SaccharinSlayer157
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Issues Synthesizing Saccharin from Anthranilic Acid
So I’ve been attempting to synthesize saccharin from anthranilic acid using the reaction outlined in this video for the past few weeks, but I’ve run into some persistent issues that I can’t seem to resolve. Here’s the slightly scaled-down
reaction scheme I’m working with:
Diazonation
Dissolve 1 g of anthranilic acid in 5 mL of 20% HCl, cool the mixture to 0 °C, and add 0.625 g of sodium nitrite (dissolved in 5 mL water) dropwise
while stirring.
I keep the temperature strictly below 3 °C throughout this step. The reaction produces a pale yellow solution, which seems consistent with diazonium
salt formation.
Sulfonation?
Add a solution of 1 g sodium metabisulfite in 25 mL of 5% HCl dropwise at 0 °C.
This is where things seem to go off track. Nitrogen gas evolution is supposed to occur here, but I’ve never observed any bubbling. The only
noticeable change is a slight yellowing of the solution.
According to the video, the sulfonyl chloride is formed directly in this step via an aryl sulfonate intermediate. However, this source suggests that sulfonic acid is formed first and must be chlorinated separately to convert it into the sulfonyl chloride. I’m not
sure which pathway is correct—or if I’m failing at this step entirely.
Cyclization
Add 1.25 g of ammonium chloride to the solution, then gradually increase the pH using NaOH to strongly basic conditions. This is supposed to induce
cyclization to saccharin.
I’ve also tried directly adding aqueous ammonia to bring the solution to basic pH, but nothing seems to work.
To troubleshoot, I’ve experimented with both chlorine gas and sodium hypochlorite to convert the presumed sulfonic acid into a sulfonyl chloride
after the SO₂ reaction step. However, these runs resulted in the same failure. All my attempts consistently produce red or orange solutions, which
makes me think the diazonation is working, but I’m stuck after that point. I suspect the key problem lies in this step since I don’t observe
nitrogen gas evolution, and I’m not sure if the sulfonyl chloride or sulfonic acid is being formed at all.
I’d appreciate any advice or insights anyone might have with this type of synthesis. Are my conditions off? Is the SO₂ addition step inherently
problematic when done this way? Or am I missing something ridiculously obvious? I don't have a ton of experience with organic syntheses like this, so
that's very possible ![:P](./images/smilies/tongue.gif)
Let me know if more details or photos of my setup would help clarify things. I’ve included photos of:
The anthranilic acid solution right after diazonation and "sulfonation".
My anthranilic acid (from methyl anthranilate, twice recrystallized)
The reaction mixture after chlorination with chlorine gas.
Thanks in advance for any help!
![IMG_0850.jpeg - 599kB](http://www.sciencemadness.org/talk/files.php?pid=698365&aid=104466)
[Edited on 13-1-2025 by SaccharinSlayer157]
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bnull
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The "improved method" is the one shown in the Wikipedia article for saccharin. Here's the figure:
![650px-Maumee_synthesis_of_saccharin.png - 27kB](http://www.sciencemadness.org/talk/files.php?pid=698369&aid=104472)
The method is described in reference 43, "Sweeteners" in Ullmann's Encyclopedia. The entry in Ullmann's has the following:
![malmee_chem.jpg - 36kB](http://www.sciencemadness.org/talk/files.php?pid=698369&aid=104474)
Notice that the reaction with sulfur dioxide is made in the presence of copper, which is absent in the Wikipedia figure. The process is given in
reference 98 of Ullmann's entry. It is the patent US 2667503, "Method of Preparing Ortho Sulfonyl Chloride Benzoic Acid Esters", by Oliver F. Senn.
