Stereoelectronic Effects

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Chapter: Organic Chemistry : Stereochemical and Conformational Isomerism

In addition to determining its shape and surface characteristics, the conforma-tional preferences of a molecule can also contribute to its chemical reactivity.


In addition to determining its shape and surface characteristics, the conforma-tional preferences of a molecule can also contribute to its chemical reactivity. Many reactions require that reacting groups achieve a particular spatial relation-ship so that overlap of appropriate orbitals leading to the needed electron redis-tribution can take place. These geometry-dependent orbital interactions which influence chemical reactivity are described generally as stereoelectronic factors. A very well known example of a reaction with distinct stereoelectronic require-ments is the Sn2 reaction. Here the incoming nucleophile must approach from the side opposite the leaving group. This permits electron donation into the σ antibonding orbital and results in the inversion stereochemistry found for these processes. Structural features which prevent the stereoelectronic requirements of the reaction from being met, such as the cage structure of the norbornyl skeleton which prevents the incoming nucleophile from approaching from in back of the leaving group, will slow or prevent the reaction entirely.

In other reactions a particular disposition of groups in a molecule is required for the reaction to proceed efficiently. Moreover it is often found that the proper stereoelectronic requirements of that reaction can be met only if a particular conformation of the molecule is populated. If the needed conformation is ener-getically accessible and thus populated, the reaction can proceed normally; if not, it is very slow and alternate processes might intervene. Classic examples are E2 reactions which require an anti-periplanar relationship between the proton being removed and the leaving group which departs. In open-chain systems this rarely presents a problem since the barriers to rotations about single bonds are low and reactive conformers are easily populated. Nevertheless this stereoelec-tronic requirement can have stereochemical consequences. d,l-Stilbene dibromide undergoes dehydrohalogenation in hot pyridine whereas the meso isomer reacts much more slowly. As seen below, the reactive conformation of the d,l isomer has the bulky phenyl groups anti to each other and is energetically favored, whereas the reactive conformation of the meso isomer has the phenyl groups gauche to each other and is energetically unfavorable. Thus the reactive conformer of the d,l compound is populated and reacts effectively; the reactive conformer of the meso compound is not populated significantly and the rate of elimination is much slower. (Eclipsing of the phenyl groups in the transition state also slows the reaction of the meso isomer.)

In cyclic systems where conformational motions are more restricted, stereo-electronic effects can play a much larger role in determining the outcomes of reactions. For example, base-promoted elimination in cis-4-(t -butyl)-cyclohexyl tosylate occurs 70 times faster than in the trans isomer. The reason is that the t-butyl group controls the conformation of the cyclohexane ring (it occupies an equatorial valence nearly exclusively); consequently, the cis isomer has an axial tosylate group which is antiperiplanar to axial hydrogens in the β positions. The trans isomer has an equatorial tosylate group which has no antiperiplanar hydrogens. The cis isomer meets the stereoelectronic requirements for base-promoted elimination and thus reacts significantly faster than the trans isomer, which does not.

The pyrolysis of acetate esters yields olefins by a concerted syn elimination of acetic acid. In open-chain systems where rotations are facile, it is possible for the acetate group to achieve a syn relationship with any of the vicinal protons, and the major product primarily reflects the energies of the products (trans is favored).

In contrast, it is found that trans-1-acetoxy-2-phenylcyclohexane gives 1-phenylcyclohexene as the major product (86.5%) upon heating, whereas cis-1-acetoxy-2-phenylcyclohexane gives 3-phenylcyclohexene as the major product (93%). Comparing these two isomers, it is calculated from A values that the trans diequatorial isomer is favored by 3.4 kcal/mol over the trans diaxial iso-mer. The diequatorial conformer has a proton at C-2 syn to the acetate group in an axial– equatorial disposition which undergoes elimination to produce the more stable conjugated product. (In this case, even the less stable diaxial con-former has a syn proton available in an axial– equatorial relationship with the acetate group and gives the same product.) In contrast, the cis isomer has only one conformation with a syn proton in an axial– equatorial relationship with the acetate group, and that elimination gives the less stable, nonconjugated 3-phenyl cyclohexene as the major product.

A more striking example of the influence of conformation on the reaction outcome is seen in the nitrous acid deamination of 2-aminocyclohexanols which takes place by rearrangement of a group on the carbinol carbon that is anti to the developing carbocation. The deamination reaction is very fast and the products reflect the population of the chair conformers. The trans isomer exists mainly in the diequatorial conformer; thus the only group anti to the amino group is a ring bond. Indeed ring contraction is the only process observed. In the cis isomer, however, both chair forms are populated (the A values of OH and NH2 are similar), so products of both ring contraction and hydride migration are obtained.

A particularly revealing example is seen in the reaction of 2-bromo-4-phenylcyclohexanols with Ag[I]. In the secondary carbinol, reaction takes place from the higher energy conformer because, even though its population is low, hydride migration by the hydrogen anti to the bromide assists the loss of axial bromide so it is the fastest reaction. Placement of a methyl group at the carbinol carbon raises the energy of the axial bromide conformation even higher, and its population is further reduced. Now because of its greater relative concentration, the conformer with bromide in the equatorial position reacts faster and leads to ring contraction.

The examples presented above point out some important features about organic reactions. First, many have distinct stereoelectronic requirements that must be met if the reaction is to proceed efficiently. Second, the correct stereoelectronic relationships are primarily dependent on the conformations of the substrate. Finally, the populations of various conformers determine if stereoelectronic requirements can be satisfied and thus play a significant role in product partitioning.

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