Steric effects correlation equations

Set 0X14, l-oximino-3-X-5-methyl-l,2-benzoquinones, is of interest because the substituents in this data set do not differ significantly from each other in electrical effects. As chemical reactivities in water normally do not depend on polarizability, it would seem that the variations in pXa in this data set should be a function of steric effects. Correlation with the two parameter segmental steric effect equation gave best fit with the v/ parameters. The correlation is significant at the 99.0% confidence level and is good. It seems probable that the pXa values of these compounds are dependent on steric effects. 

The carbonyl stretching frequencies in the ir spectra of cis-3-substituted methyl acrylates (set 12-18) were also correlated with eq. (24) and eq. (2). Barely significant correlations were obtained with both equations. The value of i// obtained in the correlation with eq. (24) was not significant. We may therefore probably exclude cases (a) and (b). As the hcaic is not significantly different from hobs > we may exclude case (c). This set is therefore probably an example of case (d) that is, there is no meaningful steric effect. 

The best fits to the linear equation 8, for temperature differentials (from equation 7) versus reactant state steric effects, are obtained for reaction 4 (Table III). A modest correlation for equation 8 is obtained for reaction 1. Essentially no fit to equation 8 is found for reactions 2 and 3 (small correlation coefficients and small N slopes). 

In its original form the Hammett equation was appropriate for use with para and meta substituted compounds where the reaction site is separated from the aromatic group by a nonconjugating side chain. Although there have been several extensions and modifications that permit the use of the Hammett equation beyond these limitations, it is not appropriate for use with ortho substituted compounds, since steric effects are likely to be significant with such species. The results obtained using free radical reactions are often poor, and the correlation is more appropriate for use with ionic reactions. For a detailed discussion of the Hammett equation and its extensions, consult the texts by Hammett (37), Amis and Hinton (12), and Johnson (47). 

The choice of correlation equations. In choosing a correlation equation there are several factors that must be considered. They include the number of data points in the set to be studied, the experimental conditions, the type of data to be correlated and the possibility of steric effects. 

These methods of modelling steric effects will be discussed in detail in Section III of this work. With the exception of the correlation of a for the Si(OAk)MePh groups with equation 22, all of the results were significant. The data sets were small but the overall trend seems clear there is generally a dependence on steric effects for these substituent constants. We have therefore generally excluded the values determined by this method from the tables of substituent constants given in this work. Exceptions have been made in a few cases for groups for which values have not been determined by any other methods. 

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 ... 

A similar system, (CH3)2C=CH X, was studied by Endrysova and Kraus (55) in the gas phase in order to eliminate the possible leveling influence of a solvent. The rate data were separated in the contribution of the rate constant and of the adsorption coefficient, but both parameters showed no influence of the X substituents (series 61). A definitive answer to the problem has been published by Kieboom and van Bekum (59), who measured the hydrogenation rate of substituted 2-phenyl-3-methyl-2-butenes and substituted 3,4-dihydro-1,2-dimethylnaphtalenes on palladium in basic, neutral, and acidic media (series 62 and 63). These compounds enabled them to correlate the rate data by means of the Hammett equation and thus eliminate the troublesome steric effects. Using a series of substituents with large differences in polarity, they found relatively small electronic effects on both the rate constant and adsorption coefficient. 

As only the localized electrical effect and a possible steric effect need be considered in this data set, the AH values for the alcohols were correlated with equation 26 ... 

Due to the small size of this data set no reliance can be placed on these results. We have carried out the correlation only to illustrate the method. In an earlier paper Arnett and Moe reported AH prin for the deprotonation of i-PrOH by lithium A-alkyl and N,N-diaUcyl amides, and by lithium alkyls (sets CR3 and CR4, Table 9). As the electrical effects of alkyl groups are constant within experimental error, only the number of alkyl groups, their steric effects and their polarizabilities can be variables. Values of AH pm for the amides were correlated with equation 28 ... 

Haloform reaction, 237, 296 Halogenation alkanes, 300, 323 alkenes, 179,186, 313 benzene, 138,316 ketones, 295 Hammett equation, 362 additional parameters, 374, 388, 395 derivation of, 362 deviations from, 375 empirical nature of, 395 implications of, 394 reaction pathway, and, 375 solvent effects and, 388 spectroscopic correlations, 392 standard reaction for, 362, 395 steric effects and, 361, 383 thermodynamic implications of, 394 Hammett plots, 359 change in rate-limiting step and, 383 change in reaction pathway and, 378... 

In a parallel development, structural effects on the chemical reactivity and physical properties of organic compounds were modelled quantitatively by the Hammett equation 8). The topic is well reviewed by Shorter 9>. Hansen 10) attempted to apply the Hammett equation to biological activities, while Zahradnik U) suggested an analogous equation applicable to biological activities. The major step forward is due to the work of Hansch and Fujita12), who showed that a correlation equation which accounted for both electrical and hydrophobic effects could successfully model bioactivities. In later work, steric parameters were included 13). 

Our objective in this work is to present surveys of the methods now available for the quantitative treatment of steric effects in the design of bioactive molecules. Commonly, this consists in the modification of a lead compound by structural changes which result in a set of bioactive substances. The bioactivity is determined and then related to structure. This is generally carried out by means of multiple linear regression analysis using a correlation equation of the type... 

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... 

In order to include an group in a data set in which the substituents exhibit an steric effect it is necessary to know 0 so that the appropriate values of the delocalized electrical effect parameter, ctd and the steric parameter can be used. Values of 0 are usually unavailable. A method has been developed to circumvent this difficulty for chemical reactivities. The procedure is 1) A basis set, which contains only those members of the data set that show minimal dependence of their steric effect on conformation, is correlated with the LDS equation,... 

We have noted above that if steric effects are to be successfully separated from other substituent effects, it is vital that steric parameters show a minimal dependence on electrical effect parameters or transport parameters. Unger and Hansch 30) have reported that Es values of CH2X groups are significantly dependent on electrical effects. To resolve this question for the uef values we have carried out correlations of the u(CH2) Z values with the equation... 

The stetic parameter accounts for steric effects on the solvation of a-amino and carboxyl groups caused by the side chain. We have not attempted to account for any charge transfer interactions as none of the compounds studied is a very effective charge transfer acceptor, and the water and n-octanol phases can only function as change transfer donors. Further support is provided by the correlation of log P values for Ph(CH2)mX (m = 1, 2, 3) with the equation... 

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