88

174

Chapter 20: Carboxylic Acids and Nitriles

20.1 Naming Carboxylic Acids (please read)In general, the same for alkanes; replace the terminal

-e of the alkane name with -oic acidThe carboxyl carbon atom is C1Compounds with -CO2H group on a ring are named

using the suffix -carboxylic acid

The -CO2H carbon is not numbered in these cases

Many non-systematic names: Table 20.1

175

20.1 Naming Nitriles (please read) If derived from open-chain alkanes, replace the terminal

-e of the alkane name -nitrile as a suffix The nitrile carbon numbered C1Complex nitriles are named as derivatives of carboxylic

acids. Replace -ic acid or -oic acid ending with -onitrile

89

176

20.2 Structure and properties of carboxylic acidsThe carboxylic acid function group contains both a

hydrogen bond donor (-OH) and a hydrogen bondacceptor (C=O)

Carboxylic acids exist as hydrogen bonded dimers

H3C C

O

O H

CH3C

O

OH

H3C OC

O

H

acetic acid

H-bonddonor

H-bondaceptor

177

20.3 Dissociation of Carboxylic acids Acidity Constant and pKa

Carboxylic acids react with base to give carboxylate salts

Bronsted Acidity (Chapter 2.7):Carboxylic acids transfer a proton to water to give H3O+ and

carboxylate anions, RCO2−

R OC H

O

+ NaOH

R OC

O

+ H2ONa

R OHC

O

+ H2O

R OC

O

+ H3O

[RCO2-] [H3O+]

[RCO2H]Ka= pKa= - log Ka

typically ~ 10-5 for carboxylic acid

typically ~ 5 forcarboxylic acid

90

178

CH3CH3 CH3CH2OH PhOH CH3CO2H HClpKa ~50-60 16 10 4.75 -7

Increasing acidity

H3C OHC

O

H3C OC

O

+ H3O

H2O

H3C OC

O

H3C-H2C-OH

H2O

H3C-H2C-O + H3O

The negative charge of a carboxylate is resonance stabilized

4 electron delocalizedover three p-prbitals

C-O bond length of a carboxylates are the same

H3C

O

C

OO

!

!

C

O

pKa~ 16

pKa~ 4.7

179

20.4 Substituent Effects on AciditySubstituents on the α-carbon influence the pKa of carboxylic

acids largely through inductive effects. Electron-withdrawing groups increase the acidity (lower pKa) and electron-donating groups decrease the acidity (higher pKa)

Inductive effects work through σ-bonds, and the effect falls off dramatically with distance

also seeTable 20.4

91

180

20.5 Substituent Effects in Substituted Benzoic AcidsAn aromatic or substituted aromatic rings has dramatically less

influence on the acidity of benzoic acids, pKa ~ 4.2 (when compared to acetic acid) than in the case of phenols

OH

R

CO2H

R

H3CH2C-OHH3C-CO2H

pKa ~ 16 R=H, pKa ~9.9 pKa ~ 4.75 R=H, pKa ~ 4.2 Cl 9.4 Cl 4.0 NO2 7.1 NO2 3.4 CH3 10.2 CH3 4.3

OCH3 10.2 OCH3 4.5

The charge of the carboxylate ion cannot be delocalize intothe aromatic ring

Electron-donating groups decrease the acidityElectron-withdrawing groups increase the acidity

181

20.6 Preparation of carboxylic acids1. Benzoic acids are prepared from the oxidation of alkyl

benzene with KMnO4 (Chapter 16.10)

2. Oxidation of primary alcohols with chromic acid (CrO3/HCl)(Chapter 17.18)

3. Oxidation of aldehydes with chromic acid or Ag2O(Chapter 19.3)

CH2CH3CH3

O2N

KMnO4

CO2H

O2N

Alkyl benzene

1° alcohol

CrO3/HCl

Aldehyde

CrO3/HCl

-or-Ag2O

OH

CHO

CO2H

CO2H

92

182

20.6 Preparation of carboxylic acids4. Acid or basic hydrolysis of a nitrile (mechanism, Fig. 20.4)

cyanide ion is an excellent nucleophile and will react with1° and 2° alkyl halides and tosylates to give nitriles. Thisreaction add one carbon.

H3CH

2CH

2CH

2C-Br

NaC!N

DMSO

H3CH

2CH

2CH

2C-C!N

H3O+

H3CH

2CH

2CH

2C-CO

2H

C4

C5

C5

PhO

BrNaC!N

DMSO

C!NH

3O+

PhO

CO2H

O NaC!N CNHO

-or-

NaOH

-or-

NaOH

H3O+

CO2HHO. . . and don’t forget

183

20.6 Preparation of carboxylic acids5. Carboxylation of Grignard reagents Reaction of a Grignard reagent with CO2 gives a carboxylic acid

Br Mg(0) MgBr CO2 C

O

O

H3O+

COH

O

MgBr

_C

O

O

93

184

20.7 Reactions of carboxylic acids: an overview

OHH

O

OH

O

base

OHH

[H]HH

OHR

O

YH

O

Deprotonation(chapters 20.3 - 20.5)

Reduction(chapters 17.5 & 20.8)

α-Substitution(chapter 22)

Nucleophilic acylsubstitution (chapter 21)

185

20.8 Reductions of carboxylic acids Carboxylic acids are reduced to primary alcohols by LiAlH4 (Chapter 17.5) and borane (BH3) but not by NaBH4

