Sciencemadness Discussion Board

anthranilic acid acetylation in various conditions

Templar - 24-4-2015 at 01:19

Hello everyone,

I have been attempting an interesting procedure I found from an old journal entry of the acetylation of the sodium salt of anthranilic acid in basic aq. conditions.

This is being attempted in light of several failures in regards to acetylating small amounts of anthranilic acid isolated from methyl anthranilate, a commercial bird repellent. The anthranilic acid used was the HCl salt, which had a melting point of 168C.

Basically, anthranilic acid is placed into a solution of aq. sodium hydroxide with crushed ice, and acetic anhydride added rapidly with vigorous stirring. HCl is added to hydrolyze the intermediate and precipitate the anthranilic acid. Reportedly this should result in n acetyl anthranilic acid in high yield, but I have barely been getting a 10% yield. The reaction has been performed small scale, at 0.1mol of anthranilic acid.
Upon addition of the anthranilic acid to the sodium hydroxide, a milky tan coloured oil precipitated and did not dissolve. Upon addition of the acetic anhydride, the oily precipitate dissapeared, which re-appeared on addition of 25ml 33% HCl aq (0.1mol anthranilic acid scale).

The reaction is mentioned again in the later paper, with the author adding that conc HCl is required to hydrolyze the intermediate and precipitate the final acetylated anthranilic acid. This indicates the reaction may have been attempted again by other chemists, and worked.

Upon addition of the anthranilic acid to the sodium hydroxide, a milky tan coloured oil precipitated and did not dissolve. Upon addition of the acetic anhydride, the oily precipitate dissapeared, which re-appeared on addition of 25ml 33% HCl aq (0.1mol anthranilic acid scale).

I hadn't been having any luck at all acetylating anthranilic acid I had isolated from the bird repellent, a mix of methyl anthranilate and soya bean oils.

A white crystalline precipitate had been forming upon addition of 20% HCl soln to the bird repellent (40% methyl anthranilate, on the label) which had been purified by redissolving in sodium hydroxide, dissolution into a non polar solvent, and washing again with HCl solution. This yielded a 70% of the estimated achievable amount of anthranilic acid.

Sadly, I could not isolate it as the zwitterion, as addition of acetic acid to a basic solution of the anthranilic acid simply resulted in a strange amber oil that did not crystallize after many hours. However, the supposed anthranilic acid precipitates when mineral acids are added (HCl, sulfuric acid)

Acetylation of the HCl salt of anthranilic acid was attempted at one stage using approximate 2x molar excess of acetic anhydride (15g anthranilic acid HCl salt, 20g acetic anhydride) but no reaction was observed even at reflux.

I'm just absolutely baffled.

Attachment: n acetyl anthranilic acid basic.pdf (147kB)
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[Edited on 24-4-2015 by Templar]

From vogel, pg 1248 ed. 5, it is mentioned that acetylation can be facilitated by addition of acetic anhydride to molecules with hydroxy or amino groups in alkaline conditions.

[Edited on 24-4-2015 by Templar]

From what Im reading in vogel, it doesn't seem possible to acetylate amine salts using acetic anhydride. But wouldn't acetate salts of amines form from the acetic acid byproduct of acetylation with acetic anhydride?

[Edited on 24-4-2015 by Templar]

AvBaeyer - 24-4-2015 at 20:01

Templar,
You are doing this the hard way. Acetylate the ester first, then a mild hydrolysis to the acetylated anthranilic acid. This the way I do it and it works fine.

AvB

Templar - 28-4-2015 at 01:41

Quote: Originally posted by AvBaeyer  
Templar,
You are doing this the hard way. Acetylate the ester first, then a mild hydrolysis to the acetylated anthranilic acid. This the way I do it and it works fine.

"Mild hydrolysis to the N-acetyl anthranilic acid"

Then it doesn't readily re-esterfy in these conditions? Something like a 5% soln of sulfuric acid for the hydrolysis of the ester?

The acetylated ester would be an oil or a crystalline solid insoluble in water... if it is an oil this would make the process quite simple, but if not, how can you be sure it doesn't re-esterfy?

