Chapter 21. Carboxylic Derivatives and Nucleophilic Acyl Substitution Reactions General mechanism: O leaving O O acyl C O group R Y group + Y: C C C R Y R Nu R Nu :Nu Y tetrahedral intermediate derivatives: Increasing reactivity

O O O O O O C C C C C C R OH R N R OR' R O R' R Cl carboxylic acid acid parent O O O C C P Chapter 21.8 function group R SR' R O O O please read acyl 197

21.1 Naming Carboxylic Acid Derivatives: (Please read) Acid : Derived from the carboxylic acid name by replacing the -ic acid ending with -yl choride or replacing the -carboxylic acid ending with -carbonyl chloride O O O C C Cl C Cl H3C Cl

Cyclohexancarbonyl chloride (from ) (from ) (from cyclohexane carboxylic acid) Acid Anhydrides: Name symmetrical anhydrides as the carboxylic acid except the word acid is replaced with anhydride



100 :

Primary amides (RCONH2) are named as the carboxylic acid except the -ic acid ending is replaced with -amide or the -carboxylic acid ending is replaced with -carboxamide. O O O C C NH C 2 NH2 H3C NH2

benzamide Cyclohexancarboxamide (from acetic acid) (from benzoic acid) (from cyclohexane carboxylic acid)

Substituted amides are named by first identifying the (s) with an N- in front of it, then naming the parent amide

O O O C CH2CH3 C CH CH C CH3 N 2 3 H3C N N H CH 3 CH2CH3 N-methylacetamide N-ethyl-N-methylbenzamide N,N-diethylcyclohexancarboxamide 199

Esters: are named by first identify the group on the , then identifying the carboxylic and replacing the -oic acid with -ate.


ethyl methyl benzoate tert-butylcyclohexancarboxylate

21.2 Nucleophilic acyl substitution reactions

O Y = a O O + Y: -OH, -OR’, -NR , -Cl, C C C 2 R Y R 2- Nu R Nu -O2CR’, -SR’,-OPO3 :Nu Y tetrahedral intermediate 200

101 Relative reactivity of carboxylic acid derivatives: The mechanism of nucleophilic acyl substitution involves two critical steps that can influence the rate of the overall reaction: 1) the initial addition to the carbonyl groups, and 2) the elimination of the leaving group.

The nature of the : The rate of addition to the carbonyl is slower as the steric demands of the R group increase. Branching at the α-carbon has the largest effect. Increasing reactivity O O O O R C < R C < R C H C C Y C Y C Y < C Y R R R H H H H H

Recall from Chapter 4: -CH3 ΔG°= 7.6 KJ/mol -CH2CH3 8.0 R -CH(CH ) 9.2 Keq 3 2 R H -C(CH3)3 > 18 -CH2C(CH3)3 8.4 H 201 -C6H5 12.6

Nature of the leaving group (Y): In general, the reactivity of acyl derivatives correlate with leaving group ability. Increasing reactivity

O O O O O C C C C < C R N < R OR' < R O R' R Cl

amide ester acid anhydride acid chloride What makes a good leaving group?

R’2N-H R’O-H R’CO2-H Cl-H pKa: 30-40 16-18 4-5 -7 The reactivity of the acyl derivative inversely correlates with their electron-donating ability

Resonance effect of the Y reduces the O O electrophilicity of the carbonyl carbon. C C R NH2 R NH2 Partial character of the C-N bond makes it harder to break. 202

102 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)

acid chloride

acid anhydride ester amide y t

acid anhydride i v i t c a

carboxylic e r

acid ester amide g n i s a e r

ester c n I


amide 203

Nucleophilic acyl substitution reactions O C Y= -Cl, -O2CR', -OR', -NR'2 R OH H2O carboxylic acid

O C Y= -OH, -Cl, -O2CR', -OR' R NR' R'2NH 2 amide

O O C alcoholysis R Y C Y= -OH, -Cl, -O2CR' R OR' Carboxylic acid R'OH ester derivative Y= -OH, -Cl, -O CR', O H H 2 reduction Y= -OH, -Cl, -O CR', -OR' -OR', -NR'2 C C 2 H R H R OH H H

C Y= -NR2 R NR2

O R'' R'' C C R''-M R R'' R OH

R''-M = R''2CuLi R''-M = R''-MgBr, R''-Li Y= -Cl Y= -Cl, -OR' 204

103 21.3 Nucleophilic acyl substitution reactions of carboxylic acids Nucleophilic acyl substitution of carboxylic acids are slow because -OH is a poor leaving group Reactivity is enhanced by converting the -OH into a better leaving groups However, acid chlorides, anhydrides, esters and amides can be prepared directly from carboxylic acids

O C R OH carboxylic acid

O O O O O C C C C R Cl R O R' R OR' R NR'2 acid chloride acid anhydride ester amide


