Antoncho continues to discover for himself the wonderful world of organic chemistry…
This time he found something that really blew his mind. Please, read on - especially
if you have access to Beilstein and other scientific literature – some investigation is still needed to complete the proposed synthetic routes.
It is a scientific fact
that phenols react with aqueous formaldehyde to give compounds called methylols – which is another name for a benzylic alcohol, a –CH2-OH group. Now, this reaction proceeds pretty fast and usually more than one methylol groups are added. That’s why it’s not widely used for preparative purposes. In fact, in case of phenol, 2,4,6-trimethylolphenol can bee obtained.
These methylols can bee oxidized to the corresponding aldehydes by any known means.
And, eventually, these (poly)aldehydes can bee subjected to Dakin rxn (H2O2 in aq. alkali) to exchange –CHO groups to hydroxyls, most mportantly,
if a –OH group is situated meta- to the formyl – it won’t split off and will remain essentially intact. More than that, this rxn, under certain conditions, will not oxidize polyphenilyc compounds to quinones – thus giving polyhydroxybenzaldehydes! And even more – these can (and should) bee then alkylated in the same pot!
Practically, this means that:
Phenol ---> tricarbinolylphenol ---> triformylphenol ---> 3,4,5-trimethoxybenzaldehyde.
Not to mention all sorts of (substituted) polyphenols that can bee made via this route - see the patent if you're interested in that.
Some will undoubtedly say
that it’s still longer than the ‘classic’ routes - but think of it, it is SO OTC and SO cheap! One can produce a huge amt of 3,4,5-TMBA from household ingredients and it won’t cost him more than 10$ (at least where I live
) Antoncho’s private little imaginary friend is a low-income kitchen chemist – so he likes to fancy about things like that very much…
The only “narrow” place in this synth is that in the patent that describes these rxns the oxidation of methylols to BA’s is done w/O2 on platinum/palladium catalyst. But there are some obvious alternatives, the simplest being bichromate/H2SO4, found in Beilstein – see the ref. below.
And here are the proc’s:
US Patent #4,435,601
Stage 1: Preparation of 2,4,6-trimethylolphenol
100 g of a 30% strength solution of formaldehyde in water (1.0 mol) and 23.5 g of phenol were mixed in a 250 ml glass conical flask fitted with a magnetic stirrer. The volume was adjusted to 125 ml with about 10 ml of water, and 10.2 g of sodium hydroxide pellets (0.25 mol) were then added, under stirring. The mixture was cooled with an ice bath such as not to exceed 30.degree. to 40.degree. C. When the temperature had dropped to 25.degree. C., the flask was purged with argon, the stirring was terminated and the homogeneous solution was left to stand for 24 hours at ambient temperature (22.degree. to 23.degree. C.).
After this period, no more than 315 millimols of free formaldehyde were determined. The reaction mixture was then introduced into 800 ml of cold isopropanol, under stirring. The heterogeneous mixture was stirred for an additional 10 minutes and the copious pinkish-white precipitate was then filtered off on Buchner apparatus. The precipitate was rinsed with isopropanol and then with ether. It was dried in an oven at 40.degree. C. under a pressure of 1 mm of mercury, and this provided 40 g of a powder in which the following were determined by NMR:
11.5 mol % of a sodium dimethylolphenate;
83 mol % of sodium, 2,4,6-trimethylolphenate;
5.5 mol % of the disodium salt of a tetramethylolbis-hydroxydiphenylmethane.
Stage 2. Oxidation of the methylols
23.4 g of freshly prepared, crude sodium trimethylolphenate, containing 0.10 mol of substrate, and 400 ml of water were introduced into a 500 ml five-necked round-bottomed flask fitted with a central stirrer, a glass double electrode for measuring the pH, a thermometer, a dropping funnel and a gas inlet. The apparatus was purged with argon.
1 g of 4.3% strength by weight platinum-on-charcoal and 60 mg of bismuth (III) sulfate were added. The apparatus, connected to an oxygen supply at atmospheric pressure, was then purged with pure oxygen; the stirring rate was adjusted to 1,050 rpm.
The temperature was raised to 45.degree. C. and at the same time the pH was raised to 11.0 by introducing 30% strength by weight sodium hydroxide solution (12 g, i.e., 0.09 mol).
