Functional Derivatives of Carboxylic Acids

R CNH2

O

R CO

O

R CCl

O

R COR'

O

CO

R

acid chlorideanhydride

amide ester

R may be H or Ar

Nomenclature: the functional derivatives’ names are derived from the common or IUPAC names of the corresponding carboxylic acids.

Acid chlorides: change –ic acid to –yl chloride

Anhydrides: change acid to anhydride

CCl

OCH3CH2CH2C

O

Cl

butanoyl chloridebutyryl chloride

benzoyl chloride

H3C CO

H3C CO

O

O

O

O

O

O

O

ethanoic anhydrideacetic anhydride

phthalic anhydride maleic anhydride

Amides: change –ic acid (common name) to –amide

-oic acid (IUPAC) to –amide

Esters: change –ic acid to –ate preceded by the name of the alcohol group

CNH2

OCH3CH2CH2C

O

NH2

butanamidebutyramide

benzamide

CO CH2CH3

O

ethyl benzoate

CH3CH2CH2CO

O CH3

methyl butanoatemethyl butyrate

Nucleophilic acyl substitution:

R CZ

OR C

W

O+ :Z R C W

O

Z+ :W

-W = -OH, -Cl, -OOCR, -NH2, -OR'

R CO

= "acyl" group

R CZ

O

R CW

O+ :Z R C W

O

Z

+ :WR C W

O

Z

RDS

Mechanism: Nucleophilic Acyl Substitution

1)

2)

R CZ

O

R CW

OH+ :ZH R C W

OH

ZH

+ HW + H+R C W

OH

ZH

RDS

R CW

OHR C

W

O+ H+

Mechanism: nucleophilic acyl substitution, acid catalyzed

1)

2)

3)

nucleophilic acyl substitution vs nucleophilic addition to carbonyl

aldehydes & ketones – nucleophilic addition

functional deriv. of carboxylic acids – nucleophilic acyl substitution

R CZ

OR C

W

O+ :Z R C W

O

Z+ :W

-W = -OH, -Cl, -OOCR, -NH2, -OR'

R CR'

O+ :Z R C R'

O

Z

YR C R'

OY

Z

Acid Chlorides

Syntheses: SOCl2

RCOOH + PCl3 RCOCl PCl5

COH

O+ SOCl2 C

Cl

O

benzoic acid benzoyl chloride

OH

O

+ PCl3Cl

O

3-methylbutanoic acidisovaleric acid

3-methylbutanoyl chlorideisovaleryl chloride

Acid chlorides, reactions:

1. Conversion into acids and derivatives:

a) hydrolysis

b) ammonolysis

c) alcoholysis

2. Friedel-Crafts acylation

3. Coupling with lithium dialkylcopper

4. Reduction

acid chlorides: conversion into acids and other derivatives

Cl

O H2O

OH

OHydrolysis

isovaleryl chloride3-methylbutanoyl chloride

isovaleric acid3-methylbutanoic acid

Ammonolysis CH3CH2 CCl

O NH3CH3CH2 C

NH2

O

propionyl chloridepropanoyl chloride

propionamidepropanamide

AlcoholysisC

O

Cl

CH3CH2OHC

O

OCH2CH3

benzoyl chloride ethyl benzoate

Schotten-Baumann technique – aromatic acid chlorides are less reactive than aliphatic acid chlorides. In order to speed up the reactions of aromatic acid chlorides, bases such as NaOH or pyridine are often added to the reaction mixture.

O2N

O2N

COClpyridine

CH3CH2CH2OHO2N

O2N

CO

OCH2CH2CH3

3,5-dinitrobenzoyl chloride n-propyl-3,5-dinitrobenzoate

acid chlorides: Friedel-Crafts acylation

R CO

Cl+ ArH

AlCl3R C Ar

O+ HCl

phenone

CH3CH2CH2C

O

Cl CH3+

toluene

butyryl chloride

AlCl3CH3CH2CH2C

O

CH3 + ortho-

p-methylbutyrophenone

CH3CH2CH2C

O

Cl

butyryl chloride

+ NO2

AlCl3No reacton

acid chlorides: coupling with lithium dialkylcopper

R CO

Cl

+ R'2CuLi R C R'

