Org Prep Daily

July 25, 2007

2-Chloro-5-iodobenzoic acid tert-butyl ester

Filed under: procedures — milkshake @ 6:26 pm


2M oxalyl chloride solution in dichloromethane 60mL (120 mmol) was added to a slurry of 2-chloro-5-iodobenzoic acid 19.41g (68.71mmol, Lancaster) in dichloromethane 40mL followed by 4 drops of DMF. The flask was equipped with a Drierite-filled tube as a gas outlet and the mixture was stirred for 4 hours. The homogenous reaction mixture was diluted with toluene 25 mL and evaporated to dryness. The obtained solid acyl chloride was dissolved in anh THF 20mL under Ar and the solution was added dropwise into a stirred slurry of sodium tert-butoxide 7.2g (74.9 mmol, 97%, Aldrich) in anh. THF 150mL at 0C. (The acyl chloride flask and syringe was washed with anh. THF 2x10mL and washing also added to the reaction mixture). The mixture was stirred at 0C for 90 min, warmed up to RT, silica (30g) was added to the reaction mixture followed by water 0.4mL, stirred for 20 min, filtered through a plug of silica (2×1 in) , the silica was washed with additional THF (200mL).  The filtrates were evaporated and the residue was dried on highvac overnight.
Y=22.69g (97.5%) of a pale yellow oil.

1H(d6-DMSO, 400MHz): 7.987(d, 2.2Hz, 1H), 7.862(dd, 8.5Hz, 2.2Hz, 1H), 7.331(d, 8.5Hz, 1H), 1.538(s, 9H)


  1. Milkshake, in your 1st step, do the DCM & DMF have to be dry? What’s the yield % of the acyl chloride? Thanks.

    Comment by Taitauwai — July 25, 2007 @ 8:39 pm

  2. I guess the acyl chloride yield was quantitative but I was in hurry and did not want to wait until all toluene traces were gone on highvac so I took it right to the next step.

    DCM does not have to be that dry – as long as there is no ethanol stabilizer in DCM. I usually take anhydrous grade but in this case I was lazy and took a bottle from the shelf because I had an old dubious bottle of oxaloyl chloride solution that was a bit yellow and bottle cap was corroded all over – and I wanted to finish it off so I added excess of oxalyl chloride, almost 2 equivs whereas 1.4 equivs is more than plenty. I figured that given the sloppy circumstances, a little moisture woun’t hurt anything.

    DMF is added in catalytic amount (the lesser the better because the produced Vilsmeyer reagent – that works as the actual catalyst – [Me2N=CHCl](+)Cl(-) can interfere in the next step and the gas evolution during acyl chloride formation can be too fast if you add too much DMF). So it does not matter if the tiny quantity of used DMF is that dry – but there should be no fishy dimethylamine in DMF, if possible.

    If you get a good oxaloyl chloride, using just 1.1 equivs plus 2 drops of DMF is enough for any small scale.

    Comment by milkshake — July 25, 2007 @ 8:53 pm

  3. What are the pros and cons of the various chlorinating agents? Oxalyl chloride, thionyl chloride, phosgene, etc…
    I have always used the [SOCl2 / DMF cat] like many others, but I am clueless as to why it would be better.

    Comment by Spiro — July 25, 2007 @ 8:56 pm

  4. I don’t know – my impression was that oxalyl chloride was somewhat more powerful and less messy than thionyl chloride but this could have been just my impression and bias. Phosgene is probably even more powerful than oxalyl chloride – but there is the price issue and the toxicity – and oxalyl chloride always worked fine for me.

    Comment by milkshake — July 25, 2007 @ 9:03 pm

  5. RE #3: Oxalyl chloride usually gives cleaner products, but it is more expensive (0.15 $/mmol) than thionyl chloride (0.02 $/mmol) on larger scale. I’ve only encountered sulfur containing byproducts from SOCl2 on a few occasions. I’ve always avoided phosgene because of the safety concerns.

    Comment by atompusher — July 30, 2007 @ 12:45 pm

  6. Will DCC, DMAP, t-BuOH work

    Comment by Yuming — July 30, 2007 @ 6:30 pm

  7. I am following a prep (DOI: 10.1021/jm070125f See molecule 6a) where they are using the (COCl)2 to go from ArCOOH to ArCONHR. Here the additions are made at zero degrees. Any comment on reaction temp difference going from your butoxide to their amine? Also, I much rather use (COCl)2 than SOCl2. No need for heating or smelling up your rotovap!

