Continuous-flow synthesis of an important liquid crystal intermediate

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Kinetics, Catalysis, and Reaction Engineering

Continuous-flow synthesis of an important liquid crystal intermediate using a microreaction system siting xia, Xifeng Ding, Yujun Wang, and Guangsheng Luo Ind. Eng. Chem. Res., Just Accepted Manuscript • DOI: 10.1021/acs.iecr.8b02839 • Publication Date (Web): 27 Aug 2018 Downloaded from http://pubs.acs.org on September 1, 2018

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Industrial & Engineering Chemistry Research

Continuous-flow synthesis of an important liquid crystal intermediate using a microreaction system Siting Xia, Xifeng Ding, Yujun Wang*, Guangsheng Luo

State Key Laboratory of Chemical Engineering, Department of Chemical Engineering, Tsinghua University, Beijing 100084, P. R China

Corresponding author: Tel: 86-10-62783870, Fax: 86-10-62770304 Email address: [email protected]

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Industrial & Engineering Chemistry Research 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ABSTRACT In this work, a microreaction system consisting of membrane-dispersion micromixers and microtube reactors was developed for the continuous synthesis of 4-(bromo-difluoro-methyl)-4'cyclopentyl-3,5-difluoro-biphenyl, an important intermediate of liquid crystal compounds. Due to the high mass and heat transfer of the reaction, Ortho-lithiation can be performed at -20 °C, which is much higher than the -70 °C required for the respective batch reaction. In addition, bromodifluoromethylation of aryllithium specie can be achieved continuously with fewer byproducts. The yield of 4-(bromo-difluoro-methyl)-4'-cyclopentyl-3,5-difluoro-biphenyl can reach 80.1% within 3 min. By contrast, in stirred tanks, the yield of 4-(bromo-difluoro-methyl)-4'cyclopentyl-3,5-difluoro-biphenyl only reaches 70.1% in 70 min and requires approximately 3 h at the industrial scale. Continuous-flow synthesis of 4-(bromo-difluoro-methyl)-4'-cyclopentyl-3,5difluoro-biphenyl in a microreaction system shows great potential for industrial applications.

Keywords: microreactor; liquid crystal; Ortho-lithiation; bromodifluoromethylation; process intensification;

For Table of Contents Only：


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1. Introduction The Ortho-lithiation(proton-lithium exchange) and bromodifluoromethylation reaction play an important role in the introduction of a CF2Br group in the synthesis of a series of liquid crystalline compounds1. In addition, both of these reactions have been widely used in the fields of medicine, agriculture and materials, especially for positron emission tomography imaging2-3 and fluoroparacyclophanes4. Many reports have shown that compounds containing a –CF2OAr moiety are very well-suited materials in the field of modern displays5-8. A series of novel compounds containing a difluoromethyleneoxy-linkage group have been developed to achieve lower driving voltage and quicker response times in active matrix liquid crystal displays (AMLCDs)9-11. 1- bromo-1,1- difluoro methyl-containing compounds are important intermediates for liquid crystal compounds containing a –CF2OAr moiety, especially 4(bromo-difluoro-methyl)-4'-cyclopentyl-3,5-difluoro-biphenyl (F is used in this work to represent 4-(bromo-difluoro-methyl)-4'-cyclopentyl-3,5-difluoro-biphenyl for readability) 12

. Currently, there is a considerable annual output of over 10 tons for F. Therefore, the

development of an efficient and economical method for the production of F is in strong demand. F

