Esters Hammett relationship

Reference to Chapter 3 (Scheme 3) shows that the alkaline hydrolysis of aryl carbamate esters has a large Hammett p coefficient (2.54) whereas that for the alkaline hydrolysis of aryl acetate esters is only small (0.67) (Scheme 2). The small p value for alkaline hydrolysis of the acetate case is consistent with little bond fission in the transition structure and the large p for the carbamate case (see Chapter 3 for mechanism) indicates substantial bond fission and a gross difference in mechanism between the two reactions. The simple Hammett relationship only correlates the alkaline hydrolysis rates of the carbamate when meta substituents are employed. Para substituents, which withdraw negative charge by resonance (4-NO2, 4-CN, etcf require values to obtain a good correlation. This is interpreted to mean that the transition structure has sufficient aryl oxide ion character for resonance to occur. In... 

Hammett (and related sigma) relationships have been applied to aquatic reactions of several classes of aromatic contaminants. For example, alkaline hydrolysis of triaryl phosphate esters fits a Hammett relationship (Table 3) is t he sum of the substituent constants for the aromatic groups and k0 is the hydrolysis rate constant for triphenyl phosphate (0.27 M 1 s-1 t1/2 = 30 days at pH 8). Triaryl esters thus hydrolyze much more rapidly than trialkyl or dialkyl-monoaryl esters under alkaline conditions. Rates of photooxidation of deprotonated substituted phenols by singlet oxygen have been found to be correlated with Hammett a constants (Scully and Hoigne, 1987). The electronic cllects of substituents on pKa values of substituted 2-nitrophenols also fit a I lammett relationship this, of course, is not a kinetic LFER. Two compounds (4-phenyl-2-NP and 3-methyl-2-NP) did not fit the relationship and were not included in the regression. Steric effects may account for the discrepancy for the latter compound. Nitrophenols are used as intermediates in synthesis of dyes and pesticides and also used directly as herbicides and insecticides. 

Taking advantage of the LFER treatment of the electrochemical data, we have found an irregularity in reduction of all compounds where the phenyl ring is substituted in p-position by methyl ester function [23] (I e, II e, V e, VI e). While all other substituents follow the linear Hammett relationship, the derivatives substituted by the p-carbonyl group are always reduced more easily and the observed values of red are always shifted by 150 mV toward less negative potentials (cf., anomalous values in Fig. 48.4). This observation points to a different reduction mechanism, caused by a different, more-delocalized system where the carbonyl is involved. 

The most frequently encountered hydrolysis reaction in drug instability is that of the ester, but curtain esters can be stable for many years when properly formulated. Substituents can have a dramatic effect on reaction rates. For example, the tert-butyl ester of acetic acid is about 120 times more stable than the methyl ester, which, in turn, is approximately 60 times more stable than the vinyl analog [16]. Structure-reactivity relationships are dealt with in the discipline of physical organic chemistry. Substituent groups may exert electronic (inductive and resonance), steric, and/or hydrogen-bonding effects that can drastically affect the stability of compounds. A detailed treatment of substituent effects can be found in a review by Hansch et al. [17] and in the classical reference text by Hammett [18]. 

A situation similar to that in acetyl phosphate is also encountered in benzoyl phosphate76 . Electron-attracting substituents on the phenyl ring accelerate the hydrolysis of the dianion (a linear relationship exists between log khydrol and the Hammett a constants with q = 1.2 and the linear log ki,j,drol./pKa relationship is the same as for the phosphoric monoaryl ester dianions65 . On the other hand, hydrolysis of the monoanion is influenced only slightly by substituents in the phenyl ring. These observations can also be rationalized in terms of the decomposition mechanism to the POf ion formulated for 116 and 117. 

The first such relationship, on a thoroughly established basis, was observed by Hammett as long ago as 1933. He showed that for the reaction of a series of methyl esters (1) with NMe3,... 

Any of these conditions constitutes an extremely stringent limitation, and there has always been some doubt expressed over the extent to which any one of them is indeed satisfied in reactions which nevertheless give quite good straight line Hammett plots thereby making the linear relationships that are observed all the more mysterious Examples are, however, known that can indeed be shown to conform to one or other of the above conditions. Thus for the base-induced hydrolysis of the esters (58),... 

