4-nitrophenyl acetate, reaction with phenolate

Bruice and Sturtevant, (1959) and Bruice, (1959) found extremely facile intramolecular nucleophilic attack by neighbouring imidazole in the hydrolysis of p-nitrophenyl 7-(4-imidazoyl)butyrate [19]. The rate constant for imidazole participation (release of p-nitro-phenolate) in this reaction is nearly identical with the rate constant for a-chymotrypsin catalysed release of p-nitrophenolate ion [190 min in equation (11) at pH 7 and 25°] from p-nitrophenyl acetate. Comparison of the rate constant for intramolecular imidazole participation to that for the analogous bimolecular reaction (imidazole attack on p-nitrophenyl acetate) (s" /m s )... 

Bruice and Lapinski (1958) reported that logarithms of second-order rate constants for reaction of p-substituted phenoxide ions with p-nitrophenyl acetate were a linear function of the p/sfa-value of the phenol with a slope of 0-8. Phenolate ions cannot displace... 

Fig. 11.8 The quasi-symmetrical reaction of phenolate ions with 4-nitrophenyl acetate.

The concept of bifunctional catalysis was first introduced to account for the unusually large catalytic efficiency of 2-hydroxypyridine in the mutarotation of tetramethylglucose (42). In this reaction, phenol acts as an acid catalyst and pyridine as a basic catalyst and it was, therefore, concluded that a compound with the phenolic hydroxyl and the basic nitrogen at the proper spacing should be able to produce a concerted attack on the sensitive bond of the reactive molecule, with a corresponding reduction of the required activation energy. A similar effect was invoked to explain the unusual pH dependence of the hydrolysis of p-nitrophenyl acetate in the presence of poly-4(5)-vinylimidazole (PVI) (43). 

It is essential to demonstrate that both the measured forward and reverse rate constants refer to the same rate-limiting step and that there is no change in rate-limiting step in the extrapolated range. Consider the quasi-symmetrical reaction of phenolate ions with 4-nitrophenyl acetate (Equation 13). 

Calculate the identity rate constant, for the reaction of 4-nitrophenolate ion with 4-nitrophenyl acetate given that the Bronsted equation for the attack of substituted phenolate ions on the ester is ... 

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. 

Effective Charge Map for a Putative Stepwise Process. Effective charge maps can also be employed to discount a stepwise process if estimates of the effective charge change from reactant and product to putative intermediates are not consistent with expectation. Consider the Bronsted dependence for reaction of substituted phenolate ions with 4-nitrophenyl acetate (Figure 6). The value of Pnu is approximately 0.80 for attack of substituted phenolate ions on 4-nitrophenyl acetate when the second step of the putative two-step mechanism (decomposition of the putative tetrahedral intermediate) would be rate limiting (pA pA a ) (Scheme 11). 

Materials. N,N-Dimethylformamide (DMF) and N-methyl-2-pyrrolidone (NMP) were stirred over powdered calcium hydride overnight, distilled under reduced pressure, and then stored over 4-A molecular sieves. 4-Aminobenzhydrazide (5) was prepared from methyl 4-aminobenzoate and hydrazine monohydrate according to the reported procedure (6). 4,4 -Thiobisbenzenthiol (6) and isophthalic acid (7) were purified by reciystdlization. Phenyl acrylate and 4-nitrophenyl acetate were prepared by the reactions of acryloyl chloride or acetyl chloride with phenol or 4-nitrophenol in the presence of triethylamine and tetahydrofuran, respectively. TrieAylamine (TEA) and tetahydrofuran (THF) were purified by the usual method. Other reagents and solvents were obtained commercially and used as received. 

Relative rates of hydrolysis were determined with 0.5 ml reaction mixtures in 0.1 M sodium acetate buffer, pH 5.0, at 37°. Liberated phosphate was measured by the method of C. H. Fiske and Y. SubbaRow [JBC 66, 375 (1925)]. The amounts of enzyme used were 0.22 unit of crystalline enzyme and 0.24 unit of peak II enzyme. The concentration of substrate and inhibitor was 1.0 mM. For inhibitor study, 1.0 mM p-nitrophenyl phosphate was used as substrate. Inhibition was calculated from the amount of p-nitro-phenol released and expressed as fractional inhibition. 

Thus, two types of active esters are of interest those formed from an acid and a substituted phenol (12-15) and those formed from an acid and a substituted hydroxylamine (16-19). Both types are reactive by virtue of the electron-withdrawing properties of the OR moiety in 2. The level of activation of the substituted phenyl esters varies directly with the electronic effect going from 4-nitrophenyl to 2,4,5-trichlorophenyl, pentachlorophenyl, and pentafluorophenyl, which corresponds with the increasing acidity of the phenols. A diminution in the rate of aminolysis is caused by the presence of a substituent in the ortho position of the ring.f l An additional phenomenon contributes to the reactivity of the esters formed from substituted hydroxylamines, namely anchimeric assistance. Since the anoinolysis of active esters is a bimolecular reaction, it is dependent on concentration and can be forced to completion by an excess of one of the reactants. Aminolysis is also characterized by a pronounced dependence on the polarity of the solvent in particular for the esters formed from substituted phenols, the half-life of a 2,4,5-trichlorophenyl ester in the presence of benzylamine being one hundred times less in dimethylformamide than in benzene. Furthermore, aminolysis is catalyzed by mild acid such as acetic acid. The rate of anoinolysis is slowed if the side chain of the active ester contains a P-methyl substituent. 

On the other hand, phosphorane intermediates are not expected to be involved in the hydrolysis of phosphate monoesters, so the effective observed catalysis by the carboxyl group of salicyl phosphate 3.21 [51] (Scheme 2.26) is presumed to be concerted vith nucleophilic attack. (The hydrolysis reaction involves the less abundant tautomer 3.22 of the dianion 3.21, and the acceleration is >10 -fold relative to the expected rate for the pH-independent hydrolysis of the phosphate monoester dianion of a phenol of pK 8.52.) However, this system differs from the methoxy-methyl acetals discussed above, in that there is a clear distinction between neutral nucleophiles, which react through an extended transition structure similar to 3.16 in Scheme 2.23, and anions, which do not react at a significant rate, presumably because of electrostatic repulsion. This distinction is well-established for the dianions of phosphate monoesters with good leaving groups (p-nitrophenyl [52] and... 

Active esters of amino acids, o-and p-Nitrophenyl esters of amino acids (1, 743 5, 477) can be prepared in about 45-95% yield by reaction of an N-pro-tected amino acid with phosphonitrilic chloride and triethylamine in chloroform, ethyl acetate, or THF. After 15 min. the phenol is added and the reaction is stirred for about 12 hr. ... 

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