Cyclic diester from 2,2'-oxydibenzoic acid?

Hi fellow chemists.

I recently made 2,2'-oxydibenzoic acid (btw check that fucked up image on SigmaAldrich ).

Looking at the structure, could a double fischer esterification happen with a diol like ethylene glycol or longer? I wasn't able to find any reference. I don't see any reason why it shouldn't happen, but maybe some of you have actual experience.

I'm thinking something like this:



Edit: anyone try to name the product? My knowledge of naming is not enough here.

[Edited on 14-6-2020 by michalJenco]

Quote: Originally posted by UC235

You're trying to make an 11-membered ring which is really unfavorable, but perhaps the structure is twisted in a way that makes it less terrible.

Interesting molecule, but I predict this might not work b/c of tar formation. once the ethylene glycol forms an ester with one carboxylic acid... the other alcohol group on the ethylene glycol could form ester with the carboxylic acid of another molecule.

I'm brainstorming ideas here. esterification with 1 molar equivalent of 2-bromoethanol will give a mixture of diester, monoester, and no ester products. You could use fractional distillation to isolate the monoester, if the boiling points of all 3 are different enough. If the monoester is diluted in a large volume of organic base such as pyridine (to minimize intermolecular reactions), an intramolecular SN2 reaction could happen.

Quote: Originally posted by Pumukli

Have you checked the price of the acid what you've just synthetized? :-) Sigma wants a pleasant pile of money for a mere 25 mg (!) :-) The demand may be low though... :-( Otherwise what a lucrative (and legal) business we may miss! :-)

I have checked the price and it really is bonkers, considering how trivial the precursors and synthesis are. I tend to view these prices as signatures of non-existent demand as anyone who will search for that specific chemical is definitely capable of synthesizing it themselves I previously made 40g of this stuff (4-methyldaphnetin) - worth roughly $280,000 - so that thinking is the only way to sleep at night for me.

Edit: Or, you know, maybe I didn't make what I think I did and it actually is harder to make and the price justified. I will write a full write-up in this thread (as someone is interested) later so you can judge my procedure.

[Edited on 15-6-2020 by michalJenco]

Quote: Originally posted by UC235

You're trying to make an 11-membered ring which is really unfavorable, but perhaps the structure is twisted in a way that makes it less terrible.

Quote: Originally posted by Cou

Interesting molecule, but I predict this might not work b/c of tar formation. once the ethylene glycol forms an ester with one carboxylic acid... the other alcohol group on the ethylene glycol could form ester with the carboxylic acid of another molecule. I'm brainstorming ideas here. esterification with 1 molar equivalent of 2-bromoethanol will give a mixture of diester, monoester, and no ester products. You could use fractional distillation to isolate the monoester, if the boiling points of all 3 are different enough. If the monoester is diluted in a large volume of organic base such as pyridine (to minimize intermolecular reactions), an intramolecular SN2 reaction could happen.

Yeah I presumed tar would form as there is no reason ethylene glycol would not connect two separate reactant molecules. It might even make some amount of this monster, analogous to the side product of reaction of catechol and diiodimethane:



I love that you actually thought about it and proposed a mechanism, I didn't know about the last organic base-catalysed mechanism. I really appreciate that! Unfortunately I don't have access to 2-bromoethanol and its synthesis is beyond my current capabilities. This will be a great thread to come back to if I do.

The official name will haunt me.

Quote: Originally posted by Sigmatropic

If you could dehydrate it to the cyclic anhydride then that would be a nice access point to the bromoethyl monoester.

Quote: Originally posted by Sigmatropic

If you could dehydrate it to the cyclic anhydride then that would be a nice access point to the bromoethyl monoester.

Quote: Originally posted by Boffis

I would be interested in the procedure you used to prepare the acid. Can you give us a reference or some details of what you did? Very interesting stuff.

Synthesis of 2,2'-oxydibenzoic acid

I think of this synthesis as a Williamson ether synthesis. I am not educated as a chemist so I piece things together from the internet. Similar reactions are described, though (e.g. salicylaldehyde + chloroacetic acid on the Williamson ether synthesis wiki, which I did and it worked), so I work assuming the principle is general. In general, you want enough base to depronate all carboxyl and phenol groups in all your reactants and then an excess to achieve a very basic mixture even with everything deprotonated. I used 1.5x molar here.

Materials:

1. KOH - 54.8g (977mM)
   
2. Salicylic acid - 30g (217mM)
   
3. 2-chlorobenzoic acid - 34g (217mM)
   
4. 35% Hydrochloric acid - as needed
   
5. Water - 160g + enough to get to ~430mL of reaction mixture
   

Procedure:

Magnetic stirring on a hotplate is implied throughout the reaction, heating starts off. Fits neatly into a 500mL erlenmeyer flask. Solid stirring is required as a lot of precipitate has to be stirred.

