Sciencemadness Discussion Board - synthesis of 2,3,5-trimethyl-4-aminophenol

synthesis of 2,3,5-trimethyl-4-aminophenol

photosyn - 7-7-2024 at 15:33

Hi everyone -

I plan to synthesize some 2,3,5-trimethyl-4-aminophenol, which is cited as a photographic developer. This would be my first organic synthesis since leaving university 35+ years ago, so I'm asking for some advice.

The basic plan is to follow the procedure described in this patent
https://patentimages.storage.googleapis.com/0f/14/e8/feae4ea... copied here for convenience:

Screenshot 2024-07-07 at 19.27.37.png - 611kB

I'm fairly sure the reference to sodium nitrate is a typo and should be sodium nitrite - is that correct?

Is it reasonable to conclude that I need basically just a flask, a heated stir plate, and a buchner funnel and a vacuum source for filtration?

Can anyone forsee any gotchas or difficulties with this? Thanks for any advice.

[Edited on 7-7-2024 by photosyn]

bnull - 8-7-2024 at 07:09

Welcome to the forum.

Quote: Originally posted by photosyn

I'm fairly sure the reference to sodium nitrate is a typo and should be sodium nitrite - is that correct?

Yes, it is a typo. Nitrate, ha ha.

Quote: Originally posted by photosyn

Is it reasonable to conclude that I need basically just a flask, a heated stir plate, and a buchner funnel and a vacuum source for filtration?

Two flasks but you're essentially right.

photosyn - 8-7-2024 at 08:18

Thank you - very helpful to have some assistance.

When it says "the diazo slurry was then added" does that suggest the quantities given generate a precipitate of the diazonium chloride salt? I have a concern, generated by this page ("Supersaturated Diazonium salt causes Fatality")
https://web.archive.org/web/20181006095115/http://www.crhf.o...

I found this more detailed description of essentially the same synthesis, on this page:
https://www.benchchem.com/product/b046268 - very close to equal molar quantities of sulfanilic acid, sodium nitrite and 2,3,5-TMP in both cases.

In which textbook might I find another verified recipe for creating a safe solution of the sulfanilic diazide?

[Edited on 8-7-2024 by photosyn]

[Edited on 8-7-2024 by photosyn]

EF2000 - 8-7-2024 at 09:52

Quote: Originally posted by photosyn

Thank you - very helpful to have some assistance.

When it says "the diazo slurry was then added" does that suggest the quantities given generate a precipitate of the diazonium chloride salt? I have a concern, generated by this page ("Supersaturated Diazonium salt causes Fatality")
https://web.archive.org/web/20181006095115/http://www.crhf.o...

In which textbook might I find another verified recipe for creating a safe solution of the sulfanilic diazide?
[Edited on 8-7-2024 by photosyn]

[Edited on 8-7-2024 by photosyn]

Not sulfanilic diazide, but rather p-benzenediazonium sulfonate.

I found two recipes: one lab manual from Truman University (Missouri) for synthesis of Orange II. First step is sulfanilic acid diazotization: https://chemlab.truman.edu/files/2015/07/Synthesis-of-Orange... (2nd page). It says that "white, powdery precipitate" forms.

And another from OrgSyn procedure: 1,2-AMINONAPHTHOL HYDROCHLORIDE. First step in second procedure. They say that "p-benzenediazonium sulfonate separates on stirring" and forms a suspension. Note below says that solution of the diazoic acid is much less stable than suspension of the salt.

So it appears that suspension of diazonium sulfonate is more safe than diazoic acid solution. If the reaction is included in university lab manuals, it should be safe enough for undergrads, right?

Quote: Originally posted by photosyn

Is it reasonable to conclude that I need basically just a flask, a heated stir plate, and a buchner funnel and a vacuum source for filtration?

You will also need a bucket or other container with ice. Diazonium compounds are stable only at 0-5 °C.

[Edited on 8-7-2024 by EF2000]

bnull - 8-7-2024 at 10:59

From Vogel's Textbook of Practical Organic Chemistry (p. 591):

Quote:

Solid diazonium salts are very sensitive to shock when perfectly dry and detonate violently upon gentle heating: they are, therefore, of little value for preparative work. Happily, most of the useful reactions of diazonium compounds can be carried out with the readily-accessible aqueous solutions, so that the solid (explosive) diazonium salts are rarely required.

