Elimination carboxylic acid esters

Before discussmg the mechanism of cleavage of carboxylic acid esters and amides by hydrolases, some chemical principles are worth recalling. The chemical hydrolysis of carboxylic acid derivatives can be catalyzed by acid or base, and, in both cases, the mechanisms involve addition-elimination via a tetrahedral intermediate. A general scheme of ester and amide hydrolysis is presented in Fig. 3. / the chemical mechanisms of ester hydrolysis will be... 

A few examples of ester prodrugs that are activated by intramolecular reactions have been mentioned in Sect. 8.3.1, 8.5.1, and 8.5.2. Here, we discuss the special case of some carboxylic acid esters of active alcohols or phenols that are released following an intramolecular cyclization-elimination reaction [168], The general reaction scheme of such reactions is shown in Fig. 8.8. 

The first term, representing acid-"catalyzed" hydrolysis, is important in reactions of carboxylic acid esters but is relatively unimportant in loss of phosphate triesters and is totally absent for the halogenated alkanes and alkenes. Alkaline hydrolysis, the mechanism indicated by the third term in Equation (2), dominates degradation of pentachloroethane and 1,1,2,2-tetrachloroethane, even at pH 7. Carbon tetrachloride, TCA, 2,2-dichloropropane, and other "gem" haloalkanes hydrolyze only by the neutral mechanism (Fells and Molewyn-Hughes, 1958 Molewyn-Hughes, 1953). Monohaloalkanes show alkaline hydrolysis only in basic solutions as concentrated as 0.01-1.0 molar OH- (Mabey and Mill, 1978). In fact, the terms in Equation(2) can be even more complex both elimination and substitution pathways can operate, leading to different products, and a true unimolecular process can result from initial bond breaking in the reactant molecule. 

The difference is in the mechanism of reaction. In the case of carbaryl, the reaction proceeds by an elimination process in which the proton acidity on the nitrogen atom determines the reactivity. On the other hand, the chlorpropham reaction proceeds in a manner analogous to the hydrolysis of carboxylic acid esters. Much like carboxylic acid esters, electron-withdrawing substituents in carbamates accelerate the reaction by an amount that depends on whether the substituents are on N or O. Conversely, electron-donating substituents (methyl in the case of chlorpropham, above) slow the rate of hydrolysis. 

Tertiary alcohols, tertiary ethers, or carboxylic acid esters of tertiary alcohols can undergo El eliminations, but only in the presence of Bronsted or Lewis acids. Anyone who has prepared a tertiary alkoxide by a Grignard reaction and treated the crude reaction mixture with HC1 and obtained the alkene knows that tertiary alcohols can be converted into alkenes even with dilute hydrochloric acid. 

Dioxathiolan-4-one 2-oxides (50) decompose rapidly in the presence of water and mineral acids to form a-hydroxy carboxylic acids, the detailed mechanism of hydrolysis being unknown. Nucleophilic attack on (50) by alcohols occurs at the acyl carbon atom and, with elimination of sulfur dioxide, gives a-hydroxy carboxylic acid esters (76CRV747). In a similar fashion to (50), l,2,3-oxadithiolan-5-one 2-oxides react rapidly with water to yield the parent a-mercaptocarboxylic acids (77MI43301). 

Formation of exocyclic iminium ions can be achieved under special circumstances where a functionality other than hydrogen is lost during the elimination step. One version of this technique takes advantage of the fact that carboxylic acid esters are readily hydrolyzed to the parent acids during iV-oxide formation with hydrogen peroxide. Thus, on sequential treatment of the A/-oxide (19) with hydrogen peroxide, trifluoroacetic acid and potassium cyanide the exocyclic, rather than the endocyclic, aminonitrile (20) is produced in 48% yield (equation 9). ... 

A multi-step (Grignard reaction, elimination, oxidative cleavage) procedure for chain degradation of carboxylic acids (esters) (see 1st edition). 

A nucleophilic attack by N occurs. Chloride ion is eliminated and a substitution product is obtained. Water, ammonia, and alcohols usually serve as the nucleophiles in the reactions with acyl chlorides. The products of these reactions are carboxylic acids, esters, or carboxamides. 

The structural features of organophosphorus esters, which are very similar to those of the carboxylic acid esters, suggest that nucleophilic displacement at the central phosphorus atom will occur by an addition-elimination mechanism. Mechanistic studies, however, have demonstrated that hydrolysis occurs through direct nucleophilic displacement at phosphorus and does not involve formation of a pen-tavalent intermediate with H2O or OH (Hudson, 1965 Kirby and Warren, 1967). Accordingly, hydrolysis rates for phosphorus esters will be sensitive to electronic factors that alter the electrophilicity of the central phosphorus atom and steric interaetions that impede nucleophilic attack. 

Carbonyl addition-elimination n. The single most important type of reaction mechanism which has been applied to the preparation of step-growth polymers is the addition-elimination reaction of the carbonyl double bond of carboxylic acids and carboxylic acid derivatives included in this general type of reaction are esterification amidation and anhydride formation from carboxylic acids, esters, amides, anhydrides and acid halides. 

Geometrical trans to cis isomerization of 3,3 -, 4,4 -, and 5,5 -disubstituted 2,2 -diphenoquinones has been studied by computational methods.The double bond isomerization of butene-catalysed l-ethyl-3-methyl-imidazolium chloride ionic liquid has been similarly examined and stepwise isomerization is suggested.The reaction of l,2-di(l-adamantyl)-2-thioxoethanone with diazomethane and 2-diazopropane gave 2-acylthiiranes via 2 - - 3-cycloaddition, elimination of nitrogen, and 1,3-dipolar electrocyclization of the intermediate acyl-substituted thiocarbonyl ylides. Rearrangement of pyrimidine-5-carboxylic acids esters to 5-acylpyrimidones does not occur in the examples studied and a [l,4]-phospho-Fries rearrangement has been reported. ... 

Coupled pyrolytic elimination of carboxylic acid esters... 

Heating A (a carboxylic acid ester see Chapter 20, Section 20.5) to about 450°C leads to elimination to give 2-methyl-l-butene. Provide a mechanism for the reaction and speculate on why the elimination requires such high temperatures when compared to the Hofmann ehmination. 

---