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Author: Subject: my crackpot theory of brominations in acetic acid
clearly_not_atara
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[*] posted on 16-9-2023 at 06:54
my crackpot theory of brominations in acetic acid


There are a few papers describing brominations in acetic acid using a bromide salt + oxidant, such as NH4Br + H2O2 from Rhodium's Archive (link below), LiBr + O2 + cat Cu(OAc)2 (Menini et al 2007, attached) and LiBr + O2 + cat CuBr2 (Yang et al 2009, attached). Strangely these often seem to use a weird source of bromide ions.

There are a few other methods which are less interesting to me, that use N-bromoamides or peracetic acid + bromide salts, but which accomplish basically the same reactions.

Some papers have attributed these reaction to acetyl hypobromite:
https://onlinelibrary.wiley.com/doi/abs/10.1002/kin.20974
https://chemistry.mdma.ch/hiveboard/rhodium/pdf/bd2gbl.perac...
In fact, a Google Scholar search for "acetyl hypobromite bromination" shows dozens of papers claiming to form acetyl hypobromite for the aromatic brominations.

However, this theory is probably wrong. Acetyl hypobromite is unstable to homolytic radical decomposition, aka "the Hunsdiecker reaction". The compound has been isolated and decomposes above 15 C to methyl bromide:
https://pubs.acs.org/doi/pdf/10.1021/jo00936a032

But these reactions generally do not produce methyl bromide, and furthermore solutions of NBS in acetic acid or similar do not produce methyl bromide. I have never seen any paper using these systems describe the evolution of any methyl bromide or side products caused by methyl bromide.

So instead I propose the formation of the dicoordinate Br(OAc)2- anion, which would be analogous to the BrCl2- anion (stable in fuming HCl) and the Br3- anion (some stable tribromide salts). This could form by the following equilibrium:

Br2 + 2 LiOAc <> LiBr + LiBr(OAc)2

particularly via a possible unstable intermediate:

Br2 + AcO- <> AcOBrBr- (tribromide anion with one Br replaced by AcO)
AcOBrBr- + AcO- <> Br(OAc)2- + Br- (nucleophilic substitution)

In general, hydrogen peroxide is not strong enough to oxidize bromide to bromate, and in fact reduces bromate to bromine or bromide:
https://pubs.acs.org/doi/10.1021/ja01367a020
So it was always a little suspect to suppose that "naked" Br+ forms in the reaction with peracetic acid and bromide salts. But when a complex forms, unfavorable oxidations become favorable.

So now we are prepared to suggest the role of Li+ or NH4+ in these reactions: these more acidic cations stabilize the diacetylbromate (I) ion by hydrogen bonding (NH4+) or Lewis-acidic coordination (Li+) where more inert alkali metal cations are less effective. Br+ generally forms linear dicoordinate species (I think VSEPR theory predicts trigonal bipyramidal?), which would leave two oxygens to coordinate to NH4+ or Li+.

NH4Br/H2O2/HOAc: https://erowid.org/archive/rhodium/chemistry/aromatic.bromin...

Attachment: menini2007.pdf (118kB)
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Attachment: yang2009.pdf (602kB)
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[*] posted on 16-10-2023 at 18:51


Hi clearly_not_atara . I’ve often come across your name on these forums over the years of lurking. First and foremost, thank you for the insights and contributions you’ve made to this forum. I’ve only recently joined Sciencemadness, but I have often found your posts to be quite helpful during my days of lurking.

Regarding the Bromination, i agree it is unlikely to be a naked Br+ that is responsible for the reaction. Although Br is known to possess a positive charge in select circumstances, it is usually as a 3 membered cyclic intermediate or bound to other ions like that example you gave of BrCl2(-).

Based on the types of oxidizing agents used in oxidative Brominations (H2O2, CuBr, oxone, etc) I suspect it is likely a radical based Bromination rather than an ionic one. Your diacetyl proposal is plausible certainly, but given that Single electron transfers are a common denominator for the reagents that are typically used I think that a radical mechanism is most likely.

