Introduction to General and Organic Chemistry III

Chapters 20 & 21 Carboxylic Acids & Derivatives

Department of Chemistry

Introduction
The functional group of carboxylic acids consists of a C=O with -OH bonded to the same carbon. Carboxyl group is usually written -COOH. Aliphatic acids have an alkyl group bonded to -COOH. Aromatic acids have an aryl group. Fatty acids are long-chain aliphatic acids. =>
Chapter 20

Common Names
Many aliphatic acids have historical names. Positions of substituents on the chain are labeled with Greek letters.

Cl O CH3CH2CHC OH

a-chlorobutyric acid
Chapter 20 3

IUPAC Names
Remove -e from alkane (or alkene) name, add -oic acid. The carbon of the carboxyl group is #1.
Cl O CH3CH2CHC OH
2-chlorobutanoic acid
Ph H H C C COOH

trans-3-phenyl-2-propenoic acid (cinnamic acid)

Chapter 20

=> 4

Naming Cyclic Acids

Cycloalkanes bonded to -COOH are named as cycloalkanecarboxylic acids. Aromatic acids are named as benzoic acids.
COOH

COOH
OH

CH(CH3)2

2-isopropylcyclopentanecarboxylic acid o-hydroxybenzoic acid (salicylic acid) =>

Chapter 20 5

Dicarboxylic Acids
Aliphatic diacids are usually called by their common names (See Table 20-2). For IUPAC name, number the chain from the end closest to a substituent. Two carboxyl groups on a benzene ring indicate a phthalic acid.
=>
Chapter 20 6

Dicarboxylic Acids
Br HOOCCH2CHCH2CH2COOH
CO 2H CO 2H o-Phthalic acid

3-bromohexanedioic acid -bromoadipic acid

Chapter 20

Structure of Carboxyl Group

Carbon is sp2 hybridized. Bond angles are close to 120. O-H eclipsed with C=O, to get overlap of orbital with orbital of lone pair on oxygen.

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Chapter 20 8

Boiling Points
Higher boiling points than similar alcohols, due to dimer formation.

Acetic acid, b.p. 118C

Chapter 20

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9

Melting Points
Aliphatic acids with more than 8 carbons are solids at rt. Double bonds (especially cis) lower the melting point. Note these 18-C acids:
Linoleic acid (2 cis double bonds): -5C Oleic acid (1 cis double bond): 16C Stearic acid (saturated): 72C =>
Chapter 20 10

Solubility
Water solubility decreases with the length of the carbon chain. Up to 4 carbons, acid is miscible in water. More soluble in alcohol. Also soluble in relatively nonpolar solvents like chloroform because it dissolves as a dimer. =>
Chapter 20 11

Acidity

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Chapter 20 12

Resonance Stabilization

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Chapter 20 13

Substituent Effects on Acidity

COOH

COOH

COOH

COOH

COOH NO 2

NO 2 OCH3 p-methoxy
pKa = 4.46

benzoic acid
pKa = 4.19

m-nitro
pKa = 3.47
Chapter 20

NO 2 p-nitro
pKa = 3.41

o-nitro
pKa = 2.16

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14

Salts of Carboxylic Acids

Sodium hydroxide removes a proton to form the salt. Adding a strong acid, like HCl, regenerates the carboxylic acid.
O CH3 C OH NaOH O CH3 _ + C O Na

HCl
Chapter 20 15

Naming Acid Salts

Name the cation. Then name the anion by replacing the -ic acid with -ate.
Cl CH3CH2CHCH2COO K
+

potassium -chlorovalerate

potassium 3-chloropentanoate
Chapter 20

=> 16

Properties of Acid Salts

Usually solids with no odor. Carboxylate salts of Na+, K+, Li+, and NH4+ are soluble in water. Soap is the soluble sodium salt of a long chain fatty acid. Salts can be formed by the reaction of an acid with NaHCO3, releasing CO2. =>
Chapter 20 17

Some Important Acids

Acetic acid is in vinegar and other foods, used industrially as solvent, catalyst, and reagent for synthesis. Fatty acids from fats and oils. Benzoic acid in drugs, preservatives. Adipic acid used to make nylon 66. Phthalic acid used to make polyesters. =>
Chapter 20 18

IR Spectroscopy 2-Methylpropenoic acid

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Chapter 20 19

CPS Question
List the following weak acids in order of increasing acidity (from lowest to highest.).

