Sciencemadness Discussion Board

Sulphonation of chlorophenol

Boffis - 20-5-2019 at 06:33

I am trying to prepare an azoic dye intermediate: 2-amino-4-chlorophenol-6-sulphonic acid. I have been unable to find a synthesis of this important dye intermediate so I decided to try the following route from 4-chlorophenol which I already have.

4-chlorophenol ---via sulphonation---> 4-chlorophenol-2 and possibly 2,6-disulphonic acids ---nitration---> 2-nitro-4-chlorophenol-6-sulphonic acid ---reduction---> desired product

The problem is that the 4-chlorophenol seem very resistent to sulphonation. I would expect it to be less reactive than phenol but the compound is very unreactive inspite of the fact that it nitrates fairly easily to 2,6-dinitro-4-chlorophenol.

Does anyone have any experience/reference to such sulphonations? I have an entire book on naphthalene derivatives but I can't find a similar book dealing with the basic benzene derivatives. Alternatively a reference to chlorophenol chemistry, even an old or German one would be a great help.

Attachment: chlorophenolsulphonic acid.emf (19kB)
This file has been downloaded 500 times

Keras - 20-5-2019 at 06:51

Arene Chemistry, edited By Jacques Mortier, Wiley 2016 maybe?

Also what did you use to sulphonate? Sulphuric acid?


[Edited on 20-5-2019 by Keras]

Boffis - 20-5-2019 at 07:10

Yes I am using conc sulphuric acid at about 150-180 C, its been cooking now for 2 hours. The chlorophenol is now disssolving slowly.

Keras - 20-5-2019 at 07:43

Quote: Originally posted by Boffis  
Yes I am using conc sulphuric acid at about 150-180 C, its been cooking now for 2 hours. The chlorophenol is now disssolving slowly.


I'd be concerned that at that temperature and concentration you'd get the sulphuric acid to react with the OH group and get some sort of ester. Cl - Ph - O - SO2(OH). But maybe I'm way off base.

Boffis - 20-5-2019 at 08:19

Found it!! Organic Chlorine Compounds by Huntress 1948; Its nice to have some of these really old chemistry books on ones shelf sometimes.

It the bible of organic chlorine chemistry to that date!

Got some refs: Petersen et al., Annalen 157, p128-147 [1871] and Guantlett, JCS v127, p2745-2746 [1925]

CuReUS - 20-5-2019 at 08:44

you could try using stronger sulphonating agents like oleum or chlorosulphonic acid

the other thing you could do is

1.sulphonate phenol - https://pubs.rsc.org/en/content/articlelanding/1985/p2/p2985...

2.chlorinate o-phenol sulphonic acid using bleach -https://pubs.acs.org/doi/abs/10.1021/ed025p514?journalCode=j...

3.Nitrate and reduce to 2-amino-4-chlorophenol-6-sulphonic acid
Quote:
I am trying to prepare an azoic dye intermediate..
could you tell what dye you want to make ?

Keras - 20-5-2019 at 09:20

My textbook suggests that sulphonation is a slow reaction anyway, because it relies on the auto-protonation of a sulphuric acid molecule. Nitration is much quicker because if you add sulphuric acid to nitric acid, the former, which is more powerful, protonates the latter, which releases a water molecule and the NO2+ cation which proceeds to attacking benzene.

Boffis - 20-5-2019 at 12:03

@CuReUS, yep looking at the references both oleum (20%) and chlorosulphonic acid have been used in the past. Its interesting to note that phenol reacts much more quickly. I have found in the past that conc sulphuric acid does most of the things that oleum does, it just take a lot longer as Keras points out sulphonation is generally slow.

The 4-chlorophenol dissolved completely after about 4 hours.

4-chlorophenol-2-sulphonic acid.jpg - 38kB


The chlorination of o-phenolsulphonic acid sounds interesting but how do you selectively o sulphonate phenol? The alternative is general sulphonation and then separation which is a pain but doable.

This azoic intermediated when diazotized couples with resorcinol (Lumogallion reagent for In and Ga), barbituric acid (Lumomagneson, reagent for Mg) and chromotropic acid etc

Keras - 20-5-2019 at 20:57

Quote: Originally posted by Boffis  

The chlorination of o-phenolsulphonic acid sounds interesting but how do you selectively o sulphonate phenol? The alternative is general sulphonation and then separation which is a pain but doable.


The -OH group is highly nucleophilic, it will favour the addition of electrophiles such as HSO3 in o- and p- positions. The yield should be ⅔ o- ⅓ p- just for geometrical reasons. Both isomers should have very different properties and b.p. so separating them by fractional distillation shouldn’t be much of a hassle.

