Mannich reaction steric factors

In conclusion, besides steric and electronic effects, the nature of the aminomethy-lating agent also has a notable influence on the regioselcctivity of the Mannich reaction on phenolic substrates, with the obvious consequence that a correct interpretation of the experimental results ealls for consideration of all the factors involved. 

Bisaminomethylation, occurring when the active methylene compound contains more than one acidic hydrogen, is another possible side reaction. Reported cases of bisaminomethylation are rather infrequent, however, suggesting that the protonated P-ammonium group slows down the rate of enolization of the Mannich base relative to the unreacted active methylene compound. Thermodynamic factors reflected in the steric congestion of the bisaminomethylated product may also be important. 

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