Steric parameters difference

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. 

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 ... 

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. 

It is found in practice that the value of the steric parameter, Eg, for a particular group, R, differs to some extent from one reaction to another. This is not altogether surprising as both the local environment of R and the size of the attacking reagent will vary from one reaction to another. It means, however, that on incorporating Es into the Hammett type equation, [12], it is necessary to introduce a yet further parameter, 8, as a measure of a particular reaction s... 

With aquated Pt(II) compounds, numerous studies have revealed the kinetic preference of the 6-oxopurine N7 site [15,35]. In addition to the favorable electrostatic potential mentioned above [23] also steric factors seem to favor coordination to the guanine N7 site, in particular [36]. Estimated relative steric parameters (in parenthesis) suggest that the guanine N7 (1.00) and hypoxanthine N7 (1.03) atoms are the least sterically hindered binding sites in alkylated nucleobases, followed by the adenine N7 (1.17) and deprotonated hypoxanthine N1 (1.17) sites and the deprotonated N3 atoms of the different pyrimidine bases (1.39 for U, 1.44 for T, and 1.56 for C), while the adenine N1 (1.58) and... 

To verify such a steric effect a quantitative structure-property relationship study (QSPR) on a series of distinct solute-selector pairs, namely various DNB-amino acid/quinine carbamate CSPpairs with different carbamate residues (Rso) and distinct amino acid residues (Rsa), has been set up [59], To provide a quantitative measure of the effect of the steric bulkiness on the separation factors within this solute-selector series, a-values were correlated by multiple linear and nonlinear regression analysis with the Taft s steric parameter Es that represents a quantitative estimation of the steric bulkiness of a substituent (Note s,sa indicates the independent variable describing the bulkiness of the amino acid residue and i s.so that of the carbamate residue). For example, the steric bulkiness increases in the order methyl < ethyl < n-propyl < n-butyl < i-propyl < cyclohexyl < -butyl < iec.-butyl < t-butyl < 1-adamantyl < phenyl < trityl and simultaneously, the s drops from -1.24 to -6.03. In other words, the smaller the Es, the more bulky is the substituent. The obtained QSPR equation reads as follows ... 

Topological Parameterization of Sterle Effects We have noted that different rv based steric parameters will be required for conformatlonally dependent groups in order to account for phenomena with different ster-ic requirements This must result in a multiplicity of steric parameters for different types of phenomena ... 

STERIMOL and MTD (Minimum Topological Difference) steric parameters to account for steric influences in QSAR of pesticides have been described and applied in the literature. We have recently developed an improved version of the Simon MTD method, i.e. MTD parameters. The MTD and MTD methods will be described. The scope and limitations of the STERIMOL,... 

On the condition that two subsets have a structural feature whose parameterization is essentially the same, they can be combined into a single data set. As an example consider set 0X13, anfi-Ak—iyw-X—C=NOH, where Ak is either Me or Et. The electrical effects of these groups for Me and Et, respectively, are a , —.01, —,Q ad, —.14, —.12 ae, —.030, —. 036 the values of the steric parameter v are. 52 and. 56. A significant difference is found only in the polarizability parameter a, where the values for Me and Et are. 046 and. 093, respectively. Combination of oxime pXa values for Ak = Me or Et results in set 0X13 the best correlation was with the LDR equation. As only three substituent types are present in this data set and is 0.33, this data set cannot be considered as proof of anything. The only acceptable conclusion is that it is in accord with the combination of the two subsets. 

In the second step the bas is recognized by the receptor site and the bas-rep complex forms. As was noted above, the complex is generally bonded by inter-molecular forces. The bas is transferred from an aqueous phase to the receptor site. The receptor site is very much more hydrophobic than is the aqueous phase. It follows, then, that complex formation depends on the difference in intermolecular forces between the bas-aqueous phase and the bas-receptor site. The importance of a good fit between bas and receptor site has been known for many years. The configuration and conformation of the bas can be of enormous importance. Also important is the nature of the receptor. If the receptor is. a cleft, as is the case in some enzymes, steric effects may be maximal as it may not be possible for a substituent to relieve steric strain by rotating into a more favorable conformation. In such a system, more than one steric parameter will very likely be required in order to account for steric effects in different directions. Alternatively, the receptor may resemble a bowl, or a shallow, fairly flat-bottomed dish. Conceivably it may also be a mound. In a bowl or dish, steric effects are likely to be very different from those in a cleft. Possible examples are shown in Fig. 1, 2, and 3. 

