Esterification & Reduction of 3,4,5-TMBA ?

[Mountain_Girl]

Question 1:
Why is the conversion of 3,4,5-TMBA to the benzyl alcohol usually done by making the ester first and then reducing with LAH ?
Why not reduce the acid directly with LAH ?
(This quest. has been asked before but afaik it wasn't answered)
Is it perhaps because the overall yields are higher ?

Question 2:
Can the esterification be done with MeOH/(H2SO4 or HCl) instead of (Me)2SO4 ?

Question 3:
Can the ester reduction be done with Na/EtOH instead of LAH ?

[uemura]

Why is the conversion of 3,4,5-TMBA to the benzyl alcohol usually done by making the ester first and then reducing with LAH ?
In the literature the 3,4,5 Trimethoxybenzoic-acid is made from gallic acid via methylation with DMS. DMS in excess also esterises the -cooh to its metyhlester. So you get the methylester in one step from gallic acid.
 
Why not reduce the acid directly with LAH ?
1) because of the above preparation. 2) the acid is likely not very soluable in ether but the ester is.

Can the esterification be done with MeOH/(H2SO4 or HCl) instead of (Me)2SO4 ?
Yes, of course.

Can the ester reduction be done with Na/EtOH instead of LAH ?
Think so, but Uemura isn't absolutely sure. Sometimes NaBH4 also reduces esters to alcohols.

There are also ways to arrive at the alcohol. But when you intend to go from the alcohol to the chloride, then to the nitrile and at the end to the amine, the alcohol to chloride step is a bit 'ugly'.
Carpe Diem

[Sunlight]

Check this :

https://www.thevespiary.org/rhodium/Rhodium/chemistry/phenethylamines.dibah.html

Preparation of 3,4-Disubstituted Benzyl Alcohols (II).

A. To a solution of 100 g of the aldehyde (I) in 1000 ml of methanol was added 40 g of NaBH4 in the course of 5 h. The mixture was left overnight. After the solvent had been distilled off, the residue was mixed with water and extracted with chloroform. The extract was washed twice with water and was dried with Na2SO4. The residue after the solvent had been driven off was the required alcohol. Yield 98%.

Then chlorinate the alcohol, make the nitrile and reduce it. It is also explained in the article.

[Mountain_Girl]

(Hey why didn't my text go blue?)

Uemura:
Thanks for the reply. Your answers make sense.
When you say the alc. to choride step is 'ugly', I assume you mean the yields are low ?
If I look at the synth on Rhodiums page (

https://www.thevespiary.org/rhodium/Rhodium/chemistry/mescaline.txt

), the yield is 13g chloride from 25g alc. = 48%, which ain't great.
Although there are better methods using SOCl2 that are available.
But that's all beside the point since SWIM actually would like to synth the aldehyde from the alc. using MnO2 if she could get a procedure for this.

Sunlight:
SWIMs target is actually the aldehyde .

[uemura]

Moutain_Girl,

yield is 13g chloride from 25g alc. = 48%, which ain't great.

In his youth Uemura did this once. Beside the low yield, attempts to xtalise the chloride have been difficult.

Another way to the aldehyde from the acid would be to prepare the acide chloride and reduce this one with NaBH4 to the aldehyde.

Carpe Diem

[Mountain_Girl]

Unfortunately swim has the TMBA, but no SOCl2,PCl5,PCl3 etc. to convert to the acid chloride, otherwise she would do it and try Rosenmund (got Pd).
That's why she's considering the alternative route:
1. TMBA + CH3OH/H2SO4  ^__> Methyl Ester
2. Methyl Ester + Na/EtOH ^__> TM Benzyl alc.
3. TM Benzyl alc. + MnO2 ^__> TM Benzaldehyde

Btw, swim has LiAlH4 but feels step 2 is safer (she may be wrong in this perception) with Na/EtOH, although yields may be lower.

