Stereoelectronic features

The form and shape of a molecule (i.e. its steric and geometric features) derive directly from the molecular genotype , but they cannot be observed without a probe. Furthermore, they vary with the conformational, ionization and tautomeric state of the compound. Thus, the computed molecular volume can vary by around 10% as a function of conformation. The same is true of the molecular surface area, whereas the key (i.e. pharmacophoric) intramolecular distances can vary much more. 

A similar argument can be made for electronic features such as electron density, polarization and polarizability. These are critically dependent on the ionization state of the molecule, but the conformahonal state is also highly influential. One highly approximate yet useful reflection of electron density is afforded by the polar surface area (PSA), a measure of the extent of polar (hydrophilic) regions on a molecular surface (see Chapter 5). 

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The stereoelectronic features produce actions at a distance by the agency of the recognition forces they create. These forces are the hydrophobic effect, and the capacity to enter ionic bonds, van der Waals interactions and H-bonding interactions. The most convenient and informative assessment of such recognition forces is afforded by computahon in the form of MIFs, e.g. lipophilicity fields, hydrophobicity fields, molecular electrostatic potentials (MEPs) and H-bonding fields (see Chapter 6) [7-10]. 

Like the stereoelectronic features that generate them, the MIFs are highly sen-sihve to the conformahonal and ionization state of the molecule. However, they in turn have a marked intramolecular influence on the conformahonal and ionization equilibria of the compound. It is the agency of the MIFs that closes the circle of influences from molecular states to stereoelectronic features to MIFs (Fig. 1.3). 

Scheme 9.7 gives examples of each of these types of stereoselectivities. The analysis of any particular system involves determination of the nature of the reactant, e.g., has transmetallation occurred, the coordination capacity of the Lewis acid, and the specific steric and stereoelectronic features of the two reactants. 

One of the factors directing the alkylation of an enolate is the Jt-facial selectivity. The differences in reactivity of the two diastereotopic faces of the enolate, due to steric and electronic features, contribute to the steric control of the alkylation (for extensive reviews, see refs 1, 4, and 30). Likewise, stereoelectronic features are important control elements for C- versus O-alkylation, as illustrated by the cyclization of enolates 1 and 3 via intramolecular nucleophilic substitution 39. 

STEREOELECTRONIC FEATURES OF THE WAGNER-MEERWEIN REARRANGEMENT IN SYNTHESIS... 

Photoisomerization of the 9,10-epoxy-enones (679) and (680) gives abeo-9-ketones. At —65 °C, with n— rr excitation, the reactions take the paths indicated (Scheme 17) but at higher temperatures, or with triplet sensitization, the 9a,10a-epoxide gives a mixture of all three enediones. Further irradiation of the products affords their A -unsaturated isomers. The reaction mechanisms are discussed in terms of stereoelectronic features of the biradicals resulting from initial rupture of the activated C-10—O bond of each epoxide. ... 

Most stereoelectronic effects involve interactions of orbitals at least one of which corresponds to a o-bond. Consequently, they are classified under the umbrella of hyperconjugative interactions. However, also included are n-jt, p-jt, and conjugative effects that display similar stereoelectronic features. 

Another way to use oxygen substitution to decrease the importance of amide resonance is to allow the lone pair of oxygen to compete directly with the lone of pair of nitrogen for donation to the carbonyl acceptor. Such competition between n and n t c=o defines unusual stereoelectronic features of carbamates... 

Stereoelectronic features of vinyl anions are associated with their bent geometries and usual configurational stabilities in solution. Theory predicts a sizable inversion barrier for the parent vinyl anion (28.7kcal/ mol at the MP2/6-31+G(d)//HF/6-31 -nG(d) level). The two conformers of 1-propenyl anion can be formed stereospecifically in the gas phase (via desilylation of E- and Z-l-trimethylsilylpropene) and show different reactivity patterns. ... 

Figure 7.25 Stereoelectronic features associated with the introduction of heteroatoms.

If X is connected with the back lobe of a orbital, it leads to a migration of X to the adjacent atom Z. If X is eliminated, this process leads to a fragmentation. The two reactions share common mechanistic and stereoelectronic features. We will discuss these features below, starting with the eliminations. 

Figure 7.32 Stereoelectronic features of E2 elimination reactions from alkyl and vinyl substrates.

So, where does all of this mechanistic richness come from In the following discussion, we will outline the key stereoelectronic features of phosphate substitution reactions and illustrate how the unique features of anionic oxygen and pyramidal intermediates/transition states explain the abovanentioned idiosyncrasies of this functional group and combine to make the key reactions of biology possible. 

To explain this process, Berkessel and Thauer proposed the mechanism outlined in Figure 11.63. In this proposal, they extended, for the first time, the idea of superelectrophilic activation, a concept that had previously been postulated only under superacidic conditions, into the realm of enzymatic reactions. Furthermore, this mechanism has a number of interesting stereoelectronic features that we will discuss below. 

In summary, this mechanistic hypothesis has a number of stereoelectronic features that are tightly coordinated to create an efficient enzymatic process. Formation of H MPT via removal of the axial C-H is favored by the combined stereoelectronic assistance of the lone pairs of the three nitrogen atoms. However, the fnU power of snch assistance in an enzyme would be counterproductive because it would overstabilize the cationic part of the catalytic cycle. Instead, the enzyme imposes a non-planar conformation where excessive stereoelectronic stabilization is avoided. This system illnstrates an interesting connection between geometry, reactivity and enzymatic fnnction. 

The Bohimann effect is also observed in C-H bonds antiperiplanar to lone pairs in systems where the lone pair containing heteroatom is donbly bonnd to the C-H carbon (i.e. aldehydes, imines, etc.). The additional stereoelectronic feature of imines is the presence of geometric isomers that allow clear distinction between syn- and antiperiplanarity effects (Figure 12.2). The stretching IR frequencies for the C-H bonds antiperiplanar to the nitrogen lone pair are noticeably red-shifted. 

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