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Keras
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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]
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Boffis
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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]
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Boffis
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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.
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Keras
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Do you know what your final result should look like?
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Boffis
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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.
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Keras
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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?
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Boffis
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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).
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Keras
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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?
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Boffis
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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.
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Boffis
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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]
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Keras
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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! 
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Boffis
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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!
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