Sciencemadness Discussion Board - Large scale anthranilic acid prep

Large scale anthranilic acid prep

mr_bovinejony - 20-2-2021 at 20:09

All credit goes to a user formerly known as loft on another forum.

45 grams of methyl anthranilate is added to 200 ml of a 2M solution of NaOH. This is refluxed for 4 hours with stirring. After the 4 hours this is cooled down and the top water layer is decanted from the small bit of oil at the bottom. 20% hardware store hcl is added until the stir bar doesn't work, and this is filtered. Presumably the anthranilic acid but still waiting for it to dry so I can get a melting point.

Probably the most easiest synthesis for this stuff that I've found. The product filtered off is pure white. I have reason to believe this is the product because the mother liquor which was filtered off was acidifed again to crash out more, but more acid than necessary was added and it all dissolved again. Zwitterionic I think is the word used for anthranilic acid, which dissolves when ph is too high or too low. But I made no effort to recover it.

I think I probably have around 30 to 35 grams of the powder but I'll update after it's dried. Reflux should be held longer until no oil remains after cooling for a higher yield. Loft gets a 99% yield in his prep which I think is definitely achievable. Don't know why people struggle with this one, it seems very simple

Bubbles - 22-2-2021 at 12:46

Methyl anthranilate 50ml or 58g was added to 150ml 3M NaOH solution and heated to 80C in a 600ml beaker. Quickly, all dissolved (about 30 min), indicating conversion to anthranilic acid. After 45 min there was added 40ml GAA in 160ml water. Beaker, now full of precipitate, was cooled with a cold water bath and then placed in freezer for a bit until ~8C. The off-white precipitate was filtered and washed with water. Yield=49g or 94%

[Edited on 22-2-2021 by Bubbles]

karlos³ - 22-2-2021 at 12:59

Oh bubbles you're here too!

Of course you are

I miss the very nice grape flavour of that stuff, guess next time I'm going to get me some too, making IBX and DMP.

Quote: Originally posted by mr_bovinejony

All credit goes to a user formerly known as loft on another forum.

He's called attic on here

[Edited on 22-2-2021 by karlos³]

Benignium - 22-2-2021 at 21:16

Quote: Originally posted by karlos³

I miss the very nice grape flavour of that stuff, guess next time I'm going to get me some too, making IBX and DMP.

Have you made IBX and/or DMP before? I wasn't aware of these compounds, they seem very useful and I'd appreciate any writeups you may have.

Texium - 22-2-2021 at 21:47

It’s something that I was really wanting to do, back before I became a grad student and thus forfeited all my time to do my own chemistry. I got as far as making some 2-iodobenzoic acid.

mr_bovinejony - 23-2-2021 at 06:30

I got as far as ibx but the dmp failed for some reason

https://www.thevespiary.org/talk/index.php?topic=18228.0

SuperOxide - 26-3-2021 at 08:43

Very interesting... I have 500g of phthalimide that I will probably never use, which I could make the anthranilic acid from. But I was wondering if this was a viable reaction route (which I was sure it was).

Good job guys, glad I found this.

mr_bovinejony - 26-3-2021 at 08:59

I recently did a run of 150 grams of the grape stuff, ill have more product than I'll ever need now. Recrystalization is fun too, although the size of the run made it difficult. I have one half of pure white and the other half is the tan color

SuperOxide - 26-3-2021 at 10:04

Quote: Originally posted by mr_bovinejony

I recently did a run of 150 grams of the grape stuff, ill have more product than I'll ever need now. Recrystalization is fun too, although the size of the run made it difficult. I have one half of pure white and the other half is the tan color

Pictures, or it didn't happen

Fery - 26-3-2021 at 10:50

Btw the methyl anthranilate is available at https://shop.es-drei.de/ester/11927/anthranilsaeuremethylest...
I've bought it from there
1 L for 73 EUR
100 ml 14 EUR
check also the price of delivery and countries where they send by currier (DHL, DPD).

