A Direct and Simplistic Bromination of Commercially Important Organic Compounds in Aqueous Media by Eco-friendly AlBr3-Br2 Reagent System

A facile, simplistic, highly efficient, environmentally safe, regioselective, controllable and economical method for the bromination of organic compounds using aqueous AlBr3-Br2 reagent system.


Introduction
To date, available research on bromination of organic aromatic compounds in aqueous medium is very few and far between, except only few examples. Ganchegui et al. described the oxybromination of phenol (C 6 H 5 OH) and aniline C 6 H 5 NH 2 subsidiary products using NaBr-H 2 O 2 in H 2 O/scCO 2 (water/supercritical carbon dioxide) biphasic system, howbeit low conversion rate, high temperature (40 °C), longer duration (from 4 to 20 h) and use of surplus amount of reagent (substrate : NaBr : H 2 O; 1 : 3 : 3) are some of the concomitant inadequacies. Furthermore, experiments using dense gases must only be conducted in appropriate equipment and under apposite safety precautions. In recent times, Padgorsek et al. defined an interesting oxidative bromination of triggered arenes using H 2 O 2 -HBr/"on water" system is advantageous since water is the only by-product; though, a very high reaction time (from 8 hr to 28 hr) and the several threats associated with H 2 O 2 make the process of limited industrial utility. The highly lethal 48 per cent aqueous HBr reacts aggressively with many metals with the generation of extremely flammable hydrogen gas, which may burst, which further limits its usage. Other described-on water ‖ and -in water ‖ brominating system are limited only to the synthesis of bromohydrins, α-bromoketones, iodination and benzylic bromination.
Factually hundreds of Br2-based and oxidative bromination reagents have been described for the bromination of organic compounds, some latest reports are given in  3 ,53f poly(4-vinylpyridinium tribromide), DABCO-bromine, pentypyridinium tribromide, ethylene bis(N-methylimidazolium) ditribromide. The bromination of polymer latex has been carried out using bromine emulsion which is prepared by liquefying bromine (Br 2 ) into an aq. solution of wetting agent/surfactant. On the other hand, nothing like such reagent commercialized till date, because of its costly nature, very bad retrieval and recycling of used reagent/agent, waste treatment for large quantities of HBr-byproduct and poor stability of reagents and storage challenges in long period; therefore they are suitable for laboratory-scale requirements only with narrow application range. In the Previous section of the chapter, we have described aq. Al Br 3 -Br 2 system in acetonitrile (MeCN) as a highly effective brominating agent which provided a rapid bromination of industrially important compounds in outstanding yields and pureness. The method is advantageous due to the cost-effective nature of the brominating reagent and high pureness of the wanted products, whereas the usage of organic solvents acetonitrile (MeCN) and the further utility. Consequently, to make the system more industrially-oriented and environmentally-approachable, we tried the bromination of liquid substrates using aq. Al Br 3 -Br 2 can diffuse through the dews of aniline leading to bromination. During the reaction process the bromine (Br 2 ) color vanished instantly resulting the instantaneous synthesis of 2,4,6-tribromoaniline in 96 per cent yield (HPLC pureness 99.7 per cent) within 15 min of reaction time (Table no. 7, entry 19). This result heartened us to brominate the solid substrate (4-nitroaniline) under the similar conditions. As we noticed an instantaneous loss of reddish-brown hue in the round bottom flask and whole Br 2 Organic Compounds in Aqueous Media by Eco-friendly AlBr3-Br2 Reagent System get used within 2-3 minutes of magnificent signifying a prompt interface between the Br 2 and 4-nitroaniline has occurred in the aqueous system. Yellow color crystalline powder in 98 per cent yield of 2,6-dibromo-4-nitroaniline (HPLC purity of 99.08 per cent) was achieved (Table no. 7, entry 16). Cheered by the above resulted outcomes, the bromination of industrially-important