Sciencemadness Discussion Board

Is it possible to perform O-methylations in acetonitrile

NaK - 11-7-2020 at 03:54

I'm having a hard time to find resources on O-alkylations in acetonitrile. I want to use methyl iodide as methylating agent but I don't have good access to DMF and acetonitrile seems like a suitable replacement. I have considered polarity boiling point and solubility.

Is there something that I missed that would be a problem or prevent this type of reaction work in acetonitrile?

clearly_not_atara - 11-7-2020 at 09:19

It should be fine, I think it's just unpopular because the bp of acetonitrile is kind of low.

In theory a very strong alkylating agent like methyl iodide might form some amount of nitrilium, but even MeI isn't usually strong enough for this so it shouldn't be a concern. Nitriliums tend to require alkyl triflates or oxoniums.

karlos³ - 11-7-2020 at 09:32

Maybe try NMP, N-methylpyrrolidine?

NaK - 12-7-2020 at 06:38

that's banned because it "may damage the unborn child". Might need to order from outside germany again *sigh*

[Edited on 12-7-2020 by NaK]

NaK - 12-7-2020 at 09:58

Quote: Originally posted by clearly_not_atara  
It should be fine, I think it's just unpopular because the bp of acetonitrile is kind of low.

In theory a very strong alkylating agent like methyl iodide might form some amount of nitrilium, but even MeI isn't usually strong enough for this so it shouldn't be a concern. Nitriliums tend to require alkyl triflates or oxoniums.


Shouldn't 82C be more than enough considering the boiling point of MeI is only at 42C?

Dr.Bob - 12-7-2020 at 16:39

ACN works well for alkylating phenols and sulfonamides with MeI and K2CO3, as does acetone and DMF, usually. Sometimes, you can just dump the reaction into water to ppt the product, much like DMF. Or just filter/decant away from the salts and then evaporate. As noted MeI boils low, so you almost always need an excess of it to get a complete reaction. If you have a hindered phenol, amide, or other weakly acidic H, you may need to go to NaH in THF or such. in that case acetone and ACN are not as good.

clearly_not_atara - 12-7-2020 at 21:21

Quote: Originally posted by NaK  

Shouldn't 82C be more than enough considering the boiling point of MeI is only at 42C?

Not exactly -- the volatility of a mixture depends on a number of factors and some high-boiling polar solvents allow methylation at higher temperatures than would otherwise be possible (NB: I am not the best person to ask about this). It probably isn't a concern for your conditions; I was just explaining why it isn't typical to use MeCN for this reaction. However, in most cases, it works fine.