2,5-dimethoxybenzaldehyde Rhodium synth review?

thenewrunne · Chemically Balanced

Would anyone here have the 2,5-dimethoxybenzaldehyde synth review that was on Rhodium's site that was put up just before he went down? It was a great file on synthing it. Any help would be appreciated locating that information.

icecool · Insistent Chemist

SWIM happened to have the synthese on his computer so here it is.
It took me like 40minutes to post this and edit it over and over again but finally it is exactely like it was on rhodium with the smileys and colors and font size and colour and everything.
Hopefully this was the right one you wanted... Laughing

It isn't on rhodium.moppy.net this one...so that's why I posted it in the whole.

OK, here's a working synth for 2C-B (2,5-dimethoxy-4-bromophenethylamine) from 2,5-diMeO-Benzaldehyde in three easy steps...

The only reagents needed are ethylenediamine, lots of acetic acid, bromine, nitromethane, 2,5-diMeO-Benzaldehyde, zinc dust (or Al foil and HgCl2), NaOH, HCl, H2SO4, NaHCo3, NaCl, diethyl ether (or other lowboiling np), dH2O, methanol, ethanol and isopropanol - maybe a bit acetone too... Cool

2,5-Dimethoxynitrostyrene
The procedure has been optimized for the preparation of 2,5-Dimethoxynitrostyrene, and the yield is typically very high for this product, usually exceeding 95%.

2,5-Dimethoxybenzaldehyde (83.1g, 500 mmol) and ethylenediammonium diacetate (9.0g, 50 mmol) was dissolved with stirring in 400ml isopropanol with gentle heating until a clear solution was obtained. Nitromethane (36.6g, 600 mmol) was then added, and during the next hour the solution turned a deep orange, and stirring was discontinued. The solution was then allowed to stand at room temp for 36h, and the orange crystalline mass was broken up with a large spatula and was filtered with suction until no more liquid came through. The crystals was then washed with 100ml cold isopropanol in the buchner funnel, and sucked as dry as possible. After air drying overnight, the crispy and intensely orange 2,5-dimethoxynitrostyrene weighed 100.5g (480 mmol, 96%).

Now two different low-cost reductions:

A) Nitrostyrene reduction by Al/Hg.

Recently I was dreaming about to reduce 2,5-dimethoxynitrostyrene to the amine 2C-H with Al/Hg and acetic acid. I anticipated a yield of about 50-60% but I got only 35%. Yields are not good, but Shulgin reports 40% for 2C-B and 50% for 2C-H with LAH, so might be interesting to avoid buy / use LAH.

Proportions used:

* 1 g 2,5-Dimethoxynitrostyrene
* 10 ml Acetic acid
* 15 ml 96% Ethanol
* 5 ml Water
* 50 mg HgCl2
* 2 g Aluminum foil
The reaction must be carried at about 60øC, otherwise all of the starting nitrostyrene won't be dissolved. Some tips are:
* Make a solution of everything but the Al, then add the foil, cut to oneinch squares at a rate enough to keep the temp around 60øC, and add until the orange colour disappear. About the double weight of nitro will be enough, maybe less.
* Filter off the Al sludge, wash it with alcohol, then basify the solution with 25% NaOH. Filter again to remove the crystallized sodium acetate, and wash the filter cake with water.
* Remove the solvent under vacuum, dissolve the residue in dilute H2SO4, and wash with 3x20 ml CH2Cl2. Basify with 25% NaOH and extract the solution with 3x25 ml CH2Cl2. Dry the pooled extracts over MgSO4, remove the solvent under vacuum, dissolve the residue in anhydrous ether, and saturate the solution with anhydrous HCl gas to precipitate pure 2C-H hydrochloride. To recover the 2C-H freebase, distill the residue above under vacuum instead.

B) Zn/HCl nitrostyrene reduction ("leminger reaction")

(just replace "3,5-dimethoxy-4-allyloxy-w-nitrostyrene" with "(2,5-dimethoxy)-beta-nitrostyrene" gotton from above condensation between aldehyde and nitromethane...)

Experimental:

We reduced alcoxylated w-nitrostyrenes to corresponding b-phenethylamines with zinc and hydrochloric acid, the temperature slowly went from 3 deg.C to 20 deg.C. Reaction is described by equation:
w-nitrostyrene + 4 Zn + 9 HCl ---> b-phenethylamine.HCl + 4 ZnCl2 + 2 H2O
Products were isolated as free bases by extraction to benzene. This bases quickly reacted with CO2 in air and were difficult to obtain in analytically pure state, so sulphates were prepared. Sulphates crystallized good and weren't so soluble as hydrochlorides. Prepared b-phenethylamines were identified as chloroplatinates. As an example of this good-yielding readuction the preparation of 3,5-dimethoxy-4- allyloxy-b-phenethylamine is described.

