Stereoelectronic effect

[2] Phrased differently, stereoelectronic effects can also be defined as the geometric constraints placed on the ground and/or transition states of molecules that arise from considerations of orbital overlap.

[3] Thus, a stereoelectronic effect explains a particular molecular property or reactivity by invoking stabilizing or destabilizing interactions that depend on the relative orientations of electrons (bonding or non-bonding) in space.

In spite of the relatively straightforward premises, stereoelectronic effects often provide explanations for counterintuitive or surprising observations.

As a result, stereoelectronic factors are now commonly considered and exploited in the development of new organic methodology and in the synthesis of complex targets.

The scrutiny of stereoelectronic effects has also entered the realms of biochemistry and pharmaceutical chemistry in recent years.

A stereoelectronic effect generally involves a stabilizing donor-acceptor (i.e., filled bonding-empty antibonding, 2-electron 2-orbital) interaction.

Whenever possible, if this stereoelectronic effect is to be favored, the donor-acceptor orbitals should have (1) a small energy gap and (2) be geometrically well disposed for interaction.

When moving from fluorine to chlorine, then to bromine, the electronegativity of the halogen and the energy level of the σ*(C–X) orbitals decreases.

at the β-position of carbocation, the positive charge could be stabilized which is also due largely to the stereoelectronic effect (illustrated below using –SiR3 as an example).

For example, in HIF-α subunit fragments containing (2S,4R)-4-hydroxyproline, the gauche interaction favors the conformer that can bind to the active site of pVHL.

Generally, the substitution of hydrogen by fluorine could be regarded as a way to tune both the hydrophobicity and the metabolic stability of a drug candidate.

[11] Although the energy difference between coplanar anisole and its isomer is quite large, the rotation between the O–CH3 bond becomes favorable when the electronic properties of methoxy group on aromatic rings need to be altered to stabilize an unusual intermediate or a transition state.

This in turn results in the lone pair antiperiplanar to the 4-methoxyphenyl binding preferentially to the catalyst, leading to well-defined facial selectivity.

The stereoelectronic effect that affect the equilibrium is the interaction between the delocalized “banana bonds” and the empty p orbital on the boron atom.

In another case, the stereoelectronic effect can result in an increased contribution of one resonance structure over another, which leads to further consequences in reactivity.

[16] The C2-C3 double bond also selectively undergoes Diels–Alder reaction with cyclopentadiene, despite the increased steric hindrance on that side of the molecule.

The authors argue that the donation from nN to σ*C4-C3 orbital lengthens the C4–C3 bond (C4 is the carbon bearing the nitrogen substituent), which reduces the p-p overlap between these two atoms.

[19] A systematic research of facial selectivity using substituted cyclopentadiene or permethylcyclopentadiene derivatives have been conducted and the results can be listed as below.

Molecular recognition events mediated through orbital interactions are critical in a number of biological processes such as enzyme catalysis.