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Author: Subject: Experimental Preparation of Chlorobutanol
jon
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[*] posted on 19-1-2006 at 20:49


has anyone messed around with clomethiazole I hear it's a superb hypnotic it's made from vitamin b-1 thiamine.
you split off the thiamine with sodium hydrosulfite to yeild the pyrimidine portion which crystalizes. seperate that. then you you perform acid base work up on the sulfurol 4-methyl-5-hydroxyethyl-thiazole this you chlorinate to yeild clomethiazole not scheduled not an analouge of any controlled substance so no way to schedule it.
you can chlorinate with thionyl chloride or by heating in a sealed tube with conc. HCl at 140 celcius for three hours and then workup.
very potent stuff.
very tricky to crystalize though it only forms salts with ethylene disulfonic acid.
though there are some literature reports of it forming crystalizable salts with HCl.

[Edited on 20-1-2006 by jon]
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Mechaton
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[*] posted on 21-5-2006 at 13:09


Hey, I actually have something useful to add! I know a fairly easy way to purify the nasty orange crud generally obtained from making chorobutanol with readily available reagents.

First, get a baby medicine syringe with the bottle adapter and some standard glass capillary tubing. The tubing should fit inside the bottle adapter so you can use the syringe to pull liquid into the tube. You'll need this later.

To purify the orange crystals place them in a round bottom flask and swirl it a bit to cover the bottom. It's fine if the crystals are a little moist. Sit the flask about a quarter way into a sand bath, so there is a good bit of flask left in the cooling air. Stopper the flask and apply a decent bit of heat. The chlorobutanol will start to sublimate. With continuous moderate heat the vapors will form fluffy white crystals all over the upper part of the flask. Keep the heat up until a dark orange liquid forms in the bottom, though you'll probably need to peek through the stopper to see it given how many crystals you'll get on the flask.

This liquid is partially molten chlorobutanol but if you fiddle with the heat right and wait for maximum crystal growth it'll be mostly waxy impurities. Now it's time to use your syringe doohickey. Unstopper the flask and stick the capillary tubing down into the liquid. Be careful of crystals blowing out of the hot flask, but it won't be under too much pressure. Use the syringe to draw the liquid out of the flask and into the tubing. Try to avoid getting it in your syringe, because its going to harden and you're going to have to dip the tubing in boiling water to get it out later on.

When you have as much liquid as you can get very carefully take the flask out of the hot sand and let it cool. The remaining impurities will cool and stick to the bottom of the flask. The pure crystals will be stuck to the sides of the flask above the line of the sand bath. When the flask is cool you can flip it over and smack it lightly to get most of the chlorobutanol crystals out. For the rest just wash the inside of the flask with water. Neither waxy impurities nor chlorobutanol dissolve well in water, but the crystals wash off whereas the wax sticks to the glass. The wax can be removed from your flask by pouring in a handful of BBs with a little water and swirling it Vigorously.

I hope that technique is helpful and not hidden somewhere else on this forum. It produces beautiful white crystals with asharp melting point from the home-made chloroform, department store acetone, and lye catalyst method.



[Edited on 21-5-2006 by Mechaton]
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[*] posted on 30-1-2011 at 11:25


Quote: Originally posted by Hermes_Trismegistus  
STABILITY: the half-life at 25 for chlorobutol(chloretone) in a solution buffered at pH 3 was calculated to be 90 years, whereas at pH7.5 it was 0.23 year.

Similarily for the decomposition in aqueous sol'n when heated for 30 min at 115 degrees was calculated to be 13% at pH 5 and 58% at pH 6.
--- A.D. Nair and J. L. Lach, Journal of the American Pharmaceutical Association, scient. Edn., 1959, 48, 390.

A 0.5% sol'n of chlorobutol with a pH of 5 to 6 lost 10% of its potency when stored for six weeks at between 25 and 30 degrees. Neutral or alkaline sol'n's were less stable.
--- N.V. Patwa and C.L. Huyck Journal of the American Pharmaceutical Association, 1966, NS6, 372.

