Author Topic: Chloromethylation of 2,5-dimethoxytoluene  (Read 4289 times)

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  • Guest
Chloromethylation of 2,5-dimethoxytoluene
« on: March 09, 2003, 02:13:00 PM »
Writeup on the production of 4-methyl-2,5-dimethoxy-chloromethyl-benzene:

The following was made using Chimimanie's procedure: Synthesis of 2-Chloromethyl-5-alkyl-DMB

Using 15 grammes of the prepared 2,5-dimethoxytoluene, a chloromethylation was attemped as described by the following:

Using a hydrogenchloride generator made with HCl(aq) dripped into sulfuric acid, gaseous hydrogen chloride was bubbled into a well-stirred mixture of 20ml of 37% commercial formaldehyde stabilized with 15% methanol, 10 ml of 30% hydrochloric acid and 40 ml of dioxane for 15 min. The temperature was limited by the refluxing of the dioxane. To this mixture 15,2g (0.1 mole) of home made 2,5 dimethoxytoluene was added, dropwise, over a period of 5 min, while the temperature was maintened between 55-60°.

When the addition was completed, the passage of hydrogen chloride maintained for an additional couple of minutes. The mixture was cooled and poured into 0,2 L of ice water and 50 mL's DCM. The aqueous layer was extracted twice more with 50 mL's of DCM. The combined DCM extracts were washed with cold water until the washings were neutral to litmus. Only two water washes was needed to accomplish this. The DCM was yellow in color.

The DCM was removed on an oil bath and the residue was distilled directly under reduced pressure. The temperature of the oil bath reached 210 degrees celc. before the product came over. The gas temperature was 160-165 degrees. The original patent used a vigourex column, but the oil was so viscious than the column was omitted. The distillated soldified somewhat in the condensor. Only 50% of the original "goo" could be distillated. The condensor was rinsed with ether to pull the clog into the reciever.

The flask which was distilled from was full of poly/dimerized crap. I think the temperature in the oild bath was too high for the distillation. Either a better vacuum pump is to be used next time or the distillation should be omitted and directly used for either a sommelet or NaCN swap.

The product crystallized very nicely upon standing in the flask. It consisted of crystals, resembling 2,5-dimethoxybenzaldehyde, with a slightly yellow tint. No yeild has been evaluated yet, but i will post it once it has been measured.

This is a very nice and quite OTC way of preparing 4-methyl-2,5-dimethoxychloromethylbenzene. The yeild could be improved somewhat, but the reaction works nice and fast. It should be mentioned that the chloromethylation reactants are very toxic(as rumored by Hest), and every possible protection was used.

The title compound will be subjected to a Sommelet, to give 4-methyl-2,5-dimethoxy-benzaldehyde. A writeup of this reaction will follow soon.



  • Guest
Further processing
« Reply #1 on: March 09, 2003, 03:38:00 PM »
The product is -in theory- going to be subjected to the following reaction conditions very soon:

Patent US4321412

Any comments?


  • Guest
Very nice find !!
« Reply #2 on: March 09, 2003, 05:57:00 PM »
Great ! Considering the horribly high boiling points of many substituted benzylchlorides, a major frustrating step can bee omitted, yet still getting a decent yield of pure aldehyde. ;D  Thanks Bandil!


  • Guest
To avoid distillation:
« Reply #3 on: March 10, 2003, 02:30:00 AM »
In order to avoid distillation of the chloro-product, do you think that it can be substituted by a direct recrystallization in acetonitrile after the DCM has been removed?

How about the benzaldehyde, will that be as prone to poly/dimerize as the chlorocomound?


  • Guest
Rextalisation from pet.ether or acetonitril is
« Reply #4 on: March 10, 2003, 06:19:00 AM »
Rextalisation from pet.ether or acetonitril is deff. worth a shot.
at 14-16mmHg the boiling temp is 140-150°C so a more effective vacum would help alot.
And no, the aldehyde is solid as a rock.


  • Guest
benzyl chloride -> benzaldehyde
« Reply #5 on: March 10, 2003, 11:52:00 AM »
If you have access to 2-nitropropane, then a high-yielding alternative to the sommelet reaction is

Have you figured out your yield yet?


  • Guest
No final yeild yet...
« Reply #6 on: March 10, 2003, 11:59:00 AM »
No final yeild yet... Its probably only around 30%, but i will have the final answer within some days. I think the low yeild was due to HCl shortage and some excessive heat during destillation. Could 220 degrees celc. during destillation i theory ruin some of the chloro comound?

The article i posted stated yeilds around 90% using the sommelet. The nitropropane is about the same right? Is there any advantage in the nitropropane conversion instead of sommelet?`

The article on nitropropanes, says 49% yeild on benzylchloride->BA... Thats quite low compared to sommelet



  • Guest
4-methyl-2,5-dimethoxybenzyl chloride reactions
« Reply #7 on: March 10, 2003, 01:48:00 PM »
Yes, 220°C is a bit high to distill anything but hydrocarbons and other unreactive stuff (like essential oils).

Sorry for giving a bad suggestion (2-Nitropropane), I just remembered that the yield of MDP2P from bromosafrole was 90% using that method, and wrongly assumed that was the case for benzyl chlorides too...