mr_bovinejony - 17-4-2021 at 10:58

https://imgur.com/ujQ4mhy

https://imgur.com/tnqXB1u

https://imgur.com/p92ZDLC

Here are some pictures from a 200 ml prep. The one I am holding came from the glass pie dish, it shows nicely the crystalline structure and difference of color when left in open air. These were both from the same batch, and recrystallized from boiling dilute hcl. Evaporated over 3 weeks

karlos³ - 17-4-2021 at 11:14

Quote: Originally posted by Fery

Btw the methyl anthranilate is available at https://shop.es-drei.de/ester/11927/anthranilsaeuremethylest...
I've bought it from there
1 L for 73 EUR
100 ml 14 EUR
check also the price of delivery and countries where they send by currier (DHL, DPD).

Yeah I order that from the thais, perfumersworld.
Its not exceptionally cheaper, not at all, but it slips right through the EU customs, so its much better to order from there than from the inside.

By the way(hint, hint!), check their products, they have LOTS of other cool things for the home chemist

I just made an order of almost 200$, and it landed here(DE) in just four days!
Only once in seven orders I had to pick it up from customs(despite having phenylacetic esters, helional and whatnot included), but only had to pay importation tax.

SuperOxide - 17-4-2021 at 13:44

Quote: Originally posted by mr_bovinejony

https://imgur.com/ujQ4mhy

https://imgur.com/tnqXB1u

https://imgur.com/p92ZDLC

Here are some pictures from a 200 ml prep. The one I am holding came from the glass pie dish, it shows nicely the crystalline structure and difference of color when left in open air. These were both from the same batch, and recrystallized from boiling dilute hcl. Evaporated over 3 weeks

Heyy, very nice. I was expecting some nice white crystals though from your original post ;-)

RustyShackleford - 17-4-2021 at 14:29

Wow. Your anthranilic acid looks awful considering you started from the ester. Recrystallize it from water bare minimum, or better soxhlet it with heptane to get pure white crystals.

mr_bovinejony - 17-4-2021 at 14:44

Eh that's what happens when its left out in the open for 3 weeks!

SuperOxide - 17-4-2021 at 16:19

Quote: Originally posted by RustyShackleford

Wow. Your anthranilic acid looks awful considering you started from the ester. Recrystallize it from water bare minimum, or better soxhlet it with heptane to get pure white crystals.

Are you spying on me?! jk. That's what I'm doing - literally right now

I have 20g of anthranilic acid (which was already through a water recryst), with some distilled/dried heptanes. Been in the soxhlet for a few hours now. I may just let it run overnight (though I'm slightly uncomfortable knowing there's boiling heptane in the kitchen), and see how well it works. I did a small scale earlier and it went for like 5 hours and it was less than a ~28% yield (only got 2.8g out of 10g), so it needs to run for a lonnnng fricken time.

I'm sure you got this from the anthranilic acid purification thread by B.D.E, which is where I will post the results (yield and photos) after I'm done. Likely tomorrow.

[Edited on 18-4-2021 by SuperOxide]

SuperOxide - 17-4-2021 at 20:42

Quote: Originally posted by mr_bovinejony

Eh that's what happens when its left out in the open for 3 weeks!

This got me thinking - Have you ever had a white (or even slightly off white) purified product? Or does it always end up taking on that brownish color? I ask because when I synth anthranilic acid from phthalimide (ACS grade, even), the crude product looks almost white, as seen here:

But when I recrystallize the crude product in boiling water, the product comes out looking light brownish in color:

I've tried tweaking various things such as the temperature during the reaction or how quickly/slowly I add the reagents, how concentrated they are, or what solvent I use in the recryst, it always comes out the same:

anthranilic-acid-recryst-multi.jpeg - 195kB

(The middle one is a different color because I took it out of the ice bath a little too early when adding the phthalimide. All other runs were the same color as on the two sides).

