problem 18.33b - = 128.7 123.9 179.7 146.8 147.4 45.3 18.0 161 hapter 19: arboxylic Acid Derivatives: ucleophilic Acyl Substitution 19.1: omenclature of arboxylic Acid Derivatives (please read) carboxylic acid -oic acid ' ester -oate ' lactone cyclic ester l acid chloride -oyl chloride acid anhydride -oic anhydride ' '' amide -amide '' ' lactam cyclic amide nitrile -nitrile 162 81
19.3: ucleophilic Acyl Substitution Mechanisms The general mechanism of nucleophilic acyl substitution occurs in two stages. The first is addition of the nucleophile (u) to the carbonyl carbon to form a tetrahedral intermediate. The second stage in collapse of the tetrahedral intermediate to reform the carbonyl with expulsion of a leaving group (Y). There is overall substitution of the leaving group (Y) of the acid derivative with the nucleophile (u). Y :u u u Y tetrahedral intermediate + Y: Y = a leaving group -l, - 2, -, -, - 2, 163 19.2: Structure and eactivity of arboxylic Acid Derivatives Increasing reactivity < ' < ' < l amide ester acid anhydride acid chloride All acyl derivatives can be prepared directly from the carboxylic acid. Less reactive acyl derivative (amides and esters) are carboxylic acid more readily prepared from more reactive acyl derivatives (acid chlorides and anhydrides) acid chloride acid anhydride ester amide acid anhydride ester amide ester amide amide 164 82
The reactivity of the acid derivative is related to it resonance stabilization. The - bond of amides is significantly stabilized through resonance and is consequently, the least reactive acid derivative. The -l bond of acid chlorides is the least stabilized by resonance and is the most reactive acid derivative. amide ' ester ' acid anhydride l acid chloride 165 19.4: ucleophilic Acyl Substitution in Acyl hlorides Preparation of acid chlorides from carboxylic acids: eagent: Sl 2 (thionyl chloride) Sl 2, Δ l + S 2 + l Acid chlorides are much more reactive toward nucleophiles than alkyl chlorides l 2 l 2 k rel = 1000 k rel = 1 ucleophilic acyl substitution reactions of acid halides (Table 19.1) 1. Anhydride formation (h. 19.4): Acid chlorides react with carboxylic acids to give acid anhydrides 166 83
2. Ester formation (h. 15.8): Acid chlorides react with alcohols to give esters. eactivity: 1 alcohols react faster than 2 alcohols, which react much faster than 3 alcohols 3. Amide formation (h. 19.4): Acid chlorides react with ammonia, 1 or 2 amines affords amides. 4. ydrolysis (h. 19.4): Acid chlorides react with water to afford carboxylic acids 167 19.5: ucleophilic Acyl Substitution in Acid Anhydrides Anhydrides are prepared from acid chlorides and a carboxylic acid eactions of acid anhydrides (Table 19.2): Acid anhydrides are slightly less reactive that acid chlorides; however, the overall reactions are nearly identical and they are often used interchangeably. 1. Ester formation (h. 15.8): 2. Amide Formation (h. 19.14): 3. ydrolysis to give carboxylic acids (h. 19.5): 168 84
19.6: Physical Properties and Sources of Esters (please read) 19.7: eactions of Esters: A Preview. Preparation of esters (Table 19.3, p. 782) 1. Fischer esterification (h. 15.8 & 18.14) 2. eaction of acid chlorides or acid anhydrides with alcohols (h. 15.8,19.4 & 19.5) 3. Baeyer-Villiger oxidation of ketones (p. 732) 169 ucleophilic acyl substitution reactions of esters (Table 19.4): Esters are less reactive toward nucleophilic acyl substitution than acid chlorides or acid anhydrides. 1. Amide formation (h.19.11): Esters react with ammonia, 1 and 2 amines to give amides 2. ydrolysis (h.19.9-19.10): Esters can be hydrolyzed to carboxylic acids and an alcohol with aqueous base or acidcatalysis. 170 85
19.8: Acid-catalyzed Ester ydrolysis. everse of the Fischer esterification reaction. (Mechanism 19.2, p. 784-5) Protonation of the ester carbonyl accelerates nucleophilic addition of water to the carbonyl carbon giving the tetrahedral intermediate. Protonation of the - group then accelerates the expulsion of 171. 19.9: Ester ydrolysis in Base: Saponification Mechanism of the base-promoted hydrolysis (Mechanism 19.3, p. 789) Why is the saponification of esters not base-catalyzed? 172 86
19.10: eaction of Esters with Ammonia and Amines. Esters react with ammonia, 1, and 2 amines to give amides. 173 19.11: eaction of Esters with Grignard and rganolithium eagents and Lithium Aluminum ydride Esters react with two equivalents of an organolithium or Grignard reagent to give tertiary alcohols. 2 3 + 2 3 -MgBr 1) TF 2) then 3 + 3 3 Esters (and carboxylic acids) are reduced to 1 alcohols with LiAl 4 (but not ab 4 or catalytic hydrogenation). Esters 2 3 1) LiAl 4, ether 1) LiAl 4, ether 2) 3 + 2) 3 + 1 alcohols (hapter 15.3) arboxylic acids 174 87
