Hydrogen neighboring group effects

Evidence comes from comparative rate studies.216 Thus 71 was hydrolyzed about 105 times faster than benzamide (PhCONH2) at about the same concentration of hydrogen ions. That this enhancement of rate was not caused by the resonance or field effects of COOH (an electron-withdrawing group) was shown by the fact both o-nitrobenzamide and terephthal-amic acid (the para isomer of 71) were hydrolyzed more slowly than benzamide. Many other examples of neighboring-group participation at a carbonyl carbon have been reported.2 7 It is likely that nucleophilic catalysis is involved in enzyme catalysis of ester hydrolysis. 

Reaction at a carbon atom may be inhibited by the proximity of neighboring groups. Steric effects of hydrogen atoms on carbon atoms, five atoms removed from the site of attack, are important. This principle, called by Newman (150) the rule of six, has been used (63) to explain yield distribution in hydrocarbon oxidation. Steric effects are probably important in the high resistance of some tertiary C—H bonds to attack (63,... 

Figure 21. Effects of neighbor groups on N(6)H2 acidity of N1,N7 diplatinated adenine Low pA"a by efficient hydrogen bonding between —NH2 donor and —NH versus high pA"a due to repulsion between —NH and O acceptor.

Primary and secondary kinetic isotope effects are of general importance in the study of neighboring group participation. Isotopic substitution a to the incipient carbo-cation produces a secondary isotope effect whereas 0 and y substituents may give rise to both primary and secondary effects. For example, if the rate determining step of a solvolytic reaction involves a hydrogen shift or elimination, primary deuterium isotope effects are clearly implicated. 

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