Stereoelectronic effect

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The stereoelectronic effect is defined as the effect on molecular structures, physical properties, and reactivities due to the molecules' electronic structures, in particular the interaction between atomic and/or molecular orbitals.[1] Stereoelectronic effect contains a large variety of subtopics, some of them are well known as anomeric effects and hyperconjugation.[2] Typical stereoelectronic effects with specific orbital overlaps generally lead to a specific molecular conformation, or energy differentiation among various transition states which would lead to a particular reaction selectivity.

Stereoelectronic effect generally includes a donor–acceptor interaction. The donor is usually a high-lying bonding or nonbonding orbital and the acceptor is often a low-lying antibonding orbital as shown in the scheme below. As known from the orbital–orbital interaction requirement, if this setereoelectronic effect is to be favored, the donor–acceptor orbitals much have a low energy gap and they must retain antiperiplanar geometry to allow for perfect interacting direction.

Trend of different orbitals

Take the simplest CH2X–CH3 system as an example; the donor orbital is σ(C–H) orbital and the acceptor is σ*(C–X). When moving from fluorine to chlorine, then to bromine, the electronegativity of the halogen would decrease and so will the energy level of the σ*(C–X) orbitals.[3] Consequently, the general trend of acceptors can be summarized as: π*(C=O)>σ*(C–Hal)>σ*(C–O)>σ*(C–N)>σ*(C–C), σ*(C–H). For donating orbitals, the nonbonding orbitals, or the lone pairs, are generally more effective than bonding orbitals due to the high energy leves. Also, different from acceptors, donor orbitals require less polarized bonds. Thus, the general trends for donor orbitals would be: n(N)>n(O)>σ(C–C), σ(C–H)>σ(C–N)>σ(C–O)>σ(C–S)>σ(C–Hal).[4]

Stereoelectronic effect can be directional in specific cases. The radius of sulfur is much larger than the radius of carbon and oxygen thus the differences in C–S bond distances will generate a much amplified difference in the two stereoelectronic effects in 1,3-dithiane(σ(C–H) → σ*(C–S)) than in 1,3-dioxane(σ(C–H) → σ*(C–O)).[3] The differences between C–C and C–S bonds shown in the scheme below causes a significant difference in the distances between C–S and two C–H bonds. The shorter the difference is, the better the interaction, and the stronger the stereoelectronic effect.[3]

Influence on stability

If there is an electronegative substituent (e.g. –SiR3, –SnR3, –HgR, etc.) 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). Also, the orientation of the tow interacting orbitals can also have a significant effect on the stabilization effect (σ(C–Si) → empty p orbital), where antiperiplanar (180°) > perpendicular (90°) > syn (0°).[5]

Influence on conformation

Gauche effect

One of the famous structural consequence of acyclic systems due to stereoelectronic effect is the gauche effect.[6] In 1,2-difluoroethane, despite the steric clash, the preferred conformation is the gauche one because σ(C–H) is a good donor and σ*(C–F) is a good acceptor and the stereoelectronic effect (σ(C–H) → σ*(C–F)) requires the energy minimum to be gauche instead of anti.[7]

This gauche effect also has a profound effect in bio-chemical research. In (2S,4R)-4-hydroxyproline fragment, the gauche interaction favors one of the conformers which can bind selectively to the active site of pVHL, a domain in collagen, one of the most abundant protein structures in animals, and can lead to proteasomal degradation of HIF-α subunit.[8]

