[dipesh747]

Hello,

The reaction I am evaluating is the following:

Cystine + Hydrogen peroxide ---> Cysteic acid

I have evaluated my results and I have obtained a pseudo second order rate constant in respect of Cystine. So this indicates that the stoichiometry of the reaction is the following:

2 Cystine + 6 H2O2 ----> 4 Cysteic acid + (either 8H+ or 4H2 not sure which.)

From the literature it is noted that the rate for this reaction is increased in the presence of paramagnetic Cu  2+ ions. It is also noted that the rate for this reaction is not increased when there are diamagnetic Fe 3+ ions in solution.

An explanation to this is that interaction between Cu 2+ ions and hydrogen peroxide in the presence of base (the pH of the reaction conditions were 10) forms Cu + cations and super oxide anion radical: O2 - (radical)

This indicated to me that the reaction is following a radical anion mechanism for the oxidation of a disulphide bridge involving the superoxide. (I have assumed this because Fe 3+ when reacting with peroxide will not form this superoxide, it may form a hydroxyl radical however, but as the reaction was not faster I assumed this was not the correct reaction path)

So I have got to the stage where I think there is a radical anion mechanism involved and I also think a cyclic formation of of 2 cystines are involved (due to the second order rate)

However I am completely stuck as to proposing a mechanism. If anyone has any ideas as to how this reaction proceeds please let me know!

[dipesh747]

I have come up with this; can anybody tell me if it looks plausible? (I'm not great at organic so I'm not too sure)

R-S-S-R is Cystine

H2O2 + 2OH- ---->  O2- (radical) + 2H2O + e-

O2- (radical) + R-S-S-R -----> O2 + [R-S-S-R (radical)] -  

[R-S-S-R (radical)] -  -----> RS (radical) + RS- this step I'm really not sure about

RS (radical) + R-S-S-R ------> RS+ + [R-S-S-R (radical)] -

RS -  + 3 eqv H2O2 ---------> Cysteic acid

RS+ + OH- ---> RSOH

RSOH + 2H2O2 ---> Cysteic acid

[AWK]

This is not the hydrolysis, this is an oxidation. Oxidation usually show radical chain mechanisms that are difficult for exact presentation.

[dipesh747]

Ok. Do you have any opinions on the mechanism I proposed?

[AWK]

http://tchie.uni.opole.pl/freeECE/S_16_3/Barbusinski_16(3).pdf

[orgopete]

This is not the hydrolysis, this is an oxidation. Oxidation usually show radical chain mechanisms that are difficult for exact presentation.

I really like reactions and mechanisms. I believe one can learn a lot of chemistry from them. It was also useful to read the Barbusinski review of Fenton's reagent or reaction. None the less, I do not find these mechanisms particularly illuminating. For my thinking, I found the mechanism that did not involve radicals the most plausible. I don't want to argue that radical reactions do not occur, they do. In free radical halogenation reactions, I see the logic in a reaction in which an initiation step first occurs which generates radical that then seem to react to reverse the radical forming step. It also seems important that the (each?) radical forming species has sufficient reactivity to drive the reaction forward.

Why should this be a radical reaction? In what way is a radical reaction more plausible than an ionic reaction? I wrote an ionic mechanism for the reductive workup of ozonization reactions with dimethyl sulfide to give an aldehyde and dimethylsulfoxide. I could conceive of similar ionic steps involved in this oxidation.

[AWK]

Why should this be a radical reaction? In what way is a radical reaction more plausible than an ionic reaction? I wrote an ionic mechanism for the reductive workup of ozonization reactions with dimethyl sulfide to give an aldehyde and dimethylsulfoxide. I could conceive of similar ionic steps involved in this oxidation.

Of course, very often we can write a few plausible mechanisms - sometimes more than one  take place in the course of reaction.
But in this case dipesh747 wrote just about Fenton's reaction ("

From the literature it is noted that the rate for this reaction is increased in the presence of paramagnetic Cu  2+ ions. It is also noted that the rate for this reaction is not increased when there are diamagnetic Fe 3+ ions in solution.

")
The presence of very reactive radical species can be  proved by EPR.

[dipesh747]

Why should this be a radical reaction? In what way is a radical reaction more plausible than an ionic reaction? I wrote an ionic mechanism for the reductive workup of ozonization reactions with dimethyl sulfide to give an aldehyde and dimethylsulfoxide. I could conceive of similar ionic steps involved in this oxidation.

