[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?


  1. Joule, J. A.; Mills, K. Heterocyclic Chemistry, 5th ed.; Wiley: Chichester, U.K., 2010, p 257.
  • $\begingroup$ This is a simple enough system that it might be amenable to computation... $\endgroup$
    – Zhe
    Aug 7, 2017 at 18:49
  • $\begingroup$ It's maybe not as obvious as you might think, @Zhe. If you go via just the electron density (or even just the NMR shifts/how deshielded) it kinda looks like it should go the other way round. $\endgroup$
    – NotEvans.
    Aug 7, 2017 at 18:51
  • 1
    $\begingroup$ My question is linked anyways. I've also synthesized and calculated 2- and 4pyrimidyl compounds and in ym case the 4-pyrimidyl residue is more electron withdrawing than the 2. $\endgroup$
    – DSVA
    Aug 7, 2017 at 19:01
  • $\begingroup$ @notevans I specifically chose not to make assumptions about electronics or orbital overlap factors. If the computed preference agrees with experiment, you can then proceed to rationalize based on the results. $\endgroup$
    – Zhe
    Aug 7, 2017 at 19:17
  • $\begingroup$ What kinda mechanism does this reaction undergo ? $\endgroup$
    – Suraj S
    May 14, 2020 at 12:58

2 Answers 2


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.


Try drawing the resonance hybrides out. You'll soon realise that the intermediate formed when substitution accours at the c4 position can be stabilised by three resonance hybrids!


  • 4
    $\begingroup$ Unless I’m gravely mistaken, the same can be said of the intermediate for C2 substitution. $\endgroup$
    – orthocresol
    Dec 8, 2017 at 10:30

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