    Comment by VTChris — August 9, 2007 @ 4:37 pm

  8. It is better to cool it on ice: these acylation tend to have a strong exotherm so if you do it on a scale or in a concentrated reaction mixture and you add acyl chloride too quickly, it can jump at you right back.

    Comment by milkshake — August 10, 2007 @ 3:58 am

  9. Is yet another great blog going by the wayside???

    I’d just like to say I truly look forward to your articles. Keep up the great work!


    Comment by Javaslinger — August 13, 2007 @ 7:23 pm

  10. I just currently have nothing worth posting. Sorry kids. When I have anything, you will see it here. If you want more content, send me a good procedure, I will be delighted to put it up here, with full credits given. You can get the admin rights, too.

    Comment by milkshake — August 14, 2007 @ 10:00 am

  11. Thionyl chloride just fricking sucks. Too stinky/messy for my taste.

    Oxalyl chloride’s decent. It’s not messy, but just stinky. But milkshake, I gotta ask you, do you just rotavap the oxalyl chloride off using the water aspirator? I once used a pump, and ended up having to replace a part on it that set us back 400 bucks. So I normally use the water aspirator, but I feel uneasy about the amount of HCl vapors going down the sink, despite a basetrap being present…

    Comment by wisemanleo — August 15, 2007 @ 4:12 am

  12. We use teflon (piston) dry pump from KNF for our rotavaps and we had no trouble with them so far (the Buchi teflon pump are a poorly designed and unreliable piece of clunk and Welsh teflon pumps are mediocre in terms of their reliability) We use the basic Buchi rotavaps with dry ice/acetone cold finger as a condenser. I think it is a good idea to clean up the rotavap from HCl, when done.The rotavap seals will last longer and there will be less smoke if somebody evaporates triethylamine mixture afterwards.

    For unprotected metal surface, HCl is exceptionally corrosive and non-teflon pumps are eaten if you let them sit with HCl in them. I killed a nice oil pump with HCl (accidental product decomposition during vac distillation) and the pump re-building cost was $800 and the pump is not as good as it used to be any more. So for oil pump one should have a HCl vacuum trap, with soda lime or KOH – if it is likely that lots of HCl can get in.

    Comment by milkshake — August 15, 2007 @ 5:55 am

  13. Great info, thank!

    Comment by wisemanleo — August 15, 2007 @ 10:26 am

  14. Hi all,
    Thionyl chloride, despite its less reactivity is preferred on large scale due to the high reactivity of oxalyl chloride.

    Comment by vasili — January 20, 2008 @ 2:04 pm

  15. Hi, thionyl chloride is preferred on the large scale because it produces only one mole of gas whereas oxalyl chloride produces two.
    Oxalyl chloride is great however lately i’m having problems with it because my acid chloride is slightly volatile and so i cannot isolate it after the acylation. Tried other methods like DCC, DCC/HoBt, EDC, HBtU and HAtU however i’ve got a free alcohol on the amine which screws things up…. the joy of chemistry 🙂

    Comment by D — March 20, 2008 @ 12:26 pm

  16. The nice thing about oxaloyl chloride is that you can use it in stoechiometric ratio, like 1.02 equiv, if you need – just give it a drop of DMF and a good stir overnight.

    There is the TFFH reagent available from Aldrich that makes acyl fluorides in situ. (It is very expensive because Carpino has patent on it and it is exceedingly easy to make on large scale, the procedure was posted here on Sept 5 2006)

    Comment by milkshake — March 20, 2008 @ 9:14 pm

  17. We were very satisfied with the use of Boc2O + DMAP for synthesizing t-Butyl esters.

    Comment by kat — August 20, 2008 @ 12:19 am

  18. You are right – Boc2O/DMAP is a much milder alternative (but I have not tried it myself). I have been using the iPrNHC(OtBu)=NiPr reagent previously but the cleanup and yield wasn’t that good.

    In this simple case it was fairly convenient to use t-butoxide because the cleanup was quick – just the silica plug filtration.

    I think tBu esters are fairly under-used in the synthesis – they are robust and often help to make the products more crystalline.

    Comment by milkshake — August 20, 2008 @ 1:12 am

  19. just wondering why you added toluene? i’ve also seen examples of the addition of benzene during the work-up.

    is this some kind of azeotropical removal? if so, what is happening here?

