I was looking into heterocyclic compounds and their alkylation (i.e. the regioselectivity of the alkylation of the compound).

People are able to give pretty exact numbers, for an experiment done in solution. Take, for example, 1,2,4-triazole, the alkylation can occur in one of two positions and papers state that the yield is about 9:1 in the 1 to 4 position.

How would one go about the separation of the solution to validate these claims? Or is there a method where this can be quantified in solution?


Joule and Mills Heterocyclic Chemistry [1] confirms that 1,2,4-triazoles alkylate with ~9:1 selectivity for N1 over N3, citing a paper in Tetrahedron Letters from an industrial group at Merck as the source of the data[2].

The ratios reported were based on 1H-NMR of the crude product.[#] In this case, all of the compounds formed are known compounds, and as such it was easy to compare the data for 1-alkyl vs 3 alkyl. If the compounds formed were completely novel, it may be harder to tell which is which, though more complex NMR methods such as H-N or C-N correlation are often used in the pharmaceutical industry where this issue of regioselectivity often arises.

As an aside, the paper points out that the N1 and N3 alkylated products are easily separable, in this case by distillation, but in normal cases, silica gel chromatography (or HPLC if needed) can usually be used to separate the different regioisomers, with sufficient effort!

[1]: Mills, K.; Joule, J. A. Hetrocyclic Chemistry; Wiley:Chichester- Sussex, 2010

[2]: Bulger, P. G.; Cottrell, I. F.; Cowden, C. J.; Davies, A. J., Dolling, U-H. Tetrahrdron Lett., 2000, 41, 1297

[#]: The reaction was worked up, but not purified prior to working out the ratios. This is good practice, as it assures that you haven’t accidentally columned away some of the minor product, as is often the case

  • 2
    $\begingroup$ I can confirm from my own work that these regioisomers are readily separable by silica flash chromatography. $\endgroup$
    – jerepierre
    Aug 28 '17 at 20:25
  • $\begingroup$ Is anyone aware if TLC will work? $\endgroup$
    – AS_1000
    Aug 28 '17 at 20:36
  • 1
    $\begingroup$ @AS_1000 In all likelihood, yes. If it separates on a flash column using silica gel, then it will likely separate on a TLC place using the same eluent. You might be able to find this yourself if you look up the Rf values from the paper referenced (usually found in the Supporting Information section, and always available for free without subscription). $\endgroup$
    – NotEvans.
    Aug 28 '17 at 21:48

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