[Edited on 14-1-2004 by Hermes_Trismegistus]


Given this I think it is probably a bad idea to be heating it to distill the acetone as many of us are doing, unless the non-hydrate is much more stable, I think (correct me if I am wrong) these figures are all on the hydrate as it is listed as being in aqueous solution.

I used 50 ml of acetone, .6 grams of lab grade NaOH (just bit more mols catalyst per mol chloroform than the 1 gram of KOH which was reported to be the ideal quantity for 5 ml of chloroform) and 5 grams chloroform. I used mass so it is a bit less than 3.5 ml equivalence. I added a bit of methanol to help dissolve the sodium hydroxide in the mixture. Everything was damned near dry, the acetone and chloroform was dried with anhydrous Magnesium sulfate overnight. Reaction temperature was always between -4 to -8 C.

During the reaction the liquid became cloudy as expected, a bit like coconut milk. I put this in the freezer to let it settle out a bit. The vast majority fell out quickly as a fine white powder, but there was still a bit of cloudiness after 30 minutes. Decanting once or twice is diffidently the way to go unless you have some kind of small scale vacuum filtration device like a Gooch crucible setup, after the first decantation 2 coffee filters work pretty fast and then a piece of folded lab filter paper to get the last bit out.

I was a bit foolish and added cold water with a bit of HCl to the acetone mixture right after filtering in hopes of improving stability before distillation; it was at a pK of 2-3 afterwords. I noticed when It was heated there was a small amount of oil on the bottom, but when stirred it disappeared. In the end this procedure yielded nothing after an attempt to crystallize anything cooling, adding ice water did not help.

I then tried to recover anything I could from the filtered precipitate. I added near freezing water, nearly all of the precipitate (which is what I think was almost all sodium hydroxide) went into solution. However I noticed that floating in solution were these small flake-like crystals beautify glittering as they floated around. I filtered this once and washed the crystals with a bit of ice water. I was left with a small off white pile of amorphously packed crystals, and as the filter paper dried all the way I noticed that it sparkled as I turned it in the light, as if there was clear sequence or glitter powder on it. I scraped off what I thought looked like 2-3 mg and put it on the tip of my tongue. A strong astringent taste which was mostly what I think to have been residual NaOH, but after 5 seconds an unmistakable numbing of the tip of my tongue was noticed. Not the kind from chemical astringency, more like having a menthol cough drop but without the flavor, maybe something like a phenol based product like chloraseptic.

I strongly suspect that this was chlorobutanol. I am just wondering if anyone knows why the NaOH percipitated like it did, it was in solution prior to this, did it undergo reaction to NaCl or something? I would doubt it but besides the possibility of the chlorobutanol displacing it from solution that is all I can think of.
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atomicfire
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[*] posted on 7-2-2011 at 09:38


I've been browsing these forums for awhile now, and just recently decided to test some things out I saw on here, this synthesis being one of them.

I took ~90ml acetone and about 0.5g NaOH and placed them into a 150ml beaker. I added 10ml chloroform(acs not stuff I made) and let this stir on a stirplate for a while. After a few minutes it went 'milky' and I could see a precipitate. I let this stir for about 30min.

Having done this on a friday and having more things to do, I let this sit in a fume hood with a watchglass over it so the leftover acetone/chloroform or whatever was left could evaporate. Monday I found a small mass of white(not snow white, but not off white) precipitate still very wet. I let this sit in a dessicator for a few hours to try to dry it some more, but the mass still had some liquid in it. I tried a melting point test on it and it seems to be around 75C.

This looks like I got something similiar to a previous poster. Any thoughts on what to do to 'purify' it or what exactly do we have here?