A. B. C. D. E.

4<3<2<1<5 4<1<3<2<5 5<2<3<1<4 4<1<2<5<3 1<2<4<3<5

Chapter 20

20

Question
List the following weak acids in order of increasing acidity (from lowest to highest.).

A) 4 < 3 < 2 < 1 < 5 B) 4 < 1 < 3 < 2 < 5 C) 5 < 2 < 3 < 1 < 4 D) 4 < 1 < 2 < 5 < 3 E) 1 < 2 Chapter <4< 20 3 < 5

21

Question
In an aqueous solution, which of the following acids would be most dissociated?
A. B. C. D. E. p-nitrobenzoic acid (pKa = 3.41) acetic acid (ethanoic acid) (pKa = 4.74) hexanoic acid (pKa = 4.88) octanoic acid (pKa = 4.89) Water (pKa = 15.7)
Chapter 20 22

Question
At pH 4.5, which of the following acids would be most dissociated? A) p-nitrobenzoic acid (pKa = 3.41) B) acetic acid (ethanoic acid) (pKa = 4.74) C) hexanoic acid (pKa = 4.88) D) octanoic acid (pKa = 4.89) E) water
Chapter 20 23

Synthesis of Carboxylic Acids (Review) Oxidation of primary alcohols and aldehydes with chromic acid. Cleavage of an alkene with hot KMnO4 produces a carboxylic acid if there is a hydrogen on the double-bonded carbon. Alkyl benzene oxidized to benzoic acid by hot KMnO4 or hot chromic acid. =>
Chapter 20 24

Grignard Synthesis
Grignard reagent + CO2 yields a carboxylate salt. Protonation of the salt yields the carboxylic acid.

MgBr

1) CO2 2) H3O+

CO2H

=>
Chapter 20 25

Hydrolysis of Nitriles
Basic or acidic hydrolysis of a nitrile produces a carboxylic acid.
Br CN

NaCN

H H2O

COOH

=>
Chapter 20 26

CPS Question
An acid which could not be prepared by the reaction of an organic halide with cyanide ion followed by acid hydrolysis of the nitrile is:

A. B. C. D. E.

CH3CH2CO2H, propanoic acid PhCH2CO2H, phenylacetic acid CH3CO2H, acetic acid (CH3)3CCO2H CH3(CH2)14CO2H]
Chapter 20 27

Question
An acid which could not be prepared by the reaction of an organic halide with cyanide ion followed by acid hydrolysis of the nitrile is:

A) propanoic acid B) phenylacetic acid C) acetic acid D) (CH3)3CCO2H E) CH3(CH2)14CO2H

Chapter 20 28

Acid Derivatives
The group bonded to the acyl carbon determines the class of compound:
-OH, carboxylic acid -Cl, acid chloride -OCOR, acid anhydride -OR, ester -NH2, amide

These interconvert via Nucleophilic Acyl Substitution.

Chapter 20 29

Acid Derivatives

Chapter 20

30

Acid Derivatives
All can be converted to the carboxylic acid by acidic or basic hydrolysis. Esters and amides common in nature.

