Substitution reactions prediction under basic conditions

Two of the four general carbonyl-group reactions—carbonyl condensations and a substitutions—take place under basic conditions and involve enolate ion intermediates. Since the experimental conditions for the two reactions are so similar, how can we predict which will occur in a given case When we generate an enolate ion with the intention of carrying out an < alkylation, how can we be sure that a carbonyl condensation reaction won t occur instead ... 

Neighboring group participation is also another important factor for predicting the reactivity of secondary hydroxyl groups, particularly at the C-2 position. Under basic conditions, the C-2 hydroxyl tends to be more acidic than the C-3 hydroxyl and this may be advantageously exploited in certain cases such as partial benzylation under phase-transfer catalysis. The latter reaction conditions also contribute to the relatively good selectivity for substitution at a primary hydroxyl group in preference to a secondary one at either C-3 or C-4. 

A carbocationic intermediate is formed in both the SnI and the El mechanisms. After the carbocation is formed, addition of a nucleophile leads to an overall substitution reaction, whereas fragmentation leads to an overall elimination reaction, so there is a competition between the two modes of reaction. It is possible to predict whether substitution or elimination dominates, just as it is possible to predict whether Sn2 or E2 will predominate under basic conditions. Predicting which pathway dominates is easier under acidic conditions, though. Addition is favored in hydroxylic (i.e., nucleophilic) solvents (RCO2H, ROH, II2O) and when the nucleophile is contained in the same molecule, whereas fragmentation is favored in aprotic solvents. In other words, substitution occurs when the carbocation intermediate can be rapidly intercepted by a nucleophile, and elimination occurs when it cannot. 

Rough guidelines for the prediction of regioselectivity in epoxide ring openings are summarized in Scheme 4.60. Under neutral or basic reaction conditions alkyl-or aryl-substituted epoxides react with most nucleophiles at the less substituted carbon atom [248-253]. Under acidic reaction conditions, however, product mixtures or preferential attack at the most substituted carbon atom can be observed. Acids can usually be used to enhance the reactivity of epoxides and to promote substitution at the site of an epoxide which forms a carbocation more readily. 

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