Hydrolysis of phthalamic acid

Many sigmoid rate curves have been reported. A typical example is provided by the hydrolysis of phthalamic acid. ... 

For an example, see 10-9.) When this happens internally, we have an example of a neighboring-group mechanism at a carbonyl carbon. For example, the hydrolysis of phthalamic acid (77) takes place as follows ... 

The pH-rate constant profile for hydrolysis of phthalamic acid showed participation by the undissociated carboxyl group, and an anhydride intermediate was detected (Bender, 1957 Bender et al., 1958b). Hydrolysis was 10 times faster than in the case of p-carboxybenzamide. A four-center mechanism [58] was postulated. 

The mechanism of the intramolecular general acid catalysis of the oxygen esters has not been established since the possible formation of anhydride intermediates has not been thoroughly investigated. The hydrolysis of phthalamic acid has been shown to proceed through an anhydride intermediate, detected by double labeling experiments (Bender et al., 1958a), as does the aminolysis of succinic acid. In these cases, the reaction may involve either a four-center path, symbolised by 40, or involve prior protonation followed by intermolecular attack by the carboxylate anion (41). 

Detection of an intermediate by double labelling is well exemplified in the hydrolysis of phthalamic acid to phthalic acid [49]. One mechanism involves phthahc anhydride as an intermediate and this may be checked by labelling the amide carbon with C and the water with 0 (Eqn. 68). 

It is now evident that the acmal rate enhancement due to intramolecular carboxylic-acid-assisted hydrolysis of phthalamic acid is °o, because for the hydrolysis of benzamide under identical experimental conditions is nearly zero. However, if one compares the for the hydrolysis of phthalamic acid... 

Bender, M.L. General acid-base catalysis in the intramolecnlar hydrolysis of phthalamic acid. J. Am. Chem. Soc. 1957, 79, 1258-1259. 

Blackburn, R.A.M., Capon, B., McRitchie, A.C. The mechanism of hydrolysis of phthalamic acid and N-phenylphthalamic acid the spectrophotometric detection of phthaUc anhydride as an intermediate. Bioorg. Chem. Wll, 6, 71-78. 

The hydrolysis rate of phthalamic acid is 105 times faster than that of benzamide. Formation of a phthalic anhydride intermediate has been demonstrated in C13- and 018-labeling experiments (13). These results and the degradation data are consistent with the previously proposed mechanism of intramolecular displacement of the protonated amide moiety by the carboxylate anion (7,13,14). 

The hydrolysis and alkylaminolysis products of phthalimide are phthalamic acid and A-substituted phthalamide, respectively, and these products show an insignificant absorption at 300 nm. The values of molar extinction coefficients of phthalamic acid and phthalic acids are same as 40 Af cm- at 300 nm. ° Thus, the calculated value of A for the reaction mixtures containing 0.50-M trimeth-ylamine at pH 10.95 (A 0.0, Table 7.2) is plausible in view of insignificant absorption of phthalamic acid at 300 mn. 

Requests for larger samples for field testing necessitated the examination of alternate routes to AC 94,377. One of these started with 1-amino-1-cyclohexanecarboxamide and 3-chloro-phthalic anhydride. Attempted cyclization of the intermediate phthalamic acid 4 with cold trifluoroacetic anhydride gave, albeit in low yield, the readily isolated imidazoisoindole Biological evaluation of indicated that it had very similar PGR properties to that of AC 94,377 yet was perhaps slower acting. This was attributed to the slow hydrolysis of back to AC 94,377. 

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. 

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... 

Pure Folpet is a white crystalline solid with a reported melting point of 177 °C. Solubility in water is only 1 ppm at room temperature. In the dry state, it is stable at room temperature, but it is hydrolysed in an aqueous solution at a rate that depends on the pH. Degradation products and hydrolysis in water can be carbon dioxide, hydrochloric acid, hydrogen sulfide, phthalamic acid, and phthalic acid. 

The substituted phthalimides can be cleaved by ca. 20% hydrochloric acid at the boiling point or in a sealed tube at higher temperatures in some cases Posner s method may be used, in which the phthalimide is cleaved by potassium hydroxide solution to the phthalamic acid, whose hydrolysis is completed by hydrochloric acid.445 The phthalimides are, however, more conveniently cleaved by short boiling with a stoichiometric amount of hydrazine hydrate in ethanol 446 this gives the desired amine and phthalazone the latter may be hydrolysed by hydrochloric acid. Carbonyl groups present in the Aralkyl group of a phthalimide may be protected as acetal from the hydrazine fission.447 Phenylhydrazine is also useful for cleavage of phthalimido carboxylic acids.448... 

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