US 3,867,458 - Tweetios

[GC_MS]

A Process for Preparing 2-Alkoxy-5-methoxybenzaldehyde

Patent US3867458

Abstract - A process for preparing 2-alkoxy-5-methoxybenzaldehyde, said alkoxy group being a methoxy or an ethoxy group, which comprises reacting, in the pressence of potassium carbonate, 2-hydroxy-5-methoxybenzaldehyde with a dialkyl sulfate, said alkyl group being a methyl or an ethyl group, is enclosed.

Example 1 - 50 g of 2-hydroxy-5-methoxybenzaldehyde, 68 g of potassium carbonate and 50 g of dimethyl sulfate were refluxed in 250 mL of acetone for about 3 hours under stirring. After the reaction, the reaction mixture was filtered and the acetone was distilled off from the filtrate and then the residue was poured into 300 mL of water. The precipitated crystals were collected by filtration and dried whereby 45 g of 2,5-dimethoxybenzaldehyde having a melting point of 48°C were obtained (Yield: 82.5%).

Example 2 - On standing the mixture of 2-hydroxy-5-methoxybenzaldehyde, potassium carbonate and dimethyl sulfate as in Example 1 at room temperatures the reaction was completed in 7 days. This was confirmed by gas chromatography. By treating the reaction mixture as described in Example 1, 44.5 g of 2,5-dimethoxybenzaldehyde having a melting point of 47°C were obtained (Yield: 81.5%).

Example 4 - By repeating the procedures described in Example 1 except that 31 g of diethyl sulfate were used instead of 50 g of dimethyl sulfate, 53 g of 2-ethoxy-5-methoxybenzaldehyde having a melting point of 47-48°C were obtained (Yield: 97.5%).

[Mountain_Girl]

"50 g of 2-hydroxy-5-methoxybenzaldehyde, 68 g of potassium carbonate and 50 g of dimethyl sulfate were refluxed in 250 mL of acetone for about 3 hours under stirring. After the reaction, the reaction mixture was filtered and the acetone was distilled off from the filtrate and then the residue was poured into 300 mL of water. "

Here it is, all wonderfully laid out recipe-style and still I fucked it up      
Now I'm hoping that someone can suggest reasons for how I managed to inflict serious damage on my ego as a bee.

This is my story:

1. Dried acetone with MgSO₄. Not that I thought it was necessary, just thought I had nothing to lose and maybe something to gain.
2. Didn't have any K₂CO₃. So I bubbled CO₂ through a warm KOH soln for about 2 hrs and evaporated the water, leaving, I believe, K₂CO₃.3/2H₂O. Later, I left the white powder in the oven at ~150°C to drive off the water.
3. Mixed the aldehyde, acetone and anhydrous K₂CO₃, which didn't dissolve, surprise, surprise. But still, it was a surprise.
4. Added DMS and refluxed for 3 hrs, all the while K₂CO₃ remaining undissolved and looking suspiciously inert.
5. Filtered and boiled off acetone. Dumped residue in water. Crystals did not precipitate. Instead there was a viscous black oil that sank to the bottom and never even  solidified on cooling to rt.

Any ideas where I went wrong ?

[GC_MS]

2-hydroxy-5-methoxybenzaldehyde:

1. Was it synthesized by yourself?
2. If yes, what is its colour?
3. Tried to form the bisulfite adduct of the "black oil"?

[Mountain_Girl]

2-hydroxy-5-methoxybenzaldehyde:

1. Was it synthesized by yourself?
Yes by R-T of p-meo phenol. One thing I can say is when this particular batch was synthd I ran out of CHCl₃ using about 1.7 moles/mole phenol instead of the required 2 moles/mole phenol. This didn't seem to affect yields though.

2. If yes, what is its colour?
Dark yellow oil with lovely [to me] nutty smell.

3. Tried to form the bisulfite adduct of the "black oil"?
No, threw it away in disgust knowing that I should have a whitish solid. Previously I performed the methylation by adding KOH and DMS to the aldehyde and leaving overnight. The yield was low but at least it worked. I was hoping to improve things by using the patented method with K₂CO₃.

[GC_MS]

The patent works as advertised... I was thinking that your aldehyde might have been impure, but as it is a yellow oil, it should be sufficiently pure.

I can't tell what has gone wrong though...  

[Mountain_Girl]

Ok, last questions then I'll file it with the rest of the my unexplained chemistry mishaps,

1. Is there any reason why my method of preparing K₂CO₃ may not be valid ?

2. Should the K₂CO₃ dissolve at all ? Should there not be any bubbling/fizzing ? Is it supposed to just sit there, appearing to react not much more than a stirrer bar ? Method says 'in the presence of' so I'm not sure.

