Steric effects hydrogen exchange

Hydrogen exchange can occur under either acid- or base-catalyzed conditions. Both can be considered electrophilic aromatic substitutions, the latter involving attack of the electrophile upon an aromatic anion, zwitterion, or ylide. The former reaction is aided by electron supply, the latter by electron withdrawal (particularly by -/ effects) as the ratedetermining step is the initial proton loss. Steric hindrance, negligible in virtually all cases under acid-catalyzed conditions, appears to be of slightly greater importance under base-catalyzed conditions. 

Since the base must attack the ring hydrogens in the plane of the ring, but away from it, one would expect steric effects to be minimal, and certainly no more than for acid-catalyzed exchange. This appears to be the case for attack by amide, but the bulkier cyclohexylamide shows evidence of some steric hindrance [72MI2(266)]. 

The methyl substituent effects are approximately additive, confirming that (as in benzene) steric effects toward hydrogen exchange are effectively absent. 

It is also important to note that several factors influence both the stereoselectivity of hydrogen exchange and enolate formation in base-promoted reactions. Houk, Ando and co-workers found that differing conju-gative stabilization by CH p-orbital overlap does not directly influence stereoselectivity.205 Steric effects only dominate is exceptionally crowded transition structures, but torsional strain involving vicinal bonds contributes significantly to the stereoselectivity of all cases studied. 

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