Sadly The methyl anthranilate in the bird repellent is mixed in with soybean oil, which has a smoke point 20C lower than the boiling point of methyl anthranilate.

Attachment: alkylation anthr.pdf (260kB)
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Orsyn - 4-6-2015 at 09:59

Quote: Originally posted by AvBaeyer  
Templar,
You are doing this the hard way. Acetylate the ester first, then a mild hydrolysis to the acetylated anthranilic acid. This the way I do it and it works fine.

AvB


I'm also interested in the optimum hydrolysis conditions proposed here, can anyone else comment?

Initially I thought the hydrolysis might be effected best in hot alkaline H2O sltn., but it seems maybe HCl or even H2SO4 is what's being used? I think it was in wikipedia where I read cleaving a methyl from an aromatic could happen in hot, possibly NaOH.

Does hydrolysis of the methyl group happen upon the acidification of MA with HCl, or is it in fact easier to acetylate the ester first?


[Edited on 4-6-2015 by Orsyn]

Dr.Bob - 4-6-2015 at 11:54

I am guessing that in the original prep you make the acetylated amine and then the mixed anhydride of the acid group. That is why the hydrolysis of the product back to the acid. This is a mess, and likely requires 2 eq. of acetic anhydride to go well.

I agree with AvBaeyer, use the methyl ester, acetylate the amine, then cleave the methyl ester with 1N LiOH or NaOH in water and some cosolvent, like dioxane, THF, or even methanol, overnight at RT. Use only about 3-5 eq of the base, or you will start cleaving the amide. The better way to make those amides is with isatoic anhydride, which is like an anhydride of anthranilic acid. Just dissolve, mix with amine, stir (at RT or higher temp, depending on the amine) and collect the product.

CuReUS - 4-6-2015 at 22:06

try doing the reaction in a microwave.maybe you could acetylate it using plain acetic acid itself
http://www.sciencemadness.org/talk/viewthread.php?tid=61802&...

Templar - 5-6-2015 at 07:47

Duly noted cureus. I was originally put off microwave acetylations with acetic acid because they required a ridiculous amount of some kind of salt... but it was at least 10x molar to the anthranilic acid, and it was an indian research paper.

I remember only a few years ago, how I thought there were correlations and explanations for all but the most cutting edge studies.

Yeah highschool was nice. Uncharted terroritory, again.

Orsyn - 5-6-2015 at 10:33

Quote: Originally posted by Templar  
Duly noted cureus. I was originally put off microwave acetylations with acetic acid because they required a ridiculous amount of some kind of salt... but it was at least 10x molar to the anthranilic acid, and it was an indian research paper.

I remember only a few years ago, how I thought there were correlations and explanations for all but the most cutting edge studies.


I'm learning this about chemistry (and loving it), that just because some method is established, doesn't mean there aren't many other ways to skin the problem.

Fantastic paper in the thread, CuReUs, my mind is blown.. This should keep me busy for a couple days at least! ;)

Luderlasse - 6-6-2015 at 03:28

What about acetylation using acetylsalicylic acid?

I think i read somewhere on this forum that it works on aniline, would be interesting to see if it works on this substrate as well.

Templar - 6-6-2015 at 08:20

Quote: Originally posted by Luderlasse  
What about acetylation using acetylsalicylic acid?

I think i read somewhere on this forum that it works on aniline, would be interesting to see if it works on this substrate as well.


Its a possibility. But I received 100g of PCl5 a while ago and I will probably make acetyl chloride with that.

But the problem isnt the acetylating agent, I think it is that (for whatever reason) the anthranilic acid im meant to be getting isn't anthranilic acid.

I mean, an anthranilic acid from hydrolysis of methyl anthranilate in bird stop using acidic conditions, which doesnt solidify after days when at the isoelectric point of 3.5pH or in neutral conditions.

@ orsyn, when you dont have proper analytical equipment, you'd be surprised at how many "legit" research papers turn out to be bullshit, or largely exaggerated, particularly non peer reviewed ones from asia. You'll find this out in due course, lol

The acetylation in the microwave used a 9 fold molar catalyst of Zn acetate and needs a seal tube capable of withstanding..