3,5-dimethoxy-4-allyloxy-b-phenethylamine (I)

To ice-cooled and stirred mixture of 42 ml 35 % HCl and 42 ml ethanol were alternately in small portions introduced 5.31 g 3,5-dimethoxy-4-allyloxy- w-nitrostyrene (20 mmol) and 16.5 g zinc powder. Temperature was held at 5 deg.C during this addition, which took 75 min. Mixture was then 1 h stirred at temperature slowly raising from 5 to 10 deg.C and 2 h at 10-12 deg.C. Then 12.5 ml 35% HCl was dropped to mixture during 1 h at 10-15 deg.C. Next 1 h additional 3 g zinc powder were added and stirring was continued 1.5 h at 15-20 deg.C. Remaining zinc was filtered 12 h later and washed with 23 ml water. Clear filtrate was extracted twice with 23 ml benzene to remove non-basic contaminants. Separated water phase was then treated slowly and with cooling with solution 75 g NaOH in 125 ml water; first precipitated Zn(OH)2 finally almost dissolved. Amine was extracted four times 25 ml benzene, united benzene extracts were extracted twice 25 ml water, settled and filtered. Clear slightly yellow filtrate was distilled to remove benzene and then distilled at 10 torr. Amine remained at flask as 4.05 g dense yellow oil (85 %), which solidified on cooling to almost colourless crystals with mp 47 deg.C. Free amine was crystallized from hot n-hexane (1:10) to form snow-white prisms, mp 50-51 deg.C (dried over KOH at 5 torr). Anal. calcd. for C13H19NO3: C, 65.80; H, 8.08; N 5.91. Found: C, 65.95; H, 8.01; N, 5.75.

3,5-dimethoxy-4-allyloxy-b-phenethylamine sulphate (II)

3.56 g 3,5-dimethoxy-4-allyloxy-b-phenethylamine (15 mmol) were dissoved in 16 ml 96 % ethanol and 1.48 g 50 % H2SO4 (7.5 mmol) were added with stirring and rinsed with 6 ml ethanol. Suspension of crystals was warmed at water bath. After cooling crystals were formed. Product was filtered with suction, washed 15 ml 96 % ethanol and dried at 60 deg. C. Colourless, glistening plates weighed 4.20 g (92 % of theory). Compound II is soluble in hot, slighthly soluble in cold ethanol. Sulphate II is also soluble in water; in ether almost insoluble. Crystallization from hot 96 % ethanol (1:10) provided big glistening thin plates, which after drying over H2SO4 at 5 torr had mp 200-204 deg.C and formula (C13H19NO3)2.H2SO4.2H2O.
(You now would have (2C-H)2*H2SO4 or 2C-H sulfate...)

Improved bromination of 2C-H to 2C-B

This method is based on the one found in Pihkal #20 for the synthesis of 2C-B. However, some tips and tricks has been added, and the isolated and purified salt is the hydrobromide instead of the hydrochloride made by Shulgin.

The hydrobromide salt of 2C-B is relatively water-soluble, as opposed to the hydrochloride, which is nearly insoluble. This makes the insufflation of this salt (if desired) much less painful than with the more common hydrochloride. There is still a nasty burn, but not at all as sharp. Due to the higher molecular weight of this salt, 29mg of 2C-B hydrobromide is equivalent to 25mg of 2C-B hydrochloride.

Experimental:

