Sciencemadness Discussion Board

Attempted Methylation of Paracetamol with TMP

mnick12 - 2-5-2012 at 19:31

Hello everyone, I would like to share my experience of methylating paracetamol with trimethyl phosphate.

In the past various members have shown interest in the methylation of phenols with alternative methylating agents. Of these members, a few have attempted the methylation of a various phenols with trimethyl phosphate or TMP. http://www.sciencemadness.org/talk/viewthread.php?tid=9921

Having a good quantity of TMP I decided to conduct a methylation of some paracetamol extracted from store brand pain relievers. I chose paracetamol as the substrate since the methylated derivative can be hydrolyzed into p-anisidine, which I need for another synthesis. Anyway I will relate my experience at the O-methylation of paracetamol with TMP.

Reagents:
N-(4-hydroxyphenyl)acetamide - 14g (~90mmol)
potassium carbonate-13.8g (100mmol)
trimethyl phosphate-14.0g (100mmol)
DMF-40ml

A 250ml 3-necked rbf equiped with magnetic stirring, a reflux condensor, and a pressure equalizing addition funnel was charged with 13.8g of freshly fused potassium carbonate. After this addition the third neck was stoppered, and in a 250ml beaker 14g of paracetamol was dissolved in 30ml of fresh DMF. Dissolution produced a slightly cloudy yellow solution (most likely due to some binder present in the pain reliever), and after a quick filtration this solution was transferred to the addition funnel. The stopcock was then opened all the way, and the solution quickly drained into the flask. Stirring was initiated and maintained @400rpm, and the formerly yellow solution began to foam indicating the deprotonation of the phenol. The now booger-green solution was allowed to stir in an oil bath @~80C until gas evolution ceased (15mins). While this was occurring 14.0g of TMP was transferred into the addition funnel along with 2X5ml rinses of DMF. After the offgasing ceased the TMP/DMF combo was allowed to drip into the mixture over a period of 5mins. Following this addition the once booger-green solution took on a light pink/brown color over the coarse of about an hr. The bottom of the apparatus was shielded with Al foil in an attempt to minimize heat loss, and the reaction was allowed to continue overnight. The next evening the slurry was poured into 200ml of water, and within 45 seconds the flask was saturated with tiny crystals. These crystals were collected by vacuum filtration, and washed three times with cool water. The collected product had a mass of 11.45g which makes for a 75% yield. Not the best yield but good enough for me.

Anyway I hope this experience proves useful for some of you who had questions about TMP's ability as a methylating agent. Certainly MeI and others are superior in terms of yield, but they posses high acute toxicity and are known carcinogens.

Questions, suggestions, and comments are welcome.

Nicodem - 2-5-2012 at 22:33

Thank you very much for your useful contribution.

How did you check the product identity?
Also, did you check the conversion by TLC, or otherwise, before finishing the reaction? I ask because in this particular case the yield is not indicative of the reaction efficiency due to the isolation method (the losses must be considerable because p-methoxyacetanilide should be somewhat soluble in 40 mL DMF + 200 mL water even in the presence of the salts). If the reaction was essentially complete by TLC then there would be no reason to believe that "MeI and others are superior in terms of yield". Methyl iodide and dimethyl sulfate are no doubts superior to trimethyl phosphate in terms of reactivity, but not necessarily in terms of yields.

Boffis - 3-5-2012 at 07:40

Hi Mnick12,

Interesting write up. Your detailed observations allow detailed discussion too.

You mixed roughly equimolar amounts of 4-hydroxyphenolacetamide and potassium carbonate at room temperature and you reported effervescense (presumable from CO2 release) but in equimolar amounts I would expect the potassium salt of the deprotonated acetamide and potassium hydrogen carbonate (hence no CO2 release at low temperature) unless you were hydrolysising the amide moiety. The potassium hydrogen carbonate decomposes to normal carbonate, water and CO2 at about 65-70 C I believe so there should be little release of CO2 until you heat the reaction mixture. So you may be generating free 4 aminophenol before you start the alkylation.