From Fieser's Experiments in Organic Chemistry, "Diazotization of Sulfanilic Acid" (p. 208):

Quote:

The product is not collected but is used in the form of the suspension. It is more stable than most diazonium salts, and it will keep for a few hours, but not indefinitely.

@photosyn: You may want to take a look at Gattermann's Laboratory Methods of Organic Chemistry, "Aromatic Diazo-Compounds" (p. 281), Cheronis' Semimicro and Macro Organic Chemistry, "Preparation of Diazonium Salts" (p. 271), and the two books above. We have copies in the Library.

Quote: Originally posted by EF2000

If the reaction is included in univerity lab manuals, it should be safe enough for undergrads, right?

Are you sure?

EF2000 - 8-7-2024 at 12:35

Quote: Originally posted by bnull

Gatterman's, page 300 (link), synthesis of Helianthine (methyl orange) starts with diazotation of sulfanilic acid and apparently a solution is formed, not a suspension.

bnull - 8-7-2024 at 14:11

Strange. And it is even more concentrated than Fieser's. Supersaturated perhaps?

photosyn - 9-7-2024 at 05:15

Thank you everyone, this is enormously helpful. I will report back with any progress.

photosyn - 9-7-2024 at 18:14

In the mean time, I read up on some more background information. The diazonium salt is also called Pauly's Reagent, used for testing for histidine and tyrosine - https://microbenotes.com/paulys-test/

In the webpage I linked to above referring to a fatality caused by sudden decomposition of a diazonium chloride salt, it doesn't say which one.

When the OrgSyn website says the "solution of the diazoic acid is much less stable than suspension of the salt" perhaps it doesn't mean (un)stable in quite the way I was afraid of, and perhaps I'm fussing about nothing.

bnull - 10-7-2024 at 06:49

Quote: Originally posted by photosyn

When the OrgSyn website says the "solution of the diazoic acid is much less stable than suspension of the salt" perhaps it doesn't mean (un)stable in quite the way I was afraid of, and perhaps I'm fussing about nothing.

Better safe than sorry.

Boffis - 11-7-2024 at 14:48

The bigger problem as I see it is obtaining 2,3,5-trimethylphenol. Are you going to purchase it?

photosyn - 12-7-2024 at 11:45

I have some now, alongside some 2,3,6-trimethylphenol for the parallel synthesis.

Methyl groups are (o,p) directing - so I wonder why the reaction product doesn't contain a sizeable proportion of 2,3,5-trimethyl-6-aminophenol: the 6- position is o- to both the hydroxyl group and one methyl, m- to one other methyl group, and p- to the third. The 4 position is p- to the hydroxyl group, o- to two methyl groups, and m- to the third. Hard to see why the -4-aminophenol is preferred over -6-, no?

[Edited on 12-7-2024 by photosyn]

EF2000 - 12-7-2024 at 12:49

4- position is surrounded by two methyls, 6- position have methyl on one side and more bulky (?) hydroxy group. So I guess, bulky p-benzenediazonium sulfonate attacks para-position as less sterically hindered.

J. McMurry's Organic Chemistry, p. 984 says about diazonium coupling reactions that:

Quote:

Reaction usually occurs at the para position, although ortho attack can take place if the para position is blocked.

He doesn't specify why, but the mechanism on the same page suggest that para-position is favored due to resonance effects (not sure). Also, phenol (hydroxy group) is much stronger activator than alkyl group, so its effect outweight effects of methyls. Something like that.

Maybe the answer is somewhere in Organic Reactions volumes in our library.

Also, about sulfanilic acid diazotation, you may find that post (and video) by palico useful: https://www.sciencemadness.org/whisper/viewthread.php?tid=16...
It's yet another Orange II synth. They got diazonium salt suspension in the first step, and survived.

