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Using the Hell–Volhard—Zelinksy (HVZ) reaction, we can get alpha-chloro or alpha-bromo carboxylic acids:

HVZ reaction scheme

Is it possible to similarly make alpha-iodo carboxylic acids with the help of HVZ reaction? I could not find any reference of HVZ reaction forming alpha-iodo carboxylic acids.

Though $\ce{PI3}$ is much less stable than $\ce{PBr3}$ and $\ce{PCl3}$, it has a decent shelf life of few months and is actually widely available reagent. But still, $\ce{PBr3}$ and $\ce{PCl3}$ is seemed to be used in HVZ reaction. Why not $\ce{PI3}$? Is the reaction thermodynamically unfavourable? Is so, what is the reason?

If $\ce{PI3}$ is used instead of $\ce{PBr3}$ or $\ce{PCl3}$, will the reaction proceed to form alpha-iodo carboxylic acids? If so, why?


Update (I was visiting some of my older questions and encountered this question and thought of providing a little more information)

I found this information from a handbook:

Carboxylic acid derivatives can react with iodine without any intermediate enolate ion to produce alpha-iodocarboxylic acids. Alpha-iodocarboxylic acid chlorides can be produced when hexanoic acid reacts with iodine and thionyl chloride at 85°C to give 80% yield of 2-iodohexanoyl chloride. Similarly, butanoic acid reacts with chlorosulfonic acid and iodine to give 94% of 2-iodobutanoyl chloride. These examples are nothing more than the iodine analog of Hell-Volhard-Zelinsky reaction.

  1. Why are these reaction considered as iodine analog of HVZ reaction? Doesn't HVZ reactions strictly uses phosphorus halides?
  2. If these examples are iodine analog of HVZ reaction, why are they producing 2-iodoacyl chloride? They should be producing 2-iodocarboxylic acid.
  3. If it is producing 2-iodoacyl chloride, how to get rid of the chloride atom to get 2-iodocarboxylic acid?

In this site, it is mentioned that only iodine cannot simply iodinate carboxyl acid due to thermodynamic reasons and alternative and noble ways were discovered to overcome this problem. The reactions mentioned were with carboxylic acid dianions, acyl chlorides with iodine in thionyl chloride and iodination with iodine in the presence of cupric salts. There is no mention of phosphorus triiodide where I later found that with phosphorus diiodide, $\ce{P2I4}$, it can produce 1-iodopropanoic acid and not 2-iodopropanoic acid). Is it considered HVZ reaction?

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    $\begingroup$ Ketones differ from their reactivity from carboxylic acids and the HVZ is about the later substrate. This in mind, Denis and Krief published 1981TetLet22 a paper already stating in the abstract «$\ce{PI3}$ and $\ce{P2I4}$ clearly reduce $\alpha$-bromo and $\alpha$-iodo ketones», testing on multiple substrates (in DCM, 25 C, 1-8h, 51-91% yield), stating «The methods proposed can be advantageously compared to the ones already described.» Their substrates were obtained via epoxide opening (TMS-iodide) and oxdidation ($\ce{CrO3/H+}$). $\endgroup$
    – Buttonwood
    Apr 21, 2021 at 10:24
  • $\begingroup$ I doubt if there is enough research done on $PX_3$ or $PX_5$ reagents. Your question is still unanswered properly inspite of being heavily upvoted (my doubt too +1) $\endgroup$
    – D13G
    Sep 16, 2023 at 10:49
  • $\begingroup$ pubs.acs.org/doi/abs/10.1021/jo00299a042 $\endgroup$
    – Mithoron
    Dec 20, 2023 at 19:57
  • $\begingroup$ Here is a nice starting point (with references) on ways to add iodine in the alpha position: chemia.manac-inc.co.jp/en/archives/1461 $\endgroup$
    – Karsten
    Dec 24, 2023 at 21:29
  • $\begingroup$ It is possible to make the acyl iodide from an anhydride and red phosphorus/iodine, which seems to make phosphorus triiodide in situ: mentioned in thieme-connect.com/products/ejournals/abstract/10.1055/…. Maybe the problem is the direct synthesis of the acyl iodide from the carboxylic acid that does not happen (i.e. blame the intermediate rather than the reagent). $\endgroup$
    – Karsten
    Dec 24, 2023 at 22:35

1 Answer 1

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[OP] 1. Why are these reaction considered as iodine analog of HVZ reaction? Doesn't HVZ reactions strictly uses phosphorus halides?

If you look at the mechanism (pasted below from Wikipedia), you see that the phosphorus halides are used in catalytic amounts to make some acyl halide. Once the reaction starts, further acyl halide is made from the reaction intermediate.

enter image description here

Source: commons.wikimedia.org/wiki/File:HVZhalogenation.png

So while a strict iodine analog of the HVZ reaction would involve a phosphorus iodide, you could make an argument that adding iodine to an enol of a carboxylic acid derivative is somewhat analogous to the HVZ reaction.

[OP] 2. If these examples are iodine analog of HVZ reaction, why are they producing 2-iodoacyl chloride? They should be producing 2-iodocarboxylic acid.

The bromine version of the HVZ reaction also initially produces 2-bromoacyl bromide. So that is not so different.

[OP] 3. If it is producing 2-iodoacyl chloride, how to get rid of the chloride atom to get 2-iodocarboxylic acid?

I would guess you could carefully add water after the intermediate has formed.

[OP] Is it possible to similarly make alpha-iodo carboxylic acids with the help of HVZ reaction?

It seems that alpha-iodination is much slower than alpha-bromination (for the chlorosulfonic acid promoted reaction, there is a 100-fold difference even when the slower reaction is done at 20 degree higher temperature). Also, it is difficult to make the acyl iodide directly (one way is to convert the acyl chloride). So it is possible that the first, catalytic step to form the acyl halide fails in the case of iodine. At least, it is not described in the literature yet.

An aside

There was an alternate reaction mechanism proposed involving a ketene intermediate by Ogata and Watanabe (1979). However, Ogata and Adachi (1982) found that reaction rates of ketenes with iodine were too fast to explain the reaction kinetics found for the alpha-iodination starting with the carboxylic acid, so they updated their mechanistic proposal, to invoke an enol intermediate as well. So it seems that many, if not all, of the alpha-halogenation mechanisms proceed via an enol intermediate, stabilized in various ways.

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