1. Carboxylic acids are more acidic than alcohols due to resonance stabilization of the carboxylate ion by the carbonyl group and inductive electron withdrawal by the carbonyl.
2. Electronegative substituents increase acidity by stabilizing the carboxylate ion through resonance. The effect decreases with increasing distance between the substituent and carboxyl group.
3. Carboxylic acids can be prepared from nitriles via hydrolysis or from alkyl halides via cyanohydrin formation followed by hydrolysis.
1. Carboxylic acids are more acidic than alcohols due to resonance stabilization of the carboxylate ion by the carbonyl group and inductive electron withdrawal by the carbonyl.
2. Electronegative substituents increase acidity by stabilizing the carboxylate ion through resonance. The effect decreases with increasing distance between the substituent and carboxyl group.
3. Carboxylic acids can be prepared from nitriles via hydrolysis or from alkyl halides via cyanohydrin formation followed by hydrolysis.
1. Carboxylic acids are more acidic than alcohols due to resonance stabilization of the carboxylate ion by the carbonyl group and inductive electron withdrawal by the carbonyl.
2. Electronegative substituents increase acidity by stabilizing the carboxylate ion through resonance. The effect decreases with increasing distance between the substituent and carboxyl group.
3. Carboxylic acids can be prepared from nitriles via hydrolysis or from alkyl halides via cyanohydrin formation followed by hydrolysis.
1. Carboxylic acids are more acidic than alcohols due to resonance stabilization of the carboxylate ion by the carbonyl group and inductive electron withdrawal by the carbonyl.
2. Electronegative substituents increase acidity by stabilizing the carboxylate ion through resonance. The effect decreases with increasing distance between the substituent and carboxyl group.
3. Carboxylic acids can be prepared from nitriles via hydrolysis or from alkyl halides via cyanohydrin formation followed by hydrolysis.
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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 5
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 7
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
10
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.
11
Mechanism of Fischer Esterification
12
Nucleophilic Acyl Substitution
Carboxylic acid derivatives have an acyl group bonded to an electronegative element and have nucleophilic acyl substitution as their characteristic reaction.
13
General Mechanism for Nucleophilic Acyl Substitution
14
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
15
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. 16
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. 19
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. 20
Carboxylate Ions O R C O
O R C O
Very efficient electron delocalization and dispersal of f negative ti charge h Maximum stabilization 21
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). ) 22
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. 24
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%) 25
Reactions of Acyl Chlorides
Acyl chlorides react with alcohols to give esters: O C6H5CCl + (CH3)3COH pyridine py O C6H5COC(CH3)3 (80%)
26
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
27
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. 29
Esterification by treating with an acid anhydride in the presence of f pyridine All -OH groups react
30
Catalyzed by acids Water and other nucleophiles add to a protonated carbonyl group (step 2) much faster than they add to a neutral one.
31
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
32
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 33
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 34
Mechanism of acid catalyzed acid-catalyzed ester hydrolysis
35
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) 36
Mechanism of base-induced ester hydrolysis h d l i (saponification)
37
Reactions of Esters Esters react with ammonia or amines to give amides:
38
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'
39
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
