Environmentally-Benign and Rapid Bromination of Industrially

Dec 17, 2010 - Lalit Kumar,* Tanu Mahajan, Vivek Sharma, and Dau Dayal Agarwal. Department of Industrial Chemistry, Jiwaji UniVersity, Gwalior-474011,...
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Ind. Eng. Chem. Res. 2011, 50, 705–712

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Environmentally-Benign and Rapid Bromination of Industrially-Important Aromatics Using an Aqueous CaBr2-Br2 System as an Instant and Renewable Brominating Reagent Lalit Kumar,* Tanu Mahajan, Vivek Sharma, and Dau Dayal Agarwal Department of Industrial Chemistry, Jiwaji UniVersity, Gwalior-474011, Madhya Pradesh, India

Selective bromination of various industrially and pharmaceutically important substituted aromatics using an aqueous CaBr2-Br2 system as an instant and renewable brominating reagent is disclosed. The direct bromination of anilines and phenols with molecular bromine in solution often results in polybromination, and when brominated in the presence of oxidants, they also get oxidized rather than undergoing substitution and, in some cases, require protection of the amino (-NH2) group. We report instantaneous, facile, and regiospecific bromination of industrially important substituted anilines, phenols, aldehydes, and anilides in excellent yields and purity under ambient conditions. The byproduct HBr waste has been utilized effectively, and the brominating reagent has been rejuvenated and reused in the subsequent brominations without any significant loss of reactivity. Introduction Brominated aromatics are key intermediates in the synthesis of a wide variety of pharmaceutically active molecules1 and fine chemicals2 that find applications as antitumor, antifungal, antibacterial, antiviral, pesticides, and flame retardants. The use of molecular Br2 for large scale bromination is very common in industries, in spite of its corrosive nature, under-brominated or polybrominated products, and low selectivity at ambient temperature. A variety of new bromination techniques have been employed along with the conventional reagent “bromine” to increase the efficiency and selectivity. Examples are Br2/ SO2Cl2,3 Br2/SbF3/HF,4 Br2/Ag2SO4,5 Br2/H2O2,6 Br2/H2O2/ LDH-WO4,7 Br2-silica or clay supported ZnBr2,8 etc. However, the use of toxic/corrosive materials (SO2Cl2, SbF3/HF, H2O2) or volatile organic solvents and discharge of hazardous HBr waste as effluent makes these processes cumbersome with respect to (wrt) both industrial and environmental viewpoints. Oxybromination (e.g., LiBr/CuBr2/O2,9 NaBr/HNO3/H2O2-WOx supported on SBA-15,10 Bu4NBr/AlBr3/NH4VO3/O2,11 KBr/ HNO3/(CH3CO)2O,12 etc.), on the other hand, can be a good alternative, yet these reactions require a great excess of the reagents (LiBr),9 strongly acidic conditions (H2SO4, HNO3),10,12,13 expensive metal or other catalysts (e.g., V, Mo, Cu, TiOx, WOx),10,11,13 and hazardous oxidants (H2O2, HNO3-(CH3CO)2O)10,12 which raise reagent prices and release dangerous pollutants to the environment. Consequently, no such oxidative method has been commercialized until now for the synthesis of industrially important brominated compounds because of the hazards14 associated with H2O2. Alternative analogues of bromine, such as tetralkylammonium tribromides,15 pentylpyridinium tribromide,16 ethylene bis(N-methylimidazolium)ditribromide,17 [BMPy]Br3,18 and [Hmim]Br319 have also been used for the bromination of aromatic compounds. Nevertheless, these brominating agents are saddled with various drawbacks including their low atom economy, disposal of toxic and corrosive HBr byproduct waste, poor recycling of spent reagent, and the molecular bromine required for their preparation. Hence, to eliminate a two-step bromination wherein these reagents are first * To whom correspondence should be addressed. Telephone: +919993267029. E-mail: [email protected].