BTW, I just uploaded another route to your target compound here:


  • Guest
« Reply #8 on: March 10, 2003, 03:20:00 PM »
Nice to see some experiment on that reaction Bandil!

For the sommelet, I have only see yield of 50-60% for the chloro dimethoxy benzyl chloride to the 2,5 dmb, because of the bad influence of the methoxy groups, have you got a ref with 90% yield on these dimethoxy compounds, or 90% yield on other substrate?

good continuation!


  • Guest
« Reply #9 on: March 10, 2003, 04:24:00 PM »
I'm know I sound like an old mann, but take some care.
2-nitropropane is caracinogenic and so is chloromethylether. Not like chloroform, benzene ect. but real carcinogenic.


  • Guest
Reaction mechanism
« Reply #10 on: March 11, 2003, 03:43:00 AM »
Can anyone explain to me, how this reaction actually works?

I cant seem to find proper information on the reaction mechanism.


  • Guest
one pot
« Reply #11 on: March 11, 2003, 05:50:00 AM »
4-methyl-2,5-dimethoxy-phenylacetonitrile can be prepared easily from 4-methyl-2,5-dimethoxy-chloromethyl-benzene and subjected to:

to yield racemic DOM. In my opinion phenylacetonitriles are better precursors to amphetamines than benzaldehydes are.


  • Guest
Yeah, i've seen that one, and it looks really...
« Reply #12 on: March 11, 2003, 06:04:00 AM »
Yeah, i've seen that one, and it looks really sweet! It would also give a nive starting material for 2CD.

The problem is that damn cyanide. Swim is not to fond of asking permission to purchase sodiumcyanide as required by the govt.

Is there a way to utillize cuprousyanide in that particular reaction? Its insoluble as hell, but its way more easy to get. In fact AFOswim has 1 kg of the stuff lying around...



  • Guest
potassium ferrocyanide(II) trihydrate
« Reply #13 on: March 11, 2003, 06:18:00 AM »
NaCN can bee prepared from potassium ferrocyanide(II) trihydrate. I've got some (300 g i think) beautifully orange K4[Fe(CN)6]3 lying around.


Another method is BaO + 3C + N2 ----> Ba(CN)2 + CO.


for details...



  • Guest
Grignard reaction?
« Reply #14 on: March 11, 2003, 02:23:00 PM »
As far as i can see, the reaction proposed is a grignard reaction right? Is it as tedious to get to work in this case as stated many times here on the page?


  • Guest
copper (I) cyanide
« Reply #15 on: March 11, 2003, 03:27:00 PM »
I think that you can use copper (I) cyanide for the preparation of the nitrile from halide. So there is no need for fucking around, I think. In Vogel's allylcyanide is prepared from allylbromide (halide) and copper (I) cyanide so that might be a hint. If you want I can type out the procedure. Genereally alkylbromide or iodide reacts better than corresponding chloride when it comes to halides, so bee prepared for lower yields with benzylchloride.

Yes, the reaction that you refer to is a typical Grignard reaction (this first step in the nitrile to amphetamine synth at rhodium's that is). It's not hard to get a Grignard going, but you have to dry everything that you work with in a oven before the reaction and flush it with nitrogen or argon during the reaction. Flushin is not nescessary, I've done Gringards without it, so, but use a guard tube. The ether must be dry ether, if you have elemental Na, then you can toss some wire in the ether flask and put in freezer. Remember, water will destroy Grignard, so dry everything. It's kinna cool to see it kick in, it's a visual reaction so you know when it starts, bubbles hehe...


  • Guest
Other method to nitriles
« Reply #16 on: March 11, 2003, 05:12:00 PM »
Otherwise there is also the aryne road to the nitriles from acetonitrile

Post 374179

(Chimimanie: "Important advance in the propagation of 2C-H", Novel Discourse)

Or also you can make them from acetone cyanohydrin.

Post 414380 (missing)

(Chimimanie: "The article are here, can you help please?", Russian HyperLab)

BTW pharmacist thank you to show me that good little article i missed till now!


  • Guest
Prep of 2,5-Dimethoxy-4-methylbenzyl chloride
« Reply #17 on: January 14, 2004, 07:28:00 PM »
L. D. Taylor & H. S. Kolesinski
Polymer Letters, Vol. 1, p 117-119 (1963)

2,5-Dimethoxy-4-methylbenzyl alcohol

A mixture of 54 g. of 2,5-dimethoxy-4-methylbenzaldehyde, 0.5 g platinum oxide, and 0.1 g. ferrous sulfate in 175 ml. absolute ethanol was hydrogenated on a Parr shaker. The solvent was evaporated yielding 46 g. (85%) of the alcohol. The product was recrystallized from ligroin, mp 78°C.

2,5-Dimethoxy-4-methylbenzyl chloride

A sample of the above alcohol (18.2 g) was dissolved in 200 ml. of toluene and saturated with gaseous hydrogen chloride. The solution became turbid and the water layer was removed with a separatory funnel. Evaporation of the toluene left an oil which crystallized from ligroin, 13 g (65%), mp 63°C.

2,5-Dimethoxy-4-methylbenzyltrimethylammonium chloride

Gaseous trimethylamine was bubbled into a solution of 13 g. of the benzyl chloride in 100 ml. of dry acetone for 10 min. A white solid crystallized which was hygroscopic, 15.5 g (90%), mp 198°C.