Dissolve the base in the first portion of water.
When clear solution is reached, add B which dissolves quickly.
Wait for 5 minutes and add C which also dissolves quickly.
Turn on heating and bring the reaction mixture right below its boiling point (around 118 °C) and hold it there for two hours.
Turn off heating and add the other portion of room temperature water (temperature of reaction drops to ~80 °C) and acidify with D until pH 0-1.
A substantial of insoluble solids are formed - our product.
Turn on heating and bring near boiling point and keep just under it for 10 minutes.
This makes a lot of the product actually dissolve, and the undissolved part melts into a bottom golden layer (droplets while stirring but they settle into a layer when stopped).
Stop the heating and let the reaction mixture cool while stirring until the product is no longer melted, then you can turn off stirring.
The whole flask fills with plate-like pure white crystals.
If left unstirred while cooling, a lot of the product collects in a bottom layer which, when left to solidify, is very hard to break up and get out of the flask.

Workup as usual - vacuum filter, wash with water until filter water is not acidic.
The wet product can be recrystallised as such, no need to dry.
I recrystallised from about 350mL of 1:3 (volume, roughly) EtOH:water, but I would use even less EtOH because product is extremely soluble in it even at room temperature. The amount of product from this synthesis could be recrystallised entirely from like a liter of water, I think.
Wash with cold water after recrystallisation. Let the white fluff dry on air for a few days.

The yield is 52.8g (204mM, 94.2%) of pure white powder-like mass of tiny crystals. Faintest or no smell at all.

Rationale:

I have done several similar reactions between ortho and para chlorobenzoic acids acid phenols, because the procedure is simple, I have access to both of these groups of chemicals and I am curious. I condensed both phenol and hydroquinone with both o- and p-chlorobenzoic acid to make the following products:



The underlying motivation is my curiosity for smells (of esters), so I made methyl esters of all of those 4 molecules. They have a beautiful smell. The 2- substituted esters smell very similar to methyl salicylate, while the 4- substituted ones are more similar to 4-acetphenetole.

For the sake of interest - methyl esters of the first three are solids while the 4th is actually a liquid, which surprised me a lot.


[Edited on 15-6-2020 by michalJenco]

Quote: Originally posted by Cou

Quote: Originally posted by Sigmatropic   If you could dehydrate it to the cyclic anhydride then that would be a nice access point to the bromoethyl monoester. In that case, maybe you could just react ethylene glycol with the anhydride to get a mono ester, then intramolecular esterification after dilution to minimize intermolecular reaction.

Quote: Originally posted by Cou

but I predict this might not work b/c of tar formation. once the ethylene glycol forms an ester with one carboxylic acid... the other alcohol group on the ethylene glycol could form ester with the carboxylic acid of another molecule.

Quote: Originally posted by Cou

What does 2,2'-oxydibenzoic acid smell like?

Quote: Originally posted by CuReUS

Quote: Originally posted by Cou   but I predict this might not work b/c of tar formation. once the ethylene glycol forms an ester with one carboxylic acid... the other alcohol group on the ethylene glycol could form ester with the carboxylic acid of another molecule. Why should it take the trouble to react with another molecule when it has a COOH right in front of its face! I suggest you slowly drip ethylene glycol into a pot containing your diacid and TCT.By keeping the concentration of the smaller(and more reactive) component low ,you can minimise the chances of side reactions