[Edited on 21-5-2019 by Keras]

Pumukli - 20-5-2019 at 21:34

"⅔ o- ⅓ p- just for geometrical reasons"

I'm almost sure that the ratio will be different, more p, less o, - just for geometrical reasons. :-)

I mean: there is the OH group at position 1 and it requires some space. Not too much, but some. The big and bulky sulfonating species prefers "empty" space around it so statistically somewhat more than 33% p and consequently less than 67% o isomers will form.

I'd be really surprised if the ratio would be what you stated.
(Although chemistry left me surprised numerous times, especially when it was about preparations.)

Keras - 21-5-2019 at 00:17

Quote: Originally posted by Pumukli  
"⅔ o- ⅓ p- just for geometrical reasons"

I'm almost sure that the ratio will be different, more p, less o, - just for geometrical reasons. :-)

I mean: there is the OH group at position 1 and it requires some space. Not too much, but some. The big and bulky sulfonating species prefers "empty" space around it so statistically somewhat more than 33% p and consequently less than 67% o isomers will form.


Okay, there might be steric hinderance, but at least when you do the nitration of phenol, you get 2/3 o-, 1/3 p-.

But you're right. It seems temperature is key here. At low temp (r.t. or below, such as what's need for single nitration), ortho- form is preferred, but as the temp increases, more and more para- is formed since this is the thermodynamically preferred form.

CuReUS - 21-5-2019 at 05:34

Quote: Originally posted by Boffis  
how do you selectively o sulphonate phenol?
You can't. You have to sulphonate and separate the isomers.But you get a decent yield of the o-product (49%)
Quote: Originally posted by Pumukli  
I'm almost sure that the ratio will be different, more p, less o, - just for geometrical reasons. :-)
You are right,but barely.The ratio is almost 1:1 - o-49%:p-51% (see the paper i linked above)
Quote:
I mean: there is the OH group at position 1 and it requires some space. Not too much, but some. The big and bulky sulfonating species prefers "empty" space around it so statistically somewhat more than 33% p and consequently less than 67% o isomers will form.
steric hindrance isn't the only factor determining regioselectivity.Other factors are:
1.diffusion control of reaction rate
2.Hydrogen bonding
3.Complexation of substrate and electrophile ( reason for high o-yield in phenol)
Quote: Originally posted by Keras  
when you do the nitration of phenol, you get 2/3 o-, 1/3 p-.
It seems temperature is key here. At low temp (r.t. or below, such as what's need for single nitration), ortho- form is preferred, but as the temp increases, more and more para- is formed since this is the thermodynamically preferred form.
the concentration of the sulphuric acid used in the nitration determines the o/p ratio.The o/p ratio of phenol varies from 1.9 to 0.9 over the acid range of 61 to 83% H2SO4

Keras - 21-5-2019 at 06:38

Quote: Originally posted by CuReUS  
The o/p ratio of phenol varies from 1.9 to 0.9 over the acid range of 61 to 83% H2SO4


That’s what the article claims from a reference, but the authors' own findings indicate that the yield is 50/50 over 73 to 90% concentration range. Also the reaction here is made at r.t. Also the authors warn that with concentrated (> 88%) sulphuric acid, the reaction produces the 2,4-product.

I also found this, might be interesting.

Boffis - 21-5-2019 at 06:44

Actually when I looked through my stash of chemicals I discovered that I have already done the sulphonation of phenol and have about 150g of barium p-phenolsulphonate and about 100g each of sodium and barium o-phenolsulphate from many years ago. I had completely forgotten about them. However, since I already have 4-chlorophenol this seem like the obvious starting material.

I cooked the sulphuric acid/chlorophenol mixture for 4 hours at 160 C in the end and got a light brown homogenous solution which I then nitrated without isolation by adding 6.51g of sodium nitrate (1 molar equivalence) in small amounts. The reaction proved to be very slow so I warmed it gently and a very quiet reaction set in with the separation of a pale yellowish brown powdery substance. After warming (to about 60 C) for an hour I drowned the slurry into 200ml of cold water. I expected to get a clear solution apart from perhaps a little un-sulphonated 4-chlorophenol and nitro-4-chlorophenol. In fact I got a significant amount of yellow-brown insoluble material. It is partly soluble in dilute alkali giving a faintly brownish solution that gives an amazingly intense violet with tap water even at insanely low concentrations. It doesn't give a distinctive colour with ferric chloride even when carefully neutralised. Mmmmm

The solid is drying and the light orange filtrate is about to be neutralised and evaporated down to see what I can find in it.

Keras - 21-5-2019 at 06:59

Quote: Originally posted by Boffis  

The solid is drying and the light orange filtrate is about to be neutralised and evaporated down to see what I can find in it.