Special effects of fluorine substituent

Stereoelectronic effect can also have a significant influence in pharmaceutical research. Generally, the substitution of hydrogen by fluorine could be regarded as a way to tune both the hydrophobicity and the metabolism rate. However, it also has a profound influence on conformations. In anisole, the methyl group prefers the coplanar geometry with the phenyl group by about 3.0 kcal/mol, while the trifluoromethoxybenzene favors the O–CF3 bond to be perpendicular to the phenyl group. One explanation is the enhanced steric size of trifluoromethyl group compared to methyl group; yet, more importantly, once the trifluomethyl group rotates outside the phenyl plane, which orienting the C–F bond antiperiplanar (with the [C(aryl)–C(aryl)–O–C(H2F)] dihedral angel in the energy minimized structure being around 90°) to the nonbonding orbital (the lone pair) on the oxygen atom which can benefits more of the stereoelectronic effect (n(O) → σ*(C–F)).[9]

Further studies illustrate that even with only one or two fluorine substituted methyl group, the distortion in structure can also be significant, with the [C(aryl)–C(aryl)–O–C(H2F)] dihedral angel in the energy minimized structure being around 24° and the [C(aryl)–C(aryl)–O–C(HF2)] dihedral angel 33°.[9]

Influence on reaction selectivity

Bergman reaction

Although the energy difference between coplanar anisole and its isomer is quite large, the rotation between the O–CH3 bond can also significantly alters the electronic properties of methoxy group on aromatic rings. In the following reaction, the regioselectivity could be rationalized as the out-of-plane rotation of the O–C bond which changes the methoxy group from an in-plane donor group to an out-of-plane acceptor group.[10]

The intermediate of the above reaction is the di-anion and the stereoelectronic effect that stabilizes this intermediate over the other one is the fact that the anionic charge at the para position could delocalized to the oxygen atom via orbital interaction: π(benzene) → σ*(O–CH3).[10]

Hydrogenation reaction

The other substituents on the benzene ring can also affect the electron density on the aromatic ring and in turn influence the selectivity. In the hydrogenation of ketones using CBS catalysts, the ketone coordinate to the boron atom with the lone pair on the oxygen atom. In the following example, the substituent's influence can be passed to differentiate the two lone pairs on the oxygen atom.[11]

The stereoelectronic interaction in the starting material is the n(O) → σ*(Ccarbonyl–Caryl). The electron withdrawing substituent on the benzene ring will deplete the electron density on the aromatic ring and thus makes the σ*(Ccarbonyl–Caryl(nnitrile)) orbital a better acceptor than σ*(Ccarbonyl–Caryl(methoxy)) and these two stereoelectronic interactions would use different lone pairs on the oxygen atom. Also, the better the stereoelectronic interaction is, the less reactive to coordinate to the boron atom. This would result the intermediate to coordinate boron atom with the oxygen lone pair syn to the nitrile-aryl group.[11]

Influence on thermodynamics

Influence on equilibrium

Stereoelectronic effect also has a vital influence on the thermodynamics of equilibrium and even between different resonance structures. For example, the following equilibrium could be achieved via a cascade of pericyclic reactions.

Though nearly every step is reversible, one of the two structures is strongly favored. This could be explained with the following reasoning. With an oxygen atom in the ring, the double bonds cannot resonate with each other and the double bonds are localized. As the σ*(C(sp2)–C(sp2)) orbital is a better acceptor than σ*(C(sp3)–C(sp3)), the stereoelectronic interaction of n(O) → σ*(C(sp2)–C(sp2)) has a much stronger stabilizing effect than n(O) → σ*(C(sp3)–C(sp3)); and thus the structure with better stereoelectronic interaction is favored thermodynamically in the equilibrium.[12]

Another example of the preference in the equilibrium within the area of pericyclic reaction is shown below. The stereoelectronic effects affecting the quilibrium is the interaction between the delocalized “banana bonds” and the empty p orbital on the boron atom.[13]