3. Any advice or reference to an alternative procedure using KOH or NaOH with DMS?

Thanks for your responses so far GC_MS  

[GC_MS]

The potassium carbonate does not go into solution. There should not be bubbling or sizzling from a chemical reaction, just the normal reflux phenomena.
Note: did your yellow 2-OH-5-MeO-benzaldehyde solidify? If yes, it was impure (even when it was yellow...). However, turning 'black'.. never seen it.

[catastrophe]

Sorry, SWIM doesn't want to intrude on the discussion but he/she thought they could offer some useful information.

A bee tried to methylate the same 2-OH aldehyde in NaOH(aq) with DMS as described in pihkal (for the methylation of toluhydroquinone in the entry for 2C-D

http://www.erowid.org/library/books_online/pihkal/pihkal023.shtml

). Instead of waiting for days, they refluxed for 6 hours and obtained a 75% + yield of 2,5-DMB. Curiously, that particular member was also investigating methylating the compound in acetone for an even high yield.

As a side note, a VERY intriguing methylation procedure for this compound can be found in US4065504

http://l2.espacenet.com/espacenet/viewer?PN=US4065504

. Solventless, and near theoretical yield. This procedure has been proven to work on 5-hydroxyvanillin, and the patent states it is applicable for any substituted phenols.

Hopefully this method will get you on the bus    mountain_girl. Good luck.

PS. Oh almost forgot your problem! Was the DMS homemade as well? SWIM would most probably suspect the problem was your K2CO3. Slightly impure aldehyde, like yours, really shouldn't effect a rxn like this. Why didn't you use Na2CO3 instead?? From US3855306...

Into a 1-l. round-bottomed flask equipped with a magnetic stirrer and a reflux condenser were placed: 50 g (0.298 mol) 5-hydroxyvanillin, 500 ml acetone, 91.0 g (0.716 mol) dimethylsulfate, 100 g (0.806 mol) finely ground Na2CO3.H2O, 10 ml of 10% KOH in methanol. Of course equimolar amounts of anhydrous Na2CO3 or K2CO3 can be used.
... Yield 90%

[Mountain_Girl]

Thanks Cat.

I'm hesitant to try

Patent US4065504

since it is not specifically for my aldehyde. Also, by now I mistrust patents seeing that I've been raped by their lack of success so many times.
Instead I think I'll use the method in Pihkal#23 with your reflux modification.

DMS was not home made, although it is a few years old.
I understood that K₂CO₃ simply works better than Na₂CO₃.

[GC_MS]

I tried the patent several times and it does work as advertised. Usually gives 75-85% yield, considering that I don't purify my R-T product if it does not solidify on standing within half a day and the colour is an attractive yellow.

Example 4 - By repeating the procedures described in Example 1 except that 31 g of diethyl sulfate were used instead of 50 g of dimethyl sulfate, 53 g of 2-ethoxy-5-methoxybenzaldehyde having a melting point of 47-48°C were obtained (Yield: 97.5%).

That should be 61 g diethyl sulfate. Just make sure the reaction mixture is stirred well.

[catastrophe]

Yes, SWIM thinks the solventless procedure is by far the best and most attractive. The patent clearly states it will work for any substituted hydroxybenzene.
It is not time consuming, workup is an absolute breeze, it works on impure aldehydes just as effectively, uses less DMS than many other procedures (1.6 - 2 molar excess), and it always affords high yields. In addition to that, it doesn't have to be anhydrous, like acetone. Your not going to get a quantitative yield from your R-T product, because it is not 100% pure. Maybe if GC_MS had distilled his product under N2 (no way!), he/she would have had near quantitative.

What SWIM would be very curious to know, is if the same procedure works on alkyl sulphates as well (EtBr,...). THAT would be very nice!

GC have you done any analysis on the crude R-T product? It has to contain some unreacted p-methoxphenol, and probably a little benzoquinone as well. As well as some side-rxn products.

MG, when you failed the procedure, did you use the 50g of aldehyde as in the patent??? If so, then ouch   !! SWIM really mourns for you. Also, if your DMS is very old a good method of purification is to wash with equivalent volume ice cold H2O, then 1/2 volume cold saturated NaHCO3 solution. Or you can place your DMS under K2CO3 until neutral via congo red. From Vogel of course   . Good luck!

[Mountain_Girl]

GC_MS,

"I don't purify my R-T product if it does not solidify on standing within half a day and the colour is an attractive yellow."

My R-T product only solidifies if I put it in the freezer.


Catastrophe,

Used only 5g of aldehyde, but it was all I had after days of work.
Haven't considered purifying the DMS as yet cos I don't think the problem lies there.
The patent may sound promising, but they always do. I won't risk trying it until another bee does, and then still maybe not.
Will hopefully try the methylation again this weekend.

[ribbon13]

Sorry if it sounds like an utterly stupid questin but what exactly is it? The closet related item I could think of is something in the 2C-X series...

[GC_MS]

2,5-dimethoxybenzaldehyde = precursor for alot of stuff, like 2C-X
Tweetio = one ethoxy and one methoxy, or two ethoxies in 1,4-position.