F

Li

Bu-Li

R

F

F CF2Br

CF2Br2

R

F

R

R=

Figure 1. Ortho-lithiation and bromodifluoromethylation reaction


F


There are several ways to produce F13-14. For example, SF4 could be used as fluorinating agent in a reaction with benzaldehyde. Then, the resulting product can be reacted with bromine for the synthesis of 4-(Bromo-difluoro-methyl)- benzaldehyde15. Due to the high toxicity and strong corrosivity of SF4, this process would not normally be applied in industry. Instead, another effective process for the synthesis of 1- bromo-1,1difluoro-methyl is now widely available in industry. As shown in Figure 1, in this process in theory, 1 molecule of n-BuLi is used as a strong base to react with 4'-cyclopentyl-3,5difluoro-biphenyl. Then, 1 molecule of dibromodifluoromethane is added to the product. However, there are several limitations in this process, wherein these two reactions are performed in a stirring tank. First, to prevent local acceleration and overheating of the reaction, low temperatures (-70 °C) and long feeding times (over 30 minutes for the Ortholithiation and over 30 minutes for bromodifluoromethylation) are needed, since the Ortholithiation and bromodifluoromethylation reaction are both strongly exothermic. Long feeding times mean low efficiency and a less safe process in industry due to the flammable and explosive properties of n-BuLi and bromodifluoromethylation. Low temperatures may lead to a low reaction rate, which causes a long reaction period of over 30 minutes for the Ortho-lithiation and over 90 minutes for bromodifluoromethylation, and lots of energy is required to cool down the reactions. Moreover, the reaction temperature plays a key role in this process. Not only it is very difficult to control these two highly exothermic, extremely fast reactions at high temperature16 but also high reaction temperatures may lead to the formation of undesirable byproducts (the standard enthalpy change of the carbene reaction during bromodifluoromethylation was calculated by Gaussian View, and the details are


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shown in the ESI.) However, an appropriate increase in the reaction temperature helps to accelerate the reaction. Therefore, it is necessary to precisely control the reaction temperature to speed up this process. In our previous work, a membrane-dispersion microreactor with great mass and heat transfer performance was developed, in which the residence time could be well-designed to achieve high yields17-20. We applied a microreactor to the hydrogenation of streptomycin21. In this reactor, the fluid phase is sheared into small droplets and then dispersed into another fluid, where the size of the droplets was determined by the size of the membrane. This led to a significant increase in the mass-transfer surface area and the homogeneous distribution of the reactant in less than 1 s17. The transformation rate of streptomycin reached 99.81 wt% within 3 min, compared to the 99.5 wt% in 30 min in stirred tanks, with a minimum amount of KBH4 used in the membrane-dispersion microreactor that was 35.71% lower than that used in traditional tanks. In addition to the synthesis of medical materials, this microreactor has been applied in many areas, such as the synthesis of inorganic nanoparticles and the continuous flow synthesis of organic reactions22-24. There are many examples in the literature of lithium proton exchange reactions (and also lithium halogen exchange reactions using alkyl lithiums) being performed in continuous flow25-31, demonstrating the advantages of superior mixing and heat exchange32, as well as better control of residence time and easy scale-up etc33. For example, Yoshida et al. showed that precise control of the residence time of reactive intermediates would make two different reaction pathway of lithiated 1,2‐dichloroethene in microreactors, they could produce either alkenes or alkynes through this way29. Kwang Ho et al. developed a two-stage continuous microreactor system to synthesize the materials for an organic light emitting diode, through which the naphthyl-substituted anthracene was obtained with 97%



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purity 27. However, few studies have applied microsystems to the synthesis of F. In this study, the Ortho-lithiation and bromodifluoromethylation reaction were performed in a microreaction system consisting of membrane-dispersion micromixers and microtube reactors. The reactions were also performed in a traditional stirring tank for comparison. First, the mechanism of this process was analyzed. The effect of the total flow rates, the concentration of the reactants, the ratio of the concentration of the reactants, the reaction

temperature

and

the

residence

time

on

the

Ortho-lithiation

and

bromodifluoromethylation reaction and the yield of F were systematically analyzed to optimize the entire process.

2. Methods 2.1 Preparation of the reactant 4'-Cyclopentyl-3,5-difluoro-biphenyl (99.9%), n-butyllithium (2.5 mol/L, dissolved in n-heptane) and dibromodifluoromethane (liquid, 99.9%) were provided by Shijiazhuang Slichem Liquid Crystal Materials Co. Ltd.

