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Chapter 20: Chapter 20: Carboxylic Acid Derivatives:Carboxylic Acid Derivatives: NucleophilicNucleophilic
Acyl Acyl SubstitutionSubstitution
20.1: 20.1: Nomenclature of Carboxylic Acid DerivativesNomenclature of Carboxylic Acid Derivatives
(please read) (please read)
O R^ C^ OH O R^ C^ OR'
carboxylic acid
- oic acid
ester
- oate O R^ C^ O R'
lactone
cyclic ester
O R^ C^ Cl
acid chloride
- oyl chloride O R^ C^ O O C (^) R
acid anhydride
- oic anhydride O R^ C^ N R' R''
amide
- amide O R^ C^ N R'
lactam
cyclic amide
R'' R C N
nitrile
- nitrile 166
Y = a leaving group
-Cl, -O 2 CR’, -OR’, -OH, -NR 2 ,
20.3: General Mechanism for Nucleophilic Acyl Substitution
Mechanism occurs in two stages. The first is addition of the
nucleophile to the carbonyl carbon to form a tetrahedral
intermediate. The second stage in collapse of the tetrahedral
intermediate to reform a carbonyl with expulsion of a leaving
group (Y). There is overall substitution of the leaving group (Y)
of the acid derivative with the nucleophile.
R Y
C
O
:Nu-H Nu
C
O
Y
R (^) R CNu
O + Y:H
tetrahedral
intermediate
H
20.2:20.2: Structure and Reactivity of Carboxylic Acid DerivativesStructure and Reactivity of Carboxylic Acid Derivatives
Increasing reactivity R CCl O R CN O R CO O C (^) R' O R COR' O amide ester acid anhydride acid chloride
All acyl derivatives
are prepared directly
from the carboxylic acid.
Less reactive acyl
derivative (amides
and esters) are more
readily prepared from
more reactive acyl
derivatives (acid
chlorides and anhydrides)
carboxylic acid amide acid chloride acid anhydride ester (^) amide acid anhydride ester (^) amide ester amide 168
The reactivity of the acid derivative is related to it resonance
stabilization. The C-N bond of amides is significantly stabilized
through resonance and is consequently, the least reactive acid
derivative. The C-Cl bond of acid chlorides is the least stabilized
by resonance and is the most reactive acid derivative
R CCl O R CN O R CO O C (^) R' O R COR' O amide^ ester acid anhydride acid chloride
20.5: Nucleophilic Acyl Substitution in Acid Anhydrides20.5: Nucleophilic Acyl Substitution in Acid Anhydrides
Prepared from acid chlorides and a carboxylic acidPrepared from acid chlorides and a carboxylic acid
Reactions of acid anhydrides
Acid anhydrides are slightly less reactive reactive that acid
chlorides; however, the overall reactions are nearly identical and
they can often be used interchangeably.
1. Alcoholysis to give esters
2. Aminolysis to give amides
3. Hydrolysis to give carboxylic acids
20.6: Sources of Esters
Preparation of esters (Table 20.3, p. 843)
1. Fischer Esterification (Ch. 15.
2. Reaction of acid chlorides or acid anhydrides with alcohols
3. Baeyer-Villiger oxidation of ketones (Ch. 17.16)
4. SN2 reaction of carboxylate anions with alkyl halides
20.7: Physical Properties of Esters. (please read)
20.8: Reactions of Esters: A Review and a Preview.
Esters react with Grignard reagents to give tertiary alcohols.
two equivalents of the Grignard reagents adds to the carbonyl
carbon. (Ch. 14.10)
Esters are reduced by LiAlH 4 (but not NaBH 4 ) to primary alcohols.
(Ch. 15.3)
Nucleophilic acyl substitution reactions of esters (Table 20.5).
Esters are less reactive toward nucleophilic acyl substitution than
Acid chlorides or acid anhydrides.
1. Aminolysis: Esters react with ammonia, 1° amd 2° amines to
give amides
2. Hydrolysis: Esters can be hydrolyzed to carboxylic acids under
basic conditions or acid-catalysis.
20.11: Reaction of Esters with Ammonia and Amines.
Esters react with ammonia, 1°, and 2° amines to give amides
Mechanism, Fig. 20.5, p. 853.
NH 2 + OCH 3 NH +^ HOCH 3
pKa~ 10 pKa~^16
20.12: Amides
N H O H 3 C CH 3 N H O H 3 C CH 3 N O coplanar
amide bond has a large
dipole moment ~ 3.5 Debye
H 2 O = 1.85 D
NH 3 = 1.5 D
H 3 CNO 2 = 3.
