Chemical Forums

Chemistry Forums for Students => Organic Chemistry Forum => Topic started by: sharbeldam on June 11, 2019, 02:42:55 PM

Title: How is this reaction done?
Post by: sharbeldam on June 11, 2019, 02:42:55 PM

There is this drug called Selexipag which gets active by this reaction in the liver, can someone direct me to what this reaction called (Converting NHSO2R to OH) ? and what is the mechanism of it?

Title: Re: How is this reaction done?
Post by: jeffmoonchop on June 11, 2019, 02:53:46 PM

Just a guess, is it hydrolysis?

Title: Re: How is this reaction done?
Post by: sharbeldam on June 11, 2019, 03:01:16 PM

I honestly knew someone was going to say that, but I want a deeper answer, like I know the mechanism of ester hydrolysis, but this is different I guess, No?

Title: Re: How is this reaction done?
Post by: Borek on June 11, 2019, 03:30:10 PM

If it is vitro most likely some enzyme is responsible.

Title: Re: How is this reaction done?
Post by: sharbeldam on June 11, 2019, 04:40:13 PM

the enzyme is carboxylesterase 1 but do you think the mechanism is the same as the ester/amide hydrolysis? as in the nitrogen will be protonated and then the NH2+SO2R become a leaving group just like the OR in ester?

Title: Re: How is this reaction done?
Post by: clarkstill on June 11, 2019, 04:44:01 PM

I think more likely the latter - the pKa of methanesulfonamide is 17.5 according to Bordwell (https://www.chem.wisc.edu/areas/reich/pkatable/ (https://www.chem.wisc.edu/areas/reich/pkatable/)), only 2 units or so higher than an alcohol so you'd expect a similar leaving group ability. I don't think it's plausible that the N becomes protonated - that nitrogen is a terrible base (at least not by specific acid catalysis, i guess a general acid catalysis mechanism is plausible).

Title: Re: How is this reaction done?
Post by: David Tan on June 14, 2019, 04:46:53 PM

Treat it as an amide and don't let the "sulfoxide" distract you. Just perform an acidic hydrolysis on an amide and you would get the carboxylic acid group. Do the same for this molecule. Hope it helps.

Title: Re: How is this reaction done?
Post by: hollytara on June 15, 2019, 02:02:36 PM

This is a mixed imide: one side is a carboxylic acid, the other side a sulfonic acid.  The sulfonamide is the better leaving group.  Bordwell lists pKa of methanesulfonamide in DMSO as 17.5, but other references have pKas that are more acidic (in the range of 4-10).  The phenylsulfonamides can be deprotonated and solubilized in water. 

I could see either ester or amide hydrolysis enzymes working on this.

Title: Re: How is this reaction done?
Post by: rolnor on June 15, 2019, 03:56:31 PM

Hollytara, I sent you a PM about something, can you please respond, its important.
Thanx.