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I was about to set up the following reaction, but before I do, I wanted to see if anyone has some suggestions or thinks this will not work:

  • 24mmol Nboc protected ethyl 2-amino-1H-imidazole-5-carboxylate
  • 2mmol 1,800Da bPEI (should have ~12 amines available for reaction according to this https://www.sciencedirect.com/science/article/abs/pii/S0014305720317316)
  • 10mL methanol
  • 5 days at room temp
  • Ive seen reactions like this performed under nitrogen, is this absolutely necessary and should I also bubble nitrogen through my reagents for a while before letting it run?
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  • $\begingroup$ Also, should I add something to catalyze the reaction? Is there anything less exotic than these ionic liquids that I might have on hand that would help but will not cleave my Boc? chemistry-europe.onlinelibrary.wiley.com/doi/abs/10.1002/… $\endgroup$
    – toodles
    Feb 10, 2023 at 0:42
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    $\begingroup$ The nitrogen is to keep the reaction mixture dry as MeOH will absorb water from the atmosphere if left open, it also reduceds evaporative loss of MeOH. $\endgroup$
    – Waylander
    Feb 10, 2023 at 7:35

1 Answer 1

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PEI stands for Poly(ethyleneimine). There would be variety of PEI solutions (e.g., PEI1800), each of which have different numbers of free primary amine groups. Therefore, make sure the solution you are using have the correct amount of $\ce{NH2}$ groups available for the reaction. In Ref.1 (the reference you have given as example), the authors have capped different number of $\ce{NH2}$ groups in PEI1800 using different amounts of capping agents (reaction with at different molar ratios) as needed (capping agent examples: Imidazolyl and guanidyl). Although the procedures are different for each and different capping reagent, the authors have let each capping reaction stirring at $\pu{75 ^\circ C}$ for $\pu{8 h}$ with nitrogen.

The important fact you have forgot to mention when using PEI is that you may need to lyophilize the material in order to remove all water in the solution before subjected to undergo further reactions like capping $\ce{NH2}$ groups. According to the Ref.1, PEI1800 was lyophilized before use and the product was also lyophilized after, before they use them in the intended research. Also, in the text of the Ref.1 says that free $\ce{NH2}$ groups in PEI1800 is 16 (not 12 as you mentioned). Thus, if you want to cap all of free $\ce{NH2}$ groups, you may need to uses excess capping reagents.

As Waylander suggested and the authors of the Ref.1 have done, keeping the reaction under nitrogen would be better. However, a 5-day reaction time is too long and asking for trouble. Thus, I'd like to suggest to use a catalyst to shorten the reaction time. The one good, cheaper catalyst would be cyanide ions $(\ce{NaCN})$, which would dissolve in methanol (Ref.2). If you like to use an organic catalyst instead, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) would be a good addition (Ref.3) in aminolysis of ester. Regardless of what you have used, your protective group would be safe as long as you have avoided acidic conditions.


References:

  1. Jie Song, Dongli Wang, Jing Wang, Qing Shen, Cao Xie, Weiyue Lu, Ruifeng Wang, and Min Liu, "Low molecular weight polyethyleneimine modified by 2-aminoimidazole achieving excellent gene transfection efficiency," European Polymer Journal 2020, 140, 110017 (11 pages) (DOI: https://doi.org/10.1016/j.eurpolymj.2020.110017).
  2. Thomas Hoegberg, Peter Stroem, Michael Ebner, and Sten Raemsby, "Cyanide as an efficient and mild catalyst in the aminolysis of esters," J. Org. Chem. 1987, 52(10), 2033–2036 (DOI: https://doi.org/10.1021/jo00386a025).
  3. Cyrille Sabot, Kanduluru Ananda Kumar, Stéphane Meunier, and Charles Mioskowski, "A convenient aminolysis of esters catalyzed by 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) under solvent-free conditions," Tetrahedron Letters 2007, 48(22), 3863-3866 (DOI: https://doi.org/10.1016/j.tetlet.2007.03.146).
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  • $\begingroup$ I dissolved my ester and bPEI in methanol, rotovapd it dry, then redissolved into methanol that i freshly dried with magnesium sulfate, added half a handful of molecular sieves, suba sealed the flask and flushed with nitrogen. You think it might turn out okay or should I just reset it up once the catalyst comes in next week? Didnt have any cyanide on hand $\endgroup$
    – toodles
    Feb 11, 2023 at 0:10
  • $\begingroup$ Did your PEI in powdered form to bigin with? If so, your set up would be good enough for me. If PEI is in a solution, lyophilization (freeze-driing) is important. $\endgroup$ Feb 11, 2023 at 16:03
  • $\begingroup$ I didnt lyophilize it before hand, im using a 99% pure viscous liquid thats been open and in use for a couple years in our lab. i suppose it might still have had some moisture even after I rotovapd it since it was still bubbling slightly when I stopped the rotovap, at the time I thought that was either the ester or the PEI starting sublime/evaporate. Instead of lyophilizing can I also just dissolve it in methanol and dry that with MgSO4 before mixing with my ester and then do the rest of my process? $\endgroup$
    – toodles
    Feb 11, 2023 at 22:55
  • $\begingroup$ Do the reaction in small scale to see it would work. If it didn't give a good yield, you should lyophilize the substrate. $\endgroup$ Feb 12, 2023 at 3:23
  • $\begingroup$ Yeah fair enough, thanks very much for bearing with me and answering all that! $\endgroup$
    – toodles
    Feb 12, 2023 at 4:22

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