Quote: Originally posted by michalJenco

Quote: Originally posted by Boffis   I would be interested in the procedure you used to prepare the acid. Can you give us a reference or some details of what you did? Very interesting stuff. Synthesis of 2,2'-oxydibenzoic acid I think of this synthesis as a Williamson ether synthesis. I am not educated as a chemist so I piece things together from the internet. Similar reactions are described, though (e.g. salicylaldehyde + chloroacetic acid on the Williamson ether synthesis wiki, which I did and it worked), so I work assuming the principle is general. In general, you want enough base to depronate all carboxyl and phenol groups in all your reactants and then an excess to achieve a very basic mixture even with everything deprotonated. I used 1.5x molar here. Materials: KOH - 54.8g (977mM) Salicylic acid - 30g (217mM) 2-chlorobenzoic acid - 34g (217mM) 35% Hydrochloric acid - as needed Water - 160g + enough to get to ~430mL of reaction mixture Procedure: Magnetic stirring on a hotplate is implied throughout the reaction, heating starts off. Fits neatly into a 500mL erlenmeyer flask. Solid stirring is required as a lot of precipitate has to be stirred. Dissolve the base in the first portion of water. When clear solution is reached, add B which dissolves quickly. Wait for 5 minutes and add C which also dissolves quickly. Turn on heating and bring the reaction mixture right below its boiling point (around 118 °C) and hold it there for two hours. Turn off heating and add the other portion of room temperature water (temperature of reaction drops to ~80 °C) and acidify with D until pH 0-1. A substantial of insoluble solids are formed - our product. Turn on heating and bring near boiling point and keep just under it for 10 minutes. This makes a lot of the product actually dissolve, and the undissolved part melts into a bottom golden layer (droplets while stirring but they settle into a layer when stopped). Stop the heating and let the reaction mixture cool while stirring until the product is no longer melted, then you can turn off stirring. The whole flask fills with plate-like pure white crystals. If left unstirred while cooling, a lot of the product collects in a bottom layer which, when left to solidify, is very hard to break up and get out of the flask. Workup as usual - vacuum filter, wash with water until filter water is not acidic. The wet product can be recrystallised as such, no need to dry. I recrystallised from about 350mL of 1:3 (volume, roughly) EtOH:water, but I would use even less EtOH because product is extremely soluble in it even at room temperature. The amount of product from this synthesis could be recrystallised entirely from like a liter of water, I think. Wash with cold water after recrystallisation. Let the white fluff dry on air for a few days. The yield is 52.8g (204mM, 94.2%) of pure white powder-like mass of tiny crystals. Faintest or no smell at all. Rationale: I have done several similar reactions between ortho and para chlorobenzoic acids acid phenols, because the procedure is simple, I have access to both of these groups of chemicals and I am curious. I condensed both phenol and hydroquinone with both o- and p-chlorobenzoic acid to make the following products: The underlying motivation is my curiosity for smells (of esters), so I made methyl esters of all of those 4 molecules. They have a beautiful smell. The 2- substituted esters smell very similar to methyl salicylate, while the 4- substituted ones are more similar to 4-acetphenetole. For the sake of interest - methyl esters of the first three are solids while the 4th is actually a liquid, which surprised me a lot. [Edited on 15-6-2020 by michalJenco]

Hmm that is worrying. I didn't do a m.p. test on the bottled product but it was liquid in the reaction mixture until around 80 °C. Salicylic acid has a m.p. of 158 °C and 2-chlorobenzoic acid melts at 142 °C, so I definitely made something.

I just did a FeCl3 test and I got an intense purple coloration immediately. Looks like I failed miserably .

But I wonder. Molbase suggests you can make my product from the chloroacid alone. "Surely" throwing in a deprotonated salicylic acid should make it even better?

Quote: Originally posted by Boffis

@michaljemco; Thankyou for posting details of your prep. @myr; how different is this reaction to the preparation of N-Phenylanthranilic acid (See Vogel, Practical Organic Chemistry, 3rd, page 991) from aniline and o-chlorobenzoic acid? Except that the preparation in Vogel uses a copper oxide catalyst? Would a copper or copper oxide catalyst help in this reaction?

Quote: Originally posted by michalJenco

This also makes me wonder about what I actually made when I did this procedure with phenol and 2- and 4- chlorobenzoic acids, where the products after Fischer esterification with methanol were solids with amazing smells. Methyl 2-chlorobenzoate is a liquid so I didn't make that. I also don't think a 2-chlorobenzoate ester would smell exactly like salicylate with a twist, which my presumed methyl 2-phenoxybenzoate (2-PB) absolutely does smell like. They smell exactly how you would imagine them based on the molecule - my presumed 2-PB is spicy like salicylate and 4-PB is somehow round and sweet, anisic, like 4-acetphenetole (that I coincidentally also made, which makes me able to compare). Also, I made methylparaben a while ago and it has no smell at all, so my 4-chlorobenzoic acid after reaction with phenol and base didn't turn (at least not fully) into a 4-hydroxybenzoic acid. This is proof to me that some - maybe a lot - of my product actually is the diaryl ether carboxylic acid in these types of reactions. Also also the pungent smell of the chloroacids disappears during the reaction, so the chlorine is leaving the benzene ring. If it is leaving and it is not leaving a hydroxy group behind at least some of the time, what other options besides diaryl ether are there? Yeah, my only analytical instruments are my senses but you see that the evidence does seem to stack up. [Edited on 17-6-2020 by michalJenco]

After some time I have an update.

I followed this paper's procedure (sci-hubbed it) with phenol and 2-chlorobenzoic acid to make 2-phenoxybenzoic acid. I did it on 3x their scale and used pyridine.HCl instead of the freebase (I used more K2CO3 accordingly). As expected, the product is completely different from my previous attempt with the flawed procedure. I refluxed for 3.5h. My yield was only 20% while the paper is around 50%, however. Not sure why.

I used the full 5g in the Fischer esterification with 20x molar excess of MeOH and 1.5x molar excess of H2SO4. After some 3h of reflux I got a slightly viscous, heavier than water liquid product with a weak smell similar to methyl salicylate, but less beautiful. Also the yield was very poor, I have less than 1g of product, not sure why again. Took a whole night to gravity filter also.

Nevertheless this is one of the most prized products I have so far, as it is such an obscure compound and I only made small amount of it.

Next time it might be interesting to decarboxylate the acid to make diphenyl ether, which as I understand it is pretty hard to make directly.



[Edited on 2-7-2020 by michalJenco]