[hest]

I think the routhe sound good, I'l give beilsten a look at it today (and charge your hive account for 10$  ). Iff you have a lot of LAH then use it to all the reductions, but i guess you want to use it later :-)

[hest]

Na and methanol sounds good (70%) NaBH4 works damm well, but that might not bee an option.
The best way to reduce with Na is to melt the Na in (dry)toluene, then stir and let the toluene cool down to 60°C now wee have a fine Na powder in toluene. To this you add your ester disolved in dry(use sodium) methanol and drip this into the toluen fast (keep the temp at 60-80°C) when all the ester is added you are home.
Use 6 mole of Na per mole of acid. (less might work)
This is from O.S. Col.vol.II page 372

[obia]

a little nomenclature note 3,4,5-TMBA of commerce is usually the benzaldehyde and I think it is used in making trimethoprim.. I forget the price exactly but it is less than $40 per kg in china for small qtys

[Mountain_Girl]

Thanks once again Hest, feel free to charge my Hive account as you see fit.
Sorry but more questions:
* Are you saying substitute methanol for ethanol ?
* Swim's Na is in kerosene. How to transfer it to toluene ?
* You say dry the methanol with sodium !?

[hest]

Is your Na a 'powder'(like Li) or in a stick(the usual way)?
Do you have acces to MeOH ?

I don't think the type of alcohol is importent, i look it up tomorow.
The alcohol has to be dry (as in 99% not the usual 96%) just add a bit of Na. (if you have the 96% ad 5mole% if you have 99% ad 1mole%)

[hest]

Alcohol type not importent. But drynes is werrye importent

[uemura]

TMBA + CH3OH/H2SO4  __> Methyl Ester

Uemura came across a note in one of his books yesterday, which said: methyl esters cannot be prepared by azeotrope destillations of MeOH, acid and H2SO4 . Just wanted to add this, so use an access of MeOH + acid + H2SO4, reflux and the isolate the ester.

Carpe Diem

[Mountain_Girl]

Hest:

* The Na is lumps in paraffin. I assume it can just be transferred lump by lump with forceps.
* MeOH is available but toluene is not. Maybe xylene (xylol actually) can be used instead.
* The type of alc. is probably not important, except that MeOH will be more reactive than EtOH from my understanding.
* I'm still confused about using Na to dry the alc. - will the Na not react with the alc. ? Isn't that the point of Na/alc. reduction ?

[I thought of something interesting: If MeOH is used in the reduction, it is both a reagent and a product. Should it then not be possible to add a small amount of MeOH & Na initially, and then only Na after that to react with the MeOH as it is formed. I was wondering if this might increase yields from an an equilibrium point of view, i.e. a product is being removed from the reaction as it is formed ?]

[Mountain_Girl]

Uemura:

methyl esters cannot be prepared by azeotrope destillations of MeOH, acid and H2SO4

My understanding is that when it is an ethyl ester that is being prepared, the water that is produced can be removed as it is formed as the EtOH/water azeotrope. This will drive the reaction forward (altough it should also remove EtOH but you'll be using a large excess of that anyway).

Since MeOH doesn't form an azeotrope with water, the same principle would not apply to the preparation of methyl esters. (All the MeOH would boil off first before any water).

Hmm..now you've got me thinking - would it be better to make the Me or Et ester... ?

[hest]

When yau add the Alc. solution to the Na two reaction are running. One, the red. of the acid and two the formation of NaOMe (or NaOEt).
You want the reaction to go fast, else you are just making NaOMe, thats why the OS. synt melt the sodium and let it solidfy into a slurry.
Wather in the alcohol lower the yeald alot, so you dont want anny wather in the alcohol. The point with Na is to make the wather to NaOH and H2 (Na+H2O->NaOH+½H2)

Xylene=xylol will work as well as the solvent.

So i sugest the following routhe
Put 5g Na into 250mL methanol, let it stir a day or two, we now have a mixture of NaOH NaOMe and MeOH, but no wather, (iff you want the pure dry alcohol just destil it off, but it is not nessecery)

Add 22g(1mol) Na to 250mL xylen. heat until the Na melts, then let it cool under stirring.
Disolve 35g(0.2mol) TMB-acid in 200mL dry methanol. Drip the solution to the Na/Xylen slurry in such a rate that it boils gently (5-10min?)
Let it cool down, add wather and seperate. Wash the xylen two times with wather, dry and ewaporate. You now have TMB-Alcohol (Expected yeald ~60%)
(this is all teory I have no personal experience)
 
 
 

[uemura]

Mountain_Girl,

My understanding is that when it is an ethyl ester that is being prepared, the water that is produced can be removed as it is formed as the EtOH/water azeotrope. This will drive the reaction forward (altough it should also remove EtOH but you'll be using a large excess of that anyway).

