Sciencemadness Discussion Board

sulfonylchloride to thiol

DNA - 16-8-2008 at 00:42

I am having a problem with the reduction of 2,5-dimethoxysulfonyl chloride to 2,5-dimethoxythiophenol.
I've tried as described in the book of shulgin the Zn/H2SO4 method.
And I tried direct reduction with LiAlH4 in dry THF.
Both didn't give the desired product.

I'm also planning on making the disulfide via NaI and NaHSO3 in acetic acid and then reducing the disulfide, but it should be possible to do a direct reduction.

Does anybody have TLC (Rf) values of the product.
I'm still trying to order a very small sample so I can compare the Rf values while doing a reaction.

But well to make a long story short, who has got experience with this reaction?
Thanks in advance.
DNA

DNA - 20-8-2008 at 02:46

Come on, nobody?

Klute - 20-8-2008 at 04:46

I have tried a somewhat similar reaction, reduction of 2,5-dihydroxyphenylthiosulfate, and poisionned myself with the emmited H2S... not something I'd like to try again. I obtained a neglieable amount of the thiophenol.

I also tried the reduction of the corresponding disulfide, with Zn/HCl, and that was a pretty foamy/sludgy experience, and to my horror, when extracting the thiophenol with toluene, in a matter of minutes it got reoxidized to the disulfide (hardly soluble yellow paste/gummy solid)...

I don't have the Rf's anymore, but when using ACoEt/Pet ether, the thiophenol was under the disulfide by a healthy margain.


On the other hand, thiophenol being often unsatbel and very easily oxidized to the disulfide, you can keep the disulfide, which can be directly alkylated, forming the thiophenol insitu, using 1°/ Zn and 2°/RX in DMF, or suing Rongalite/dithionite and RX in DMF too IIRC. There are a few articles on that matter in the refs forum.

Honestly, sulfur compounds are a mess to work with, I contaminated my base bath with sulfides, which later partially poisionned my Pd/C catalyst, even afetr a good rince... Not to mention the stench...

Would you care to elaborate on the Zn reduction of the sulfonyl chloride? this is a pretty common reaction, well used for the preparation of thiophenols, I'm surprise dit didn't work. Please let us knwo how you initiated the recation, the scale, reaction time, appearance, etc

DNA - 21-8-2008 at 00:29

I obtained the 2,5-dimethoxyphenylsulfonyl chloride by reacting 1,4-dimethoxybenzene with SO2Cl2 then it formed a yellow solid after evaporating the organic layer after extraction.
The 2,5-dimethoxyphenylsulfonylchloride was added to 10% H2SO4 solution in water, then Zn was added by small spatula tips placing on the top of the floating sulfonylchloride and then mixing it and heating it on the water bath.
There was a disapearance of the SO2Cl and an oil floating around (I guess this is the SH). But couldn't see any new spot on TLC

[Edited on 21-8-2008 by DNA]

stoichiometric_steve - 21-8-2008 at 01:22

does the reduction of the sulfonyl chloride also evolve H2S?

Nicodem - 21-8-2008 at 03:06

Quote:
Originally posted by DNA
I obtained the 2,5-dimethoxyphenylsulfonyl chloride by reacting 1,4-dimethoxybenzene with SO2Cl2 then it formed a yellow solid after evaporating the organic layer after extraction.

May I ask what is the reference for this reaction? What kind of an analysis have you done (at least tell what's the mp?)?
The only reaction I know of 1,4-dimethoxybenzene with SO2Cl2 is the ring chlorination yielding a mixture of 2-chloro-1,4-dimethoxybenzene (liquid), 2,5-dichloro-1,4-dimethoxybenzene (solid) and some side products resulting from the ipso electrophilic attack.

DNA - 21-8-2008 at 03:57

HOSO2Cl I used insted of the previously mentioned SO2Cl2 the Reference is:

Journal of Medicinal Chemistry, 2005, Vol 48, No 7, pag. 2407-2419
I can post it if anyone is interested.
I also have other references which I will all try out.
I've got several experiments planned so if there is interest in it I can post my findings.
The 2,5-dimethoxysulfonylchloride was confirmed by TLC and LC-MS and mp and 1H-NMR and 13C-NMR.
The 2,5-dimethoxythiophenol has not been analysed after the experiment due to no acces to the analytical equipment anymore. Only TLC and mp is still available as analysis.
P.S Another nice paper I found is this one:

Tetrahedron Letters, 40(16),pag 3179-3182, 1999

[Edited on 21-8-2008 by DNA]

Klute - 21-8-2008 at 04:36

No, reduction of the sulfonyl chloride doesn't evolve H2S, only H2 and HCl IIRC.