Please keep us posted!
EDIT: To be honest, I think you should have filtered and purified your product before proceeding to nitrating it. I'm sure you ended up with a ton of side products…

[Edited on 21-5-2019 by Keras]

Boffis - 21-5-2019 at 15:00

@Keras. Yep, as I start to isolate products its quite clear that I have a real cocktail. The insoluble solid when dried weighed 6.51g but is clearly a mixture under the microscope. Recrystallizing it from isopropanol generates beautiful almost colourless six-sided monoclinic plates several mm across. On further evaporation tiny yellow granules form. The former I suspect will turn out to be un-reacted 4-chlorophenol but the latter are less clear. I thought the compound may be 4-chloro-2-nitrophenol but this is clearly not the case as I have this compound prepared from p-dichlorobenzene via nitration to 2-nitro-p-dichlorobenzene then via pressure-cooking with NaOH the Cl in the 1 position is replaced to give the appropriate phenol derivative.

This latter route makes me wonder if the route to my desired compound into via 2-nitro-p-dichlorobenzene to 2-nitro-4-chlorophenol then via sulphonation to the 6-sulphonic acid and finally reduction the the amine. I suspect that the sulphantion of the nitrochlorophenol will be slow and difficult without oleum too.

via p-dichlorobenzene.bmp - 283kB

Keras - 21-5-2019 at 22:42

I’m surprised you didn't start from phenol, but maybe that makes sense since chlorinating phenol will give you a mix of p-choloro and o-chlorophenol, I suppose.

Why don't you run a TLC test to find out how many different compounds you have in your mix?

Also, maybe this could be useful to you? It's an excerpt from Vogel's Textbook of Practical Organic Chemistry.


[Edited on 22-5-2019 by Keras]

Attachment: p-toluenesulfonic_acid.pdf (344kB)
This file has been downloaded 345 times

Boffis - 22-5-2019 at 08:40

I have encountered a slight problem. Chlorophenol is supposed to have a low melting point and faint unpleasant smell. My 4-chlorophenol has almost no smell, perhaps faintly clinical. I have also just done a melting point test and it didn't melt below 62 C at which point I gave up; the published values range up to 42 C. So I think I have a problem with my starting material.

I can prepare 4-chlorophenol from phenol and sulphuryl chloride and I am currently checking out the detail of this prep.

Also reading some of the old German literature it appears that when most chlorophenol sulphonic acids (both 2 and 4 Chlorophenol) are nitrated the sulphonic acid group is replaced by a nitro group giving one or more nitro-chlorophenols. So this does seem to suggest that I will have to go via sulphonation of the 2-nitrochlorophenol after all.

Some years ago I prepared heaps of 2-nitro-1,4-dichlorobenzene (>200g) as I had lots of p-dichlorobenzene and this seemed to be the only reaction it would undergo. The problem with converting it to 2-nitro-4-chlorophenol is that it needs an autoclave that with operate at 3-5 Bar AND has internal stirring, my autoclave is rated at 90 bar but doesn't have a facility for stirring. Do you think that I could convert this compound to the appropriate 2-nitro-4-chloroaniline by fusing with urea in a similar method to producing trinitroaniline from from picryl chloride? The aniline would then be converted into a diazonium compound and hydrolysed to give the appropriate phenol.

In the mean time I have isolated beautiful yellow plates from my crude nitration product, god only knows what it is. I will report back later on progress and also further investigations into my "4-chlorophenol".

Pumukli - 22-5-2019 at 09:21

I'd try. :-) I don't know how the nucleophilicity of NH3 compares to the NH2's in urea though. But amines are stronger nucleophiles than water in general and maybe at the temperature of the melt it could be used for advantege.

Keras - 22-5-2019 at 22:27

Quote: Originally posted by Boffis  
I can prepare 4-chlorophenol from phenol and sulphuryl chloride and I am currently checking out the detail of this prep.


Prepchem has this.
Quote: Originally posted by Boffis  
Some years ago I prepared heaps of 2-nitro-1,4-dichlorobenzene (>200g) as I had lots of p-dichlorobenzene and this seemed to be the only reaction it would undergo. The problem with converting it to 2-nitro-4-chlorophenol is that it needs an autoclave that with operate at 3-5 Bar AND has internal stirring, my autoclave is rated at 90 bar but doesn't have a facility for stirring. Do you think that I could convert this compound to the appropriate 2-nitro-4-chloroaniline by fusing with urea in a similar method to producing trinitroaniline from from picryl chloride? The aniline would then be converted into a diazonium compound and hydrolysed to give the appropriate phenol.


It doesn't seem absurd, but that'll need further researching.
Quote: Originally posted by Boffis  
In the mean time I have isolated beautiful yellow plates from my crude nitration product, god only knows what it is. I will report back later on progress and also further investigations into my "4-chlorophenol".