Influence on resonance structures

In another case, stereoelectronic effect can result in a preference for one resonance structure over the other which leads to further consequences in reactivity. For 1,4-benzoquinone monoxime, it has long been recognized that there is significant differences between the physical properties and reactivities between C2-C3 double bond and C5-C6 double bond with the J23 higher than J56 [14] and C2-C3 double bond is more isolated and tend not to undergo Diels–Alder reaction with ethylene.[15] This illustrates a preference of resonance structure B against structure A which is quite unusual for the fact that for most molecules, each resonance structure would tend to contribute equally to the actual structure of the molecule. The reason for the preference in 1,4-benzoquinone monoxime is the fact that the σ*(C(sp2)–C(sp2)) orbital is a better acceptor in single bonds than in double bonds. The stereoelectronic interaction of n(N) → σ*(C(sp2)–C(sp2)-single bond) is more favorable than n(N) → σ*(C(sp2)–C(sp2)-double bond).[16]

Application in asymmetric Diels–Alder reactions

In the asymmetric Diels–Alder reactions, instead of using chiral ligands or chiral auxiliaries to differentiate the side selectivity of the dienolphiles, the differentiation of face selectivity of the dienes (especially for cyclopentadiene derivatives) using stereoelectronic effects have been reported by Woodward since 1955.[17] A systematic research of the facial selectivity using substituted cyclopentadiene or permethylcyclopentadiene derivatives have been conducted and the results can be listed as below.[18]

The stereoelectronic effect affecting the outcome of the facial selectivity of the diene in Diels–Alder reaction is the interaction between the σ(C(sp2)–CH3) (when σ(C(sp2)–X) is a better acceptor than a donor) or σ(C(sp2)–X) (when σ(C(sp2)–X) is a better donor than an acceptor) and the σ* orbital of the forming bond between the diene and the dienophile.[18]

If the two geminal substituents are both aromatic rings with different substituents tuning the electron density, the differentiation of the facial selectivity is also facile where the dienophile approaches to the diene anti to the more electron-rich C–C bond where the stereoelectronic effect in this case is similar to the previous one.[19]

The ring opening of cyclobutene under heating conditions can have two products: inward and outward rotation.

The inward rotation transition state of the second shown below is relatively favored for acceptor R substitutents (e.g. NO2) but is especially disfavored by donor R substituents (e.g. NMe2).[20]

Stereoelectronic effect vs. steric clash

Sometimes, stereoelectronic effects can even win over extreme steric clash. In a similar cyclobutene ring-opening reaction, the trimethylsilyl group, which is very bulky, still chooses to favor the inward rotation. The stereoelectronic effect, which is the interaction shown above when the acceptor orbital is the σ*(Si–CH3), appears to be a more predominant factor in determining the reaction selectivity against the steric hindrance and even wins over the penalty of the disrupted conjugation system of the product due to steric clash.[21]

Furthermore, the acceptor orbitals are not simple limited to the antibonding orbitals of carbon-heteroatom bonds or the empty orbitals; in the following case, the acceptor orbital is the σ*(B–O) orbital. In the six-membered ring transition state, the stereoelectronic interaction is σ(C–X) → σ*(B–O).[22]

Summary

Stereoelectronic Effects, along with steric effect, inductive effect, mesomeric effect, etc., is one of the key theories in illustrating unusual selectivity, reactivity, and stability cases in the course of organic chemistry. Its application has been widely spread in organic methodology and organic synthesis; and some of the recent publications have guided this well-studied topic into the rising arena of biochemistry and pharmaceutical chemistry.