Column 1, lines 19-25:
Quote: | The present invention is based upon a different series of reactions, which have the advantage of being cleancut, involving no difficultly separable
isomers or side reactions. The resultant saccharin does not have the bitter after taste, which has previously retarded its acceptance as a flavoring
material and a sugar substitute. |
Sounds good, eh? Column 1, lines 26-30:
Quote: | In the practice of the invention, an ester of 2,2'-dicarboxy-diphenyl-disulfide (dithiosalicylic acid), which may be prepared as described in
the application for U. S. Letters Patent by George F. Schlaudecker, Serial No. 239,007, filed concurrently herewith, is oxidized by
suspending it in cold water and passing in chlorine under controlled conditions, while agitating the suspension. |
Uh-oh. Here's the reaction in US 2667503:
![sacch.png - 9kB](http://www.sciencemadness.org/talk/files.php?pid=698369&aid=104476)
Blimey, it's not the same as in Ullmann's or Wikipedia. Schlaudecker gave up on that application and filed another, which became US2705242,
"Esterification of Dithiosalycilic Acid". Cor blimey, it has nothing on the preparation of dithiosalycilic acid. The whole thing is useless.
It is a series of errors: by Gert Lipinski, who edited the entry in Ullmann's and didn't bother to revise the referencesNote; by the
Wikipedia editors, who didn't bother to verify the patent given in Ullmann's and committed an error in the figure; by the guy in the video, who
apparently didn't check either Ullmann's or the patent, otherwise he'd have seen it's the wrong patent or at least that there is a mistake in the
figure.
Your diazotization seems fine, it is the rest that is messed up. My advice is: check the references. If you see a process and they give a reference,
check it. If they don't, try to find where it came from and check it.
Note: I think the correct process is explained by one of the references between 90 to 104 of Ullmann's
entry (https://onlinelibrary.wiley.com/doi/10.1002/14356007.a26_023). No, I didn't bother to check them, except for number 98. It may also be that
Lipinski misplaced the correct reference. Anyone can forget where they put a paper.
Edit: Typo. Oops.
[Edited on 13-1-2025 by bnull]
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chempyre235
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Quote: |
Blimey, it's not the same as in Ullmann's or Wikipedia. Schlaudecker gave up on that application and filed another, which became US2705242,
"Esterification of Dithiosalycilic Acid". Cor blimey, it has nothing on the preparation of dithiosalycilic acid. The whole thing is useless.
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Shouldn't mild oxidation of thiosalicylic acid yield the disulfide? If so, then you could use thiosalicylic acid, which is prepared from anthranilic
acid via diazotization, followed by reaction with sodium sulfide, according to Wikipedia.
Edit: I see now that part of the synthesis referenced calls for reduction with zinc. Maybe it forms the disulfide without oxidation?
[Edited on 1/13/2025 by chempyre235]
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bnull
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The issue here is that the "improved method" is developed nowhere in either Ullmann's or the patents above, and these are associated with the wrong
picture, or rather the wrong patents are associated with the correct picture (from Ullmann's). It's like having the picture of a Lancashire hotpot
illustrating an apple pie recipe in a cookbook; if you make the pie and expect it to look like the hotpot, you'll be disappointed.
I found the correct patent: US4464537, "Preparation of Saccharin". From the Abstract:
Quote: | A process for the preparation of saccharin by reacting an aqueous hydrochloric acid solution of o-methylcarbonylbenzenediazonium chloride with sulfur
dioxide, wherein
- the aqueous diazonium salt solution is reacted with sulfur dioxide at from 0 °C to 100 °C, in the presence of a water-immiscible
or only partially water-miscible inert organic solvent,
- in order to decompose the diazonium salt, the reaction mixture is treated simultaneously or subsequently with a diazonium salt decomposition
catalyst,
- the aqueous organic reaction mixture, or the organic phase obtained after removing the aqueous phase, is treated with an oxidizing agent at from
0 °C to 100 °C, and
- the organic phase is reacted with aqueous ammonia at from 0 °C to 50 °C, and the saccharin is isolated from the aqueous phase in a
conventional manner by acidifying with a strong acid.
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Attachment: US4464537 - Preparation of Saccharin.pdf (525kB) This file has been downloaded 36 times
Edit: One more thing: you can use your methyl anthranilate as it is instead of making anthranilic acid from it. Methyl probably acts as a protecting
group for the -COOH. If the reaction proceeds the same way with anthranilic acid is a good question.
[Edited on 13-1-2025 by bnull]
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SaccharinSlayer157
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Wow, that's incredibly helpful! I actually enjoy digging through patents and references so I'll have no trouble finishing up what you started. I think
I'll try the biphasic/copper catalyst next and report what I find, that patent looks hopeful.
Thanks again for the insights!
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