Yellow colour (to me at least) is highly redolent of nitrated compounds (picric acid, for one, or trinitroaniline you just cited). Given the propensity of nitrated aromatic compounds to explode, I would approach those crystal warily.

Oh also in attachement an excerpt from Purification of Laboratory Chemicals about chlorophenol.

[Edited on 23-5-2019 by Keras]

Screenshot 2019-05-23 at 08.28.16.png - 89kB

Boffis - 23-5-2019 at 14:32

Thanks for the comments Keras. Waffles ran some reaxys searches for me that give references to the preparation of the nitro and amino sulphonic acid and it seems that most of the routes discussed above and a few other have been tried. I am checking the references at the moment to see which route seems most feasible but the route from p-dichlorobenzene looks like a possibility.

If I do go via 4-chlorophenol I will have to prepare it as I mentioned above. I have now investigated my jar of "4-chlorophenol" and it is not a chlorophenol not even a very impure chlorophenol. the Mp is >100 C, unfortunately my old SM-10 melting point instrument died while I was running this compound. The compound is fairly soluble in water, the solution is alkaline, it gives a flesh coloured ppt with ferric chloride (no oxidation so possibly an aliphatic amine), an immediate deep brown flocculent ppt with copper sulphate (no hint of a blue amino type complex) and with sulphuric acid it generates an intense chlorine like smell though the volume of gas evolved is very small and the smell doesn't persist for long. Further investigations in progress.

The nitration product is easily separated into 3 compounds. The most abundant is a tiny colourless needles, less abundant but easily purified are the yellow plates I mentioned earlier and a small amount of thin blades stick to the surface of the water when recrystallized. The yellow plates are not soluble in sodium carbonate and do not give a deep yellow/orange solution with NaOH either.

This I guess is one of the problems of being an amateur and having to rely on ebay suppliers and the like. You can never be sure what you are getting.

Keras - 24-5-2019 at 09:15

Sorry I didn't notice you answered… I'm still flummoxed by the ergonomics of this forum.

I should have a crack at CAS. My uni doesn't subscribe to Reaxys. Oh, it suggested an article called Sulfonation and sulfation in the reactions of the chloro- and dichlorophenols, 3-fluorophenol and (2,3-,2,4-and 3,4-dichlorophenoxy)acetic acid with concentrated aqueous sulfuric acid and sulfur trioxide by Peter de Wit and Hans Cerfontain. That's published by Wiley.

Your perplexity reminds me of the old chemists before those sophisticated machines existed. I wonder how those guys during the 19th century were able to work out the formula of compounds…

I don't buy stuff on eBay. Besides, I don't get anything from China, I source from European dealers only. At least I'm sure to get decent quality supplies.

Keep me posted!

[Edited on 24-5-2019 by Keras]

Boffis - 25-5-2019 at 11:46

Actually the p-chlorophenol I bought was from a guy in Poland from whom I bought quite a bit of material and had very few problems. I have investigated the material further and have found that it is rather impure but the main constituent is a salt of an a weak organic acid. It is freely soluble in water with the small amount of brown insoluble material being removed by filtration. The addition of dilute sulphuric or hydrochloric acid to a hot dilute solution and then cooling deposits a pure white odourless compound that is freely soluble in alcohol but extremely insoluble in water. This compound cannot be nitrosated and is nitrated only with great difficulty. It burn on foil with a smoky flame and leaves only trace of soot on the foil. I have a sample drying with the aim of determining water of crystallisation. Once I have an anhydrous compound I will do some quantitative analysis and determine its acid value.

Back to the original theme: I have checked out all of the references on the Reaxys searches done for me by Waffles and there is some really interesting chemistry particularly the routes from p-dichlorobenzene. These references lead to an interesting paper in JACS about uses for p-dichlorobenzene, which was then a waste product, via combinations of nitration and sulphonation. I may come back to this in another thread because I have so much of it. Several possible routes to the title compound are emerging one from 4-aminophenol-2-sulphonic acid.

This last route is mentioned in passing in one of the German patents as not a cheap (ie commercial) route but it looks interesting if this compound can be prepared from paracetamol (Tylenol). What do people think about the possibility of sulphonating and de-acetylating paracetamol in one go with conc sulphuric acid? Do you think the sulphuric acid will oxidize the 4-aminophenol produced by de-acetylation?

Pumukli - 25-5-2019 at 23:30

If sulfuric acid is not concentrated enough then it won't oxidize it.
I don't know, maybe 75-85% acid would do the trick. It would most probably deacetylate and maybe sulfonate in one step as you imagined.

