In most of the textbooks of fundamental organic chemistry, writers emphasized substituent effect when talking about the selective organic reactions, including the inductive effect, conjugative effect and steric hindrance. Stereoelectronic effect ^[1], also called orbital orientation, commonly receives minimal attention despite of its importance in some stereoselective organic reactions, especially those regarding cyclic substrates with restricted free rotation of sigma bonds.

Hybrid orbital theory (HOT) classifies carbon into three categories: sp³, sp², and sp hybridized carbons, possessing tetrahedral, planar and linear structures respectively. When two sp³ hybridized carbons get close enough to form a covalent σ ($ {{\rm{C}}_{s{p^3}}}$―$ {{\rm{C}}_{s{p^3}}}$) bond, the two sp³ hybridized orbitals are oriented as head-to-head in order to have a maximum overlap of two sp³ hybridized orbitals and to form σ-bonding and σ-antibonding molecular orbitals (MOs). Two electrons occupying the σ-bonding orbital with the lower energy are called σ-electrons (Scheme 1).

In the case of ethylene, except for the oriented formation of σ ($ {{\rm{C}}_{s{p^2}}}$―$ {{\rm{C}}_{s{p^2}}}$) bond, the remaining two non-hybridized p orbitals adopt shoulder-to-shoulder orientation to reach a maximum overlap and form π-bonding and π-antibonding orbitals (Scheme 2). Two electrons occupying the π-bonding orbital are called π-electrons. From the structures of ethane and ethylene, we have the impression that the orbital is of the orientation in space. These orbital orientations, head-to-head or shoulder-to-shoulder, play key roles not only in the relative stabilities of the molecular structures but also in the stereoselectivities during the reaction progresses. The following examples illustrate the importance of orbital orientation in details.

Molecular structure determines physical and chemical property of the molecule. Having the electrostatic potential map of a molecule in mind, we can understand the reactive sites of a molecule towards nucleophile or electrophile, thus predicting the outcome of the reaction. In consideration of drawing the resonance structures properly, orbital orientation is a vital component.

Within a p-π conjugation, three p orbitals orient parallel, providing a conjugated system for four delocalized electrons (Scheme 3). The derived hybrid structure implies that the terminal carbon shows higher reactivity towards electrophile than the internal carbon does, as it holds a larger electron density than the internal one does.

However, to an azabicyclic carbocation (1), the lone-pair electrons occupy one of orbitals belonging to the sp³-hybridized nitrogen, which is almost perpendicular to the empty p orbital of the adjacent carbocation (Scheme 4). Therefore, p-p conjugation is absent in this system, and the lone-pair electrons only localize around the nitrogen atom. In other word, the electron-deficient carbocation could not be stabilized by forming a resonant structure with the adjacent electron-rich nitrogen.

Similar situation occurs in 3-acetylpyridine (2, Scheme 4). The lone-pair electrons of nitrogen occupy one of its sp² orbitals, which is in the plane of pyridine, making it geometrically impossible to overlap with other p-orbitals to form a viable conjugation. Therefore, even though there is an electron-withdrawing group (carbonyl) attached to the pyridine, the lone-pair electrons localize on nitrogen and could not be delocalized to the plane of pyridine.

Unlike other primary carbocation, cyclopropylcarbinyl cation (3) is very stable and its salt could be isolated and characterized (Scheme 5) ^[2]. Cyclopropylcarbinol or cyclobutanol on reaction with SbF₅-SO₂ClF at -80 ℃ gave identical NMR spectra. Only two signals (δ 108.4 and 55.2) were observed and assigned respectively for methine carbon and methylene carbons. This unique stability arises from the formation of a non-classic carbocation, or so-called pentacoordinated σ-delocalized bicyclobutonium ion, via the super-conjugation between the empty p orbital of carbocation and the occupied σ-bonding orbital of $ {{\rm{C}}_{s{p^3}}}$―$ {{\rm{C}}_{s{p^3}}}$ bond through spatial interaction since these two orbitals are parallel.

Carbocations are likely to undergo rearrangements to form more stable carbocations during the reaction processes since the energy required for the rearrangement could normally be compensated by the energy released from the formation of more stable carbocation. In order to have a successful rearrangement, or alkyl migration, the effective overlap between the occupied σ ($ {{\rm{C}}_{s{p^3}}}$―$ {{\rm{C}}_{s{p^3}}}$) bonding orbital and the empty p orbital of the adjacent carbocation is the premise and these two orbitals should be aligned in a plane (Scheme 6).

Due to the nature of a linear structure, such need of the plane alignment could always be satisfied because of the free rotation of σ ($ {{\rm{C}}_{s{p^2}}}$―$ {{\rm{C}}_{s{p^2}}}$) bond. The migration tendency of the alkyl depends on the electronic effect of the migrated alkyl and the migration tendency is ordered as follows: tertiary alkyl > secondary alkyl > primary alkyl > methyl.

As for the case of a cyclized structure, free rotation of σ-bond is restricted and the migration tendency depends on the orbital orientation ^[3]. For instance, as for the carbocation ^[4], methyl group migrates although the primary alkyl has the higher priority than the methyl to migrate (Scheme 7). Orbital overlap between the carbocationic vacant orbital and the migrating σ-bond in the transition state is important.