Conversion of carboxylic acids into acid chlorides

Reagent: SOCl2 ()

O SOCl2, !" O C C + SO2 + HCl R OH R Cl

Recall the conversion of 1° and 2° to chlorides Mechanism (p. 780), please read


104 Conversion of carboxylic acids into acid anhydrides (please read) Reagent: heat

Reaction is best for the preparation of cyclic anhydrides from di-carboxylic acids

Conversion of carboxylic acids into esters 1. Reaction of a carboxylate with 1° oXXXr 2° alkyl halides Reagents: NaH, R’-X, THF O O O H CH C Br C NaH, THF C 3 2 OH C O O CH2CH3 SN2 Na

Note the similarity to the Williamson synthesis (Chapter 18.3) 207

Conversion of carboxylic acids into esters 2. Fisher esterification reaction: acid-catalyzed reaction of carboxylic acids with 1° or 2° alcohols to give esters Reagents: ROH (usually solvent), HCl (strong acid)

HO H HO H H3CH2C OH C OH C OCH2CH3 C C + H2O HCl O O Mandelic acid Ethyl mandelate Mechanism: (Fig. 21.5, p. 782)


105 Conversion of carboxylic acids into amides Not a particularly good reaction for the preparation of amides.

Amines are organic bases; the major reaction between a carboxylic acid and an is an acid- reaction (proton transfer)

21.4: Chemistry of Acid Halides Preparation of acid halides (Chapter 21.3)

Reaction of a carboxylic acid with thionyl chloride (SOCl2)

O SOCl2, !" O C C + SO2 + HCl R OH R Cl


Reactions of acid halides Friedel-Crafts (Chapter 16.4): reaction of an acid chloride with a derivative to give an alkyl .

O O SOCl O C 2 R C C + HCl R OH R Cl AlCl3 carboxylic acid acid chloride

Nucleophilic acyl addition reactions of acid halides 1. hydrolysis O H2O O C C R Cl NaHCO3 R OH acid chloride -or- carboxylic acid NaOH


106 2. Alcoholysis: Acid chlorides react with alcohols to give esters. reactivity: 1° alcohols react faster than 2° alcohols, which react faster than 3° alcohols

O O Cl OH + C + C N R Cl R O H acid chloride ester

3. Aminolysis: Reaction of acid chlorides with , 1° or 2° gives amides.

O O + H2NR2 Cl C + HNR2 C R Cl R NR2 amine acid chloride (two equiv) ester


4. Reduction: Acid chlorides are reduced to primary alcohols

with lithium aluminium (LiAlH4)

5. Reaction of acid chlorides with organometallic reagents: Reacts with two equivalents of a to give a 3° alcohols (recall reaction with esters) a) THF O + OH b) H3O + MgXCl + H C MgX C CH C 3 R 3 R Cl CH3 Grignard reagent acid chloride 3° (two equiv.)


107 Reaction of acid halides with diorganocopper reagents

a) ether O + O b) H3O C + (H3C)2 CuLi C R Cl R CH3 diorganocopper acid chloride ketone reagent Mechanism (page 787), not typical, specific to diorganocopper reagents. please look it over if you like Diorganocopper reagent can be alkyl, aryl or vinyl O a) 4 Li(0) H C O H H H b) CuI H3CH2CH2C Cl H C C C 2 C C H CH CH C C H C Cu Li 3 2 2 H Br H H 2 Fill in the reagents: O O OH O O



OH Cl CH2CH3 Ch. 21.6 213

21.5 Chemistry of acid anhydrides Preparation of acid anhydrides

O Na O O O O O + NaCl C + C C C C C R Cl O R' R O R' R O R' Cl acid chloride sodium acid anhydride carboxylate

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.

They do not react with diorganocopper reagents to give ketone


108 21.6 Chemistry of esters Preparation of esters Na 1. O O O NaH, THF H3C I Limited to 1° alkyl halides C C C R OH R O R O CH and tosylates SN2 3

2. O O H3CH2C-OH Limited to simple 1° and 2° C R OH C alcohols (used as solvent) HCl R O CH2CH3

H3C CH 3. O SOCl2 O HC OH O 3 Very general method, 1°, 2° and C C H3C C CH 3° alcohols usually work fine R OH R Cl R O CH pyridine 3

Reactions of esters O C R OR' ester

H2O + (NaOH, H2O or H3O ) R'2NH RMgX H- O O OH O H- H H C C C C R OH R NR' R'' C 2 R R'' R H R OH carboxylic acid amide 3° alcohol 1° alcohol 215

Hydrolysis of esters: esters can be hydrolyzed to the carboxylic acids with aqueous () or aqueous acid.