Boffis - 28-5-2019 at 13:39

I ran a few more experiments today; 1st I tried out the p-chlorophenol from phenol and sulphuryl chloride then I tried out the sulphonation of paracetamol.

The chlorination of phenol with sulphuryl chloride worked surprisingly well. The reaction in the cold is slow and I found that I could mix 10g of phenol crystals with 10ml of sulphuryl chloride (a slight excess) and virtually nothing happened until it was warmed slightly. At about 25-30 C a fairly vigorous reaction set in and the mixture homogenized into a yellowish liquid and gave of copious amounts of of sulphur dioxide and hydrogen chloride (needs a good fume hood!!) but the reaction didn't get out of hand. When the evolution of gas ceased, I washed the oily product with water then dilute sodium hydrogen carbonate solution until it no longer effervesced. I have washed it again with water and I am currently waiting for the two layer to clear a bit more before I separate and dry the heavy, pungent, slightly orange oil before I distil it. According to the literature references I have examined some 2- isomer is also formed so the chlorophenol does not solidify at room temperature.

The next experiment was an attempt at the simultaneous hydrolysis and sulphonation of paracetamol to 4-aminophenol sulphonic acid. 10g of recrystallised paracetamol were mixed with 15ml of sulphuric acid "monohydrate" ie 85% sulphuric acid and warmed until a homogeneous liquid was achieved, the liquid darkened with time and further heating. The flask was placed on a hotplate at 190-200 C but the internal temperature steadied at about 160 C +/- a few degrees. After 2 hours the contents of the flask was a black crystalline solid with a distinct smell of acetic acid. It looked very unpromising but I persevered adding 50ml of water and heating then 7ml of 50% NaOH solution, 1g of decolourising charcoal and finally another 50ml of water before bringing to the boil and filtering hot to obtain a dark brown solution. On cooling nothing precipitated or crystallised so I added dilute hydrochloric acid until the solution was weakly acid, about pH 4. A thick, flesh coloured, flocculant precipitate formed from the dark liquor, so I heat and stirred until it was almost boiling and then stared adding more water to try and dissolved the solid (4-aminophenol sulphonic acid is reported to be sparingly soluble). By the time the solution was at 150ml and boil with much undissolved solid I abandeoned this policy and left it to cool. A fine but granular crystalline flesh coloured solid has collected at the bottom of the beaker. I will filter it off tomorrow to see what I have. It is not certain that this is the sulphonic acid as both p-aminophenol and paracetamol are both soluble in alkalis and precipitated by acids but by all accounts it can be converted via Sandmeyer reaction into the chlorophenol sulphonic acid which is more soluble.

I wonder if it would not be better to mononitrate the paracetamol before attempting to sulphonate it (I suspect that mixed acid will hydrolyse the acetyl group) in order to make it less sensitive to oxidation? Then carry out Sandmeyer chlorination on the 2-nitro-4-aminophenol sulphonic acid.

Keras - 29-5-2019 at 10:54

The first experiment is nice!
For the second, did not the sulphuric acid break the amide bond and form acetic acid and 4-aminophenol? After that, would you not reform an amide bond with the sulphuric acid, leading to a sulphonamide (i.e. 4-sulfonamidophenol)?

[Edited on 29-5-2019 by Keras]

Boffis - 29-5-2019 at 12:21

I distilled my chlorophenol today, I mixed together several batches of chlorophenol from a total 36.5g of phenol and got 26g of 4-chlorphenol Bp 200-220 and 12g of "middling" boiling between 120 and 200 though mostly between 170 and 190 C which suggests that it is mainly 2-chlorophenol. About 3ml, say 4g, was left in the flask. I have saved the flask residue and the middlings and may set up my micro-fractionation column and see if I can recover the 2-chlorophenol and more 4-chlorophenol. My plan is to try sulphonation on one half and mono-nitration on the other.

The pale pinkish grey crystals from the sulphonation of paracetamol have now dried and weighed 8.73g, they seem quite stable and have not darkened on drying which is promising. I will carry out some characterisation and also see if I can improve the purity. Some prelimenary nitration tests may be in order too.

Hi Keras. No I don't think sulphuric acid monohydrate would be capable of reforming the amide fast enough to stop the acetic acid boiling off at the reaction temperature used.

[Edited on 29-5-2019 by Boffis]

Boffis - 3-6-2019 at 03:09

I attempted to sulphonate my own 4-chlorophenol and found that it sulphonates easily at room temperature simply on mixing the molten chlorophenol with an equal volume of conc. sulphuric acid and allowing it to stand for 3 days the whole lot solidifies into a mass of radiating fibres that are readily soluble in a small amount of water.

