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[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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  • $\begingroup$ This is a simple enough system that it might be amenable to computation... $\endgroup$ – Zhe Aug 7 '17 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 '17 at 18:51
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    $\begingroup$ 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 '17 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 '17 at 19:17
  • $\begingroup$ What kinda mechanism does this reaction undergo ? $\endgroup$ – Suraj S May 14 at 12:58
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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.

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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!

:)

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    $\begingroup$ Unless I’m gravely mistaken, the same can be said of the intermediate for C2 substitution. $\endgroup$ – orthocresol Dec 8 '17 at 10:30

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