SO2Cl2 doesn't give any sulfonyl chloride indeed. You might to check your stoechiometry of the chlorosulfonic acid, asif it is degraded or not used in exces, only the sulfonic acid is formed which cna't be reduced by Zn/H+ IIRC. If you keep on getting your starting materail back, check it by forming the sulfonamide, to be sure it's the sulfonyl chloride and not the acid...

Please do post any further results

DNA - 22-8-2008 at 03:20

I just found a very nice paper which describes the following:

Non-aqueous Reduction of Aromatic Sulfonyl Chlorides to Thiols
Using a Dichloromethylsilane-Zinc-dimethylacetamide System.

Only "problem" is, for the more electrodonative molecules dimethylacetamide doesn't perform well; it forms 50% disulfide and 50% thiol.
But when 1,3-dimethylimidazolidin-2-one is used one will get 96% thiol.
If there is interest in this paper please let me know and I'll upload it.

[Edited on 22-8-2008 by DNA]

Klute - 22-8-2008 at 16:18

Hum, seems a bit like a waste of dichloromethylsilane IMHO. Zn reduction of sulfonyl chlorides usually work well, i would give another try if I were you

If you do try this reaction, please post the details. Is the DMA used in stoechiometric amouts?

DNA - 23-8-2008 at 01:54

they use dichloromethylsilane combined with 1,3-dimethylimidazolidin-2-one insted of DMA because 2,5-dimethoxysulfonyl chloride is a electrodonative molecule.
With the non electrodonative molecules they use 3 eq of the DMA.
1,2-dichloroethane as solvent IIRC.
and the silane compound isn't that expensive, but well yeah if you consider the price of Zn and H2SO4 it is a expensive route with the silane and imidazolidinone.

DNA - 24-9-2008 at 03:16

Does anyone have an idea what happens or can happen if you reduce 2,5-dimethoxysulfonylchloride too far.
Normally this would be reduced to 2,5-dimethoxythiophenol but what if you keep refluxing this with LiAlH4 in THF for like ages will there be any byproduct? Can anyone think of what could happen?

panziandi - 24-9-2008 at 04:00

LiAlH4 is not able to reduce the benzene ring! I can't picture any other reactions occuring tbh.

Klute - 24-9-2008 at 10:15

Are you 100% sure you have the sulfonyl halide and not part sulfonic acid? Notsure what the reduction products of the acid with LiAlH4 will be, but I know Zn stops at the sulfinic acid... Did you form the sulfonamide? Or another derivative to confirm you have the sulfonyl halide? I think some chlorosulfonations form the acid first, which is then chlorinated by excess chlorosulfonic acid to the sulfonyl chloride..

Good luck with the reaction, it seems more tricky that what it looked.

NMR impurities

DNA - 1-10-2008 at 01:15

Dear people,

I've got a sample of "most likely" 2,5-dimethoxythiophenol.
I have the ability to run an NMR and on TLC I see that this sample contains 2 compounds one major spot and a smaller one if I need to guess it is 80% product and 20% impurity.
If I would run an NMR of this should I still clearly see the spectrum of my product or will it be a mess and still not be able to tell if it is actually 2,5-dimethoxythiophenol.

