3,4,5-TMBA again (methylation succes)

[otto]

hello bees,

for your weekend otto has some nice results. relax and read...

in a dream 6 g of 82 % 5-bromovanillin [1], 8 g of NaOH, 100 mg of copper powder and 60 ml water were heated to 120°C in pressure tubes [2] for 24 hours. the resulting black solution was acidified with HCl which caused a sticky grewish-black precipitate to form. the mixture was checked against pH-paper to be acidic, diluted with 150 ml water and extracted 7 times [3] by means of ethyl acetate. the combined organic phases were then dried over MgSO4 [4] and evaporated to dryness to yield 4 g of an almost black solid having the smell of vanillin [5].

to 4 g of previously prepared 5-hydroxyvanillin and 10 g (72 mmol) of K2CO3 in a 250 ml RBF equipped with reflux condenser, bubble valve [6] and magnetic stirrer there were added 9 ml (72 mmol) of dimethyl sulfate [7] and the mixture was heated to 80 °C using an oil bath for half an hour. at this point 6 ml of water were added and stirring was applied overnight at 80°C. [8]
to the still hot solution there was added HCl until acidic. the aqueous phase was then cooled to r.t. and extracted 3 times using DCM [9]. the combined extracts were dried over MgSO4 and evaporated to a brown solid [10].
this was subjected to column chromatography (silica gel, Merck, type 60; eluent: hexane/ethyl acetate 4:1). the following fractions were collected:

-   0,4 g   3,4,5 TMB-acid methyl ester, mp 77-79°C (lit. 81°C)

-   0,2 g   3,4,5 TMB-acid methyl ester + 3,4,5 TMB-aldehyde ~ 1 : 2

-   3,5 g    3,4,5 TMB-aldehyde, mp 67-71°C (lit. 77°C)

-   0,5 g   3,4 DMB-aldehyde + 3,4,5 TMB-aldehyde ~ 1 : 2 [11]

isolated over-all-yield: 3,5 g of snow white crystals of 3,4,5 TMB-aldehyde (69 % th.) [12]

marks

[1] the 5-bromovanillin was made by stirring vanillin in a solution of KClO3, H2SO4 and KBr in water at r.t. the vanillin didn't dissolve, reaction was almost complete the next day. the product obtained thus was only ~80% pure (vanillin and the corresponding acids).

[2] the amount is four times of what fits into ottos pressure tube. so he did it four times. alternatively refluxing the mixture in inert atmosphere can be applied. for details see

https://www.thevespiary.org/rhodium/Rhodium/chemistry/mmda.mescaline.html

[3] dont shake! otto ended up with an emulsion that refused to separate. setting the sepfunnel into intense rotation worked. it might be that actually 5 extractions are sufficient or even three. the first and the seventh extract only were checked by GC. the latter contained almost nothing. this is about when extracts are near to colorless.

[4] otto is shure that this step can be omitted if next reaction will be applied immediately.

[5] the powder contains mainly 5-hydroxyvanillin amongst vanillin and 5-hydroxyvanillic acid. this was checked by GC.

[6] to prevent additional air from entering the reaction vessel. inert atmosphere is not needed though.

[7] procedure and respective amounts are adapted from

Patent US4065504

, discussed previously on the hive (

Post 299247

(flipper: "patent 4065504", Methods Discourse) by flipper in thread "How to prepare hydroxyvanillin")

[8] before adding water the mixture is a whet dark solid and stirring is not really possible. the reaction time is likely to be shorter, otto simply went to bed.

[9] twice may be enough, other solvents may be used...

[10] the powder contains mainly 3,4,5 TMB-aldehyde amongst 3,4 DMB-aldehyde and 3,4,5 TMB-acid methyl ester. checked by GC.

[11] apparently separation was poor. the 3,4 DMB-aldehyde was actually coming within the 3,4,5 TMB-aldehyde fractions.