compounds using aqueous Al Br 3 -Br 2 solution under aqueous conditions at room temperature without using any organic solvent before and after the completion of reaction, the reaction have successfully been performed While bromination was carried out in water using aq. Al Br 3 system, it offers the following benefits: (1) absence retrieval step and loss of solvent during the recycling procedure that makes the present reaction more appropriate, (2) no addition of water is obligatory after completion of reaction as the brominated product too is insoluble in water in case of acetonitrile solvent, 15 ml water has to be added for 10 ml acetonitrile (MeCN) solvent to separate the precipitated product. This upsurges the overall volume of filtrate thereby upturn the cost of recovery of Al Br 3 from the aq. medium at the completion of reaction, (3) the reaction is functionally-easy and friendly which don't requires heating or cooling, (4) the brominated compound and Al Br 3 recuperated at the end of reaction are in unadulterated form as there is no organic solvent in the reaction mixture for their adulteration and also the only HBr byproduct present in the aqueous filtrate has to be transformed to Al Br 3 (5) the present method leads to zero waste discharge to the surroundings, since from the three components of the reagent, i.e., Al Br 3 , Br 2 and water; one atom of Br 2 was shifted to organic substrate and the other half-forming HBr is again employed back to Al Br 3 by its neutralization with Ca(OH) 2 .
The Al Br 3 of the fresh reaction and additional Al Br 3 produced from HBr nullification was recovered as a crystalline solid by concentrating the aqueous filtrate (14 g Al Br 3 in 20 ml H 2 O similar to collected works procedure). The recovered Al Br 3 has possible industrial value in different sectors i.e; Pharmaceuticals, preservers, and fire retardants etc. have also been employed effectively to rejuvenate the brominating reagent for bromination in consequent batches without any substantial loss of reactivity. Henceforward, at the end of the reaction we have nonentity to dispose to the environment which is justified in view of green chemistry.
Bromination of substituted aromatics compounds using aqueous Al Br 3 -Br 2 system

Objective
Clean and green reaction methods that do not use dangerous organic solvents are reinvigorated and are in excessive demand now. A modern report on "green solvents" determined that the use of solvents like dioxane, acetonitrile, 1-butanol, propanol, acids, acetone, ethyl, formaldehyde and THF are not suggested from an environmental viewpoint. Water, on the other hand, is an auspicious solvent because it is readily available, non-flammable, non-toxic and can give the easy split-up of catalysts or reagents from many aromatic products. To date, water is rarely used in accessible research on bromination of aromatic compounds, which is very limited except few examples. Factually hundreds of Br 2 -based and oxidative bromination reagents have been described for the bromination of organic compounds. On the other hand, no such commercial reagent is available till date, due to their costly nature, poor retrieval and recycling of used reagent, waste treatment for large quantities of HBr-byproduct and poor stability of reagents and storage challenge in long periods; therefore they are suitable for laboratory-scale requirements only with narrow application range. The usage of aqueous AlBr 3 -Br 2 system as the most inexpensive brominating agent and H 2 O as a reaction media exemplifies the most logical and reasonable choice of brominating reagent to fulfill the need of inexpensive, cleaner and most effective system. In simple words, H 2 O fulfills all the requirements in direct synthesis of commercially-important brominated aromatic compounds. In current study, we are presenting, for the first time, a simple and direct bromination of C 6 H 5 OH and C 6 H 5 NH 2 subsidiary products with strong electron-withdrawing groups (EWG) such as carboxylic (-COOH), nitro (-NO 2 ) and formyl (-CHO) as examples of pharmaceutical reaction intermediates under absolutely aqueous conditions.