[Edited on 12-7-2024 by EF2000]

bnull - 13-7-2024 at 06:06

I forgot to check March's Advanced Organic Chemistry 7th Edition^*. On pages 788-790 (attached) there is a brief discussion of diazotization with several references, one of which is a book edited by S. Patai, Diazonium and Diazo Groups part 1.

Since both books are published by Wiley, they're unavailable at Internet Archive. But I'm pretty sure you will find them somewhere else.

Attachment: March's, 13-19 Diazotization.pdf (142kB)
This file has been downloaded 121 times

*: I also forgot to include the edition. Thanks for the reminder, @EF2000.

[Edited on 13-7-2024 by bnull]

EF2000 - 13-7-2024 at 08:38

Quote: Originally posted by bnull

Since both books are published by Wiley, they're unavailable at Internet Archive. But I'm pretty sure you will find them somewhere else.

As always, there's Eastern European way to get sources. Anna's Archive has:
The chemistry of diazonium and diazo group part 1 (cover is wrong, but the file is correct)
Search for "March's Advanced Organic Chemistry", a lot of results (I'm not sure what edition you used)
Download links may require some patience, sometimes may be blocked (at least here, thanks to RKN agency), if one has Telegram, Nexus Search bot can be faster.
Edit: 7th edition

[Edited on 14-7-2024 by EF2000]

photosyn - 15-7-2024 at 18:20

I am still waiting for a Būchner funnel and a heated stirplate to arrive, but I assembled all the reagents today. So I thought I would try a small scale synthesis in the mean time - using 10% of the quantities listed in the graphic I posted above.

This is the diazo- slurry referred to:

This is the solution of trimethylphenol:

This is immediately after the combination of the two. The diazotization is very fast:

And this is what it looks like after the hydrosulphite is added and after about 15 minutes of stirring at around 60°C, as the reduction to the amine takes place:

About 30 minutes after that the colour is a pale tan. I gravity filtered the contents of the flask into two funnels and washed a few times with ice water. Now I've turned the filter papers out to dry. There's a good quantity of pale tan crystals, that look very much like the probably not very pure p-aminophenol sitting in a jar on my shelf. I'll post some pictures of the dry crystals when I have them, along with their weight. Then I can see how they work as a developer.

I have a product - and I didn't lose any fingers. I have to say - I'm quite pleased! Thanks to everyone for their advice.

photosyn - 16-7-2024 at 06:01

To follow up -

Final yield was 0.65g, from 1.1g of TMP, representing a yield of 53%. However on drying, the tan powder turned a much darker brown leaving purple staining on the filter paper.

This is entirely consistent with the behaviour of the traditional developer p-aminophenol which if not kept dry 'spoils' by darkening. The prepared p-aminophenol developer Rodinal takes on a very dark purple hue, and the comments here may be relevant: https://www.sciencemadness.org/talk/viewthread.php?tid=14372

I think drying under vacuum would minimize oxidation so I'll look into trying that.

bnull - 17-7-2024 at 05:02

Quote: Originally posted by photosyn

I think drying under vacuum would minimize oxidation so I'll look into trying that.

Try converting it to hydrochloride and then vacuum drying.

photosyn - 9-8-2024 at 18:04

This stuff is a real challenge: it browns in solution and goes purple in air as it dries. But after a lot of hard work, I (think I) finally isolated a clean dry sample of the reaction product.

If it's still the same pale pink colour tomorrow I shall be very very happy.

To get it I vacuum filtered under an argon stream, and transferred the solids as quickly as I could into to an improvised vacuum oven (two-stage rotary HVAC vacuum pump piped to a 1 gallon stainless steel resin degassing chamber, with a hot air gun pointed at the bottom to add heat) and dried for three hours. Then I pumped in argon to release the vacuum and transferred the now dry powder into the glass jar. Then using the chamber I vacuumed the air out of the jar and replaced it with with argon - then quickly applied the lid to the jar.

Unfortunately I forgot to weigh the empty jar so I can't report a yield but it looks pretty good.

I have two other batches on which I followed up with a boiling water recrystalization with activated charcoal, and I have some flaky white crystals forming. I will try to use the same drying technique to isolate them.

Then I can check if the purer product shows any advantages over the pink powder when it comes to developing images.