[Edited on 7-2-2011 by atomicfire]
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Paddywhacker
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[*] posted on 24-2-2011 at 01:29


Hey, what does the acetate ester of chlorobutanol smell like?
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Eclectic
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[*] posted on 24-2-2011 at 15:14


Seems it might be advantageous to neutralize the alkali with HCl before workup.
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I Like Dots
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[*] posted on 5-7-2013 at 17:25


Hey guys,

I had a go at this synthesis, and like most was left with slightly yellow, watery crystals. I noticed a lot of argument about what chlorobutanol should look like, so here you go!


I recrystallized in pure MeOH and had this in a few days after sitting in the fridge.

I dissolved 4gm of wet crystals in ~20ml methanol. enough to completely dissolve and then some.

Then I placed it in the refrigerator and "forgot" about it for a few days.

This is what it looked like after 2 days:




Final yield was 1.5 grams, I will try to purify the top layer that started forming and creeping up the sides.


[Edited on 6-7-2013 by I Like Dots]
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sargent1015
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[*] posted on 12-7-2013 at 09:23


That is simply beautiful! Reviving an old thread to finally show us what the compound looks like was a good idea. I wonder if some of those 2006 posters are still on the forum.

Now I am tempted to try this... Just for the pretty crystals :P




The Home Chemist Book web page and PDF. Help if you want to make Home Chemist history! http://www.bromicacid.com/bookprogress.htm
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bfesser
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[*] posted on 12-7-2013 at 09:39


<strong>I Like Dots</strong>, thanks for the contribution. Photos of pretty crystalline products are always appreciated. Those remind me of the jar of basement <a href="http://www.magusbooks.com/category/Herbs" target="_blank">'new-age' bookstore</a> <img src="../scipics/_ext.png" /> grade <a href="http://en.wikipedia.org/wiki/Menthol" target="_blank">menthol</a> <img src="../scipics/_wiki.png" /> crystals I have stored away in my closet awaiting purification.

By the way, for anyone in the Twin Cities, MN area; that shop is a source for small amber Polyseal&reg; bottles and some basic reagents (menthol, sulfur, camphor, etc.)&mdash;if you don't mind the pagans and incense.

[Edited on 7/12/13 by bfesser]




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softbeard
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[*] posted on 23-7-2013 at 18:41


Through my own experimentation, I found a good way to get most of chlorobutanol to crystallize out of water is to salt it out with magnesium sulfate. Following the standard preparation using excess acetone [basis: ~ 75 ml acetone] (3-4 parts acetone/ 1 chloroform, by volume), small quantities of NaOH, and was allowed to reflux for ~ 30 min. Further, small portions, of NaOH were added until there was no more refluxing. The resulting yellowish milky product was heated until most acetone was distilled off. To this, about 100ml tap water was added, enough to dissolve all the NaCl/sodium formate. This resulted in a two-phase system. The organic phase (deep red) was separated and further heated to evaporate residual acetone/chloroform. A semi-crystalline mass resulted with a strong odor of chlorobutanol.
The aqueous phase was saturated with magnesium sulphate. After ~10 minutes, it precipitated copious amounts of chlorobutanol hemi-hydrate, which was filtered and washed with water.
I realize this is a very qualitative description, but thought it might be useful. Frankly, for chlorobutanol preps, there is probably little reason for quantitative descriptions.
For purification, I think recrystallization from aqueous magnesium sulfate might be one of the more efficient routes.
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softbeard
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[*] posted on 25-7-2013 at 11:56


I forgot to add; pH control is, of course crucial here. Make sure we're on the neutral-acidic side with HCl, or your favourite acid, prior to adding magnesium sulfate.
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I Like Dots
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[*] posted on 20-8-2013 at 13:45


Now im thinking about other this reaction with other halogens.. I saw bromic acid possibly produced bromobutanol ( Chemspider calls it brometone) id like to try that as well.

From PubChem
"PREPD FROM ACETONE & BROMOFORM IN THE PRESENCE OF SODIUM OR POTASSIUM HYDROXIDE."
So basically same process.

Interestingly i could only find sparse info on the iodine version. (iodobutanol?) but im assuming it would be the same again.

edited for formatting.

[Edited on 20-8-2013 by I Like Dots]




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