We have remarked above that the Taft Es values suffered from a number of deficiencies. In fact, the only direct evidence that they were a measure of steric effects was their successful correlation with rv values, a correlation limited to symmetrical top tetrahedral substituents such as CH3 and CF3 and to H. The evidence presented above indicates that rv values are a useful measure of steric effects and suggested that they might be used directly as steric parameters in correlation analysis. They were so used by Charton 6,n,13,14). They did meet the first and third criteria for steric parameters in full and the fourth in part. They did not meet the second, fifth and sixth, however. The Taft Es values met the first criteria only if it could be assumed that the use by Taft of average values of data obtained under different experimental conditions was valid. Our results indicate that this is not the case. Es values did meet the third condition, but were unable to meet the other criteria. It seemed more reasonable to base a set of steric parameters on the van der Waals radii than to do so upon Es values and to attempt to remove their deficiencies. By defining a set of steric parameters, designated values, from the equation... 

A different procedure was required for the definition of steric parameters of OZ, SZ, and NZ Z2 groups as no MCD or NCD groups were available to make possible the use of the method used above. Following the treatment of Charton M), we may write any group X in the form M2Z where M1 is that atom of the group X which is bonded to the skeletal group G, and Z is the remainder of X. Then we assume that the steric parameter ux is given by the equation... 

The variation in activity is governed mainly by the steric effect of substituents within the compounds examined in both series. However, the mode of interactions seems to be different, as revealed by the different steric parameters incorporated. The significance of the Arw in Eq. 52 may be that the meso-substituents interact in such a manner that they come into contact with the receptor surface of walls, whereas that of the AVW in Eq. 53 may indicate the importance or fitting into a cavity or pocket on the receptor surface in the region where the (//-substituents direct. The AVW value for C1(0.0) is nearest to the optimum steric condition (AVW 2 —0.24) calculated from Eq. 53. Thus, (//-Cl substituents in lindane are thought to be those which best fit the receptor cavity among the (//-substituents. 

In a similar fashion, Shirai et al. constructed a modified Taft correlation for the hydrolysis of a series of triaikylalkoxysilanes of R,SiOR structures (in which R was varied to include different alkyl groups) in 55% aqueous acetone using a similar extraction/quenching technique [35]. The resulting modified Taft equation was log(fcHO//cHO ) = 1.50 silane esters and the reaction conditions were very different for the Pohl and Shirai studies, the values of p and s were quite similar, (p and a are empirically derived coefficients for the polar parameter and the steric parameter, respectively.)... 

Now that the steric parameter can be evaluated, the inductive parameter is available. Taft noted that the transition-state structures for acid- and base-catalyzed hydrolysis of esters (15 and 16, respectively) differ from each other by only tiny protons. Therefore the steric effect of a substituent should be approx-... 

Hammett s success in treating the electronic effect of substituents on the equilibria rates of organic reactions led Taft to apply the same principles to steric, inductive, and resonance effects. The Hammett o constants appear to be made up primarily of two electronic vectors field-inductive effect and resonance effect. For substituents on saturated systems, such as aliphatic compounds, the resonance effect is rarely a factor, so the o form the benzoic acid systems is not applicable. Taft extended Hammett s idea to aliphatics by introducing a steric parameter ( .). He assumed that for the hydrolysis of esters, steric and resonance effects will be the same whether the hydrolysis is catalyzed by acid or base. Rate differences would be caused only by the field-inductive effects of R and R in esters of the general formula (XCOOR), where X is the substituent being evaluated and R is held constant. Field effects of substituents X could be determined by measuring the rates of acid and base catalysis of a series XCOOR. From these rate constants, a value a could be determined by Equation (5.9) ... 

Taft s o has nearly the same meaning as Hammett s c (with different numerical values), Es is the steric parameter for substituent X, and 8 is a measure of the sensitivity of the reaction to changes in steric properties near the reaction center (similar to p). Extensive compilations of values of o, o and Es appear in Perrin et al. (1981) and McPhee et al. (1978), respectively. 

Predicting Hydrolysis Rate Difference Based on Substituents Sizes PROBLEM Based on Taft steric parameters, how much faster than ethyl acetate would you expect ethyl formate to hydrolyze ... 

Equation 12.22 correlates both the Hammett constant ( -, ) and the Taft steric parameter (Es) of the R-group to the experimental activity of the molecule (log I//50). As with the other examples, the requisite activity and parameter values must be entered into a spreadsheet. The only significant difference in this example is that the Jt-values argument for LINEST must include two columns of data (Figure B.7). One includes the Hammett constant data, and the other is for the Taft steric parameter. 

The chiral discrimination found in the minima and TS structures of these dimers are gathered in Table 3.3. Herein, no clear tendency was observed with a relatively large number of homochiral dimers (R,R or SS) being more stable than its corresponding heterochiral ones. Attempts to explain these results based on secondary interactions using the AIM methodology resulted in poor correlations with steric parameters such as Taft s Es, an indication that a more complex mechanism controls these energetic differences. 

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