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Chemistry Forums for Students => Organic Chemistry Forum => Topic started by: Jfalken on March 13, 2019, 02:31:42 AM

Title: How to chose methylating agent?
Post by: Jfalken on March 13, 2019, 02:31:42 AM: I am supposed to discuss the pros and cons of different methylating agents and what to look for when choosing a proper methylating agent yet I have no idea where to start.
I can discuss it from a safety standpoint but not from a standpoint in regards to efficiency and when to use and not use certain agents. What could limit the use of one.
My overall impression was that Grignard reagents could do the trick but apparently Grignard is Grignard and methylating agents are methylating agents.
Could someone please enlighten me on the topic of methylating agents and how to choose a proper one?
Title: Re: How to chose methylating agent?
Post by: AWK on March 13, 2019, 05:49:46 AM: Methylation in textbook or Wikipedia may be a good starting point.
Title: Re: How to chose methylating agent?
Post by: Jfalken on March 13, 2019, 06:36:59 AM: Quote from: AWK on March 13, 2019, 05:49:46 AM
Methylation in textbook or Wikipedia may be a good starting point.

Could not find anything related on wikpedia.
If there's a website I can learn more about this I would really appreciate if you could link it.
I know there are a lot of websites comparing Sn2/Sn1/E1/E2 rxn but havent seen any of the like for methylating agents.

How to chose a proper methylating agent so to speak. Depending on substrate that will be methylated and solvent of choice or if there's a solvent free rxn.
Title: Re: How to chose methylating agent?
Post by: chenbeier on March 13, 2019, 07:03:52 AM: Check methyl iodide or dimethylsulfate
Title: Re: How to chose methylating agent?
Post by: AWK on March 13, 2019, 07:11:04 AM: Quote from: Jfalken on March 13, 2019, 06:36:59 AM
Quote from: AWK on March 13, 2019, 05:49:46 AM
Methylation in textbook or Wikipedia may be a good starting point.

Could not find anything related on wikpedia.
If there's a website I can learn more about this I would really appreciate if you could link it.
I know there are a lot of websites comparing Sn2/Sn1/E1/E2 rxn but havent seen any of the like for methylating agents.

How to chose a proper methylating agent so to speak. Depending on substrate that will be methylated and solvent of choice or if there's a solvent free rxn.
English Wikipedia under "Methylation" contains quite useful information.
Solvent free means also an excess of methylating agents. Sometimes you can get only side products.
Title: Re: How to chose methylating agent?
Post by: wildfyr on March 13, 2019, 07:21:44 AM: Methyl tosylate should be on the list too.
Title: Re: How to chose methylating agent?
Post by: Jfalken on March 13, 2019, 07:40:38 AM: Quote from: chenbeier on March 13, 2019, 07:03:52 AM
Check methyl iodide or dimethylsulfate

Thanks!
I see that dimethylsulfate is very limited in use today due to its toxicity, from wikipedia.
Wikipedia also suggests that trifluoromethanesulfonic acid and Methyl trifluoromethanesulfonate would be "the next best thing" but how can one reason around that?
What should I look for (properties) in methylating agents so to speak.
Title: Re: How to chose methylating agent?
Post by: Babcock_Hall on March 13, 2019, 09:35:01 AM: IMO you may want to differentiate between cases in which the methyl carbon is electrophilic versus nucleophilic. Also, have you thought about the reactivity-selectivity principle?
Title: Re: How to chose methylating agent?
Post by: Mitch on March 13, 2019, 09:40:45 AM: It sounds like a very open-ended question. Methylation of aromatic rings will be different than methylation of proteins or DNA. You will need to limit your scope.

This review paper covers methylation in medicinal chemistry: The Methylation Effect in Medicinal Chemistry (https://pubs.acs.org/doi/10.1021/cr200060g)
Title: Re: How to chose methylating agent?
Post by: Jfalken on March 13, 2019, 03:29:45 PM: Quote from: Mitch on March 13, 2019, 09:40:45 AM
It sounds like a very open-ended question. Methylation of aromatic rings will be different than methylation of proteins or DNA. You will need to limit your scope.

This review paper covers methylation in medicinal chemistry: The Methylation Effect in Medicinal Chemistry (https://pubs.acs.org/doi/10.1021/cr200060g)

Geez, thanks for that. It will keep me busy for the weekend for sure. Appreciate it! :)

Quote from: Babcock_Hall on March 13, 2019, 09:35:01 AM
IMO you may want to differentiate between cases in which the methyl carbon is electrophilic versus nucleophilic. Also, have you thought about the reactivity-selectivity principle?

I haven't given it much thought to be honest, but I will consider it during the weekend and get back you guys here when I know a bit more on the subject!
Title: Re: How to chose methylating agent?
Post by: Babcock_Hall on March 13, 2019, 06:24:51 PM: Quote from: Jfalken on March 13, 2019, 03:29:45 PM

Quote from: Babcock_Hall on March 13, 2019, 09:35:01 AM
IMO you may want to differentiate between cases in which the methyl carbon is electrophilic versus nucleophilic. Also, have you thought about the reactivity-selectivity principle?

I haven't given it much thought to be honest, but I will consider it during the weekend and get back you guys here when I know a bit more on the subject!
What got me thinking about the first issue is that Grignard reagents are nucleophilic, whereas methyltosylate is electrophilic. The reactivity-selectivity principle is not really much of a principle (it might qualify as a generalization). However, there are times when it is useful.
Title: Re: How to chose methylating agent?
Post by: AlphaScent on March 14, 2019, 01:12:04 PM: Diazomethane.
Title: Re: How to chose methylating agent?
Post by: wildfyr on March 14, 2019, 02:12:00 PM: "Magic" methyl aka methylfluorosulfonate :o hideously toxic and volatile. Mostly outdated by methyl triflate.