So when you say:

Quote:

The product filtered off is pure white.

are you talking about the crude product?... because if that's the case, then I'm a little less impressed, lol. (don't take that as an insult, this is still a much better synthesis route than using phthalimide).

[Edited on 18-4-2021 by SuperOxide]

mr_bovinejony - 18-4-2021 at 04:35

From what I've seen, the hoffman route usually gives a brown product. When I was filtering this product from the boiling dilute hcl, it turned to pure white crystals when it hit the cold crystallizing dish which is where that statement came from. It was very nice to look at, I should have covered it before it was left alone

SuperOxide - 18-4-2021 at 07:07

Quote: Originally posted by mr_bovinejony

From what I've seen, the hoffman route usually gives a brown product. When I was filtering this product from the boiling dilute hcl, it turned to pure white crystals when it hit the cold crystallizing dish which is where that statement came from. It was very nice to look at, I should have covered it before it was left alone

For sure. I would love to see if it can yield a more pure product than the Hoffman route.

mr_bovinejony - 18-4-2021 at 07:23

I definitely think so, even with the brown discoloration it had a very sharp melting point.

SuperOxide - 18-4-2021 at 08:16

Quote: Originally posted by mr_bovinejony

I definitely think so, even with the brown discoloration it had a very sharp melting point.

As did the recryst product from the Hoffman route.

Regardless, this route is still wayyyy better, and much higher yielding. You just teased me with the "yields a white product" part - especially considering I just spent over 12 hours running a soxhlet extractor with heptane to purify some anthranilic acid, and while it's almost white (just barely off white), it's so low yielding that I'll never try it again, lol.

mr_bovinejony - 18-4-2021 at 08:31

The hoffman reaction is bullshit for any chemical lol. I weighed all this yesterday and it was 210 grams. Way more than I'll ever need.

Just remembered I added my old batch to the new stuff. So 180 grams from 200 mls of the grape stuff

[Edited on 18-4-2021 by mr_bovinejony]

SuperOxide - 18-4-2021 at 15:23

Quote: Originally posted by mr_bovinejony

The hoffman reaction is bullshit for any chemical lol. I weighed all this yesterday and it was 210 grams. Way more than I'll ever need.

Pardon my noobness - but why do you say that? Chemistry is a relatively new hobby to me, and the anthranilic acid synthesis from phthalimide was my first hofmann rearrangement reaction (I think... in the beginning I was just copying procedures online without looking into the chemistry behind it, so perhaps I did it and didn't even realize it). But I'm curious why you say it's bullshit for any reaction and what you mean by that.

Quote: Originally posted by mr_bovinejony

Just remembered I added my old batch to the new stuff. So 180 grams from 200 mls of the grape stuff

I too have more than I will likely ever use (I think 100g of the anthranilic acid), so I doubt I'll ever need to make more, but if I do then I definitely will use this route!

karlos³ - 18-4-2021 at 15:56

Quote: Originally posted by mr_bovinejony

The hoffman reaction is bullshit for any chemical lol

Said the guy who uses the hofmann for his favorite substance

mr_bovinejony - 18-4-2021 at 17:45

@oxide I just don't like the reaction, titration of store bought bleach is a pain and temperature control during the reaction is hard. It may be different now that I upgraded my hotplate, but I'm in no rush to do it again

@carl I've done the hoffman twice and it's provided me with enough compound to last at least two more years

sometimes you gotta go through pain to get to the good stuff

SuperOxide - 19-4-2021 at 13:00

Quote: Originally posted by mr_bovinejony

@oxide I just don't like the reaction, titration of store bought bleach is a pain and temperature control during the reaction is hard. It may be different now that I upgraded my hotplate, but I'm in no rush to do it again

The bleach titration is a little tedious, but nothin too bad. As for the temperature, just lots of salt and ice does the trick for me.