19.12: Amides 3 3 3 3 1 and 13 M of formamide amide bond has a large dipole moment ~ 3.5 Debye 2 = 1.85 D 3 = 1.5 D 3 2 = 3.5 coplanar The - bond of an amide is a good hydrogen bond donor and the = is a good hydrogen bond acceptor. 175 Acidity of Amides: The resulting negative charge from deprotonation of an amide - is stabilized by the carbonyl 3 2 2 pk a ~ 35-40 ~ 15 ~10 ~5 Increasing acidity + 2 pk a ~ 15 + 3 + 2 pk a ~ 17-19 hapter 20 + 3 176 88
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. 3 ammonia 2 mono-substituted 1 amide Sl 2 carboxylic acid l acid chloride ' 2 1 amine ' 2 2 amine ' ' ' di-substituted 2 amide tri-substituted 3 amide When an acid chloride or anhydride is used, a mole of acid (l or carboxylic acid) is produced. Since amines are bases, a second equivalent (or an equivalent of another base such as hydroxide or bicarbonate) is required to neutralize the acid 177 19.13: ydrolysis of Amides. Amides are hydrolyzed to the carboxylic acids and amines. Acid-promoted mechanism (Mechanism 19.4, p. 797) 2 3 + + 3 Base-promoted mechanism (Mechanism19.5, p. 799) 2 a, 2 + 3 178 89
19.16: Lactams. (please read) cyclic amides β-lactams (4- membered ring lactams) are important acni-bacterial agents. S 2 3 3 2 S 2 3 3 2 S Penicillin G Amoxicillin ephalexin 19.17: Preparation of itriles (Table 19.6, page 802) 1. eaction of cyanide ion with 1 and 2 alkyl halides this is an S 2 reaction. (h. 8.1 & 8.10) 2. yanohydrins reaction of cyanide ion with ketones and aldehydes. (h. 17.7) 3. Dehydration of primary amides with Sl 2 (or P 4 10 ) 2 3 2 Primary amide Sl 2 -or- P 4 10 Δ nitrile Dehydration: formal loss of 2 from the substrate 179 19.16: ydrolysis of itriles. itriles are hydrolyzed in either aqueous acid or aqueous base to carboxylic acids. The corresponding primary amide is an intermediate in the reaction. Base-promoted mechanism (Mechanism. 19.6, p. 804) Acid-promoted hydrolysis: 180 90
19.19: Addition of Grignard eagents to itriles. ne equiv. of a Grignard eagent will add to a nitrile. After aqueous acid work-up, the product is a ketone. δ - δ + 3 MgBr TF aldehydes & ketones µ ~ 2.8 D MgBr 3 δ - δ + 3 + nitriles µ ~ 3.9 D 3 3 Must consider functional group compatibility; there is wide flexibility in the choice of Grignard reagents. Br a + - MgBr S 2 3 + ketones 2 carboxylic acids 181 19.20: Spectroscopic Analysis of arboxylic Acid Derivatives I: typical = stretching frequencies for: carboxylic acid: 1710 cm -1 ester: 1735 cm -1 amide: 1690 cm -1 aldehyde: 1730 cm -1 ketone: 1715 cm -1 acid chlorides: 1800 cm -1 anhydrides: 1750 and 1815 cm -1 onjugation (= π-bond or an aromatic ring) moves the = absorption to lower energy (right) by ~15 cm -1 3 3 3 aliphatic ester conjugated ester aromatic ester 1735 cm -1 1725 cm -1 1725 cm -1 2 2 2 aliphatic amide conjugated amide aromatic amide 1690 cm -1 1675 cm -1 1675 cm -1 182 91
1 M: Protons on the α-carbon (next to the =) of esters and amides have a typical chemical shift range of δ 2.0-2.5 ppm. Protons 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 - proton is typically between δ 5-8 ppm. It is broad and often not observed. δ= 4.1 q, J=7.2 z, 2 δ= 2.0 s, 3 δ= 1.2 t, J=7.2 z, 3 3 2 3 δ 3.4 2, q, J= 7.0 δ 2.0 3, s δ 1.1 3, t, J= 7.0 183 13 M: very useful for determining the presence and nature of carbonyl groups. The typical chemical shift range for = carbon is δ160-220 ppm. Aldehydes and ketones: δ 190-220 ppm arboxylic acids, esters and amides: δ 160-185 ppm 3 2 3 60.3 21.0 14.2 170.9 Dl 3 3 2 3 34.4 21.0 14.8 170.4 Dl 3 184 92
itriles have a sharp I absorption near 2250 cm-1 for alkyl nitriles and 2230 cm-1 for aromatic and conjugated nitriles (highly diagnostic) The nitrile functional group is invisible in the 1 M. The effect of a nitrile on the chemical shift of the protons on the α-carbon is similar to that of a ketone. 3 3 The chemical shift of the nitrile carbon in the 13 spectrum is in the range of ~115-130 (significant overlap with the aromatic region). δ= 119 185 11122 13 M 130.2 128.8 127.9 I 144.5 134.9 M δ 7.5 δ 7.3 2, m 3, m δ 7.7 1, d, J= 15.0 δ 6.4 1, d, J= 15.0 δ 4.2 2, q, J= 7.0 14.3 Dl3 166.9 1 60.5 118.2 TMS δ 1.3 3, t, J= 7.0 186 93
1011 129.0 128.0 127.3 38.9 29.2 11.4 135.8 120.7 Dl3 TMS 1.92 (2, dq, J=7.4, 7.1) 3.72 (1, t, J=7.1) 1.06 (3, t, J=7.4) 7.3 (5, m) 187 hapter 20: Enols and Enolates E+ Enolate E carbonyl E+ Enol 20.1: Enol ontent and Enolization β' γ' α' β α γ 188 94