Methyl amine w/ a sulfonyl chloride

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Discussion Overview

The discussion revolves around the challenges of synthesizing sulfonamides using methyl amine and sulfonyl chlorides. Participants explore various experimental conditions and techniques to facilitate the reaction, which is typically straightforward with secondary amines.

Discussion Character

  • Experimental/applied, Technical explanation, Debate/contested

Main Points Raised

  • One participant reports difficulty in obtaining the desired sulfonamide product when using methyl amine with sulfonyl chloride, despite it being a straightforward reaction with secondary amines.
  • Another suggests adding a base and inquires whether the methyl amine is used in its neat form or as an aqueous solution, and proposes heating the reaction.
  • A participant mentions using a 2.0 M solution of methyl amine in THF, observing the formation of a white precipitate that is not the desired product, and questions if the proton on the amine could react with something else.
  • One participant proposes adding triethylamine and suggests that the precipitate might be methylamine-HCl, while also recommending an inverse addition method for the sulfonyl chloride.
  • A later reply indicates success with the hydrochloride salt of methyl amine and the use of DIEA, acknowledging the previous suggestions.

Areas of Agreement / Disagreement

Participants express varying opinions on the best approach to achieve the reaction, with no consensus on a single effective method. Multiple strategies are proposed, and some participants share their experiences without agreement on the underlying issues.

Contextual Notes

Participants mention the potential formation of unexpected byproducts and the influence of reaction conditions, such as the solvent and temperature, on the outcome. There are also references to the confidentiality of materials being used, which limits detailed descriptions.

Who May Find This Useful

Researchers and practitioners in organic chemistry, particularly those working with amines and sulfonyl chlorides, may find this discussion relevant for troubleshooting similar reactions.

gravenewworld
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Does anyone have any secret tricks to get this rxn to go? Usually a secondary amine with a sulfonyl chloride gives the sulfonamide really easily, but I am now trying it w/ methyl amine, which is obviously primary, and it does not want to go at all. I tried dissolving the sulfonyl chloride in ethyl acetate and adding the amine which LC/MS said didn't work. I also tried dissolving the sulfonyl chloride in ethyl acetate, adding 15 eq. of methyl amine, and some DMAP, still without success according to LC/MS. Anyone have any bright ideas on how to get this one to go?
 
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Maybe add a little base? That's really weird. That reaction should go like a shot. Are you using neat MeNH2 or the aqueous solution? What about heating it up for a while?
 
I am using methyl amine in THF 2.0 M solution. When I add the amine to the solution a white precipitate forms, but its not my product. It is some mystery compound w/ a mass I don't recognize in the LC/MS. Can that extra proton on the amine moiety fall off and react w/ something else in the reaction? The UV trace on the LC/MS didn't show a peak for my desired compound at all. Would heating still help it then? I wish I could be more descriptive w/ the material I am working with, but its confidential.
 
Heh, I understand the confidentiality thing. Is it a heterocycle by any chance?

I would start by trying to add 2 equiv of triethylamine. The solid might be methylamine-HCl, but you should get at least some of your desired produce.

Does the LCMS hit for MeNH2 reacting with 2 equivalents of sulfonyl chloride? If that is the case then try an inverse addition (add a solution of the sulfonyl chloride dropwise to the MeNH2 solution).

Any other reactive functionalities in the sulfonyl chloride part?

You might also just try a test reaction with MeNH2 and tosyl chloride just to make sure that it isn't a problem with your technique or something. There ought to be a procedure for that exact reaction out there somewhere.
 
Last edited:
Hmm for some reason I got the reaction to go using the hydrochloride salt of methyl amine w/ some DIEA. Thanks for the suggestions though.
 
Hey, whatever works!
 

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