Sciencemadness Discussion Board

Boric Acid Catalyzed Amidation of Carboxylic Acids

Rich_Insane - 11-3-2012 at 20:32

Hello folks!

So I just wanted to post a little proposition or curiosity I have. I've been looking for an efficient, cheap and clean way to convert carboxylic acids into their corresponding amides without use of acyl halides. Even more of a problem, I want the primary amide -- meaning for many methods, I would have to mess with ammonia gas. So I searched and searched until I realized that I had actually found something when I first began my search, but had ignored it in exchange for more conventional methods. It turns out that this method is excellent. Now I will stop being vague. I'm referring to the utilization of H3BO3 (10-25 mol %) to form a mixed-anhydride intermediate that will react with amines to form an amide (because amines are nucleophilic and will readily give up electrons to break that anhydride, my idiot understanding of organic chemistry tells me). Look at the bottom for the OrgSyn reference.

So here's my proposition: Say I've got a carboxylic acid called 3-(1,3-benzodioxol-5-yl)-2-methylpropanoic acid (I suppose that would also be methylenedioxyphenyl-2-methylpropanoic acid). I follow the method detailed in the OrgSyn reference, but as an extra precaution I utilize 50 mol% H3BO3 (to encourage formation of the intermediate I suppose -- as a precaution, unless of course that would be a detriment to the reaction). The reaction solvent is toluene, as per the references. Here's the part I'm skeptical about. I want to bubble NH3 gas through the mixture. I want the primary amide. None of the sources mention using NH3 to produce the primary carboxamide. They all use aliphatic or aryl amines. Don't quote me on this, but the simplest amines Tang used were benzylamine on 4-phenylbutanoic acid and a piperidine derivative on 4-phenylbutanoic acid. Is this feasible? Are there going to be problems using NH3 gas generated using Ammonium sulfate and NaOH (or other ammonium salts with NaOH)? That's the primary question I have here.

Some secondary (newbish) questions: Why are they removing the water (by way of a Dean-Stark trap hooked up to the reflux)? Is it because water is detrimental to the formation of the anhydride or because there is some equilibrium issue that water affects? Would I isolate the amide by washing with another solvent, or would I simply evaporate off the toluene?

Anyways, thanks in advance. I really appreciate any guidance. For those of you who did not want to read my rambling, I'm basically wondering if I could use H3BO3 to form the mixed anhydride intermediate shown below, then bubble generated (excess) NH3 gas to form the carboxamide.

The scheme (drawn in ChemSketch, the arrows did not show up, but I the first row is the COOH to the intermediate, the second is the intermediate to the amide):



Reference: Boron Catalyzed Amide Formation

Also, I have attached a paper from Organic Process Research & Developement 2007, Issue 11, p 1065-1068 titled "Boric Acid Catalyzed Amidation in the Synthesis of Active Pharmaceutical
Ingredients" by Ravi Kumar Mylavarapu, Kondaiah GCM, Naveenkumar Kolla, Raju Veeramalla, Purandhar Koilkonda,
Apurba Bhattacharya, and Rakeshwar Bandichhor.

Attachment: op700098w.pdf (89kB)
This file has been downloaded 2254 times

[Edited on 12-3-2012 by Rich_Insane]

UKnowNotWatUDo - 11-3-2012 at 21:39

In the reference you posted they state that 5 mol% boric acid catalyst was generally fine for most reactions, and that 25 mol% was only necessary for certain, less nucleophilic, amines. With this in mind, ammonia will probably not need 25% boric acid to sufficiently react.

I would look up the solubility of ammonia in toluene to get an idea of the concentration you'll be able to achieve in solution.

Also, I assume you'd be planning on using the amide in a hofmann rearrangement (or perhaps not, what do I know) but out of curiosity how did you plan to synthesize the carboxylic acid?

Rich_Insane - 12-3-2012 at 07:37
Quote:

Also, I assume you'd be planning on using the amide in a hofmann rearrangement (or perhaps not, what do I know) but out of curiosity how did you plan to synthesize the carboxylic acid?


