Sciencemadness Discussion Board - Chlorinating Carboxylic Acids

Chlorinating Carboxylic Acids

Maui3 - 30-1-2025 at 04:28

Is it possible to chlorinate a carboxylic acid without hard-to-get chlorinating agents, such as thionyl and oxalyl chloride and phosphorus chlorides?

I saw a paper saying it was possible with TCCA, but you still needed a bit of the acyl chloride first.

bnull - 30-1-2025 at 05:34

Yes. It is something that pops up here from time to time. You'll need: sulfur for in situ preparation of sulfur chloride (forgot which one), that is the chlorinating agent; dry chlorine gas, which comes almost dry and oxygen-free from TCCA (check out the procedure by @len1 or the book by Lerner, both guys being apparently the same); anhydrous carboxylic acid; a solvent if necessary. The details depend on the carboxylic acid and the final product (mono-, di-, trichlorinated and so on). This is a preparation of chloroacetic acid, for example.

Edit: Just one more thing. Don't mix TCCA and organics, especially large quantities of the former. Something^* may or may not happen, but it is better for it not to happen.

*: Chemically-induced laboratory equipment rearrangement.

[Edited on 30-1-2025 by bnull]

DraconicAcid - 30-1-2025 at 08:11

Are you trying to get acyl chlorides, or 2-chlorocarboxylic acids?

Maui3 - 30-1-2025 at 08:28

Acyl chlorides. I should have been more specific.

Maui3 - 30-1-2025 at 08:31

I might be able to use sulfur chlorides? - but I heard that reaction is quite messy..

Fery - 30-1-2025 at 10:41

S chlorides are generated in situ and consumed during the reaction. S acts like a catalyst.

Maui3 - 30-1-2025 at 10:46

Thank you for clarifying!

But will that the acyl chloride or a monochloro carboxylic acid?

Niklas - 30-1-2025 at 13:31

The acyl chloride.
Another thing I‘d have in mind would be to use DMF catalysis, as TCCA should form a type of Vilsmeier reagent here as well, and those are generally able to chlorinate carboxylic acids to their acyl chlorides. In the end that‘s the same idea the chlorination using oxalyl chloride is based on as well, which only works reasonably quickly with catalytic DMF.

zed - 30-1-2025 at 17:30

I don't know what products you are interested in producing.

But, Phosphorus Oxychloride can be produced via the reaction of Phosphorus Pentoxide.

Phosphorus Oxychloride

Not the most economical route, but viable.

One of our members here, has published a procedure.

Look up Leonid Lerner's procedure.

https://www.routledge.com/Small-Scale-Synthesis-of-Laborator...

[Edited on 31-1-2025 by zed]

Lionel Spanner - 1-2-2025 at 13:54

If you can get hold of it, cyanuric chloride is a relatively safe alternative to sulphur or phosphorus chlorides - see DOI 10.1016/S0040-4039(00)71006-9.
The catch is that yields are worse on molecules with multiple carboxylic acid groups, or groups that can react with the acid chloride (alcohols, amines, phenols), and it fails completely with acids that have beta-carbonyl groups, e.g. malonic acid.

davidfetter - 2-2-2025 at 18:07

Quote: Originally posted by Niklas

The acyl chloride.
Another thing I‘d have in mind would be to use DMF catalysis, as TCCA should form a type of Vilsmeier reagent here as well, and those are generally able to chlorinate carboxylic acids to their acyl chlorides. In the end that‘s the same idea the chlorination using oxalyl chloride is based on as well, which only works reasonably quickly with catalytic DMF.

Do we have some idea of how this catalytic cycle works, or is it a thing people have noticed but don't yet have a mechanistic explanation for?

Niklas - 3-2-2025 at 00:33

Quote: Originally posted by davidfetter

Do we have some idea of how this catalytic cycle works, or is it a thing people have noticed but don't yet have a mechanistic explanation for?

The mechanism first proceeds by formation of a Vilsmeier reagent in either case.
With oxalyl chloride:

With TCCA (according to https://link.springer.com/article/10.1007/s42452-019-1023-1):

Which can then chlorinate the carboxylic acid regenerating the DMF:

davidfetter - 4-2-2025 at 15:48

Quote: Originally posted by Niklas

Quote: Originally posted by davidfetter

Do we have some idea of how this catalytic cycle works, or is it a thing people have noticed but don't yet have a mechanistic explanation for?

The mechanism first proceeds by formation of a Vilsmeier reagent in either case.
With oxalyl chloride:

With TCCA (according to https://link.springer.com/article/10.1007/s42452-019-1023-1):

Which can then chlorinate the carboxylic acid regenerating the DMF:

Nifty!