Would love to hear anybody’s thoughts or criticisms on this.

[Edited on 18-10-2023 by SyntheticFunk]
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[*] posted on 17-10-2023 at 03:45


Quote: Originally posted by SyntheticFunk  

Based on the types of oxidizing agents used in oxidative Brominations (H2O2, CuBr, oxone, etc) I suspect it is likely a radical based Bromination rather than an ionic one. Your diacetyl proposal is plausible certainly, but given that Single electron transfers are a common denominator for the reagents typically used I think that a radical mechanism is more likely than an ionic one.


I would agree there. Peroxides are often used to initiate radicalar reactions, and Br• is a known radical, so that seems likely. The best way to test this would be to try and brominate a terminal alkene and see if that results in a Markovnikov (likely bromonium addition) or anti-markovnikov (radical addition) product.
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clearly_not_atara
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[*] posted on 18-10-2023 at 06:13


Keras, I'm not sure I follow. In hydrohalogenation, radical and ionic processes give different regioselectivity because the initiator is either a bromine radical or a hydrogen ion, in either case giving the more substituted carbocation or radical intermediate. But when we have oxidative bromination, we have either a bromine radical or bromine ion, which would seem to give similar effects.

So, I think that some other process would be necessary to distinguish between radical and ionic reaction mechanisms. My expectation would be that a radical reaction with toluene would go to the alkyl, while an ionic reaction would go to the ring. But toluene might not be reactive enough, so you'd have to use a methoxytoluene or something.




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[*] posted on 18-10-2023 at 08:58


I have to agree that this looks like a radical reaction to me as well, not that I am any expert, but those are easy to initiate in many cases, and I think that in acetic acid, it would be easy to create enough radicals to work. If you added some radical scavengers and looked for a decrease in reaction, or added more radical initiators and looked for an increase, that might help prove the mechanism. But there is also the possibility that more than one mechanism may be occurring, as that happens in some cases, like for SN1 or SN2 in secondary carbons, where sometimes there is some of each.
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[*] posted on 18-10-2023 at 11:48


I think a couple of y’all are missing the point: not all oxidative brominations go by a radical mechanism. That is abundantly clear because you can access products that couldn’t reasonably come from reaction with Br• while avoiding products that would. You don’t get aromatic ring bromination with radicals. That points to the formation of a Br+ species of some kind. The question is what exactly is this species.



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[*] posted on 20-10-2023 at 12:37


Hmm, yes it appears as though I spoke without reading the attached links carefully enough. Such as the Erowid link which features an aromatic bromination using NH4Br and H2O2 with quite good regioselectivity (even when a benzyl carbon is available to be brominated).

The selectivity arises because benzyl radicals are resonance stabilized, but phenyl radicals are rather unstable due to the radical-containing orbital lying perpendicular to the conjugated pi-orbitals. Thus is in all likelihood not a radical based mechanism as I had suggested earlier. Come to think of it, I did an oxidative bromination on benzene a while back using oxone which would also be required to follow an ionic mechanism.

In this case, a hypobromite species as initially suggested by cleary_not_atara seems plausible. I'm not too familiar on the homolysis he mentioned, but I would believe it. But if the characteristic MeBr byproduct is not observed...hmm... I've seen several methods which have some amine (usually an inorganic amine) present, perhaps it proceeds through a haloamine intermediate? One could test this by comparing the results of using different amines. Once using an inorganic ammonium compounds, once with an amino acid (oxidative decarboxylation should occur yielding CO2 which is easily detecting), an amide (to see if a Hoffman rearrangement occurs), and lastly a tertiary amine (perhaps quarternary?) amine to see if the reaction can still proceed if a N-Br bond is unable to form as an intermediate.

There are likely easier ways, just spitballing here.



[Edited on 20-10-2023 by SyntheticFunk]
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