Aceotrope destillation is normally based on a non-polar solvent which forms an azeotrop with water (e.g. toluene). The touluene/water destills off, seperates when cooled and the touluene is moved back to the rxn (e.g with a DeanStark trap). This works for all alcohols but not MeOH (that's what the book says) because the MeOH destills also off with the water and the toluene so that no water seperates when cooled down.

Anyway, to make the methylester just take a big excess of MeOH (eg. 5 times molar amount), the acid and add H2SO4 to catalise the esterisation. The big amount of MeOH drives the equilibrioum towords the ester and after x hrs of relux, just dump the rxn into water and work up.

Carpe Diem

[Mountain_Girl]

Hest:

Thanks. I now conclude:

In terms of drying the MeOH, I should add just enough Na to react the water away. Any extra Na will just use up some MeOH. Okay that's cool.

In terms of the redn. of the ester it's become clear to me that I don't really understand the mechanism of the reaction. I think it's best that I go away and do some more reading before I ask any further questions.

[Mountain_Girl]

Uemura:

This works for all alcohols but not MeOH (that's what the book says) because the MeOH destills also off with the water and the toluene so that no water seperates when cooled down.

Okay that makes sense, but why wouldn't it happen with EtOH ?

after x hrs of relux, just dump the rxn into water and work up.

I assume the MeOH would be distilled off first ?

[Mountain_Girl]

Hest:

Last night I read this in Vogel:

*Na alone cannot be used for the complete removal of water in an alcohol owing to the equilibrium between the resultant NaOH and the alcohol,
NaOH + ROH = RONa + H2O
An ester must then be added to remove the NaOH by saponification.*
*

However I think this only becomes a consideration if perfectly anhydrous alcohol is required, i.e. Na will sufficiently dry the alcohol for swim's purposes.

[Rhodium]

Yes, I believe so. Otherwise, CaO is a great drying agent for alcohols, forming Ca(OH)2 irreversibly with water.

[hest]

Yes but in the O.S. synth they specify that CaO dry alcohol isn't dry enough

[uemura]

Mountain_Girl,

This works for all alcohols but not MeOH (that's what the book says) because the MeOH destills also off with the water and the toluene so that no water seperates when cooled down.

Okay that makes sense, but why wouldn't it happen with EtOH ?

This is good question where Uemura has no precise answer for. It seems that so much MeOH/H2O gets over that no seperation will occur. In the case of EtOH/H2O (and higher alcohols) this does not happen any more.

I assume the MeOH would be distilled off first ?

This is not a good idea. By destilling the MeOH off you shift the equilibrium you have moved towords the ester by reluxing again back towards the alcohol which you remove from the equilibrium. Uemura would just dump the ester/alcohol mix in enough water to seperate the ester as liquid or as solid (in the case of the 345tmbenzoeacidmethylester) and extract it with a solvent of your choice.

Carpe Diem

[Mountain_Girl]

Uemura:

By destilling the MeOH off you shift the equilibrium you have moved towords the ester by reluxing again back towards the alcohol which you remove from the equilibrium

Thanks, I didn't think of that.

[Mountain_Girl]

Some results of the esterification reaction if you guys are interested:

*18 g TMBA + 50 ml MeOH (dried by frac. distln) + ~1 ml H2SO4 (95-97%). Refluxed 6hrs. Work up (extract with DCM, recrystallize with Norit, etc.) gave 12.6 g methyl ester (65.7% yield), with sharp mp of 81°C (Lit. 82-84°C & 84°C). Recovery of TMBA = 2 g.

