Acyl-oxygen fission

Isotopic substitution. A classic example is the demonstration by Polanyi and Szabo (37) of acyl-oxygen fission in the alkaline hydrolysis of -amyl acetate. An ester could undergo cleavage at two locations, as indicated in 3. 

The designation Ac signifies acyl-oxygen fission, whereas A1 is alkyl-oxygen fission. When n-amyl alcohol was hydrolyzed in 0-enriched water, the 0 appeared in the product acid rather than the alcohol, showing that alkyl-oxygen fission could not have occurred. Carpenter gives many examples of isotopic studies. 

Transesterification occurs by mechanisms that are identical with those of ester hydrolysis—except that ROH replaces HOH—that is, by the acyl-oxygen fission mechanisms. When alkyl fission takes place, the products are the acid and the ether. 

Isotopes can also be used to solve mechanistic problems that are non-kinetic. Thus the aqueous hydrolysis of esters to yield an acid and an alcohol could, in theory, proceed by cleavage at (a) alkyl/ oxygen fission, or (b) acyl/oxygen fission ... 

If the reaction is carried out in water enriched in the heavier oxygen isotope 180, (a) will lead to an alcohol which is 180 enriched and an acid which is not, while (b) will lead to an l80 enriched acid but a normal alcohol. Most simple esters are in fact found to yield an lsO enriched acid indicating that hydrolysis, under these conditions, proceeds via (b) acyl/oxygen fission (p. 238). It should of course be emphasised that these results are only valid provided that neither acid nor alcohol, once formed, can itself exchange its oxygen with water enriched in 180, as has indeed been shown to be the case. 

A c2 pathway, 241, 384 A,4 1 pathway, 241, 380 acid-catalysed, 240, 378 acyl-oxygen fission, 88, 240, 242 alkyl-oxygen fission, 240 isotope labels in, 88, 241 steric effects in, 242 Esters... 

Since there are but two possibilities, acceptable evidence may be pos tive or negative. It is sufficient, for example, in order to establish acyl-oxygen fission, to show either that the acyl-oxygen bond is cleaved, or that the alkyl-oxygen bond is not, and both types of evidence have been used. Some of the evidence, for reactions involving alkyl-oxygen fission, has already been discussed in the sections dealing with the AA) 1 reaction (p. 87). 

A considerable number of investigations using, sO as a tracer confirm that, except under the special circumstances which favour alkyl-oxygen cleavage described above (pp. 86 and 100), acyl-oxygen fission is the normal route for... 

Comparative studies on carboxylic and sulfonic esters of some simple, aliphatic alcohols (see p. 167) brought to light the fact that, whereas an ester of a carboxylic acid (R"COOH) usually reacts by acyl-oxygen fission 28... 

The acid-catalysed esterification reaction usually proceeds via an acyl-oxygen fission process. This involves the cleavage of the bond between the original carbonyl-carbon atom and an oxygen of an hydroxyl group in the intermediate (6) arising from nucleophilic attack by an alcohol molecule on the pro-tonated carboxylic acid group (5). 

The disconnection underlying this procedure is an alkyl-oxygen fission and not the acyl-oxygen fission as in the reactions discussed above. The non-nucleophilic base used in this reaction is l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) which converts the carboxylic acid into its carboxylate ion but does not interact in a competing substitution reaction with the alkyl halide. The ester-forming reaction may therefore be regarded as an SN2 reaction between the carboxylate ion and the alkyl halide.162... 

An ester can be split either at point A (acyl oxygen fission) or at point B (alkyl oxygen fission) ... 

However, most nucleophiles attack 5-oxazolones at the carbonyl group and the products are derivatives of a-amino acids formed by acyl-oxygen fission. Thus the action of alcohols, thiols, ammonia and amines leads, respectively, to esters, thioesters and amides orthophosphate anion gives acyl phosphates (Scheme 18). The use of a-amino acids in this reaction results in the establishment of a peptide link. Cysteine is acylated at the nitrogen atom in preference to the sulfur atom. Enzymes, e.g. a-chymotrypsin and papain, also readily combine with both saturated and unsaturated azlactones. A useful reagent for the introduction of an a-methylalanine residue is compound (202). Both the trifluoroacetamido and ester groups in the product are hydrolyzed by alkali to give a dipeptide. The alkaline hydrolyzate may be converted into the benzyloxycarbonyl derivative, which forms a new oxazolone on dehydration. Reaction with an ester of an amino acid then yields a protected tripeptide (equation 45). 

The 5(2H)-oxazolones (213) present two sites, C(4) and C(5), to nucleophilic attack they usually react at the latter. The benzylidene derivative (214), the most thoroughly studied member of this class, possesses an additional electrophilic centre at the exocyclic carbon atom. However, alkaline hydrolysis of this compound affords phenylacetamide and benzoylformic acid by acyl-oxygen fission (equation 50). a-Keto acids are also obtained when 2-trifluoromethyl-5(4//)-oxazolones are hydrolyzed, the reaction involving preliminary isomerization to a 5(2//)-oxazolone. The example shown in equation (51) represents the first non-enzymatic synthesis of an optically active a-keto acid. An instance of nucleophilic attack at C(4) of a 5(2//)-oxazolone is the formation of the oxazolidinone (215) in a Grignard reaction (equation 52). However, the typical behaviour of unsaturated pseudooxazolones like (214) is conjugate addition of a nucleophile, followed by further transformations of the resulting 5(4F/)-oxazoIones. This is illustrated by the reaction of compound (214) with benzene in the presence of aluminum chloride to yield, after aqueous work-up, the acylamino acid (216 equation 53). 

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