Substituent effects, cross interaction

Equations (37)—(39), where the non-additivity of multiple substituent effects is described by a cross-term, express correctly the rate data for bromination and other reactions of polysubstituted substrates. The question arises, therefore has the interaction constant, q, any physicochemical meaning in terms of mechanism and transition state charge To reply to this question, selectivity relationships (42) that relate the p-variation to the reactivity change and not to any substituent constant, have been considered (Ruasse et al., 1984). 

The above observations on intersite reactions and site-isolations in polymeric matrices show that by a judicious choice of the various experimental conditions, the desired effect — intersite interaction or site-site non-interaction — could be brought about. The mobility of the polymer chains depends on the degree of cross-linking, solvent, temperature, flexibility of the chain segments and the distribution of the substituents. High cross-link density, non-swellability, low temperature etc. tend the... 

CROSS AND SELF INTERACTION BETWEEN TWO OR MORE SUBSTITUENT EFFECTS... 

Interestingly, the effects of the two substituents are not additive, which is shown by the so called cross-interaction constant[35] of 0.4. From equation (10), we can also see that 1-substituted benzene radical cations with low one-electron reduction potentials are less sensitive to 4-substitution than 1-substituted benzene radical cations with high one-electron reduction potentials. 

The kinetics and mechanism of the aminolysis of phenyl-substituted phenyl phosphonyl chlorides (136) with anilines (135) were investigated in MeCN at 55.0 °C. Very sensitive variation of /Oy(5/Oy2>0) with the change of substituent on the nucleophile Sax) led to a large negative cross-interaction constant, pxY = Spy)/ Sox) = —1.31. The secondary kinetic isotope effects observed with deuteriated aniline nucleophiles were of the inverse type (/th/ d = 0.61-0.87), and small A// (1.6-9.7kcalmor ) and large negative A5 (—43 to —65 e.u.) values were... 

Moreover, a final 3D-QSAR model vahdation was done using a prospective study with an external test set. The 82 compounds from the data set were used in a lead optimization project. A CoMFA model gave an (cross validated) value of 0.698 for four relevant PLS components and a conventional of 0.938 were obtained for those 82 compounds. The steric descriptors contributed 54% to the total variance, whereas the electrostatic field explained 46%. The CoMSIA model led to an (cross vahdated) value of 0.660 for five PLS components and a conventional of 0.933. The contributions for steric, electrostatic, and hydrophobic fields were 25, 44, and 31%. As a result, it was proved that the basic S4-directed substituents should be replaced against more hydrophobic building blocks to improve pharmacokinetic properties. The structural and chemical interpretation of CoMFA and CoMSIA contour maps directly pointed to those regions in the Factor Xa binding site, where steric, electronic, or hydrophobic effects play a dominant role in ligand-receptor interactions. 

The hydrophobic character of a drug is crucial to how easily it crosses cell membranes (see Section 8.1.3.) and may also be important in receptor interactions. Changing substituents on a drug may well have significant effects on its hydrophobic character and hence its biological activity. Therefore, it is important to have a means of predicting this quantitatively. 

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