Hammett linear free energy relationship

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]. 

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 Hammett linear free-energy relationship is expressed in the following equations for equilibria and rate data, respectively ... 

The Hammett linear free energy relationship is a widely used extrathermody-namic relationship for organic reactions. Although developed specifically for dissociation constants, in principle the method is applicable to any organic reaction. 

L.P. Hammett, Linear free energy relationships in rate and equilibrium phenomena, Trans. Faraday Soc. (1938), 156-165. 

Let us illustrate this with the example of the bromination of monosubstituted benzene derivatives. Observations on the product distributions and relative reaction rates compared with unsubstituted benzene led chemists to conceive the notion of inductive and resonance effects that made it possible to explain" the experimental observations. On an even more quantitative basis, linear free energy relationships of the form of the Hammett equation allowed the estimation of relative rates. It has to be emphasized that inductive and resonance effects were conceived, not from theoretical calculations, but as constructs to order observations. The explanation" is built on analogy, not on any theoretical method. 

Hammett [7] was the first to develop an approach that was later subsumed under Linear Free Energy Relationships (LFER). He showed that the addity constants of a... 

Brown developed the selectivity relationship before the introduction of aromatic reactivities following the Hammett model. The former, less direct approach to linear free-energy relationships was necessary because of lack of data at the time. 

C. D. Johnson, The Hammett Equation, Camhndge University Press, Cambridge, 1973. P. R. Wells, Linear Free Energy Relationships, Academic Press, New bik, 1968. 

The second aspect is more fundamental. It is related to the very nature of chemistry (quantum chemistry is physics). Chemistry deals with fuzzy objects, like solvent or substituent effects, that are of paramount importance in tautomerism. These effects can be modeled using LFER (Linear Free Energy Relationships), like the famous Hammett and Taft equations, with considerable success. Quantum calculations apply to individual molecules and perturbations remain relatively difficult to consider (an exception is general solvation using an Onsager-type approach). However, preliminary attempts have been made to treat families of compounds in a variational way [81AQ(C)105]. 

The basic Hammett scheme often does not offer a perfect correlation and a number of variants on this scheme have been proposed to better explain reactivities in radical reactions.-0 However, none of these has achieved widespread acceptance. It should also be noted that linear free energy relationships are the basis of the Q-e and Patterns of Reactivity schemes for understanding reactivities of propagating species in chain transfer and copolymerization. 

Linear free energy relationships, see Bronsted equation, Dual substituent parameter (equations), Hammett equation(s), Quantitative structure-activity relationships, Ritchie nucleophilicity equation... 

The Hammett equation is the best-known example of a linear free-energy relationship (LFER), that is, an equation which implies a linear relationship between free energies of reaction or activation for two related processes48. It describes the influence of polar meta-or para-substituents on reactivity for side-chain reactions of benzene derivatives. 

In contrast to the steric effoits, the purely electronic influences of substituents are less clear. They are test documented by linear free-energy relationships, which, for the cases in question, are for the most part only plots of voltammetrically obtained peak oxidation potentials of corresponding monomers against their respective Hammett substituent constant As a rule, the linear correlations are very good for all systems, and prove, in aax>rdance with the Hammett-Taft equation, the dominance of electronic effects in the primary oxidation step. But the effects of identical substituents on the respective system s tendency to polymerize differ from parent monomer to parent monomer. Whereas thiophenes which receive electron-withdrawing substituents in the, as such, favourable P-position do not polymerize at all indoles with the same substituents polymerize particularly well... 

The Hammett equation is a linear free energy relationship (LFER). This can be demonstrated as follows for the case of equilibrium constants (for rate constants a similar demonstration can be made with AG instead of AG). For each reaction, where X is any group,... 

It is perhaps interesting, in view of the very considerable success of Hammett plots, to say a word finally about the thermodynamic implications of linear free energy relationships in general. We have already mentioned (p. 359) the relationship between free energy change, AG, and log k or log K and each AG term is, of course, made up of an enthalpy, AH, and an entropy, AS, component ... 

Having said all that, it is equally important to remember that the number and variety of useful correlations to which Hammett plots have given rise is quite astonishing, particularly when we consider the simplicity and convenience of the approach. Indeed, linear free energy relationships in general constitute a testament to the theoretical utility of concepts that are purely empirical in their genesis ... 

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