Sciencemadness Discussion Board

Ferric chloride and HCl halogenation of hydroxyl groups

ChemichaelRXN - 18-10-2020 at 05:21

Hello,

I wasnt able to find any information on this...
Do you think the yield would be improved if you use a combination of ferric chloride and concentrated hydrochloric acid to chlorinate a hydroxyl group of an organic compound as opposed to just concentrated hydrochloric acid alone? I will definitely test it out, but does anyone have any input.

(I know it is a potent mixture because you can dissolve gold apparently with ferric chloride and hydrochloric acid mixture)

Have a great day!

njl - 18-10-2020 at 10:19

I don't think its ability to dissolve gold is a good indicator of chlorinating strength for organic compounds. The problem with using HCl for chlorinating alcohols is not that it isn't "potent" it's that Cl- is a much better leaving group than OH- so any formed alkyl halide can quickly be hydrolyzed back to an alcohol, except in certain cases where the intermediate carbocation is stabilized (i.e. benzylic or tertiary alcohols). That's why compounds like SOCl2 are used to chlorinate irreversibly. I guess the answer is yes, it could probably help but it depends more on the substrate you plan on chlorinating and reaction conditions.

ChemichaelRXN - 18-10-2020 at 11:23

Thanks for the information!
I was thinking of reacting sulfurol with a mixture of concentrated HCl and FeCl3 and neutralizing it to separate out the clomethiazole freebase. I have freebased clomethiazole HCl with NaOH in the past and it doesnt go back to sulfurol. I think FeCl3 is the catalyst needed for the yield, but we’ll see. I will be sure to post what happens when I try this out.

For a compound like sulfurol (primary alcohol), to produce clomethiazole and other than HCl alone, what catalyst would you use for the halogenation? I cant obtain thionyl chloride unfortunately.

njl - 19-10-2020 at 06:03

To be honest, your experiment would be more valuable than my input. Given the availability of the reagents I would say just give it a try.

ChemichaelRXN - 19-10-2020 at 07:31

Glad I have some free time.
I am going to make a solution with both:

HCl: 2g / 143.207g/mol x 2/1 (2moles because of forming hydrochloride and remaining mole to halogenate) x 36.46g/mol= 1.02 / 0.37 = 2.76g / 1.19g/ml = 2.32ml conc. HCl
FeCl3.6H2O: 2g / 143.207g/mol x 1/1 x 270.29g/mol = 3.77grams FeCl3.6H2O / 2 (just catalyst use) = 1.9grams (50%)

1.9g FeCl3.6H2O dissolved in 2.32mL HCl added to 2 grams sulfurol. Heat for 15minutes and neutralize.

1.9g / 270.29g/mol x 3 / 1 x 40g/mol NaOH = 0.84g NaOH + extra required to basify the solution from remaining HCl
Remaining HCl; 1.16 mL conc HCl or 0.51g HCl at 100% conc. / 36.46g/mol x 1/1 x 40g/mol NaOH = 0.56grams

0.56g + 0.84g = 1.4g+ NaOH required to neutralize FeCl3 with 50% of the HCl added that makes the hydrochloride salt. You will need a bit more from incomplete reaction, so carefully add it.

Looking forward to seeing the result. Will post it later today or tomorrow.

Texium - 19-10-2020 at 07:33

First things first, is your ferric chloride anhydrous, or did you prepare it from aqueous solution? If it isn’t anhydrous it will be completely useless.

Either way though, as njl said, the comparison to dissolution of gold is completely meaningless, because in that case the oxidizing potential of ferric chloride is being taken advantage of, and it’s reacting with a metal, not an organic compound.

There’s a chance that the alcohol would act as a Lewis base and react with the ferric chloride to form a better leaving group, and give you hydrous ferric chloride as a byproduct. You might need to use a stoichiometric amount of the ferric chloride to achieve this though.

Once again, this is assuming anhydrous conditions- HCl being bubbled into solution, not added as an aqueous solution.

ChemichaelRXN - 19-10-2020 at 08:03

I am trying just 1.9g Ferric Chloride hexahydrate crystals dissolved in 2.32mL conc HCl. Thought I’d just experiment, but we’ll see if any product.

njl - 19-10-2020 at 08:34

The reaction you're working is documented, there will be product with or without ferric chloride (unless it hinders the reaction somehow). You need to run at least one control to see if the yield is any different.

ChemichaelRXN - 19-10-2020 at 08:34

Ah nevermind...the reaction didnt work. I need something stronger. It did smell like clomethiazole, but it didnt separate as freebase when water was added. I am on a horrible streak of failing reactions, but I guess that is experimentation for you. I need to get some dioxane for a NaBH4/ CuCl2 reduction now...

Texium - 19-10-2020 at 08:34

Make sure to compare it to just HCl on the same scale so that you have a control.

Edit: Jeez, three posts popped up at the same time. Yeah I figured it wouldn't work. Way too much water in there, and with a primary alcohol... no dice.