Had difficulties with recrystallizing the ester. Seems it's too soluble in DCM or MeOH, so that a deposit is left on the surface of glass and the beaker becomes coated with the ester, rather than having a filterable suspension. What eventually worked was recrystallization from aqueous MeOH (~ 80% H2O). Subsequent fucking around and some absent mindedness resulted in loss of about 0.5 g. Therefore real yield is closer to 68%.
Also TMBA been lying around for 15 months and reagents probably could have been drier so a yield of about 70% is probably possible.
Thinking of repeating the prep. with the recovered TMBA in order to generate another gram of ester or so.

[uemura]

Hello Mountain_Girl,
Congratulation for your success. Uemura checked his old papers and found a references which uses MeOH for recristallisation. The key point is, you must not use too much MeOH! Try to start with 1ml MeOH per 1grm ester. And cool down very slowly. The ester should cristallise as colourless long rods. Carpe Diem

[Mountain_Girl]

Uemura:

I found that even when using a small amount of straight MeOH, it evaporated too easily leaving a thick sludge and a deposit along the sides of the beaker. It worked a lot better when water was added.

But thanks for the support and the info!

[Mountain_Girl]

So swim tried the Na/MeOH reduction of the ester as follows,

Reagent prep:
Xylene dried with MgSO4 overnight then distilled.
MeOH dried with MgSO4 overnight, some Na added and then distilled.
Ester left in oven at ~ 50°C for about 10 hrs.

Reaction:
Na melted in the xylene and allowed to cool to ~ 60°C. Ester in MeOH dripped in as fast as possible over about 15 min (fast enough ?). Mixture heated for further 10 min and then allowed to cool.
Most of MeOH was distilled off.
Water was then added and here the problem arose. There appeared a fair amount of a third phase between the water and xylene. This gray stuff is more of a scummy ppte than an emulsion. Exactly what is it ? Should I just separate it and the water from the xylene and evaporate the latter ?
Did swim fuck up anywhere in the above procedure ?

[hest]

How much wather did you add, could it bee NaOH ?
I would extract it all tree times with xylene, the you shuld have all the goodies. The leftower acid can be recovered from the watherphase (just make it acid and extract))

[Mountain_Girl]

I don't believe it's NaOH because there should be sufficient water to dissolve it (started with 8.4 g Na in reaction which should have left 14.6 g NaOH afterwards, then added ~ 80 ml water). The xylene was washed a 2nd time with water (20 ml I think).
Swim has decided to do as told, i.e. separate the scum, wash with xylene, evaporate pooled xylene extracts and see what's left behind.
Will recover the acid to see how much ester was converted.

[hest]

That's the way to doo it.
I look forward to hear abouth the results.
And yes you'r right, 80mL is enough to disolve the NaOH formed.

[Mountain_Girl]

 &  
-After evaporating xylene there was virtually nothing left.
-When water extracts were acidified, there was enough ppte to suggest that not much of the ester was converted.
Therefore I would say yield was negligible or non-existent.

Possible reasons for failure:
* Reagents not dry enough.
* Had to use a huge excess of MeOH. It seems that the ester's solubility increases dramatically with temp of MeOH but swim had no way of warming once it was in addn (sep) funnel so she just had to keep adding more cold MeOH until it all dissolved. This may have resulted in all Na getting used up before ester addn was complete.

So swim is in a rotten mood after what feels like her zillionth failed synthesis (maybe we should start a clandestine chemist support group...)
At least most of the acid has been recovered but she's not sure if she should try the whole thing again or maybe a direct redn with LAH. She'll sulk on it for a few days...

[Thanks for all the help so far   ]

[hest]

LAH works as a sharm, disolve 200g(0,88mol) of the ester in dry THF or ether, then add 20g(0,5mol) af LAH (app 10% to much)let it stir to the nex day. Add 30% NaOH(aq) until no more H2 formation (stir and take your time, it take some time for the leftowers to react, don't ad to muc at the time) Then ad some MaSO₄ filter off, wash the filtercake and ewaporate. Yeald over 90%.
Iff you use the acid instead of the ester use 25% more LAH. And for those who think they can cut down on the LAH in the red, of the acid DON'T make the Na salt of the acid, it wont disolve, only the Li salt works.
I doo feal sorry for you Mountain_Girl, you have made a dam hard work here.

