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

[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