Steric parameters, ortho

A classical Hansch approach and an artificial neural networks approach were applied to a training set of 32 substituted phenylpiperazines characterized by their affinity for the 5-HTiA-R and the generic arAR [91]. The study was aimed at evaluating the structural requirements for the 5-HTiA/ai selectivity. Each chemical structure was described by six physicochemical parameters and three indicator variables. As electronic descriptors, the field and resonance constants of Swain and Lupton were used. Furthermore, the vdW volumes were employed as steric parameters. The hydrophobic effects exerted by the ortho- and meta-substituents were measured by using the Hansch 7t-ortho and n-meta constants [91]. The resulting models provided a significant correlation of electronic, steric and hydro-phobic parameters with the biological affinities. Moreover, it was inferred that the... 

We will see in the next section that quaternization of azines and azoles has been used to test the applicability and validity of steric parameters, to show their conformational dependence, and to propose new steric parameters suitable for ortho positions. 

Evidently, Es parameters cannot be used when strong conformational preferences exist, and for heteroaromatics ortho-steric parameters are required. 

For describing the nucleophilicity of 2-alkylpyridines, Popov and Gelbina (770R145) proposed ortho-steric parameters N, but values given were limited to the a-alkyl series where good correlations are usually observed. 

A new scale of ortho-steric parameters S° was determined by Berg et al, from the N-methylation of pyridines (80JCS(P2)1350). It is based on the fact that all ortho-substituted pyridines fall below the Bronsted line obtained under the same conditions with non-ortho-substituted pyridines (Fig. 4). 

For each ortho substituent, the deviation from the reference line is far greater than the error in the slope of this line. A steric parameter for each... 

The ortho-steric parameters given in this paragraph are derived from N-methylation of pyridines. The basic set was calculated by the general equation... 

The substitution pattern of the 4-aromatic residue is also important for the activity, the ortho-substitution being the best one in terms of potency and selectivity. A Hansch analysis on a series of ortho-derivatives has shown a significant correlation between calcium antagonist activity and steric hindrance of the substituent, while no relationship was found for either electronic or lipophilic parameters [3]. The best SAR correlation was obtained when the B1 steric parameter (the Verloop parameter) was introduced into the analysis [4]. The calcium channel-blocking activity increases as B1 increases, which probably indicates that steric hindrance in the ortho-position is required to fix the dihydropyridine structure into a favorable conformation in which the aromatic group is approximately perpendicular to the dihydropyridine ring (Fig. 7.12). 

The 95% confidence intervals of the coefficients in Equations 11 and 12 indicated little significance of the electronic and steric parameters of the ortho substituents. In fact, better correlations were obtained when they were omitted and further separation of the hydrophobic constants was introduced as in Equations 13 and 14. All the parameters are highly significant except the linear w term for the ortho substituents (tt ). The correlation coefficient and standard deviation improved only slightly when a ( 2-4)2 term was added, as shown in Equation 15 (Figure 6). 

Figure 10 Theoretical (a) and practical (b) representation of QSARs. Panel b describes a QSAR for the methanotrophic oxidation (activity of methane monooxygenase) of 6>r /i6>(Ci2)-substituted biphenyls. The structural backbone was biphenyl, and the substituents considered included all halogens, methyl-, methoxy-, hydroxyl-, nitro-, and amino-moieties (Lindner et al, 2003). The molecular descriptors used in (b) are (charge on the ortho-csubon), (Taft s steric parameter), and log ow...

As usual, h is introduced in case the observed property of the unsubstituted molecule, (Qfi), is not equal to zero. The steric parameter ry was estimated from van der Waals radii in various ways. For ortho substituents it was found that the contributions from inductive and resonance terms outweigh by far the steric contribution, indicating the relative unimportance of the latter in the ortho effect. By contrast in aliphatic systems the contribution from r has been found to dominate all the others. The validity of this substituent constant has to be evaluated, but the correspondence between the ry from aliphatic compounds and Eg was shown by the good correlation between them (98, 99). Since the van der Waals radii do not contain directional information, the correlation between r and Eg indicates that the Eg constants reflect the size and bulk of the substituent and lack the important property of directionality. 

Dash, S.C. and Behera, G.B. (1980) A new steric parameter to explain ortho-substituent effect. Indian J. Chem., 19, 541-543. 

Although steric parameters in the ortho position have not been selected into the equation, the fact that ortho substituents often seem to decrease the inhibitory activity, relative to other compounds of the scune lipophiliclty, shows possible steric hindrance. It has been suggested (12) that the high specificity of JHE to the natural substrates (JHs) is due to a "recognition" of the a-fi double bond in the substrate, and that the P sulfur in the title compounds is biolsosteric with the P sp carbon of this double bond. The ortho substituents of the phenyl ring possibly... 

First, we examined the kinetic parameters (Kj and k(.jt) of some orf/jo-substitu-ted compounds, as well as a control substrate. The results are shown in Table 8. The Kj and k(.jt values of a standard substrate (X, R=H) are 13.9 mM and 353 s, respectively. Introduction of a chlorine atom on the ortho-position of the benzene ring (X=Cl,R=H) accelerates the rate of reaction obviously because of its electron-withdrawing property. The steric effect of this substituent is con-... 

Taft also defined the Es parameter for aromatic ortho substituents in a fashion similar to Eq. 3 4). Charton advanced evidence that the original value is linked rather with the polar substituent effect despite the original definition51. We have shown that the set of Es parameters defined by Eq. 3 and 4 can also be used to rationalize the steric effect of aromatic ortho substituents 7). In general, the ortho substituent effect in biological activity is analyzable as linear combination of substituent parameters 8) (Eq. 5),... 

The data for acid-catalyzed ester formation in cyclohexanol are doubly interesting. The activation parameters are closely similar to those for the acid-catalyzed hydrolysis of the corresponding ethyl esters. The enthalpy of activation is considerably higher than for esterification in methanol this is probably a result of steric inhibition of solvation, as well as non-bonded compression in the transition state, as suggested by the entropies of activation, which are also significantly higher than with methanol, especially for compounds without ortho substituents which presumably have more transition state solvation to lose. 

An effective QSAR parameter should correlate only to its specific property, be it electronics, lipophilicity, sterics, or something else, a- Values for R-groups in the meta and para positions have been found to account for only electronic effects. Substitution at the ortho position, however, is another story. Because ortho substituents are physically so close to the carboxylic acid, ortho R-groups affect the acid-base equilibrium through both electronic and steric effects. Therefore, the ortho tr-value (electronic parameter for QSAR studies. Despite their limitations, Hammett constants are by far the most commonly encountered electronic parameter in Hansch analysis. 

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