Torsional and Stereoelectronic Effects on Reactivity

This stereoelectronic requirement would lead to a large distortion of the normal geometry of a five-membered ring and introduce strain. It is this distortion and strain that disfavor the 5-endo-trig cyclization. In contrast, 5-endo-dig cychzation is feasible because the acetylenic system provides an orbital that is available for a nearly planar mode of approach. 

In agreement with these analyses, it was found that conqiound S was unreactive toward base-catalyzed cyclization to 6, even though the double bond would be expected to be reactive toward nucleophilic conjugate addition. On the other hand the acetylene 7 is readily cyclized to 8  

The terms favored and disfavored imply just that. Other factors will determine the absolute rate of a given ring closure, but these relationships point out the need to recognize the specific stereoelectronic requirements which may be imposed on the transition state in ring-closure reactions. 

Torsional strain refers to the component of total molecular energy that results from nonoptimal arrangement of vicinal bonds, as in the eclipsed conformation of ethane. The origin and stereoelectronic nature of torsional strain were discussed in Section 1.1.1. The 

For example, cyclohexanone is reduced by sodium borohydride 23 times faster than cyclopentanone. The explanation for this difference lies in the relative torsional strain in the two systems. Converting an sp atom in a five-membered ring to sp increases the torsional strain because of the increase in the number of eclipsing interactions in the alcohol. A similar change in a six-membered ring leads to a completely staggered (chair) arrangement and reduces torsional strain. 

Conversely, processes that convert sp carbons to sp carbons are more favorable for five-membered than for six-membered rings. This can be illustrated by the data for acetolysis of cyclopentyl versus cyclohexyl tosylate. The former proceeds with an enthalpy of activation about 3 kcal/mol less than for the cyclohexyl compound. A molecular mechanics analysis of the difference found that it was largely accounted for by the relief of torsional strain in the cyclopentyl case. Notice that there is an angle strain effect operating in the opposite direction, since there will be some resistance to the expansion of the bond angle at the reaction center to 120 in the cyclopentyl ring. 

There is another stereoelectronic aspect to the reactivity of the carbonyl group in cyclohexanone. This has to do with the preference for approach of reactants from the axial or the equatorial direction. The chair conformation of cyclohexanone places the carbonyl group in an unsymmetrical environment. It is observed that small nucleophiles prefer to approach the carbonyl group of cyclohexanone from the axial direction. How do the differences in the C—C bonds (on the axial side) as opposed to the C—H bonds (on the equatorial side) influence the reactivity of cyclohexanone  

Torsional effects also play a major role in the preference for axial approach. In the initial ketone, the carbonyl group is almost eclipsed by the equatorial C-2 and C-6 C—H bonds. This torsional strain is relieved by axial attack, but equatorial approach increases it somewhat since the oxygen atom must move through a fully eclipsed arrangement.  

More bulky nucleophiles usually approach the cyclohexanone carbonyl from the equatorial direction. This is called steric approach control and is the result of van der Waals type repulsions. Larger nucleophiles encounter the 3,5-axial hydrogens on the axial approach trajectory. 

Bicyclo[3.3.1]nonan-9-one is another ketone that exhibits interesting stereoselectivity. Reduction by hydride donors is preferentially syn to electron-attracting substituents at C-5 (X = EWG in the structure shown below) and anti to electron-releasing substituents (X = ERG below). These effects are observed even for differentially substituted phenyl 

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