prepared using molecular Br2 prior to bromination of organic compounds, we have effectively utilized molecular Br2 at the first place along with an environmental-friendly reagent CaBr2 for an instant and facile bromination of industrially important compounds. Due to the above reasons, molecular Br2 is still a target alternative for industrial chemists to develop an environmental-friendly brominating system which works under ambient conditions. Keeping this in mind, we find an aq CaBr2-Br2 system to be a better alternative. An aqueous CaBr2-Br2 solution as brominating agent has several advantages: costeffectiveness, low toxicity to humans, easy availability, rapid bromination under ambient conditions, regeneration and reusability of reagent up to four cycles by an inbuilt recycling of HBr to CaBr2, and the exceedingly simple and clean workup of products that represent an important goal in the context of “green” synthesis. We have recently studied the synthesis of tetrabromobisphenol-A (largest-selling flame retardant), including kilogram-scale bromination.20 The work was extended and found that aq CaBr2 is a good choice as solvent for bromine and as catalyst in the bromine-transfer reaction. This system (CaBr2-Br2) has the following advantages: (a) the CaBr2-Br2 system is an instant and superior brominating agent compared to the KBr-Br2 system21 in terms of yield and reaction conditions when it comes to the bromination of anilines and phenols containing an electron-withdrawing group, (b) Ca2+ is more environmentallyfriendly than K+, (c) organic compounds (Table 1) are brominated in higher yields using acetonitrile as solvent while the KBr-Br2 system requires acetic acid and H2SO4 as solvent and catalyst, respectively. A comparison of the brominating ability of the aq KBr3 and aq CaBr2-Br2 system is reported in Table 1. We report how an aqueous CaBr2-Br2 system without added catalyst and oxidant is an efficient and “greener” method for bromination of commercially important aromatics under mild and HBr waste-free conditions (Scheme 1). A series of industrially important substituted anilines, phenols, aldehydes, and anilides were subjected to bromination (Scheme 2). Aromatic amines were also examined and show a remarkable reactivity,

10.1021/ie101498p  2011 American Chemical Society Published on Web 12/17/2010

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Table 1. Comparison of Bromination of Substituted Anilines and Phenols between Aq KBr3 and Aq CaBr2-Br2

a Reaction conditions: Substrate, 10 mmol; Substrate/KBr/Br2 ) 1:1:1 (for mono-), 1:2:2 (for di-), and 1:3:3 (for tribromination); AcOH, 10 mL; water, 5 mL; H2SO4, 1 mL; temp, 25 °C; ref. 21. b Reaction conditions: Substrate, 10 mmol; Substrate/CaBr2/Br2 ) 1:1:1 (for mono-), 1:2:2 (for di-), and 1:3:3 (for tribromination); MeCN, 10 mL; water, 5 mL; temp, 25 °C.

Scheme 1

Scheme 2. Bromination of Substituted Aromatics Using an Aq CaBr2-Br2 System

which actually get oxidized under usual bromination conditions rather than undergoing substitution.22 Experimental Section General. Analytical reagent grade starting material, reagents, and solvents were obtained from commercial suppliers and were used without further purification. HPLC analyses were conducted using a Waters 2695 instrument with PDA detector, column C18 (250 mm ×4.6 mm × 5 µm), solvent system of

70% CH3OH + 30% H2O, and flow rate of 1 mL/min. HPLC purity is reported by area %. 1H NMR spectra were recorded at 400 MHz in CDCl3 solution on a Bruker Avance II 400 NMR spectrometer and are reported in ppm using tetramethylsilane (TMS) as an internal standard. Mass spectra were recorded on Micromass Quattro Micro API triple quadrupole MS equipped with a standard APCI ion source. The UV spectra were recorded on a Chemito Spectrascan UV-2600 double beam UV-visible spectrophotometer in the wavelength range of 200-400 nm. Typical Procedure for the Bromination. Synthesis of 2,6-Dibromo-4-nitroaniline 1l. To a solution of CaBr2 (3.99 g, 20 mmol) in water (5 mL) was added bromine (3.2 g, 20 mmol), and the resulting mixture was stirred at 25 °C to form a dark reddish-brown clear solution. This solution was added rapidly to a stirred mixture of 4-nitroaniline (1.3813 g, 10 mmol) in MeCN (10 mL) taken in a 100 mL round-bottom flask by utilizing a pressure-equalizing funnel within 2 to 3 min. The bromine color disappeared at once and yellowish thick precipitates of 2,6-dibromo-4-nitroaniline were obtained within 5 min (monitored by TLC) of reaction time at 25 °C. The reaction was quenched by adding water (15 mL) to separate the precipitated product. The precipitated reaction mass was separated by vacuum filtration utilizing a Buchner funnel, then washed twice with deionized water, and dried in oven at 100 °C to get a yellow powder of 2,6-dibromo-4-nitroaniline. The total isolated yield was 2.9033 g (98.11%) with an HPLC purity of 99.52%. The filtrate was rescued for the next run. The