I tried to nitrate the sulphonation mixture directly without isolating the sulphonic acid. I added a little extra 85% sulphuric acid and the just sufficient 40% nitric acid to mononitrate the sulphonic acid dropwise maintaining the internal temperature at between 25 and 31 C. The reaction was rapid and the mixture became a homogenous orange liquid within seconds. The addition took about 10minutes. I let the mixture stand for 30 minutes and then drowned it in 50ml of cold water. An orange brown milky suspension formed which is now settling. I was expecting a clear solution but it is possible that sulphonation was not complete as a amount of suspended material seem small. This was confirmed by filtering the suspension to give a small cake of minute brownish crystals. The residue was neutralised with 50% NaOH when it deposited masses of orange red clumpy crystals.

I did not weigh the starting chlorophenol I used the slighly less than 3ml of dark chlorophenol left in the distillation flask so all of the quantities were a little uncertain but it served as an orientation experiment. I will repeat this with purer and precisely quantified reagents shortly.

Keras - 4-6-2019 at 05:50

Do you know what your final result should look like?

Boffis - 4-6-2019 at 12:23

Yes the final amino-sulphonic acid is a white, sparingly soluble solid. The sparingly soluble nature seems to be a characteristic of amino sulphonic acids (for example sulphanilic acid).

The yield of orange-red sodium 2-nitro-4-chlorophenol sulphonic acid was almost quantitative assuming 3ml (about 4g) of p-chlorophenol though some colourless crystals, presumably sodium sulphate, were present in the product. I am currently recrystallizing it. A small test sample shows it can be reduced with tin and HCl to the sparingly soluble amino compound.

I have also prepared a larger batch of chlorophenol using 47.2g of phenol. A prelimenary fractionation has given me 33ml or about 43g of p-chlorophenol though I also have about 14ml of "midddlings" to re-fractionate (partly 2-chlorophenol). The high boiling fraction doesn't solidifiy at 15 C so I suspect that it still contains some 2-chloro isomer and I will have to fractionate it again in a more efficient column.

Keras - 5-6-2019 at 00:28

Hasn't p-chlorophenol a m.p. of ca. 40 °C?
2-chlorophenol seems to melt at 8.8 °C if the data I have is correct, so it shouldn't be too difficult to separate — one is liquid at r.t. whereas the other isn't?

Boffis - 5-6-2019 at 01:57

The o and p isomers form a eutectic mixture which, if I remember correctly, hits a low Mp at about 35% p isomer of -20 C. It may still be possible to using freezing as a method of purification but I haven't tried it yet. The two isomers boil at about 172-174 (o) and 218-220 (p) so its possible to separate them by fractional distillation but when I came to assemble my small (B14 cone size) distillation I could not find one piece, an RA4/11 receiver. I have had to purchase one but it will be a few day before I can complete the distillation. I do have a very small Claisen flask with a built-in short vigreux column so I might try using this on say just 20ml (I have 54ml of >200 C boil fraction).

Keras - 5-6-2019 at 03:21

I wonder if you could separate 2- from 4-chlorophenol by reacting the mixture with a bulky alkoxide (t-BuOK?). Because of steric hinderance, I'd expect the 2-chlorophenol to be less reactive than 4-chlorophenol.

You could then recover chlorophenol and t-BuOH by mixing the product with HCl?

Maybe a reagent that could react with both the -OH and the Cl in meta position, too, would leave the 4-chlorophenol alone?

Boffis - 8-6-2019 at 13:33

Hi Keras; no I think fractional distillation looks like the best option open to me. I will have another go tomorrow with a vigreux column and slow distillation.

I recrystallised my small scale sample of sodium 2-nitro-4-chlorophenol-6-sulphonate and recovered 3.2g of stunning orange-red fibrous sodium salt plus a further 1.4g of less pure material containing a little colourless prismatic material which appears to be sodium sulphate. I did an experiemental reduction on the final filtrate with sodium dithionite. This appeared to work and the deep orange colour quickly disappeared. I adjusted the pH to about 5-6 and evaporated down the solution to a small volume and cooled it over night. Large crystals of colourless sodium sulphate formed leaving a pale straw coloured solution which on further evaporation deposited abundant pale brownish crystals which I hope will be the 2-amino-4-chlorophenol-6-sulphonic acid. They are rather more soluble than I was expecting.

Boffis - 20-6-2019 at 02:21

Success. I succeeded in fractional distillation of the mixed chlorophenol isomers and now have about 40g of solid 4-chlorophenol, about 20ml (c 25g) of short boiling range 2-chlorophenol and about 20ml of "middlings" which I am currently re-distilling in a smaller distillation set up to see if I can recover further isomers. The 4-chlorophenol sulphonates easily.