In a 100ml beaker with good magnetic stirring, 24.8g 2,5-Dimethoxyphenethylamine (2C-H) was dissolved in 40ml glacial acetic acid, which caused heat evolution and the deposition of a clear crystalline mass of 2C-H acetate, which upon continued stirring redissolved to form a clear solution. Elemental bromine was chilled to -5°C (as to minimize evaporation), and 7ml (22g) was pipetted up and added to 40ml of glacial acetic acid, and this solution was added in one portion to the stirred 2C-H solution, and the beaker covered with aluminum foil.
After a few minutes, the dark brown solution begun to crystallize with the evolution of heat and hydrobromic acid gas (hence the Al foil cover). When the suspension had solidified to a solid crystalline mass, the stirring was turned off and the beaker with its contents was allowed to stand until it had returned to room temperature. The light brown crystalline mass was crushed against the sides of the beaker with a spatula to give a thick light brown paste, which was transferred to a fritted glass funnel and filtered at the pump and washed with 20ml glacial acetic acid. The filtrate was poured out of the filter flask and set aside. The precipitate in the funnel was then washed with another 20ml glacial acetic acid and 2x20ml dry ether (this filtrate was also set aside), to give a light tan powder of 2C-B.HBr, which was air dried and sifted through a metal mesh to make it finely powdered. It was then boiled for 15 min in 200ml dry ether, filtered and washed with 50ml ether and air dried to give 36.42g 2C-B Hydrobromide as a white powder. No significant amounts of 2C-B.HBr could be recovered from the ether washes.
The black filtrate set aside earlier was diluted with 50ml ether and put in the freezer overnight, making it solidify almost completely, and after thawing it in the fridge, it was filtered and washed with a little ether to give 1.91g tan 2C-B.HBr after air drying. The other filtrate saved earlier (a light amber in color) was subjected to the same treatment, yielding 0.56g tan 2C-B.HBr. Both crops were combined, and recrystallized from a boiling mixture of 60ml acetonitrile and 6ml methanol. When the solution had cooled somewhat, 30ml dry ether was added, and the salt was allowed to slowly precipitate in the fridge overnight. The solution was then suction filtered and the precipitate washed with a little ether to yield 1.55g 2C-B.HBr as very fine, off-white needles.
The combined crops together weighed 37.9g, representing a total yield of 81% from 2C-H freebase.

Notes:

The most important part in the purification of the salt is to thoroughly remove all the dark brown bromine and bromination byproducts directly in the intitial washing of the precipitated 2C-B.HBr, which is ensured by breaking up the light brown crystalline mass after the bromination so that no lumps at all are present, which could otherwise trap impurities. Then this mass has to be carefully washed, first with two acetic acid washes, followed by two ether washes to wash out dirty acetic acid and to facilitate drying of the powder. Even if you are doing an acid/base extraction of the hydrobromide followed by precipitation of the hydrochloride salt, this careful purification is absolutely necessary to ensure nice white crystals, unless you are planning to vacuum distill the 2C-B freebase before crystallization. Most people skip that step, and I feel that vacuum distillation of the 2C-H freebase followed by this cleaning procedure is a fully adequate alternative to obtain a product of good quality. Not vacuum distilling the 2C-B freebase also avoids having gaseous hallucinogens around. To really perfect the color and appearance of the product, it is dried, finely powdered and boiled in ether to remove the last traces of colored impurities. The ether does not dissolve any of the product, and is afterwards yellow-colored, indicating that it has taken up unwanted stuff from our product.
The reason the washings are collected in two separate portions is that by doing so, more 2C-B.HBr can be recovered from these solutions. If both acetic and etheral washes are combined, the solution forms two layers and much less salt is precipitated on cooling.
The recrystallization of the crude 2C-B.HBr is not optimized, better results may be obtained by using an isopropanol/ether recrystallization instead of this using acetonitrile:

Alternative recrystallization

1.55g off-white 2C-B.HBr was suspended in 25ml isopropanol in a 75ml beaker with magnetic stirring, and was heated until all the salt had dissolved*, then removed from the heat, and 15ml ether added to the light amber solution. A suspension of white crystals slowly appeared, and after the solution had returned to room temperature it was put in the fridge for a few hours to ensure complete crystallization, the precipitate filtered, washed with 2x10ml ether and sucked free of solvents. After air drying overnight, the resulting fluffy white powder weighed 1.40g (90% recovery).
* As everything dissolved already at ~40-50°C, using 25ml IPA was unnecessary. Better aim for 10ml IPA and 5ml ether per gram 2C-B.HBr to minimize the required solvent volume when working with larger amounts. Using the freezer after the fridge may also allow to cut down on the ether, as most of the salt will crystallize anyway.

IndoleAmine · Dreamreader Deluxe

IndoleAmine · Dreamreader Deluxe

I didn't find anything directly related to 2,5-diMeO-benzaldehyde in particular on Rhodium's, but one good way is to start from the (almost) OTC available hydroquinone, make the 2,5-dihydroxybenzaldehyde via "Reimer-Tiemann"-formylation with HCHO, and then methylate with MeI (maybe a simple methoxide swap will work too?) to get 2,5-diMeo-benzaldehyde...
http://12.162.180.114:90/synthetika/hiveboard/novel/000416548.html

Another possibility would be the duff formylation using hexamine/trifluoroacetic acid.... (not very OTC.. Laughing

)
https://www.synthetikal.com/Rhodiums_pdfs/chemistry/formylation.duff-hmta-tfa.html

The original aldehyde synthesis review you probably meant was usually found under "https://www.synthetikal.com/Rhodiums_pdfs/pdf/aromatic.aldehyde.synthesis.pdf", but isn't "revived" yet...

i_a

thenewrunne · Chemically Balanced

Thank-you for the help.