2.2 Reaction in a stirred tank


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Figure 2. Reaction in a three-necked flask

As shown in Figure 2, comparative experiments were conducted in a three-necked flask. 4'cyclopentyl-3,5-difluoro-biphenyl was dissolved in tetrahydrofuran to obtain a 1 mol/L solution of 4'-cyclopentyl-3,5-difluoro-biphenyl, and 100 mL of the solution was placed in a three-necked flask. A 2.5 mol/L n-BuLi solution (46.8 mL) was slowly added into the solution for approximately 60 min with vigorous stirring (600 rpm (revolutions per minute)). Then, 2.25 mol/L dibromodifluoromethane was dissolved in tetrahydrofuran (78 mL) and slowly added into the flask over 20 min with the same stirring rate. The three-necked flask was kept in an ethanol bath cooled with liquid nitrogen to -70 °C during the entire process. During the whole procedure, 1 mL of the mixture could be taken from the flask and added to 1 mL of distilled water to terminate the reaction, and samples were taken from the supernatant.

2.3 Reaction in a microreactor system The experimental setup for the microreaction system is shown in Figure 3. A 1 mol/L 4'cyclopentyl-3,5-difluoro-biphenyl solution (dissolved in tetrahydrofuran), a 2.5 mol/L n-BuLi solution (dissolved in n-heptane), and a 2.25 mol/L dibromodifluoromethane solution (dissolved in tetrahydrofuran) were pumped into the microreaction system by three metering pumps, respectively. Before the reactants were pumped into micromixer1 and micromixer2, respectively, they were pre-



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cooled to a steady temperature in a 2-m-long stainless-steel tube. As shown in Figure 3, there are two membrane-dispersion micromixers in the microreaction system, which are respectively connected with two capillary SS tubes to increase the residence time for reaction. Micromixer1 and micromixer2 are the same, and more details are in the ESI, with the same structure as that reported in our previous paper21. The 4'-cyclopentyl-3,5-difluoro-biphenyl solution was the continuous phase, while the n-BuLi solution was the dispersed phase. The two phases were pumped into micromixer1, and then the Ortho-lithiation occurred in a delay loop reactor1 made from a stainless-steel tube that was added after micromixer1. The residence time can be controlled by the length of the delay loop reactor and the flow rates of the reactants. Almost the same units were set for the bromodifluoromethylation of aryllithium specie, except the length of the delay loop reactor was changed. The final mixture was delivered to a beaker via a 10-cm-long stainless-steel tube. A 1 mL mixture could be taken from the flask and added to 1 mL of distilled water to terminate the reaction, and the samples were taken from the supernatant. The pre-heat exchange unit, micromixer and delay loop reactor were all kept in two ethanol baths that were cooled by liquid nitrogen. All the stainlesssteel tubes mentioned above were the same, except for their lengths, and the inner and outer diameter of the stainless-steel (type 316) tubes are 1.6 mm and 3 mm, respectively.

Dibromodifluoromethane R3

Ethanol bath 1

Metering pump3

Et hanol bath 2

Pre-heat exchange unit3

Pre-heat exchange unit2 n‐butyllithium R2

Metering pump2

4-(bromo-difluoro-methyl)4'-cyclopentyl-3,5-difluoro-bi phenyl F Delay loop reactor1 4'‐Cyclopentyl‐3,5‐difluorobiphenyl R1

Delay loop reactor2

Pre-heat exchange unit1 Metering pump1

micromixer1

micromixer2

Figure 3. The experimental setup of the microreaction system(R1, R2, R3, and F are used to represent 4'cyclopentyl-3,5-difluoro-biphenyl, n-butyllithium, dibromodifluoromethane and 4-(bromo-difluoromethyl)-4'-cyclopentyl-3,5-difluoro-biphenyl, respectively)