[12] calculated from 6 g of 82% 5-bromovanillin. actually the yield must have been higher (somewhere around 75%) since some 3,4,5 TMB-aldehyde was collected within other fractions.

conclusions / outlook

he ba-bees!

finally otto methylated the 5-hydroxyvanillin! excess dimethyl sulfate overnight is brute force, there was no hydroxy-product (like syringaldehyde) found. thus base wash of the methylation product was skipped.
the patent is right. it works as described, no solvent (other than water). the yield is pleasant and with a little more care (better 5-Br-vanillin preparation according to uemura or rhodiums site) otto thinks 80% from vanillin to the 3,4,5 TMB-aldehyde can be achieved and chromatography won't be needed.
the procedure would be fully OTC by replacing the DMS.
it took otto some time time to figure out that the one byproduct was the 3,4,5 TMB-acid methyl ester. long time he thought this was the methylated 5-Br-vanillin, left in the aromatic substitution as he assumed in his

Post 298744

(otto: "ottos low yields in methylation", Methods Discourse). but the mp of 5-Br-vanillin is reported in literature many times as being 66°C, so the 79°C for otto's crystals didnt fit.
so the exchange of the aromatic bromine in 5-Br-vanillin in the first step is complete. the acid was already present in otto's 5-Br-vanillin.
all the hydroxy- and methoxy-aldehydes turned out to be not so sensitive. they can be easily handled with.

otto

[Rhodium]

Very good write-up, with several novel procedures, and also on a very interesting substrate, which really should be investigated further.

Some comments:

6 g of 82 % 5-bromovanillin, 8 g of NaOH, 100 mg of copper powder and 60 ml water were heated to 120°C in pressure tubes for 24 hours.

The addition of a gram of disodium hydrogen phospate to the still hot reaction mixture makes the dissolved copper precipitate as cupric hydrogen phosphate when the solution cools, and filtering this off before acidification makes for easier cleanup.

(...) evaporated to dryness to yield 4 g of an almost black solid having the smell of vanillin. To 4 g of previously prepared 5-hydroxyvanillin

5-Hydroxyvanillin can be purified easily in very good yield by dissolving it in 10 parts boiling toluene, treating it with 1 part finely powdered activated charcoal with good stirring, and quickly filtering the solution while still hot to give a computer-beige filtrate. The filtrate is cooled in the freezer overnight to give only slightly off-white crystals of 5-hydroxyvanillin, which are suction filtered and air dried^*.

the 5-bromovanillin was made by stirring vanillin in a solution of KClO3, H2SO4 and KBr in water at r.t. the vanillin didn't dissolve, reaction was almost complete the next day. the product obtained thus was only ~80% pure (vanillin and the corresponding acids).

Aromatic bromination by chlorate oxidation of KBr has never been covered here at the hive to my knowledge. Could you please elaborate some more on that step?

To remove vanillic and 5-bromovanillic acids, wouldn't it just be to dissolve the crude reaction mixture in a non-polar solvent, and wash with dilute NaHCO₃? That should deprotonate the acids (but not the phenols) making them dissolve in the aqueous layer.

_{* Synthetic Communications 28(9), 1517-1524 (1998)}

[otto]

thanks rhodium,

to your questions:

for the prep of 5-Br-van otto doesnt have the notes here, but he is shure that almost anything that is suited to give bromine will do the job since vanillin is an easy substrate where nothing can go wrong.
and yes, a NaHCO3-wash would eliminate the acids.

otto

p.s. maybe a write-up for OTC mescalin from otto one day? uemura will shurely be faster.

[Mountain_Girl]

Mountain Girl/Boy has always dreamt of climbing Mt. Mescaline.
When I get there I'll plant the Hive flag.
But I'll need some help en route:

In the prep of 5-hydroxyvanillin, Otto extracted 7 times with ethyl acetate, with the suspicion that 5 times was actually sufficient. This was the alternative approach to the laborious continuous extraction quoted in the literature (batch extraction repeated enough times approaches continuous extraction). It would be more practical for me to do it his way.

