Amides, acid-catalysed hydrolysis

Hydroxy imine Primary amide Fig. Acid-catalysed hydrolysis of nitrile to carboxylic acid. 

The most widely used homogeneous catalysts are simple acids and bases which catalyse well-known reactions such as ester and amide hydrolysis, and esterification. Such catalysts are inexpensive enough that they can be neutralized, easily separated fi om organic materials, and disposed of. This, of course, is not a good example of green chemistry and contributes to the huge quantity of aqueous salt waste generated by industry. 

Another feature of the kinetics of acid-catalysed hydrolysis of amides may be of relevance in connection with the nature of the protonated cation, that is the rate maximum which is found at 3-6 M acid for all amides. The usual interpretation of this is that increasing... 

Acid-catalysed hydrolysis. Under acidic conditions, the hydrolysis of an amide resembles the acid-catalysed hydrolysis of an ester, with protonation of the carbonyl group yielding an activated carbonyl group that undergoes nucleophilic attack by water. The intramolecular proton transfer produces a good leaving group as ammonia. Simultaneous deprotonation by water and loss of ammonia yields a carboxylic acid. 

Kinetic investigations of amide hydrolysis showed that the rate of hydrolysis in basic media is proportional to the concentration of amide and hydroxide ion. Similarly, early work180-183 on the acid-catalysed hydrolysis of amides showed that the rate of acidic hydrolysis is, in general, proportional to the concentration of amide and hydroxonium ion. In several acidic hydrolyses, however, a maximum is observed in the pH-rate profile at 3-6 pH units, a phenomenon first reported by Benrath184 and since supported by other workers185"190. This behaviour of amides is in contrast to the hydrolysis of nitriles whose rate constant increases continuously with the hydrogen ion concentration191. 

The alkaline hydrolysis of the compounds (118)-(123) in 70% (v/v) dioxane-water at various temperatures has been investigated.101 Intramolecular catalysis by the neighbouring carbonyl group occurs in the alkaline hydrolysis of (118)-(121) and the alkaline hydrolysis of (122) and (123) is rapid owing to their lactone structures. The hydrolyses of C-terminal amides of a-amino acids was dealt with earlier.56 Also, the acid-catalysed cleavage of A-(2-aminophcnyI)phthalamic acid (82) was discussed earlier.72... 

Nitriles (RCN) get hydrolysed to carboxylic acids (RC02H) in acidic or basic aqueous solutions. The mechanism of the acid-catalysed hydrolysis (Following fig.) involves initial protonation of the nitrile s nitrogen atom. This activates the nitrile group towards nucleophilic attack by water at the electrophilic carbon. One of the nitrile n bonds breaks simultaneously and both the n electrons move onto the nitrogen yielding a hydroxyl imine. This rapidly isomerises to a primary amide which is hydrolysed under the reaction conditions to form the carboxylic acid and ammonia. 

In the acid-catalysed hydrolysis of an ester, only a catalytic amount of acid is needed since the protons used during the reaction mechanism are regenerated. However with an amide, at least one equivalent of acid is required because of ionisation of the amine. 

Much of the a-deprotonation chemistry of the amides is mirrored by hindered thioamides, imides, ureas, carbamates and phosphonamides,28 and the important asymmetric versions of these reactions are discussed in chapters 5 and 6. Difficulties removing the heavily substituted groups required for protection of the carbonyl group in these compounds have been overcome in such cases as the urea 75, which is resistant to strong base, but which undergoes acid-catalysed hydrolysis and retro-Michael reaction to reveal the simpler derivative 76.54... 

An H acidity function scale has been constructed for methoxide ion in methanol and its mixtures with DMSO (10-80%, v/v) using the dissociation of 11 amides (114) as the anchors for the scale.The degradation pathways of the anti-flammatory and analgesic lomoxicam (115), which contains an amide bond, have been examined recently. In acid, cleavage of the amide bond was the main reaction path and in alkaline and neutral solution the proton shift of the enolic hydroxyl initiated the major degradation pathway. The mechanism of hydrolysis of some A-nitrobenzamides (116) in strong acid follow an -1 mechanism with O-protonation but, in more moderate acid, they exhibit a neutral water-catalysed mechanism. /V-Methyl-/V-nitroacetamide (117) shows only the neutral water-catalysed process. Nitrourea follows an, 4-1 acid-catalysed mechanism. ... 

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