2.4 Analysis of the sample The concentration of 4'-cyclopentyl-3,5-difluoro-biphenyl and F in the samples was analyzed by GC with an ultraviolet detector, using the external standard calibration GC method. The method is


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the same as that reported in the literature5. Some byproducts could be determined by GC-MS. The yield of 4-(bromo-difluoro-methyl)-4'-cyclopentyl-3,5-difluoro-biphenyl (F) is calculated by the following equations: 𝑌 where 𝐶

𝐶

𝑄 𝐶

𝑄 𝑄

𝑄

100%

is the concentration of 4-(bromo-difluoro-methyl)-4'-cyclopentyl-3,5-difluoro-

biphenyl (F) in the final product; 𝐶 in the Solution R1; 𝑄

is the concentration of 4'-cyclopentyl-3,5-difluoro-biphenyl

is the flow rate of Solution R1; 𝑄

is the flow rate of Solution R3. The value of 𝐶 and 𝐶

is the flow rate of Solution R2; 𝑄 can be obtained by making mixture or

solution samples mentioned above and using the external standard calibration GC method. The details are shown in the supporting information.

3. Results and Discussion 3.1 Mechanism of this process

Figure 4. Mechanism of the bromodifluoromethylation reaction

According to the literature5, 34 and the appearance of products G and J (see Figure 4) as analyzed by GC-MS, the proposed mechanism of the bromodifluoromethylation reaction is shown in Figure 4. The byproduct B can further react with excess n-BuLi to give intermediate A and another byproduct I (n-BuBr) in a lithium-halogen exchange reaction. The difluorocarbene, D, can dimerize to give G, and then C can react with G by a nucleophilic attack. Finally, the byproduct H (polymer) appears. The (bromodifluoromethyl)lithium, C, reacts with dibromodifluoromethane (CF2Br2) to give another byproduct, J.



According to the mechanism of the reaction shown in Figure 4, n-BuLi and the short-lived reactive intermediate A tend to decompose at high temperatures or over long reaction times16.On that basis, it is very important to transfer these products to another location to be used in the next reaction (bromodifluoromethylation) before the intermediate A decomposes. Additionally, it is very important to obtain homogeneous distributions of n-BuLi at the beginning of the Ortho-lithiation to accelerate the reaction rate and prevent the decomposition of n-BuLi. Meanwhile, the appearance of 4-bromo-4'-cyclopentyl-3,5-difluoro-biphenyl B is unavoidable, and the true product cannot be obtained until the difluorocarbene appears. Once difluorocarbene is obtained, the intermediate A tends to react with the difluorocarbene, instead of dibromodifluoromethane, due to the high activity of the difluorocarbene, which causes a chain reaction to occur. It is important to ensure that less 4bromo-4'-cyclopentyl-3,5-difluoro-biphenyl B is obtained before the chain reaction occurs, which means the homogeneous distributions of difluorocarbene is needed at the very beginning of the reaction. This means quick, thorough mixing is strongly required, and a microreaction system may show great performance in this process. 3.2 Effect of the total flow rates and concentration of the reactants on the yield of F

80

residence time=100 s+150 s 75

Yield(%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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70

65

60 15

20

25

30

35

40

Total Flow Rate(mL/min)

Figure 5. Effect of the total flow rates on the yield of F. The initial concentration of reactants: 4'-cyclopentyl-3,5difluoro-biphenyl (0.5 mol/L), n-butyllithium (1.25 mol/L) and dibromodifluoromethane (1.125 mol/L). The temperatures of ethanol bath1 and ethanol bath2 were both -70 °C.