O

ketone

CO

Cl+ (CH3CH2CH2)2CuLi C CH2CH2CH3

O

benzoyl chloride lithium di-n-propylcopper butyrophenone

CCl

O+

2CuLi

O

2,4-dimethyl-3-pentanoneisobutyryl chloride lithium diisopropylcopper

acid chlorides: reduction to aldehydes

R CCl

O LiAlH(t-BuO)3R C

H

O

CO

ClC

O

H

LiAlH(t-BuO)3

mechanism, nucleophilic acyl substitution by hydride :H-

R CCl

O1) + :H R C Cl

O

H

RDS

2) R C Cl

O

H

R CH

O+ Cl

Anhydrides, syntheses:

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Anhydrides, reactions:

1) Conversion into carboxylic acids and derivatives.

a) hydrolysis

b) ammonolysis

c) alcoholysis

2) Friedel-Crafts acylation

O

O

O

phthalic anhydride

+ H2O

COOH

COOH

(CH3CO)2O + NH3 CH3 CNH2

OCH3 C

ONH4

O+

acetic anhydride

phthalic acid

acetamide

O

O

O

+ CH3CH2OH

succinic anhydride

CH2COCH2CH3

O

CH2COH

O

ethyl hydrogen succinate

ammonium acetate

2) anhydrides, Friedel-Crafts acylation.

(RCO)2O + ArHAlCl3

R COH

O+R C Ar

O

phenone

(CH3CO)2O + CH3AlCl3

H3C C

O

CH3 + CH3CO2H

acetic anhydridetoluene p-methylacetophenone

O

O

O

phthalic anhydride

+AlCl3

C

O

CO

OH

o-benzoylbenzoic acid

Amides, synthesis:

Indirectly via acid chlorides.

R COH

O SOCl2R C

Cl

O NH3R C

NH2

O

[ carboxylic acids form ammonium salts when reacted directly with ammonia ]

CH3CH2CH2CO2H CH3CH2CH2CO

Cl

PCl3 NH3CH3CH2CH2C

O

NH2butyric acid butyryl chloride butyramide

COOHPCl5

CCl

O NH3C

NH2

O

benzoic acid benzoyl chloride benzamide

Amides, reactions.

1) Hydrolysis.

R CNH2

O H2O, H+ or OH-

heatR C

OH

O

CH3CHCH2C

CH3

NH2

O

isovaleramide

+ H2OH+

heatCH3CHCH2C

CH3

OH

O

isovaleric acid

HN CHC

O

R

HN CHC

R

OHN CHC

R

OHN CHC

R

OHN CHC

R

OHN CHC

R

O

proteins are polyaminoacids

H2N CHC

R

OH

O

aminoacids

"peptide bond"

hydrolysis

Wool, hair, silk, spider web: fibrous proteins.

Silk is an extremely strong, thin, lightweight fiber, perfect for making sheer stockings for women as well as parachutes. It is made by the silkworm, a domesticated moth larva raised in Japan and China. During World War II a substitute material was needed and developed by DuPont – Nylon-66, a synthetic polyamide of adipic acid and hexamethylenediamine:

C(CH2)4C

O O

Cl

adipoyl chloride

+ H2N (CH2)6 NH2

hexamethylenediamine

C(CH2)4C

O O

NH (CH2)6 NHC(CH2)4C

O O

NH (CH2)6 NH

Nylon-66

Cl

Esters, syntheses:

1) From acids

RCO2H + R’OH, H+ RCO2R’ + H2O

2) From acid chlorides and anhydrides

RCOCl + R’OH RCO2R’ + HCl

3) From esters (transesterification)

RCO2R’ + R”OH, H+ RCO2R” + R’OH

RCO2R’ + R”ONa RCO2R” + R’ONa

Esters often have “fruity” or “floral” odors:

isopentyl acetate banana oil

n-pentyl butyrate apricot

isopentyl isovalerate apple

ethyl butyrate peach

ethyl heptanoate cognac

ethyl nonate flower bouquet

ethyl laurate tuberose

methyl butyrate pineapple

octyl acetate orange

C

O

OH

isovaleric acid

+ CH3CH2OH

ethyl alcohol

H+

C

O

O

ethyl isovalerate

+ H2O

SOCl2

C

O

Cl

isovaleryl chloride

+ CH3CH2OH

ethyl alcohol

C

O

O

ethyl isovalerate

+ HCl

“Direct” esterification is reversible and requires use of LeChatelier’s principle to shift the equilibrium towards the products. “Indirect” is non-reversible.