Also I have done further tests on the reaction product between sulphuric acid monohydrate and paracetamol and it is an amino sulphonic acid but I can't see a simple way to determine the position of the sulphonic acid group. My gut feeling is that the sulphonic acid group will have entered the molecule ortho to the phenolic group since the para- position is blocked by the amino group (I am pretty sure that hydrolysis of the N-acetyl group will occur before sulphonation). The sulphonic acid displaces CO2 from carbonates and bicarbonates and is re-precipitated by HCl providing it is not added in excess. Next experiment is to see if I can use Sandmayers reaction to replace the amino group with a chloro group.

[Edited on 20-6-2019 by Boffis]

Keras - 20-6-2019 at 03:14

Quote: Originally posted by Boffis  
Success. I succeeded in fractional distillation of the mixed chlorophenol isomers and now have about 40g of solid 4-chlorophenol, about 20ml (c 25g) of short boiling range 2-chlorophenol and about 20ml of "middlings" which I am currently re-distilling in a smaller distillation set up to see if I can recover further isomers. The 4-chlorophenol sulphonates easily.


Excellent. Congratulations! :)

Boffis - 21-8-2019 at 02:30

The following is a summary of my current progress into the preparation of the azo-dye intermediate 2-amino-4-chlorophenol-6-sulphonic acid.

Experiments with the chlorination if phenol

I have now had an opportunity to carry out further experiments into the chlorination of phenol and the separation of the isomers. I have carried out four chlorination experiments using sulphuryl chloride on phenol at an increasing scale. These used 9.6, 26.9, 47.23 and 95.0g of phenol and should have yielded a total of 244.1g of mixed chlorophenol isomers, the actual yield overall was about 209g or about 85% of theory base on phenol. The actual conversion is probably significantly higher but I discovered that chlorophenols are appreciably soluble in water; therefore washing is a likely major loss and needs to be kept to a minimum. From these experiments I have found the recoverable yields to be roughly one-third 2-chlorophenol and two-thirds 4-chlorophenol. However, I ended up with a fair amount of “middlings” that contain both isomers but not worth distilling separately because the volume was small and there is always some loss resulting from the amount of chlorophenols required to flood the column so I mixed them together. This made me look into other means of separation or means of utilizing the raw mixed isomers.

Experiments into the separation and sulphonation of chlorophenols

I found that 2 and 4-chlorophenols actually have some interesting differences in chemistry and reactivity. 4-chlorophenol reacts with 85% sulphuric acid mildly exothermically and on standing for 24 hours the mass sets solid were as 2-chlorophenol is much more resistant to even 96-98% sulphuric acid and only reacts on warming for a prolonged period, even then the resulting sulphonic acid does not crystallise. By contrast, 2-chlorophenol can be nitrosated in acetic acid with sodium nitrite in sulphuric acid were as 4-chlorophenol does not react. The problem with both methods is separating out the unreacted isomer using a simple procedure, the partial sulphonation mixture can be carefully neutralised and steam distilled but even salt saturation of the distillate and extract become tedious and the recovery poor; without neutralisation steam distillation of the acid mixture seems to decompose the sulphonic acid. I am sure that either method could be developed into a workable procedure but I have discovered that the salts of the sulphonic acids are easily separated and according to one of the patents that I have examined the required 2-nitro-4-chlorophenol-6-sulphonic acid can be prepared by the direct nitration of the sodium 4-chlorophenol-2-sulphonate.

I have found that sodium 4-chlorophenol-2-sulphonate is much less soluble than its 2-chlorophenol isomer and simply crystallised from the neutralised sulphonation mixture. The sodium 2-chlorophenol-4-sulphonate remains in solution with the sodium sulphate from which it is difficult to separate by crystallisation. If it is required to recover the 2-chloro compound this is easily done by precipitating the sulphate ions with 1M barium chloride until the liquid gives a faint red spot-test on filter paper with sodium rhodizonate indicator and then vacuum filtering, evaporating the solution down to a small volume and allowing to crystallise. The crystals are filter off and the filtrate may be evaporated down further until salt begins to crystallise out during evaporation when further, less pure, sodium 2-chlorophenol-4-sulphonate crystallises out.