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characteristic data recorded for the isolated product were mp 206 °C (lit.23b 206-208 °C). IR (KBr): 3480, 3372, 3084, 2922, 2666, 2363, 1605, 1501, 1474, 1383, 1300, 1270, 1126, 943, 897, 821, 737, 695, 575, 532, 457 cm-1. 1H NMR (400 MHz, DMSO) δ: 8.21 (s, 2H, Ar), 6.79 (s, 1H, NH2) ppm. MS (APCI): calcd. for C6H4Br2N2O2 [M]+ 295.9; found, 295.2. Procedure for Regeneration and Reuse of CaBr2 (Recycle 1). The filtrate (30 mL) originating from the above reaction was neutralized by adding CaCO3 (1 g, 10 mmol) to convert HBr into CaBr2. Acetonitrile was distilled-off, and bromine (3.2 g, 20 mmol) was added to the aqueous solution to regenerate the brominating reagent. In a 100 mL roundbottom flask, 4-nitroaniline (1.3813 g, 10 mmol) and acetonitrile (distilled-off in the above experiment) were charged. The aq CaBr2-Br2 solution was added rapidly within 3 to 4 min to the stirred solution of 4-nitroaniline by utilizing a pressureequalizing funnel. Instantly following addition, the bromine color disappeared and yellowish thick precipitates of 2,6dibromo-4-nitroaniline were obtained within 10 min of reaction time at 25 °C. The precipitated 2,6-dibromo-4-nitroaniline was separated from the mother liquor by vacuum filtration and then washed twice with deionized water and dried in oven at 100 °C. The 2,6-dibromo-4-nitroaniline was obtained in 2.9006 g (98.02%) yield with mp of 206 °C and purity of 99.42%. The characteristic data recorded for the isolated product were found to be same as given in the above general procedure. The HBr evolved was again neutralized; solvent was distilled-off, and the aqueous layer was reused in the next run with an additional amount of Br2. Procedure for Recycle 2, 3, and 4. Identical to the above procedure of Recycle 1, bromine (3.2 g, 20 mmol) was added to the aqueous layer obtained after the separation of 2,6dibromo-4-nitroaniline and the reaction proceeded in a similar fashion with 4-nitroaniline (1.3813 g, 10 mmol) in every cycle. Procedure for the Synthesis of 4-Bromoacetanilide 1a. The procedure was the same as that given in the general procedure for the synthesis of 2,6-dibromo-4-nitroaniline except 1 mol equiv of CaBr2-Br2 was charged wrt 1 mol of acetanilide. Starting with acetanilide (1.3517 g, 10 mmol), the workup afforded shining-white crystals of 4-bromoacetanilide in 2.1186 g (99%) yield within 10 min of reaction time (monitored by TLC) at 25 °C; mp 167 °C (lit.23a 165-169 °C). IR (KBr): 3293, 3260, 3186, 3115, 3052, 1668, 1644, 1601, 1586, 1532, 1487, 1394, 1309, 1290, 1255, 1007, 831, 819, 740, 687, 504 cm-1. 1H NMR (400 MHz, DMSO) δ: 2.1 (s, 3H, CH3), 7.25 (d, J ) 8.4 Hz, 2H, Ar), 7.52 (d, J ) 8.8 Hz, 2H, Ar), 9.73 (s, 1H, NH). MS (APCI): calcd. for C8H8BrNO [M]+ 216.07; found, 216. Procedure for the Synthesis of 2,4,6-Tribromoaniline 1c. Here, 3 mol equiv of CaBr2-Br2 was taken wrt 1 mol equiv of aniline, and the reaction progressed in a manner as described above in the general procedure. Starting with aniline (0.9313 g, 10 mmol), the workup afforded shining-white fine needles of 2,4,6-tribromoaniline instantaneously within 5 min of reaction period at 25 °C in 3.202 g (97%) yield (monitored by TLC); mp 120 °C (lit.23a 120-121 °C). IR (KBr): 3414, 3293, 1452, 1383, 1285, 1225, 1063, 858, 729, 706, 673, 546, 486 cm-1. 1 H NMR (400 MHz, CDCl3) δ: 7.5 (s, 2H, Ar), 4.54 (br. s, 2H, NH2). MS (APCI): calcd. for C6H4Br3N [M]+ 329.816; found, 328.8. Experimental Procedure for UV-Visible Measurements. The measurements were carried out at 25 °C in the 200-400 nm wavelength range. An aqueous CaBr2-Br2 solution was prepared by adding a solution of 2.6 × 10-4 M Br2 to a solution