A range of total flow rates for the reactants were studied to test the mixing performance while other conditions were maintained. When the total flow rate was increased, the mass transfer of n-


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BuLi was enhanced, leading to less time for completing mixing to occur. As shown in Figure 5, the yield of F remained nearly unchanged over a range of total flow rates of the reactants, which means that mass transfer is not a key factor affecting the yield of the product. To be more exact, the mixing performance in the micromixer is good enough to handle this experiment under a range of total flow rates. 3.3 Effect of the concentration and molar ratio of the reactants on the yield of F

80

residence time=100s+200s

75

Yield(%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


70

65

0.5

0.6

0.7

0.8

0.9

1.0

C(4'-Cyclopentyl-3,5-difluoro-biphenyl)

Figure 6. Effect of the concentration of the reactants on the yield of F. The molar ratio of the reactants was maintained at 1:1.3:1.95. (4'-Cyclopentyl-3,5-difluoro-biphenyl:n-butyllithium:dibromodifluoromethane).The temperature of ethanol bath1 and ethanol bath2 were both -70 °C. The total flow rate was 22.48 mL/min.

As shown in Figure 6, the concentration of 4'-cyclopentyl-3,5-difluoro-biphenyl had little influence on the yield of the product with the other conditions maintained. Excellent mixing performance in the microreaction system contributes to it. Moreover, as the concentration of 4'cyclopentyl-3,5-difluoro-biphenyl increased, the reaction generated more heat. The greater heat exchange performance for the microreaction system makes heat removal timely, leading to good control over these two extremely fast reactions. However, tube block occurred when the concentration of 4'-cyclopentyl-3,5-difluoro-biphenyl reached 0.7 mol/L. The entire microreaction system needed to be cleaned from time to time. This phenomenon happened because the intermediate A is an ionic compounds with low solubility in the mixture of n-heptane and tetrahydrofuran, as dissolution is best in a material with a similar structure and the viscosity of intermediate A in the mixture of n-heptane and tetrahydrofuran is high (which can be observed in



the traditional tank). This led to blockage in delay loop reactor2. More details and the solutions to this problem can be found in 3.4.

80

75

Yield(%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

70

65

60

residence time=100 s+200 s

1.0

1.1

1.2

1.3

1.4

Ratio(n-BuLi/4'-Cyclopentyl-3,5-difluoro-biphenyl)

Figure 7. Effect of the molar ratio of the concentration of the reactants on the yield of F. The initial concentration of the reactants: 4'-cyclopentyl-3,5-difluoro-biphenyl (1 mol/L), n-butyllithium (2.5 mol/L) and dibromodifluoromethane (2.25 mol/L). The temperature of ethanol bath1 and ethanol bath2 were both -70 °C.

Keeping the molar ratio of dibromodifluoromethane to 4'-cyclopentyl-3,5-difluoro-biphenyl as follows: （ n  BuLi）（dibromodifluoromethane） C C  1.5* C ( 4 ' Cyclopentyl  3, 5  difluoro  biphenyl ) C ( 4 ' Cyclopentyl  3, 5  difluoro  biphenyl ) ,

ensured enough dibromodifluoromethane was present, and a positive correlation between the yield of the product and the molar ratio of n-BuLi to 4'-cyclopentyl-3,5-difluoro-biphenyl is shown in Figure 7 by changing the ratio of the flow rate of n-BuLi to 4'-cyclopentyl-3,5-difluoro-biphenyl. According to our calculations, the ratio of n-BuLi to 4'-cyclopentyl-3,5-difluoro-biphenyl should be (1 mol)/(1 mol). In this process, about one fifth of the n-BuLi was wasted due to the extremely active chemical properties of n-BuLi and the instability of intermediate A, as shown in Figure 1. Usually, the value used in actual manufacturing is (1 mol)/ (1.3 mol). The main reason for this improvement is that the micromixer has an excellent mixing performance compared to the traditional tanks applied in factories. When the molar ratio of n-BuLi to 4'-cyclopentyl-3,5-difluorobiphenyl reached 1.2 or higher, the yield of the product improved slightly with a higher feed of nBuLi because the Ortho-lithiation was carried out fully, and extra n-BuLi could react with