I thought I truly remembered Rhodium putting a new file called "2,5-dimethoxybenzaldehyde synth review". Since I'm such a freak about not keeping anything on my computer, I didn't download it. Sad

But, maybe I don't need it. Indoleamine (glad you made it over from the Hive BTW), could you give your opinion on the synth starting with anisaldehyde as compared to the hydroquinone start point?

Given ease of chemical aquisition equal for both paths.

Thanks.

nyarlothotep · Thu Apr 07, 2005 7:12 am

This one?
Synthesis of 2,5-Dimethoxybenzaldehyde

HTML by Rhodium
Preparation of 4-Methoxyphenol
Quinol Monomethyl Ether3

The method of Ullmann4 for the semi-methylation of quinol (hydroquinone) was found to give poor yields and the following process was adopted after numerous trials. A solution of quinol (110 g) in sodium hydroxide (100g) and water (700 ml), contained in a flask filled with hydrogen, was cooled to 12 degrees and vigorously shaken after the addition of dimethyl sulphate (120 ml) in one portion. After about 5 minutes the mixture was cooled and the dimethyl ether collected (33g, mp 56°C). The filtrate and washings were acidified with hydrochloric acid and cooled to about 8 degrees for about 1 hour, thereafter the monomethyl ether was collected, washed with ice water, and dried (45 g., mp 52-54°C). The aqueous solution was extracted with ether and the residue after evaporation of the solvent yielded to benzene a further 30g of less pure quinol monomethyl ether, mp 41-46°C. For our purposes, it was necessary to ensure the absence of quinol from the product. The material was dissolved in benzene and any quinol which crystallized was separated; the solution was then distilled and a product, mp 53-54°C, collected at 243-246°C. This was redissolved in benzene, and the solution repeatedly shaken with small quantities of cold water. The ether was then again distilled, bp 243-244°C, mp 56°C. No coloration was developed in alkaline solution in contact with air. The substance crystallised from light petroleum has mp 56°C, but when heated to about 200°C and quickly cooled, the mp is 53°C, changing in a week or two to 55°C. Crystals, mp 56°C, also change on keeping and the mp becomes 55°C. Although these changes are small, the phenomenon is a real one.

Related are also a few older german refs for basically the same reaction sans the hydrogen atmosphere4,5,6
Hydroquinone Monomethylation7

5.0 g of hydroquinone, 40 mL of methanol and 1.0 g of cupric chloride are fed into a teflon-lined autoclave having an internal capacity of 100 mL . The autoclave is purged with nitrogen and is kept for 2.5 hours at 105°C. On termination of the reaction, an analysis of the mixture indicates the formation of 4.1 g of hydroquinone monomethyl ether (conversion 85%, selectivity 87%).
4-Methoxyphenol from Benzoquinone8
Sample

Benzoquinone

4-MeO-Phenol

Hydroquinone
After 3 h

0.12 g

14.6 g

3.6 g
After 6 h

0.00 g

15.8 g

2.8 g

Hydroquinone (18 g) and benzoquinone (2 g) in methanol (100 ml) with p-toluenesulfonic acid (5 g) were heated under reflux for 6 hours. Samples taken at 3 and 6 hours were analyzed by GLC and found to have the compositions indicated in the table.
Formylation of 4-Methoxyphenol

Formylation of 4-Methoxyphenol (4-hydroxyanisole, hydroquinone monomethyl ether) yields 2-Hydroxy-5-Methoxybenzaldehyde (5-Methoxysalicylaldehyde). The most promising procedures include Reimer-Tiemann formylation (CHCl3/KOH) and Mg-mediated phenol ortho-formylation with paraformaldehyde. A few variations on this theme is presented below.

Formylation with Paraformaldehyde/Magnesium Methoxide

Written by DTT, Translation from Russian by Dioulasso

This formylation method can be a superior alternative to the much discussed Reimer-Tiemann formylation (a selective ortho-formylation of phenols).
Experimental

A 2000 mL RBF equipped with a reflux conenser, a mechanical stirrer, and an addition funnel is charged with 32g of magnesium followed by 200ml dry Methanol. It is possible to ad more MeOH so Mg dissolves faster. The reaction is vigorus. Sometimes the flask has to be cooled to prevent the condenser from spitting around. When the mixture is beginnig to get thick, 250g of 4-methoxyphenol in 300-500ml of hot toluene is added in a slow stream from the addition funnel. The mixture is heated up with good stirring. (Watch out - the precipitated phenolate can stick to the bottom).