Mechanism of the base-promoted hydrolysis (Figure 21.9)

O a) NaOH, H2O O b) H O+ C 3 C R OCH3 R OH ester carboxylic acid


109 Acid-catalyzed hydrolysis of esters (Figure 21.10, p. 793) (reverse of the Fischer esterification)

O + O H3O C C R OCH3 R OH ester carboxylic acid


Aminolysis: Conversion of esters to amides

O HN O C C R OCH3 R N ester amide

Reduction of esters

LiAlH4 reduces esters to primary alcohols

O O LiAlH4 O LiAlH4 H H C R C OCH3 R OCH3 C C H R H fast R OH 218 H

110 Reduction of esters Diisobutylaluminium hydride (DIBAH) can reduce an ester to aldehyde



Esters do not react with NaBH4 or BH3 Reaction of esters with Grignard reagents: Esters will react with two equivalents of a Grignard reagent to give 3° alcohols

O 1) 2 H3CMgBr + 2) H3O HO C CH3 OCH CH 2 3 CH _ 3 H3C H3CMgBr + the H3O

MgX _ _ O - CH CH O O CH 3 2 C 3 C CH OCH2CH3 _ 3 H3C The Grignard reagent can be alkyl, vinyl or aryl 219

21.7 Chemistry of Amides Preparation of amides: amides are prepared from the reaction of an acid chloride with ammonia, 1° or 2° amines

O SOCl2 O C C R OH R Cl carboxylic acid acid chloride

NH3 R'NH2 R'2NH O O O C C R' C R' R NH2 R N R N H R' unsubstitiuted mono-substitiuted di-substitiuted (1°) amide (2°) amide (3°) amide

Reactions of amides: Amides bonds are very stable do to resonance between the lone pair and the π-bond of the carbonyl


111 Hydrolysis- Amides are hydrolyzed to the carboxylic acids and amine with either aqueous acid or aqueous hydroxide. Acid promoted mechanism:

O + O H3O C C + NH3 R NH2 R OH

Base promoted mechanism O NaOH, H O O 2 + NH C C 3 R NH2 R OH


Proteases: catalyzes the hydrolysis of amide bonds of

O R O R O O R O R O H H H H H3N N N H3N N + N N N N CO H O N O H3N N CO H H 2 2 H 2 H O R O R H O R O R

Asp–Arg–Val–Tyr–Ile–His–Pro–Phe–His–Leu–Val–Ile–His–Asn angiotensinogen ACE inhibitors

aspartyl renin protease

N N O N CO2H N NH Asp–Arg–Val–Tyr–Ile–His–Pro–Phe–His–Leu angiotensin I (little biological activity) Diovan HS Zn2+ angiotensin converting O protease N (ACE) HO2C

Captopril Asp–Arg–Val–Tyr–Ile–His–Pro–Phe angiotensin II (vasoconstriction → high blood pressure) 222

112 Reduction of amides to primary amines: amides can be reduced

by LiAlH4 or BH3 (but not NaBH4) to give primary amines Mechanism:

O SOCl O H C-NH O H H 2 3 2 LiAlH4 C C C CH3 C CH3 R OH R Cl R N R N H H

21.8 and Acyl : Biological Carboxylic AcidDerivatives (please read) 21.9 and : Step-Growth (please read) 223

21.10 Spectroscopy of Carboxylic Acid Derivatives IR: 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

Conjugation (C=C π-bond or an aromatic ring) moves the C=O -1 absorption to lower energy (right) by ~15 cm O O O


aliphatic ester conjugated ester aromatic ester -1 1735 cm 1725 cm-1 1725 cm-1


NH NH2 NH2 2

aliphatic amide conjugated amide aromatic amide -1 224 1690 cm 1675 cm-1 1675 cm-1

113 1H 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

δ 2.0 δ 1.2 3H, s 3H, t, δ 4.1 J= 7.1 2H, q, J= 7.1

δ 2.0 O 3H, s H3C C N CH2CH3 H δ 1.1 δ 3.4 3H, t, J= 7.0 2H, q, J= 7.0 NH 225

13C NMR: very useful for determining the presence and nature of carbonyl groups. The typical chemical shift range for C=O carbon is δ160 - 220 ppm and : δ 190 - 220 ppm Carboxylic acids, esters and amides: δ 160 - 185 ppm

O 14.2 H3C C O CH2CH3 60.3 21.0 CDCl 170.9 3

O 21.0 H C C N CH CH 14.8 3 2 3 34.4 H

170.4 CDCl3


114 1 C11H12O2 H NMR δ 1.3 δ 7.5 δ 7.3 3H, t, 2H, m 3H, m J= 7.0 δ 4.2 2H, q, J= 7.0 6.4 δ 7.7 δ 1H, d, 1H, d, J= 15.0 J= 15.0


130.2 128.8 127.9 144.5 60.5 134.9 118.2 14.3

166.9 CDCl3 TMS