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Chapter 19: Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution
19.1: Nomenclature of Carboxylic Acid Derivatives (please read)
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Y = a leaving group-Cl, -O2CR’, -OR’, -OH, -NR2,
19.3: General Mechanism for Nucleophilic Acyl SubstitutionMechanism occurs in two stages. The first is addition of the Nucleophile (Nu) to the carbonyl carbon to form a tetrahedral intermediate. The second stage in collapse of the tetrahedralintermediate 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 (Nu).
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19.2: Structure and Reactivity of Carboxylic Acid Derivatives
Increasing reactivity
All acyl derivatives can be prepared directly from the carboxylic acid.Less reactive acyl derivative (amidesand esters) are morereadily prepared frommore reactive acylderivatives (acidchlorides and anhydrides)
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The reactivity of the acid derivative is related to it resonancestabilization. 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
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19.4: Nucleophilic Acyl Substitution in Acyl ChloridesPreparation of acid chlorides from carboxylic acidsReagent: SOCl2 (thionyl chloride)
Nucleophilic acyl substitution reactions of acid halides (Table 19.1)
1. Anhydride formation (Ch. 19.4): Acid chlorides react with carboxylic acids to give acid anhydrides
Acid chlorides are much more reactive toward nucleophiles than alkyl chlorides
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3. Aminolysis (Ch. 19.4): Reaction of acid chlorides with ammonia, 1° or 2° amines to afford amides.
4. Hydrolysis (Ch. 19.4): Acid chlorides react with water to afford carboxylic acids
2. Alcoholysis (Ch. 15.8): Acid chlorides react with alcohols to give esters. reactivity: 1° alcohols react faster than 2° alcohols, which react faster than 3° alcohols
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19.5: Nucleophilic Acyl Substitution in Acid AnhydridesAnhydrides are prepared from acid chlorides and a carboxylic acid
Reactions of acid anhydrides (Table 19.2)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 (Ch. 15.8):
1.Aminolysis to give amides (Ch. 19.14):
1.Hydrolysis to give carboxylic acids (Ch. 19.5):
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19.6: Sources of Esters Preparation of esters (Table 19.3, p. 826)
1. Fischer Esterification (Ch. 15.8 & 18.14)
2. Reaction of acid chlorides or acid anhydrides with alcohols (Ch. 15.8 & 19.4):
3. Baeyer-Villiger oxidation of ketones (p. 772)
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19.7: Physical Properties of Esters. (please read) 19.8: Reactions of Esters: A Review and a Preview. Nucleophilic acyl substitution reactions of esters (Table 19.4).Esters are less reactive toward nucleophilic acyl substitution thanacid chlorides or acid anhydrides.
1. Aminolysis (Ch.19.11): Esters react with ammonia, 1° and 2° amines to give amides
2. Hydrolysis (Ch.19.9-19.10): Esters can be hydrolyzed to carboxylic acids under basic conditions or acid-catalysis.
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Table 19.5Esters react with Grignard reagents to give tertiary alcohols. two equivalents of the Grignard reagent adds to the carbonylcarbon. (Ch. 19.12)
Esters are reduced by LiAlH4 (but not NaBH4) to primary alcohols.(Ch. 19.13)
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19.9: Acid-catalyzed Ester Hydrolysis. Reverse of the Fischeresterification reaction. (Mechanism 19.3, p. 830)
Protonation of the ester carbonyl accelerates nucleophic additionof water to give the tetrahedral intermediate. Protonation ofThe -OR’ group, then accelerates the expulsion of HOR.
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19.10: Ester Hydrolysis in Base: SaponificationMechanism of the base-promoted hydrolysis (Mechanism 19.4, p. 835)
Why is the saponification of esters not base-catalyzed?
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19.11: Reaction of Esters with Ammonia and Amines. Esters react with ammonia, 1°, and 2° amines to give amides(Mechanism 19.5, p. 837).
pKa~ 10 pKa~ 16
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19.12: Reaction of Esters with Grignard Reagents: Synthesis of Tertiary Alcohols – mechanism 19.5, p. 837
19.13: Reaction of Esters with Lithium Aluminium Hydride. Esters are reduced to 1° alcohols by reduction with LiAlH4 (but not NaBH4 or catalytic hydrogenation).
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19.14: Amidesamide bond has a largedipole moment ~ 3.5 Debye
H2O = 1.85 DNH3 = 1.5 DH3CNO2 = 3.5
The N-H bond of an amide is a good hydrogen bond donor andThe C=O is a good hydrogen bond acceptor.