When all the magnesium has dissolved, the MeOH is evaporated (it is also possible not to evaporate allNote 1). A suspension of 180g of ParaformaldehydeNote 2 in Toulene is added in small portions every 10 minutes (exotermic!), with good stirring of the thick mixture. This takes about an hour. The mixture turns yellow and gets less thick. The mixture is than stirred for another 30 min and acidified with dilute Sulfuric AcidNote 3. The toluene layer is separated and the toluene is driven off. The rest is 2-Hydroxy-5-Methoxy-Benzaldehyde.

The thus obtained product is not contaminated with 4-methoxyphenol, but containes the dimer as an inpurity. It may be cleaned via the bisulphite adduct or it can be distilled under reduced pressure. Yield is around 80%. The aldehyde may stain the skin yellow.
Notes:

1. IMHO it is not necesseary…Once I have tried not to evaporate all of it and all seemed to work fine.
2. Dry paraformaldehyde was used.
3. In the patent the acidified mixture is stirred for 5h. I'm not sure about that half an hour figure - just act by the situation. You can see the decomposition of phenolate visually as it dissolves in toluene. One has to scratch it diligently off the flask's wall, though.

Some final notes by Dioulasso:

* It might be necesseary to efficently stir the acidified mixture in order to achive full conversion of the phenolate. Swim experienced a lot of tar like residue after steam distilling his Reimer-Tiemann product. Is it possible that unconverted phenolate was extracted from the not fully acidified reaction mixture, and partially that was the residue left behind? This would explain his low yields (less than 50%)...
* For smaller batches, it might be advantageous to initiate the Mg(MeO)2 formation with small crystals of Iodine.

Magnesium-mediated ortho-formylation of phenols1

2-OH-5-MeO-benzaldehyde from 4-MeO-phenol, Mg(OMe)2, and paraformaldehyde in MeOH/toluene. Yield: 97% The procedures are described for (nonyl)Phenol, simply use an equimolar amount of 4-Methoxyphenol instead.

Experimental

Phenol (37.6 g, 0.4 mol) was added to magnesium methoxide (259 g of 8% (w/w) solution in methanol; 20.7 g, 0.24 mol) and the mixture was heated to reflux. Approximately half of the methanol was distilled off and toluene (300 g) was added to the residue. The azeotropic mixture of toluene and and methanol was removed by fractional distillation, until the temperature of the reaction rose to 95°C. A slurry of paraformaldehyde powder (43.2 g, 1.44 mol) in toluene (75 g) was added in small portions over 1 h to the reaction mixture at 95°C with concurrent removal of the volatile materials by didtillation. Stirring was continued at 95°C for 1 h, after which the mixture was cooled to 25°C and added slowly to 10% sulfuric acid (450 g), The resulting mixture was stirred at 30-40°C, after which the aqueous layer was separated and extracted with toluene (2x100 g). The combined organic layers and extracts were washed with 10% sulfuric acid (50 g) and water (50 g) and evaporated under reduced pressure to give the aldehyde as a pale yellow oil (48.35 g, 84% w/w by GC and 1H-NMR comparisn against a reference standard and against a commercial sample of known purity; 83% yield).

In similar reactions they used the following conditions:

Magnesium raspings (7.3 g, 0.3 mol), methanol (112 g), toluene (48.5 g) and magnesium methoxide (1.6 g of 8% w/w solution in methanol; 1.5 mmol) were heated under reflux for 2 h untile the magnesium had dissolved and hydrogen evolution had ceased. 4-Nonylphenol (112 g, 0.5 mol) was added to the mixture [...]

Convenient method for the ortho-formylation of phenols2

2-OH-5-MeO-benzaldehyde from 4-MeO-phenol, MgCl2, Et3N, and paraformaldehyde in MeCN.
Yield: 97% Reaction time: 2 h

Phenolic derivs. are formylated selectively ortho to the hydroxy group by paraformaldehyde with magnesium dichloride-triethylamine as base. With alkyl-substituted phenols, e.g., 2-, 3-, 4-Methylphenols, excellent yields of the corresponding salicylaldehyde derivs. were obtained. Similar results were obtained with 2-, 3-, and 4-chloro-substituted phenols and with 3-and 4-methoxyphenol, while 2-methoxyphenol was unreactive. A good yield of Methyl 3-formyl-4-hydroxybenzoate was obtained by this method as well, but generally phenols with electron-attracting groups reacted sluggishly; the long reaction times required caused the formation of byproducts, particularly MOM-derivs. of the phenols.

