Org Prep Daily

August 26, 2008


Filed under: procedures — milkshake @ 12:35 am

meta-Hydrazinobenzoic acid 1.552g (10 mmol) was suspended in concentrated HCl 50mL. Arnold hexafluorophosphate salt 7.10g (15 mmol) was added, followed by acetic acid 100mL. The mixture was stirred for 10 min, then placed on a 100C oil bath and stirred under reflux for 3h 30 min. The reaction mixture was cooled to room temperature, filtered (the insoluble fraction was washed with water) and the combined filtrates were evaporated to dryness. The residue was suspended in water 100mL and stirred on ice bath for 1 hour, the precipitate was collected by filtration, washed with ice-cold water and dried by suction. The crude product was dissolved in a mixture of ethanol 45mL and water 140mL at reflux, charcoal 0.5g was added and refluxed for 5 min, then filtered while warm, the charcoal was washed with 3:1 (v/v) water-ethanol mixture (2x15mL) and the combined filtrates were allowed to cool to ambient temperature, filtered again from a small amount of oil, and the filtrates were stirred vigorously on ice bath for 1 hour. The precipitated product was collected by filtration, and re-crystallized for the second time (from a mixture of ethanol 100mL and water 200mL, 0C, fridge overnight) to provide 1.176g of a 95% pure product as a yellow-white solid (54.5% th)

LC/MS(+ESI): 217(M+1); 1H(d6-DMSO, 400MHz): 13.340(br s, 1H), 9.927(s, 1H), 9.370(s, 1H), 8.437(br t, 1.8Hz, 1H), 8.308(s, 1H), 8.176(ddd, 8.1Hz, 2.3Hz, 1.0Hz, 1H), 7.959(dt, d:7.8Hz, t:1.3Hz, 1H), 7.690(t, 7.9Hz, 1H)

Note: In the absence of conc HCl, the main product is the m-carboxyphenyl hydrazone of the pyrrole aldehyde (= 2:1 condenzation product of arylhydrazine with triformyl methane). HCl slows down the hydrolysis of the iminium groups. Arnold salt preparation was posted here on Feb 24, 2008.


  1. Nice scaffold

    Comment by horks — August 27, 2008 @ 10:45 am

  2. Cool post. This rxn with Arnold Reagent reminds me of the (H.)Gold Reagent that reacts with hydrazines to give triazines but having the aldehyde functionality is indeed a nice handle to do more things.

    Comment by CMC guy — August 27, 2008 @ 11:04 am

  3. the other alternative would be to make the plain pyrazole, with (MeO)2CHCH2CH(OMe)2, then do Vilsmeyer formylation on pyrazole etc – but the carboxyl would have to be protected.

    Comment by milkshake — August 27, 2008 @ 3:51 pm

  4. I am curious: does charcoal really help? I have been told that it just removes traces of colored (polymeric?)impurities. But if I don’t care about the color, does it bring something else? Can it really adsorb NMR-visible amount of impurities? Is it easier to recrystallize a purified with charcoal product?

    Comment by Alexey — August 28, 2008 @ 6:36 am

  5. I can only imagine what kind of a dark-brown mess was it before you came in with your crystallization skills…

    Comment by LiqC — August 28, 2008 @ 7:59 am

  6. milkshake if you went Vilsmeyer route do you think it would be clean? I would have to push the arrows but wonder if you could lack exclusive regiochem control to a degree and also prevent multiple additions. Vilsmer is one reagent/rxn where I have had great results followed by complete mess even though the substrates where similar.

    Alexey can’t speak to this case but I have found charcoal treatments can be very useful for more than colour removal although sometimes you need to just get the correct charcoal as there is variability (acidified, neutral, etc.). I used routinely and not sure if it helped but I did lots of successful recystalliizations. Think there was a OPRD paper on this a few years ago.

    Comment by CMC guy — August 28, 2008 @ 11:16 am

  7. Charcoal is nature’s own reverse phase, I use it quite often. It is nice for removing a smal amount of oil emulsion in polar media like water or alcohol – the oil sticks to charcoal and does not pass through the filter. I suppose I could have poured there C18 reverse phase instead but charcoal is cheaper. The mix was not too colored but there were some greasy impurities I wanted out, the hydrazone for example.

    Normally one would column such a reaction mix but the presence of unprotected carboxyl made it harder to purify it on silica.

    I have not done Vilsmeyer on pyrazole (only on pyrrole) but I know that pyrazoles halogenate or nitrate (with Ac2O+fuming nitric) into the 4-position reasonably cleanly.

    Comment by milkshake — August 28, 2008 @ 3:40 pm

  8. to CMC guy and milkshake: thanks for the hints.

    Comment by Alexey — August 28, 2008 @ 10:35 pm

  9. Does Celite have a similar role like charcoal (absorb greasy impurities)?

    Comment by pmgb — September 7, 2008 @ 3:23 pm

  10. pmgb I think Celite has some ability to absorb certain things but would guess not strong relative to Carbons (think it is component in Kitty Liter although role may be just to soak up water). Recall mainly silicate although think somewhat different than silica gel so not as powerful for chromo. I have mainly used for “physical” separations to remove catalysts and polymeric junk and obsreved did get rid of “baseline” crap and since cheap is good for scale if it works. If compound sensitive to acid or base can prewash with opposite to aid the stability. Best suggestion is to TLC before and after running through a Pipette Plug and see if it helps.

    Comment by CMC guy — September 7, 2008 @ 5:16 pm

  11. Celite is a brand of filtration material made from diatomaceous earth, it is mostly fossilized silica shells left after plankton and it is hydrophilic. (You can actually remove dropplets of water in nonpolar solvents by filtering the emulsion through Celite but MgSO4 works better). Celite does not have strong absorbtion properties like silica gel towards organic molecules – so absorbents based on diatomite (such as Kieselguhr) are rarely used nowadays. The main use of Celite is removal of fine colloids that would normally pass through Buchner funnel filter or gunks that would clog it. (Of course one has to make sure to use fine porosity filter with Celite because it has quite small particle size).