Experimental i) Reagents and analytics
Reagents and initial material were procured from across, Aldrich and Merck and were used as usual. Only fine powdered form substrates were used during complete reaction process, granulated and scaly substrates were grinded and transformed into fine powder prior to reactions to improve the dissolution factor. Twice as distilled water was used during the complete study, Water model no. 2695 instrument with PDA detector was used for HPLC analysis purpose, column C18 (250mm× 4.6× 5 µ ), solvent scheme of 70 per cent CH3OH + 30 per cent H 2 O, and 1 mL/minute flow rate. HPLC purity is represented by area per cent. Bruker Avance II 400 NMR spectrometer was used for NMR studies and chemical shifts were described by δ ppm; spectra were recorded in DMSO and CDCI3, 1H NMR (comparative to TMS referenced as 0.00 ppm) and 13C NMR (comparative to DMSO referenced as 39.50 ppm). GCMS studies were performed by using "Agilent GC-5893" with chemstation software; HP5-MS-column, with specification 30m × 0.25mm × 0.25µ; constant flow of-2 ml/minutes; mass-director; mass range-14 to 650 amu; detector temp-290℃; injector temp-280℃; injected sample volume-1 microliter of 5 per cent solution in methanol. Mass spectroscopical (MS) data were documented on "Micromass Quattro Micro API triple quadrupole MS" which was equipped with a ordinary APCI ion source. Infrared spectra studies were carried out on a Shimadzu Prestize 21 FT-IR Instrument (KBr, 3400-430 cm -1 ). Isolated compounds were acknowledged on the basis of physical determination and spectroscopic data (13C NMR, 1H NMR, Infrared and Mass Spectroscopy).
ii) A typical synthesis path of 2, 6-dibromo-4-nitroaniline (16) A solution was prepared using AlBr 3 (3.95 g, 20 mmol) in aqueous media (10 ml) and was added to Br 2 (3.25 g, 20 mmol), the resultant mixture was stirred continuously at room temperature till it give clear dark pale yellow solution. Immediately this solution was added to a fine powdered form of 4-nitroaniline (1.3733 g, 10 mmol) booked in a round-bottom flask (100 ml capacity) equipped with a magnetic stirrer using a pressure-equalizing funnel within 2 -3 minutes of time. The bromine color vanished immediately and 2,6-dibromo-4-nitroaniline was achieved (yellowish thick precipitates) within 20 minutes (Monitored by Thin Layer Chromatography) at room temperature. The filtration of precipitated mass was done by vacuum filtration method using Bunchner funnel, and then washed-off with Na 2 S 2 O 3 solution and dehydrated in oven at 100℃. The filtrate was saved for the Later runs. The product was achieved as yellow powder ( iii) Procedure for recycling of Hydrogen Bromide as AlBr3 and reformation of brominating reagent (Recycle 1) The neutralization of filtrate originated from above reaction done by Al(OH) 3 (0.7401 g, 10 mmol) to convert hydrogen bromide into AlBr 3 . Consequently, (3.23 g, 20 mmol) Br 2 was added to the aq. solution containing recycled aluminium tribromide solution was then added fine powder of 4-nitroaniline (1.3813 g, 10 mmol) quickly within 5 minutes taken in a round-bottom flask (100 ml) equipped with a pressure-equalizing funnel and magnetic stirring bar. The thick yellowish precipitates of 2, 6dibromo-4-nitroaniline were attained within 20 minutes at room temperature immediately after adding Br2 color disappeared. By using vacuum filtration the end product was separated from the mother liquor (solution left over after crystallization) and then washed-off with sodium thiosulfate (Na 2 S 2 O 3 ) solution (10 per cent, 10 ml × 3) and dried out in vacuum drying oven at 100℃. A high purity (99 per cent) 2, 6-dibromo-4-nitroaniline yellow powder was achieved in 2.82 g (98.08 per cent) yield with melting point 206℃. The distinguishing data was documented for the isolated product and found similar as given in the above distinctive method.
The hydrogen bromide evolved was again nullified and the aqueous solution was uninterruptedly recycled in the next run with an additional amount of Br 2 .