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of 2.0 × 10 M CaBr2, and the UV spectrum was recorded by taking the above solution in a cuvette using a micropipet. When higher than expected absorption occurred in the 200-400 nm range, the solution was discarded and a suitable diluted aliquot of aq CaBr2-Br2 solution was drawn into the cuvette with the help of a micropipet, and a spectrum was recorded that gave an intense band of Br3- at 266 nm. An aliquot of 2 × 10-4 M solution of salicylic acid dissolved in MeCN was then added to a cuvette which was half-filled with aq CaBr2-Br2 solution. The spectrum was recorded, and an absorption peak at 312 nm was obtained that corresponds to 5-bromosalicylic acid. Results and Discussion Aqueous CaBr2-Br2 is a mild, efficient, and cheap brominating reagent which is readily prepared by adding molecular Br2 to an aqueous solution of CaBr2 at room temperature (25 ( 1 °C). The brominating reagent was rapidly added to a stirred solution of 10 mmol of substrate dissolved in 10 mL of solvent (Table 2). In our system, a maximum quantity of brominated product is formed within minutes. When the reaction was completed, the reaction mixture was quenched into water and solid brominated product was filltered-off, washed with water, and dried. The end product does not require further purification. The products were identified by melting point, mass, and NMR; the yields were calculated by the weight. The system has been successfully applied to a variety of industrially important substrates (Table 2). Moreover, the regioselectivity of the reactions is in agreement with the known directing ability of the substituent groups. The para-substituted product was the only isomer isolated where both ortho- and para-substitution was possible. Para-substituted aromatics were brominated in the ortho-position. Introduction of an electron-withdrawing group to the aromatic ring substantially decreased the rate of ring bromination. Initially, the dibromination of 4-nitroaniline (4-NA) 1l as a model compound using 2 equivalents of aq CaBr2-Br2 in various solvents was examined. The solvents acetonitrile, methanol, acetic acid, and dichloromethane were tried. It was found that acetonitrile has proved to be excellent in the dibromination of 4-nitroaniline to obtain 2,6-dibromo-4-nitroaniline (DBNA) within 10 min wrt yield (98%), melting point (206 °C), color (yellow crystalline powder), and texture of the product. Next, the effects of the concentration of Br2 and CaBr2 on the yield and melting point of 1l were examined in acetonitrile. It is quite obvious from Figure 1 that the quality of the product is strongly dependent on the mole ratio of Br2/ 4-NA. It has been found that the optimum yield (98%) of DBNA and the desired melting point of 206 °C (lit.23b 206-208 °C) are obtained at the mole ratio of Br2/4-NA ) 2/1 in the bromination of 4-NA using an aq CaBr2-Br2 system as brominating agent. The yield of the product becomes static if we further increase the mole ratio from Br2/4-NA ) 2.0 to 2.2. The yield of the product drops to 93% with a melting point of 198-200 °C (not within the required standards) if we decrease the mole ratio of Br2/4-NA from 2.0 to 1.8. An under-brominated product (yield: 88%) is obtained which melts from 160 to 170 °C when we further decrease the mole ratio from 1.8 to 1.65. It is noticed that at mole ratio of Br2/4-NA ) 1.5 and 1.25, monobrominated 4-nitroanilines were obtained that melt at 102 °C and 100-101 °C, respectively (mp of 2-bromo-4-nitoaniline is 104 °C23b). Figure 2 shows an identical pattern in the increase of mole ratio of CaBr2/4-NA from 0.25 to 2.0 in the bromination of 4-NA using an aq CaBr2-Br2 system as brominating agent; the optimum yield and desired melting point are obtained at