The N-H bond of an amide is a good hydrogen bond donor and
The C=O is a good hydrogen bond acceptor.
R N O H R N O H N N O R H O N N R O H R N N N N H R O H O H R R H O O R R H H O N H O
Acidity of Amides: The resulting negative charge from
deprotonation of an amide N-H, is stabilized by the carbonyl
O H H O H
- H 2 O
- H 3 O O H N O H
- H 2 O (^) N O N O pKa ~ 17 - 19 pKa ~ 15
- H 3 O
CH 3 CH 2 NH 2 N
O H H N O H O OH O p Ka ~ 35 - 40 ~ 15 ~ 10 ~ 5 Increasing reactivity 180
Synthesis of Amides: Amides are most commonly prepared from
the reactions of ammonia, 1° or 2° amines with acids chlorides,
acid anhydrides or esters. This is a nucleophilic acyl substitution
reaction.
When an acid chloride or anhydride is used, a mol of acid (HCl
or carboxylic acid) is produced. Since amines are bases, a
second equivalent is required (or an equivalent of another
base such as hydroxide or bicarbonate) is required to
neutralize the acid
R CCl
O
R CN
O
acid chloride
R'NH 2
R COH
O
carboxylic acid SOCl 2 R' 2 NH
NH 3
di-substitiuted R' ( 3 °) amide R'
R CN H
O
R'
R CNH 2
O
mono-substitiuted ( 2 °) amide unsubstitiuted ( 1 °) amide
20.16: Hydrolysis of Nitriles. Nitriles are hydrolyzed in either
aqueous acid or aqueous base to give carboxylic acids. The
corresponding primary amide is an intermediate in the reaction.
Base-promoted mechanism (Fig. 20.8, p. 865)
Acid-promoted hydrolysis:
20.17: Addition of Grignard Reagents to Nitriles. One equiv.
of a Grignard Reagent will add to a nitrile. After aqueous acid
work-up, the product is a ketone.
aldehydes
& ketones
μ~ 2.8 D
C
O
R
N
C! +
nitriles
μ ~ 3.9 D
R C N
H 3 C MgBr
R
N
C
CH 3
MgBr THF H^3 O
R
NH
C CH
3 R
O
C
CH 3
Must consider functional group compatibility; there is wide
flexibility in the choice of Grignard reagents.
Na+^ - CN Br C!N (^) O MgBr H 3 O+ CO 2 H ketones carboxylic acids SN 2
20.18: Spectroscopic Analysis of Carboxylic Acid Derivatives
IR: typical C=O stretching frequencies for:
carboxylic acid: 1710 cm-
ester: 1735 cm-
amide: 1690 cm-
aldehyde: 1730 cm-
ketone 1715 cm-
anhydrides 1750 and 1815 cm-
Conjugation (C=C π -bond or an aromatic ring) moves the C=O
absorption to lower energy (right) by ~15 cm-
OCH 3 O OCH 3 O OCH 3 O NH 2 O NH 2 O NH 2 O aliphatic ester 1735 cm-^1 conjugated ester 1725 cm-^1 aromatic ester 1725 cm-^1 aliphatic amide 1690 cm-^1 conjugated amide 1675 cm-^1 aromatic amide 1675 cm-^1 186
1 H NMR:
Protons on the α-carbon (next to the C=O) of esters and amides
have a typical chemical shift range of δ 2.0 - 2.5 ppm
Proton on the carbon attached to the ester oxygen atom have a
typical chemical shift range of δ 3.5 - 4.5 ppm
The chemical shift of an amide N-H proton is typically between
5-8 ppm. It is broad and often not observed.
δ 3. 2H, q, J= 7. δ 1. 3H, t, J= 7. δ 2. 3H, s
NH
O H 3 C C N C H 2 C H 3 H δ = 4. q, J =7.2 Hz, 2H δ = 2. s, 3H δ = 1. t, J =7.2 Hz, 3H C C O O C C H H H H H H H H
C 11 H 12 O 2
166.9^ CDCl 3
δ 7. 1H, d, J= 15. δ 6. 1H, d, J= 15. δ 7. 2H, m δ 7. 3H, m (^) δ 4. 2H, q, J= 7. δ 1. 3H, t, J= 7.
1 H NMR
13 C NMR
TMS
IR
C 10 H 11 N
(5H, m)
**(1H, t, J=7.1)
(3H, t, J=7.4)**
(2H, dq, J=7.4, 7.1) CDCl 3 120.7 TMS
