Substitution constant

Substitutent Constants from Sources other than Ref. (23) and Ref. (29)... 

Hansch, C., Leo, A. Substituted Constants for Correlation Analysis in Chemistry and Biology, Wiley-Interscience, New York, 1979. 

The second extrathermodynamic method that we discuss here differs from Hansch analysis by the fact that it does not involve experimentally derived substitution constants (such as o, log P, MR, etc.). The method was originally developed by Free and Wilson [29] and has been simplified by Fujita and Ban [30]. The subject has been extensively reviewed by Martin [7] and by Kubinyi [8]. The method is also called the de novo approach, as it is derived from first principles rather than from empirical observations. The underlying idea of Free-Wilson analysis is that a particular substituent group at a specific substitution site on the molecule contributes a fixed amount to the biological activity (log 1/C). This can be formulated in the form of the linear relationship ... 

Let us calculate this quantity for the most slowly burning mixtures with u — 5 cm/sec (6% methane, 94% air), and the fastest burning mixtures with u = 1000 cm/sec (the detonating mixture 2H2+02) substituting constants for a temperature of about 500° C, where the velocity is higher as well, we find... 

Table 4.5 Examples of the different electronic substitution constants used in QSAR studies. Inductive substituent constants (crO are the contribution the inductive effect makes to Hammett constants and can be used for aliphatic compounds. Taft substitution constants (cr ) refer to aliphatic substituents but use propanoic acid (the 2-methyl derivative of ethanoic acid) as the reference point. The Swain-Lupton constants represent the contributions due to the inductive (.F) and mesomeric or resonance (R) components of Hammett constants. Adapted from An Introduction to the Principles of Drug Design and Action by Smith and Williams 3rd Ed. (1998) Ed. H.J.Smith. Reproduced by permission of Harwood Academic Publishers.

Hammett substitution constants suffer from the disadvantage that they only apply to substituents directly attached to a benzene ring. Consequently, a number of other electronic constants (Table 4.5) have been introduced and used in QSAR studies in a similar manner to the Hammett constants. However, attempts to relate biological activity exclusively to the values of Hammett substitution and similar constants have been largely unsuccessful, since electron distribution is not the only factor involved (see section 4.4). 

Sometimes the chelation process is characterized by the substitution constant defined as the equilibrium constant (lg Keq) for the following reaction... 

Addition of OH to olefinic and aromatic compounds is also very rapid usually k = 109-1010 M -1 s"1. Despite the high rates, a reasonable correlation with Hammett s substitutent constants was obtained for the series of substituted benzenes and demonstrated the electrophilic behaviour of OH in its addition to aromatic compounds (Neta and Dorfman, 1968). 

The use of Hammett substitution constants as design aids for identifying acid-acid supramolecular s)mthons characterized by the presence of a... 

K. Chadwick, G. Sadiq, R.J. Davey, C.C. Seaton, R.G. Pritchard, A. Parkin, Designing acid-acid cocrystals the use of Hammett substitution constants, Cryst. Growth Des. 9 (2009) 1278-1279. 

As a result, Hendriks et al. [11c] found a relation between the initial rate constants of the anaerobic oxidation of meta- and para-substituted toluenes by Co " acetate and the Hammett substitution constant (at 93 °C Figure 1). 

The search for an influence of steric effects on biological activity results from their well-established effects in chemical systems. As far back as 1894 (85), "steric hindrance" was invoked to account for the difficult esterification of 2,6-disub-stituted benzoic acids. However, inspection of equation 53 suggests that the substitutent constant, Eg, should include contributions from electronic effects as well. Indeed, acidic hydrolysis of esters of benzoic acids (4) have p values in the range -0.2 to +0.5. These p values are small and lie on both sides of zero, leading to the conclusion that electronic contributions to E are negligible (90). Proof for the existence of electronic effects in Es comes from Hancock s work (15) in which the electronic effects were attributed to a hyperconjugative effect of a-hydrogen atoms. 

As far as substituents on an aromatic ring are concerned, the measure used is known as the Hammett substitution constant which is given the symbol a. 

The Hammett substitution constant (a) is a measure of the electron withdrawing or electron donating ability of a substituent and has been determined by measuring the dissociation of a series of substituted benzoic acids compared to the dissociation of benzoic acid itself. 

It has been shown by Nath and Rydon that, in general, the acid hydrolysis of substituted phenyl /3-i)-glucopyranosides is facilitated by any electron-repelling properties of the substituents, and there seems to be a direct relationship between the Hammett substitution constant velocity constant of the reaction, especially for the meta- and pora-sub-stituted derivatives. For instance, with 0.1 N hydrochloric acid at 60°, the rate of hydrolysis of the p-cresyl (k = 2.32 X 10 min , [Pg.32]

Rydon and coworkers determined the rate constants for the acid hydrolysis of aryl a- and 3-D-glucopyranosides (see Table XXVI). For the )3-D-pyranosides, they found that electron-releasing substituents in the aglycon facilitate acid-catalyzed hydrolysis. A plot of the logarithm of the rate constants against the Hammett substitution constant, v,... 

Table I. Electronic substituted constants determined from magnetic circular dichroism spectra of simple substituted benzene derivatives 1A1g+1B2u transition.

A. Hammett Substitution Constant (o). It is a measure of either the electron-withdrawing or electron-donating capability of a substituent i.e., the functional moiety). Hammet substitution constant may be determined conveniently by actual measurement of the dissociation of a series of benzoic acid substituted derivatives vis-a-vis the dissociation of pure benzoic acid itself. 

Now, the Hammett substitution constant [0x1 with reference to a specific substituent X is usually defined by the following expression ... 

Therefore, for all benzoic acids essentially possessing electron-withdrawing substituents shall have larger Kx values than the parent benzoic acid itself (Kjj) thereby the value of Hammett substitution constant Ox for an electron-withdrawing substituent shall be always positive. 

Similarly, for most benzoic acid variants essentially having electron-donating substituents shall have comparatively smaller Kx values than benzoic acid itself and, therefore, the value of Hammett substitution constant Ox for an electron-donating substituent will always be negative. 

Furthermore, the Hammett substitution constant essentially and importantly takes cognizance of two vital and critieal supportive efieets, sueh as resonance effect, and inductive effect Consequently, the value of O with respeet to a speeifie substituent may exclusively depend upon whether the attached substituent is loeated either at meta-ox at ara-position. Conventionally, such particular substituent is invariably indicated by the subscript moxp first after the symbol O. 

Interestingly, most quantitative structural activity relationship (QSAR) studies usually commence by considering o (Hammett substitution constant) and, in case there exists more than one substituent, the a values are represented in a summed up manner as Za. Keeping in view the enormous quantum of synthetic newer target drug molecules, it has now become almost necessary and possible either to modify/refine or fine tune-up the QSAR equation. In fact, a substituent s resonance effect (R) and inductive effect (F) may be quantified as far as possible with the help of available tables of constants . In certain instances one may evidently observe that ... 

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