In transesterification, an ester is made from another ester by exchanging the alcohol function.

CH3CH2CH2CO

OCH3

methyl butanoate

+

isopropyl alcohol

H+

CH3CH2CH2CO

O

isopropyl butanoate

+ CH3OHCHCH3

CH3CHCH3HO

CH3

CH3CH2CH2CO

OCH3

methyl butanoate

+

CH2ONa

benzyl alcoholCH3CH2CH2C

O

O+

CH2

CH3ONa

benzyl butanoate

Esters, reactions:

1) Conversion into acids and derivatives

a) hydrolysis

b) ammonolysis

c) alcoholysis

2) Reaction with Grignard reagents

3) Reduction

a) catalytic

b) chemical

4) Claisen condensation

COCH2CH3

O H2O; H+ or OH-

heatC

OH

O+ CH3CH2OH

ethyl benzoate

CH3CHC

CH3 O

O CH3

methyl isobutyrate

NH3CH3CHC

CH3 O

NH2

+ CH3OH

CH3CO

OCH2CH3+ OH

H+

CH3CO

O + CH3CH2OH

ethyl acetate cyclopentyl acetate

R C18O R'

O OH-

H2O, heat

H+

R COH

O+ R'18OH

OH-

R C

O-

18O

OH

R

Tracer studies confirm that the mechanism is nucleophilic acyl substitution:

H2C

HC

OOCR

OOCR'

H2C OOCR''

triglycerides, fats/oilstriesters of glycerol

NaOH, H2O

heat

H2C

HC

OH

OH

H2C OH

glycerol

+

RCOO-Na+

R'COO-Na+

R''COO-Na+

"SOAP"

Hydrolysis of a fat or oil is also called "saponification

Esters, reaction with Grignard reagents

R CO

O R''+ R'MgX

H2OR C R'

OH

R'

+ R''OH

3o alcohol

nucleophilicacyl substitution

R C R'

O

ketone

+ R'MgX

nucleophilicaddition

CH3CH2CH2CO

OCH3

methyl butanoate

+ MgBr

phenyl magnesium bromide

H2O

CH3CH2CH2C

OH

1,1-diphenyl-1-butanol

Esters, reduction

a) catalytic

b) chemical

RO R'

O+ H2, Ni NR

RO R'

O H2, CuO, CuCr2O4

150o, 5000 psiRCH2OH + R'OH

RO R'

O LiAlH4 H+

RCH2OH + R'OH

O

O

isopropyl isobutyrate

H2, CuO, CuCr2O4

150o, 5000 psi

OH

OH

+

isobutyl alcohol isopropyl alcohol

CH3CH2CO

O

phenyl propanoate

1. LiAlH4

2. H+ CH3CH2CH2OH +

OH

n-propyl alcohol phenol

Spectroscopy:

Infrared: strong absorbance ~ 1700 cm-1 for C=O

RCO2R 1740 ArCO2R 1715-1730 RCO2Ar 1770

Esters also show a strong C—O stretch at 1050-1300

Amides show N—H stretch at 3050 –3550 and N—H bend in the 1600-1640 region.

Nmr: NB in esters the protons on the alcohol side of the functional group resonate at lower field than the ones on the acid side.

RCOO—C—H 3.7 – 4.1 ppm

H—C—COOR 2 – 2.2 ppm

methyl propionate

C=O

C--O

butyramide

N—H

C=O

N—H bend

Ethyl acetate

CH3CO2CH2CH3

b c a

Note which hydrogens are upfield.

c b a

Methyl propionate

CH3CH2CO2CH3

a b c

Note which hydrogens are upfield.

c b a