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Chemistry Forums for Students => Organic Chemistry Forum => Organic Chemistry Forum for Graduate Students and Professionals => Topic started by: Reddart on December 16, 2016, 08:20:36 AM

Title: Methylating a tertiary amine with MeI in the presence of a carboxylic acid or OH
Post by: Reddart on December 16, 2016, 08:20:36 AM
Is it possible to make the quat amine salt from a tertiary amine and MeI in the presence of an acid, or an alcohol?

I would think I would get methyl ester/methyl ether formation. I'm going with the protection route for now, but it would be nice not to have to do that.

Title: Re: Methylating a tertiary amine with MeI in the presence of a carboxylic acid or OH
Post by: rolnor on December 17, 2016, 02:36:24 AM
I think you will get the methylester but not methylether. You could perhaps protect the acid and ether with hexamethyldisilazan to give the TMS-ester and TMS-ether? :)
Title: Re: Methylating a tertiary amine with MeI in the presence of a carboxylic acid or OH
Post by: Dan on December 17, 2016, 05:32:35 AM
I suppose it is theoretically feasible provided your compound is not in zwitterionic form. If you can run the reaction without deprotonating the carboxylic acid, I guess it should be possible.

So it's probably not possible in water (due to zwitterions), but in a non-protic solvent maybe it could be done given that the pKas of acetic acid and triethylammonium in DMSO are 12 and 9 respectively source (http://www.chem.wisc.edu/areas/reich/pkatable/) (i.e. very little formation of triethylammonium acetate in DMSO). I would give it a shot on test scale.
Title: Re: Methylating a tertiary amine with MeI in the presence of a carboxylic acid or OH
Post by: Optimist on December 17, 2016, 08:28:30 PM
In my point of view better first to protect carboxylic acid using tert-butyl group and then react amine with Methyl trifluoromethansulfonate or MeI in the presence of some base (TEA, DIPEA). There is high probability that you end with methyl ester without carboxylic acid protection.



Title: Re: Methylating a tertiary amine with MeI in the presence of a carboxylic acid or OH
Post by: Dan on December 18, 2016, 05:07:29 AM
Also, does methyl ester formation really matter? You could just saponify during workup.

Reddart, have a look at the literature, there is precedent (e.g. carnitine (analogue) synthesis). However, it is not always clear in these examples whether methyl ester forms but is hydrolysed in workup.
Title: Re: Methylating a tertiary amine with MeI in the presence of a carboxylic acid or OH
Post by: pgk on January 11, 2017, 05:57:55 AM
1). Etherification of an alcohol with alkyl halides (Williamson synthesis), demands the formation of the corresponding alkoxide which cannot be effectuated with a mild base such as a tertiary amine. Thus, quaternization of a tert-aminalcohol can be effectuated by addition of an alkyl halide without preliminary protection of the alcohol group.
2). The reaction of a free carboxylic group and tertiary amine leads to the formation of the corresponding tert-ammonium carboxylate salt. The so formed carboxylate anion is rather a strong base, as deriving from a rather weak carboxylic acid. Thus, the so formed carboxylate anion can attack to the MeI and form the corresponding methyl ester by removing iodine, which is an easily eliminating group, via a SN2 mechanism. Even a little formation of the tert-ammonium carboxylate salt (e.g in DMSO) is enough because the reaction propagates according the Le Chatelier’s principle. Furthermore, the little amount of quaternary ammonium iodide that is simultaneously formed, behaves as a phase transfer catalyst that accelerate the reaction that can so occur under mild conditions. Thus, preliminary protection of the carboxylic group is necessary prior quaternization.
Selection of the protecting methods depends on the particular molecular structure and the neighboring functional groups (e.g. alcohol, phenol groups, etc.)
If esterification is the selected protecting method, don’t worry about farther amine catalyzed transesterification by the free OH group, because transesterification demands high temperatures and long reaction times, in general. 


Title: Re: Methylating a tertiary amine with MeI in the presence of a carboxylic acid or OH
Post by: rolnor on January 12, 2017, 03:46:19 AM
Boil a few minutes in hexamethyldisilazane, evaporate, dissolve in dichloromethane, add MeI och wait, add some MeOH end evaporate, you get the Q-salt.
Title: Re: Methylating a tertiary amine with MeI in the presence of a carboxylic acid or OH
Post by: pgk on January 12, 2017, 06:07:30 AM
Question: Does TMS deprotection procedure in the next step, affect the so formed quaternary salt?
Title: Re: Methylating a tertiary amine with MeI in the presence of a carboxylic acid or OH
Post by: rolnor on January 13, 2017, 02:27:48 AM
No, the Q-salt is very stable.
Title: Re: Methylating a tertiary amine with MeI in the presence of a carboxylic acid or OH
Post by: pgk on January 13, 2017, 03:55:12 AM
Indeed, quaternary amine salts are very stable.
On the other hand, the usual method of TMS deprotection is treatment with aqueous or etheral (THF included) HCl solution. As a consequence, there will be many different ions in the reaction medium, such as H+, R4N+, Cl-, I- , as well their corresponding non-ionized compounds, in equilibrium; which means that at end, there will be obtained a mixture of R4NI and R4NCl that both are very stable, of course. 
Title: Re: Methylating a tertiary amine with MeI in the presence of a carboxylic acid or OH
Post by: rolnor on January 14, 2017, 02:00:49 AM
You dont need HCl to cleave a TMS, MeOH och water is enough, my experience.
Title: Re: Methylating a tertiary amine with MeI in the presence of a carboxylic acid or OH
Post by: pgk on January 14, 2017, 02:14:59 AM
It is OK then, because HMDS protective method is simple and convenient.