Of course not! That would be illegal :D

I was thinking of using 2.5 to 5 mol % NiCl2 with NaOCl (bleach grade, 5-10%) to oxidize the corresponding aldehyde, which is a fragrance known as helional or "ocean propanal". The method is detailed in a paper that can be found on this site ("An Efficient and Practical System for Catalytic Oxidation of Alcohols, Aldehydes and a,B-Unsaturated Carboxylic Acids)

A friend of mine can confirm this method producing at least something from helional; he noticed an off-white precipitate in the reaction mix after leaving ~45 mmol of helional with 1.5 mol % of crude NiCl2 to react. Unfortunately neither of us have really good access to an NMR, although I may ask the O Chem people on the third floor if there's some sort of student NMR that could be used for just a quick sample. On another note, how useful are UV-VIS for characterization of compounds? Are they not useful at all?

Regarding the boric acid, I'm just being paranoid. I'm just afraid that something might go wrong and I'll end up with gunky tar.

[Edited on 12-3-2012 by Rich_Insane]

[Edited on 12-3-2012 by Rich_Insane]

GreenD - 12-3-2012 at 08:05

Read your U2U-

Beyond that, using more catalyst will probably only hurt you. Since Aromatic amines like aniline are less nucleophilic and more bulky than ammonia gas, they require more catalyst.

As a thank you I will give you another U2U.

Vogelzang - 12-3-2012 at 15:26

I thought this patent was interesting. It uses urea to make amides.

US 2109941 Preparation of amides
phenylpropionic acid & urea 1/0.5 mole ratio, table 1 2nd page, 4-5 hrs, 160
degrees, yield 86%

Rich_Insane - 12-3-2012 at 21:24
Quote:

Beyond that, using more catalyst will probably only hurt you. Since Aromatic amines like aniline are less nucleophilic and more bulky than ammonia gas, they require more catalyst.


Ah, alright. But I should use an excess of NH3, right? I was thinking of using either chloroform or some sort of ether (According to the ATSDR Toxprofiles, Ammonia is soluble up to 20% w/w in anhydrous ethanol at 0 C and soluble in chloroform and ether).

On another note, will the NH3 generation idea work, or would in situ generation of ammonia be too much of a stretch here?

GreenD - 13-3-2012 at 06:17

I would assume that unless you keep your source dry of NH3 you may end up with some carboxylic acid.

I don't know how you would make an anhydrous 20% ethanol solution of NH3, perhaps the chloroform may work but you'll have to know how soluble.

An excess of amine will be fine.

But in all seriousness this topic needs to be changed.

Out_of_Range - 30-4-2012 at 06:15

Rich_Insane wrote:

Why are they removing the water (by way of a Dean-Stark trap hooked up to the reflux)? Is it because water is detrimental to the formation of the anhydride or because there is some equilibrium issue that water affects?

Yes, they are removing water, because the reaction will go in both directions, and without removing the water that is generated in the reaction, it won't get very far.

Also, Rich_Insane wrote:


I was thinking of using 2.5 to 5 mol % NiCl2 with NaOCl (bleach grade, 5-10%) to oxidize the corresponding aldehyde, which is a fragrance known as helional or "ocean propanal".

Unless I am mistaken, the aldehyde you are trying to oxidize is the aldehyde protecting group on the aromatic diol (catechol). This aldehyde is formaldehyde, and liberating it would probably be a bad idea. Also, you would need to remove it first, by adding acid and water (Note - this is kind of what you are doing during the amidation).

Rich_Insane - 30-4-2012 at 21:26
Quote:

Unless I am mistaken, the aldehyde you are trying to oxidize is the aldehyde protecting group on the aromatic diol (catechol). This aldehyde is formaldehyde, and liberating it would probably be a bad idea. Also, you would need to remove it first, by adding acid and water (Note - this is kind of what you are doing during the amidation).


Not exactly sure what you're trying to say -- I'm oxidizing the carbonyl group to a COOH group (the corresponding carboxylic acid).

Vogelzang - 3-5-2012 at 12:22

Some related patents.

US 2898353 Preparation of amides
boric carboxylic mixed anhydrides

US 3772389 PROCESS FOR THE SYNTHESIS OF PHENYL ESTERS

US 1987559 Process of producing boron tricarboxylates
554/77, 562/882