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dibromodifluoromethane first, leading to the early appearance of difluorocarbene. Sequentially, slightly more F would be obtained instead of the byproduct 4'-cyclopentyl-4-bromo-3,5-difluorobiphenyl. Another observation is that the yield did not increase with the increase in the molar ratio of dibromodifluoromethane to 4'-cyclopentyl-3,5-difluoro-biphenyl. The steady-state approximation can explain this observation because the main bromodifluoromethylation reaction is a free-radical chain reaction. Because the amount of the byproducts G, J, and H were so small, and too much nBuLi was not added, the reaction listed in Figure 4 can be simplified as follows in Figure 8: F Li

(a)

+ CF2 R

CF2Li

k1 R

F

F

D

A

E

F

F Li

+ CF2Br2

(b) R

A

Br

+

F

R

C

k3

Li-Br

CF2 D

+

F

F CF2Li

(d)

+ CF2Br2 R

(e)

k4

CF2Br

Li-CF2Br C

F

E Li-CF2Br C

Li-CF2Br

F

B

Li-CF2Br C

(c)

k2

k5

Li-Br

+

+ R

F

F

CF2 D

R=

Figure 8. Elementary steps of the bromodifluoromethylation reaction

The concentration of intermediates A and E and difluorocarbene D are observed to be constant, so:

d[C]  2k3[C]  k2 [A][CF2 Br2 ]  k4 [E][CF2 Br2 ]  0 dt d[D]  2k3[C]  k1[A][D]  0 dt d[E]  k1[A][D]  k4 [E][CF2 Br2 ]  0 dt

(1) (2) (3)

where ki (i=1,2,3,4,5) is the reaction rate constant, and k3=k5. The production rate of product F and the main byproduct B can be described as follows:

d[F]  k4 [E][CF2 Br2 ] dt d[F]  k4 [E][CF2 Br2 ] rB  dt rF 

(4) (5)



Then, by transforming and integrating the equations,

rF 

k2 k4 [A][CF2 Br2 ] 1  k4

(6)

rB  k2 [A][CF2 Br2 ]

(7)

So,

rF k  4 rB 1  k4

(8) .

This calculation indicates that the concentration of dibromodifluoromethane had little influence on the ratio of the production rate of product F to that of the main byproduct B. 3.4 Effect of the temperature and residence time on the yield of F

80

60

Yield(%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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40

time(r1)=15 s time(r1)=30 s time(r1)=45 s

20

0 -80

-60

-40

-20

0

T1(℃)

Figure 9. Effect of the temperature of ethanol bath1and the residence time1 on the yield of F. The flow rates of the 4'-cyclopentyl-3,5-difluoro-biphenyl solution (1 mol/L), n-butyllithium (2.5 mol/L) and dibromodifluoromethane (2.25 mol/L) were set to 10 mL/min, 4.68 mL/min, and 7.8 mL/min, respectively. The temperature of ethanol bath2 was -70 °C. The residence time in delay loop reactor2 was 200 s. The total flow rate was 22.48 mL/min.

As mentioned above, when the concentration of 4'-Cyclopentyl-3,5-difluoro-biphenyl reached 0.7 mol/L, delay loop reactor1 would occasionally clog. It is very essential to solve this problem, to apply this new microreaction system in industry. Since the clogging is caused by the low solubility of intermediate A in the mixture of n-heptane and tetrahydrofuran, and the viscosity of the intermediate A in the mixture of n-heptane and tetrahydrofuran is high, there are three solutions to


