Steric considerations

These insights, incomplete as they must be, are more difficult to attain mathematically, and often hard to visualize when expressed numerically as the coefficients of unfamiliar descriptors. A remedy which the bench chemist can take is to synthesize analogues of the most active drug, each analogue equipped with a bulky substituent inserted in a different place. The biological tests then give information about the space available around each position in the molecule. Many have attempted this approach, but it is tedious. Hence the frequent endeavours to find short cuts to the goal by calculation. A selection of these methods will now be reviewed. 

The chlorinated cyclodiene insecticides act in a biologically different way from the DDT—pyrethrin group of insecticides and have different steric requirements. Soloway (1965) examined 106 cyclodienes and concluded that, for high activity, they should be nearly spherical. Proceeding to detail, he projected a model of aldrin on to a plane and obtained the outline of a highly modulated circle. Molecules which could just traverse through an aperture of these dimensions, see 6.47), scored well as insecticides. In addition, the presence of two electron-attracting substituents (usually chlorine atoms) was necessary. 

Balaban s group in Romania devised three methods for relating a drug to its receptor from consideration of volume relationships. The methods are known briefly as MSD, MTD, and MCD, arranged in order of increasing complexity. 

Several Taft values can be used in one regression equation, as was done by Kutter and Hansch (1969) who studied the preventive effect of substituted benzoic acids on the combination of ovalbumin antigen with its antibody, each benzoic acid being incorporated as a hapten in the antigen. They obtained this multiple regression equation  

In this equation, there is a term for each of the three positions of substitution, and it is evident that the ortho and para positions are the most significant. Little benefit was obtained by adding a log F or a Hammett term, yet the index of correlation (r) is excellent. 

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The interaction between ions of the same sign is assumed to be a pure hard sphere repulsion for r < a. It follows from simple steric considerations that an exact solution will predict dimerization only if i < a/2, but polymerization may occur for o/2 < L = o. However, an approximate solution may not reveal the fiill extent of polymerization that occurs in a more accurate or exact theory. Cummings and Stell [ ] used the model to study chemical association of uncharged atoms. It is closely related to the model for adliesive hard spheres studied by Baxter [70]. 

Resonance, polarity, and steric considerations are all believed to play an important role in copolymerization chemistry, just as in other areas of organic chemistry. Things are obviously simphfied if only one of these is considered but it must be remembered that doing this necessarily reveals only one facet of the problem. Nevertheless, there are times, particularly before launching an experimental investigation of a new system, when some guidelines are very useful. The following example illustrates this point. 

The addition of P—H bonds across a carbonyl function leads to the formation of a-hydroxy-substituted phosphines. The reaction is acid-cataly2ed and appears to be quite general with complete reaction of each P—H bond if linear aUphatic aldehydes are used. Steric considerations may limit the product to primary or secondary phosphines. In the case of formaldehyde, the quaternary phosphonium salt [124-64-1] is obtained. 

Now let s consider the effect of the substrate on the rate of an E2 process. Recall from the previous chapter that Sn2 reactions generally do not occur with tertiary substrates, because of steric considerations. But E2 reactions are different than Sn2 reactions, and in fact, tertiary substrates often undergo E2 reactions quite rapidly. To explain why tertiary substrates will undergo E2 but not Sn2 reactions, we must recognize that the key difference between substitution and elimination is the role played by the reagent. In a substitution reaction, the reagent functions as a nucleophile and attacks an electrophilic position. In an elimination reaction, the reagent functions as a base and removes a proton, which is easily achieved even with a tertiary substrate. In fact, tertiary substrates react even more rapidly than primary substrates. 

These investigators also observed that cleavage of the carbon-sulfur bond of aryl sulfones, a very difficult process to carry out by other means, proceeds smoothly at a mercury electrode even with sterically hindered sulfones, although the direction of cleavage of the latter appears to be governed by steric considerations, e.g. 11 >,... 

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