Para-Nitrophenyl acetate

In earlier work we had demonstrated that a zinc complex of pyridyl-2-carboxaldoxime (7) could be effective in cleaving esters. The interesting point is that the oxime anion is available as a nucleophile and the zinc as an electrophile, but they are not coordinated to each other - which would of course destroy the catalytic effect. To amplify catalysis we attached such oxime-zinc complexes to j8-cyclodextrin on both the secondary and primary faces of the cyclodextrin and examined their reaction with p-nitrophenyl acetate. We observed burst kinetics, in which there was an extremely rapid release of one mole of nitrophenoxide ion, followed by a slower release in a second phase. This indicated that we first rapidly produced the acetate of the oxime, and this then slowly hydrolysed to regenerate the oxime anion for further catalytic reaction. Such burst kinetics is very commonly seen in enzymatic reactions of para-nitrophenyl acetate, reflecting the same kind of two-step overall mechanism. 

In analogy to the derivative prepared by Breslow and Overman, the cyclohexaamylose-iV-methylhydroxamic acid displays a pronounced specificity for p-nitrophenyl acetate as opposed to n-nitrophenyl acetate. This specificity is probably again derived from the geometry of the inclusion complex i.e., a more favorable location of the reactive center of the para-isomer relative to the hydroxamate function within the inclusion complex. 

At the start of this section the cleavage of meta- and para-substituted phenyl acetates by a- and )S-CD was discussed in detail and a variety of evidence was cited that is consistent with the mechanisms A and B, in Scheme 2. Further support for the view that para-substituents tend to force the phenyl group out of the cavity (Scheme 2B) comes from the different effects that neutral additives (potential inhibitors) have on the cleavage of m- and p-nitrophenyl acetate (mNPA and pNPA). In brief, species which bind to CDs, and inhibit the reaction of mNPA, do not necessarily inhibit that of pNPA (Tee and Hoeven, 1989 Tee et al., 1993b). 

N-(4-nitrophenyl)-amino acids N-(2,4-dinitrophenyl)-amino acids 8) and 3-nitro-2-pyridyl amino acids have been of considerable interest. A generally applicable mechanistic scheme does not exist so far, and except for 3-nitrophenyl acetate in ortho and/or -para position of the phenyl (pyridyl) ring seems to be a prerequisite for efficient decarboxylation. 

Apart from the use of a set of benzene derivatives with a constant ortho substituent, another case where the ortho substituent can be employed is where the steric effect is likely to be small or where the ortho group can take up a conformation during reaction where it does not interact with the reaction centre. A good example of this is the nucleophilic reaction of phenolate ions with 4-nitrophenyl acetate (Figure 10) where phenolate ions with single ortho substituents fit the Bronsted line defined by the meta and para substituent points. 

The first compound described as an artificial enzyme in the literature was the one we reported in which we attached a metal ion binding group to a-cyclodextrin. We found that this would bind p-nitrophenyl acetate into the cavity and a bound nickel ion then catalysed the hydrolysis of the substrate. This was a direct hydrolysis, not an acylation of a cyclodextrin hydroxyl (which is not in reach with the para esters). This type of catalyst then extends metal-catalysed reactions to substrates that do not intrinsically bind to metal ions, which was formerly required for such catalysis. 

Bodanszky et al. 1969) is accompanied by diminished sensitivity to steric hindrance and also by decreased dependence of the reaction rates from the nature of the solvent used in the coupling step. Para-nitrophenyl esters are most active in highly polar media, such as dimethylformamide or dimethylsulfoxide, less active in ethyl acetate, dioxane or tetrahydrofurane and rather inert in methylene chloride or chloroform. In spite of these advantages mainly the para derivatives are used, probably because a major improvement in peptide synthesis rendered these differences less important, to wit, the discovery of the catalytic effect of 1-hydroxybenzotriazole (Konig and Geiger 1973) on aminolysis of active esters. This effect could be rationalized by the assumption of a ternary complex between active ester, amine and catalyst... 

Kurono, Y., Maki, T., Yotsuyanagi, T., and Ikeda, K. 1979. Esterase-like activity of human-serum albumin— structure-activity-relationships for the reactions with phenyl acetates and para-nitrophenyl esters. Chem Pharm Bull 27 2781-86. 

Methyl-3-phenylisoxazole is also nitrated via the conjugate acid in mixed acid to yield the 3-nitrophenyl product and as the free base to give the 4-nitrophenyl product. The proportion of meta para nitration varies with the acidity of the medium. 5-Methyl-3-phenylisoxazole, in nitric acid acetic anhydride, yields 4-nitro-3-(4-nitrophenyl)isoxazole. The standard rates of nitration at 25°C and H0 -6.6 have been calculated [75 JCS(P2) 1627]. 

In another study of the nitration of 5-phenyl- and 3-methyl-5-phenylisox-azole the action of nitric acid sulfuric acid on 5-phenylisoxazoIe produced a 1 1 1 mixture of the ortho, meta, and para 5-(nitrophenyl) products with minor amounts of 4-nitro-5-(3-nitrophenyl)- and 4-nitro-5-(4-nitrophenyl)-dinitro products. The action of nitric acid acetic anhydride produced 4-nitro-5-phenylisoxazole as the major product with some nitrophenyl compounds as minor products. 3-Methyl-5-phenylisoxazole also gave a mixture of the ortho, meta, and para 5-(nitrophenyl) products when mixed acids were used, but no dinitro products were observed. The use of nitric acid acetic anhydride resulted in nitration at the 4-position of the isoxa-zole ring as the largely predominant product, with some phenyl ring substitution (89H1965). 

The first study of the nitration of 2-phenyl-1,2,3[2//]-triazole suggested that the products, using mixed acid at 20°C, were the ortho and para isomers (48JOC815). However, later work showed the two products to be the para isomer and the 4-nitro-2-(4-nitrophenyl) dinitrated product. Further nitration gives the 4-nitro-2-(2,4-dinitrophenyl) trinitrated product. Exclusive mononitration to produce the 4-nitrophenyl product can be effected using nitric acid in acetic anhydride (63CJC274). 

Fused oxazoles have been prepared by heating aryl azides containing electron-withdrawing groups at the para position with czurboxylic acids in polyphosphoric acid. j -Nitrophenyl azide and acetic acid yielded (83%) 2-methyl-6-nitrobenzoxazole (203)... 

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