R-CO2H RCH2OH

a. LiAlH4, THF

b. H3O+

Lithium aluminium hydride will also reduce ketones, aldehydesesters, nitriles, amides, acid chlorides alkyl halides, epoxides and nitro groups

Borane reacts most rapidly with carboxylic acids to give primary alcohols and it is possible to reduce carboxylic acids inthe presence of some other functional groups

O2N

CO2H

a. BH3 , THF

b. H3O+

O2N

OH

94

186

20.9 Chemistry of Nitriles: Preparation of nitriles

1. Reaction of cyanide ion with 1° and 2° alkyl halides- this is an SN2 reaction.

2. Cyanohydrins- reaction of cyanide ion with ketones and aldehydes (Chapter 19.7)

3. Dehydration of primary amides with POCl3 or SOCl2

R NH2C

O SOCl2 -or-POCl3

Primary amide

R NCbenzene, 80°C

nitrile

Dehydration: formal loss of H2O from the substrate

Mechanism (p. 751, please read): the carbonyl oxygen of an amide is nucleophilic, and can react with electrophiles

R NH2

C

O

R NH2

C

O A very important resonance form of anamide, which contributes significantlyto their properties and reactivity

187

20.9 Chemistry of Nitriles: Reactions of NitrilesThe C≡N bond has a large dipole moment like carbonyls,

making the carbon a potential site for nucleophilic attack

aldehydes & ketonesµ~ 2.8 D

nitrilesµ ~ 3.9 D

C

O

:Nu

NuC

O

NuC

OHH-A

R

N

C

C

O

! +

! -

! +

! -

R

N

C:Nu

N

C

NuR

H-ANH

C

NuR

H3O+ O

C

NuR

N

C

NuR

-or-

HO

:Nu

N

C

NuR

Nu

NH2

C

NuR

Nu

H-A

Cl ClS

O

R NH2

C

O

R NH2

C

O

R NH2

C

OS

Cl

OCl

R NC

O ClS

O

H

HCl

R NC

O ClS

O

H

R NC H Cl- SO2,

- Cl -R NC

- HCl - HCl

95

188

1. Hydrolysis of nitriles to carboxylic acids and amides:Nitriles are hydrolyzed in either aqueous acid or aqueousbase to give carboxylic acids. The corresponding primary amide is an intermediate in the reaction.

Mechanism of the base-promoted reaction (Figure 20.4)Please try the acid-promoted mechanism

189

2. Reduction of nitriles to primary aminesNitriles can be reduced by LiAlH4 or BH3 (but not NaBH4)

to give primary amines

Reduction of a nitrile with Diisobutylaluminium hydride(DIBAH) give an imine, which easily hydrolyzes to thealdehyde (not in book)

R NC

HLiAlH4

ether R

N

CH

H

R

N

C

H

H

2

H3O+

R

NH2

C

H

H

R NC

HDIBAH

tolueneR

N

CH

H3O+

Al(iBu)2

RCH R

O

CH

NH

96

190

3. Reaction of nitriles with Grignard reagents: general methodfor the preparation of ketones

R NC

H3C MgBr

R

N

CCH3

MgBr

THF H3O+

R

NH

CCH3

R

O

CCH3

Must consider functional group compatibility; there is wide flexibility in the choice of Grignard reagents.

Summary:

Na+ -CN

Br C!N

LiAlH4

CH2NH2

DIBAH

CHO

O

MgBr

H3O+

CO2H

primary amines

aldehydes

ketones

carboxylic acids

SN2

191

20.10 Spectroscopy of Carboxylic Acids and NitrilesInfrared SpectroscopyCarboxylic acids:

Very broad O-H absorption between 2500 - 3300 cm−1

Strong C=O absorption bond between 1710 - 1760 cm−1

Usually broader than the O-H absorption of an alcohol

OH

carboxylic acid alcohol

97

192

Nitriles show an sharp C≡N absorption near 2250 cm−1 for alkyl nitriles and 2230 cm−1 for aromatic and conjugated nitriles (highly diagnostic)

C NC NH3CH2CH2C

193

1H NMRThe -CO2H proton is a broad singlet near δ ~12 When D2O is added to the sample the -CO2H proton is replaced

by D causing the resonance to disappear (same for alcohols)

-CO2H

98

194

δ= 2.3 (2H, t) 1.7 (2H, m) 1.1 (3H, t)

C NH3CH2CH2C

The nitrile function group is invisible in the proton NMR. The effect of a nitrile on the chemical shift of the protons on

the α-carbon is similar to that of a ketone.

195

13C NMRThe chemical shift of the carbonyl carbon in the 13C spectrum is

in the range of ~165-185. This range is distinct fromthe aldehyde and ketone range (~190 - 220)

The chemical shift of the nitrile carbon in the 13C spectrum isin the range of ~115-130 (significant overlap with thearomatic region).

CDCl3

TMS

C NH3CH2CH2C

119.8

19.3,19.0

13.3

Ph-H2C-CO2H

178.2

133.2129.3128.5127.3

CDCl3

41.1

99

196

C10H11N

7.3(5H, m)

3.72(1H, t, J=7.1)

1.06(3H, t, J=7.4)

1.92(2H, dt, J=7.4, 7.1)

CDCl3TMS120.7

129.0128.0127.3

135.8

38.929.2

11.4