Sciencemadness Discussion Board - Would it be possible to make 2-bromobenzoyl chloride from salicylic acid

Would it be possible to make 2-bromobenzoyl chloride from salicylic acid

jmister28 - 19-12-2018 at 08:57

Due to the similarities of 2-bromobenzoyl chloride and salicylic acid, would it be possible to synthesize it? If so, what reagents and reactions would be necessary to synthesize such a molecule. Any contribution helps

Nakhimov - 19-12-2018 at 09:09

It would definitely be viable! If I were doing the synthesis in my own lab
1. Protection of carboxylic acid
2. Bromination of alcohol group (Appel rxn, HBr, or similar)
3. Deprotection of COOH
4. Chlorination of carboxylic acid
5. Workup

jmister28 - 19-12-2018 at 09:23

what would you use for the protection of the carboxylic acid and the deprotection of COOH?

Loptr - 19-12-2018 at 09:55

Nope, not like that.

Phenol cannot undergo an SN1, E1 or SN2 reaction. For SN1 and E1, it's because an unfavorable phenyl cation would have to be formed. As for SN2, which is done by a backside attack, and given the planar nature of phenol, the nucleophile cannot attack.

An E2 reaction would be possible to produce the very reactive benzyne intermediate, but you are not guaranteed where it will end up or that it will react like you want it to. My guess is that you would get biphenyl.

[Edited on 19-12-2018 by Loptr]

Nakhimov - 19-12-2018 at 09:58

Depends on what you have available to remove the PG. Probably a benzyl ester.

edit: oops, good point! You're right that the aryl alcohol would be a bit stubborn. You could go through the Sandmeyer reaction. That would actually make things easier, I think.

[Edited on 12-19-2018 by Nakhimov]

Loptr - 19-12-2018 at 10:08

Quote: Originally posted by Nakhimov

Depends on what you have available to remove the PG. Probably a benzyl ester.

edit: oops, good point! You're right that the aryl alcohol would be a bit stubborn. You could go through the Sandmeyer reaction. That would actually make things easier, I think.

[Edited on 12-19-2018 by Nakhimov]

But then you are talking about starting from an anthranilic acid, and not salicylic acid.

Nakhimov - 19-12-2018 at 10:24

Quote: Originally posted by Loptr

Quote: Originally posted by Nakhimov

But then you are talking about starting from an anthranilic acid, and not salicylic acid.

Good point. Think it would be easier to start from benzene, brominate, then acylate followed by SOCl2?

clearly_not_atara - 19-12-2018 at 10:44

The answer is probably not unless you can use Tf2O or chlorodiphenylimidazolium.

CuReUS - 20-12-2018 at 05:49

Quote: Originally posted by Nakhimov

1. Protection of carboxylic acid
2. Bromination of alcohol group (Appel rxn, HBr, or similar)

you can simultaneoulsy convert the OH and COOH of salicylic acid to bromobenzoyl bromide using appel reaction alone.

AvBaeyer - 20-12-2018 at 07:23

Does anyone bother to do a simple google search before making somewhat useless comments?

The critical part of the OP's problem: is it possible to convert a phenolic OH to an aryl halide? Search: "phenol to aryl halide." You will find some answers which are informative but perhaps not imminently practical. Will these reactions work with salicylic acid/esters? Follow it up as there are hints that they might.

By the way, the Appel reaction will not work at all. Look it up.

Google and Google Scholar are extremely powerful for leading to possible answers for questions of the type being asked. I do not understand why these resources are not used more so that good questions can be asked and more informative answers provided.

AvB

CuReUS - 21-12-2018 at 06:24

Quote: Originally posted by AvBaeyer

By the way, the Appel reaction will not work at all. Look it up.

https://www.sciencedirect.com/science/article/pii/0040402093...

https://www.thevespiary.org/rhodium/Rhodium/Vespiary/talk/fi...

Chemi Pharma - 26-12-2018 at 10:09

Reading the papers @Cureus brought, I remembered about another paper telling how to convert carboxilic acids into acid chlorides and alcohols to chlorides using TCCA and triphenylphosphine in anhydrous acetonitrile. It seems the mechanism of the reactions are similiar: triphenylphosphine forms triphenylphosphine halide and this intermediate promotes the substitution of the (OH) group in acids and alcohols by chlorine.

Although the paper (attached below) didn't exemplificates this kind of reactions with phenols, based in @Cureus papers, I guess both phenolic and carboxilic groups at first and second positions of the benzene ring in salicylic acid will be replaced at once, giving the product OP's desire: 2-chloro benzoyl chloride.

If it doesn't work, I sugest the conversion of salicylic acid into anthranilic acid with chloroacetamide, K2CO3, KI and DMF, like the paper I attached below say --> Sandmayer reaction on anthranilic acid to substitute the amino group by an halide group --> Formation of the acid chloride with TCCA and triphenylphosphine in anhydrous acetonitrile like I've said above, following the guidelines inside the paper I've attached too.

Attachment: acid chlorides with TCCA and triphenylphosphine.PDF (172kB)
This file has been downloaded 307 times

Attachment: phenols to anilines with chloroacetamide, K2CO3, KI and DMF.PDF (1.9MB)
This file has been downloaded 319 times

Loptr - 26-12-2018 at 12:19

@chemi pharma,

Why do you think that reagent pair will form the acyl halide? I only see an example of forming an ester in that paper, which would have been through formation of the alkyl chloride, and then reaction with the carboxylic acid, and not the other way around.

Also, remember the formation of an acyl halide is through the double bonded oxygen, and not just a simple substitution of the hydroxyl. Also, the carboxyl group is a resonance structure, and acts as a single unit, and does not behave the same as its individual parts.

[Edited on 26-12-2018 by Loptr]

[Edited on 26-12-2018 by Loptr]

Chemi Pharma - 26-12-2018 at 12:42

Quote: Originally posted by Loptr

@chemical pharma,

Why do you think that reagent pair will form the acyl halide? I only see an example of forming an ester in that paper, which would have been through formation of the alkyl chloride, and then reaction with the carboxylic acid, and not the other way around.

Also, remember the formation of an acyl halide is through the double bonded oxygen, and not just a simple substitution of the hydroxyl. Also, the carboxyl group is a resonance structure, and acts as a single unit, and does not behave the same as its individual parts.

[Edited on 26-12-2018 by Loptr]

I do not desagree with you. The paper I brought I have catched with @AVBayer and really don't explain the things too much clear. But I have another paper explaining better the mechanisms envolved with the same couple reactions (TCCA and triphenylphosphine) used to achieve acyl chlorides from carboxilic acids and also amides and esters. I'm attaching it right now.

You can use cyanuric chloride and TEA too, to convert carboxilic acids into acid chlorides. I'm attaching another paper related below.

Of course you are right and I know its not a simple (OH) substitution. I wrote this way only to simplify the things. I didn't want to explain the mechanisms of the reaction. I think is boring and takes a long time. Let the papers explain it for me in a better way.

Enjoy the papers.

Attachment: acids to amides with TCCA and triphenylphosphine.PDF (105kB)
This file has been downloaded 264 times

Attachment: Acid chlorides from acids with Cyanuric Chloride and TEA.pdf (86kB)
This file has been downloaded 268 times

AvBaeyer - 5-1-2019 at 13:45

I do not want to reopen an old discussion, but attached is the text part of an Organic Reactions chapter on "oxyphosphonium" chemistry, which mechanistically includes the Appel reaction. Hopefully, folks here will find this interesting and useful.

AvB

Attachment: Oxyphosphonium chemistry OrgRxns castro1983.pdf (1.8MB)
This file has been downloaded 327 times