Taft’s steric factor

Attempts have been made to quantify the steric features of substituents by using Taft s steric factor (Es). The value for Es can be obtained as described in Section 9.3.2. However, the number of substituents which can be studied by this method is restricted. 

The stereochemistry of a-alkylation of ester (63) seems to be governed not simply by a steric bulkiness of substituent R, but by stereochemically oriented attack of electrophiles to the chelated intermediates (64). The less bulky fluoromethyl compound provided higher stereoselectivity than did the isopropyl analogue, in spite of the smaller Taft s steric factor of the CH2F group (Scheme 3.13) [28]. It can be seen from Table 3.5 that one fluorine in substituent R is good enough to control the stereochemistry for the a-alkylation. 

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. 

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 most popular of these approaches is multiple regression analysis, introduced by Hansch in 1968. In this method, the most favoured variables are (i) partition coefficients (P), from the system octanol/water (ii) the sigma (cr) and rho (p) values derived from Hammett s Linear Free Energy Equation (Section 17.2) and (iii) Taft s steric factors E ) which are used to determine what space for substituents exists between a nominated small region of the lead molecule and its receptor (Section 16.2). These variables are correlated in the following equation ... 

The sigma values of or fc-substituents present problems similar to those of />am-substituents plus, very often, those introduced by steric distortion and by hydrogen-bonding. The most determined attack on this multifactorial problem was made by Fujita and Nishioka (1975) who set (Tq as equal to dp, plus a fraction of the Swain and Lupton field constant (to deal with the greater proximity), plus a fraction of Taft s steric factor see p. 627). When hydro-... 

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 ... 

FIGURE 1.11 Systematic optimization of structural binding and stereorecognition increments of amino acid side chain (Rsa) carbamate residue (Rso)- Dependency of separation factors on the steric bulkiness of amino acid and carbamate residues as quantified by their corresponding Taft s steric parameters Es sa Eg so- (1) ionic interaction (2) jr-jr-interaction (3) hydrogen bonding (4) steric interaction. (Reproduced from M. Lammerhofer et al., J. Sep. ScL, 29 1486 (2006). With permission.)... 

A comparison of these scales with Taft s induction constants a and Taft s steric constants for different alkyl groups leads to the conclusion that both electronic and steric factors influence the doublebond activity in stereospecific catalysis but that steric factors seem to be more important. An especially significant decrease in the olefin activity was found for olefins branched vicinally to the double bond (3-methyl-pentene-1,3-methylbutene-l, vinylcyclohexane, styrene). This is protebly connected with the space limitations for monomer coordination in the stereospecific active sites (IS, 16). 

Finally, in this account of multiparameter extensions of the Hammett equation, we comment briefly on the origins of the a, scale. This had its beginning around 1956 in the a scale of Roberts and Moreland for substituents X in the reactions of 4-X-bicyclo[2.2.2]octane-l derivatives. However, at that time few values of o were available. A more practical basis for a scale of inductive substituent constants lay in the o values for XCHj groups derived from Taft s analysis of the reactivities of aliphatic esters into polar, steric and resonance effects . For the few o values available it was shown that o for X was related to o for XCHj by the equation o = 0.45 <7. Thereafter the factor 0.45 was used to calculate c, values of X from o values of XCH2 . ... 

Decisive role of the VM factor during the adsorption process of the solvents by coal is in agreement with the determined in the work [25] proportionality for the alcohols between Igk and steric factor Es of the Hammet-Taft s equation. 

The major electronic factor influencing the activity has been Hammett s constant a. In some cases, the steric factors were also found to be important, e.g., Bs the Sterimol parameter for the largest width of substituents and L the Sterimol parameter for the length of the substituents. The positive coef-Acients of these parameters give an important positive contribution of width and length of substituents to the inhibition. The values of Taft steric param-... 

The factor 2.48 puts a on the same scale as Hammett s er, and the k0 values are rate constants for acid and base hydrolysis of acetic acid esters (i.e., R is a methyl group in the reference compound). Usually R is an ethyl or methyl group, but in many cases the rate constants do not depend on the nature of R. Equation 8 is based on the fact that acid hydrolysis rates of substituted benzoic acid esters are only slightly affected by the nature of the substituent, but acid hydrolysis rates of aliphatic esters are strongly affected by substituents. These effects were taken to be caused by steric factors thus log(/c//c0)acid defines s. It is reasonable to assume that steric factors affect base-catalyzed rates in the same way. Substituent effects on base hydrolysis of aliphatic compounds are composed of both polar and steric effects, and subtraction of the latter yields a measure of the former. The parameter a is important because it allows one to evaluate substituent effects on aliphatic reaction rates by a formula analogous to the Hammett equation, or by a bivariate relationship, the Taft-Pavelich equation (Pavelich and Taft, 1957) ... 

Since the lipophilic character was found important for physiological dispositions of barbiturates, several workers investigated the relationship between partition coefficient and structural parameters (Taft s polar and steric substituents constants, number of C-atoms) of these compounds.548,549 Partitioning of barbiturates was also proved to be a significant factor for their... 

Application of the multipaxaineter extrathexmodynamic technique to this series, where and R were alkyl groups, reveeded a good relationship between the A inhibitory pot cy (isorelative activity to DSG) and the substitu t partition constant (rr) and Taft steric factor (Es) in the position (equation 1, where the figures in parentheses are we Student t vedues for the coefficients of the equation and n, r, s, F and p have their usual statistical meaning). 

A new structure-activity relationship, Xjj =yS+l, where y is a negative constant, S is the total steric effect, and 4 is the total inductive effect, correlated strongly with available measurements of ozonolysis. New rate coefficients were measured for ozonolysis of a number of unsaturated heteroatomic compounds and it has been emphasized that the inductive effect rather than the steric effect is important in predicting their reactivity %, the inductive effect index, was compared with the Taft a constant and rates of reaction of hydroxyl radical with a given species it correlated strongly in both cases (which should be unaffected by steric factors) suggesting a universal response by olefinic species towards electrophilic addition. ... 

X-xan = 0-substituted xanthate) in benzene at 25°C. This reaction represents the addition of a bidentate ligand to give an octahedral complex. The latter presumably has the cis configuration so a substitution process is involved in the reaction. Values of kf and K are dependent upon the nature of the substituent X, as are the equilibrium constants (calculated from kfikr as they are too large to be measured directly with accuracy). For the reaction in which X = cyclohexyl the activation parameters are A/// = 5.4 0.6 kcal mol = 24 1 kcal mol-, Sf = -21 4 cal K mol and A5f = 26 3 cal K" moF. These values reflect the nature of the processes involved and are similar to values found for analogous reactions of Ni(II) substrates when steric factors were absent. The substituent effects are discussed in terms of Taft s a parameters. Reactions... 

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