General procedure:

Dry (P2O5) paraformaldehyde (135 mmol) was added to a mixture of the phenolic derivative (20 mmol), commercially available anhydrous magnesium dichloride (30 mmol) and dry (Na) triethylamine (75 mmol) in acetonitrile (100 mL; distilled over CaH2), and the mixture was heated under reflux for the reaction time recorded. The mixture was cooled to room temperature after which 5% aq. HCl was added and the product extracted with ether. The dried (MgSO4) extract was evaporated and the residue purified by flash chromatography on silica gel.
3-Hydroxy-Benzaldehyde to 2,5-dihydroxybenzaldehyde

Neubauer and Flatow9 prepared 2,5-dihydroxybenzaldehyde by the oxidation of salicylaldehyde but the present method with m-hydroxybenzaldehyde as initial material gives an improved yield of a less crude product.
Experimental10

A solution of m-hydroxybenzaldehyde (61 gr) and NaOH (25 gr) in water (400 cc), while being vigorously stirred and kept at 30-35°C, is treated simultaneously from separate dropping funnels with aqueous solutions of potassium persulphate (150 gr in 1500 cc) and NaOH (200 cc, 40%), the additions being made during 90 min. at such rates that the mixture is always alkaline. After 36 hours of standing, the deep brown solution is rendered faintly acidic (Congo Red paper), and unchanged m-hydroxybenzaldehyde (31 gr) is extracted with ether. The solution is then strongly acidified (350 cc of conc HCl) and heated slowly to 70°C, the dark brown amorphous precipitate which forms gradually, being filtered off (this substance, which chars above 330°C, is almost insoluble in all organic solvents, but readily soluble in aq. Na2CO3 - it contains the aldehyde group as shown by the formation of the p-nitrophenylhydrazone, and invariably constitutes about 40% of the yield). The 2,5-dihydroxybenzaldehyde is extracted from the filtrate by ether, ether removed by evaporation, and the residue extracted by benzene. Yield 13g, mp 89-92°C. This substance crystallises from benzene in bright yellow needles, but they still contain solvent. They rapidly effloresce at room temperature, leaving yellow needles, mp. 98-99°C.

Gentisinaldehyde could not be obtained from 2-nitro-5-hydroxybenzaldehyde by reduction, diazotisation and decomposition of he azo-compounds. The latter however could be obtained in 30% yield.
2-Hydroxy-5-Methoxybenzaldehyde
to 2,5-Dimethoxybenzaldehyde

Written by Antoncho

4,7 g of crude dark-brown 2-hydroxy-5-MeO-benzaldehyde obtained by Reimer-Tiemann formylation (steam-distilled) was placed into a 150ml three-necked RBF. There was added 25mls dioxane (undried, but kept over FeSO4 to remove peroxides), 5g freshly fused potassium carbonate, 1ml MeOH (Note 1) and, at last, 2mls (4,6g = 25% molar xcess) methyl iodide. The central neck of the flask was fitted w/a condenser, one of the side-necks - w/a thermometer, and the 3rd one was plugged to bee later used for various tests and additions. The apparatus was flushed w/butane and all was brought to a very gentle reflux on a waterbath.

The temp, measured inside the boiling liquid, at first was ~77°C, increased to 85°C in ~30mins, and went up to 92°C over the next 3 hours. Boiling was cont'd overnight (Note 2)

An aliquot of the liquid was taken w/a syringe, acidified, evaporated under draught to remove carcinogenic dioxane and smelled. The specific smell of unreacted starting material was apparent, mixed w/a somewhat similar, but sweet, aroma of p-diMeO-benzene (Note 3).

So 0,7mls of MeI were added and reflux recommenced. After 4 hrs (internal temp 92°C) another test was taken which again indicated the presence of the starting material. Another 0.7 mls MeI were added and refluxed for several more hours; the third test revealed the completion of the rxn.

The rxn was flooded with 60 ml of 20% KOH, saturated w/NaCl and xtracted w/30+15 mls of IPA. Alcohol was separated, some 10g of Na2SO4 were added in a faint attempt of drying, followed by 90mls of saturated aq. metabisulfite. The mixtr was subjected to vigorous mech stirring for 7 min and the precipitate (which ended up in the alcohol layer) was filtered, washed twice with a lil IPA to almost completely remove yellow coloration (Note 4), pressed between filter paper and somewhat dried under draught. Still containing some IPA, it weighed 8.7g.

