Photocatalytic Oxidative Bromination of 2,6-Dichlorotoluene to 2,6-Dichlorobenzyl Bromide in a Microchannel Reactor

Photocatalytic oxidative benzylic bromination with hydrobromic acid (HBr) and hydrogen peroxide (H2O2) is a green process for the synthesis of benzyl bromides, but suffers from the risk of explosion when performing it in a batch reactor. This disadvantage could be overcome by running the reaction in a microchannel reactor. In this work, a green and safe process for the synthesis of 2,6-dichlorobenzyl bromide (DCBB) was developed by conducting selective benzylic bromination of 2,6-dichlorotoluene (DCT) with H2O2 as an oxidant and HBr as a bromine source in a microchannel reactor under light irradiation. The reaction parameters were optimized, and the conversion of DCT reached up to 98.1% with a DCBB yield of 91.4% under the optimal reaction conditions.


INTRODUCTION
2,6-Dichlorobenzyl bromide (DCBB) is an important intermediate in the synthesis of bioactive molecules such as functionalized [1,4]-thiazines, 4,6-diarylpyrimidin-2(1H)-ones, and 2-benzyloxybenzamides ( Figure 1). 1−3 DCBB is commonly obtained by benzylic bromination of 2,6-dichlorotoluene (DCT) with bromine in the presence of the free radical initiator or under light irradiation. 4,5 The benzylic bromination with bromine suffers from the disadvantages of the low utilization rate of bromine due to transformation of half bromine to hydrogen bromide as a byproduct and dangers in transport and storage of bromine due to its toxicity and high vapor pressure. 6 Therefore, many reagents and protocols instead of bromine have been developed for the selectively benzylic bromination, such as H 2 O 2 /HBr/NBS, 7 BBr 3 , 8 and NBS/SiCl 4 , 9 and various oxidative bromination systems including NaBrO 3 /NaHSO 3 , 10 NaBrO 3 /KBr − /H + , 11 KBr/ Oxone, 12 NaNO 2 /KBr/HCl, 13 and HBr/H 2 O 2 . 14−17 Among them, the oxidative bromination with HBr/H 2 O 2 is the most recommended because of low cost of both hydrobromic acid (HBr) and H 2 O 2 , 100% utilization of bromine source, and water as the only byproduct avoiding the environmental problems being frequently involved with other oxidants. 18 Traditionally, the oxidative bromination was performed in a batch reactor, 14,17 which suffers from the disadvantages of low reaction efficiency owing to the short radiation distance of light, risk of explosion, especially in large-scale production.
In recent years, significant progresses have been achieved in microchannel reactor technology for the chemical transformations with the advancement of science and technology. 19−22 Compared with traditional batch reactors, microchannel reactors have the essential characteristics of high efficiencies of mass and heat transfer, as well as an enhanced specific surface area, affording its high safety, good operability, precise control of the reaction conditions for getting high selectivity of the target product, and easiness of scale-up. Actually, microchannel reactors have been found to have wide applications in the field of photocatalytic chemistry for their abovementioned advantages and easy reaching reactants of light, including photoredox catalysis, 23 elemental fluorination of β-dicarbonyl compounds, 24 conjugate addition of acrolein with glycosylradicals, 25 trifluoromethylation of heterocycles, 26 oxidation of benzene to phenol, 27 and light-initiated benzylic chlorination 28 as well as alicyclic compounds. 29,30 In particular, microreactors 31−34 were also applied to the benzylic bromination with Br 2 or HBr/H 2 O 2 under light irradiation. On the other hand, it is expected that the oxidative bromination with HBr/H 2 O 2 in a microchannel reactor can reduce the severe decomposition of H 2 O 2 catalyzed by bromine generated in situ in a batch reactor, 35 due to the less contact time of reactants in the microchannel reactors.
Herein, the benzylic bromination of DCT with HBr as the bromine source and H 2 O 2 as the oxidant was conducted in a microchannel reactor under light irradiation for the safe and environmentally friendly production of DCBB. The effects of reaction temperature, reactant molar ratios, residence time, and light intensity as well as material concentration were investigated, from which the optimal reaction conditions for the preparation of DCBB from DCT were obtained.

RESULTS AND DISCUSSION
2.1. Effect of Temperature. For the benzylic oxidative bromination of DCT in a microchannel reactor irradiated with a light of specific wavelength and intensity, the reaction temperature is a key factor to affect the reaction. Therefore, the effect of reaction temperature on the reaction was investigated first. The main reaction products were determined to be DCBB and DCBA. No aryl substitution products were observed, indicating excellent selectivity toward benzylic substitution of the reaction in the microchannel reactor under the reaction conditions. As shown in Figure 2, the conversion of DCT increased from 15.5 to 67.8% with the temperature increased from 30 to 70°C, and the selectivity of DCBB increased from 68.7 to 75.3%. Both DCT conversion and DCBB selectivity increased slightly with a further increase in reaction temperature above 70°C. Meanwhile, the selectivity of DCBA almost remained constant around 10   min; reaction pressure = 0.8 MPa; reaction temperature = 70°C .

Effect of Residence Time.
In a microchannel reactor, the residence time of reactants is another key factor to affect the reaction, and it also indirectly reflects the irradiation time of light on the reactants in a photocatalytic reaction. Therefore, the effect of residence time on the reaction was investigated at 70°C and HBr/H 2 O 2 /DCT molar ratios of 1.5:1.5:1. As shown in Figure 4, the conversion of DCT increased with the increase in residence time initially, reached its maximum of 76.1% at the residence time of 5.88 min, then decreased slowly with the residence time until the residence time reached 9.43 min, and then dropped sharply. The sharp decline of DCT above the residence time of 9.43 min could be ascribed to the poor mixing of aqueous and organic phases in the microchannel reactor at long residence time. The selectivity of DCBB increased slowly with residence time and also reached its maximum of 73.8% at the residence time of 5.88 min and then always decreased slightly with further extending residence time. Similar to the other cases, the selectivity of DCBA changed slightly around 12.7% with residence time. Thus, the residence time was determined to be 5.88 min.       Figure 7, the solutions B and C were mixed through a three-way valve first and met with solution A in the second valve pumped by three 10 mL liquid feed pumps. The mixture finally entered the microchannel reactor to complete the reaction at given temperature and pressure. The reaction liquid flowed out of the reactor and was quenched at low temperature in a cold trap (0°C). The reactor pressure is monitored by a pressure gauge at the inlet and controlled by a back pressure valve at the outlet throughout the process.
After reaction, the reaction mixture was analyzed by HPLC. First, a standard curve was established using high performance liquid chromatography (HPLC) for the quantitative analysis of DCT, DCBB, and 2,6-dichlorobenzoic acid (DCBA).
The conversion rate of DCT and the selectivities toward DCBB and DCBA were calculated using the following formulas n DCT, initial and n DCT, converted are the initial and converted amounts of DCT in moles, respectively. n DCBB and n DCBA are the amounts of DCBB and DCBA formed in moles, respectively.