I am forming succinimide ester:

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Below is the experimental protocol I have adapted from (ACS Chem. Biol. 2012, 7(2), 316–321) pg 7 in supporting information:

Formation of Activated Ester

N-Succinimidyl Trifluoroacetate (15.0 mmol, 5 equiv) was placed in a flask. The flask was backfilled with Nitrogen, capped with a rubber septum, and maintained under an argon atmosphere. To the flask were added THF (15 mL, 0.2 M) and 2,2-dimethoxyacetic acid (3.00 mmol, 1 equiv). Pyridine (1.69 mL, 21.0 mmol, 7 equiv) was added by syringe dropwise (over 3 min, slightly exothermic). The mixture was stirred in the dark (3 h, producing a homogeneous solution), quenched with water (5 mL, 5 min), and diluted with DCM (45 mL) and water (50 mL). The organic phase was isolated, the aqueous phase was further extracted with a mixture of DCM and THF (3:1, 25 mL), and the combined organic phases were washed with sodium bisulfate (0.1 M aqueous, 40 mL) and dried with sodium sulfate. Volatiles were removed under reduced pressure

  1. Could somebody provide the mechanism of this reaction? My guess is that pyridine abstracts hydrogen in the carboxylic acid, and the lone pair on oxygen attacks the carbonyl centre in N-Succinimidyl Trifluoroacetate.. Is this correct? I could not rationalise why 5 equiv. would be needed.

  2. The reaction did not quite work out and I think it may be attributed to the fact that I did not have pure N-Succinimidyl Trifluoroacetate to begin with. When forming N-Succinimidyl Trifluoroacetate, I saw two peaks in 19F NMR at $\delta \: \pu{-72.14 ppm}$ and $\delta \: \pu{-75.62 ppm}$. I believe a peak at $\delta \: \pu{-75.62 ppm}$ was unreacted Trifluoroacetic anhydride. The 1H NMR showed that there was some unreacted N-OH succinimide. I want to figure out what kinds of side products these unreacted materials have led, but to do that, I believe I must understand the mechanism of this reaction first.

Would appreciate any help or guidance

  • 1
    $\begingroup$ Your suggested mechanism is only the first step which would generate the mixed anhydride of TFA and dimethoxy acetic acid. What has to happen then is the O- of the N-hydroxysuccinimide has to attack the mixed anhydride. Remember the pyridine that is present can also act as a nucleophile displacing the hydroxy succinimide from the starting material. I think the mixed anhydride is the key intermediate. $\endgroup$
    – Waylander
    May 23 '19 at 14:48
  • 1
    $\begingroup$ @Waylander: Agreed! The pyridine cleaves the TFA (exotherm) group and the resultant salt forms the mixed anhydride. This step should be reversible back to the starting material because the TFA half of the mixed anhydride is more reactive. Ultimately, the dimethoxy acetic acid half of the mixed anhydride reacts irreversibly with N-hydroxysuccinimide. $\endgroup$
    – user55119
    May 23 '19 at 20:35
  • $\begingroup$ @Waylander thank you. But by the sound of it, I still should have got some product out but I don't see anything. Do you think there is any chance that sodium bisulfate has hydrolysed the acetal group? $\endgroup$
    – chemrese
    May 24 '19 at 5:24
  • $\begingroup$ The pKa of sodium bisulfate is 1.99 so yes it is quite possible you hydrolysed the acetal $\endgroup$
    – Waylander
    May 24 '19 at 7:05
  • $\begingroup$ @Waylander Would using brine, NaHCO3 and NH4Cl solve the issue? $\endgroup$
    – chemrese
    May 24 '19 at 8:08

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