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



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


Joule, J. A.; Mills, K. Heterocyclic Chemistry, 5th ed.; Wiley: Chichester, U.K., 2010, p 257.
An explanation can be provided by frontier molecular orbital theory.  The LUMO coefficient is higher on the C4 vs C2.  This is a general effect meaning that an EWG para to the leaving group is more reactive than ortho.  See 4-halopyridines vs 2-halo and 4-nitrobenznes vs 2-nitro.  There could also be an effect from the repulsion between the nitrogen lone pairs and the approaching electron rich nucleophile, which would be greater in proximity to 2 nitrogens rather than 1.