Further more you have added a considerable excess of alkyl phosphate. All three alkyl groups can be used to methylate the reactant so you may have over methylated the amide even if you haven't hydrolysed it (see Vogel 5 ed page 905 where he uses a 50% excess you have used 200%). I cannot lay my hands on an electronic reference just yet but I am sure that I have read about a laboratory method of preparing mono-N-alkylaniline by alkylating acetanilide (you are using 4 hydroxyacetanilide) and hydrolysis the product (I will pursue this one). Certainly N-methyl-N-acetyl aniline is stable since in the reference above (Page 901) Vogel describes the removal of the mono alkylaniline from the dialkyl anilines by reacting with acetic anhydride and distillation, the acetanilides are much less volatile.

In summary I don't think N-acetylation of an amine is a suitable blocking group to prevent N-alkylation by an alkyl phosphate. You may therefore have created either N-methyl-N-acetyl-4-anisidine or N,N dimethylanisidine (or via hydrolysis of the former) N-methyl-4-anisidine too.

I don't know if potassium carbonate will hydrolyse paracetamol at low temperatures; does anyone else? It is my own anecdotal observation that paracetamol is more readily hydrolysed that acetanilide.

mnick12 - 3-5-2012 at 18:09

Hi thank you for the replies.

Nicodem,
I did not run TLC during the course of this synthesis, but I plan on repeating it some time in the future. The next time I attempt this synthesis I will run TLC, and perhaps try a different solvent. Thank you for pointing out the solubility issues I was not aware of that. I am not asking to be spoonfed, but what would you suggest for a work up? I myself do not have a whole lot of experience in organic chemistry, so I often times do goofy things that end up being detrimental to the reactions I am conducting. Would increasing the amount of water help, say to 500ml? Also just ran a mp for the compound, 131C sharp. So I assume it is of reasonable purity, however I do not have access to precision instruments to confirm this suspicion.

@Boffis
I should have made this more clear in my report, but I was not paying close attention when I wrote down the procedure. The flask was in the process of heating up during the addition of the paracetamol solution into the K2CO3, and while I did not measure the temp at this time I would say it was pretty close to 60 or 70C. So that could explain the evolution of what is assumed to be CO2. As for the seemingly large excess of TMP, I was under the impression that the after loosing a Me- TMP's ability to methylate decreased drastically. However I could be wrong.

Nicodem - 4-5-2012 at 00:44

Quote: Originally posted by mnick12  
Thank you for pointing out the solubility issues I was not aware of that. I am not asking to be spoonfed, but what would you suggest for a work up? I myself do not have a whole lot of experience in organic chemistry, so I often times do goofy things that end up being detrimental to the reactions I am conducting. Would increasing the amount of water help, say to 500ml?

The isolation protocol you used is what most synthetic chemist would initially try as well. For such a substrate it would be unreasonable and uneconomic to do anything else but a precipitation with water. The amount of water you used is appropriate for that volume of DMF and using more would not help. The morphology of the crystalline precipitate and the sharpness of the mp demonstrate the product is most likely of good purity and that the isolation is optimal as it is. The losses due to solubility are negligible from the economical perspective (for example, obtaining an 85% instead of 75% yield by using an extraction/recrystallization based protocol is not worth it when considering the work and solvent value).
Quote:
Also just ran a mp for the compound, 131C sharp. So I assume it is of reasonable purity, however I do not have access to precision instruments to confirm this suspicion.

Very good. Even if perhaps the sharpness and the top value would be due to a rapid measurement or apparatus inexactness, it is still enough to confirm the product identity. The literature values are mainly in the range from 124 to 130 (for examples see: ChemSpider data, DOI: 10.1016/j.tet.2008.10.024 and DOI: 10.1021/jo070297k).
Quote: Originally posted by Boffis  
Further more you have added a considerable excess of alkyl phosphate. All three alkyl groups can be used to methylate the reactant so you may have over methylated the amide even if you haven't hydrolysed it (see Vogel 5 ed page 905 where he uses a 50% excess you have used 200%).

