We could draw a resonance form with the pi electrons shifting, placing a positive charge on C-4, to which a $\ce{H+}$ along with 2 electrons are added. Thus we get an NADH molecule as shown in the picture.

If this is how the reaction happens, then why doesn't the hydrogen get added to C-2 (or C-6 which is equivalent)? There's also a resonance form where C-2 has a positive charge and could accept a hydride ion. Why doesn't this happen?

  • 3
    $\begingroup$ In a synthetic setting, they could add to C-2. But in the body, these reactions are mediated by enzymes which hold the reactants in a very specific orientation. I'd guess that the regioselective delivery of hydride to C-4 is controlled in that way. $\endgroup$ Commented Jan 27, 2017 at 17:50
  • $\begingroup$ I'm sure that additions to pyridinium rings are well studied and should be well documented in the literature. $\endgroup$
    – Zhe
    Commented Jan 27, 2017 at 18:53

1 Answer 1


Living organisms utilize protein based enzymes to catalyze otherwise unfavorable reactions under very mild conditions. They achieve this by bringing the substrates together in a very specific manner. Dehydrogenases are a class of oxidoreductases that oxidize substrates using NAD$^+$. Here is the active site of lactate dehydrogenase:

lactate reductase

As you can see, carbon-4 of the nicotinamide ring is oriented towards the substrate. The orientation of the molecules is why carbon-4 is selectively reduced.


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