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Table 2. Bromination of Various Aromatics Using an Aq CaBr2-Br2 Systema

mole ratio of CaBr2/4-NA ) 2/1. The melting point does not change considerably, but the yield of the product increases from 91 to 98% when we increase the mole ratio of CaBr2/4-NA from 0.25 to 2.0. The role of CaBr2 was confirmed by conducting a reaction for 1 h at 25 °C using molecular Br2 as the only brominating agent where a complex mixture of under-brominated 4-nitroaniline was obtained that melts from 160 to 190 °C. Thus, from the above observations, it is concluded that the optimum mole ratio of 4-nitroaniline to CaBr2 to Br2 (1:2:2) was found to be ideal for the dibromination of 1l. It is noticed that the LC-MS analysis of final product obtained at the above mole ratio shows 99.52% pure 2,6-dibromo-4-nitroaniline,

0.42% monobrominated 4-nitroaniline, and 0.06% starting material (Table 3, entry 6). Under these conditions, bromination of acetanilide 1a and benzanilide 1b took place selectively and only para-brominated products were isolated in excellent yields, with no detectable ortho-bromo or dibromo compounds. Aniline 1c and phenol 1d were instantaneously tribrominated to their corresponding bromo-derivatives in excellent yields (97% with 1:3:3 molar ratio of substrate/CaBr2/Br2). If both meta- and o,p-directing groups are present on the ring, it is the o,p-directing group that directs the incoming bromonium ion as observed in case of o-nitrophenol 1e. The brominating system was also used to

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Table 2. Continued

a Confirmed by comparison with authentic samples. All the reactions were carried out on 10 mmol scale; molar equivalents of substrate/CaBr2/Br2 ) 1:1:1 (mono-), 1:2:2 (di-), and 1:3:3 (tribromination); MeCN, 10 mL; water, 5 mL; temp, 25 °C. b Yield of isolated pure product.

Figure 1. Effect of mole ratio of Br2/4-nitroaniline on the yield and melting point in the bromination of 4-nitroaniline to 2,6-dibromo-4-nitroaniline using aq CaBr2-Br2. Reaction conditions: Substrate, 10 mmol; CaBr2, 20 mmol; MeCN, 10 mL; temp, 25 °C; time, 10 min.

Figure 2. Effect of mole ratio of CaBr2/4-nitroaniline on the yield and melting point in the bromination of 4-nitroaniline to 2,6-dibromo-4nitroaniline using aq CaBr2-Br2. Reaction conditions: Substrate, 10 mmol; Br2, 20 mmol; MeCN, 10 mL; temp, 25 °C; time, 10 min.

