Tetrahedral intermediate amides

Primary or secondary amine Acyl chloride Tetrahedral intermediate Amide... 

Acylating agent Amine Tetrahedral intermediate Amide Conjugate acid of leaving group... 

Stage 2 The tetrahedral intermediate dissociates to give an amide The O—H and C—O bonds may break m the same step or m separate steps... 

All these reactions proceed by nucleophilic addition of the amine to the carbonyl group Dissociation of the tetrahedral intermediate proceeds m the direction that leads to an amide... 

Mechanistically amide hydrolysis is similar to the hydrolysis of other carboxylic acid derivatives The mechanism of the hydrolysis m acid is presented m Figure 20 7 It proceeds m two stages a tetrahedral intermediate is formed m the first stage and disso ciates m the second... 

FIGURE 20 7 The mecha nism of amide hydrolysis in acid solution Steps 1 through 3 show the for mation of the tetrahedral intermediate Dissociation of the tetrahedral inter mediate is shown in steps 4 through 6... 

In base the tetrahedral intermediate is formed m a manner analogous to that pro posed for ester saponification Steps 1 and 2 m Figure 20 8 show the formation of the tetrahedral intermediate m the basic hydrolysis of amides In step 3 the basic ammo group of the tetrahedral intermediate abstracts a proton from water and m step 4 the derived ammonium ion dissociates Conversion of the carboxylic acid to its corresponding carboxylate anion m step 5 completes the process and renders the overall reaction irreversible... 

Step 3 The tetrahedral intermediate dissociates to an amide and N N dicyclohexylurea... 

There are large differences in reactivity among the various carboxylic acid derivatives, such as amides, esters, and acyl chlorides. One important factor is the resonance stabilization provided by the heteroatom. This decreases in the order N > O > Cl. Electron donation reduces the electrophilicity of the carbonyl group, and the corresponding stabilization is lost in the tetrahedral intermediate. 

Insight into the factors that govern breakdown of tetrahedral intermediates has also been gained by studying the hydrolysis of amide acetals. If the amine is expelled, an ester is formed, whereas elimination of an alcohol gives an amide ... 

The principal difference hes in the poorer ability of amide ions to act as leaving groups, compared to alkoxides. As a result, protonation at nitrogen is required for breakdown of the tetrahedral intermediate. Also, exchange between the carbonyl oxygen and water is extensive because reversal of the tetrahedral intermediate to reactants is faster than its decomposition to products. 

In some amide hydrolyses, the breakdown of the tetrahedral intermediate in the forward direction may require formation of a dianion ... 

The usual hydrolysis mechanism in strongly acidic solution involves addition of water to the O-protonated amide, followed by breakdown of the tetrahedral intermediate ... 

The characteristic reaction of acyl chlorides, acid anhydrides, esters, and amides is nucleophilic acyl substitution. Addition of a nucleophilic reagent Nu—H to the carbonyl group leads to a tetrahedral intermediate that dissociates to give the product of substitution ... 

The mechanism for the lipase-catalyzed reaction of an acid derivative with a nucleophile (alcohol, amine, or thiol) is known as a serine hydrolase mechanism (Scheme 7.2). The active site of the enzyme is constituted by a catalytic triad (serine, aspartic, and histidine residues). The serine residue accepts the acyl group of the ester, leading to an acyl-enzyme activated intermediate. This acyl-enzyme intermediate reacts with the nucleophile, an amine or ammonia in this case, to yield the final amide product and leading to the free biocatalyst, which can enter again into the catalytic cycle. A histidine residue, activated by an aspartate side chain, is responsible for the proton transference necessary for the catalysis. Another important factor is that the oxyanion hole, formed by different residues, is able to stabilize the negatively charged oxygen present in both the transition state and the tetrahedral intermediate. 

As early as 1899, 8tieglitz proposed a tetrahedral intermediate for the hydrolysis of an imino ether to an amide. Thns it was clear qnite early that a complicated overall transformation, imino ether to amide, would make more sense as the result of a series of simple steps. The detailed mechanism proposed, althongh reasonable in terms of what was known and believed at the time, wonld no longer be accepted, but the idea of tetrahedral intermediates was clearly in the air. 8tieglitz stated of the aminolysis of an ester that it is now commonly snpposed that the reaction takes place with the formation of an intermediate prodnct as follows referring to work of Lossen. (Note that the favored tautomer of a hydroxamic acid was as yet unknown.)... 

Aminolysis of simple esters is snrprisingly difficnlt, despite the greater thermodynamic stability of amides than esters the problem is that the initial tetrahedral intermediate preferentially reverts to starting material (not only is the amine the better leaving gronp, bnt loss of alkoxide would lead to an A-protonated amide), and only trapping of this intermediate by proton transfer allows the reaction to proceed. ... 

Tetrahedral intermediates vary enormonsly in stability relative to the corresponding carbonyl componnds, from extremes like hexaflnoroacetone hydrate where it is difflcnlt to remove the nncleophile from the addnct, to amide hydrates where the obligatory intermediate in acyl transfer is present at nndetectably low concentrations. Linear free-energy relations provide a route to calculating the eqnilibrinm constant... 

This is the same mechanism as that given above for esters, in equation (42). The difference between esters and amides is apparent from a comparison of the two tetrahedral intermediates [5] and [17], The former contains three oxygens, any of which can be protonated, resulting in much lsO exchange being observed when the reaction takes place in 180-enriched water,275,276 but [17] contains a much more basic nitrogen, which will be protonated preferentially and lead to much less 180 exchange, as observed.274 277,278 Also, ammonium ion formation makes the overall reaction irreversible, unlike ester hydrolysis. The calculated solvent isotope effect for the Scheme 15 process is 1.00,280 exactly in accord with experimental observation.278,279... 

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