Sciencemadness Discussion Board - Theoretical synthesis of p-chlorobenzylcyanide

Theoretical synthesis of p-chlorobenzylcyanide

MeshPL - 21-4-2016 at 23:39

Hello everybody!
So many of you probably now Nurdrage, a quite well-known youtuber, currently working on synthesis of pyrimethamine. While it is not entirely clear what exact approach he (they actually) will take, it seesms pretty obvious he will need parachlorobenzylcyanide. I'm not going to discuss what he is exactly doing, but instead ask you if the following synthesis of pchlorobenzyl cyanide, I came up with is feasible. It is nearly amateur friendly, apart from last step.

1. Make styrene from polystyrene.
Basic pyrolisys. I've seen a video on youtube about it somewhere. Should be rather doable.

2. Reduce styrene to ethylbenzene.
Should be doable using red P and I2. Aquous HI produced will add H2O to double bond, than HO in benzylic position will be reduced just like in synthesis of methamphetamine from ephedrine.

3. Chlorinate ethylbenzene.
Using FeCl3 or other Lewis acid. Discard ortho product, save para.

4. Oxidise to parachloroacetophenone.
CH2 in benzylic position is vulnerable to oxidation using chromates and permanganates, acetophenone is final product.

5. Do Wilgenrodt rearrangement.
Using aquous ammonia and sulphur. Parachlorophenylacetamide is produced.

6. Dehydrate amide to nitrile.
The only problematic step, final product, p-chlorobenzylcyanide is produced.

What do you think?

[Edited on 22-4-2016 by MeshPL]

[Edited on 22-4-2016 by MeshPL]

CuReUS - 22-4-2016 at 02:49

http://www.sciencemadness.org/talk/viewthread.php?tid=65197

Cryolite - 22-4-2016 at 04:41

According to a comment he posted on his last video, he is currently trying to prepare p-chloro toluene, which he will presumably chlorinate on the benzylic position and then form the nitrile with NaCN. However, he doesn't want to directly chlorinate his toluene, as that will yield a massive amount of o- and di-chlorotoluenes which are difficult to separate out from the desired isomer. Even if you did complete the separation, you would then have the issue of what to do with all of those rather nasty chlorinated benzene derivatives. He is looking for a more efficient route to the desired p-chlorotoluene. The regioselective chlorination is possible with certain zeolite-based catalysts, but those are beyond the reach of the amateur.

The only route I could come up with was to sulfonate on the para position by boiling the toluene in sulfuric acid (forming p-TSA), and then fusing this with copper (ii) chloride to swap the sulfonic acid group with a chlorine. Reaxys claims that that second reaction comes from Journal of the Indian Chemical Society, 1939 , vol. 16, p. 460, but I couldn't find a copy of this paper anywhere! I guess I'll have to try it and see if it works.

MeshPL - 22-4-2016 at 09:12

I know what Nurdrage is doing, and I don't want to discuss it here. I just wanted to ask, if this route for parachlorobenzylcyanide is doable, even if less efficient than toluene approach.

Nicodem - 22-4-2016 at 10:46

Quote: Originally posted by MeshPL

1. Make styrene from polystyrene.
Basic pyrolisys. I've seen a video on youtube about it somewhere. Should be rather doable.

You should have seen it in UnintentionalChaos' thread in Prepublication.

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2. Reduce styrene to ethylbenzene.
Should be doable using red P and I2. Aquous HI produced will add H2O to double bond, than HO in benzylic position will be reduced just like in synthesis of methamphetamine from ephedrine.

That would be quite an unpractical method, yielding all kind of oligomeric crap along ethylbenzene. Considering that hydrogenation of styrene is quantitative even with 0.1 mol% Pd-C at 1 atm, any alternative is a waste of time. Besides, reducing something that you actually want oxidized at the end is not a good strategy. Be rational with electrons.
You could just use styrene in the Willgerodt reaction to get a phenylacetamide (a morpholide or, if you have a pressure reactor, directly to plain phenylacetamide) which can be chlorinated and the isomers separated by recrystallizations.

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3. Chlorinate ethylbenzene.
Using FeCl3 or other Lewis acid. Discard ortho product, save para.

Using TCCA instead of chlorine, you only need a catalytic amount of protic acid. It is as easy as it can get.

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What do you think?

Too much work for something that can be prepared much more easily by a number of other routes. However, if you insist on starting from polystyrene and use the Willgerodt reaction, there is a more rational approach you could try. You could chlorinate polystyrene in dichloromethane (or ethyl acetate) with TCCA in the presence of few mol% of an acid catalyst (MsOH, TFA, etc.). This should give you a much better than statistical selectivity for para chlorination. You could then depolymerize to (mainly) p-chlorostyrene. You can then prepare (mainly) 2-(p-chlorophenyl)-2-methoxy-1-chloroethane (e.g., with TCCA in MeOH). This can be treated with KOH in EtOH and then with 1M HCl(aq) to give (mainly) p-chloroacetophenone. You can then use this in a Willgerodt reaction to obtain the p-chlorophenylacetic acid morpholide (or directly to plain amide with a pressure reactor). This can be finely purified by recrystallization to get rid of any ortho isomer. Hydrolysis to p-chlorophenylacetic acid gives another opportunity for a recrystallization. Amide formation with urea or CDI/ammonia and dehydration to nitrile with any published method.
Still way too much work for a product as trivial, but you would be doing something admirable and innovative.

