Parameters steric

The unique revelation and wisdom of a latest eomputerresearehed programme termed as sterimol has indeed helped a long way in measuring the steric factor to a reasonably correet extent. It essentially aids in the ealculation of desired steric substituent values (otherwise known as Verloop steric parameters) based on various standard physical parameters, such as Van der Waals radii, bond lengths, bond angles, and ultimately the proposed most likely conformations for the substituent under examination. It is, however, pertinent to mention here that unlike the Taft s steric factor (E ) (see Section 2.9.1) the Verloop steric parameters may be measured conveniently and accurately for any substituent. 

Carboxylic acid (say, Benzoic Acid) The ensuing Verloop steric parameters for 

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  

Integrating various factors, namely Taft s steric factor, resonance, inductive, Verloop steric parameters with the partition behaviour of drug molecules Hansch and Fuj ita exploited these principles in determining the establishing quantitative structure-activity relationship (QSAR) of drugs, which has rmdergone a sea change both in expansion and improvement with the help of computer researched softwares. 

The hydrophobic characteristic, designated by n, may be correlated to a drug s distribution pattern, within which a given substituent x affects molecular behaviour and conduct with regard to its - distribution and transport, and - drug-receptor activities. 

---

The fundamental assumption of SAR and QSAR (Structure-Activity Relationships and Quantitative Structure-Activity Relationships) is that the activity of a compound is related to its structural and/or physicochemical properties. In a classic article Corwin Hansch formulated Eq. (15) as a linear frcc-cncrgy related model for the biological activity (e.g.. toxicity) of a group of congeneric chemicals [37, in which the inverse of C, the concentration effect of the toxicant, is related to a hy-drophobidty term, FI, an electronic term, a (the Hammett substituent constant). Stcric terms can be added to this equation (typically Taft s steric parameter, E,). 

Matsui et al.82) have analyzed the same data of log l/Kd(X) for cyclodextrin-phenol systems from a somewhat different standpoint. They computed the minimal van der Waals interaction energies (Emin) for the systems by using the same method as described in a previous section (Table 4). The calculated Emin values were applied, in place of such steric parameters as Ibrnch and B1( to the correlation analysis. The correlations obtained are given in Eqs. 24 to 27. 

A few examples have been reported in which no steric parameter is involved in the correlation analysis of cyclodextrin catalysis. Straub and Bender 108) showed that the maximal catalytic rate constant, k2, for the (5-cyclodextrin-catalyzed decarboxylation of substituted phenylcyanoacetic acid anions (J) is correlated simply by the Hammett a parameter. 

Charton, M. The Upsilon Steric Parameter Definition and Determination, 114, 57-91 (1983). Charton, M. Volume and Bulk Parameters, 114, 107-118 (1983). 

It has been suggested that the discrepancies between the value of k ikK observed and that predicted on the basis of simple statistics may reflect the greater sensitivity of combination to steric factors. Beckhaus and Rtichardt164 reported a correlation between log(A )/ ,<.,) (after statistical correction) and Taft steric parameters for a scries of alkyl radicals. 

The approach Taft has presented gives rise to an equation that is obviously more powerful than the Hammett relation. It correlates more reactions and can be extended to include steric parameters. It takes the form... 

Two other steric parameters are independent of any kinetic data. Charton s v values are derived from van der Waals radii/ and Meyer s values from the volume of the portion of the substituent that is within 0.3 nm of the reaction center. The V values are obtained by molecular mechanics calculations based on the structure of the molecule. Table 9.7 gives v and value.s for some groups. As can be seen in the table, there is a fair, but not perfect, correlation among the Ei, v, and values. Other sets of steric values, (e.g., and have also been proposed. ... 

The data to be examined are correlated with eq. (24). Successful correlation with eq. (24) is a necessary but not sufficient condition for the existence of case (a). Strong evidence for case (a) is provided by a confidence level of Ij greater than or equal to 90.0. The confidence level of p is obtained by means of a student t test of. If is not significant, then this fact implies either the existence of cases (b), (c), or (d), or the use of an incorrect steric parameter. The data are now correlated with eq. (2). If the correlations with... 

The rates of radical-forming thermal decomposition of four families of free radical initiators can be predicted from a sum of transition state and reactant state effects. The four families of initiators are trarw-symmetric bisalkyl diazenes,trans-phenyl, alkyl diazenes, peresters and hydrocarbons (carbon-carbon bond homolysis). Transition state effects are calculated by the HMD pi- delocalization energies of the alkyl radicals formed in the reactions. Reactant state effects are estimated from standard steric parameters. For each family of initiators, linear energy relationships have been created for calculating the rates at which members of the family decompose at given temperatures. These numerical relationships should be useful for predicting rates of decomposition for potential new initiators for the free radical polymerization of vinyl monomers under extraordinary conditions. 

The steric parameters for the estimation of reactant state effects were chosen to be the conformational free energy differences for cyclohexane axial-equatorial equilibria (A-values) (8). In order to establish the methyl group as the standard size group, modified A-values (A ) for the various groups were used, by simply subtracting the A value for the methyl group (1.70) from the A values of the various substituents ... 

Fio. 9. Detenninatiun of two steric parameters (Ai and Ah) associated with carbene ligands in Cp Ru(L)Cl complexes. 

The nucleophilic carbcnes are phosphine-mimics but they are much more. They reside at the upper end of the Tolman electronic and steric parameter scales. Much remains to be explored with these ligands. With a rudimentary understanding of ligand stereoelectronic properties, we feel confident much exciting chemistry remains to be explored. 

The importance of lipophilicity to bitterness has been well established, both directly and indirectly. The importance of partitioning effects in bitterness perception has been stressed by Rubin and coworkers, and Gardner demonstrated that the threshold concentration of bitter amino acids and peptides correlates very well with molecular connectivity (which is generally regarded as a steric parameter, but is correlated with the octanol-water partition coefficient ). Studies on the surface pressure in monolayers of lipids from bovine, circumvallate papillae also indicated that there is a very good correlation between the concentration of a bitter compound that is necessary in order to give an increase in the surface pressure with the taste threshold in humans. These results and the observations of others suggested that the ability of bitter compounds to penetrate cell membranes is an important factor in bitterness perception. 

E Taft steric parameter. E reflects the effective volume... 

Taft electronic factors (a ), and, in some cases, steric parameters (E ) (JJ., n). 

In this chapter, an attempt has been made to present a total number of 20 QSAR models (12 QSAR models for topo I inhibitors and eight QSAR models for topo II inhibitors) on 11 different heterocyclic compound series (an-thrapyrazoles, benzimidazoles, benzonaphthofurandiones, camptothecins, desoxypodophyllotoxins, isoaurostatins, naphthyridinones, phenanthridines, quinolines, quinolones, and terpenes) as well as on some miscellaneous heterocyclic compounds for their inhibition against topo I and II. They have been found to be well-correlated with a number of physicochemical and structural parameters. The conclusion, from the analysis of these 20 QSAR, has been drawn that the inhibition of topo I is largely dependent on the hydrophobicity of the compounds/substituents. On the other hand, steric parameters (molar refractivity, molar volume, and Verloop s sterimol parameters) are important for topo II inhibition. 

Charton, M. The Upsilon Steric Parameter Definition and Determination, 114, 57-91 (1983). 

To refine this model qualitatively, the binding of several of these compounds was subjected to a CoMFA (Comparative Molecular Field Analysis) [39], This program examines electrostatic and steric parameters... 

---