I've decided I'm going to do it one more time (even though I have a lot of anthranilic acid), I want to test a recryst of the crude product (which is almost white) with solvents other than water (MeOH, ether, chloroform/heptane, etc). I have a feeling that may yield some nicer crystals.

karlos³ - 19-4-2021 at 13:16

Quote: Originally posted by mr_bovinejony

@carl I've done the hoffman twice and it's provided me with enough compound to last at least two more years

sometimes you gotta go through pain to get to the good stuff

Oh look who's talking, its mister large scale bragging again

Hehehe

SuperOxide - 19-4-2021 at 13:27

MJ-popcorn.gif - 308kB

njl - 19-4-2021 at 14:06

Quote: Originally posted by karlos³

Quote: Originally posted by mr_bovinejony

The hoffman reaction is bullshit for any chemical lol

Said the guy who uses the hofmann for his favorite substance

Details?

karlos³ - 19-4-2021 at 14:43

Quote: Originally posted by SuperOxide

No need for this, we are actually quite good friends and I'm just teasing my pal

mr_bovinejony - 19-4-2021 at 15:32

My inability to do reactions under a 3 gram scale has been my downfall. But when it works its the greatest feeling ever

SuperOxide - 19-4-2021 at 16:45

Quote: Originally posted by karlos³

Quote: Originally posted by SuperOxide

No need for this, we are actually quite good friends and I'm just teasing my pal

Oh I know. I got the feeling you two were just messing about.

Quote: Originally posted by mr_bovinejony

My inability to do reactions under a 3 gram scale has been my downfall. But when it works its the greatest feeling ever

I know how you feel! When I do a reaction on a small scale, even when it works it's not too exciting. I try to keep smaller scale reactions to test runs or POC's.

[Edited on 20-4-2021 by SuperOxide]

SuperOxide - 18-9-2022 at 23:07

Quote: Originally posted by mr_bovinejony

Don't know why people struggle with this one, it seems very simple

Well, embarrassingly enough, I can't get this to work

Your procedure that you outlined in the first post was basically as follows:

Add 45g of methyl anthranilate to a flask.
To the same flask, add 200mL of 2M NaOH solution
Reflux for 4 hours with stirring, then let cool.
Upon cooling the reaction mixture should separate into a biphasic mixture.
Separate the bottom layer and add 20% HCl until enough AA precipitates that the stir bar will no longer work.
Filter and purify.

Which seems dead simple... I tried this first with the same scale that you did (45g MA + 200mL of 2M NaOH), and after the refluxing I let it come to room temperature, but it remained one phase. I tried salting out the oil phase with varying amounts of salt with no success.

I assumed it was the (likely) low purity methyl anthranilate I got off ebay, so I decided to get some decently pure methyl anthranilate from HiMedia off of Amazon. I was so sure that it would work this time that I bumped the scale up 2x (90g MA + 400mL 2M NaOH), but after refluxing for 4 hours and letting it cool, I was disappointed to find out that there was no second phase.

More pictures here.

The NaOH solution was freshly made by adding 40.0g of NaOH to some distilled water, once dissolved and cooled to 25 °C, it was added to a 500mL volumetric flask and enough distilled water was added to get it to the 500mL volume line. Then 400mL of that was added to the 1L RBF for the reflux.

What could I be doing wrong here? I'll let it sit over night, maybe something will separate over night (doubtful).
Unless someone here has any suggestions, I may try distilling off some of the volume to see if that helps the denser phase containing the MA to separate.

Tsjerk - 19-9-2022 at 05:51

mr_bovinejony just describes he had an oily contamination (unreacted methyl anthranilate?) which he got rid of by decanting the reaction mixture. If your starting material is pure and the reaction goes to completion, I don't expect any separation.

All that is in there is sodium anthranilate, NaOH, methanol and water. Sodium anthranilate dissolves in water.

Just add a calculated amount of HCl (exactly enough to neutralize the NaOH you used) and filter the precipitated anthranilic acid.