    Comment by steve — June 2, 2009 @ 3:55 am

  20. I just needed something higher-boiling than oxalyl chloride, so that I could do a simple evaporation and not to worry about oxalyl chloride leftover trapped in the product. Benzene would have worked too for the purpose

    Comment by milkshake — June 2, 2009 @ 3:58 am

  21. Hi MS,

    I am having problem in protecting the carboxyl group of L-cystine as tert butyl (Amino group is free). Used tert butyl acetate under perchloric acid conditions but the reaction gave inconclusive reaction mixture. Please suggest me any other conditions if you have any experience.



    Comment by marto — April 19, 2011 @ 3:10 am

  22. Please do you have a good literature precedent? Cystine is a simple aminoacid dimer, people must have tried to make tBu ester from it, so if you cannot find a procedure in Scifinder it probably cannot be done. I think the problem is with sulfur: you have it protected as disulfide (which is not a very robust protection) and you generate tBu cation which is a strong electrophile. I think disulfide is not compatible.

    I would recommend to find some acid-stable sulfur protecting group, for example AcNH-CH2-S, and use S-protected cystein to make the ester.

    Comment by milkshake — April 19, 2011 @ 7:39 pm

  23. Hi MS,

    Thanks for the suggestions.
    There are literature procedures for this conversion (Tet 2002, 58 (44), 9101-9110 & Angew. Chem. Int. Ed. Engl 2008, 47 (49), 9472-9475.). But strangely we are not able to reproduce this reaction.


    Comment by marto — April 20, 2011 @ 7:48 am

    • I don’t have experience with this procedure. The only change I can think of is to use triflic acid instead of perchloric (less explosion hazard that way) and start at lower temperature. Are you sure you are using cystine (the S-S dimer), not cystein (SH)?

      Comment by milkshake — April 20, 2011 @ 8:45 pm

  24. I am wondering if doing the reaction in THF will cause any problems? I did a similar one with THF instead of DCM and the Proton NMR did not look right? I used THF as my acid substrate is insoluble in DCM.

    Comment by charles — June 1, 2012 @ 6:22 am

    • if you are just trying to prepare acyl chloride, please stick with chlorinated solvents like DCM, chloroform (alcohol-free) or 1,2-dichloroethane. It is very common that the starting acid is highly crystalline and poorly soluble in chlorinated solvents but the acyl chloride is oily and very soluble in it. Try the oxalyl chloride (+ 1 drop of DMF) method, it should go into solution with gas evolution gradually overnight at room temperature. If everything else fails you can prepare acyl chloride by reflux with neat thionyl chloride which is a pretty good solvent on its own, the only issue is then the difficulty to remove all sulfurous impurities from the acyl chloride product, this usually requires a vacuum re-distillation.

      THF is poorly suitable because it reacts with thionyl chloride or POCl3 at refluc to produce bis-(4-chlorobutyl)-ether. It reacts with ZnCl2 and benzoyl chloride to produce chlorobutyl benzoate. Diluted phosgene solution (by diluting commercial 20% phosgene in toluene with THF) is compatible with THF for few hours at 50 C so I suppose in desperation you can use phosgene with 1 drop of NMP as a catalyst in anh THF (at room temperature) to generate acyl chloride in situ, but please try the more conventional methods first

      Comment by milkshake — June 1, 2012 @ 4:20 pm

  25. Maybe I am missing the obvious, but why are you quenching the reaction with silica?

    Comment by MasterChief — September 26, 2013 @ 9:50 am

    • silica mops up the salts and a slight excess of tBuONa used in the reaction better than filtration alone

      Comment by milkshake — September 26, 2013 @ 10:41 am

  26. Can we make Di Tert-Butyl oxalate using the same method?

    Comment by Vasantha — January 29, 2018 @ 9:29 pm

    • I think so, yes. Since oxalyl chloride is extremely reactive, I would try the reaction at -78C first, in THF and mabe use KOtBu from Acros, KOtBu is slightly more soluble and also less expensive in bulk than NaOtBu, it just used to have filling and packaging-related quality problem due to its extreme hygroscopicity but Acros product is good, if you use fresh bottle. You need to transfer KOtBu fast, using wide funnel, measure just some approximate amount of KOtBu into the reaction flask (before adding THF) and adjust oxalyl chloride amount based on that

      Comment by milkshake — January 30, 2018 @ 6:46 am

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