    Comment by milkshake — September 8, 2008 @ 1:51 am

  12. Stumbled across the cite for article mentioned in 6 in case anyone interested: OPRD 2000, 4, 43-45 “Observed Acidities of Charcoals, Clays, and Common Laboratory Purification Reagents in Aqueous and Organic Solutions”

    Comment by CMC guy — September 9, 2008 @ 11:26 am

  13. Iam strugling to protect the carbonyl of the codeinone either using ethylene glycol or triethyl formate using ptsa or ppts or fumaric acid under dean stork conditions. I see lot of michael addition of alcohol or migration of the double bond, etc. one could use oteras tin based catalyst. but on a grand scale they might be a pain in terms of cost and disposal. could u suggest a method to protect the carbonyl on the codeinone.

    Comment by pashu — September 24, 2008 @ 12:12 am

  14. I dont know, there must be a huge literature precedent on the subject and I am not familiar with it – I just faintly remember that morphine is quite acid-sensitive and likes to re-arrange to apomorphine.

    I would suggest to use something mild, like TMS-OCH2CH2O-TMS with a catalytic Lewis acid like ZnBr2 – but I don’t know. You need to do a literature search first.

    Comment by milkshake — September 24, 2008 @ 1:50 pm

  15. thx a ton

    Comment by pashu — September 25, 2008 @ 2:55 am

  16. This one added here:

    Comment by ChemSpiderMan — March 25, 2009 @ 9:35 pm

  17. Hi MS,

    I am struggling to make acid chloride of cyclopropyl acetic acid. I used few conditions, 1. Oxalyl chloride, cat DMF 2. thionyl chloride, DCM rt stirring..but I failed to get the yellow solid (as mentioned in the literture)..I really dont know wahts happening in the reaction mixture..What i get is a colurless oil (very low amount) to find out whether acid chloride was generated or not?

    I removed the solvents after the reported time (4 h) in rotavap under argon atmoshpere..I was planning to use the residue for the cyclization reaction to form triazoles..please help me..i have to meet the timeline for this compound..



    Comment by marto — May 15, 2009 @ 9:43 am

  18. cyclopropylacetyl chloride is a liquid, no melting point is reported in Beilstein/Crossfire. It is quite low-boiling, bp = 120C at atmospheric pressure. It is probably not very stable, because of the cyclopropyl ring acid-catalyzed opening.

    I would recommend preparing it and using it in situ, for example method is here: JOC (1994) 59, 4791. You could probably replace benzene solvent in the preparation with another similar-boiling solvent, such as 1,2-dichloroethane. If you absolutely need to isolate the acyl chloride in neat form, I would recommend doing a fractional distillation at 50-100 Torr (it should boil at around 60C at these pressures).

    Please note that benzene and dichloroethane are slightly higher-boiling than oxalyl chloride – a good thing if you want to remove oxalyl chloride. Use only the slightest excess of oxalyl chloride, like 1.05 equiv., and concentrate your reaction mix only to one half of the original volume, that way you remove most of the unreacted oxalyl chloride without losing too much of your product on the rotovap.

    You can also use chloroform (stabilized with amylene) as a solvent. That way you can directly sample your reaction mix and take NMR in CDCl3, to watch the progress of acylchloride formation – and to confirm its purity. But I never had to to this, usually when the bubbling stops I would stir for few more hours then concentrate

    Comment by milkshake — May 15, 2009 @ 5:35 pm

  19. Hi MS,

    Thanks very much for your timely help..


    Comment by marto — May 16, 2009 @ 1:36 am

  20. Dear Ms,

    I prepared 3-halo piperazine from the corresponding 3-halo aniline and bis (2-chloroethyl) amine hydrochloride in n-butanol at > 100 C. (Sodium carbonate) for 4 days with ~ 50 % yield (10 % Sm remains). I tried many conditions (including aq / other polar solvents) but the reaction is sluggish and also the base is added after 48 h for the better convesrion. The first reaction is intermoelcular and second is intramoelcuar and I am yet to find the optimal volume for the better conversion and also the stability of bis (2-chloroethyl) amine hydrochloride need some undertstanding. My target yield is ~ 65% with the reaction completion in two days time (multi Kg scale), it would be helpful if you could throw more light on what needs to be addressed for these improvements.



    Comment by marto — August 28, 2014 @ 10:52 am

    • First, I don’t have any experience with this particular system, but it does seem messy. If you want the reaction to proceed faster, I would add maybe half equivalent of lithium bromide to it as a catalyst (to do Finkelstein halogen exchange reaction in situ). I would consider using a less basic inorganic base: I think solid KHCO3 (or NaHCO3) should work fine for your purposes – KHCO3 has a slightly better solubility in alcohols than NaHCO3. Maybe with bicarbonate you could load the base all at once, and would have less problem with decomposition. Also Ca(OH)2 is quite nice, and cheap. There is one good solvent that I like, and is relatively under-used: 1-methoxy-2-propanol aka Dowanol PM. It is a less-toxic version of cellosolve. It is water soluble, dissolves inorganics better than n-butanol, its hydroxy group is less reactive, the boiling point is reasonable (120C) and its odor is not bad. It is also nearly invisible on HPLC with UV detection, which makes monitoring the reaction easy. I would give it a try, in your system. Also, I would re-distill the starting aniline and run the reaction under nitrogen, just to limit the light-catalyzed oxidation with air.

      Comment by milkshake — August 28, 2014 @ 12:08 pm

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