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Chapter 21 31

Naming Esters
Esters are named as alkyl carboxylates. Alkyl from the alcohol, carboxylate from the carboxylic acid precursor.
CH3 O
O HCOCH2

CH3CHCH2OCCH3

isobutyl acetate 2-methylpropyl ethanoate

benzyl formate benzyl methanoate

=>
Chapter 21 32

Cyclic Esters - Lactones

Reaction of -OH and -COOH on same molecule produces a cyclic ester, lactone. To name, add word lactone to the IUPAC acid name or replace the -ic acid of common name with -olactone.
O H3C O CH3
Chapter 21

4-hydroxy-2-methylpentanoic acid lactone a-methyl--valerolactone =>

33

Amides
Product of the reaction of a carboxylic acid and ammonia or an amine. Not basic because the lone pair on nitrogen is delocalized by resonance.
_ O C H N H H O C + H N H H Bond angles around N are close to 120.
Chapter 21

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34

Classes of Amides
1 amide has one C-N bond (two N-H). 2 amide or N-substituted amide has two C-N bonds (one N-H). 3 amide or N,N-disubstituted amide has three C-N bonds (no N-H).

Chapter 21

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35

Naming Amides
For 1 amide, drop -ic or -oic acid from the carboxylic acid name, add -amide. For 2 and 3 amides, the alkyl groups bonded to nitrogen are named with N- to indicate their position.
O CH3 CH3CHC N CH2CH3 CH3
Chapter 21 36

N-ethyl-N,2-dimethylpropanamide N-ethyl-N-methylisobutyramide
=>

Cyclic Amides - Lactams

Reaction of -NH2 and -COOH on same molecule produces a cyclic amide, lactam. To name, add word lactam to the IUPAC acid name or replace the -ic acid of common name with -olactam.
O N H CH3

4-aminopentanoic acid lactam -valerolactam

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Chapter 21 37

Nitriles
-CN can be hydrolyzed to carboxylic acid, so nitriles are acid derivatives. Nitrogen is sp hybridized, lone pair tightly held, so not very basic. (pKb about 24).

Chapter 21

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38

Naming Nitriles
For IUPAC names, add -nitrile to the alkane name. Common names come from the carboxylic acid. Replace -ic acid with -onitrile.
Br CH3CHCH2CH2CH2CN
C N

5-bromohexanenitrile -bromocapronitrile

Cyclohexanecarbonitrile =>
Chapter 21 39

Acid Halides(1)
More reactive than acids; the halogen withdraws e- density from carbonyl. Named by replacing -ic acid with -yl halide.
O C Cl
Br O

CH3CHCH2C Br

benzoyl chloride
Chapter 21

3-bromobutanoyl bromide -bromobutyryl bromide =>

40

Acid Halides(2)
Acid chlorides from alkane carboxylic acids are named using the suffix carbonyl chloride. O

Cl

Cyclohexanecarbonyl chloride
Chapter 21 41

Acid Anhydrides
Two molecules of acid combine with the loss of water to form the anhydride. Anhydrides are more reactive than acids, but less reactive than acid chlorides. A carboxylate ion is the leaving group in nucleophilic acyl substitution reactions.
O R C O H O H O C R
Chapter 21

O R

R C O C

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42

Naming Anhydrides
The word acid is replaced with anhydride. For a mixed anhydride, name both acids. Diacids may form anhydrides if a 5- or 6membered ring is the product.
O

O CH3 C O

O C CH3
O O

ethanoic anhydride acetic anhydride

1,2-benzenedicarboxylic anhydride phthalic anhydride =>

Chapter 21 43

Multifunctional Compounds
The functional group with the highest priority determines the parent name. Acid > ester > amide > nitrile > aldehyde > ketone > alcohol > amine > alkene > alkyne.
O C CN
Chapter 21

OCH2CH3

Ethyl o-cyanobenzoate
=>
44

Examples:
O NH 2

3-Formylcyclohexanecarboxamide
H O O CH 2CH 3 N CH 3

N-Ethyl-5-aminohexanoic acid lactam

O O

Cyclohexyl cyclopentanecarboxylate
Chapter 21 45

Boiling Points

Even 3 amides have strong attractions.

