I am trying to follow a published paper. It is a one-pot synthesis of pyrazole from a ketone and and acid chloride via a diketone intermediate.

Here is the produre from the paper:

General Procedure: Ketone (2 mmol) was dissolved in 5 mL dry toluene in a screw cap vial (with septum) and then the solution was cooled to 0°C under nitrogen. LiHMDS(2.1 mL, 1.0 M in THF, 2.1 mmol) was added quickly via syringe with agitation stirring and the formed anion was allowed to sit for approximately 1 minute before the addition via syringe of acid chloride (1 mmol) in one portion with stirring. The vial was then removed from the ice bath and allowed to stand for 1 minute, then 2 mL AcOH was added with stirring. 10 mL EtOH and 5 mL THF was added to form a homogeneous mixture, and then hydrazine hydrate (2 mL, 1.1 g, 34.3 mmol) or substituted hydrazine(5 mmol) was added and the mixture was allowed to auto-reflux and was held at that temperature for 5 minutes, when LCMS showed that all diketone had reacted. The resulting solution was added to 1.0 M NaOH solution and extracted with EtOAc. The organic fraction was then washed with brine, dried over Na2SO4, and evaporated under reduced pressure.See specific compounds for purification details.

My questions are:

  1. What is the purpose of excess hydrazine hydrate, acetic acid, and enolate in producing the pyrazole?
  2. How many molar equivalents of sodium hydroxide should I use at the end of the reaction?
  • $\begingroup$ It would be helpful if you copied the text of the exact procedure. As is, it's impossible to tell when or what is added. $\endgroup$
    – Zhe
    Commented Feb 28, 2018 at 3:14
  • $\begingroup$ Good general question, but please narrow it down to specifics. As it stands, it's too broad and a bit unclear (to me). $\endgroup$ Commented Feb 28, 2018 at 4:00

1 Answer 1


Excess hydrazine hydrate to neutralise the AcOH and ensure complete reaction of the diketone.

Excess AcOH to protonate all anions arising from the LiHMDS, mostly to completely protonate the anion of the diketone.

Excess enolate (and LiHMDS) to ensure all the enolate reacts. The diketone product is more acidic than the enolate and will hence protonate the enolate, so you need 2 eqs or more of base/enolate to get complete reaction.

How much NaOH for the wash at the end? More than eqs of AcOH. Don't see why they specify a base wash as everything you want to remove into the aq phase would be aq soluble anyway.

  • $\begingroup$ Making the solution basic helps keepimg the pyrazole in the organic phase. $\endgroup$
    – aventurin
    Commented Feb 28, 2018 at 17:49
  • $\begingroup$ Can pyrazole be deprotonated then? Also, I am assuming hydrazine hydrate replaces the OH of AcOH. Does that make the solution less acidic, hence fewer equivalents of NaOH needed? $\endgroup$ Commented Feb 28, 2018 at 18:32
  • 1
    $\begingroup$ Pyrazole is a relatively weak base (pKb 11.5). It can be deprotonated but that requires strong base. Hydrazine is a strong base so will be fully protonated by AcOH, but the free base is extensively water soluble. $\endgroup$
    – Waylander
    Commented Feb 28, 2018 at 18:48
  • $\begingroup$ One last question. How would a basic solution keep the pyrazole in the organic layer? Why would I need the equivalents of NaOH to be more equivalents of AcOH? $\endgroup$ Commented Mar 1, 2018 at 6:09
  • $\begingroup$ You need more eqs of NaOH than AcOH to ensure the aq is basic. It is possible to protonate pyrazoles and the protonated form is more aq soluble $\endgroup$
    – Waylander
    Commented Mar 1, 2018 at 8:25