Sciencemadness Discussion Board

Methyl Sulfate?

careysub - 12-11-2014 at 12:04

I have started a little project to tabulate various alkylating agents, and their area of applicability, and their relative hazards.

The purpose is to construct a guide of sorts to using minimally hazardous alkylating agents. Traditional chemistry has often used really aggressive reagents, that may be highly toxic, and the trend in recent years has been to look for milder, more selective, and just plain safer alternatives (usually under the rubric "green chemistry").

My personal motivation is to avoid using dimethyl sulfate at all costs.

I will post my results for comment when they are farther along.

Which beings me to the purpose of my post today.

In doing research on alkylations with the available on-line resources I ran into references in several Shulgin syntheses to using "methyl sulfate". At other times he specifically refers to dimethyl sulfate.

There is however also methyl hydrogen sulfate (CAS 75-93-4) that is used as an alkylating agent, which goes also by such names as monomethyl sulfate and methyl bisulfate.

There seems to be no well-known common use of plain "methyl sulfate".

His brief write-ups appear to be collections of laboratory notes, and they aren't consistent in format or the use of the same names for the same chemicals, so it occurs to me that "methyl sulfate" may be sloppy short-hand.

Do you think methyl hydrogen sulfate is Shulgin's "methyl sulfate"?

Dr.Bob - 12-11-2014 at 19:21

Dimethyl sulfate is the alkylating agent used to methylate things and your DNA. It is commonly also called methyl sulfate. Every time I have seen the term methyl sulfate used, it meant the dimethyl sulfate, much the way that ethyl ether is normally taken to mean diethyl ether.

I would guess that only the terms monomethyl sulfate or methyl bisulfate would refer to the methyl hydrogen sulfate (CAS 75-93-4). I have never seen it used for methylations or even seen a bottle of it.

For most chemistry, methyl iodide is more practical. It is also quite dangerous if misused, but more practical for small scale chemistry. It is highly volatile, so you can (and normally must) use an excess and evaporate any excess material. And if used with K2CO3 and acetone, the only side product is KI, which is easy to remove by decanting or filtration. There are some other methylating agents, but MeI is my favorite by far. Of course diazomethane can also methylate many things, but it also blows up much easier.

BTW, if you want to see how well MeI alkylated things, spill some on a vinyl floor and then watch the dyes all change color as you want. (Don't breath while watching). Saw a spill once and it made a large stain in the floor that never went away, even after the floor was decon'd. By the time the hazmat people came in (I was one of them), it had mostly evaporated, but we washed the area with NH4OH and a few other things to try to neutralize any remaining MeI. It made a wild tie dye pattern in the floor.

careysub - 13-11-2014 at 05:13

Quote: Originally posted by Dr.Bob  
Dimethyl sulfate is the alkylating agent used to methylate things and your DNA. It is commonly also called methyl sulfate. Every time I have seen the term methyl sulfate used, it meant the dimethyl sulfate, much the way that ethyl ether is normally taken to mean diethyl ether.


I suspected that was the case, but wanted to confirm from someone with actual experience.
Quote:
I would guess that only the terms monomethyl sulfate or methyl bisulfate would refer to the methyl hydrogen sulfate (CAS 75-93-4). I have never seen it used for methylations or even seen a bottle of it.


ChemSpider thinks that "methyl sulfate" is methyl hydrogen sulfate, NOT dimethyl sulfate.

It is the first decomposition product of dimethyl sulfate and is a fairly weak methylating agent, but is not mutagenic. It seems to be getting some attention from the green chemistry movement, which has tended to try milder less toxic agents when possible.
Quote:
For most chemistry, methyl iodide is more practical. It is also quite dangerous if misused, but more practical for small scale chemistry. It is highly volatile, so you can (and normally must) use an excess and evaporate any excess material. And if used with K2CO3 and acetone, the only side product is KI, which is easy to remove by decanting or filtration. There are some other methylating agents, but MeI is my favorite by far. Of course diazomethane can also methylate many things, but it also blows up much easier.


MeI is also fairly easy to make. Diazomethane requires a specialized precursor, which I do not see on sale anywhere.

Dr.Bob - 13-11-2014 at 05:53

The starting materials for diazomethane are getting very hard to find, likely due to environmental and legal fears. Trimethylsilyldiazomethane was popular for a while, as a replacement for it, but I think it also has had issues.

It may well be that methyl hydrogen sulfate works fine, but I think people in industry want the cheapest, fastest, simplest way to do things, so the dimethyl is that. Plus, if the monomethyl also alkylates, you could theoretically use only 1/2 equivalent, but again, most people use an excess of cheap reagents to drive reactions to completion if possible. I would use MeI for almost any reaction if I need to methylate things. Same for Ethyl iodide. Once you get larger than propyl or butyl, the iodides are often less stable or not readily available, and you have to go to the bromides or other substrates, like tolsylates or triflates.

AvBaeyer - 13-11-2014 at 10:09

Careysub,

Regarding your interest in compiling alkylating agents and their uses, you should take a look at the attached paper. Much of the work has been done for you.

AvB



Attachment: A comparison of several modern alkylating agents.pdf (417kB)
This file has been downloaded 511 times

Dr.Bob - 13-11-2014 at 12:43

Great review there. I had forgotten about dimethyl carbonate, it is not nearly as reactive, and might be quite as easy to get rid of in the workup, but it is safer, non-explosive, and more available than many other alkylators. But it would work with K2CO3 for many reactions and still could be worked up by filtration and concentration. You will likely need to use an excess still, maybe even use it as the solvent. I have used diethyl carbonate that way before.

Of course for acids, just boiling in MeOH/HCl or EtOH/HCl works pretty well, giving 90% yields in many cases, and the starting materials are cheap and easy to get.

careysub - 13-11-2014 at 13:02

Quote: Originally posted by AvBaeyer  
Careysub,

Regarding your interest in compiling alkylating agents and their uses, you should take a look at the attached paper. Much of the work has been done for you.

AvB



Reading this paper (while looking for alternatives to dimethyl sulfate) actually got me started on this.

Things it is missing include discussions of availability and hazard assessment. My interest is in the unique combination of considerations appropriate to the amateur chemist.

It is also missing some alkylating agents that are reasonably accessible to the amateur chemist - like trimethyl phosphate (yes, I consider making phosphoryl chloride using a 400 C reaction and then reacting it with methanol "relatively accessible").

Examining and sorting out the relative hazard/safety of these various agents is a main focus.

chemrox - 13-11-2014 at 17:24

@AvBaeyer
Thanks for the article. This is one of those little treasures I surf SM for.

NexusDNA - 13-11-2014 at 18:06

I believe the alkyl halides are the safest and most cost-efficient for the amateur. Does someone have experience with bromomethane? I remember of reading a post here somewhere claiming excellent results in the preparation of MeBr in situ for a reaction with virtually no leaking.

*also, completely off topic, this week a not-so-sane teacher of mine used iodomethane to disinfect brewing glassware because he was out of iodoform. Mutated yeast surely gives the man's ale a spice!