Chapter 21

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46

Melting Points
Amides have very high melting points. Melting points increase with increasing number of N-H bonds.
O H C N CH3 CH3 O CH3 C N H CH3 O CH3CH2 C N H H

N,N-Dimethylmethanamide

N-Methylethanamide

Propanamide

m.p. -61C

m.p. 28C
Chapter 21

m.p. 79C
47

Solubility
Acid chlorides and anhydrides are too reactive to be used with water or alcohol. Esters, 3 amides, and nitriles are good polar aprotic solvents. Solvents commonly used in organic reactions:
Ethyl acetate Dimethylformamide (DMF) Acetonitrile
Chapter 21

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48

IR Spectroscopy

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Chapter 21 49

Ethyl octanoate

Chapter 21

50

Methyl benzoate

Chapter 21

51

Lactones & Lactams

Chapter 21

52

Propanoic anhydride

Chapter 21

53

Interconversion of Acid Derivatives

Nucleophile adds to the carbonyl to form a tetrahedral intermediate. Leaving group leaves and C=O regenerates.

Chapter 20

54

Reactivity Reactivity decreases as leaving group becomes more basic.

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Chapter 20 55

Interconversions

More reactive derivatives can be converted to less reactive derivatives.

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Chapter 20 56

Fischer Esterification
Acid + alcohol yields ester + water. Acid catalyzed for weak nucleophile. All steps are reversible. Reaction reaches equilibrium.
O COOH + CH3CH2OH H
+

COCH2CH3 + HOH

Chapter 20

57

General Mechanism(1)
Protonation of carbonyl and attack of alcohol, a weak nucleophile.

Chapter 20

58

General Mechanism(2)
Protonation of -OH and loss of water.

Chapter 20

59

Transesterification
One alkoxy group can be replaced by another with acid or base catalyst. Use a large excess of preferred alcohol.

Chapter 20

60

Cyclic Esters - Lactones

Reaction of -OH and -COOH on same molecule produces a cyclic ester, lactone.
4-hydroxy-2-methylpentanoic acid lactone a-methyl--valerolactone

O H3C O CH3
Chapter 20

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61

Lactones
Formation favored for five- and sixmembered rings.
OH COOH H+ O + H 2O O

For larger rings, remove water to shift equilibrium toward products

OH COOH H
+

O O

H2O

Chapter 20

62

Important Lactones

Macrolide antibiotic
Chapter 20 63

Thioesters Formed from a carboxylic acid or acid choride and a thiol.

O OH + SH
Cyclohexyl thiobenzoate
Chapter 20 64

O S + H2O

Thioesters(2)
More reactive than esters because: -S-R is a better leaving group than -O-R Resonance overlap is not as effective.

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Chapter 20 65

Acetyl coenzyme A
- CoA is a thiol whose thioesters serve as acyltransfer agents.

Chapter 20

66

Acid Chlorides
An activated form of the carboxylic acid. More reactive than acid anhydrides. Chloride is a good leaving group, so undergoes acyl substitution easily. To synthesize acid chlorides use thionyl chloride or oxalyl chloride with the acid.

Chapter 20

67

Acid Chloride Synthesis

Chapter 20

68

Mechanism(1)

Chapter 20

69

Mechanism(2)
Nucleophilic acyl substitution by chloride.

Chapter 20

70

Esters from Acid Chlorides

Acid chlorides react with alcohols to give esters in good yield. Mechanism is nucleophilic addition of the alcohol to the carbonyl as chloride ion leaves, then deprotonation.
O CCl + CH3OH
Chapter 20

O COCH3 + HCl
71

Acid Hydrolysis of Esters

Reverse of Fischer esterification. Reaches equilibrium. Use a large excess of water.
O CH3 C OCH3 + HOH O CH3 C OH + CH3OH

=>
Chapter 20 72

Saponification
Base-catalyzed hydrolysis of ester. Saponification means soap-making. Soaps are made by heating NaOH with a fat (triester of glycerol) to produce the sodium salt of a fatty acid - a soap. One example of a soap is sodium stearate, Na+ -OOC(CH2)16CH3. =>
Chapter 20 73

Saponification

Chapter 20

74

Amides from Acid Chlorides

Acid chlorides react with ammonia and amines to give amides. A base (NaOH or pyridine) is added to remove HCl by-product.
O CCl + CH3NH2 NaOH O CNHCH3 + NaCl + H2O

Chapter 20

75

Amides from Acids

Amine (base) removes a proton from the carboxylic acid to form a salt. Heating the salt above 100C drives off steam and forms the amide.
O C OH CH NH + 3 2 O C O- + NH CH 3 3 heat O C NHCH 3 + H2 O

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Chapter 20 76

Lactams Cyclic Amides

Five- and six-membered rings can be formed by heating - and -amino acids. Smaller or larger rings do not form readily.