Another thing, I found an Rf value for 3,4-dimethoxythiophenol, will this Rf be quite the same as for 2,5-dimethoxythiophenol ( I think it would but as I look at the eluens and the Rf it seems not to be so.)
2,5-dimethoxythiophenol has an Rf of 0,7-0,8 in 5:2 heptane/EtOAc and the Rf of 3,4-dimethoxythiophenol is 0,65 in dichloromethane/MeOH 9:1 while in pure dichloromethane the suspected (not sure if it is but probably will be) 2,5-dimethoxythiophenol has an Rf of 0,95

Nicodem - 1-10-2008 at 02:12

You should be able to see a double set of singlets for those methoxies assuming the other product also contains the 2,5-dimethoxyphenyl moiety (as well as a double pair of aromatic signals - two coupled doublets and a singlet). The pair of MeO singlets will most probably overlap (depending on what the side product is). Preferably use CDCl3 as solvent since some mercaptanes slowly oxidise to disulfides in d6-DMSO if left standing too long. The side product is most likely the disulfide which inevitably accompanies mercaptanes. In such a case you will have a double set of signals with one lacking the SH broad singlet.
Otherwise I do not fully understand your question. You can compare your spectra with the one published in the literature to get a confirmation of whether your product is the one you want or not. If your question is on the feasibility of the 1H NMR showing you the purity of the product then the answer is more or less yes, but other methods could also give you the same info. The 1H NMR will show you the proportion of the products that contain protons (assuming all the compounds in there do), but you have to know their identity in order to calculate the purity or else the proton integrals will mean little.

Rf values for TLC mean nothing. You can not positively identify a compound using a TLC unless comparing with a standard and even then it is not an identification, just a "likely identity". Almost the only hint that a TLC can gives you is whether the side product is more or less polar than your main product.

DNA - 1-10-2008 at 05:29

Well I found that a really big spot is on top and then a little bit lower I find the byproduct.
Would 2,5-dimethoxysulfonylchloride be higher or lower then 2,5-dimethoxythiophenol?
At the moment if I am actually forming the thiol then the sulfonylchloride is a little bit lower but not by much.
And where would the disulfide be compared to the sulfonylchloride and the thiol?

[Edited on 1-10-2008 by DNA]

DNA - 1-10-2008 at 05:34

Quote:
Originally posted by Klute
Are you 100% sure you have the sulfonyl halide and not part sulfonic acid? Notsure what the reduction products of the acid with LiAlH4 will be, but I know Zn stops at the sulfinic acid... Did you form the sulfonamide? Or another derivative to confirm you have the sulfonyl halide? I think some chlorosulfonations form the acid first, which is then chlorinated by excess chlorosulfonic acid to the sulfonyl chloride..

Good luck with the reaction, it seems more tricky that what it looked.



You mean that when the sulfonic acid will be reduced to the sulfinic acid by Zn?
I finally got some 33% NH3 solution so I'll make the sulfonamide tonight (any sugestions for that?)
I don't know what solvent I should use to do this for dissolving a bit of 2,5-diMeOphenylsulfonylchloride in and then adding 2 molar eq. of 33% NH3 solution to it.

[Edited on 1-10-2008 by DNA]

Klute - 1-10-2008 at 07:37

the sulfonyl chloride (and the acid IIRC) are reduced to the sulfinic acid in absence (or too small of an amount) of H2SO4.
Quote:

The sulfonamide, from this acid chloride [2,5-MeOPhSO2Cl] and ammonium hydroxide, gave white crystals from EtOH, with a mp of 147.5-148.5 °C.

PIHKAL, #40.
Quote:

176. Preparation of Benzenesulphonamide (SECTION 474).—
Put into a test-tube about 1 cc. of benzenesulphonyl chloride
and add about 5 cc. of strong ammonia. Shake until a solid is
formed and the odor of the chloride has disappeared. Pour
off the liquid and wash twice with water by decantation. Add
about 20 cc. of water; heat to boiling until the substance has
dissolved. Filter, if necessary, and set the solution aside to
crystallize. When cold, filter by suction, wash with cold water,
and dry the amide for half an hour on a porous place. Determine
the melting-point of the amide. If the crystals do not melt
sharply, recrystallize them from hot water.
Benzenesulphonamide crystallizes from hot water in needles,
which melt at 156°.
NOTE.—Sulphonamides are frequently made in the identification of sulphonic
acids or their salts. The preparation can be carried out with small
quantities in a few minutes. Proceed as follows: Warm together in a testtube
on a steam-bath about 0.5 gram of the salt with an equal volume of
phosphorus pentachloride, until the mixture liquefies. Cool, pour 5 cc. of
water into the tube, warm gently, and shake for about 1 minute. Pour off
the liquid and wash twice by decantation with 5 cc. of cold water. Add
6 cc. of ammonia and proceed as described in the experiment above.


