Steric effects quantitative treatments

The quantitative treatment of the electron-transfer paradigm in Scheme l by FERET (equation (104)) is restricted to the comparative study of a series of structurally related donors (or acceptors). Under these conditions, the reactivity differences due to electronic properties inherent to the donor (or acceptor) are the dominant factors in the charge-transfer assessment, and any differences due to steric effects are considered minor. Such a situation is sufficient to demonstrate the viability of the electron-transfer paradigm to a specific type of donor acceptor behavior (e.g. aromatic substitution, olefin addition, etc.). However, a more general consideration requires that any steric effect be directly addressed. 

The quantitative effects of steric encumbrance on the electron-transfer kinetics reinforce the notion that the inner-sphere character of the contact ion pair D+, A- is critical to the electron-transfer paradigm in Scheme 1. Charge-transfer bonding as established in the encounter complex (see above) is doubtless an important consideration in the quantitative treatment of the energetics. None the less, the successful application of the electron-transfer paradigm to the... 

The old and lasting problem of heterogeneous catalysis, the mechanism of alkene hydrogenation, has also been approached from the viewpoint of structure effects on rate. In 1925, Lebedev and co-workers (80) had already noted that the velocity of the hydrogenation of the C=C bond decreases with the number of substituents on both carbon atoms. The same conclusion can be drawn from the narrower series of alkenes studied by Schuster (8J) (series 52 in Table IV). Recently authors have tried to analyze this influence of substituents in a more detailed way, in order to find out whether the change in rate is caused by polar or steric effects and whether the substituents affect mostly the adsorptivity of the unsaturated compounds or the reaetivity of the adsorbed species. Linear relationships have been used for quantitative treatment. 

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... 

The anomeric effect dominates the conformational preference, but quantitative conformational predictions by presently described methods, based on additive treatments of steric effects taken in conjunction with the anomeric effect, do not accord with the observed data. 

The methyl group is the smallest polyhedral substituent which can interact with its neighbors. Its intimate behavior is of primary importance for the quantitative treatment of steric effects, since it is often taken (as a combined atom) as a reference for the size of alkyl groups (Section II). The conformational aspect of the steric size of a methyl and its ability to induce conformational changes was clearly evident in the study of various poly-methylisopropylpyridines or -pyridinium salts 81a-e (83T4209) (Scheme 63). 

There has been a decisive evolution in the treatment of steric effects in heteroaromatic chemistry. The quantitative estimation of the role of steric strain in reactivity was first made mostly with the help of linear free energy relationships. This method remains easy and helpful, but the basic observation is that the description of a substituent by only one parameter, whatever its empirical or geometrical origin, will describe the total bulk of the substituent and not its conformationally dependent shape. A better knowledge of static and dynamic stereochemistry has helped greatly in understanding not only intramolecular but also intermolecular steric effects associated with rates and equilibria. Quantum and molecular mechanics calculations will certainly be used in the future to a greater extent. 

The longest chapter of this volume, authored by Roger Gallo and Christian Roussel (France) and Ulf Berg (Sweden), gives a comprehensive account of the quantitative treatment of steric effects in heteroaromatic compounds—a subject that has been advanced significantly by these authors. Finally, V. N. Charushin and O. N. Chupakhin (USSR) and H. C. van der Plas (The Netherlands) review reactions of azines with bifunctional nucleophiles. 

For reviews of quantitative treatments of steric effects, see Gallo, R. Roussel, C. Berg, U. Adv. 

M. Charton, The Quantitative Treatment of the Ortho Effect, Progr. Phys. Org. Chem., 1971, 8, 235 M. Charton, Steric Effects. 1. Esterification and Acid-catalysed Hydrolysis of Esters, J. Am. Chem. Soc., 1975,97, 1552. 

Fig. 8-1) have done, therefore, is to show that this is indeed an entirely appropriate qualitative description. The HMO-treatment has, however, done more than this—it has given us some magnitudes, some quantitative information. It has also rationalised the empirical observation that attack by an N02 -ion to form a nitroaniline takes place preferentially in the ortho- and para-positions—in other words, that the —NH2 group is ortho/para-directing in an electrophilic reaction. (In addition to these electronic influences, there will of course also be some steric effects in the ortho-position but we are not considering these for the present they may be brought into the discussion as a separate consideration later on ( 8.2)). 

Analysis of the 6-parameter for alkyl substituents in reactivity correlation data suggests its possible utility in quantitative treatment of steric effects in organic reactions (see, for example, the results in Table 15.3). 

The classical treatment for the quantitative determination of the steric effects operative in molecules was developed by Westheimer. Steric effects were considered as the sum of various independent strain producing mechanisms (bond strain, angle strain, torsional strain, non-bonded interaction strain). Westheimer s assumptions proved to be the fundamental basis for the BIGSTRN program as well as for all subsequent molecular mechanics treatments of neutral hydrocarbons and carbocations. Reactivities ranging over 10 ° could be correlated by the strain differences between cation and the neutral precursor. Gleicher and Schleyer s work was a historical breakthrough in the development of molecular mechanics and provided the basis for the predictions of rate constants of solvolysis reactions. For the first time chemical reactions could reliably be predicted by the means of computational chemistry. 

As a second example, we have determined the influence of solvation on the steric retardation of SN2 reactions of chloride with ethyl and neopentyl chlorides in water, which has recently been studied by Vayner and coworkers [91]. In their study solvent effects were examined by means of QM-MM Monte Carlo simulations as well as with the CPCM model. Solvation causes a large increase in the activation energies of these reactions, but has a very small differential effect on the ethyl and neopentyl substrates. Nevertheless, a quantitative difference was found between the stability of the transition states determined using discrete and continuum treatments of solvation, since the activation free energies for ethyl chloride and neopentyl chloride amount to 23.9 and 30.4kcalmoF1 according to MC-FEP simulations, but to 38.4 and 47.6 kcal moF1 from CPCM computations. 

---