I was just following from what I read in an article, it was the only article that suggested a mechanism. They didn't actually suggest a mechanism they just suggested their results supported a radical anion mechanism. They justifed this because they did their reaction in Cu2+ and Fe3+ and the reaction rate was increased in Cu2+ and had no change in Fe3+.

They wrote " The rate of this process is significantly accelerated by   the   presence   of   paramagnetic   Cu2+   ions,   and   this supports   a   radical-anion   mechanism   for  the   oxidation   of disulphide s with hydrogen peroxide under basic conditions. This   mechanism   is   further   supported   by   the   absence   of any accelerating effect on addition of Fe3+  ions, which are incapable of stabilizing radical reacting species." Which now I have done more research into it, doesn't make much sense to me! As their proposed mechanism of Cu stabilisation requires presence of H+, and their reaction was carried out at pH 10 :s

The presence of very reactive radical species can be  proved by EPR.

This has been a group project I have been working on this academic year, however the experimental has finished now and I am doing my write up!

The reason I am trying to find a mechanism is because my supervisor hinted very strongly that I would need one in my report! However this is proving much more difficult than I envisaged

I have come up with an alternative mechanism, however I am not sure how the first step would be achieved/if it could be achieved in my reaction conditions. (H2O2, NaOH, D2O pH 10)

[orgopete]

For me, I am just looking at what you have written here. The disulfide is cleaving homolytically. Why? This suggests a reaction that is occurring in the absence of hydrogen peroxide. Does it? If you mix dimethyl disulfide with cystine, do you get a mixture (in the same time frame of your oxidation)?

When initially presented, it was H2O2 and disulfide. In the scheme, it shows Cu(+2). I can understand they could give different mechanisms. Why didn't you show copper in the initial reaction? In the Fenton reagent paper cited, the initial reaction is with iron. If copper is used, does copper react with hydrogen peroxide?

[dipesh747]

See that is what I can't figure out, I have written the disulphide cleaving like that because I don't know what is happening. If  it is split like that, then the mechanism would make sense from there on in. Is it possible that hydrogen peroxide forms o2 - (radical) and that radical then splits the sulphur sulphur bond....somehow....

The reaction does not proceed without the presence of hydrogen peroxide.

This reactions proceeds without the presence of Cu, however it has been cited that Cu 2+ increases the rate of reaction whilst Fe 3+ does not effect the rate. This is why I have drawn two processes from RS (radical) because it would explain why Cu could increase the rate where as Fe 3+ couldn't. (i.e. iron III is unable to stabilise radical species)

[orgopete]

Please give me some latitude in this. I am not looking anything up. If you have a sulfide, you can easily make a disulfide with hydrogen peroxide or other oxidants. Sulfur is special. It is a good nucleophile and a weaker acid than their  oxygen counterparts. Thioesters are the bio-equivalents of anhydrides because sulfur is a sufficiently weak base to be a leaving group. In the reduction of ozonides, sulfides are the nucleophiles to form sulfoxides. If you oxidize a disulfide, the intermediate is a thioanalog of a thioester. If you oxidize it further, the leaving group should be a still weaker base (RSO^-). RSOH groups dimerize back to RS=OSR.

You should be able to write perfectly fine ionic mechanisms for the oxidations. Since it seems as though you are doing this, if this were a radical reaction, you should be able to trap or react some of the intermediates. Certainly the oxygen radicals should be reactive enough to react with cumene for example. You could just try it and then tell us what happened.

If I remember correctly, you can use other reagents than hydrogen peroxide to do the oxidation of a mercaptan to a sulfonic acid. I think you can use a peracid or bromine. Although radical reaction could be written for them as well, but I think it is an ionic reaction. (At least I find it easier to avoid explaining why the driving force to form electron pairs should result in formation of a radical and that once formed, its objective would be to form an electron pair. I know it can be done. If the reacting species is very reactive or if energy is supplied to homolyze the bond. Then you can follow the cascade to form new and more stable bonds.)

[Babcock_Hall]

Tangential to the OP but perhaps helpful in understanding the chemistry of cysteine is this:  Van Horn, et. al. J Biol Inorg Chem (2003) 8: 601–610
DOI 10.1007/s00775-003-0454-7
Nickel apparently catalyzes formation of disulfides, but one also observes a conversion of the thiol group to a sulfinic acid.