You are comparing an O-methylation of a phenol with an N-methylation of aniline as described in Vogel's. They are not comparable in regard to stoichiometry. The methylation of aniline with trimethyl phosphate requires no base as the nucleophile is already enough nucleophilic as such, and at the same time it is only poorly basic. The low basicity of aniline and its N-methylated products assures there is always some active methylating reagent present in the reaction mixture due to the pKa of methyl phosphoric acids (furthermore the reaction is conducted neat at reflux, which is above 180 °C).
On contrary, when methylating phenols you need a base to form a phenolate. The consequence is that the trimethyl phosphate when consumed forms the stable (MeO)2PO-O<sup>-</sup> anion which is way less electrophilic than the corresponding protonated form (MeO)2PO-OH, the dimethylphosphoric acid, which would be there only when methylating in poorly basic media. For this reason, trimethyl phosphate can methylate only one equivalent of a phenol under ordinary conditions. In this respect, it behaves similarly like dimethyl sulfate which can methylate two equivalents of phenols only under extraordinary conditions.

The stoichiometry and the experimental of the methylation of iodide and other nucleophiles with trimethyl phosphate and the methyl phosphoric acids is discussed in the "Iodomethane prep." thread.
Quote:
In summary I don't think N-acetylation of an amine is a suitable blocking group to prevent N-alkylation by an alkyl phosphate. You may therefore have created either N-methyl-N-acetyl-4-anisidine or N,N dimethylanisidine (or via hydrolysis of the former) N-methyl-4-anisidine too.

A glimpse of the literature shows that just about any methylating reagent can be used for the selective O-methylation of paracetamol. Trimethyl phosphate is certainly no exception. The pKa(DMSO) of the NH in the acetanilide is about 21 while the pKa of phenol is about 18. So the difference in acidity is about 1000-fold. Even without such a difference, I still think the steric and solvation factors are more inhibitory for the N-methylation of acetanilides when compared to the O-methylation of phenols.

The selective O-methylation of paracetamol with methyl nitrate is described by smuv in the "Methylation of phenols with Methyl Nitrate" thread.

[Edited on 4/5/2012 by Nicodem]

Some more encouraging news

mnick12 - 12-5-2012 at 18:59

Well I just finished another attempt at a methylation with TMP, but with a different substrate.


United States Patent US4453017 outlines a solvent free methylation of syringaldehyde with TMP in the presence of anhydrous K2CO3. The authors claim over a 90% yield of the corresponding 3,4,5-trimethoxybenzaldehyde. I attempted to replicate one of the procedures outlined in the patent, and the results look extremely encouraging.

In a 3-necked 250ml rbf equipped with a reflux condenser, magnetic stirring, and a pressure equalizing addition funnel, there was added 15.0g (0.11mol) of freshly fused K2CO3 followed by 15.2(0.083mol) of syringaldehyde. The open neck was stoppered and the magnetic stirring was initiated and maintained at 300rpm. The flask was then gently heated to ~80C, and by means of the addition funnel 15ml(0.12mol) of TMP was added as quickly as possible. Upon contact with the aldehyde effervescence was noted. Following this observation the reactants in the flask quickly set up as a solid tan mass. It was then decided that some sort of solvent had to be added in order to facilitate proper mixing, so 30ml of DMF was added through the addition funnel. The tempurature of the oil bath was raised until the DMF just began to reflux, at which point the solid cake had dissolved forming a carmel colored solution with small amounts of particulate swirling around in it. The reaction was allowed to continue stirring for 3hrs. After this time the reaction mixture was crashed into 400ml of H20, after cooling a large amount of voluminous cream colored crystals appeared. These were collected by vacuum filtration, washed with H20, and allowed to air dry overnight. The final yield was 15.5g which makes for a 95% yield. MP confirmed

It appears as though TMP is quite effective at certain methylations.