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this problem. The first method would be to decrease the concentration of the intermediate in the mixture. This means using more solvent, which means adding more costs. Second, some solvent in which intermediate A has a higher solubility could be used, but this method was not considered in this work. Third, the temperature could be increased to enhance the solubility of and reduce the viscosity of intermediate A in the mixture of n-heptane and tetrahydrofuran. On that basis, the effect of the temperature and the residence time on the yield of F is discussed next. Figure 9 shows the trend of the yield of F with different temperatures for ethanol bath1 at given residence times in delay loop reactor1 of time (r1) = 15 s, 30 s, and 45 s, respectively. When the residence time in the delay loop reactor1 was 15 s, the yield of F first increased, followed by a sharp decrease as the temperature increased further. This phenomenon was likely observed because the Ortho-lithiation rate increased until the temperature reached -20 °C, leading to the increase in the transformation rate of 4'cyclopentyl-3,5-difluoro-biphenyl and increase in the yield of F. After that, the transformation rate of 4'-cyclopentyl-3,5-difluoro-biphenyl may reach nearly 100%, and intermediate A would decompose sharply at higher temperatures, leading to more byproducts and the reemergence of 4'cyclopentyl-3,5-difluoro-biphenyl. The low transformation rate of 4'-cyclopentyl-3,5-difluorobiphenyl (68.8%) strongly suggests this mechanism when the residence time in delay loop reactor1 in an ethanol bath at 0 °C was 15 s. The same explanation could be applied to the other two curves. The temperature that the Ortho-lithiation was carried out at had a great effect on the transformation rate of 4'-cyclopentyl-3,5-difluoro-biphenyl and the stability of intermediate A. It is better to find conditions where the transformation rate of 4'-cyclopentyl-3,5-difluoro-biphenyl is over 98% and intermediate A would not decompose significantly over a suitable residence time in delay loop reactor1. Another observation was that when the temperature in ethanol bath1 was higher than 40 °C, intermediate A in the mixture of n-heptane and tetrahydrofuran would not block the reactor. In conclusion, a 15 s residence time in delay loop reactor1 with ethanol bath1 at -20 °C as chosen as the best reaction conditions.



80

time(r2)=200s time(r2)=150s time(r2)=100s

60

Yield(%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

40

20

0

-60

-40

-20

T2(℃) Figure 10. Effect of the temperature of ethanol bath2 and residence time2 on the yield of F. The flow rates of the 4'-cyclopentyl-3,5-difluoro-biphenyl solution (1 mol/L), n-butyllithium (2.5 mol/L) and dibromodifluoromethane (2.25 mol/L) were set to 10 mL/min, 4.68 mL/min, and 7.8 mL/min, respectively. The temperature of the ethanol bath1 was -20 °C. The residence time in delay loop reactor1 was 15 s.

The effect of the temperature and the residence time in delay loop reactor2 on the yield of F was also discussed. As shown in Figure 10, when the temperature of delay loop reactor2 was higher than -50 °C, the yield of F was low. This is likely because the byproducts G, J, and H are easily obtained at high temperatures, and GC-MS analysis suggested these byproducts were formed. GC-MS also showed that the yield of F fluctuated approximately 76% from -70 °C to -50 °C with a residence time of 150 s in ethanol bath2 . Overall, a 150 residence time in delay loop reactor2 with ethanol bath2 at -50 °C were chosen as the conditions to maximize the energy saving. 3.5 Comparison of the reaction in the membrane microreactor and in a traditional tank


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80

60

Yield(%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


40

20

micromixer stirred tank

0 0

2

4

6

8

10

Time(min) Figure 11. Comparison of the reaction in the membrane microreactor and in a traditional tank. (60 min of the Ortho-lithiation is not shown, and only 10 min of the bromodifluoromethylation reaction is shown in the stirred tank)

Figure 12. Comparison of the distribution of temperature in the membrane microreactor and in a traditional tank

