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The 2020 IChO Preparatory Problem List (source here) had the following reaction as part of the solution to the first question:

Bromination of 2-isopropyl anisole

(CAN = Ceric Ammonium Nitrate).

What is the mechanism for this 'Electrophilic Substitution' of the ring? I have not encountered such a reaction before. As far as I'm aware, CAN is an oxidizing agent, whereas Lithium Bromide would dissociate to give $\ce{Br-}$, which is not an electrophile. Aromatic Nucleophilic Substitution (ArSN) is out of the question here, as the ring is highly activated by the methoxy group.

The only probable reaction I can think of is that CAN successively oxidizes $\ce{Br-}$ to $\ce{Br2}$, then to $\ce{Br+}$, but this seems unlikely, and I could not find such a reaction mentioned anywhere in literature. A mechanism for this reaction, preferably along with a reference, would be much appreciated.

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  • $\begingroup$ Is CAN and KBr a good enough similarity? $\endgroup$ – Safdar Aug 24 at 17:57
  • $\begingroup$ shodhganga.inflibnet.ac.in/bitstream/10603/119795/10/… The reaction is present with a yield of 90% Page 24 $\endgroup$ – Safdar Aug 24 at 18:00
  • $\begingroup$ I'm inclined to think that it is more likely that CAN is oxidising the aromatic to a radical cation intermediate that is then captured by Br-. If you have access (I do not) this review may cast some light pubs.acs.org/doi/10.1021/cr068408n $\endgroup$ – Waylander Aug 24 at 18:09
  • $\begingroup$ @Waylander: I think OP's suggestion is correct. This is similar to iodination of salicylamide in the presence of $\ce{NaI/NaOCl}$ (doi.org/10.1021/ed085p1426). $\endgroup$ – Mathew Mahindaratne Aug 27 at 9:25
  • $\begingroup$ You are correct as the answer below demonstrates $\endgroup$ – Waylander Aug 27 at 11:21
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First of all, the linked paper clearly points out the following:

Hint: In second step (A $\rightarrow$ B), combination of lithium bromide and cerium(IV) ammonium nitrate (CAN) is used as a brominating reagent

From a problem solving perspective, this step is trivial for someone who has read the problem well (not me, unfortunately :)


Ceric Ammonium Nitrate is a very strong oxidizing agent and has the ability of oxidizing benzene compounds first to Nitrobenzene, then to quinone or quinoid derivatives1. Assuming this line of reasoning works, the quinoid derivative could then undergo nucleophilic addition with $\ce{LiBr}$, followed by workup with acid to give the p-subsituted benzene derivative. This could be a probable reaction mechanism, if the substitutent was $\ce{-OH}$ instead of $\ce{-OMe}$ and if an acid workup step was involved. Also, this mechanism can give the unwanted product 4-bromo-3-isopropylphenol, as shown below:

Possible reaction mechanism

However, this reaction mechanism is very speculative, and it also won't hold good here, because the substituent is $\ce{-OMe}$. Some further research on the links provided in the comments2 yielded the following results:

Alkyl aromatics were brominated in the side chain using sodium bromide and CAN. Asakura et al. reported bromination of C-5 of uracil nucleosides using CAN and lithium bromide in acetonitrile.

This is also the reaction present in (3), which seems to have been lifted without a citation to Asakura et al.

Linked reaction in reference

Finally, Asakura et al. 4 provides a suitable mechanism for this reaction, which I correctly assumed arose from the oxidation of $\ce{Br-}$ to $\ce{Br2}$, and then to $\ce{Br+}$

I'm a geeenius! Yayyyy!!!

References:

  1. Nikishin, G. I., et al. “Reaction of Aromatic Hydrocarbons with Cerium Ammonium Nitrate.” Bulletin of the Academy of Sciences of the USSR Division of Chemical Science, vol. 24, no. 6, June 1975, pp. 1328–29. doi:10.1007/BF00922077.
  2. Nair, Vijay, and Ani Deepthi. “Cerium(IV) Ammonium NitrateA Versatile Single-Electron Oxidant.” Chemical Reviews, vol. 107, no. 5, May 2007, pp. 1862–91. doi:10.1021/cr068408n.
  3. Cerium (IV) Ammonium Nitrate mediated oxidative transformations of diaryl methylenecyclopropanes. Shodhganga link
  4. Asakura, Junichi, and Morris J. Robins. “Cerium(IV)-Mediated Halogenation at C-5 of Uracil Derivatives.” The Journal of Organic Chemistry, vol. 55, no. 16, Aug. 1990, pp. 4928–33. doi:10.1021/jo00303a033.
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