Tuesday, June 4, 2019

organic chemistry - Nucleophilic aromatic substitution on pyrimidines: C2 vs C4 selectivity



[There are many similar questions on Chemistry.SE (e.g. 1, 2) and a quick search will reveal all of them, but nothing on this in particular.]


The reaction of 2,4-halopyrimidines with nucleophiles generally leads to selective displacement of the halide at the 4-position:1


SNAr on 2,4-dichloropyrimidine


In their textbook, Joule and Mills don't explain why, though, simply saying that it "is the normal situation for nucleophilic – 4-chloro > 2-chloro".


I don't see any obvious difference in the stability of the anionic intermediates, either (the so-called Meisenheimer complexes).


What can explain the regioselectivity of the above reaction?




Reference



  1. Joule, J. A.; Mills, K. Heterocyclic Chemistry, 5th ed.; Wiley: Chichester, U.K., 2010, p 257.





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