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Acidity of Amides: The resulting negative charge from deprotonation of an amide N-H, is stabilized by the carbonyl
Increasing reactivity
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Synthesis of Amides: Amides are most commonly prepared fromthe reactions of ammonia, 1° or 2° amines with acids chlorides,acid anhydrides or esters. This is a nucleophilic acyl substitutionreaction.
When an acid chloride or anhydride is used, a mol of acid (HClor carboxylic acid) is produced. Since amines are bases, asecond equivalent (or an equivalent of another base such as hydroxide or bicarbonate) is required to neutralize the acid
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19.15: Hydrolysis of Amides. Amides are hydrolyzed to thecarboxylic acids and amines
Acid-promoted mechanism (Fig. 19.6, p. 844)
Base-promoted mechanism (Fig. 19.7, p. 846)
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19.16: Lactams. (please read) cyclic amides-lactams (4-membered ring lactams) are important acti-bacterialagents.
Penicillin G Amoxicillin Cephalexin
19.17: Preparation of Nitriles (Table 19.6)1. Reaction of cyanide ion with 1° and 2° alkyl halides- this is
an SN2 reaction. (Ch. 8.1 & 8.12)
2. Cyanohydrins- reaction of cyanide ion with ketones and aldehydes. (Ch. 17.7)
3. Dehydration of primary amides with SOCl2 (or P4O10)
Dehydration: formal loss of H2O from the substrate
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19.18: 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 (Mechanism. 19.8, p. 851)
Acid-promoted hydrolysis:
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19.19: Addition of Grignard Reagents to Nitriles. One equiv.of a Grignard Reagent will add to a nitrile. After aqueous acidwork-up, the product is a ketone.
aldehydes & ketones~ 2.8 D
nitriles ~ 3.9 D
Must consider functional group compatibility; there is wide flexibility in the choice of Grignard reagents.
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19.20: Spectroscopic Analysis of Carboxylic Acid DerivativesIR: typical C=O stretching frequencies for:
carboxylic acid: 1710 cm-1 ester: 1735 cm-1 amide: 1690 cm-1
aldehyde: 1730 cm-1
ketone 1715 cm-1
anhydrides 1750 and 1815 cm-1
Conjugation (C=C -bond or an aromatic ring) moves the C=O absorption to lower energy (right) by ~15 cm-1
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1H NMR:Protons on the -carbon (next to the C=O) of esters and amides have a typical chemical shift range of 2.0 - 2.5 ppm
Proton on the carbon attached to the ester oxygen atom have a typical chemical shift range of 3.5 - 4.5 ppm
The chemical shift of an amide N-H proton is typically between5-8 ppm. It is broad and often not observed.
3.42H, q, J= 7.0
1.13H, t, J= 7.0
2.03H, s
NH
= 4.1 q, J=7.2 Hz, 2H
= 2.0s, 3H
= 1.2t, J=7.2 Hz, 3H
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13C NMR: very useful for determining the presence and nature of carbonyl groups. The typical chemical shift range for C=O carbon is 160 - 220 ppm
Aldehydes and ketones: 190 - 220 ppmCarboxylic acids, esters and amides: 160 - 185 ppm
170.4
34.414.8
21.0
170.9
60.321.0
14.2
CDCl3
CDCl3
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Nitriles have a sharp IR CN absorption near 2250 cm1 for alkyl
nitriles and 2230 cm1 for aromatic
and conjugated nitriles (highly diagnostic)
The nitrile function group is invisible in the 1H NMR. The effect of a nitrile on the chemical shift of the protons on the -carbon is similar to that of a ketone.
The chemical shift of the nitrile carbon in the 13C spectrum isin the range of ~115-130 (significant overlap with thearomatic region).
= 119
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C11H12O2
118.2144.5 134.9
130.2128.8127.9
CDCl3166.9
60.514.3
7.71H, d, J= 15.0
6.41H, d, J= 15.0
7.52H, m
7.33H, m
4.22H, q, J= 7.0
1.33H, t, J= 7.0
1H NMR
13C NMR
TMS
IR
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C10H11N
7.3(5H, m)
3.72(1H, t, J=7.1)
1.06(3H, t, J=7.4)
1.92(2H, dq, J=7.4, 7.1)
CDCl3TMS120.7
129.0128.0127.3
135.8
38.929.2
11.4