Experimental organic chemistry, J.F. Norris, p.145

this method can be applied to tosyl chloride, which is a solid, so just use the same proceudre (heat the solid in conc. NH3).

You could also add slight excess NH3, then NaOH until sulfonamide dissolved, filter and wash with solvent, and acidify to precipitate the sulfonamide again. Filter, dry and recrystallize before taking mp.

Let us know how it goes!

[Edited on 1-10-2008 by Klute]

vulture - 1-10-2008 at 10:00

Quote:

If your question is on the feasibility of the 1H NMR showing you the purity of the product then the answer is more or less yes, but other methods could also give you the same info. The 1H NMR will show you the proportion of the products that contain protons (assuming all the compounds in there do), but you have to know their identity in order to calculate the purity or else the proton integrals will mean little.


In my experience, a standard 16 scans on a 300Mhz NMR machine will only show hydrogen signals of impurities which have a concentration in your sample of 2% or more, whereas TLC will readily show even very low levels of contamination (unless the Rf value doesn't differ ofcourse).

Klute - 1-10-2008 at 12:53

On a TLC plate, your compounds will basicly elute in decreasing polarity: the more polar will be "retained" more byt he silica, and elute slower.

to indentify your sulfonyl chloride, just make two deposits on the same palte, your pur sulfonyl chloride and your reduction mixture.

I would think your would have the following order, from bottom to top: sulfonyl chloride, thiophenol, disulfide. But that's just a guess. Try couplind derivation, test for thiol functionality, or disulfide etc, and work you way up to indentifying each spot.

Not sure about the test for thiols.

Look at this very valuable page for test for sulfonyl halides. Maybe some test for phenols can be applied to thiophenols:

Chemical Tests Page

You could take a sample of your reduction mixture, and add acidic H2O2 (to turn any thiophenol in disulfide, and compare by TLC. If one spot disappears, and one become smuch bigger, you have the thiophenol and disulfide. If a new spot appears, perhasp there wasn't any disulfide in the first place. If you get a complex mixture, try a more gentle oxidant (search the lit for oxidations to disulfides, there are tons)

good luck!

EDIT: I think this thread should better go with the thiophenol thread, no?

[Edited on 1-10-2008 by Klute]

Swany - 1-10-2008 at 14:26

"NMR Pure", as vulture mentioned, is not exactly pure. However, I am guessing that your impurity will show up on a proton NMR... though, without a good idea, the identity will likely not be discernible.

Why don't you run a column on it? It almost always saves work to start with clean starting material. I am guessing that tests will take longer than just running a quick flash column.

Nicodem - 1-10-2008 at 22:42

I think the reason why he does not (want to) run a column is because he is not doing a mmol scale reaction. I do not know why he does not recrystallise though.
In my experience on a 300Mhz machine with 16 scans and 10-20mg sample I often clearly see peaks for impurities even less than 2% (though my products generally have a low molecular weight, like 200-500, so a 10mg sample is a lot). Though, it could well be that they are sometimes invisible and I simply don't see them since I rarely verify on HPLC and never on GC (accessibility issues, otherwise I would). It is however true that TLC can sometimes show a pale spot of a side product while this is invisible on NMR. I think this is only the case when the side product has an unusually high UV absorption or fluorescence, since this does not happen often to me and when it does the spot most commonly shines at the 366nm light. Obviously I do not bother for such minor side products if invisible on NMR, since they can be just in ppm amounts (which for my needs is irrelevant).

Klute, in my experience the sulfonyl chlorides travel quite high on TLC - I guess they might be less polar than the corresponding thiol, but I have no actual experience comparing such a pair on TLC.

DNA - 2-10-2008 at 01:48

I'm doing reactions on 0,25-0,50 mmol scale at the moment until I have the reaction working correctly (this means 50-100mg sulfonylchloride).
I made the sulfonamide yesterdaynight by adding concentrated (33%) ammonia to 100mg sulfonylchloride.
After heating this to 60*C and stirring the yellow sulfonylchloride turned to a white solid.
The melting point of the sulfonylchloride was confirmed as to be +/- 112*C. Tonight the sulfonamide will be dry and will measure the mp of that one too. I was already thinking of doing a 100mg raw thiol and running that over a column with SiO2 then when having some pure thiol or at least the biggest spot I'll add some H2O2 (not acidic, this is what I read before about forming disulfides). Then checking TLC again comparing the disulfide with the suspected thiol. (it is yellow/amber colored liquid with a smell of thiols a little bit like gasoline).