I stumbled across some other papers that started by preparing stoichiometric rather than catalytic amounts of the adduct and starting the fun from there. I assume they tried catalytic amounts first...or just didn't care because DMF was cheap and easy to get.

To your knowledge, has anybody tried Vilsmeier-Haack chlorination on substrates as pedestrian as acetic acid and then published what they've found?

Niklas - 8-2-2025 at 10:47

Quote: Originally posted by davidfetter

To your knowledge, has anybody tried Vilsmeier-Haack chlorination on substrates as pedestrian as acetic acid and then published what they've found?

On first glance I couldn’t find any mentions of using the Vilsmeier reagent of TCCA for chlorinating carboxylic acids. Two publications that did catch my attention though would be the chlorination of carboxylic acids using TCCA / TPP and the conversion of aldehydes to acyl chlorides by the action of TCCA (without the use of a catalyst).

Attachment: 1-s2.0-S0040403905014115-main.pdf (105kB)
This file has been downloaded 52 times

Attachment: porcheddu-et-al-2015-metal-free-direct-oxidation-of-aldehydes-to-esters-using-tcca.pdf (507kB)
This file has been downloaded 52 times

DraconicAcid - 8-2-2025 at 15:22

That's a cool paper, but I am surprised at the 5-day requirement for the first step. Makes it hard to adopt for an undergraduate lab.

clearly_not_atara - 8-2-2025 at 17:41

There is a reported dehydroxychlorination of acetic acid using acetonitrile and HCl gas. IIRC this was controversial when it was first reported but it was eventually confirmed in a YouTube video. IIRC the Gibbs thermodynamics are not favorable for the rxn:

MeCN + AcOH + HCl >> AcCl + AcNH2 + H2O

but they are favorable for the rxn:

MeCN + AcOH + 2 HCl >> AcCl + AcNH3Cl + H2O

For heavy carboxylic acids there is also a reported anhydride formation by simple heating at 250 C with a catalyst like trimellitic acid.

davidfetter - 10-2-2025 at 16:26

Quote: Originally posted by clearly_not_atara

There is a reported dehydroxychlorination of acetic acid using acetonitrile and HCl gas. IIRC this was controversial when it was first reported but it was eventually confirmed in a YouTube video. IIRC the Gibbs thermodynamics are not favorable for the rxn:

MeCN + AcOH + HCl >> AcCl + AcNH2 + H2O

but they are favorable for the rxn:

MeCN + AcOH + 2 HCl >> AcCl + AcNH3Cl + H2O

For heavy carboxylic acids there is also a reported anhydride formation by simple heating at 250 C with a catalyst like trimellitic acid.

It's pretty common to use kinetic drivers like distillation of volatile things--AcCl in this case--to get things done that Gibbs' free energy suggests eventually won't work. My p-chem instructor back in the day mentioned something fascinating about the air in the room vs. a little pool of nitric acid in this context. It's been decades, and I still haven't forgotten.

Anyhow, at atmospheric pressure, AcCl has a bp of around 52°, MeCN around 82°, and AcOH high enough not to worry about. Maybe gently heat the mixture once the chlorinating agent has done its thing? Maybe reduce the pressure, too, assuming you have a suitable way to establish that your gear won't implode and turn into corrosive shards?

I'm thinking TCCA is a better candidate for the chlorinating agent than HCl is, but both are cheap and accessible, so it should be pretty easy to test both. Speaking of the TCCA, the "Metal-Free Direct Oxidation of Aldehydes to Esters Using TCCA" paper suggests it might go via a radical mechanism, so maybe shedding a little UV light on the subject could help.

Further along the TCCA line, maybe it can do double duty: first to oxidize EtOH to AcH, then to chlorinate the latter.

Does any of the above seem completely unreasonable and/or dangerous to try?

DraconicAcid - 12-2-2025 at 19:43

So I thought I'd give the aldehyde chlorination with TCCA a try, but I was only able to find the disodium salt of TCCA (Aquarius brand granules). I'm assuming those wouldn't be very soluble in DCM. Any suggestions on how to adapt the procedure?

SplendidAcylation - 17-2-2025 at 14:29

Have you considered benzoyl chloride? It can be used to convert carboxylic acids into acid chlorides, providing that the acid chloride is a volatile one, like acetyl chloride:

https://pubs.acs.org/doi/10.1021/ja01273a014

As for the benzoyl chloride, it can be made easily by the direct reaction of chlorine with benzaldehyde...

I have done both of these reactions and they are both quite easy, even for an amateur such as I...

But of course perhaps you might be after a more complex acid chloride that cannot be distilled off easily...