Fery
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2-[(Carboxymethyl)sulfanyl]benzoic acid - thioether synthesis
This thioether synthesis is suitable for home labs as it does NOT produce anything terrible stinky. Thiosalicylic acid - no scent, monochloroacetic
acid - scent like acetic acid, product - no scent.
Thiosalicylic acid contains thiol -SH group which is easier to deprotonate than -OH group of phenol. Bases like NaOH, Na2CO3, KOH, K2CO3 etc are used
for that. Thiophenolate is then coupled with chloroacetate in which S-C bond is created and chloroacetate loses its Cl. Thiosalicylic acid contains
also -COOH group for which extra base is required for creating its salt. A slight 10% excess of monochloroacetic acid was used with a hope to reduce
contamination of the product with unreacted thiosalicylic acid which is very poorly soluble in water as the product. The synthesis was done at 0,10
mol scale calculated from thiosalicylic acid.
thiosalicylic acid M=154,18 g/mol
NaOH M=40,00 g/mol
chloroacetic acid M=94,49 g/mol
K2CO3 . 1,5 H2O M=165,24 g/mol
Chloroacetic acid 10,4 g 0,11 mol (slight excess), K2CO3 . 1,5 H2O 10,0 g 0,06 mol (slight excess)
Dissolve 10,0 g K2CO3 . 1,5 H2O (0,060 mol, but it is never pure either completely dry) in 15 ml of water in 25 ml Erlenmeyer flask and add it
dropwise to solid 10,4 g monochloroacetic acid (0,11 mol) in 250 ml Erlenmeyer flask while swirling the flask in hand and slightly heating (approx 50
C) until it dissolves and CO2 evolution finishes. Use such big conical flask to reduce loses by droplets of liquid carried out by evolution of CO2
bubbles. Leave few last drops of K2CO3 to be added after neutralization completes and when CO2 evolution finishes to ensure the final solution
contains small excess of K2CO3 and that not all the excess is in the form of KHCO3 due to still CO2 evolution / high content of CO2 in the solution.
Check the pH with universal indicator paper, it must be slightly alkaline, if not (to much water in K2CO3) add a little more of K2CO3. Second sign
that the neutralization is not yet finished is bubbling of CO2 when a drop of K2CO3 solution falls into the reaction mixture, but don't confuse this
with natural CO2 evolution from its saturated solution.
Dissolve 8,0 g (0,20 mol) NaOH in 50 ml of water (exothermic) and add it slowly still hot into suspension of 15,4 g thiosalicylic acid (0,10 mol) in
50 ml of H2O in 250 ml flat bottom flask while swirling the flask in hand. That produces sodium salt from the -COOH acid group and also thiolate salt
from the thiol -SH group. The flask could be touched by bare hand as it is only about 30 C warm. Check the pH after the reaction, it must be strongly
alkaline. Anyway after that add 1,0 g K2CO3 . 1,5 H2O to ensure slight excess of alkalies (also NaOH is never 100% and always contains some H2O and
CO2). Excess of hydroxide was not used as it could dechlorinate chloroacetate, so K2CO3 was used. Also Na2CO3 could be used but I had a lot of K2CO3
at hand.
Add slowly the potassium chloroacetate from conical flask into the reaction flat bottom flask with disodium salt of thiosalicylic acid while swirling
the flask in hand, add boiling stones (5 glass balls used), attach reflux condenser and reflux for 4 hours. Then add 1,0 g of activated charcoal and
reflux for 10 minutes.
The color changed to violet similar of KMnO4 in water.
Gravity filter. Solid captured on filter paper had a violet color while filtrate dark red.
Add dropwise 35 % HCl into the filtrate while stirring, after first 5-6 ml of HCl a precipitate of dark pink solid product observed (??? contamination
with S-S dimer of oxidation of thiosalicylic acid similarly as happens in -S-S- bridge in proteins between cysteins ???). Gravity filter out (first
crop), wash on filter paper with 2x 10 ml of water, add washings into the filtrate and continue addition of HCl into the filtrate. After 12 ml HCl
added totally, the solid product in flask had visibly paler color than the first crop. 22 ml of HCl added totally (0,25 mol, slight excess). Could
monosodium salt crystallize first which only later decomposed to dicarboxylic acid??? - because of that risk, boil for few minutes to ensure possible
sodium salt decomposition (but the solid did not fully dissolve on boil in circa 200 ml volume).
Cool to room temperature in 1 hour and then in fridge for 2 hours at +4 C. Vacuum filter on Buchner funnel, wash with little of cold water on filter
paper and suck as dry as possible (second crop).
Boil the filtered out dark pink still wet product (first crop) from the addition of first 5-6 ml of HCl with 250 ml of water, quickly gravity filter
(it passed filter paper very quickly), acidify with 2 ml of 35% HCl (maybe not necessary??? but that ensures no more monosodium salt present if it was
at all) and allow to cool down to room temperature and then in fridge at +4 C. Vacuum filter crystals on Buchner funnel, stop vacuum, wash with little
of cold water on filter (+4 C, bottle from fridge), suck with vacuum as dry as possible. Dry in air for 3 days (4,5 g) and then in desiccator over
silica gel (4,2 g). Melting point 217-220 C.
Dry in air the second crop (paler) for 3 days. Weight 13,0 g. Dissolve it in 900 ml of boiling water. Maybe slightly less water could be used 600-750
ml ???, insoluble pink solid confused me so I tried to dissolve it but it didn't.
Gravity filter - a little of pink solid side-product stayed on filter paper while filtrate had salmon-orange or peach-orange color (I'm not good in
names of colors). Cool slowly to room temperature to crystallize and then in fridge at +4 C. Vacuum filter crystals on Buchner funnel, stop vacuum,
wash with little of cold +4 C water on filter, vacuum suck to as dry as possible. Air dry until the weight no more decreases. Weight 11,7 g. Melting
point 211-213. Put it finally also into desiccator over silica gel. I will tell you later whether the weight decreased and melting point increased.
https://www.fishersci.se/shop/products/2-carboxymethylthio-b...
2-[(Carboxymethyl)sulfanyl]benzoic acid
Molecular Formula C9H8O4S
Molecular Weight 212.22
Melting Point 215°C to 220°C
For those who don't have thiosalicylic acid - you could synthesize it from anthranilic acid by diazotization, reaction with sodium disulfide and
reduction of dithiosalicylic acid with Zn in glacial acetic acid.
http://www.orgsyn.org/demo.aspx?prep=CV2P0580
http://www.orgsyn.org/Content/pdfs/procedures/CV2P0580.pdf
methyl anthranilate is available from es drei:
https://shop.es-drei.de/ester/11927/anthranilsaeuremethylest...
Monochloroacetic acid is available from chemcraft
https://chemcraft.su/product/25266
[Edited on 30-8-2022 by Fery]
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Fery
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Location: Czechoslovakia
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reactants
potassium monochloroacetate preparation from monochloroacetic acid and K2CO3
   