References

  1. ↑ Cramer, Christopher J. (1996). "Hyperconjugation as it affects conformational analysis". Journal of Molecular Structure: THEOCHEM 370 (2–3): 135–146. doi:10.1016/S0166-1280(96)04567-8. ISSN 0166-1280. 
  2. ↑ Kirby, A. J. (1983). The Anomeric Effect and Related Stereoelectronic Effects at Oxygen. New York: Springer-Verlag. pp. 3–13. 
  3. ↑ 3.0 3.1 3.2 Alabugin, Igor V.; Zeidan, Tarek A. (2002). "Stereoelectronic Effects and General Trends in Hyperconjugative Acceptor Ability of σ Bonds". Journal of the American Chemical Society 124 (12): 3175–3185. doi:10.1021/ja012633z. ISSN 0002-7863. 
  4. ↑ Kirby, A. J. (1996). Stereoelectronic Effect. Oxford: Oxford University Press. 
  5. ↑ Carey, A. F. S. (2007). Advanced organic Chemistry Part A: Structure and Mechanism. New York: Springer. 
  6. ↑ Hanack, M. (1965). Conformational Theory. New York and London: Academic Press. 
  7. ↑ Anslyn, E.V. (2005). Modern Physical Organic Chemistry. Herndon: University Science Books. 
  8. ↑ Fujimori, D.G. (2009). Nat. Chem. Bio. 5: 202. 
  9. ↑ 9.0 9.1 Müller, K.; Faeh, C.; Diederich, F. (2007). "Fluorine in Pharmaceuticals: Looking Beyond Intuition". Science 317 (5846): 1881–1886. doi:10.1126/science.1131943. ISSN 0036-8075. 
  10. ↑ 10.0 10.1 Peterson, Paul W.; Shevchenko, Nikolay; Alabugin, Igor V. (2013). ""Stereoelectronic Umpolung": Converting a p-Donor into a σ-Acceptor via Electron Injection and a Conformational Change". Organic Letters 15 (9): 2238–2241. doi:10.1021/ol400813d. ISSN 1523-7060. 
  11. ↑ 11.0 11.1 Corey, E.J.; Helal, Christopher J. (1995). "Novel electronic effects of remote substituents on the oxazaborolidine-catalyzed enantioselective reduction of ketones". Tetrahedron Letters 36 (50): 9153–9156. doi:10.1016/0040-4039(95)01961-G. ISSN 0040-4039. 
  12. ↑ Venkataraman, Hemalatha; Cha, Jin K. (1989). "The scope and mechanism of rearrangement of 4,6-dialkoxy-2-pyrones". Tetrahedron Letters 30 (27): 3509–3512. doi:10.1016/S0040-4039(00)99426-7. ISSN 0040-4039. 
  13. ↑ Gridnev, Ilya D.; Tok, Oleg L.; Gridneva, Natalya A.; Bubnov, Yuri N.; Schreiner, Peter R. (1998). "Synthesis and Dynamic Properties of Cycloheptatrienyl(dipropyl)borane. Equilibrium with 7-Dipropylborylnorcaradiene". Journal of the American Chemical Society 120 (5): 1034–1043. doi:10.1021/ja9724699. ISSN 0002-7863. 
  14. ↑ Norris, R. K.; Sternhell, S. (1969). Aust. J. Chem. 22: 935. 
  15. ↑ Baldwin, J. E.; Norris, R. K. (1981). J. Org. Chem. 46: 697. 
  16. ↑ Perrin, C. L.; Engler, R. E. (1997). J. Org. Chem. 62: 687. 
  17. ↑ Winstein, S.; Shatavsky, M.; Norton, C.; Woodward, R. B. (1955). J. Am. Chem. Soc. 77: 4183. 
  18. ↑ 18.0 18.1 Mehta, Goverdhan; Uma, R. (2000). "Stereoelectronic Control in Diels−Alder Reaction of Dissymmetric 1,3-Dienes". Accounts of Chemical Research 33 (5): 278–286. doi:10.1021/ar990123s. ISSN 0001-4842. 
  19. ↑ Halterman, R. L.; McCarthy, B. A.; McEvoy, M. A. (1992). J. Org. Chem. 57: 5585. 
  20. ↑ Shindo, M.; Sato, Y.; Shishido, J. (1998). Tetrahedron Lett. 39: 4857. 
  21. ↑ Murakami, M.; Hasegawa, M. (2004). Angew. Chem. Int. Ed. 43: 4874. 
  22. ↑ Schlapbach, A.; Hoffmann, R. W. (2001). J. Org. Chem. 66: 323. 
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