Alternatively, the original sulphonation mixture may be diluted and neutralised with barium carbonate powder to pH 7-8, heated to about 90° C, vacuum filtered hot with the addition of a filter aid and evaporated down until a crystalline film forms on the surface. Cooled and allowed to crystallise, the crystals that form are the barium salt of 4-chlorophenol-2-sulphonic acid which is much less soluble than the 2-chlorophenol derivative but it has a rather flat solubility curve and so that only part of the 4-chloro derivative crystallises each time. The barium 4-chlorophenol-2-sulphonate is filtered off and the filtrate evaporated down again, this process is repeated until the mixture solidifies on cooling. At this point a little cold water is added and the mixture stirred until most of the solid has dissolved but leaves behind the last of the 4-chlorophenol derivative, this is filtered off and the filtrate evaporated to a thick paste and then slowly dried at 35-40° C until it can be readily reduced to a fine off-white powder with a pestle. Both salts are difficult to recrystallize because they have solubilities that change little with temperature and it is better to treat them with hot, dilute sodium carbonate solution to turn them into the respective sodium salts. I am still working on quantitative details of these processes, for example the equivalence of sodium carbonate require knowledge of hydration states which I am working on. Provisional data suggests that the barium 2-chlorophenol is a dihydate, the analogous sodium salt is a trihydrate while the sodium 4-chlorophenol sulphonate appears to be anhydrous (see German patent DE132423). The analogous barium 4-chloro salt has not yet been investigated.

Experiments with nitration

I did several small scale test nitrations of the of sulphonated 4-chlorophenol residues from the fractional distillation, so not on the best of material but with a high 4- isomer content. I have found that the product from treating this chlorophenol with 85% sulphuric acid and cooling can be nitrated directly with a roughly stoichiometric amount of 68% nitric acid added slowly to the chilled crystalline sulphonic acid. The crystals rapidly melt and dissolve to give a homogeneous brown solution that is kept cool (<20° C) for 2 hours and then poured into 50ml of cold water and chilled to 4° C. An insoluble brown residue as filtered off and examined, it can be recrystallized from diluted alcohol or diluted isopropanol with charcoal treatment to yield a mixture of two crystalline phases that are difficult to separate by recrystallization. One is golden brown and the other lemon yellow, they are presumably nitro-chlorophenols.

The filtrate from the nitration was neutralised with 40% sodium hydroxide solution until no further deep orange red crystals formed and then the suspension heated with the addition of further hot water until everything dissolved. The solution was cooled quickly to 5°. I have found that if this is done quickly enough the sodium salt of 2-nitro-4-chlorophenol-6-sulphonic acid crystallised out in copious amounts with minimal sodium sulphate. It is filtered off and dried but it usually contains much sodium sulphates which tend to effloresce on the surface as it dries. The recovery of more nitro compound from the filtrate is difficult due to the amount of sodium sulphate present. However, I have found that the potassium salt is mustard yellow and much less soluble. It appears that the orange red sodium salt is dibasic but if 30% hydrochloric acid is added until the mixture just turns yellow (pH about 4) the mono sodium salt does not precipitate but if saturated sodium or potassium chloride brine is added the sodium or potassium salt precipitate, the latter is easier to wash and handle but less convenient. I have yet to see if I can precipitate the appropriate alkali mono salt from the filtrate by adding brine without neutralisation. The orange red disodium salt may be recrystallized from water without decomposition although it does slowly absorb CO2 from the atmosphere, presumably turning into the monosodium salt and sodium carbonate. The hydration state and sodium content have not yet been confirmed by analysis.

Reduction of the nitro-sulphonic acid to the amino sulphonic

According to a Reaxys search carried for me by Waffles this reduction is covered in an old German patent but unfortunately I was unable to find this patent on Espacenet. However, there would appear to be three reasonably accessible techniques, sodium dithionite, metal+acid and, since the nitro group is ortho to phenol group, alkali sulphides.

I initially tried the dithionite on about 1g of the orange red di-Na salt. The sodium salt was dissolved in the minimum amount of water and powdered sodium dithionite added to the stirred solution, decolourisation was rapid and when the solution was acidified with acetic acid an almost white granular product precipitated that is sparingly soluble in water but soluble in both acids and alkalis.

The process was repeated with 1.4g of the di Na salt in the minimum of water and 1.5g of zinc powder was added. The suspension was then stirred and acidified with 30% hydrochloric acid until the colour had faded and the zinc dissolved. The solution was then filtered and neutralised with sodium acetate, chilled to 4° C and the precipitate filtered off and dried. The product initially appeared identical to the dithionite reduction product but while it has much the same properties (like solubility) it darken much more rapidly on exposure to the air and requires periodic treatment with dithionite to return the white colour. This property sounds more like a 2-aminophenol derivative rather than an aminosulphonic acid.

I haven’t yet tried to further analyse these products yet or see if they can be diazotised and coupled (the acid test after all).

When time permits I intend to carry out further experiments such as carrying out the sulphonation directly on the raw chlorination product to reduce losses during purification and then separate the sulphonic acids as their sodium salts.

I also need to determine the hydration states and nature of the salts accurately so that I can determine yields. This more detailed work for the pre-publication forum will have to wait until I get home from my current stint away.

One word of warning chlorophenols are at least as caustic as phenol!