[Edited on 19-9-2022 by Tsjerk]

SuperOxide - 19-9-2022 at 07:08

Quote: Originally posted by Tsjerk

mr_bovinejony just describes he had an oily contamination (unreacted methyl anthranilate?) which he got rid of by decanting the reaction mixture. If your starting material is pure and the reaction goes to completion, I don't expect any separation.

All that is in there is sodium anthranilate, NaOH, methanol and water. Sodium anthranilate dissolves in water.

Just add a calculated amount of HCl (exactly enough to neutralize the NaOH you used) and filter the precipitated anthranilic acid.

[Edited on 19-9-2022 by Tsjerk]

Oh wow, holy crap.. I thought he discarded the top later and did the workup on the oily bottom layer.. this makes so much more sense.

Thanks!

Edit: Here are pics of the crude results (not yet weighted out)

It's in the vacuum desiccator now. Once it's dry, I think I'll experiment with different methods of purification. I really want to try the sublimation as pointed out by Fery.

[Edited on 19-9-2022 by SuperOxide]

Tsjerk - 19-9-2022 at 12:17

That looks nice doesn't it? Let us know how the sublimation works out.

SuperOxide - 19-9-2022 at 12:21

Quote: Originally posted by Tsjerk

That looks nice doesn't it? Let us know how the sublimation works out.

It does! I have a theory that water may be part of what causes the discoloration upon recryst. When I did the purification using heptane in the soxhlet extractor it came out nearly colorless when I did the recryst using MeOH. But then I (stupidly) added some water and that's when it started ti discolor. So I want to get it 100% dry, then I will try the sublimation and also a recryst using MeOH (or EtOH).

DocX - 22-9-2022 at 10:38

This is great stuff! Wonderful to see this route successful. Now all I need is some methyl anthranilate ....

SuperOxide - 23-9-2022 at 05:23

Quote: Originally posted by DocX

This is great stuff! Wonderful to see this route successful. Now all I need is some methyl anthranilate ....

I would recommend getting it from HiMedia off Amazon... It's 102% pure. Can't beat that, lol.

DocX - 23-9-2022 at 12:33

Not the same economic area mate

. Doesn't show up when I search Amazon.

Lionel Spanner - 23-9-2022 at 12:56

This site sells it at $11 per 100 g.
https://www.perfumersworld.com/view.php?pro_id=4NC00295

As far as I know it ships from Thailand, so depending on where you are it may take some time to get to you.

Fery - 23-9-2022 at 22:12

https://shop.es-drei.de/ester/11927/anthranilsaeuremethylest...

Lionel Spanner - 24-9-2022 at 17:27

Quote: Originally posted by Fery

https://shop.es-drei.de/ester/11927/anthranilsaeuremethylest...

They have a fantastic selection of reasonably-priced chemicals; the only drawback is that they don't deliver to anywhere outside the EU.
On a totally unrelated note, has anyone had chemicals shipped to a dedicated drop point in Germany and then had them successfully forwarded on thanks to a dedicated forwarding service e.g. https://www.forward2me.com/ ?

Mateo_swe - 30-9-2022 at 05:19

es-drei.de dont deliver to all EU countries anymore.
I ordered lots of stuff from them a few years ago but now they say the paperwork to ship to Sweden is so much work so they stopped selling to Sweden.
Very sad as they have much stuff of intrest for hobby chemists.

I can understand them somewhat as my orders got stopped by DHL Sweden and they required the seller (es-drei) to deliver very much documentation on all items if they were to deliver the shippment.
DHL also didnt accept electronic documents, they required the papers to be sent by paper form.
DHL is such a hassle to use, never do the shipping with them if you order chemicals.
And es-drei has some deal with DHL to use them for all shipping (at least a few years ago), i hope they change that so i can order from them again.
Otherwise es-drei is a very good supplier that has much stuff not found anywhere else for hobby chemists.
So if you are in some other EU country check them out, very recomended.