I don't have ethyl acetate.
I do have, or can probably get:
DCM, dichloroethane, xylene, perchloroethylene, amyl acetate (bp ~140°C), petroleum ether.
I would guess that amyl acetate may be the way to go since it is polar and water immiscible.

Do other bees concur ?

Oh, and another thing:
I was planning to inert with LPG. I've discovered that LPG will most probably contain traces of ethyl mercaptan. Is this likely to have any adverse effect ?

[Mountain_Girl]

Post 435865 (missing)

(Barium: "Couch or chem activity", General Discourse)

[Osmium]

They should all work.

[ClearLight]

Distill off some non-acetone fingernail polish remover. That should give you whatever qty of ethyl acetate you need... didn't realize what that was till i got my spectra grade EtAc and opened it!

[Mountain_Girl]

Distill off some non-acetone fingernail polish remover
Tx Clearlight, I may actually end up doing that.

But,
for now,
I'm wondering,
about IPA and how you can salt it out of an aqueous solution....
Could I use it as an extraction solvent in this case....?

Please place answer here: LT/: OK :

Post 439111

(Mr_Reflux: "Distilling IPA from 70% rubbing alcohol", Newbee Forum) UTFSE with " salting out IPA , Barium "  

[LaBTop]

See above. LT/

[Mountain_Girl]

Thanks LT.
Still not sure if IPA is suitable for this purpose though..
(does it still precipitate out in an acidic environment ?)

This abstract suggests (I think) that
* KCl is a better salting out agent than KBr
* Increasing temperature enhances the effect 

http://www.maik.rssi.ru/abstract/genchem/98/genchem0227_abstract.pdf

[Mountain_Girl]

one :
IPA does not work - a separate phase does not form when it is added to the acidified post reaction mixture

two :
Is an inert atmosphere really necessary for the formation of hydroxyvanillin from bromovanillin ?
I thought so but in

https://www.thevespiary.org/rhodium/Rhodium/chemistry/mmda.mescaline.html

,
reference [3] uses N₂, no yield specified,
reference [9] does not specify inerting, yield 60%,
& reference [10] (iodovanillin) uses N₂, yield 68%.
Also in

https://www.thevespiary.org/rhodium/Rhodium/chemistry/iodovanillin.html

, no inerting is specified.

Finally in

Patent US5003091

, example 2, (found by

Post 282519

(3base: "MMDA: bromovanillin -> myristicinaldehyde", Methods Discourse)), hydroxyvanillin is prepared without inerting and reacted for only 4 hrs at 135°C. Admittedly though, the yield is only 34%.
Is this due to the lack of inerting or ..um...inertia (i.e. insufficient reaction time) ?

[GC_MS]

The inert atmosphere may or may not be necessary; it usually depends on which benzaldehyde you are using as substrate. All benzaldehydes are prone to auto-oxidation, which is a radical-involving process. The formed radicals also have a catalytic function, which means that one molecule of benzaldehyde does not simply give you a molecule of benzoic acid, but it will also catalyze the formation of new radicals. Salts of hydroxybenzaldehydes are very prone to this type of oxidation. By excluding oxygen, you render this side-reaction impossible and thus increase your yields. I'd consider using inert atmospheres especially when you use extended reaction times and elevated temperatures (or the combination).

[Osmium]

I have done small scale reactions with benzaldehydes (acetylation of phenolic hydroxies with Ac2O/pyridine, yuck), and the products obtained produced very strange NMR results that nobody could make any sense out of, until I figured out that the aldehyde function was completely oxidised to the benzoic acid.
This might only be a minor problem when done at 100g scale in a properly sized flask, but when doing 200mg reactions in a 100ml flask without N2 or Ar protective atmosphere you end up with the benzoic acid.