Benignium
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Phencyclidine
I've wanted to try my hand at the Grignard reaction for quite a while now by preparing something relatively easy. As I had a few grams of piperidine
hydrochloride sitting around that I had derived from peppercorns, I decided I would attempt to synthesize another antiquated pharmaceutical, the rabid
dodo of dissociatives commonly known as PCP. An advantage here was the use of phenylmagnesium bromide, which has a reputation of being among the
easier Grignard reagents to produce.
After preparing bromobenzene and the nitrile intermediate PCC, I sort of just forgot about the whole project for months until last week I finally
decided to spring clean it off the old backlog.
The procedure I was following can be viewed here.
Preparations
The reaction setup was simple. On top of a 50 mL flat-bottomed RBF were attached, respectively, a straight vacuum take-off/gas inlet adapter, a 300 mm
coil condenser and finally a calcium chloride drying tube. Because of the relatively small scale, I had decided against using the 250 mL addition
funnel, my only one, which could potentially contain several tens of milligrams of water vapor. In this sense, a shorter condenser would also have
sufficed, but I had managed to destroy my Liebig by using it outside, unsupervised, when it was too cold. A lesson was learned, and I digress.
Instead of the addition funnel, additions of bromobenzene and PCC would be made through the vacuum port utilizing a disposable syringe fitted with a
hypodermic needle.
Needless to say, everything was thoroughly dried beforehand. Relative humidity in the workspace was 21%.
Reaction
Chopped magnesium ribbon (0.85 grams, 35 mmol) was lightly mauled with a mortar and pestle and transferred to a 50 mL flat-bottomed RBF. The vacuum
port was sealed using cling film and the apparatus was lightly flame dried. Bromobenzene (5.12 grams, 32.6 mmol) in 10 mL THF was added in two
portions. Liberation of hydrogen was observed almost immediately and the reaction was placed in a cold water bath which was gradually heated to 60°C.
Once the reaction had died down, a further 500 milligrams of neat bromobenzene was added in one portion and heating was continued until all of the
remaining magnesium had been consumed.
Snow was added to the water bath to cool it down and 1-piperidinocyclohexanecarbonitrile (2.44 grams, 12.69 mmol) in 5 mL THF was added in small
portions. The apparatus was removed from the water bath and on warming to room temperature the reaction picked up and moderate effervescence was
observed. Once the reaction slowed down, heating was commenced and the mixture was kept at 65-66°C for three hours.
Left to right: PhBr in THF; magnesium in reaction vessel; PCC in THF
Formation of the Grignard reagent
Addition of PCC
Reaction mixture following addition of PCC
Before completion of the Grignard reaction
After completion of the Grignard reaction
Workup
To the cooled reaction mixture was carefully added dilute hydrobromic acid (26.22%, 11.50 mL). The mixture was refrigerated at 5°C for eight hours
after which no more formation of crystals was observed. After filtration and air drying, 3.03 grams of solid material was obtained. This was dissolved
in ethanol, gravity filtered through tightly packed cotton to get rid of a fine suspension of supposed magnesium salts, and combined with a solution
of sodium hydroxide (1.02 g) in ethanol. Separation of product by filtration was impossible, so the mixture was evaporated to a thick paste,
dissolved in toluene and gravity filtered through tightly packed cotton. To the clear toluene solution was added concentrated hydrochloric acid (1.10
g) followed by azeotropic distillation to remove water and excess acid. As the solution heated up, it went from straw yellow to orange. After the
removal of water, the solids were filtered, washed with heptanes and air dried resulting in 1.19 grams of tan phencyclidine hydrochloride powder.
Addition of HBr
Following addition of HBr
Precipitation of crude phencyclidine HBr
Basified ethanol solution
Gravity filtration of toluene solution
Toluene solution heating up after addition of HCl
Distillation of toluene to remove water
Formation of precipitate following removal of water
Tan phencyclidine hydrochloride
From the original reaction mixture, 1.54 grams of waxy yellow solids had precipitated on standing in open air for about one day. These were filtered
off, washed with heptanes, air dried and dissolved in ethanol. The remaining reaction mixture was washed with heptanes and evaporated to dryness. The
white residue was washed with ethanol. The ethanolic solutions were combined and sodium hydroxide (0.99 g) was added, followed by evaporation of the
ethanol. The residue was dissolved in toluene and gravity filtered through tightly packed cotton.
The tan product obtained earlier was deprotonated using NaOH and taken up in toluene. At this point the two toluene solutions were separately treated
with activated charcoal and vacuum filtered through qualitative filter paper. Both solutions ended up similarly yellow and so were combined. Like
before, hydrochloric acid was added and toluene distilled off until the distillate came over at 110°C. The final yield of off-white phencyclidine
hydrochloride powder was 1.84 grams (51.83%). Melts with decomposition at 215-230°C. (The test was conducted in a test tube heated directly on a
hotplate, so it's not as accurate as it should be.)