Modification of Chemical Structure of Drug The use of a Hammett linear free-energy relationship to investigate the effects of substituents on the rates of aromatic side-chain reactions such as hydrolysis of esters has been alluded to earlier vis-a-vis attainment of optimum stability [9,10]. Degradation of erythromycin under acidic pH conditions is inhibited by substituting a methoxy group for the C-6 hydroxyl as found for the acid stability of clathromycin, which is 340 times greater than that of erythromycin [70]. 

Exercise 26-37 Would you expect a Hammett type of relationship to correlate data for the dissociation of acids of the following type with rate data for hydrolysis of the corresponding esters Explain. 

Organic chemists have studied the influence of substituents on various reactions for the better part of a century. Linear free energy relationships have played an important role in this pursuit by correlating equilibrium and rate processes. One of the earliest examples is now known as the Hammett equation. It emerged from the observation that the acidities of benzoic acids correlated with the rates at which ethyl esters of benzoic acids hydrolyzed. The relationship was expressed as follows in which K represents an equilibrium constant and k is a rate constant. The proportionality constant, m, is the slope of the log-log data plot for the two processes. 

The structure-reactivity relationship of acidic organophos-phorus compounds is well demonstrated by mono-esters of p-substi-tuted phenylphosphonic acids. The acidity of these organic acids increased as the polar nature of the substituents enhanced. A linear free energy relationship exists between the pKa value and the Hammett cr constants in acidic p-substituted phenylphospho-nates. When these structure parameters are plotted either against the t POO" asym. or against the 31p chemical shift of their dicyclo-hexylammonium salts straight lines resulted in both cases. 

The coefficient a in eqn. (27) is between 0.8 and 1.4 in most cases. For A2 reactions, a linear relationship between log k and H0 is not expected, but k is supposed to be directly proportional to the stoichiometric concentration of the strong acid [84]. The Zucker—Hammett hypothesis has been applied most successfully to the field of ester hydrolysis. It is not generally valid, however [13]. 

Perhaps the most convincing evidence for the play of polar forces comes from copolymerization of a series of ring-substituted styrenes here relative reactivities toward a variety of monomers not only fall into a pattern consistent with the familiar electronic effects of the substituents, but show the same quantitative relationships (the Hammett sigma-rho relationship. Sec. 18.11) as do ionic reactions dissociation of carboxylic acids, for example, or hydrolysis of esters. 

The control of drug stability by modifying chemical structure using appropriate substituents has been suggested for dmgs for which such a modification does not reduce therapeutic efficacy. The Hammett linear free energy relationship for the effect of substituents on the rates of aromatic side-chain reactions, such as the hydrolysis of esters, is given by... 

The electrophilicity index also accounts for the electrophilic activation/deactivation effects promoted by EW and electron-releasing substituents even beyond the case of cycloaddition processes. These effects are assessed as responses at the active site of the molecules. The empirical Hammett-like relationships found between the global and local electrophilicity indexes and the reaction rate coefficients correctly account for the substrate selectivity in Friedel-Crafts reactions, the reactivity of carbenium ions, the hydrolysis of esters, the reactivity at the carbon-carbon double bonds in conjugated Michael additions, the philicity pattern of carbenes and the superelectrophilicity of nitronium, oxonium and carboxonium ions. This last application is a very promising area of application. The enhanced electrophilicity pattern in these series results from... 

In principle, extrathermodynamic relationships that deviate from the simple Hammett equation (equation 8) can be treated by equation 14. The major problem is the determination of the different sets of o s, (e.g., set and 0 set) in a way that will indeed reflect their relation to independent properties. An example of such a procedure is the separation of polar and steric effects (10). The need for such a separation arose when a nearly complete lack of correlation was observed between substituent effects represented by the Hammet a constants and the rates for alkaline hydrolysis of aliphatic systems (12). Inspection of the structures indicated that the proximity of the substituents to the reaction site was a common feature. The steric interaction between R and X had to be considered separately from the electronic effects. Polar substituent constants were thus defined as the difference between the rate constants of base and acid catalyzed hydrolysis of esters. From the structural similarity of the transition states for these reactions (equation 15) it was assumed that the difference in their charge reflects only the polar effect of the substituent... 

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