Org Prep Daily

September 4, 2013

nitrilotriacetic acid anhydride

Filed under: procedures — milkshake @ 1:48 pm


30 mL of acetanhydride (317 mmol) was added to a slurry of nitrilotriacetic acid N(CH2CO2H)3 50.0g (261.5 mmol) in DMF 100mL. N-methylimidazole 0.21mL (1 mol%) was added and the mixture was stirred and heated on a 60 C oil bath for 6 hours under Ar ā€“ the mixture gradually became homogenous. Neat allyl bromide 0.5mL (2.2 mol%) was then added and the heating was continued for additional 30 min, to inactivate the catalyst. The flask was finally equipped with a shortpath distillation adapter and the mixture was concentrated by vacuum distillation from a 60 C oil bath (1 to 0.1 Torr; the receiving flask was chilled with liquid nitrogen). With most volatiles removed and the distillation residue solidifying, the distillation was terminated and the distillation flask was cooled to ambient temperature under Ar. The residue was dissolved in acetone 300mL (15 min stirring at ambient temperature. Fisher histology grade acetone was used straight from the can). The obtained cloudy solution was diluted with 1,2-dichloroethane 200mL and filtered through a fine-porosity Buchner funnel. The filtrates were slowly concentrated on rotovap from an ambient water bath down to about 150mL total volume. The precipitated crude product (35g) was collected by filtration, washed with dichloroethane and dried in vacuo. The crude product was dissolved in acetone 250mL, the solution was diluted with dichloroethane 250mL and then slowly concentrated on rotovap from ambient water bath, down to about 200mL total volume. The precipitated purified product was collected by filtration, rinsed with dichloroethane and dried in vacuo. Y=31.81g (70% theory) of a light-pink colored crystalline solid that gradually turns white on storage.

1H(d6-acetone, 400 MHz): 3.920(s, 4H), 3.620(s, 2H); 13C(d6-acetone, 100 MHz): 171.18, 165.51(2C), 54.79, 52.54(2C)

Note: The crude product from reaction mixture evaporation residue contains another anhydride species, up to 15% by NMR (similar spectra but shifted downfield), which “disappears” during the workup. It is probably a dimeric bis-anhydride because it gets hydrolyzed by traces of moisture during the workup whereas the desired product is reasonably stable in non-dried acetone (in the absence of N-methylimidazole). The starting material N(CH2CO2H)3 is insoluble in acetone, so it is removed by filtration


  1. Interesting that the solid is initially light-pink and gradually turns white upon storage. I have had white solids that have gone coloured on storage but not the reverse. Is this due to some optical effect after residual solvent evaporation?

    Comment by FleaTamer — September 13, 2013 @ 12:39 pm

    • I suppose the activation produces some unstable impurity that has a pinkish color to it – it is just a faint hue and it goes away. If I had to guess, in system like this you have possibility of forming 1,3-dicarbonyl and 1,3,5-tricarbonyl compounds by condensation with acetic anhydride, and the later one can close to a pyrone, and those can be acylated to 4-acetyloxypyrilium salts, and pyryliums are highly colored (the red and purple dyes in plant leaves and flowers are usually anthocyanins = benzopyrilium salts). But it is a pure speculation

      Comment by milkshake — September 13, 2013 @ 2:14 pm

  2. Its nice to have some experimental work up on here again, Milkshake. I check back every day to look for newly added procedures.

    Comment by Dan — September 17, 2013 @ 5:28 am

    • the difficulty is that in my current position I need to be quite selective about what I put here. In case of a chemical procedure post or anything else that might bear on intel property I always get approval from my superiors first. (A company environment is a different from academia, methodology and process research is different from medchem – and I signed a confidentiality agreement). So the new post frequency here will be probably quite low in the future.

      Comment by milkshake — September 17, 2013 @ 3:46 pm

  3. Good to see you back, Milkshake!

    The tertiary amine doesn’t give you any trouble with the allyl-Br?

    Comment by Honclbrif — September 17, 2013 @ 9:00 am

    • the alkylating agent probably does eat a small part of the product but there is only 2 mol% of allyl bromide total, just enough to take care of the catalyst. Killing the catalyst is really important here so I would rather sacrifice few% on crude yield than have material that is hard to purify because it it keeps hydrolyzing due to the presence of NMI

      Comment by milkshake — September 17, 2013 @ 3:50 pm

  4. Would some kind of solid-supported catalyst be of help? Something you could just filter off and be done with it (no allyl bromide required).

    Comment by Joe Q. — September 20, 2013 @ 3:42 pm

    • But NMI works perfectly well, and it is cheap and used in 1 mol%… and you need just 2 mol% of a volatile allyl bromide to kill it.

      The starting material N(CH2CO2)3 is nearly insoluble in the reaction media and the reaction presumably occurs on the surface of the particles while the starting material is gradually dissolving into the reaction mix. If you tried to use a polymeric DMAP-like catalyst, the effective concentration of the starting material will be negligible inside the catalyst beads while outside the beads the catalyst concentration will be zero (unless the beads are shedding the catalyst). So I don’t think a polymer supported catalyst would work well with this particular substrate. But it might work with some soluble starting material – glutaric acid for example

      Comment by milkshake — September 20, 2013 @ 8:41 pm

  5. Hi,

    I was wondering what purpose the NMI serves in this reaction and why you use allyl bromide to quench it?


    Comment by Valleyofdreams — October 11, 2013 @ 2:01 pm

    • NMI is similar to DMAP – an acylation nucleophilic catalyst. So you get a more reactive acetylation species: 1-methyl-3-acetylimidazolinium salt. It transfers the acetyl to nitrilotriacetic acid (to form a mixed anhydride, which then cyclizes). You need to kill NMI at the end of the preparation by alkylating it – because it is also a very good catalyst for the product hydrolysis and it really destabilizes the crude product to the point that the losses during the recrystallization become a major problem.

      Comment by milkshake — October 11, 2013 @ 2:22 pm

  6. Dear MS,

    I need you help regarding this trasformation.

    I am trying to alkylate the heterocyclic secondary amine (crowded amine) using the tert-butyl (2-fluoro-3-iodopropyl) carbamate however the yield is low along with alkylating reagent undergoes other side reactions and forms cyclic impurity. The reaction hours are also 60 h and the convesrion is also incomplete (10 % sm remains)

    I am planning to use the diboc derivative to minimize the cyclic impurities and isolation improvement.

    Cyclic impurity:

    I am trying to minimize this impurity and exploring different protecting groups without compromising the reactivities.

    I am trying to avoid this impurity so that isolation will be much easier during the scale up.

    Please help me regarding this and how to proceed in this scenario.

    Kind regds


    Comment by marto — August 31, 2014 @ 10:44 am

    • I don’t know what your crowded secondary amine heterocycle looks like (is it aniline, is it benzylamine, is the heterocycle electron-deficient and so on) and this information is probably quite important for suggesting what to do.

      Also, I think your Boc-protected 3-iodopropyl amine is going to cyclize as long as you are using Boc protection. I presume the cyclization product is a 6-membered cyclic carbamate with -NHCO-OCH2-, formed through alkylation of Boc carbonyl oxygen and loss of tert-butyl cation. If that is the case putting second Boc on the amino group will probably not help you. These protected amino-bearing alkylation agents are problematic because of the cyclization sidereactions and if your substrate is unreactive they just decompose instead. So it is a difficult problem. Please what is the starting material that you have available for making 1-Boc-amino-2-fluoro-3-iodopropane? Can you use some other protecting groups other than Boc?

      Comment by milkshake — August 31, 2014 @ 11:01 am

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