Thus obtained adduct was thrown into 50mls of pre-chilled in the freezer 20% KOH, stirred and left for 30 mins in warm water (Note 5). Precipitated aldehyde was filtered, washed with water 3 times, pressed between filters as dry as possible, chopped on a plate and left to air-dry. Still containing a little water, it was off-white, but still pretty, vanillin-like powder without any noticeable smell and weighed 3.6g (Note 6). After drying it was 2.7g.
Notes

1. Dioxane was chosen for the following reasons:
1. a much higher bp as compared to acetone
2. unreactivity towards the carbonyl group, which is a possible disadvantage of using acetone
3. ability to dissolve both MeI and, to some xtent, alkali.

The rationale beehind addind MeOH was the following: K2CO3 reacts with it to form KHCO3 and KOCH3. The latter, being more soluble than K2CO3, was supposed to act as sort of a PTC. Unfortunately, it later turned out that SWiHKAL's MeOH was VERY wet (not to mention water in dioxane), so the effectiveness of this additive remains to bee researched. In any case, the two-fold amt of MeI that was required for the rxn, warrants further investigation. Probably, unhydrous conditions would bee better. Maybee, methanol shouldn't bee added at all - to minimize hydro/methanolysis of MeI, which is the major side rxn.
2. Probably, there is no need to reflux the mixture more than 30-60 min after the internal temp reached maximum. SWiHKAL just wanted to bee sure.
3. p-MeO-phenol is a major impurity contained in the hydroxyaldehyde isolated by steam-distillation from a RT formylation. It's hard to estimate, but there is quite a bit of it in there, probably not less than 20%.
4. This intensely colored yellow impurity is, probably, benzoquinone which survives all the transformations since its usage in methylation of hydroquinone. The next time SWiHKAL does that, he'll first try to remove it with bisulfite from the crude p-MeO-phenol.
5. SWiHKAL wanted to make sure all adduct decomposed. Since the appearance of the substance virtually doen't change, several tests were needed to confirm that. However, decomposition of the adduct seems to proceed fast even w/cold KOH.
6. The mp was measured and found to bee circa 45°C, whereas the lit value is 51°C. Could anyone suggest to what kind of (im)purity that corresponds?

References

1. R. Aldred et al., J. Chem. Soc. Perk. Trans. I, 1823 (1994)
2. N. U. Hofsløkken, L. Skattebøl, Acta Chem. Scand. 53, 258 (1999)
3. J. Chem. Soc. 393 (1926)
4. Ullmann, Annalen 327, 116 (1903)
5. Helvetica Chimica Acta, 7, 951
6. Monatsheft, 45, 581
7. US 4,469,897 (Ex. #2)
8. US 4,294,991 (Ex. #20)
9. Neubauer and Flatow, Z. Physiol. Chem. 52, 375 (1907)
10. J. Chem. Soc. 2339 (1927)

Maybee, maybee not..... Question

thenewrunne · Chemically Balanced

Well it definately fills in some holes. Give me a day or so to work it into what I have. It's definately new material for me, as I don't recall reading that stuff.

It seems that the main hurdle is to get to 4-methoxyphenol?

nyarlothotep · Thu Apr 07, 2005 7:59 pm

Appears to be so, from that write up.....but this interesting little bugger:
http://www.irevolution.org/RandolphCarter/anethole.2c-b.pdf

Shows an alternative workup to the 4-methoxyphenol from an easily availible oil....
And it looks a whole hell of a lot easier.
Once the 4-methoxy is done, SWIN sees no problem mixing and matching from any availible formylation methods....that little bit in Swin's previous post with the paraformaldehyde looks particularly tasty........

Sandmeyer · Fri Apr 08, 2005 4:08 am

java · Consumer

Reimer-Tiemann formylation process for producing aldehydes (US4755613)

The invention relates to a process for preparing aromatic or hetero-aromatic aldehydes by the Reimer-Tiemann formylation reaction. The process comprises employing a solid alkaline hydroxide in order to carry out the reaction in a solid/liquid medium. Such a process makes it possible to substantially increase the yield of the Reimer-Tiemann reaction and to avoid tar formation entirely or in large part.