After 1 hour, 15 minutes, 3.8 liters of oxygen had been absorbed and no additional oxygen was consumed during the next 25 minutes (3.83 liters). The catalyst was filtered off hot on a glass frit of porosity 4, the solid was washed with water and the filtrate was cooled to about 10.degree. C. The latter was cautiously acidified with sulfuric acid; a precipitate began to appear at about pH 8. The addition of acid was terminated when the pH reached 4 (17 ml of 25% strength by weight H.sub.2 SO.sub.4 had been used). The yellow solid obtained was filtered off on a glass frit of porosity 3, washed with 10 ml of water, drained and dried at 30.degree. C. under a pressure of 1 mm of mercury. This yielded 14.7 g of yellow powder. The yield of weight of crude material, essentially containing triformylphenol and oligomers, was 82%.
The desired purified compound was isolated from this crude product by preparative liquid chromatography in a yield of 18%, relative to the starging 2,4,6-trimethylolphenol, namely, 3.2 g.
This compound, which is not described in the literature, possessed the following characteristics:
Melting point under a pressure of 760 mm of mercury: 206.degree. C.
2,4,6-Triformylphenol is insoluble in water at 25.degree. C. and has the following solubilities in organic solvents at 25.degree. C.
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ethanol 0.5 g/liter
diethyl ether 0.25 g/liter
benzene 3 g/liter
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Stage 3. Oxidation of the triformylphenol with hydrogen peroxide at pH<7
450 mg of triformylphenol (2.5 mmols) were introduced into a 500 ml five-necked glass reactor fitted with a thermometer, an electrode, a condenser and two dropping funnels. 12.5 ml of deaerated water were added, the magnetic stirrer was started and the temperature was raised to 45.degree. C., everything being carried out under nitrogen.
The pH was raised to 4.5 with 10% strength by weight sodium hydroxide solution contained in the first funnel, and 1.96 g of 10% strength by weight hydrogen peroxide (5.8 mmols) were then dropwise introduced, over the course of 10 minutes, from the second funnel.
The solution, which was heterogeneous at the beginning, gradually became homogeneous. The reaction mixture was maintained at 45.degree. C. for:
50 minutes at pH 4.5, and
45 minutes at pH 5-5.5.
4.16 mmols of sodium hydroxide had been added in total.
Stage 4. Methylation of the 3,4,5-trihydroxybenzaldehyde
In order to more easily measure the yield of gallic aldehyde obtained during the previous step, all products obtained were methylated in the following manner:
In the apparatus described above, the dropping funnel containing 10% strength by weight sodium hydroxide solution was replaced by a funnel containing degassed 30% strength by weight sodium hydroxide solution. The funnel containing hydrogen peroxide was replaced by a funnel containing dimethyl sulfate (DMS).
The pH of the mixture was raised to 8, while maintaining a temperature of 45.degree. C. and a nitrogen atmosphere. 4.75 g of DMS (37.5 mmols) were then introduced over a period of 40 minutes, while maintaining the pH at 8-8.5. The experiment was terminated when the pH stabilized, which was after 1 hour, the amount of 30% strength sodium hydroxide solution used then being 4.2 g (31.5 mmols).
After cooling to 20.degree. C., the reaction mixture was acidified to pH 3.5 with 0.25 ml of 50% strength by weight H.sub.2 SO.sub.4 and extracted three times with 20 ml of dichloroethane. The organic extracts were washed with 10 ml of water, dried over sodium sulfate and analyzed by gas phase chromatography.
The hydroxyls had been totally methylated because neither gallic aldehyde, nor 5-hydroxy-p-vanillin, nor seringaldehyde (3,5-dimethoxy-4-hydroxybenzaldehyde) and/or its isomer, 3,4-dimethoxy-5-hydroxybenzaldehyde, were observed.
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Yield of 3,4,5-trimethoxybenzaldehyde,
216 mg = 44%
relative to the triformylphenol introduced
in step 3
Yield of 1,3,4,5-tetramethoxybenzene
24 mg = 5%
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Now please would someone really kind
answer these questions that occupy Antoncho’s fictious friend’s head:
1.
Someone with access to Beilstein, please post the procedure of methylol --- aldehyde oxidation with bichromate, found in “vol. 8, p. 31”.
2. Can anyone look up the Dutch patent #87,141 (I tried Espacenet – to no avail) – the same oxid’n with MnO2 in chloroform.
3. I guess that methylol oxidation w/Na2Cr2O7 will oxidize as well polyhydroxyBA’s to quinones. That shouldn’t appply to phenol or vanillin derivatives, right?
4. And – AFAIK, alcohols get oxidized to aldehydes pretty easily –
is it possible that methylols can bee in situ oxidised to BA’s w/H2O2? At least, it is pretty evident that H2O2 won’t make acids of them under standart Dakin rxn conditions. That’d bee really cool!
Well, that’s finally it. Any input very appreciated
,
Antoncho
