Steric relationships between molecular fragments

Molecular fragments, like whole molecules, may display steric relationships, as pioneered by Hanson [20] and Mislow [18]. When such fragments are considered in isolation, namely separated from the remainder of the molecule, morphic relationships arise. When the partial structures are considered in an intact molecule or in different intact molecules, one speaks of topic relationships. 

A scheme analogous to the upper part of Fig. 2 has been presented for topic and morphic relationships [18,20], Thus, fragments of the same atomic composition may be homotopic or heterotopic, depending on whether they are superimposable or not. If the latter have the same constitution, they are stereoheterotopic, in the other case they are constitutionally heterotopic. Stereoheterotopic fragments are enantiotopic or diastereotopic. Morphic analysis yields the corresponding classification (see [19]). 

Topic relationships are of fundamental importance when considering prostereoisomerism, and they will be discussed again and illustrated in this context (see Section 7). 

Pyramidal tricoordinate and tetrahedral tetracoordinate centers are centers of chirality when all substituents of the central atom are different. In contrast, penta- and hexacoordinate centers generate far more complex situations and may be elements of diastereoisomerism as well as enantiomerism. Selected cases will be considered. 

A tricoordinate center where the central atom is coplanar with the three substituents (Va) is obviously not chiral, since a plane of symmetry exists in the molecule. 

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Lipophilicity in particular, as reflected in partition coefficients between aqueous and non-aqueous media most commonly water (or aqueous buffer) and Z-octanol,has received much attention [105,141,152,153,176,199,232,233]. Logic )W for the octanol-water system has been shown to be approximately additive and constitutive, and hence, schemes for its a priori calculation from molecular structure have been devised using either substituent tt values or substructural fragment constants [289, 299]. The approximate nature of any partition coefficient has been frequently emphasized and, indeed, some of the structural features that cause unreliability have been identified and accommodated. Other complications such as steric effects, conformational effects, and substitution at the active positions of hetero-aromatic rings have been observed but cannot as yet be accounted for completely and systematically. Theoretical statistical and topological methods to approach some of these problems have been reported [116-119,175,289,300]. The observations of linear relationships among partition coefficients between water and various organic solvents have been extended and qualified to include other dose-response relationships [120-122,160,161,299-302]. 

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