[Edited on 10-8-2024 by photosyn]

[Edited on 10-8-2024 by photosyn]

photosyn - 15-8-2024 at 04:41

I repeated the synthesis (with 19.8g of 2,3,5-trimethylphenol precursor).

The pink precipitate browned rapidly in the filter funnel, and I transferred it to 500ml of boiling water. It dissolved to a very dark red/brown solution; on adding approximately 2 grams sodium hydrosulphite it separated into a green/yellow solution and a heavy black tar layer. Adding half a small spatula of activated charcoal which coalesced with the tar layer turned the solution a lighter green.

I sepaparated most of the tar in a separating funnel. The tar solidified on cooling to a crusty black solid that plugged the funnel and coated its walls.

The green separated solution yellows quite rapidly; It was necessary to add portions of hydrosulphite at intervals to prevent this. I added another portion of activated charcoal and filtered the hot mixture to get 450ml of clean yellow/green solution to which another portion of hydrosulphite was added, and then the flask in which it sat was covered and cooled to 5°C in a refrigerator.

The result is a cold flask of clear yellow/green solution with a significant quantity of white crystal precipitate at the bottom.

I will try to vacuum filter and dry tonight while avoiding allowing it to oxidize.

photosyn - 18-8-2024 at 07:36

I vacuum filtered the white (actually pale yellow) crystals and transferred them rapidly to my drying oven - and after drying recovered 10.1g of solid.

Unfortunately although I dried it carefully and stored them under argon, by the next day the crystal structure had gone and I had a pale brown powder, which was disappointing.

I have noticed while drying that I get a quantity of needle white crystals forming on the glass top of the chamber, so this substance is probably amenable to purification by sublimation under vacuum, which I will look at next.

[Edited on 18-8-2024 by photosyn]

photosyn - 20-8-2024 at 03:13

I had kept the results of previous syntheses where the product had browned significantly on drying (in air). So I used them to experiment with different ways to try purification by sublimation, coming up with this procedure

I cut a hole about 4" diameter in a six inch piece of cork gasket. I put the gasket on an aluminum sheet and spread 1.0g of dirty trimethyl-p-aminophenol in a thin layer in the hold in the gasket:

I covered with a coffee filter and placed an inverted glass filter funnel over the top:

Vacuum was applied to the funnel outlet to seal the assembly and it was placed on a heater pad set to 150°C.

Within a minute a dark brown stain appeared on the filter paper:

which diminished shortly after. An hour later the brown stain had disappeared and there was a quantity of pink crystaline material on the funnel.

I disassembled the setup and was able mechanically to scrape a significant quantity of white crystal from the bottom side of the filter paper. The solid residue on the aluminum plate was dark brown:

Total recovered solid white crystal was 0.34g. The combined pink material from the funnel and the dark residue was a further 0.29g

[Edited on 20-8-2024 by photosyn]

photosyn - 26-9-2024 at 04:29

After a lot of work, I have come up with a protocol to recover the dry 2,3,5-p-aminophenol from the reaction.

I vacuum filter the precipitate under an argon stream using a glass frit funnel (with filter paper as well) and a silicone gasket and polycarbonate sheet perforated with a hose barb. I suppose it's a kind of primitive schlenk setup.

I wash the solid in the funnel with a weak solution of sodium dithionite.

After 10 minutes of filtration I quickly switch the funnel to sit on a clean vacuum flask and switch the hoses so the top of the funnel is under vacuum and apply the argon to the base flask. I apply a heat gun to the base of the funnel, so the funnel acts as a drying chamber without having to disturb the product.

After an hour the solid is dry enough to transfer to a glass bottle for further drying at low pressure, with heat provided from a heated stir plate and a stir bar working to break up the solid. After 2-4 hours the product has dried to a fine powder, and is stored under argon.

I have several samples from 9 to 18 grams (reaction yield about 80%) which vary in colour from pale yellow to pale pink and very pale purple.

I am going to look into thin layer chromatography to see what's in each.

photosyn - 18-11-2024 at 19:05

I created a video of this synthesis, if anyone is interested:

https://www.youtube.com/watch?v=F34FXHh-R-Q

[Edited on 19-11-2024 by photosyn]