brominate anilines containing an electron-withdrawing group at ambient temperature. Various deactivated anilines 1g-1l were efficiently and rapidly brominated upon simple admixing with an aq solution of CaBr2-Br2, which is rather tedious by other methodologies.24 We found that oxine 1m and sulphanilamide 1n could also be effectively brominated affording pharmaceutically important 5,7-dibromo-oxine and 3,5-dibromosulphanilamide in yields of 95 and 93%, respectively, within 15 min of the reaction period. Substrates 1p and 1q showed good reactivity resulting in a clean synthesis of 2,4-dibromo-1-naphthol (97%) and 3,5-dibromosalicylic acid (91%) after 15 and 20 min, respectively. The aldehydes 1o and 1r were also smoothly

brominated in excellent yields (97 and 94%) using 2 equivalents of aq CaBr2-Br2 solution. β-Naphthol 1s was instantaneously brominated under identical reaction conditions in good yield (97%) within 5 min, while for 1t 30 min of reaction time and 2 equivalents of aq CaBr2-Br2 were necessary. Another industrially important compound 5-bromovanillin 1u was also obtained in good yield within 30 min from vanillin. This substrate undergoes bromination over longer times and with low yields.25 Table 3 features the HPLC purity of some representative brominated products which concluded that mono-, di-, and tribrominated products can be regioselectively obtained in high yields by merely increasing the molar equivalents of substrate/

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Table 3. Product Selectivity wrt Starting Material in the Bromination of Various Aromatics Using an Aq CaBr2-Br2 System

a

Isolated yields. b Purity determined by HPLC.

CaBr2/Br2, i.e., 1:1:1 for mono-, 1:2:2 for di-, and 1:3:3 for tribromination of aromatic compounds. We further upgraded our “green” approach to bromination by adopting an environmental-friendly workup procedure. The absence of organic waste and chlorinated organic solvent in the reaction enabled a simple isolation procedure composed of filtration of solid brominated product and the addition of powdered CaCO3 to the filtrate for the neutralization of HBr byproduct waste so that the bromine atom of HBr thus fixed as CaBr2. This process generates an additional amount of CaBr2 in the filtrate. The solvent was distilled-off and reused in the next run (Scheme 3) [eq 1]. 2HBr + CaCO3 f CaBr2 + CO2 + H2O

(1)

For the next run, the molecular Br2 was added to the filtrate containing recycled CaBr2 and the regenerated brominating reagent was then used to brominate the substrate. In this way, the dibromination of 4-nitroaniline has been carried out successfully for four times using Br2/4-NA (2:1) mole ratio in each run without addition of the fresh CaBr2 to afford 2,6-dibromo4-nitroaniline within 10 min at 25 °C. Details regarding the process are given in the experimental part, and the results are presented in Table 4. When concentration of CaBr2 increases in the filtrate, the filtrate was concentrated by evaporation which

Scheme 3. Bromination Cycle Showing Regeneration and Reusability of CaBr2

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Table 4. Recyclability and Reusability of CaBr2 and MeCN vs Product (2,6-Dibromo-4-nitroaniline) Yield and Purity in the Bromination of 4-Nitroanilinea cycle fresh batch recycle 1 recycle 2 recycle 3 recycle 4

appearance yellow yellow yellow yellow yellow

powder powder powder powder powder

mp, °C (lit.23b 206-208 °C)

yieldb (%)

purityc (%)

206 206 205-206 206 205-206

98.11 98.02 97.93 97.67 97.81

99.52 99.42 99.36 99.20 99.46

a Reaction conditions: 4-nitroaniline, 10 mmol; Br2, 20 mmol (4-nitroaniline and Br2 mols charged in each cycle); CaBr2, 20 mmol; MeCN, 10 mL (CaBr2 and MeCN charged only in the fresh batch); time, 10 min (each cycle); temp, 25 °C. b Isolated yields. c Purity determined by HPLC.