Activated charcoal treatment
Following addition of HCl to combined decolorized toluene solutions
Off-white phencyclidine hydrochloride
Finally, the product was recrystallized. A solution in isopropanol was gravity filtered through diatomite to get rid of a small amount of suspended
white solid that refused to dissolve. The solution was concentrated on a 125°C hotplate, maintaining its volume at 10 milliliters with small
additions of heptane. When approximately 10 mL of heptane in total was added, the beaker was covered and set to cool, first at room temperature
overnight and then at -22°C for some hours. The first crop of crystals was distinctly yellowish and weighed 1.14 grams.
Recrystallized product
Discussion
This was an interesting and gratifying reaction. I was worried that I wouldn't be able to ensure sufficient dryness but based on this experience, it
is not nearly as easy to mess up as I had originally thought. Granted, the low ambient humidity as well as the choice of Grignard reagent, I believe,
were in my favor.
While I don't particularly enjoy working with potent toxins, which I would classify phencyclidine as owing to its powerful and unpredictable
pharmacological profile, I appreciate having to pay extra attention to safety every now and then.
The workup was, somewhat unsurprisingly, pretty tedious. Compared to cleaning up methaqualone previously this was a breeze, but full of lengthy
gravity filtrations which I absolutely detest. This time I have decided to settle for a slightly discolored end product.
Using a vast molar excess of phenylmagnesium bromide can supposedly result in yields up to 70%. I tried my darndest to minimize mechanical losses, but
obviously some occurred anyway. I find it hard to believe, but not impossible, that such a loss occurred during the workup. In any case, I don't think
that 50% outright sucks and therefore I'm quite happy.
Thank you for your time! As always, questions, remarks and all manner of feedback and input is appreciated.
[Edited on 17-3-2021 by Benignium]
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zed
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Dig a hole and bury the product. Nice chemistry. Though my computer WiFi is struggling right now, and it hasn't down-loaded the pictures fully.
I do however, plan to study your work.
PCP is scary stuff, and a gram is perhaps 200 full doses. Some of my colleagues indulged, back in the day.
Made 'em totally wacko. Dangerous, State Psychiatric Hospital type Wacko.
Not especially easy to get that Grignard going. Getting the Product Cleaned up, can be odious. Though guys develop a knack for it, with experience.
Some procedures were developed, to produce it in bulk, with rudimentary equipment.
Should be a really high boiler, high molecular weight. None the less, it seems to be stable to heat. So, it can probably be sublimed or vacuum
distilled (at least via short path).
In my youth, I generally possessed the moral development of a mollusk. Still, I did have some boundaries.
And, PCP was where I drew to line. Not for Humans. My buddies proved it to me, with their bizarre personal behavior. Actually scared me.
Um... I never considered starting a Grignard with Magnesium Ribbon. I always used granules. Ribbon does have its good points. I suppose you can
clean its surface of Oxides, before starting.... Then cut it in small pieces. A good idea, I had never considered. Expensive form of Mg, but if you
have it, why not use it?
[Edited on 17-3-2021 by zed]
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Benignium
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That's very interesting, zed! Thanks for sharing! PCP is certainly deserving of its infamy. There's an awe-inspiring contrast between PCP and its
successor ketamine, another arylcyclohexylamine dissociative that is not only a very promising treatment for depression and a better anesthetic, but could also ameliorate PCP-induced cognitive deficits, as discussed here.
I believe the most famous example of such primitive bulk production is the "bucket method". The full paper can be read here, and here's the diagram contained therein:
[Edited on 25-3-2021 by Benignium]
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mr_bovinejony
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Yay another good writeup! Recently I've tried making 3-meo-pyrrolidine? Or however it's called. It was a failure but I'll outline the method as I
didn't use a cyano compound to start with. I think the pyrrolidine was trash which is why it failed.
25 grams of proline in 100 mls of xylene with 5 mls of dmso and acetophenone was refluxed for 12 hours. This was fractionally distilled to give 5
grams of what I assumed was pyrrolidine and water. Dried with sodium sulfate, the amine smelling compound was filtered and added to a solution of .5
grams of toluene sulfonic acid and 7 grams of cyclohexanone which was refluxed with a dean stark to get rid of water. The compound was brownish and
the toluene was removed under vacuum.
6 grams of ptsa in toluene was refluxed with a dean stark to get rid of water, and when it was dry the pyrrolidine was added while the solution of
toluene and ptsa was cooled on an ice bath. This was stirred for a few hours while the following grignard reagent was prepared.
6 grams of 3 bromo anisole was dissolved in 20 mls of sodium dried ether. 20 mls of this ether was added to a gram of magnesium shavings used for fire
starting. A few dribbles were added to the magnesium and the reaction started with use of a sonicator bath. When the reaction was going, the rest of
the bromoanisole was added and refluxed then for 3 hours. The amount of magnesium remaining was suspicious, but I was too far in the synthesis to give
a shit.
The supposed grignard reagent was decanted from the magnesium and added to the pyrrolidine-cyclohexanone enamine on an ice bath and stirred for 30
minutes. This was added to water with ammonium chloride dissolved. Seprated and evaporated gave a brown oil which was added to acidic ipa. Evaped and
gave no crystals, and was then trashed.
It was a fun experiment! I will definitely do it again if I get some decent morpholine somehow.
[Edited on 25-3-2021 by mr_bovinejony]
[Edited on 25-3-2021 by mr_bovinejony]
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