Acid catalysis amide hydrolysis

For acid catalysis, matters are less clear. The reaction is generally second order, and it is known that amides are primarily protonated on the oxygen (Chapter 8, Ref. 24). Because of these facts it has been generally agreed that most acid-catalyzed amide hydrolysis takes place by the Aac2 mechanism. 

As an example, experimental kinetic data on the hydrolysis of amides under basic conditions as well as under acid catalysis were correlated with quantitative data on charge distribution and the resonance effect [13]. Thus, the values on the free energy of activation, AG , for the acid catalyzed hydrolysis of amides could be modeled quite well by Eq. (5)... 

Reactive trajectories, 43-44,45, 88,90-92,215 downhill trajectories, 90,91 velocity of, 90 Relaxation processes, 122 Relaxation times, 122 Reorganization energy, 92,227 Resonance integral, 10 Resonance structures, 58,143 for amide hydrolysis, 174,175 covalent bonding arrangement for, 84 for Cys-His proton transfer in papain, 141 for general acid catalysis, 160,161 for phosphodiester hydrolysis, 191-195,... 

The same framework of eight possible mechanisms that was discussed for ester hydrolysis can also be applied to amide hydrolysis. Both the acid- and base-catalyzed hydrolyses are essentially irreversible, since salts are formed in both cases. For basic catalysis the mechanism is Bac2-... 

The amidocarbonylation of aldehydes provides highly efficient access to N-acyl a-amino acid derivatives by the reaction of the ubiquitous and cheap starting materials aldehyde, amide, and carbon monoxide under transition metal-catalysis [1,2]. Wakamatsu serendipitously discovered this reaction when observing the formation of amino acid derivatives as by-products in the cobalt-catalyzed oxo reaction of acrylonitrile [3-5]. The reaction was further elaborated to an efficient cobalt- or palladium-catalyzed one-step synthesis of racemic N-acyl a-amino acids [6-8] (Scheme 1). Besides the range of direct applications, such as pharmaceuticals and detergents, racemic N-acetyl a-amino acids are important intermediates in the synthesis of enantiomeri-cally pure a-amino acids via enzymatic hydrolysis [9]. 

The mechanism of acid hydrolysis is also different in acyclic amides and /1-lactams acid catalysis of acyclic amides proceeds via O-protonation (see Chapt. 4), whereas that of /1-lactams appears to be a unimolecular A1 type process, involving V-protonation (Fig. 5.6,b) [76], A-Protonation is not the result of reduced amide resonance but an intrinsic property of the /1-lactam structure, since bicyclic /1-lactams and monocyclic /1-lactams exhibit similar reactivity and behavior [76],... 

Dissolved metals and metal-containing surfaces play an important role in the transformation of organic contaminants in the subsurface environment. Metal ions can catalyze hydrolysis in a way similar to acid catalysis. Organic hydrolyzable compounds susceptible to metal ion catalysis include carboxylic acids, esters, amides, anilides, and phosphate-containing esters. Metal ions and protons... 

The acceleration of a reaction by a substance that is also consumed during the process. An example of such a phenomenon is the acceleration of a reaction by a Brpnsted acid present in large excess or maintained by a nearly constant concentration by a buffer. The acceleration of the hydrolysis of an amide by a certain Brpnsted acid is actually general acid promotion rather than general acid catalysis. The term promotion has been used as a synonym for pseudo catalysis. 

Nitriles are hydrolysed to 1° amides, and then to carboxylic acids either by acid catalysis or base catalysis. It is possible to stop the acid hydrolysis at the amide stage by using H2SO4 as an acid catalyst and one mole of water per mole of nitrile. Mild basic conditions (NaOH, H2O, 50 °C) only take the hydrolysis to the amide stage, and more vigorous basic condition (NaOH, H2O, 200 °C) is required to convert the amide to a carboxylic acid. 

Amides. Metal ions catalyze the hydrolysis of a variety of amides, including acylamino acids, dipeptides and tripeptides, and amino acid amides. In all these compounds it is possible for a metal ion to complex with one or more ligand groups, either amine or carboxylate ion functions, in addition to the amide group. Thus the structural prerequisites for the metal ion catalysis of amide hydrolysis are the same as those for ester hydrolysis. 

Amide hydrolysis is not only subject to acid and base catalysis, but may be also brought about by a neighbouring group in the amide, the so-called propinquity catalysis effect. Wolfrom et a/.238 were among the first to suggest this possibility, in order to explain the observed hydrolysis of aldonamides, viz. 

Divalent metal ions inhibit the hydrolysis of N-(2-pyridyl)phthalamic acid (60) and N-(2-phenanthrolyl)phthalaxnic acid (61). In the case of (61) the substrate hydrolyzes by a pathway involving intramolecular general acid catalysis, and this pathway is inhibited by metal ions. Deprotonated amide complexes may also be involved leading to catalytically inactive complexes. 

Esters and amides, on the other hand, require the presence of an acid or base catalysis to react with water. These reactions are not instantaneous but require rather strongly acidic or basic conditions and heat to proceed at a reasonable rate. For example, a typical ester saponification is usually conducted with 10% NaOH in water, and the solution is refluxed until the ester layer disappears. (Most esters are not soluble in water.) This may require from 15 minutes up to several hours of reflux. Similarly, a typical amide hydrolysis is often conducted by refluxing the amide in concentrated hydrochloric acid for a period ranging from 15 minutes up to several hours. Esters and amides are relatively stable to the near-neutral conditions found in living organisms, which is one reason why they are important functional groups in biochemistry. 

The hydrolysis of amides is normally carried out under acidic catalysis. Protonation makes the carbonyl group more sensitive to nucleophilic attack (see 3.24). 

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