Stereoelectronic structure

Pharmacodynamics is concerned with the result of the interaction of drug and body at its site of action, that is, what the drug does to the body. It is now known that a drug is most effective when its shape and electron distribution, that is, its stereoelectronic structure, is complementary to the steroelectronic structure of the active site or receptor. 

For definitions see Section 2.7. The factors affecting the pharmacokinetic phase are ADME. The factor affecting the pharmacodynamic phase is the stereoelectronic structure of the drug molecule. 

Each of these aspects of the field of chemistry is connected through the basic principle of chemical structure, which is a profound physical feature of the molecular world where we live. At its most fundamental, stereoelectronic structure is a quantum-mechanical reality of all molecules, with the intrinsic uncertainty that this reality implies. Thus, perfectly accurate structural descriptions of molecules are both elusive and potentially cumbersome. Instead, chemists have devised an exceptional model of molecular structure by inference. This model has been built over decades between evolving theory and experiments that measure various molecular properties that derive from structure itself. Closely aligned with our intuitive definition of structure , of course, are methods that provide direct information about... 

Hawthorne has introduced the carborane ligands and prepared many metallo-carborane complexes, in particular the dianion rado-carborane C2B9Hn whose frontier orbitals are analogous to those of the cyclopentadienyl (see Wade s rules for the stereoelectronic structure of the carboranes. Chap. 2.2.4). In its neutral form, this ligand is counted as a 4-electron LX2 ligand. 

The reactivity of the sec-BuLi complexes with the like-sparteine diamines has been studied for the reaction of N-Boc pyrolidine with trimethylchlorosilane Scheme 24.23 (Table 24.9) (141). These results indicate that the stereoelectronic structure of the diamine plays an important role in the reaction of carbamates deprotonation. 

The substituent effects in aromatic electrophilic substitution are dominated by resonance effects. In other systems, stereoelectronic effects or steric effects might be more important. Whatever the nature of the substituent effects, the Hammond postulate insists diat structural discussion of transition states in terms of reactants, intermediates, or products is valid only when their structures and energies are similar. 

Most dienones that have been reduced have structures such that they cannot give epimeric products. However, reduction of 17 -hydroxy-7,17a-dimethyl-androsta-4,6-dien-3-one (63) affords 17 -hydroxy-7j9,17a-dimethylandrost-4-en-3-one (64), the thermodynamically most stable product, albeit in only 16% yield. The remainder of the reduction product was not identified. Presumably the same stereoelectronic factors that control protonation of the / -carbon of the allyl carbanion formed from an enone control the stereochemistry of the protonation of the (5-carbon of the dienyl carbanion formed from a linear dienone. The formation of the 7 -methyl compound from compound (63) would be expected on this basis. 

Staudinger concept of polymer structure 1-2 stereoelectronic effects... 

The cis product must be formed through a TS with a twistlike conformation to adhere to the requirements of stereoelectronic control. The fact that this pathway is not disfavored is consistent with other evidence that the TS in enolate alkylations occurs early and reflects primarily the structural features of the reactant, not the product. A late TS would disfavor the formation of the cis isomer because of the strain associated with the nonchair conformation of the product. 

Prediction and analysis of diastereoselectivity are based on steric, stereoelectronic, and complexing interactions in the TS.82 In the case of the lactic acid auxiliary, a chelated structure promotes facial selectivity. In the TiCl4 complex of 0-acryloyl ethyl lactate,... 

Intramolecular reactions can also occur between carbonyl groups and allylic silanes. These reactions frequently show good stereoselectivity. For example, 7 cyclizes primarily to 8 with 4% of 9 as a by-product. The two other possible stereoisomers are not observed.98 The stereoselectivity is attributed to a preference for TS 7A over TS 7B. These are both synclinal structures but differ stereoelectronically. In 7A, the electron flow is approximately anti parallel, whereas in 7B it is skewed. It was suggested that this difference may be the origin of the stereoselectivity. 

From a synthetic point of view, the regioselectivity and stereoselectivity of the cyclization are of paramount importance. As discussed in Section 11.2.3.3 of Part A, the order of preference for cyclization of alkyl radicals is 5-exo > 6-endo 6-exo > 7-endo S-endo > 1-exo because of stereoelectronic preferences. For relatively rigid cyclic structures, proximity and alignment factors determined by the specific geometry of the ring system are of major importance. Theoretical analysis of radical addition indicates that the major interaction of the attacking radical is with the alkene LUMO.321 The preferred direction of attack is not perpendicular to the it system, but rather at an angle of about 110°. 

A further test of the stereoelectronic theory of reactivity of phosphate esters has been attempted using measurements of the rates of displacement of 4-nitrophenate from the esters (23) and (24), their phosphorus epimers, and also (25), in aqueous methanol the introduction of the 4a-Me group into the system would, it was hoped, reduce the the flexibility of the bicyclic structures and so possibly eliminate the participation of twist-boat conformations. The presence of the 4a-Me group has no effect of the rate of displacement of the axial ArO group... 

This affinity for metals results not only from the structural organization of the new diacids but from stereoelectronic effects at carboxyl oxygen as well. The in-plane lone pairs of a carboxylate 18 differ in basicity by several orders of magnitude 16). Conventional chelating agents17> derived from carboxylic acids such as EDTA, 19a are constrained by their shape to involve the less basic anti lone pairs [Eq. (4)]. The new diacids are permitted the use of the more basic syn lone pairs in contact with the metal 19b. These systems represent a new type of chelate for highly selective recognition of divalent ions. 

Stereoelectronic effects in chemical reactivity The bond-lengthening and -weakening influence of an antiperiplanar lone pair leads to strong stereoelectronic effects on chemical reactivity.97 In molecule 28a with lone-pair-bearing atom D adjacent to an A—B bond, a vicinal nD—s-cab hyperconjugative interaction can be associated (cf. Example 1.4 and Section 3.3.1) with a partial admixture of the alternative resonance structure 28b,... 

The importance of specific orbital alignments in the TB propagation of remote stereoelectronic influences can be assessed directly by structure-sensitive spectroscopic techniques. The results of many such studies have been summarized as various effects or rules that express the dependence on geometrical factors, such as the all-trans zig-zag or W pattern of skeletal bridge bonds. Such a W-effect 105... 

---