thiosalicylic acid into solution of disodium salt
  
reaction of disodium salt of thiosalicylic acid with potassium monochloroacetate
 
filtering the reaction mixture
  
partial acidification with first 5-6 ml of HCl - first crop of crude product
 
completing the neutralization (22 ml of HCl totally) - much paler product
  
crystallization of first crop from water
   
crystallization of second crop from water
  
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Boffis
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Nice work Fery, love those colours. Are you going to prepare thioindigo from this material? Did you keep the purple stuff and see if you can reduce
it?
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Fery
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Hi Boffis, exactly. The intermediate which I would like to prepare from the thioether by just refluxing in acetic anhydride and then alkaline
hydrolysis is air sensitive (oxidation to thioindigo), but I do not have equipment for inert gas reaction otherwise I could couple the intermediate
with a lot of other compounds, like benzaldehyde and its substituted derivates, see this:
https://doi.org/10.13171/mjc.4.1.2015.16.02.23/elyazidi
http://medjchem.com/index.php/medjchem/article/view/201/188
http://medjchem.com/index.php/medjchem/article/download/201/...
201-659-1-PB.pdf
Attachment: 201-659-1-PB.pdf (301kB)
This file has been downloaded 128 times
https://sci-hub.wf/10.1002/bkcs.12345
Attachment: bkcs.12345.pdf (846kB)
This file has been downloaded 129 times
I did not reduce the colored byproducts (violet and pink) so I do not know what they were, I just trashed them, the amount was too small so maybe even
impossible to get from the fibers of filter paper (I did not even try, maybe they could be dissolved in some solvent or maybe solution of NaOH by
washing the filter papers).
I recommend to use even more of cheap monochloroacetate to avoid unreacted thiosalicylic acid due to hydrolysis of chloroacetate to glycolic acid. I tried to avoid the hydrolysis as much as possible by using stoichiometric amount of NaOH only to
react with thiosalicylic acid and then I used K2CO3 for the reaction with monochloroacetic acid.
Attachment: ajchem.2014.17537.pdf (250kB)
This file has been downloaded 136 times
I used only 1,1x excess but if I repeat the reaction I would certainly use 1,5x or maybe rather 2-fold excess of monochloroacetic acid -
monochloroacetic acid is very soluble in water. Unlike thiosalicylic acid which dissolves well in cold water only as disodium salt with -COONa and
-SNa groups (0,1 mol dissolved fine in 100 ml, maybe even less water could be used) but is very poorly soluble as free acid with free -COOH and thiol
-SH groups (only about 1 g per 1 L at room temperature) so the risk of the product contamination with unreacted thiosalicylic acid.
I already prepared some ethers like: 1,4-dioxane, phenoxyacetic acid, and then methyl, ethyl, allyl ethers of beta naphthol. When my friend Bedlasky visited me, we saw an old flask with thiosalicylic acid and I asked him what it is good
for, but none of us knew. So I later investigated and found this reaction where thioether is formed, luckily it does not have terrible scent but it
can produce beautiful colored substances. The above phenoxyacetatic acid synthesis was similar, the difference was that it started from phenol and now
I started from thiosalicylic acid.
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Fery
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Posts: 990
Registered: 27-8-2019
Location: Czechoslovakia
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I tried to crystallize the first crop (with that good m.p.) from 85 wt% isopropanol (cca 40-50 ml was enough) by boiling, then cooling to room
temperature and finally fridge (+4 C) and I got pinkish product while the mother liquor had the color of the original substance 
This compound behaves like a chameleon...
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