Scheme 4. Br+-Transfer Mechanism through a Bromonium-Bromide Intermediate

causes the CaBr2 to precipitate as a crystalline solid, and an additional amount of CaBr2 (7 mol) was recovered after four runs: 1 mol of CaBr2 generated additionally in each run by the neutralization of HBr using CaCO3. The solvent was also distilled out from the filtrate and can be used in the subsequent brominations. In this way, starting with 2 mol of CaBr2 wrt 1 mol of 4-NA in the fresh batch, we have isolated 7 mol of CaBr2 in the end after four runs. Thus, we have successfully eliminated the problem of conventional methods associated with discharge of HBr byproduct waste which is toxic, corrosive, and environmentally polluting. Mechanism. The equilibria which are generally believed to be present in aq bromine solutions (with or without added bromides) are hydrolysis,26 Br2 + H2O T H+ + Br- + HBrO, and complex formation, Br2 + Br- T Br3- and 2Br2 + Br- T Br5-. For the first two reactions, there is abundant evidence in the literature. Neither is there any doubt that a complex exists which is richer in bromine than the tribromide because the solubility of bromine in bromides (such as KBr, CaBr2) is greater than can be accounted for as Br2, HBrO, and Br3-. The UV-vis studies were carried out to find out the active brominating species. An equimolar solution of 1 mol equiv CaBr2 and 1 mol equiv Br2 was prepared, and a UV-vis spectrum was recorded that gives an intense band at 266 nm. In agreement with many literature data,27a-c the appearance of the band at 266 nm can be readily attributed to the formation of a charge-transfer complex, CTC, between bromine and CaBr2 (Scheme 4). It is likely that the 266 nm band is due to tribromide ion, Br3- which absorbs27a in the same region and which could arise as shown via the formation of a 1:1 CaBr2-Br2 complex, [eq 2]. CaBr+Br- + Br2 T CaBr+Br3-

Figure 3. UV study of aq CaBr2-Br2 assisted bromination of salicylic acid in MeCN at 25 °C.

observed in UV-vis study. The solution of salicylic acid dissolved in MeCN was added to aq CaBr2-Br2 solution, and a UV-vis spectrum was recorded. The band at 266 nm disappeared instantaneously which concealed that the Br2 molecule has been polarized and rapidly dissociated in the presence of added metal bromide and the generated Br+ has been transferred to the salicylic acid. This was authenticated by the appearance of a peak (λmax. ) 312 nm) which corresponds to 5-bromosalicylic acid (Figure 3). It shows that Br3- is the active brominating agent that generates the electrophile Br+ in the reaction. A bathochromic shift was observed in Figure 3 in which the spectrum at 312 nm shows that absorbance occurred after the disappearance of the salicylic acid peak (λmax. ) 300 nm) and the Br3- peak (λmax. ) 266 nm) is due to that of formation of 5-bromosalicylic acid. If we look into the UV-vis results of the present study and also consider the scheme of Bellucci et al.,29 it is proposed that a tribromide type ion-pair intermediate is formed in the reaction (Scheme 4). Scheme 4 shows a transition state proposed for the reaction in which the nucleophilic attack at the bromine by the electron-rich II-system of activated ring was proposed. This yields a transfer of Br+ to thesubstratefromatribromideion-pairintermediateCa[Br+Br-(Brδ+--Brδ-)] and ring-bromination by a Br+-transfer mechanism occurs. This “salting out effect” of ions on bromine that results in the formation of an ion-dipole complex increases the activity coefficient of bromine in solutions of metal halides (such as KBr, CaBr2, etc.). The transition state would then break up to give brominated product and HBr as byproduct. The HBr byproduct waste was then converted to CaBr2 by neutralization using powdered CaCO3. Conclusions It is concluded that a new, simple, efficient, and economical bromination protocol for mono-, di-, and tribromination is disclosed. The “green” features of this protocol include the use of low-cost aq CaBr2-Br2 solution as a brominating agent that can be rejuvenated easily even on a large-scale, making it viable for industrial-scale applications. The greatest benefits is the prevention of oxidants, catalysts, and strong acids during the reaction that makes the process organic waste-free and HBr waste-free and, therefore, a good option to existing bromination methods.

(2)

Water used in the preparation of aq CaBr-Br2 solution also favors Br3- formation via the well-known water-bromine reaction28 releasing bromide ion and promoting eq 2 as is

Acknowledgment The authors wish to express their thanks to the Kapil Kumar, SRF Ltd. and Director, Sophisticated Analytical Instrumentation

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ReceiVed for reView July 13, 2010 ReVised manuscript receiVed November 22, 2010 Accepted December 1, 2010 IE101498P