Benzylic systems, reactivity toward nucleophilic

In a series of important papers, MacMillan described the alkylation of electron rich aromatic and heteroaromatic nucleophiles with a,P-unsaturated aldehydes, using catalysts based upon the imidazoUdinone scaffold, further establishing the concept and utility of iminium ion activation. In line with the cycloaddition processes described above, the sense of asymmetric induction of these reactions can be rationalised through selective (F)-iminium ion formation between the catalyst and the a,P-unsaturated aldehyde substrate, with the benzyl arm of the catalyst blocking one diastereoface of the reactive Jt-system towards nucleophilic attack (Fig. 3). 

Compared with acyclic analogues, cyclic hydrogen phosphorodithioates are highly reactive towards diphenylvinylphosphine oxide and diethyl [a-(ethoxycarbo-nyl)styryl]phosphonate, the six-membered-ring acids reacting more quickly than the five-membered-ring acids or the acyclic compounds. On the other hand, the nucleophilic reactivity of anions of the acids towards benzyl halides is less for the cyclic systems than for the acyclic ones. ... 

The extent of the rate enhancement due to adjacent substituents is dependent on the nature of the transition state. The most important factor is the nature of the TT-type orbital which develops at the trigonal bipyramidal carbon in the transition state. If this carbon is cationic in character, electron donation from adjacent substituents becomes stabilizing. If bond formation at the transition state is far advanced, electron withdrawal should be more stabilizing. Substituents such as carbonyl therefore have their greatest effect on reactions with strong nucleophiles. Adjacent alkoxy substituents can stabilize Sn2 transition states that are cationic in character. Since the vinyl and phenyl groups can stabilize either type of transition state, the allyl and benzyl systems show enhanced reactivity toward both strong and weak nucleophiles. ... 

In addition to steric effects, there are other important substituent effects that influence both the rate and mechanism of nucleophilic substitution reactions. As we discussed on p. 302, the benzylic and allylic cations are stabilized by electron delocalization. It is therefore easy to understand why substitution reactions of the ionization type proceed more rapidly in these systems than in alkyl systems. Direct displacement reactions also take place particularly rapidly in benzylic and allylic systems for example, allyl chloride is 33 times more reactive than ethyl chloride toward iodide ion in acetone." These enhanced rates reflect stabilization of the Sjv2 TS through overlap of the /2-type orbital that develops at carbon." The tt systems of the allylic and benzylic groups provide extended conjugation. This conjugation can stabilize the TS, whether the substitution site has carbocation character and is electron poor or is electron rich as a result of a concerted Sjv2 mechanism. 

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