[uemura]

Mountain_Girl,

hest was quicker than Uemura. So Uemura can only confirm what hest said: LAH reduction of the ester gives the  alcohol in high yields. Even in the kitchen, where he did it long time ago....

If you can get sodium, you should get LAH as well. Just bee careful with this stuff, no water! and don't touch it with a metall spatula. Uemura once was lucky that it was a small 'puff' only.

Please continue to report on your experiments, and good luck for the next step.
Carpe Diem

[Mountain_Girl]

Thanks for your response, Hest & Uemura, you guys have improved swim's mood.

The reasons swim didn't use LAH in the first place are:
- Don't have very much and would rather save it for redns that can be done with nothing else
- It was obtained at a time when chemicals were easily acquired but she had barely a twinkle of the knowledge required to use them wisely (she re-started the study of DIY chemicals about a year ago after a long absence). The LAH is therefore a few years old and the upper 1/3 has gone gray. Hest suggested titration with water but swim's got to admit that even opening the bottle makes her nervous*. She hasn't even calculated if she has enough.
- Swim doesn't feel it's safe to buy more LAH, but believes Na can be purchased without suspicion (got about 220g Na already anyway)
- She would have to now purchase/synth ether
- Redn with Na/ROH requires a similar amount of work in terms of drying reagents but reaction itself goes very quickly

So she's still wondering...

* Good thing you mentioned the metal spatula bit, Uemura, swim wasn't aware of that danger..

[Rhodium]

It is a good thing to have respect for LAH, but there is no reason to be afraid of it, it won't jump out of the can and bite you. The only thing to avoid like the plague is contact it with water (and other protic solvents like alcohols etc), which means wet glassware, working surfaces, fingers etc. are a no-no. It hurts to inhale even the tiniest amount of dust, wear a dust mask. If you live in a very humid area, try to work in an air-conditioned room on a dry day, I would imagine that 90% humidity is not a great thing.

There is no problem if the LAH has turned greyish, it looks like that even straight out of the can from some suppliers - only when caking has begun there is a noticable degradation of the powder.

[Mountain_Girl]

Thanks for the encouraging and useful info Rhodium.

[terbium]

and don't touch it with a metall spatula.
Eh? I was taught the exact opposite - don't use a plastic or glass spatula or spoon with LAH, always use metal. The theory, I believe, was that the non-conductive spatula moving through the dry, powdered LAH could accumulate static charge which could then spark and start the LAH burning.

[uemura]

terbium,

Uemura's recommendation doesn't come from a book but from experience. When he wanted to scratch of some (ether wet) LAH with a Ni-Cr spatula from the joint of a flask, a puff occured and a small amount of ether burned away together with the touched LAH. From this time on, he always used glas or plastic spoons to touch LAH. 

It may have been his fault, but the spatula was dry. Maybee other contaminants. He was however so 'warned' that he never did it with this spatula again.

BTW: Your statement makes sense to Uemura. Carpe Diem

[uemura]

Mountain_Girl!
Uemura came across a reference on Rhod's site: the ZnCl2/NaBH4 reductions of acids to alcohols. Perhaps this is an alternative for you to come to the 345tmbenylalc. In the paper zinc.borohydride.pdf the reduced the 345- tmbenzoeacide with 70% yield to the alcohol. You need anhydr. ZnCl2 and NaBH4. Would save you preciuos LAH for the nitrile reduction. Carpe Diem

[Mountain_Girl]

Thanks Uemura, I had a look at it and it seems promising. Don't have any ZnCl2 or NaBH4 but maybe I should get some (I assume NaBH4 is not a suspicious purchase ?)

After finding out some more about ester redn with Na/ROH, it seems the reaction is a lot more temperamental than I previously thought. So I'll most likely not re-attempt it.
Therefore the ZnBH4 or LAH route will recieve serious consideration over the next few days..

[Mountain_Girl]

Fischer Esterification of Various Aromatic Ring-Substituted
Benzoic Acids Catalyzed by Microwave Energy

http://www.heidelberg.edu/depts/chm/fischer.html

[from a link given by Aurelius]
Mountain Boy