Carboxylic Acids and Derivatives

Reference: Organic Chemistry, Seventh Edition, Francis A. Carey, 2008, McGraw Hill

Greater Acidity of Carboxylic Acids is Attributed St bili ti of Stabilization f Carboxylate C b l t Ion I by b Inductive effect of carbonyl group

Resonance stabilization of carboxylate ion O RC

O O

RC O

Substituent Effects on Acidity

Electronegative substituents withdraw electrons from carboxyl group group. The more stable the anion anion, the greater the 3 equilibrium constant for its formation.

Effect of electronegative substituent decreases as number of bonds between it and carboxyl group increases

Preparation and Hydrolysis of Nitriles

C SN2 O N RC N H3O+ heat RCOH + NH4+

RX

Converts an alkyl halide to a carboxylic acid g one more carbon atom than the having starting halide
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Example p
NaCN Na CN CH2Cl DMSO H2O H2SO4 heat CH2CN (92%)

O CH2COH (77%)

Example p
O 1. Na NaCN CN CH3CCH2CH2CH3 2. H+ CN OH CH3CCH2CH2CH3 CO2H
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OH

cyanohydrin

CH3CCH2CH2CH3

H2O HCl, HCl , heat

Synthesis of fenoprofen (a nonsteroidal anti-inflammatory drug) marketed under the trade name Nalfon

Carboxylation y of Grignard g Reagents g

Grignard reagents react with dry CO2 to yield a metal carboxylate b l The organomagnesium halide adds to C=O of carbon dioxide Protonation by addition of aqueous HCl in a separate step gives the free carboxylic acid

Preparation of phenylacetic acid from benzyl bromide

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Acid-catalyzed Esterification
(also called Fischer esterification esterification) ) O COH + CH3OH O COCH3 + H2O H+

Important fact: the oxygen of the alcohol is incorporated into the ester as shown.

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Mechanism of Fischer Esterification

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Nucleophilic Acyl Substitution

Carboxylic acid derivatives have an acyl group bonded to an electronegative element and have nucleophilic acyl substitution as their characteristic reaction.

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General Mechanism for Nucleophilic Acyl Substitution

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Reactivity
Most reactive

O RCCl O O RCOCR' RCOCR O RCOR' O RCNR'2 RCNR

Carbonyl group
Least stabilized

Least reactive

O RCO

Most stabilized

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Acyl Chlorides
O R C
Cl O

C
Cl +

Acyl chlorides have the least stabilized carbonyl group. Delocalization of lone pair of Cl into C=O group is not effective because CCl C Cl bond is too long long.
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Acid Anhydrides
O R C O

O C R R

O C + O

O C R

Lone pair donation from oxygen stabilizes the carbonyl group of an acid anhydride. Both carbonyl groups are competing for the same electron pair pair. Thus Thus, the extent to which each one 17 is stabilized is reduced.

Esters
O R C OR'

O R C + OR'

Lone pair L i d donation ti from f oxygen stabilizes t bili th the carbonyl group of an ester. Stabilization g greater than comparable p stabilization of an anhydride. 18

Amides
O R C NR'2

O R C + NR'2

Lone pair donation from nitrogen stabilizes the carbonyl group of an amide amide. N is less electronegative than O; therefore, amides are stabilized more than esters and anhydrides anhydrides.
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Amides
O R C NR'2

O R C + NR'2

Amide resonance imparts significant double-bond character to C CN N bond bond. CN C N bond distance is 135 pm in amides versus normal single-bond distance of 147 pm in amines.
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Carboxylate Ions
O R C
O

O R C O

Very efficient electron delocalization and dispersal of f negative ti charge h Maximum stabilization
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Nucleophilic Acyl Substitution

In general: O R C + X HY HY R

O C + Y HX HX

Reaction is feasible when a less stabilized carbonyl is converted to a more stabilized one (more reactive to less reactive). )
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most reactive O RCCl O O RCOCR' O A carboxylic acid RCOR' O derivative can be converted by RCNR'2 O nucleophilic p acyl y substitution to any other RCO type that lies below it in 23 this table. least reactive

Preparation of Acyl Chlorides

From carboxylic y acids and thionyl y chloride ( (SOCl2) O (CH3)2CHCOH ( SOCl2 h t heat O (CH3)2CHC ( CHCCl Cl + SO2 + HCl (90%) On treatment with the appropriate nucleophile, an acyl chloride may be converted to an acid anhydride, an ester, an amide, or a carboxylic acid.
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Reactions of Acyl Chlorides

Acyl chlorides react with carboxylic acids to give acid anhydrides: O CH3(CH2)5CCl + O CH3(CH2)5COH pyridine O O CH3(CH2)5COC(CH2)5CH3 (78(78 -83%)
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Reactions of Acyl Chlorides

Acyl chlorides react with alcohols to give esters: O C6H5CCl + (CH3)3COH pyridine py O C6H5COC(CH3)3 (80%)

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Reactions of Acyl Chlorides

Acyl chlorides react with ammonia or amines to g give amides: O RCCl RC Cl + R'2NH + HO O RCNR'2 + H2O + Cl

Synthesis of the sedative ( ) trimetozine in the presence of one equivalent of NaOH

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Reactions of Acyl Chlorides

Acyl chlorides react with water to give carboxylic acids (carboxylate ion in base): O RCCl RC Cl + H2O O RCCl RC Cl + 2HO O RCOH O RCO + Cl + HCl

+ H2O 28

Reactions of Acid Anhydrides

Carboxylic acid anhydrides react with alcohols to give esters: O O RCOCR + R'OH O RCOR' O + RCOH

Reaction can be carried out in presence of pyridine (a base) or it can be catalyzed by acids.
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Esterification by treating with an acid anhydride in the presence of f pyridine All -OH groups react

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Catalyzed by acids
Water and other nucleophiles add to a protonated carbonyl group (step 2) much faster than they add to a neutral one.

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Reactions of Acid Anhydrides

Acid anhydrides react with ammonia or amines to give amides:

Acetaminophen (Paracetamol) (), a drug used in over-the-counter th t painkillers. i kill

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Reactions of Acid Anhydrides

Acid anhydrides react with water to give carboxylic acids (carboxylate ion in base): base): O O RCOCR O O RCOCR + 2HO + H2O O 2RCOH O 2RCO + H2O
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Reactions of Esters
Acid-Catalyzed Ester Hydrolysis is the reverse of Fischer esterification esterification: : O RCOR' RCOR + H+ H2O O R'OH OH RCOH + R

Equilibrium is closely balanced because carbonyl group of ester and of carboxylic acid are comparably stabilized.

Maximize conversion to ester by removing water. M i i ester hydrolysis by having large excess of water. Maximize
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Mechanism of acid catalyzed acid-catalyzed ester hydrolysis

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Reactions of Esters
Ester Hydrolysis in Aqueous Base O RCOR' + HO O RCO + R'OH

Is called saponification Is irreversible, because of strong stabilization of carboxylate ion If carboxylic acid is desired product, product saponification is followed by a separate acidification step (simply a pH adjustment)
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Mechanism of base-induced ester hydrolysis h d l i (saponification)

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Reactions of Esters
Esters react with ammonia or amines to give amides:

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Reactions of Amides
Hydrolysis of amides is irreversible. In acid solution the amine product is protonated to give an ammonium salt. O RCN RC NHR' + H2O + H + O + R'N NH3 RCOH + R'

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Reactions of Amides
In basic solution the carboxylic acid product is s deprotonated dep oto ated to g give e a ca carboxylate bo y ate ion. o O RCN RC NHR HR' + HO O RCO + R R'N R' NH2

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