150kPa gauge (assuming the microwave gets the reaction mix up to 150C,safety margin), so thats aprox. 1.5 atmospheres of overpressure. Would probably want something for 2 atmospheres gauge.

If my eng knowledge still serves me, that would be approximately a uniform outward force of 2830N, which would be required to keep a lid on the all glass container. Ace glass says that glassware should be able to handle 170kPa gauge, but that would be best case scenario, brand new, properly made. If you're all good risking it.

Actually you could have metal in there but you would need to ground it. It will absorb microwaves.

1971g of zinc acetate dihydrate to do 135g of anthranilic acid. 197g to do 13.5g anthranilic acid. Assuming you arent getting zinc acetate dyhydrate cheaply and local or national, could cause problems if not.

Vessel would need to be at least 200ml, maybe you could squeeze it into 160 or 170. Pressure vessels on ebay for 50$ but only 150ml and no tops.

Guess all this should be in the thread for the microwave acetylation


Orsyn - 6-6-2015 at 08:46

Quote: Originally posted by Templar  
Quote: Originally posted by Luderlasse  




The acetylation in the microwave used a 9 fold molar catalyst of Zn acetate and needs a seal tube capable of withstanding..

150kPa gauge (assuming the microwave gets the reaction mix up to 150C,safety margin), so thats aprox. 1.5 atmospheres of overpressure. Would probably want something for 2 atmospheres gauge.

If my eng knowledge still serves me, that would be approximately a uniform outward force of 2830N, which would be required to keep a lid on the all glass container. Ace glass says that glassware should be able to handle 170kPa gauge, but that would be best case scenario, brand new, properly made. If you're all good risking it.

Actually you could have metal in there but you would need to ground it. It will absorb microwaves.

1971g of zinc acetate dihydrate to do 135g of anthranilic acid. 197g to do 13.5g anthranilic acid. Assuming you arent getting zinc acetate dyhydrate cheaply and local or national, could cause problems if not.





Where are you getting these figures for the catalyst?

I'm seeing references to equimolar amounts of catalyst (to amine), and another reference of .045 mole (catalytic amounts) of Zinc Acetate dh (which is extremely easy to make), but I don't see anything that mentions using 9x catalyst/substrate..

Maybe I'm missing something?

I have a 50ml round bottom GG with a GG stopper, I think it'd be fine in a microwave. I also wonder if this catalyst prep would also acetylate under similar heat conditions in an oil bath, say 120C? Seems maybe possible?

Templar - 10-6-2015 at 06:31

Here I was about to correct you, but it is actually 0.045 mmol cat to 5 mmol substrate, not 0.045mol

I was wrong.

[Edited on 10-6-2015 by Templar]

Orsyn - 10-6-2015 at 09:51

Quote:
Quote: Originally posted by Templar  
Here I was about to correct you, but it is actually 0.045 mmol cat to 5 mmol substrate, not 0.045mol


gotcha.

Orsyn - 28-6-2015 at 09:31

Yesterday I did a small scale test on some MA that afforded me a bunch of dirty purplish crystals this morning, I haven't tested the mp or for luminescence yet as I decided to re-x first; but my question is: yesterday I attempted to hydrolyze the product after acetylation with a solution of ~%5 HCl. I plan to scale this up a bit (assuming these crystals check out - I also plan to write my procedure up if this checks out) and I'm wondering what the best way to hydrolyze (acetyl) methyl anthranilate (ester) would be this next time? I read that acid hydrolysis can be reversible, but wouldn't doing this with NaOH and then acidifying produce the same results? I guess I'm wondering if I should try this hydrolysis with NaOH or just stick to what seems to be working? (ya I know I should experiment, but if someone's knowledge can save me time and chem$, I'd be obliged).

Sorry for the beginner questions, I studied computers in skool, not chem..

cheers

edit - my memory sucks, I re-read the thread and see Dr. Bob's suggestion to use NaOH for hydrolysis, so next time I'll take his advice and try that.