i) Reaction conditions screening
The dibromination of para-substituted substrate decreases the possible complex mixture of mono-and dibrominated species, thus in order to abridge the analytics, 4-nitroaniline 16 (4-NA) was castoff as a typical substrate in a first-screening in a first-screening for appropriate reaction conditions. To optimize the yield and pureness, the bromine (Br 2 ) and (AlBr 3 ) concentration effects on the end product yield and Mp of 2, 6-dibromo-4-nitroaniline (DBNA) were studied in the dibromination of 4-NA. ii) The effect on yield and melting point of DBNA by mole ration of Br 2 The excellence of the end product is strongly reliant on the mole ratio of Br 2 /4-NA which also has been confirmed by recent studies. It also been initiated that the optimal yield (98 per cent) of 2, 6-dibromo The function of aluminium tribromide (AlBr 3 ) was defensible by performing a blank reaction for 1 h at 25℃ using molecular bromine as a brominating agent which resulted in a composite fusion of under-brominated species that melt from 160 to 190℃. Thus, the result drawn in to conclusion that the optimal mole ratio 1:2:2 of 4-NA to AlBr 3 to Br 2 was establish to be best for the dibromination of 4-NA.

iv) Stirring
For mixing the hydrophobic aromatic substrate with the aqueous inorganic medium and for preventing local high concentrations of active bromo species, as the reaction was prompt, a proficient/effective stirring (750 rpm or higher) was required. The common applicability of this method was recognized when bromination of structurally-different activated aromatic compounds substituted with electron-withdrawing groups were analyzed ( Table 2). It is the revolution of the present bromination reagent (aq. AlBr 3 -Br 2 solution) over a newly reported brominating system (NBS/[Bmim]Br or dioxane) that C 6 H 5 OH and C 6 H 5 NH 2 byproducts with strong electron-withdrawing groups (EWG) such as -COOH, -NO 2 and -CHO were promptly brominated regioselectively in outstanding yields and pureness. The same reported system, however, yields a combination mix of mono-and dibromo products. In the present system, salicylic acid 1 and 4-hydroxybenzoic acid 2 were transformed with quantitative conversion resulting in clean synthesis of 3,5-dibromosalicylic acid (92 per cent yield; 96.2 per cent HPLC purity) and 3,5-dibromo-4hydroxybenzoic acid (94 per cent yield; 99.2 per cent HPLC purity) after 20 min and 15 min, respectively. Pharmaceutically-important aromatic aldehydes (Table 3, entries 3, 4, 5) were also instantaneously synthesized using aq. AlBr 3 -Br 2 system in excellent yields. Under these conditions, acetaniline 6 and benzaniline 7 were regioselectively transformed to their mono-brominated products in very good yields. The regioselectivity witnessed in these reactions matches to that predictable for an electrophilic bromination path modulated by steric effects. We observed that oxine (8) and sulfanilamide (9) could also be efficiently brominated affording pharmaceutically-important 5, 7-dibromooxine (96 per cent yield; 99.67 per cent HPLC pureness) and 3,5-dibromosulfanilamide (94 per cent yield; 96.6per cent HPLC pureness) within 15 minutes. Another antibacterial compound, 2, 4-dibromo-6-nitrophenol was isolated in excellent yield within 20 minutes from 2-nitrophenol (Table  no. 6, entry 10). With the poor reactivity 4-nitrophenol (11) shows outstanding reactivity resulting 2,6-dibromo-4-nitrophenol (94 per cent yield; 97.5 per cent HPLC pureness) within 30 minutes using two equivalent of reagent. Bromination of the same substrate with H 2 O 2 -HBr/'on water, gave 2, 6-dibromo-4-nitrophenol over a period of 24 hr. The advantages of the present system is an regioselective, effective, facilie, and fast bromination of deactivated anilines (Table no. 6, entries 12 to 16) in outstanding end product yields at 25℃ upon simple admixing with aq. CaBr 2 -Br 2 solution which is slightly challenging by other methodologies. 