Aromatic Bromination with NH4Br/H2O2/HOAc

[Rhodium]

Novel Bromination Method for Anilines and Anisoles Using NH₄Br/H₂O₂ in Acetic Acid
K.V.V. Krishna Mohan, N. Narender, P. Srinivasu, S.J. Kulkarni, K.V. Raghavan

Synthetic Communications 34(12), 2143-2152 (2004)

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/aromatic.bromination.nh4br-h2o2.html)

Abstract
A simple, efficient, regioselective, environmentally safe, and economical method for the oxybromination of anilines and anisoles without catalyst is reported. The electrophilic substitution of bromine generated in situ from ammonium bromide as a bromine source and hydrogen peroxide as an oxidant for the first time.




General Procedure for the Bromination of Anilines and Anisoles

A 25 mL two-necked round bottomed flask was charged with the substrate (2 mmol) and ammonium bromide (2.2 mmol) in acetic acid (4 mL). A 30% H₂O₂ (2.2 mmol) was added dropwise to the reaction mixture and the contents allowed to stir at room temperature. The reaction was monitored by thin layer chromatography (TLC). After the completion of the reaction, the reaction mixture was treated with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic extract was dried over anhydrous sodium sulfate and solvent evaporated under reduced pressure. The products were purified by column chromatography and confirmed by ₁H-NMR and mass spectra.

[Nicodem]

I have a similar one which uses a water/DCM two phase system and does not require acetic acid (which for me is harder to acquire compared to DCM). Besides it also makes the work up easier.
Given that this type of halogenation is quite practical and might come handy to somebee, I’ll add here a representative write up. It is however not limited to this substrate. It worked well also with anisol and even p-methoxy-benzylchloride, but would probably fail for toluene and the less activated substrates. Its major limitation however is the requirement for the substrate to bee insoluble in the acidic aqueous phase. Therefore 2,5-DMA is out of play. But if you use its N-acetyl protected version or its nitroalkane version just after the NaBH4 reduction of the nitrostyrene, well, then probably yes.

2,5-dimethoxy-bromobenzene: In a 500ml RBF with magnetic stirring were added in this sequence: 200ml 18% sulphuric acid, 23.1g potassium bromide (194mmol), 120ml dichloromethane and 25g 1,4-dimethoxybenzene (181mmol). When all the solids dissolved in their appropriate phases and the temperature of the liquid fell at about 7°C (the external level of that season ) the slow addition of 25ml 30% hydrogen peroxide (228mmol) from a dropping funnel was started drop wise to last for one hour. This generates the orange-reddish color of bromine in both phases and addition should be slow enough to give it time to get consumed. Some heat is generated and care should be taken not to let it rise above 25°C. The mixture was let stirring for one additional hour and then put on a water bath and stirred at around 35°C for half hour in order to get the bromine consumed (take care not let the bromine and DCM escape – cover the exit, but loosely).
The phases were separated and the DCM phase washed with 100ml aqueous ascorbic acid solution (~1g/100ml). This caused the color to shift from slight orange-red to light yellow. The DCM phase was further washed with 5% NaHCO3, brine and dried over anhydrous Na2SO4. The DCM was distilled off for further use and the remaining oil was freed from any remaining solvent under vacuum while on a water bath.
The remaining yellow oil was left in the refrigerator for a few days (only because I had other work) and some crystals formed. These were filtered off giving 32.5g of 2,5-dimethoxy-bromobenzene, a golden yellow oil (83%). The crystalline solids, presumably mostly 1,4-dibromo-2,5-dimethoxybenzene amounted to 2.7g (~5%).

An analogous procedure, but using KMnO4 instead of H2O2 is described in

Post 472828

(Nicodem: "2,5-Dimethoxybromobenzene Chloromethylation", Novel Discourse).