MeshPL - 22-4-2016 at 11:16

Wow, this is one of the situations when someone really regrets, they don't have glassware and some other stuff to do such things.

Truly brilliant idea, though for a synthesis. Really, really impresive.

I didn't knew that you need actual pressure reactor to make amide in willgenrodt reaction proceed to simple amide... although I knew that some of the product is always the salt of carboxylic acid. The only thing I don't quite understand is, why did you use parachloroacetophenone as intermediate between parachlorostyrene and parachlorophenylacetic acid, while wilgenrodt reaction can be carried out on (parachloro)styrene, as you mentioned before.

This made me wonder, why never have I seen mention of making phenylacetic acid, a known drug precursor, using ammonia (OTC), sulphur (kinda OTC as well) and styrene (polystyrene being OTC as HELL). Such substances tend to have many "amateurs" trying to synthesise them and coming up with new methods.

Nicodem - 22-4-2016 at 12:13

Quote: Originally posted by MeshPL

I didn't knew that you need actual pressure reactor to make amide in willgenrodt reaction proceed to simple amide...

Ammonia is a gas. That's why morpholine is generally used (high b.p., as cheap as it can get, widely available...).

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The only thing I don't quite understand is, why did you use parachloroacetophenone as intermediate between parachlorostyrene and parachlorophenylacetic acid, while wilgenrodt reaction can be carried out on (parachloro)styrene, as you mentioned before.

Because it was your choice of intermediate. I did not want to completely run over your idea.

clearly_not_atara - 22-4-2016 at 12:44

Styrene is toxic!

Anyway you can dehydrate amides to nitriles with sulfamic acid, but I'm concerned this synthesis is too long and arduous (Willgerodt generates H2S for one thing) to be practical.

Anyway -- I thought FC chlorination of phenylacetonitrile itself, or of phenethylamine, was a possibility. Fenclonine is a pharmaceutical precursor in one step with TCCA if you can get some (as long as you aren't breaking the law you might be able to).

CuReUS - 23-4-2016 at 03:14

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Too much work for something that can be prepared much more easily by a number of other routes.

could you tell another route ?

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You could chlorinate polystyrene in dichloromethane (or ethyl acetate) with TCCA in the presence of few mol% of an acid catalyst (MsOH, TFA, etc.). This should give you a much better than statistical selectivity for para chlorination.

I must say,this is a superb idea.I was busting my ass looking for ways to make p-chlorostyrene from styrene and I never even thought of this.Amazing

.All we need now is a reference

Quote: Originally posted by Nicodem

You could just use styrene in the Willgerodt reaction to get a phenylacetamide which can be chlorinated and the isomers separated by recrystallizations.

Quote: Originally posted by clearly_not_atara

Anyway -- I thought FC chlorination of phenylacetonitrile itself, or of phenethylamine, was a possibility.

I have always had this question,what do you get when you chlorinate compounds like phenylacetamide,phenylacetonitrile or phenylethlamine.Are these side chains electron donating or withdrawing ?

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Styrene is toxic!...

....like most other things in organic chemistry.Since when has that stopped anyone ?

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(Willgerodt generates H2S for one thing)

now nicodem will throw that chinese paper in your face

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Fenclonine is a pharmaceutical precursor in one step with TCCA if you can get some (as long as you aren't breaking the law you might be able to)

Nicodem - 23-4-2016 at 07:20

Quote: Originally posted by CuReUS

I must say,this is a superb idea.I was busting my ass looking for ways to make p-chlorostyrene from styrene and I never even thought of this.Amazing

.All we need now is a reference

I will point to DOI: 10.1016/0141-3910(87)90094-2 which in addition describes also the composition of depolymerisation products. There is also DOI: 10.1002/pol.1955.120168229, but both experimentals use Cl₂ for the chlorination which is annoyingly unpractical due to difficult stoichiometry control. That's why I suggested TCCA in dichloromethane. TCCA is not well soluble in dichloromethane, but it is soluble enough for the reaction to take place. Darkness and an acid catalyst are needed, or else you get substantial side chain chlorination.

By the way, ortho-chlorotoluene can be selectively removed from an ortho/para mixture of chlorotoluenes by sulfonation, see US1596325. From there, you have a simple benzylic halogenation and a substitution with cyanide. But anyway, p-chlorotoluene, p-chlorobenzyl chloride and the product itself are commercially available.

MeshPL - 23-4-2016 at 11:13

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Too much work for something that can be prepared much more easily by a number of other routes.

could you tell another route ?

Well, nurdrage is taking different approach in his synthesis, but that's not what I wanna discuss. I guess, their synthesis, from toluene has 3 steps + making cyanide. But its not a totally different approach. Maybe you could chlorinate benzene, than do Blanc chlorometylation, save para isomer, and subject it to substitution with NaCN. That would start with different material.

If one really liked to do so, he could treat parachlorostyrene with ozone, cleave ozonide with NaBH4 to get parachlorobenzyl cyanide, and finally treat that with HCl/ZnCl2 than with NaCN.

Parachlorostyrene is definitely doable by method posted by Nicodem, however, what do do with it is not straightforward.

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also found this
http://link.springer.com/article/10.1007%2Fs10971-008-1860-7
I wonder if this could be done for p-chlorostyrene

Ammoxidation isn't quite that novel... I bet it would be doable, but only industrially.