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There are a number of published procedures for the formation of benzimidazoles from 1,2-diaminobenzenes and benzaldehydes:

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Clearly, an oxidant is required.

Many procedures call for the use of sodium metabisulfite (for example, this one). Yet as far as I can tell, Na2S2O5 should generally act as a reductant, not an oxidant.

What is sodium metabisulfite really doing in these reactions and what is the oxidant? Ideas and proposals are welcome, but what I really want are experimental studies supporting them (published or otherwise).

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6 Answers

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According to paper [1], which cites annother (1965) [2], first step is a formation of aldehyde-bisulphite adduct, which is then attacked by diamine. Still it's not clear what is oxidation source (I have no access to the 2nd article), but I presume it's oxygen.

  1. dx.doi.org/10.1002/ardp.200700088
  2. dx.doi.org/10.1002/jhet.5570020424
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If you make an aldehyde-bisulphite adduct you need acidic conditions to re-form the aldehyde. The first step in these reactions is the formation of an imine which then cyclises according to my scheme above. I think that aromatisation occurs by a radical process as I propose in the scheme. – quintus Jun 20 at 11:47
in the Scheme 2 of paper 1 it is clearly showed that they use bisulphite adduct instead of aldehyde without any acid stronger than water (at least they don't mention any) – tlp Jun 21 at 6:15
Thanks for the doi's. I looked at the reactions listed in Scifinder for paper 1 and they are using acidic conditions in methanol. If you look at the reactions cited they all strike me as somewhat odd, what is the CS2 doing? I shall get the papers and have a read. – quintus Jun 21 at 13:03
In solution you have an equlibrium between the aldehyde and the bisulfite adduct, therefore the aldehyde component reacts with the amine, forcing the equlibrium over to the aldehyde side, forming the imine followed by cyclisation etc. – quintus Jun 23 at 7:00
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 So, it appears that role of metabisulphite in this reaction is to limit reactivity of aldehyde? I just can presume that it's needed for preventing some Tischenko-like side-reactions. – tlp Jun 26 at 7:44
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OK see what you think. This reaction is carried out at high temperature with microwaves. I think the metabisulfite acts as a source of radicals according to my mechanistic scheme alt text

The first steps are easy, formation of the imine, ring closure followed by a radical induced aromatisation process. The radical is a stabilised benzyllic one. Generated is SO2 and sodium bisulfite. Therefore the metabisulfite is neither an oxidant nor a reductant in this process. I would not like to try this on scale as radical processes are notorious for run-away reactions. There are easier ways to make benzimidazoles

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@quintus, interesting idea. Looks like the bisulfite is getting reduced and so is acting as an oxidant. Is there any evidence for radicals in this reaction? Couldn't this also be a concerted process? What other reactions use sodium metabisulfite as an oxidant? – Rich Apodaca Mar 25 at 22:33
I don't think it's concerted. I may have the radical structure incorrect. I am still looking into it, it may be a SO2 radical anion. See Hayon etal, JACS 1972, 91 (1), 47. Certainly the S-S bond is the weakest one here and is very likely to break, especially under these reaction conditions. The S. radical is then probably stabilised by the d-orbitals. Metabisulfite decomposes readily in water to give SO2 and NaHSO3,which led me to think about the radical process for aromatisation. I know of no other reactions using Metabisulfite as an oxidant, but I'm still looking :)) – quintus Mar 26 at 9:22
bye the way, I could not arrive at a reasonable concerted process i.e. 6 membered transition state, nor any sort or cope or other rearrangement mechanism – quintus Mar 26 at 11:04
I just did a Scifinder search, as far as I could see there are no references to sodium metabisulfite as an oxidant! – quintus Mar 26 at 14:29
The scheme of metabisulfite decomposition seems incorrect, the second Na atom would leave as Na(0) according to this scheme and considering final oxidation state of sulphur (+4 in both forms) it looks like it is sodium that oxidizes organic substrate :) I'd rather include oxygen in this scheme. – tlp Apr 20 at 11:10
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The scheme proposed by is just that, a proposal. I obtained a copy of tip's reference 2 (above) here is the scheme from that paper of 1965:

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(I apologise for the quality) They say in the paper "we suggest that the reaction proceeds by way of an alpha-aminosulfonic acid derivative, the normal product from the condensation of amines and aldehyde bisulfite adducts, followed by intra-molecular nucleophillic displacement of sodium sulfite and cyclisation to the benzinidazoline. The rapid dehydration of the latter to the benzimidazole could then be effected by the bisulfite anion acting as an oxidising agent" "An alternate mechanism, whereby the initial condensation product eliminates sodium bisulfite to form a Schiff's base which then cyclises was not supported by experimental evidence."

I can send a copy of this paper to anyone who requires it.

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I might add that I have made benzimadazoles many times, but never by this method, unfortunately you will have to believe me as I can't say how! – quintus Jun 28 at 16:06
well, if metabisulphite is the oxidant, I think some elemental sulphur must evolve during the reaction, and who dealt with this reaction should have noticed that. could you please send me the article (lastpook@gmail.com)? – tlp Jun 28 at 16:19
@quintus, this is exactly the problem I was getting at. It sounds like you found no references to benzimidazole being used as an oxidant. So apparently, there is no precedent for that last step. You might think that any author making such a claim would subject the dihydrobenzimidazole to the reaction conditions, both in the presence and absence of metabisulfite (and in the presence/absence of atmospheric oxygen) to test the hypothesis. I too don't have access to the paper; could you forward me a copy as well? – Rich Apodaca Jun 29 at 14:46
I agree. This was in 1965 from SKF they were only interested in the benzimidazoles. A copy is on it's way – quintus Jun 29 at 15:56
Hey! Quintus!can you send me the reference or the paper? – basu Jul 19 at 11:33
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Normally you have a "nitro-amine" in which you first form amine linkage, then reduce the nitro with something such as sodium dithionite or sodium metabisulfite. This allows for control of the ring position.

check out this paper for use of sodium dithionite

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Can anyone tell me the mechanism of ben-imidazole formation with sodium-metabisulphite in refluxing condition in ethanol?

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are you asking a question or answering one? I proposed a mechanism if you scroll up you will see the scheme. It is only a proposal. – quintus Jun 20 at 6:23
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What is the exact structure of sodium metabisulfite? SciFinder provides two structures, here they are: alt text

If we knew what was the form used for the benzimidazole formation perhaps we would advance in the oxidant question.

By the way, searching both structures in Scifinder as oxidants or oxidising agents or any form of oxidation gives no hits! At least in the sense we require.

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The S-O bond dissociation energy is around 87Kcal/mol, that of the S-S bond around 50-60 (google searches) – quintus Jul 3 at 4:53
I still think, that in the case of benzimidazole formation that is is a radical process, the "oxidation" being initiated by a S radical. – quintus Jul 4 at 6:05

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