1-Bromo-2-naphthol 17 (92 per cent yield; 96.2 per cent HPLC pureness) was promptly obtained under undistinguishable reaction conditions in excellent yield within 10 minutes of reaction time while for 1,6-dibromo-2-naphthol 18 (97 per cent yield; 96.5 per cent HPLC pureness), within 25 minutes and 2 equivalents of aqueous AlBr 3 -Br 2 solution were necessary. Which represents the position of the electrophilic attack and the number of inflowing Br 2 atoms during reaction process can be structured by controlling the ratio of substrate: aqueous AlBr 3 -Br 2 solution, i.e., 1/1 mono-, 1/2 for di-, and 1/3 for tribromination of aromatic compounds. The use of aqueous AlBr 3 -Br 2 system as the most economical brominating agent and H 2 O as a solvent/reaction medium denotes the most logical choice as a brominating reagent to fulfill the need of inexpensive, cleaner and most effective system for the instantaneous synthesis of commercially-significant brominated compounds. A comparative study of the brominating capability of the aqueous AlBr 3 -Br 2 system with the recently circulated methods is testified in Table 5 which clearly indicates the benefits of the present system over obtainable methods. In this present study, we are presenting, an effective reagent system for electron-withdrawing groups (EWG) like; -COOH, NO 2 and -CHO as examples of pharmaceutical reaction intermediates under purely aqueous conditions. Organic Compounds in Aqueous Media by Eco-friendly AlBr3-Br2 Reagent System  (ACN) as solvents, correspondingly. The only limitation associated with the reaction using water as a solvent is that granular and scaly substrates have to be crushed and ground proceeding to reactions to convert them into fine powders. Since the reaction operates entirely in water and generates absolute zero discharge; it seems very effective valuable from environmental safety point of view to extend this system for other commercially-important compounds. Subsequent, a desireable greener approach to the present study is following by an environmental friendly recycling procedure. The nonexistence of organic waste and organic solvents in the reaction process supported simple separation procedure comprised of filtration of solid phase brominated compounds and the addition of calcium hydroxide powdered form (Ca(OH) 2 ) to the filtrate for the nutralization of hydrogen bromide waste so that the bromine of hydrogen bromide thus fixed as Aluminum bromide. The aqueous filtrate was reclaimed in the next cycle and the reinforced brominating agent was then used to brominate the substrate successively in the next run. By this methodology, very productively and effectively the dibromination of 4-nitroaniline has been carried out for 4 cycles after the fresh batch using 4-NA: Br 2 (1: 2) mole ratio in each run without adding of the fresh aluminium tribromide (AlBr 3 ) to give 2, 6-dibromo-4-nitroaniline within 20 minutes at room temperature. Reprocessing experiments (Table no. 7) shows that for at least 4 cycles followed by the fresh batch, there is no substantial loss of reactivity of the rejuvenated brominating reagent. When the concentration of aluminium tribromide (AlBr 3 ) upturns in the filtrate, then through vaporization process filtrate was concentrated which causes precipitation of AlBr 3 as a crystalline solid and an added amount of AlBr 3 (7 mol) was recuperated after fresh batch + 4 cycles: resulted 1 mol of aluminium tribromide (AlBr 3 ) produced likewise in every cycle by the neutralization of hydrogen bromide by adding Al(OH) 3 . Therefore, starting with 1 mol of 4-NA wrt 2 mol of Aluminium tribromide in the fresh batch, At the end of reaction process we achieved 7 mol of AlBr 3 . Consequently, effectively the byproduct hydrogen bromide has been utilized, and at the end of reaction, process generates zero discharge of organic waste and effluent to the surroundings.

Conclusions
We have testified a rapid, mild, cost effective and facile method for the effective and selective synthesis of pharmaceutically-important brominated intermediates using aq. AlBr 3 -Br 2 system as an instantaneous brominating agent under aqueous conditions. The green features of this practice include no use of organic solvent and an operative utilization of HBr byproduct which lead to zero organic waste and zero waste discharge to the environment, consequently applicable for large scale bromination.