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All 18 posts Subject: Chloromethylation of 2,5-dimethoxytoluene Please login to post Down

Bandil
(Hive Bee)
03-09-03 22:13
No 415152
      Chloromethylation of 2,5-dimethoxytoluene
(Rated as: excellent)

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.

Cheers
Bandil

Bandil
(Hive Bee)
03-09-03 23:38
No 415186
      Further processing

The product is -in theory- going to be subjected to the following reaction conditions very soon:
Patent US4321412
Any comments?

Vitus_Verdegast
(Newbee)
03-10-03 01:57
No 415266
      Very nice find !!

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. laugh Thanks Bandil!

http://www.metafilter.com/comments.mefi/21638

Bandil
(Hive Bee)
03-10-03 10:30
No 415353
      To avoid distillation:

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?

hest
(Hive Adickt)
03-10-03 14:19
No 415371
      Rextalisation from pet.ether or acetonitril is

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.

Rhodium
(Chief Bee)
03-10-03 19:52
No 415425
User Picture       benzyl chloride -> benzaldehyde

If you have access to 2-nitropropane, then a high-yielding alternative to the sommelet reaction is https://www.rhodium.ws/chemistry/halide.carbonyl.html

Have you figured out your yield yet?

Bandil
(Hive Bee)
03-10-03 19:59
No 415427
      No final yeild yet...

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?`

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

Regards
Bandil

Rhodium
(Chief Bee)
03-10-03 21:48
No 415459
User Picture       4-methyl-2,5-dimethoxybenzyl chloride reactions

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: https://www.rhodium.ws/chemistry/methyldimethoxybenzaldehydes.html

Chimimanie
(Hive Bee)
03-10-03 23:20
No 415488
User Picture       Nice

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!

hest
(Hive Adickt)
03-11-03 00:24
No 415508
      Toxic

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.
crazy

Bandil
(Hive Bee)
03-11-03 11:43
No 415689
      Reaction mechanism

Can anyone explain to me, how this reaction actually works?

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

pHarmacist
(Hive Addict)
03-11-03 13:50
No 415697
User Picture       one pot

4-methyl-2,5-dimethoxy-phenylacetonitrile can be prepared easily from 4-methyl-2,5-dimethoxy-chloromethyl-benzene and subjected to:
https://www.rhodium.ws/chemistry/amphetamine.html to yield racemic DOM. In my opinion phenylacetonitriles are better precursors to amphetamines than benzaldehydes are.

Accept No Imitations, There Can Only Bee One; www.the-hive.ws

Bandil
(Hive Bee)
03-11-03 14:04
No 415700
      Yeah, i've seen that one, and it looks really...

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...

Regards
Bandil

pHarmacist
(Hive Addict)
03-11-03 14:18
No 415701
User Picture       potassium ferrocyanide(II) trihydrate

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.

Edit: NO TRADING IN THE FORUMS! /Rhodium

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

See https://www.rhodium.ws/chemistry/nacn.txt for details...

Careful...

Accept No Imitations, There Can Only Bee One; www.the-hive.ws

Bandil
(Hive Bee)
03-11-03 22:23
No 415829
      Grignard reaction?

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?

pHarmacist
(Hive Addict)
03-11-03 23:27
No 415844
User Picture       copper (I) cyanide

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...

Accept No Imitations, There Can Only Bee One; www.the-hive.ws

Chimimanie
(Hive Bee)
03-12-03 01:12
No 415894
User Picture       Other method to nitriles

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 (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!

Rhodium
(Chief Bee)
01-15-04 03:28
No 482473
User Picture       Prep of 2,5-Dimethoxy-4-methylbenzyl chloride

Poly-2,5-Dimethoxy-p-Xylene
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.

^{The Hive - Clandestine Chemists Without Borders}

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	All 18 posts		Subject: Chloromethylation of 2,5-dimethoxytoluene		Please login to post		Down


		Bandil (Hive Bee) 03-09-03 22:13 No 415152				Chloromethylation of 2,5-dimethoxytoluene (Rated as: excellent)
						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. Cheers Bandil



		Bandil (Hive Bee) 03-09-03 23:38 No 415186				Further processing
						The product is -in theory- going to be subjected to the following reaction conditions very soon: Patent US4321412 Any comments?



		Vitus_Verdegast (Newbee) 03-10-03 01:57 No 415266				Very nice find !!
						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. Thanks Bandil! http://www.metafilter.com/comments.mefi/21638



		Bandil (Hive Bee) 03-10-03 10:30 No 415353				To avoid distillation:
						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?



		hest (Hive Adickt) 03-10-03 14:19 No 415371				Rextalisation from pet.ether or acetonitril is
						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.



		Rhodium (Chief Bee) 03-10-03 19:52 No 415425				benzyl chloride -> benzaldehyde
						If you have access to 2-nitropropane, then a high-yielding alternative to the sommelet reaction is https://www.rhodium.ws/chemistry/halide.carbonyl.html Have you figured out your yield yet?



		Bandil (Hive Bee) 03-10-03 19:59 No 415427				No final yeild yet...
						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?` Edit: The article on nitropropanes, says 49% yeild on benzylchloride->BA... Thats quite low compared to sommelet Regards Bandil



		Rhodium (Chief Bee) 03-10-03 21:48 No 415459				4-methyl-2,5-dimethoxybenzyl chloride reactions
						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: https://www.rhodium.ws/chemistry/methyldimethoxybenzaldehydes.html



		Chimimanie (Hive Bee) 03-10-03 23:20 No 415488				Nice
						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!



		hest (Hive Adickt) 03-11-03 00:24 No 415508				Toxic
						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.



		Bandil (Hive Bee) 03-11-03 11:43 No 415689				Reaction mechanism
						Can anyone explain to me, how this reaction actually works? I cant seem to find proper information on the reaction mechanism.



		pHarmacist (Hive Addict) 03-11-03 13:50 No 415697				one pot
						4-methyl-2,5-dimethoxy-phenylacetonitrile can be prepared easily from 4-methyl-2,5-dimethoxy-chloromethyl-benzene and subjected to: https://www.rhodium.ws/chemistry/amphetamine.html to yield racemic DOM. In my opinion phenylacetonitriles are better precursors to amphetamines than benzaldehydes are. Accept No Imitations, There Can Only Bee One; www.the-hive.ws



		Bandil (Hive Bee) 03-11-03 14:04 No 415700				Yeah, i've seen that one, and it looks really...
						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... Regards Bandil



		pHarmacist (Hive Addict) 03-11-03 14:18 No 415701				potassium ferrocyanide(II) trihydrate
						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. Edit: NO TRADING IN THE FORUMS! /Rhodium Another method is BaO + 3C + N2 ----> Ba(CN)2 + CO. See https://www.rhodium.ws/chemistry/nacn.txt for details... Careful... Accept No Imitations, There Can Only Bee One; www.the-hive.ws



		Bandil (Hive Bee) 03-11-03 22:23 No 415829				Grignard reaction?
						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?



		pHarmacist (Hive Addict) 03-11-03 23:27 No 415844				copper (I) cyanide
						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... Accept No Imitations, There Can Only Bee One; www.the-hive.ws



		Chimimanie (Hive Bee) 03-12-03 01:12 No 415894				Other method to nitriles
						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 (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!



		Rhodium (Chief Bee) 01-15-04 03:28 No 482473				Prep of 2,5-Dimethoxy-4-methylbenzyl chloride
						Poly-2,5-Dimethoxy-p-Xylene 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. ^{The Hive - Clandestine Chemists Without Borders}

All 18 posts	End of thread	Top