Steric constants

C Hansch, A Leo, D Hoekman. Exploring QSAR Hydrophobic, Electronic, and Steric Constants. Washington, DC Am Chem Soc, 1995. 

Berg et al. defined a different ortho steric constant. The model reaction is the quatemization of substituted pyridines with methyl iodide in acetonitrile solution. 

A plot of log (kiku) against pKa (this is called a Br nsted-type plot, as we will see in Section 7.4) for meta- and para-substituted pyridines gave an LFER describing normal behavior. On this same plot the or// o-substituted pyridines all fell below the m and p reference line. The steric constant was defined as the vertical distance between the reference line [whose equation was log (k plkn) = 0.35 pK — 1.73] and the result for the ortho compound, or... 

Because 5 is not well correlated with Ei, these two steric constants contain different information. Berg et al. conclude that S is a measure of the pure steric effect. 

If the assumptions underlying the Taft treatment of the separation of electronic and steric effects are valid, then the relative rates of acid-catalyzed reactions of esters should be a measure of the steric effect. Taft " accordingly defined a steric constant Es by Eq. (7-52). 

In this definition ko is the rate constant for CH3COOR and k is the constant for RCOOR thus = 0 for R = CH3. Table 7-11 lists some values. Taft s Es steric constants are in some instances based on averages of several different reactions, so MacPhee et al. have defined a steric constant Es by Eq. (7-52) for a single reaction, namely, the acid-catalyzed esterification of carboxylic acids in methanol at 40°C. Es values are also given in Table 7-11. Additional Es and Es values are available. 

It is obvious, fipom some of the series of substituents in Table 7-11, that the steric constant reflects intuitive notions of group size, and Taft " pointed out close parallels with van der Waals radii. For asymmetrical groups a single van der Waals radius cannot be defined, and the situation is complicated by conformational flexibility. Nevertheless, empirical relationships can be established, and Kutter and Hansch gave Eq. (7-55),... 

The steric constant Es and related quantities do not constitute the only approach to the study of steric effects on reactivity. Steric strain energy calculations and topological indices are more recent approaches. Qualitative concepts have been... 

A very interesting steric effect is shown by the data in Table 7-12 on the rate of acid-catalyzed esterification of aliphatic carboxylic acids. The dissociation constants of these acids are all of the order 1(T, the small variations presumably being caused by minor differences in polar effects. The variations in esterification rates for these acids are quite large, however, so that polar effects are not responsible. Steric effects are, therefore, implicated indeed, this argument and these data were used to obtain the Es steric constants. Newman has drawn attention to the conformational role of the acyl group in limiting access to the carboxyl carbon. He represents maximum steric hindrance to attack as arising from a coiled conformation, shown for M-butyric acid in 5. 

Fujita, T., and Iwamura, H. Applications of Various Steric Constants to Quantitative Analysis of Structure-Activity Relationshipf, 114, 119-157 (1983). 

Hansch C, Leo A, Hoekman D, eds. 1995. Expoloring QSAR. Hydrophobic, electronic, and steric constants. Washington, DC American Chemical Society, 50. 

A Gst is the difference in free energy due to steric constants in reactant and transition state, k is the rate constant of the nonsterically constrained reaction. The contribution of the steric component to the transition-state energy cannot be deduced accurately from DFT calculations because van der Waals energies are poorly computed. Force field methods have to be used to properly account for such interactions. 

Hansch, C., Leo, A., Hoekman, D. Hydrophobic, Electronic, and Steric Constants. American Chemical Society, Washington, 1995, Vol. 2, p. 368. 

The works of Maurel and Tellier 82), Rhzicka and Cerveny 83, 84), Litvin, Freidlin, and Tilyaev (55) and Brown and Ahuja 86), who have used extensive series of alkenes, confirmed the Lebedev s rule. With 1-alkenes C -Cn) on palladium, platinum, and rhodium catalysts, the initial reaction rate decreased with the length of the chain, and with Pd and Pt a hnear dependence on the number of carbon atoms was obtained 83) (series 53). An example of the influence of the number of substituents on the carbon atoms of the double bond is shown in Fig. 4. It is evident that the mere presence of the substituent is more important than its nature. However, this secondary factor has been accounted for by using the sums of the Taft polar (7 or steric constants for all substituents on C=C. Cerveny and Rfizicka 84) have found excellent linear relationships between the initial hydrogenation rate of 15 alkenes on 3 different Pt catalysts and 2 (series 54), and... 

The decrease in hydrogenation rate with increasing size of the alkyl group (Table VI) (93-96) can be correlated by the Taft equation. However, the correlation of the data by Smith and Pennekamp (93) (series 70) using the polar parameter Taft equation is applied that also includes steric constants. Similarly, Kieboom (34) has discussed Yoshida s correlation of series 73 based on main conclusion has been that the data do not allow a clear distinction between steric and polar effects. It seems that both operate in the same direction. Series 72 and 73, in which the rate data have been separated into the rate constants and adsorption coefficients, show opposite trends with the latter parameter. A similar problem has been encountered by Volter, Hermann, and Heise (100) and by Najemnik and Zdrazil (103) in the series of methylbenzenes (Table VII) and is discussed in this connection. 

Steric Constants. Washington American Chemical Society. 

Regression analysis is currently the most widely used correlative method in drug design. This is because it simplifies problems within a set of compounds by using a limited number of descriptors, notably the Hansch hydrophobic constant n, Hammet constants, or other electronic characteristics of substituents, and the Taft steric constant Eg. 

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