Sublimation failure; Recrystallization success

SuperOxide - 14-10-2022 at 18:47

Hey chaps. I had some time today to give this sublimation a shot. Initially I thought that maybe I should try to recrystallize it first, then move on to sublimation. I decided against that because of how nice looking the crude anthranilic acid looked to begin with... But I will soon regret this

Link to imgur album with all photos (not all shown below). To enlarge the below images, just right click -> Open Image In New Tab.

Here's the crude AA after it was thoroughly dried over P2O5 under vacuum. See how nice it looks? Kinda why I figured why it's probably pure enough to move right onto sublimation.

Sublimation setup, in my state-of-the-art laboratory.
Note: I did flame dry the glassware used, which is totally overkill.

And right off the bat it liquified pretty quickly (as expected - it has a mp of 146 to 148 °C).

At this point, it's all entirely liquified. I continued to heat it to past 200 °C (sublimation point), but it started to boil, not sublime.

After I let it cool down, some interesting crystals started to form on the sides, but this was just from the liquids vaporizing then condensing and solidifying on the sides.

I did try a few things like heating it up slower, heating it up faster, but the result seemed to be the same.

So now I get to go back to my first instincts - recryst then sublimation. I know I've mentioned in a few AA threads that I have a suspicion that any anthranilic acid recryst using water seems to always result in dirty looking brown crystals. So I decided to go with my MeOH (which was fractionally distilled from HEET and dried with sodium).
And this yielded the best looking anthranilic acid crystals I've ever made to date:

I'll recryst the rest of the AA in the same fashion.

I still do plan on trying the sublimation with the newly purified AA, but I don't have time to do it today. But I wanted to share the above results thus far.

The takeaways:

Even though this AA prep from methyl anthranilate yields a much cleaner looking crude product, there's clearly still some impurities present that caused the entire thing to liquify very quickly under a flame.
Stay away from using water in any recrystallization for anthranilic acid. A recryst from MeOH will probably yield a pure enough result for any amateur needs.

Fery - 15-10-2022 at 00:16

Very nice experiment and a lot of effort! How strong vacuum produces your pump? Your recrystallized product looks very pure, it is very likely unnecessary to sublime it. In org chem we usually do not need extra superior purity as almost every reaction has some side reactions.

SuperOxide - 15-10-2022 at 15:47

Quote: Originally posted by Fery

Very nice experiment and a lot of effort! How strong vacuum produces your pump?

Thanks! And it's a KNF UN726FTO. I think the valve reflects that it gets down to around -25 inHg.

Quote: Originally posted by Fery

Your recrystallized product looks very pure, it is very likely unnecessary to sublime it. In org chem we usually do not need extra superior purity as almost every reaction has some side reactions.

I couldn't agree more, especially when you consider that they typically would look more like this:
http://www.sciencemadness.org/talk/files.php?pid=658533&...
http://www.sciencemadness.org/talk/files.php?pid=658511&...

If I had an actual synthesis planned for the anthranilic acid, then I would move on. But this thread has me curious about the sublimation method for purification, so I think I'll give it one more shot. Benignium suggested that I don't use a flame next time and use a more conventional heat source, so I'll probably get a smaller fabric heating mantle.

Fery - 15-10-2022 at 21:13

SuperOxide - also the. stronger vacuum the lover temperature at which anthranilic acid sublimes

SuperOxide - 16-10-2022 at 19:14

Just a quick recryst update - Whenever I do a recryst, after I pull the first and second crop out I usually let the mother liquor evaporate slowly, just to see what else comes out. And I found an odd surprise this time. imgur album

Some nice, large single crystals of anthranilic acid started to show up, but a more obvious development was several crops of a much darker substance:

Pretty peculiar.. But I guess that's to be expected when you've already pulled a couple crops out of the main component. The residual impurities tend to fall out.

But I did get some nice larger crystals of anthranilic acid:

Pumukli - 18-10-2022 at 10:48

Wow! This is separation and efficiency! Hats off, SuperOxide!
I want to do this to my "craps" too!