Based on the previously discussed results, the effect of different reaction conditions on the yield of 4-(bromo-difluoro-methyl)-4'-cyclopentyl-3,5-difluoro-biphenyl are discussed. To achieve a good mixing performance in an economical manner, the flow rates of the 4'-cyclopentyl-3,5difluoro-biphenyl solution (1 mol/L), n-butyllithium (2.5 mol/L) and dibromodifluoromethane (2.25 mol/L) were set to 10 mL/min, 4.68 mL/min, and 7.8 mL/min, respectively. A 15 s residence time in delay loop reactor1, a temperature of -20 °C in ethanol bath1, a 150 s residence time in delay loop reactor2 and a temperature of -50 °C in ethanol bath2 were chosen. As shown in Figure 11, the reaction rate in the traditional tank was slow, especially at the beginning of the reaction, mainly due



to the low temperature of the reaction. However, if the reaction was carried out in the traditional tank at high temperature, temperature control and the decomposition of intermediate A would be a huge challenge. Moreover, long residence times for the batch would lead to the appearance of more impurities due to the presence of highly active n-BuLi and intermediate A. The yield of 4-(bromodifluoro-methyl)-4'-cyclopentyl-3,5-difluoro-biphenyl reached 80.1% within 3 min. By contrast, it took 70 min (60 min for the Ortho-lithiation and 10 min for the bromodifluoromethylation reaction) to obtain a yield of 70.1% of 4-(bromo-difluoro-methyl)-4'-cyclopentyl-3,5-difluoro-biphenyl. The striking improvements with the microreaction system could be explained as follows. The microreaction system provided a reaction environment close to an ideal reactor in molecular size, leading to a homogeneous dispersion of difluorocarbene in a very short time, rather than large fluid aggregates of difluorocarbene spreading coarsely over the batch reactor. On that basis, the chain reaction can occur early and quickly. Additionally, we can see that the yield in the microreaction system was more stable and accurate than that in the batch reactor. This phenomenon could be explained by the more effective heat exchange performance in the microreaction system. As shown in Figure 12, small and uniform fluid aggregates of the mixture are spread over the microreaction system, leading to a narrower temperature distribution than that in a stirred tank. Presumably, a broad temperature distribution in the stirred tank allowed the production of undesired byproducts, but the narrow temperature distribution in the microreaction system restricted the reactions to the target product F35. What’s more, the actual overall bulk surface-area to volume ratio between the tank and the cooling bath might also come into play, which is a crucial factor for heat transfer. For microreactors have larger bulk surface-area to volume ratio than normal tanks, precise temperature control and narrow temperature distribution is achieved in the microreactors. Thus, the selectivity towards the desired product would increase, and the stability was also improved. In conclusion, the effectiveness of the membrane-dispersion microreactor is confirmed, and it is a great candidate for the synthesis of 4-(bromo-difluoro-methyl)-4'-cyclopentyl-3,5-difluoro-biphenyl on an industrial scale.

4. Conclusion In this work, a new microreaction system was applied to the synthesis of 4-(bromo-difluoromethyl)-4'-cyclopentyl-3,5-difluoro-biphenyl with a relatively short residence time (less than 3 min). This work may enable future industrial applications of the large-scale synthesis of 4-(bromo-


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difluoro-methyl)-4'-cyclopentyl-3,5-difluoro-biphenyl. Continuous synthesis of the Ortho-lithiation and bromodifluoromethylation reaction in the microreaction system were realized with excellent mixing performance and high mass/heat transfer rates. There is also potential to perform other Ortho-lithiations and bromodifluoromethylation reactions in this microreaction system, which is widely used to synthesize liquid crystal compounds. Additionally, some other reactions involved in the synthesis of liquid crystal compounds (coupling reactions, etc.) could be applied to this microreaction system, which may enable future industrial applications for the continuous synthesis of many liquid crystal compounds.

Supporting information Standard enthalpy change of the carbene reaction calculated by Gaussian View, Structure of the microreactor/micromixer, the spectroscopic data for the purified compound and GC data for the samples.

Acknowledgements This work was financially supported by the National Basic Research Foundation of China (Grant No. 2013CB733600), the National Natural Science Foundation (Grant Nos. 21276140 and 21036002), and the Specialized Research Fund for the Doctoral Program of Higher Education of China (Grant No. 20130002110020).

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Continuous-flow synthesis of an important liquid crystal intermediate

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