MeshPL
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Theoretical synthesis of p-chlorobenzylcyanide
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]
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CuReUS
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http://www.sciencemadness.org/talk/viewthread.php?tid=65197
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Cryolite
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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.
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MeshPL
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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.
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Nicodem
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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.
| Quote: |
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.
| Quote: | 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.
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.
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
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MeshPL
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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.
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Nicodem
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| 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...).
| Quote: | | 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.
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clearly_not_atara
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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).
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CuReUS
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| Quote: |
Too much work for something that can be prepared much more easily by a number of other routes. |
could you tell another route ?
| Quote: | | 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. |
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 ?
| Quote: | | Styrene is toxic!... |
....like most other things in organic chemistry.Since when has that stopped anyone ? 
| Quote: | | (Willgerodt generates H2S for one thing) |
now nicodem will throw that chinese paper in your face 
| Quote: | | 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)
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don't forget your tyrosine idea.Like I said in the thread I linked above,even that is good.
btw,if chlorination of polystrene works then there might be a 2 step method from there.
p-chlorostyrene could be converted to the epoxide and then this could be done.(if the catalyst is availabe)
http://pubs.rsc.org/en/content/articlelanding/2012/ra/c2ra20...
or, one could make phenylacetaldehyde from styrene oxide
http://www.sciencemadness.org/talk/viewthread.php?tid=22421
http://onlinelibrary.wiley.com/doi/10.1002/jhet.5570370508/f...
and from the aldehyde,there are many routes to the cyanide
http://www.sciencedirect.com/science/article/pii/S0040402099... - using NMP/hydroxylamine in MW
http://www.sciencedirect.com/science/article/pii/S0040403900...- using NH3 and H2O2
http://www.sciencedirect.com/science/article/pii/S0040403907... - using NH3/IBX
http://www.sciencedirect.com/science/article/pii/S0040403900...- using NH3/I2
http://www.sciencedirect.com/science/article/pii/S0040403998... - using peroxymonosulphate/alumina
http://www.sciencedirect.com/science/article/pii/S0040403913... - using FeCl3/hydroxylamine
http://www.sciencedirect.com/science/article/pii/S1001841710... - using ZnO/MW
http://www.sciencedirect.com/science/article/pii/S0040403908... - using sodium dichloroiodate
http://www.sciencedirect.com/science/article/pii/S0040403998... - using hydroxylamine/phthalic anhydride
also found this
http://link.springer.com/article/10.1007%2Fs10971-008-1860-7
I wonder if this could be done for p-chlorostyrene
[Edited on 23-4-2016 by CuReUS]
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Nicodem
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| 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.
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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MeshPL
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| Quote: |
Quote:
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.
Ammoxidation isn't quite that novel... I bet it would be doable, but only industrially.
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