[Edited on 10-19-2020 by Texium (zts16)]

ChemichaelRXN - 19-10-2020 at 09:09

Yea the sulfurol is quite stubborn. I though I chlorinated it to form clomethiazole before. It smelled like the product, then later I found out that it is soluble in water as the freebase meaning it was still sulfurol with a little clomethiazole in it. (I thought the sulfurol was soluble in the brine solution I separated out the reaction with because of the water, but I got the reactant as well as the product mixed.) I am just curious how they convert sulfurol to clomethiazole...what would you do? Thionyl chloride? I need to do something successfully. Lol

How about sodium hypochlorite?

[Edited on 19-10-2020 by ChemichaelRXN]

njl - 19-10-2020 at 09:35

I am a bit confused because while the primary alcohol shouldn't be chlorinated that much just by aqueous HCl, I'm reading successful reports by other SM users that say otherwise.

Edit: this is a link to one thread discussing HCl chlorination.
http://www.sciencemadness.org/talk/viewthread.php?tid=154878

[Edited on 10-19-2020 by njl]

ChemichaelRXN - 19-10-2020 at 10:17

Yes, I didnt update the thread to not bring back an old topic. The product was separated with brine, but sulfurol was the product with some clomethiazole in it. It sure smelled like the product. The clomethiazole produced became miscible because of the sulfurol and I couldnt extract the pure product by adding water when doing a purification. A headache and ended up being a bit of a waste.

In other words, the yield was lower than what was posted.

I am looking for a new method.



[Edited on 19-10-2020 by ChemichaelRXN]

njl - 19-10-2020 at 10:36

I didn't even realize that was your post, my bad.

ChemichaelRXN - 19-10-2020 at 10:45

Yea, I got ahead of myself and from all the little tests I did along with its odour, I didnt think to try mixing the product with water until after, which showed it was soluble...maybe I should try sodium hypochlorite;

Not sure if it would work with primary alcohols, but I am willing to experiment. I dont have PCl3 or thionyl chloride and it is very toxic as well.

Anisic acid (3.8 gm., 1/40 mole) was dissolved in 150 mL of water and 25 mL of 4% sodium hydroxide solution. It was cooled to 20°C., and mixed with 50 mL (1/20 mole) of sodium hypochlorite solution. The temperature was maintained at 20° C. for one hour with occasional stirring. Upon acidifying, a precipitate of almost pure 3-chloroanisic acid was obtained. The yield was 3.9 gm. (80% of theory). After one crystallization from toluene it melted at 215°C.

Texium - 19-10-2020 at 10:47

Quote: Originally posted by ChemichaelRXN  
Yea the sulfurol is quite stubborn. I though I chlorinated it to form clomethiazole before. It smelled like the product, then later I found out that it is soluble in water as the freebase meaning it was still sulfurol with a little clomethiazole in it. (I thought the sulfurol was soluble in the brine solution I separated out the reaction with because of the water, but I got the reactant as well as the product mixed.) I am just curious how they convert sulfurol to clomethiazole...what would you do? Thionyl chloride? I need to do something successfully. Lol

How about sodium hypochlorite?
Sodium hypochlorite is a definite no. Hypochlorite is a source of electrophilic chlorine (Cl+). You need a source of nucleophilic chloride (Cl-). Completely different animals. Thionyl chloride, oxalyl chloride/DMF, or phosphorus pentachloride are all examples of reagents that can accomplish this nicely, by being attacked by the alcohol to kick off chloride and form a better leaving group, which the chloride can then displace. It is essentially the same mechanism in the end as HCl reacting with an alcohol, except it is irreversible. Of course, none of these reagents are too easy for the amateur to obtain. Didn't you say you own a chemical company though? It should be easy enough and relatively inexpensive for you to order some thionyl chloride.

ChemichaelRXN - 19-10-2020 at 11:20

Ok excellent info, thanks! Yes I do own a chemical company, but some compounds are difficult to obtain though. I mainly import overseas and not sure if my usual suppliers would ship something toxic like that. I should make an account with Sigma Aldrich.

ChemichaelRXN - 19-10-2020 at 11:25

How about using Conc. HCl with addition of H2SO4? Reminds me of a nitration, but may help with replacing a hydroxy with chlorine for a higher yield. I guess the idea is similar to Ferric chloride and I will try the ferric chloride again with a larger amount. Something new is always nice.

njl - 19-10-2020 at 14:00

The conditions might be too harsh, but I would even try NaCl and H2SO4 to avoid as much water in the reaction as possible.

ChemichaelRXN - 20-10-2020 at 07:21

I’ll think about it and may try it out. I was thinking of gassing the sulfurol with HCl too, but the problem is that it forms the hydrochloride salt and will no longer stir likely. It’s a bit of a challenge. Do you think anhydrous aluminum chloride would work?

njl - 20-10-2020 at 08:37

For chlorinating? I don't know, that's something I've been wondering for a while too. I think because it is more covalent in character the reaction will at the very least proceed via a different mechanism than HCl chlorination, if it works at all.