two identical substituents

COCH3

O MgBr

C

OH

O

O

CH

OH

CH3

CH2CH2CH2CH2OHH3C

2) H3O+

, ether1) 2

2) H3O+

1) 2 CH3MgBr, ether

methyl benzoatetriphenylmethanol (96%)

valerolactone 5-methyl-1,5-hexanediol

Chemistry of Amides- amides are much less reactive than acid chlorides, acid anhydrides, and esters

Preparation- usually prepared by reaction of acid chloride with an amine

C

O

R Cl

C

O

R NH2

C

O

R NHR'

C

O

R NR'2R’NH2

NH3 R’2NH

Hydrolysis of Amides

- owing to lesser reactivity, more severe conditions are required to hydrolyze an amide (i.e. aqueous acid or base)

Acid Hydrolysis

Base Hydrolysis

C

O

R NH2C

O

R NH2

H

C

O

R O

H

H2NH

H C

O

R O

H

H3NH

C

O

R OH

OH2+

+ NH4+

C

O

R NH2

OHC

O

R OH2N

H C

O

R OH2N

C

O

R O

OH+ NH2

-

17

- the stability of amides makes the structure one of the essential blocks of life; specifically, amides linkages are the building units of proteins

C

O

OHCH

R

H2N C

O

NHCH

R

HN C

O

CH

R'

NH C

O

CH

R''

protein (polyamide)amino acid

Reduction: Conversion of Amides to Amines

- amides are reduced, similar to carboxylic acids, using LiAlH4

- the product is an amine (instead of an alcohol), with conversion of an amide carbonyl group to a methylene group (C=O → CH2)

- specific to amides and not other carboxylic acid derivatives

C

O

CH3(CH2)10 NHCH3CH3(CH2)10CH2NHCH3

1) LiAlH4, ether2) H2O

N-methyldodecanamidedodecylmethylamine (95%)

N

H

H3C

H3C

O N

H

H3C

H3C

H

H

lactam cyclic amine (80%)

1) LiAlH4, ether

2) H2O

Mechanism

C

O

R NH2C

NH H

R H

C

NH2

R HH

1) LiAlH4

2) H3O+H+

H

C

O

R H

AlH3

H2N

iminium ionamide

18

Chemistry of Nitriles- nitriles are analogous to carboxylic acids in terms of structure and reactivity

- both nitriles and carboxylic acids have a carbon atom with three bonds to an electronegative atoms and a π bond

- both nitriles and carboxylic acids undergo nucleophilic addition

R C N R COH

O

C

O

R R C

O

R NuR

R C N C

N

R Nu

:Nu-

:Nu-

products

products

Preparation of Nitriles

1) SN2 reaction with CN- with a primary alkyl halide

2) dehydration of a primary amide

RCH2Br + Na+ CN- SN2

reactionRCH2CN + NaBr

C

O

NH2CH

CH2CH3

CH3CH2CH2 CCH

CH2CH3

CH3CH2CH2 NSOCl2, benzene

80 oC

2-ethylpentanamide 2-ethylpentanenitrile (90%)

+ SO2 + HCl

Mechanism of Dehydration

- dehydration is more general since the reaction is not limited by steric hindrance

C

O

R NH2 C

O

R N

S

O

Cl

H

H

C

O

R N

S

O

Cl

H

R C N:Base :Base

+ SO2

S

O

Cl Cl

19

Nitrile

Hydrolysis of Nitriles

- nitriles are hydrolyzed in either acidic or base aqueous solution to give carboxylic acids plus ammonia or an amine

- the mechanism involves the generation of an amide intermediate

- reaction conditions are quite severe (KOH, 200oC), meaning that the amide in some instances can be isolated using milder conditions

R C N C

O

R OH

H3O+

or NaOH, H2O+ NH3

Amide

20

Reduction: Conversion of Nitriles into Amines and Aldehydes

- nitriles are reduced using either LiAlH4 or DIBAH

- with the less powerful reducing agent DIBAH, the second addition of the hydride does not occur and the intermediate imine anion is hydrolyzed to give an aldehyde

C

CH3

N CH2NH2

CH3

1) LiAlH4, ether2) H2O

o-methylbenzonitrile o-methylbenzylamine(88%)

R C N

C

N

R H

C

N

R HC

O

R H

CNH2

R H

H1) LiAlH4

2) H2O

H2O

Himine anion

imine anion

primary amine

aldehyde

CH

CH3

C

CH3

CH2C

CH2

N CH

CH3

C

CH3

CH2CH

CH2

O

1) DIBAH, toluene, -78oC

2) H2O

Reaction of Nitriles with Organometallic Reagents

- in a similar way to the reduction mechanism, Grignard reagents add to nitriles to produce an imine anion that can be hydrolyzed by addition of water to yield a ketone

- the nucleophile is a carbanion (R:-) rather than a hydride

R C N C

N

R R'C

O

R R'

:R’- +MgX H2O + NH3

C N C CH2CH3

O

1) CH3CH2MgBr, ether

2) H3O+

benzonitrile propiophenone (89%)

21

Thiol Esters

- acetyl coenzyme A (acetyl CoA) is one such ester, serving as an acylating agent in nucleophilic acyl substitution reactions

- Nature carboxylic acid derivatives are in the form of thiol esters

C

O

H3C S CH2CH2NHCCH2CH2NHCCH(OH)CCH2OP

O O CH3

CH3

O

O

O P

O

O

OCH2 O

PO

O

O

N

N

N

N

NH2

H H

OH

C

O

R SR'

acetyl CoA

Synthesis of N-acetylglucosamine

C

O

H3C SCoAC

O

H3C Nu:Nu-+

OCH2OH

NH2OH

HOHO

C

O

H3C SCoA

OCH2OH

NHOH

HOHO

COH3C

+

glucosamineN-acetylglucosamine

Polyamides and Polyesters

- reaction of a diamine and a diacid chloride produces a polyamide

- similarly, reaction of a diol and a diacid produces a polyester

- polymers are known as step-growth polymers

C

O

Cl (CH2)m C

O

ClH2N(CH2)nNH2 C

O

HN(CH2)nNH (CH2)m C

O

+

diamine diacid chloride polyamide

C

O

HO (CH2)m C

O

OH C

O

O(CH2)nO (CH2)m C

O

HO(CH2)nOH +

diol diacid polyester

22

Synthesis of Nylon

Synthesis of Dacron

C

O

HO (CH2)4 C

O

OH

C

O

(CH2)4 C

O

N(CH2)6NH

H2N(CH2)6NH2+

adipic acid hexamethylenediamine

Nylon 66

COCH3

O

CH3OC

O

+ HOCH2CH2OH

dimethylterephthalate

ethylene glycol

200 oCC

O

C

O

OCH2CH2O O

Dacron; Mylar

n

n

+ 2n H2O

+ 2n H2O

Spectroscopy of Carboxylic Acid Derivativesand Nitriles

Infrared Spectroscopy

- carbonyl-containing compounds have intense IR absorptions in the range 1650 - 1850 cm-1

- position provides information about the kind of carbonyl group

NMR Spectroscopy

- hydrogens on carbon next to carbonyl group are slightly deshielded and absorb near 2 δ in the 1H NMR spectrum

- carbon carbon atoms absorb near 200 δ in the 13C NMR spectrum

1H NMR Spectrum of Ethyl Acetate

Chemical Shift (δδδδ)