Org Prep Daily

September 25, 2006

N,N,N’,N’ -tetramethylguanidinium azide

Filed under: procedures — milkshake @ 8:54 pm


Neat azidotrimethylsilane 13.30mL (100mmol) was added to a solution of N,N,N’N’-tetramethylguanidine 12.55mL (100mmol) in cyclohexane 100mL. Methanol 5mL (125mmol) was added dropwise with cooling on ambient water bath (exothermic) and the mixture was stirred for additional 1 hour. The precipitated product was quickly transferred into a funnel for positive pressure filtration (or a fritted short chromatographic column), the supernatants were expelled under positive pressure of  dry nitrogen, the solids were washed with cyclohexane and hexane, then dried under stream of dry nitrogen. Y=15.98g (100%) of a white extremely hygroscopic solid.

This is an organic-soluble azide that that works wonderfully for substituting halides, sulfonate esters with azide in anhydrous acetonitrile. Please do not use heavy metal salts or chlorinated solvents in combination with azides if you want to live. Evans group originally reported use of this azide in refluxing DCM (which worked for their reactive substrates on small scale) but in Hruby lab there were several serious detonations caused by diazidomethane accumulation on rotavap when evaporating react. mixtures from large-scale experiments performed in DCM. Always use acetonitrile, DMF, etc. but not chlorinated solvents. Azide is a powerful nucleophile and will displace “unreactive” chlorine. 

TMS-azide has lower volatility than HN3 (and is also non-explosive) but is almost as toxic upon inhalation and skin contact because of its facile hydrolysis. Use gloves with TMSN3. Azide acute poisoning produces excruciating headaches and vertigo – old-time peptide chemists (doing azide couplings) swore that orally-administered ethanol (40-50%) in large volume was a quick antidote to hydrazoic acid. There is also a story about chemist who was trying to wipe a TMSN3 spill in glovebox and he was found unconcious – still hanging from the glovebox sleeves because TMSN3 soaked through the rubber sleeves. 

Update: TMG azide can be also generated in situ and used as a solution, see Org Prep Daily, August 27, 2008


  1. This is not just a prep, but theory+experimental+MSDS and what not. Thank you Milkshake.

    Comment by pmgb — May 14, 2008 @ 2:50 am

  2. Dear MS,
    Very good prep..
    I don’t understand how Ethanol acts as antidote? could u please explain !!!


    Comment by mangalesh — May 25, 2008 @ 12:31 pm

  3. probably just a symptomatic treatment…

    Comment by milkshake — May 26, 2008 @ 4:45 am

  4. […] [3] Fieser suggests chloroform as a solvent for the azide substitution reaction, which isn’t something I would ever recommend. […]

    Pingback by Fieser and Fieser: A Labful of Tips | Chemtips — November 25, 2013 @ 4:02 am

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