EXAMPLE 1

100.cm3 of chloroform, 9.4 g of phenol, 20 g of anhydrous sodium hydroxide and 3.6 cm3 of water are placed in a 250 cm3 reactor provided with a coolant, a mechanical stirrer and a thermometer, and the reaction medium temperature is thermostatically maintained at 50? C. These conditions of the initial mixture correspond to a hydration rate of 0.4 moles of water per mole of sodium hydroxide (2 moles of water per mole of initial compound) and to 12.6 times as much chloroform as initial compound (expressed in moles). Thereupon the temperature of the reaction medium is raised to 58? C. for one hour. Next 12 g of sodium hydroxide in powdered form are progressively added over a period of two hours, the temperature being kept constant at 58? C. The reaction proceeds for 1 hour. At the end of the reaction, the initial phenol has completely disappeared. The residual chloroform is recovered and recycled. The mixture of aldehydes is obtained in sodium form. It is neutralized until a neutral brine is obtained. The salicylaldehyde can be recovered in conventional manner at a yield close to 77% (9.4 g) with respect to the initial phenol by carrier vapor distillation or by ether extraction. The p-hydroxybenzaldehyde is recovered at a yield of 17% (2 g) by ether extraction from the acidified residual brine to pH of 1.

EXAMPLE 7

10.cm3 of methanol and 90 cm3 of chloroform, also 6.2 g of guaiacol are placed in a 250 cm3 reactor with a coolant, a mechanical stirrer and a thermometer. Next 16 g of pulverulent sodium hydroxide and 6 g of water are added while maintaining the mixture temperature at 0? C. These initial mixture conditions correspond to a hydration rate of 0.825 moles of water per mole of sodium hydroxide (6.6 moles of water per mole of initial compound [guaiacol]) and to 22.7 times as much chloroform as initial compound. Thereupon the mixture is slowly returned to ambient temperature and is very gradually raised to 58?C. Following the reaction, 16 g of pulverulent sodium hydroxide are progressively added over a period of 2 hours. The temperature is kept constant for 1 hour. Then the reaction mixture is cooled to 40? C. and the pH is returned to 2 by gradually adding sulfuric acid. The chloroform phase is then separated from the aqueous phase and is dried on sodium sulfate. The aqueous phase is extracted again with ether. The organic phases next are evaporated. They contain the aldehydes and the residual guaiacol. The yield is 32% in vanillin (2.4 g) and 38% in isovanillin (2.8 g).

EXAMPLE 8

10.cm3 of methanol, 190 cm3 of chloroform and 7.7 g of syringol are placed in a 250 cm3 reactor having a coolant, a mechanical stirrer and a thermometer. The mixture is treated ultrasonically for 6 hours in a "BRANSONIC" cleaning tank (47 kHz, 180 w, 3 ceramics). After this pretreatment, 8 g of powder sodium hydroxide and 0.9 g of water are added. These initial mixture conditions correspond to a limit hydration rate of 0.25 moles of water per mole of sodium hydroxide (0.05 moles of water per mole of initial compound) and to 25.2 times as much chloroform as initial compound expressed in moles. For a lesser hydration, the yield drops considerably. The reaction proceeds in the tank under ultrasonics, at 30? C. and for 2 hours 30 minutes. The syringaldehyde is obtained with a yield of 12% (1.1 g).

2-hydroxy-5-methoxy-benzaldehyde by Reimer-Tiemann formylation of 4-methoxyphenol

200g of 4-methoxyphenol were dissolved in a solution of 190g of NaOH in 550mls water and the resulting soln was heated to 50?C on a waterbath. To this soln maintained at 50-60?C there were added dropwise 420g of chloroform and a solution of 560g of NaOH in 500mls water from two separate dropping funnels and the rxn was heated for 1 hr at the same temperature and atmospherical pressure. After cooling, the precipitated salt of 2-hydroxy-5-methoxybenzaldehyde was filtered and washed with 100ml alcohol. The sodium salt was dissolved in 800ml water and slightly acidified (1200ml 3N H2SO4 at RT) and extracted with 200ml toluene. The solvent was dried w/CaCl2 and evap'ed and the residue distilled at reduced pressure to give 132g (48-53%) of the title product, bp 110?C/5mmHg.

Reference: British Patent 1,377,317

.........as taken from rhodiums archive mirror

http://designer-drugs.com/pte/12.162.180.114/dcd/chemistry/formylations.html

IndoleAmine · Dreamreader Deluxe

Thx for clarifying about the "Reimer-Tiemann formylation", Java!

I'm tempted to say fuck you - but I don't.

I didn't say anything about formaldehyde, just mentioned the term "formylation" - which is adding "-CHO" (= "formyl").....
So far, you are right - no HCHO is involved in this type of reaction....

i_a

IndoleAmine · Dreamreader Deluxe

Thenewrunne, you said:

IndoleAmine · Dreamreader Deluxe

Besides, hydroquinone can be had for less than 120 bucks/5lbs if you look around a bit (-> photo chem supplier *hint*)...
Wink

i_a

demorol · Sat Apr 09, 2005 3:11 pm

IndoleAmine · Dreamreader Deluxe