Tautoumerism occurs in the carbonyls bearing α-hydrogen (Scheme 8). α-Hydrogen in carbonyls is of stronger acidity than the hydrogen attached to normal alkane. In order to form a C＝C double bond in the enol product, the adjacent C―H bond of carbonyl should be perpendicular to the plane of carbonyl as shown below. In other words, the dihedral angle of H―C―C＝O should be 90 degree. In this way, effective orbital overlap between two adjacent carbons exists, yielding a C＝C bond.

In a cyclized system, σ-bond rotation is restricted. Comparing compounds 5 to 6, compound 5 is a much stronger acid (Scheme 9). The existence of two electron-withdrawing carbonyls in compound 6 does not increase the acidity of α-hydrogen, the acidity of which is the same as the acidity of hydrogen attached to the normal alkane. In compound 5, the adjacent C―H bond could be perpendicular to the plane of the carbonyl, which fits the orbital requirement for enol formation. However, in compound 6, the dihedral angle of H―C―C＝O is 0 degree and the adjacent C―H bond is in the plane of carbonyl.

In a bimolecular nucleophilic substitution reaction (S_N2), if the electron deficient carbon is a secondary carbon with different groups on it, the configuration of the carbon is inversed (Scheme 10). This is called Walden inversion. In order to have an effective bonding, nucleophile attacks the carbon from the backside of the leaving group. Electrons flow from occupied orbital of nucleophile to the empty σ (C―L) antibonding orbital of the substrate, and these two orbitals should be aligned in head-to-head for effective bonding. As the reaction goes and reaches the transition state with the highest potential energy, the nucleophile, the central carbon and the leaving group are aligned in a straight line. Finally, the leaving group leaves with two electrons in σ (C―L) bonding orbital, and the final product is formed along with the inversion of configuration of the central carbon. The head-to-head orbital alignment leads to the effective formation of σ (Nu―C) bond.

E2 elimination is a one step reaction. The dihedral angle of X―C―C―L needs to be 180 degree in order to have an effective π-bonding in the alkene-like transition state and finally yielding a C＝C double bond (Scheme 11). Electrons flow from nucleophile (or base) to σ (X―C) antibonding orbital, repelling electrons in σ (X―C) bonding orbital to σ (C―C) antibonding orbital, while leaving-groups leave with electrons in σ (C―L) bonding orbital. Reaction starts with two sp³ hybridized orbitals and ends with two sp² hybridized orbitals. The gradation from sp³ to sp² requires two σ bonds (X―C, C―L) being parallel in the starting structure for the effective development of π bond in the product. In other words, dihedral angle of X―C―C―L should be either 180 or 0 degree. Meanwhile, further consideration regarding the steric hindrance arising from the syn-elimination suggests that it is better to adopt the anti-elimination for E2. Syn-elimination occurs when the free rotation of σ-bond is restricted as shown in compound 7 (Scheme 12).

When E2 elimination takes place in cis- and trans-1-bromo-4-tert-butyl cyclohexanes (8-cis and 8-trans), respectively, 8-cis undergoes faster E2 elimination than 8-trans does (Scheme 13). Because the bulky tert-butyl tends to occupy the equatorial bond, two stable conformers A and B are presented. In the stable conformer A, both dihedral angles of H_a―C―C―Br and H_b―C―C―Br are 180 degree. In another word, both H_a―C and H_b―C bonds exist in anti-coplanar with regard to C―Br bond, a fact that fits for E2 elimination. In the stable conformer B, the anti-coplanar bonds to C―Br bond, colored in red, are C2―C3 and C6―C5 bonds. In order to have anti-coplanar alignment for E2 elimination, conformer B should be converted into an unstable conformer B'. This step requires a much higher activation energy and is the rate determining step with a much lower reaction rate. Therefore, 8-cis undergoes faster E2 elimination than 8-trans does.

Similar to E2 elimination, addition of bromine to double bonds requires anti-diaxial addition (Scheme 14) ^[4]. As shown in the Scheme 14, anti-diaxial addition of bromine to (R)-9 could potentially generate either A or B, both of which would later under reforamtion to yield final products. It is much easier for A to undergo reformation that yields (1S, 2S, 4R)-10 than that is for B to under reformation that gives (1R, 2R, 4R)-10. The difference arises from the fact that a twist-boat form B', with a much more higher potential energy, is a necessary transit on the way from B to (1R, 2R, 4R)-10. Thus, (1S, 2S, 4R)-10 is the major product of this electrophilic addition reaction although two bromine atoms occupy two axial bonds in the product.

Overall, orbital orientation or steroelectronic effect, is the effect on molecular conformation and reaction selectivity through oriented orbital overlap. More examples are shown in Wikipedia ^[5-7]. It becomes more critical when monocyclic or bicyclic compounds are involved where the free rotation of sigma bonds is restricted. When we examine these organic structures and their related reactions, orbital orientation should be considered first in comparison with others, such as inductive effect, conjugate effect and steric hindrance.