Chapter 20

77

-Lactams
Highly reactive, 4-membered ring. Found in antibiotics isolated from fungi.

Chapter 20

78

CPS Question
Amides are less basic than amines because:
A. the carbonyl group donates electrons by resonance. B. the carbonyl group withdraws electrons by resonance C. the nitrogen does not have a lone pair of electrons. D. the nitrogen has a full positive charge. E. amides do not contain nitrogen.
Chapter 20 79

Hydrolysis of Amides(1)
Prolonged heating in 6 M HCl or 40% aqueous NaOH is required.
O CH3 C
O CH3 C NHCH3 + HCl
-

NHCH3 + OH

H2O

O CH3
O CH3 C OH + CH 3NH 3 Cl
+ -

+ CH 3 NH 2

H2O

=>
Chapter 21 80

Hydrolysis of Amides(2)

Chapter 21

81

Hydrolysis of Amides(3)

Chapter 21

82

General Mechanism

Chapter 21

83

Synthesis of Nitriles
O R C NH2 POCl3 R C N

1 amide

diazonium salt

Ar

+ N N

CuCN

Ar

CN + N2

O R C R' aldehyde or ketone

HO CN HCN R C R' KCN cyanohydrin

Chapter 21

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84

Reactions of Nitriles

O H2O H+ or -OH (1) LiAlH4 (2) H2O R'MgX R C NH2

O H2O H+ or -OH R C OH

amide
R CH2NH2 N MgX R C R'

acid

1 amine
H3O
+

R C N

O R C R'

ketone
=>
Chapter 21 85

Hydrolysis of Nitriles
Under mild conditions (~50 oC), nitriles hydrolyze to an amide. Refluxing with aqueous acid or base will hydrolyze a nitrile to an acid.
O C N + H2O
-

O
-

OH

C NH 2

OH heat

C O+ NH3

=>
Chapter 21 86

Acid Reduction to 1 Alcohols

Use strong reducing agent, LiAlH4.
Borane, BH3 in THF, reduces carboxylic acid to alcohol, but does not reduce ketone.

Chapter 20

87

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Reduction to Aldehyde
Difficult to stop reduction at aldehyde. Use a more reactive form of the acid (an acid chloride) and a weaker reducing agent, lithium aluminum tri(t-butoxy)hydride.
O CCl LiAl[OC(CH3)3]3H O C H

Chapter 20

88

Question
Which of the reagents listed below would work best in the following reaction?

A. B. C. D. E.

NaBH4 LiAlH4 BH3 -THF LiAl[(OC(CH3)3]3H none of the above

Chapter 20 89

Alkylation to Form Ketones

React 2 equivalents of an organolithium reagent with a carboxylic acid.
O COOH 1) 2 CH3CH2 2) H2O Li C CH CH 2 3

Chapter 20

90

Question
Acids can be reduced to aldehydes by
A. treatment with LiAlH4 B. conversion to the acid chloride followed by treatment with LiAlH[OC(CH3)3]3. C. conversion to the amide followed by treatment with NaBH4 D. conversion to the ester followed by treatment with LiAlH4 E. conversion to the anhydride followed by treatment with Mg and H3O+.
Chapter 20 91

CPS Question
Arrange the carboxylic acid derivatives below in order of increasing reactivity towards nucleophilic acyl substitution.
O OCH3 O O O CH3 O Cl

II

III

A. I < II < III B. I < III < II C. II < I < III D. II < III < I
Chapter 20 92

End of Course!

Chapter 20

93