EDIT: Would be better indeed to put this in the sulfonylchloride to thiol topic.

[Edited on 2-10-2008 by DNA]

DNA - 2-10-2008 at 01:53

I made the sulfonamide yesterdaynight by adding concentrated (33%) ammonia to 100mg sulfonylchloride.
After heating this to 60*C and stirring the yellow sulfonylchloride turned to a white solid.
The melting point of the sulfonylchloride was confirmed as to be +/- 112*C. Tonight the sulfonamide will be dry and will measure the mp of that one too. The suspected thiol. (it is yellow/amber colored liquid with a smell of thiols a little bit like gasoline).


P.S Interesting thing is that in pihkal around page 777 (yesterday when I was reading threw pihkal I found another preparation of dimethoxythiophenol (2,4) and there he does use ice and H2SO4 so a better description than for the 2,5-dimethoxythiophenol. There is also info about the sulfonamide preparation.)

Here it is:

#125 META-DOT
Quote:
There was thus obtained 14.2 g 2,4-dimethoxybenzenesulfonyl chloride as white solids with a mp of 69-72 °C. Heating of a small portion with concentrated ammonium hydroxide gave the corresponding sulfonamide which, on recrystallization from EtOH, produced white needles with a mp of 165.5-166.5 °C.

To a stirred and gently refluxing suspension of 11 g LAH in 750 mL anhydrous Et2O, there was added 13.2 g 2,4-dimethoxybenzenesulfonyl chloride in an Et2O solution. The refluxing was maintained for 48 h then, after cooling externally with ice water, the excess hydride was destroyed by the slow addition of 600 mL of 10% H2SO4. The phases were separated, and the aqueous phase extracted with 2x200 Et2O. The organics were pooled, washed once with 200 mL H2O, and the solvent removed under vacuum. The residue was dried azeotropically through the addition and subsequent removal of CH2Cl2. Distillation of the residue provided 8.0 g 2,4-dimethoxythiophenol as a colorless oil, boiling at 89-92 °C at 0.5 mm/Hg.


#139 ORTHO-DOT
Quote:
The weight of the crude 3,4-dimethoxybenzenesulfonyl chloride was 37.1 g and it had a mp of 63-66 °C. Recrystallization raised this to 72-73 °C. Reaction with ammonium hydroxide gave the sulfonamide as colorless needles from EtOH, with a mp of 132-133 °C.

The finely pulverized 3,4-dimethoxybenzenesulfonyl chloride (33 g) was added to 900 mL of crushed ice in a 2 L round-bottomed flask equipped with a heating mantle and reflux condenser. There was then added 55 mL concentrated H2SO4 and, with vigorous mechanical stirring, there was added 50 g of zinc dust in small portions. This mixture was heated until a vigorous reaction ensued and refluxing was continued for 1.5 h. After cooling to room temperature and decantation from unreacted metallic zinc, the aqueous phase was extracted with 3x150 mL Et2O. The pooled extracts were washed once with saturated brine and the solvent was removed under vacuum. The residue was distilled to give 20.8 g of 3,4-dimethoxythiophenol boiling at 86-88 °C at 0.4 mm/Hg.


[Edited on 2-10-2008 by DNA]

[Edited on 2-10-2008 by DNA]

vulture - 2-10-2008 at 12:48

Thiophenols smell like hell, concentrated stuff will make you want to vomit, totally not like gasoline.

Quote:

It is however true that TLC can sometimes show a pale spot of a side product while this is invisible on NMR. I think this is only the case when the side product has an unusually high UV absorption or fluorescence, since this does not happen often to me and when it does the spot most commonly shines at the 366nm light.


I've had them show up on 254nm too. But then again I'm often making monomers for polycondensations, which requires you don't have any chain terminator at all present.

DNA - 3-10-2008 at 00:13

I'll determine the boiling point anywhere soon so then I can say more about if it actually is the thiol.
Also an GC-MS and NMR will be taken next week, I'll keep you updated.