[Edited on 28-6-2015 by Orsyn]

Templar - 28-6-2015 at 20:18

When I receive my 2 methoxy 4 nitro aniline I'm going to experiment with condensing it with isatoic anhydride I received recently.

Does anyone know how you could go about reasoning and justifying basic vs acidic hydrolysis of an ester with an amide functionality, like acetylated methyl anthranilate? We of course want greater ester hydrolysis.

Surely there is a "rule of thumb" regarding which of the two functionalities hydroylse faster in acidic or basic conditions? Could someone please share, or point me in the right direction? I doubt I'll be able to find rate constants for equilibrium reaction the ester/amide for this compound.

Obviously the aromaticity of the anthranilic acid molecule will influence these reactions too.

carboxylic acid + amine <-> amide
carboxylic acid + alcohol <-> ester

I know esters are commonly synthesized by acidic conditions just using the basic equilibrium reaction. But I do not think this is a common way to make amides, they're usually made using an alkylating agent, eg acetyl chloride, propanoic anhydride, sometimes in acidic or basic conditions if using anhydrides.

So I would assume that the rate of decomposition is greater than the rate of formation, or the reverse reaction of the amide equilibrium reaction is more favored than formation of products.

But what the real question is what's the rate of formation of reactants (decomposition) of the amide and the ester in acidic or basic conditions.

Both the "reactants" of amides and esters contain the component carboxylic acid, so having basic conditions will make these form ions and eliminates them as reactants. Whereas acidic conditions will leave these carboxylic acids as potential reactants to reform either the esters or amide.

The ester is more likely to re-form in acidic conditions, so assuming that the amide will hydrolyze at the same rate in either acidic or basic conditions, basic conditions would make the most sense as it would inhibit reformation of the ester.

Basic conditions:

amide <-> carboxylate + amine

ester <-> carboxylate + alcohol

Rate constants: Assuming k_forward(amide) << k_forward(ester)
If we have conditions that react with carboxylic acid, then reaction is going to be driven to the component reactants, driving it to completion.

Boy do I love speculating


[Edited on 29-6-2015 by Templar]

ChemPlayer_ - 14-7-2015 at 03:56

I just tried this using my lovely home made acetic anhydride (I was very lucky to acquire a small amount of PCl3 :)

I used a procedure I found online which was designed for Uni students - basically take 10g of anthranilic acid and 25ml of acetic anhydride (a gross excess I know but I wanted to follow the procedure for the first time I did it at least) and mix - then heat until boiling, then allow to cool, add 8ml of water, heat to boiling and then allow to cool. There was an interesting change in the reaction mixture through this process from a slurry to a tan semi-solid then back to a red solution, then to crystals!

I used anthranilic acid which I'd prepared using NaOCl Hofman rearrangement on phthalimide, but hadn't recrystallised (so it was still a very fine tan powder rather than crystals). I dried it in the oven thoroughly before use.

I got a beautiful crop of crystals on slowly allowing to cool when totally dry was a 75-80% yield on starting anthranilic acid.

But whatever I did I couldn't get them to emit flashes of light - the elusive 'triboluminescence'. Anyone know the secret of how to get this to work!?

Video of the process is here: https://www.youtube.com/watch?v=f18DswZHxGo

I did try acetylating anthranilic acid before using acetyl chloride, but the result (I think) was failure I am guess because the HCl produced immediately forms a salt with any residual anthranilic acid and I am assuming this 'protects' the N from further acylation. I presume that the acetic acid produced by the anhydride reaction isn't strong enough to do this given that I used acetic acid to precipitate the acid at the end of the Hoffman rearrangement...)

Templar - 15-7-2015 at 05:15

You do not need to use acetic anhydride to acetylate anthranilic acid, acetyl chloride will be perfectly ok for this.

The problem I had was that the anthranilic acid I thought I had, wasnt anthranilic acid, or had impurities I couldn't separate out.

When I obtained 100g actual anthranilic acid, the acetylation was easy as cake.

50g of acetic anhydride and 50g anthranilic acid were combined in a small RBF with condenser. Immediately, the mix began to warm up but needed to be heated to reflux for 1hr to get full reaction.

