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Author: Subject: Reduction of methyl 3,4,5-trimethoxy benzoate using MeOH/NaBH4
DrDevice
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[*] posted on 11-12-2017 at 21:18
Reduction of methyl 3,4,5-trimethoxy benzoate using MeOH/NaBH4


With a source of methyl 3,4,5-trimethoxybenzoate (Me-3,4,5-TMB) on hand, I have been experimenting with reduction of the ester to an alcohol using sodium borohydride and methanol.

Several references exist showing the use of methanol in this process, for example, "A simple reduction of methyl aromatic esters to alcohols using sodium borohydride–methanol system" (Boechat et al, 2004), and "Practical Procedure for the Chemoselective Reduction of Esters by Sodium Borohydride. Effect of the Slow Addition of Methanol”. (Kenso Soai et al, 1984).

Procedure:

3.9g Me-3,4,5-TMB @ MW = 226.226 = 17.2mmol, 6 equiv of NaBH4 = 3.91g was combined with 40ml tetrahydrofuran (THF) in a flask and condenser set up for reflux. An oil bath was used with a temperature set to 70C.

10ml of methanol was added drop-wise over an interval of 1 hour. I added the drops through the open top of the condenser & it trickled down into the refluxing reaction.

Gas evolved freely on addition of the MeOH, and reaction continued for several hours after the final drops were added (although some of that might have been reflux boiling).
After 12 hours, the reaction was complete (no Me-3,4,5-TMB spot on TLC, 1:1 hexane:ETOAc). It may have completed long before this - I let the reaction run overnight.

The mixture was neutralized to pH =7 with ~1.5M HCl. There was quite a lot of unreacted NaBH4, so a fair bit of acid was used. It might be better to filter first then neutralize.

The result was extracted with 2x 25ml of EtOAc, then washed with 30ml brine, and dried with Na2SO4, and solvent evaporated.

The result was 2.41g of a viscous colourless liquid (consistent with description in the literature), and assuming it is 3,4,5-trimethoxybenzyl alcohol, yield @ MW = 198.216 = 71%.

A single spot on TLC was noted, with Rf = 0.42, compared to Rf = 0.92 for the Me-3,4,5-TMP. I have done no other checks to verify it is an alcohol - I suppose it is a primary alcohol so should react to CAN test. I'll try that soon.

I have tried this experiment with reduced amounts of NaBH4, and with faster addition of MeOH, and each time yield is less.
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zed
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[*] posted on 12-12-2017 at 16:02


I'm curious. Is methanol required for this reduction to "work"? Are other alcohols effective?

Again and again, folks report using methanol as a solvent, in Sodium Borohydride Reductions.

But, Methanol is a crappy solvent for Sodium Borohydride. Decomposes it.

Do you have any idea what the proposed reaction mechanism of this reduction is?

I'm gonna check on it myself, right now.

http://www.arkat-usa.org/get-file/23589/

OK. So this is a "Thing".

Thank you!



[Edited on 13-12-2017 by zed]
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clearly_not_atara
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[*] posted on 12-12-2017 at 17:42


Methanol is not acting as a solvent; rather, it's acting as an acid, generating borane in situ. The solvent is THF.



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[*] posted on 13-12-2017 at 18:44


I do not think that the actual mechanism of ester reduction in the methanol-borohydride system is fully understood. One notable aspect of this reduction is that the yield of alcohol product is very sensitive to rate of methanol addition. Very slow addition of methanol often over several hours is best. This suggests that a species is formed from the reaction of methanol with borohydride which that reacts as fast or faster with additional methanol compared with the ester to be reduced.

It is also noteworthy that ester reduction can sometimes occur under long reaction time in hot ethanol. This is sometimes reported as a side reaction in borohydride reductions when an ester is present in the substrate.

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DrDevice
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[*] posted on 14-12-2017 at 03:48


Just on that slow-addition piece, can anyone suggest a means of doing that slow addition without too much human intervention? The dropping funnel I have goes from "no drop" to "a bit too fast" in terms of tap position.

Otherwise it is very tedious to go back every 5 minutes and add another drop...

Hmm. Maybe dilute the MeOH with THF solvent so concentration per drop is small. Might try that.
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[*] posted on 14-12-2017 at 06:20


Quote:
Quote: Originally posted by DrDevice  
Hmm. Maybe dilute the MeOH with THF solvent so concentration per drop is small. Might try that.

That's probably your best bet to be honest, it's far easier and cheaper to adjust the chemistry than the glassware. You'll have to calculate the flow rate of the methanol from literature with the best yields, so if for example your slowest addition is 10mL in half an hour then using 20mL of 50% v/v MeOH/THF would substitute nicely. Just make sure your reaction vessel has enough spare volume!

I guess you could also use an adsorbent if you're worried about the numbers, just a column with saturated and packed cotton wool that could also contain something else like silica or alumina, connected under the funnel or on its own. That should also impede the flow of methanol, and a reservoir can be built up on top (add the required amount after the saturated adsorbent no longer drips). This is just an idea and I have no practical experience so it'll be best to play around and see what sort of flow reduction you can get out of it.




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[*] posted on 14-12-2017 at 19:44


Dissolving some NaOH in the methanol will raise the pH (obviously) and thus stabilize the NaBH4. It works pretty well, especially if you need anhydrous high-pH conditions.



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[*] posted on 15-12-2017 at 09:59


DrDevice,

I re-read your first post and if you did indeed get a 71% yield of your benzyl alcohol then you did ok. In my experience the borohydride/methanol reduction of esters yields about 80% of the reduction product after work up. One of the side products, often overlooked, is the acid corresponding to the ester being reduced. This is not from hydrolysis but results from an ester interchange process during the reduction.

I have used the diluted methanol technique which you mentioned above. This works fine. In order not to end up with large volumes of reaction mixture, you need to reduce the amount of THF in the reaction pot by the amount that you use to dilute the methanol.

Usually the slow addition required for this reduction reaction is by use of a syringe pump. Alternatively, there are addition funnels with a needle type screw valve in the stopcock which can be adjusted to give very slow flow rates. However, these need constant attention as they sometimes clog or just stop. These funnels become available occasionally on ebay.

Hope all this is useful.

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