Sciencemadness Discussion Board - Methylation with dimethyl sulfite - which base is suitable?

Methylation with dimethyl sulfite - which base is suitable?

Methansaeuretier - 21-8-2010 at 13:01

Hello...
I like to methylate 4-ethoxyphenol and toluhydrochinon with dimethyl sulfite (not dimethyl sulphate!).
Which base is suitable for this reaction?

I have no K2CO3 at the time. Are there any alternates? What about KOH/NaOH, etc.? Or does KOH/NaOH saponify dimethyl sulfite fast?

Thx

Nicodem - 21-8-2010 at 13:28

What do you think, that we can read minds? Post the reference.

Methansaeuretier - 21-8-2010 at 16:14

Quote: Originally posted by Nicodem

What do you think, that we can read minds? Post the reference.

http://www.patentstorm.us/patents/4453004/description.html upsi...

Quote:

....
EXAMPLE 3

In an apparatus as in Example 1, 10.0 g (0.054 mol) of syringaldehyde and 5.00 g (0.036 mol) of potassium carbonate were heated to 100° C. and 8 ml (0.094 mol) of dimethyl sulfite was added over a 5 minute period. The pasty mixture washeated to 100° C. for 3 hours then cooled to 25° C. and quenched with 50 ml water. The mixture was extracted with 100 ml of methylene chloride. The extracts were washed with water and concentrated in vacuo to get 4.2 g (54% based onrecovered syringaldehyde) of 3,4,5-trimethoxybenzaldehyde.

Btw... they only use less than 1 eq base for the phenol... that may cause the low yield.
There are some more errors in the patent I think... the base isn't a catalyst... it will react to X2SO3 I think.

Quote:

In carrying out the invention, it is desirable to use a small amount of a base catalyst. The reaction proceeds without a catalyst but at a very reduced reaction rate. Any base may be used that neutralizes acid such as an alkali metal oralkaline earth hydroxide, an amine, ammonia or trisodium phosphate. However, the alkylation reaction does not require heavy excesses of a base nor does is require a strong base. A strong alkaline catalyst may be used but less than a molar equivalent ofthe strong alkaline catalyst will be necessary. It is preferred to use a weak alkaline catalyst and a preferred class of such catalysts are carbonate salts such as sodium, potassium, magnesium or calcium carbonate. The small amount of carbonaterequired for the reaction under normal pressure is between 0 and 10 mole percent, based on the total moles of reactant phenolic compound, although larger amounts are not deleterious. Amounts as small as 0.1 mole will sometimes be adequate. Since thereis no solvent, the alkylating agent cannot be taken up by any other reactant and hydrolytic side reactions are avoided. This leads to considerably improved product quality.

Also in alkylation with dimethyl sulfate other bases than K2CO3, for exmaple Na2CO3, are known to give only low yields. (No ref... sorry

) and KOH/NaOH are also known to kill esters even without a solvent but alkylation with dimethyl sulfate and NaOH in water at rt does work very nice (Ref: http://www.erowid.org/library/books_online/pihkal/pihkal023....). But dimethyl sulfite is very unstable in water (this makes it btw a safe methylating agent; causes no cancer as far as I know) (Ref(German): http://assets.chemportals.merck.de/documents/sds/emd/deu/de/... ).

[Edited on 22-8-2010 by Methansaeuretier]

Nicodem - 27-8-2010 at 01:44

Quote: Originally posted by Methansaeuretier

http://www.patentstorm.us/patents/4453004/description.html upsi...

Quote:

Alkali hydroxides are probably not equally efficient in such a procedure instead of K2CO3. Though, possibly at least KOH might work more or less efficiently if used only in ~10 mol% amounts, but higher amounts would be detrimental. I would not waste time trying with NaOH though. But I think you can optimistically try with K3PO4 if you have any.

For example, these patent claims are typical cover all patent claims and trust me when I tell you that what is not in the patent examples was never tried (sometimes even examples were not!):
"Any base may be used that neutralizes acid such as an alkali metal or alkaline earth hydroxide, an amine, ammonia or trisodium phosphate."... "It is preferred to use a weak alkaline catalyst and a preferred class of such catalysts are carbonate salts such as sodium, potassium, magnesium or calcium carbonate."

Hydroxides, amines and ammonia are too nucleophilic and will compete with the phenoxide and once methylated get deactivated (to quaternary ammonium, water, etc.). Sodium salts, besides being less soluble, also generally form tight ion pairs in non-enough-polar and non-enough-protic reaction media, so that they are to be avoided as they give lower conversions in such reactions, or none at all. MgCO3 and CaCO3 would be probably inert at the reaction conditions as phenols would hardly react with them at only 100°C.

The use of less than one equivalent of K2CO3 does not appear that unusual if you consider that the basicity of potassium methylsulfite is considerable, if not even comparable to that of carbonates. Thus the initially formed potassium methylsulfite should be able to deprotonate phenols at least somewhat:

PhOH + MeOSOO- <=> PhO- + MeOH + SO2

Since MeOH and SO2 can leave the reaction mixture as gasses, the reaction is pushed forward even though the base might not be strong enough to deprotonate phenols as efficiently as hydroxides or carbonates, for example. Thus, I would tend to believe the conversion could be increased, even up to useful yields, by using an efficient distillation column and keeping the reflux at such a rate that only methanol distils out on the top of the column. This is a bit of a problematic setup when working on few mmol reaction scale, but on larger scale it would be easy to perform. Try it on some cheap phenol first.

Quote:

Also in alkylation with dimethyl sulfate other bases than K2CO3, for exmaple Na2CO3, are known to give only low yields. (No ref... sorry

The methylation of phenols with dimethyl sulfate in aqueous NaOH (as typicaly described in Organikum and other lab manuals) indeed works very well on all kind of phenolic substrates, but it is a different type of reaction when compared to what we have here with dimethyl sulfite. Actually, NaOH and KOH give equal result there exactly because it is an aqueous reaction. On the other hand, this methylation with (MeO)2SO is much more alike to the methylation with dimethyl carbonate which also relies on the same catalytic base cycle:

PhOH + MeOCOO- <=> PhO- + MeOH + CO2

PS: All this is based on the presumption the patent examples are not just a bunch of bullshit!

zed - 29-8-2010 at 16:20

Use the base that the authors claimed to use. If you don't have any, buy or make some.

Syringaldehyde isn't easy to come by. Do what has the best chance of working.