Upon heating, the acetic anhydride very easily dissolved all anthranilic acid. I believe using even less acetic anhydride (and maybe acetic acid as a cosolvent, it will not react negatively) will allow even less acetic anhydride to be used. I noticed after cooling, the reaction still smelt very strongly of acetic anydride, so this had to be decomposed with water.

At this stage acetylated anthranilic acid had separated out and melted at 182C. Upon washing with water and drying, crushing against a spatula and the walls of a beaker showed beautiful triboluminescence in a dark room. So pretty! but the camera couldnt pick it up :(

Orsyn - 15-7-2015 at 08:17

Could one of you post a picture or two of these crystals?

Also for the record: Cheapskate reported on the Rhodium archives that refluxing Anthranilic Acid in GAA for 3 hrs would serve to acetylate it, but I think he was typing out his a$$, all I achieved by doing this is some by-products that definitely aren't the target compound and my starting products are very clean. Most of the stuff he's written that I've followed have been spot-on, but not that one. Guess I know where the last of my Ac2O is gonna go..

Anyway, I'd love to see some pics.

ChemPlayer_ - 16-7-2015 at 03:26

Templar, sounds familiar and I aso think that it must be possible to get away with using a lot less anhydride (not the 3.5 x molar ratio suggested in most preparations).

Apparently the oxazolinone intermediate is hydrolysed by acetic acid to N-acetylanthranilic acid, so it may be that the reason for using so much anhydride is simply to act as a convenient source of acetic acid for this second step (after water addition).

Next time I will try using 1.2 x molar excess of anhydride, refluxing for an hour, then adding a molar equivalent of acetic acid (and perhaps a tiny bit of water), bringing to boil and then cooling.

Interesting to hear how your reaction with acetyl chloride went. I tried this by mixing the two reagents directly in a small flask, and a reaction between the acid chloride and the anthranilic acid definitely occurred with the tan colour disappearing, heat being produced, HCl fumes, and a quite hard dense white solid being the product. But the solid is very water soluble and I cannot recrystallise it no matter what solvent I use (so I guess it's a hydrochloride salt of something).

Orsyn - 16-7-2015 at 09:20

Woops I missed chemplayers' youtube video, awesome! I've been scrounging the net for data on N-acetyl anthranilic acid for weeks, and this video is the first I've seen. Much thanks!!

[Edited on 16-7-2015 by Orsyn]

ChemPlayer_ - 17-7-2015 at 07:33

I tried the new acetylation process.

22g of quite brown nasty looking anthranilic acid (recrystallised but probably at too high a heat so lots of brown impurities in there, but very dry - baked in oven for a few hours at 120C) was placed into a 250ml flask.

20ml of acetic anhydride was added (1.2 molar ratio approx). As per usual a lot of heat was produced but the mixture didn't suddenly solidify with swirling the flask as it did before with the larger amount of anhydride. No spontaneous solution was formed and at the reaction temperature a lot of solid was still present in the flask (but with a red coloured supernatent liquid as before).

This was then refluxed for 30 minutes. During reflux all solids dissolved to form a red/brown solution.

On cooling, 6ml of water was added, and some heat was generated in the flask. The mixture was then bought to boil for 5 minutes, and then slowly allowed to cool.

The brown solution crystallised on cooling and after allowing this to chill and rest for an hour, filtered. The crystals in the filter were washed with 10ml of ice cold ethanol, and then with 20ml of cold DCM (both of these washings removed a lot of red/brown colour). The crystals look similar to before.

Result: 25g of crude crystalline product (with some brown impurities but not too much by the looks of things). If pure this would be an 87% yield, so completely comparable to the 'textbook' method. Just need to test it now to check it's the real deal. But looks very promising.

So yup, it looks you can get away with a lot less anhydride and still get the same bang for buck.

chemrox - 17-7-2015 at 13:50

"Anthranilic acid (10 grams) is dissolved in acetic anhydride (20 ml) and the temperature raised progressively to 190-200°C at which temperature distillation takes place. The last traces of acetic acid are removed under vacuum and after cooling to about 50-60°C, " - from erowid methaqualone synthesis.