Microfluidic Synthesis of tert-Butyl Peresters via KI-Catalyzed Oxidative Coupling of Methyl Arenes and tert-Butyl Hydroperoxide

Article abstract of DOI:10.1021/acs.oprd.7b00248

A green and efficient organic-aqueous two-phase reaction route for the synthesis of tert-butyl peresters by KI-catalyzed C-H oxidation of methyl arenes in a microfluidic chip reactor has been developed. Moreover, a series of tert-butyl perester products were obtained in moderate to good yields under metal-free conditions. A scale-up continuous flow system was constructed to verify the application of this method.

Full text of DOI:10.1021/acs.oprd.7b00248

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Full Paper
Microfluidic synthesis of tert-butyl peresters via KI-catalyzed
oxidative coupling of methyl arenes and tert-butyl hydroperoxide
Jiawei Hua, Shiyu Guo, Zhao Yang, Zheng Fang, and Kai Guo
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00248 • Publication Date (Web): 25 Aug 2017
Downloaded from http://pubs.acs.org on August 27, 2017
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Microfluidic synthesis of tertꢀbutyl peresters via KIꢀ
catalyzed oxidative coupling of methyl arenes and
tertꢀbutyl hydroperoxide
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Jiawei Hua,† Shiyu Guo,† Zhao Yang, ‡ Zheng Fang,*, † Kai Guo*,†,§
† College of Biotechnology and Pharmaceutical Engineering Nanjing Tech University, 30 Puzhu
Rd S., Nanjing, 211816, China
‡ College of Engineering China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210003,
China
§ State Key Laboratory of MaterialsꢀOriented Chemical Engineering, 30 Puzhu Rd S., Nanjing,
211816, China
Table of Contents graphic:
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ABSTRACT: A green and efficient organic–aqueous two phase reaction route for the synthesis
of tertꢀbutyl peresters by KIꢀcatalyzed CꢀH oxidation of methyl arenes in a microfluidic chip
reactor has been developed. Moreover, a series of tertꢀbutyl peresters products were obtained in
moderate to good yields under metalꢀfree conditions. A scaleꢀup continuous flow system was
constructed to verify the application of this method.
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KEYWORDS: Two phase reaction, tertꢀbutyl peresters, Methyl arenes, Microfluidic chip
reactor, Scaleꢀup
INTRODUCTION
tertꢀbutyl peresters, the common core organic compounds, play an important role in organic
synthesis.1 Traditionally, tertꢀbutyl peresters were obtained by utilizing carboxylic acid and its
derivatives with TBHP (tertꢀbutyl hydroperoxide).2 In 2011, Wan’s group reported a novel
method for the synthesis of tertꢀbutyl peresters from aldehydes which is distinguished by high
atom economy and free of base (Scheme 1, eq.1).3 Wang’s group discovered a TBAI
(tetrabutylammonium iodide)ꢀcatalyzed oxidation of alcohols to prepare tertꢀbutyl peresters at
room temperature in aqueous system.4 Transition metals are of significance in these
transformations, which might provide a chance for formation of CꢀH, CꢀN, CꢀO bonds via crossꢀ
dehydrogenative coupling (CDC) reactions.5 Recently, Niknam’s group developed a copperꢀ
catalyzed oxidative coupling of benzyl cyanides with TBHP to synthesize tertꢀbutyl peresters
under solventꢀfree conditions (Scheme 1, eq.2).6 However, these methods mentioned above still
have some apparent drawbacks. It’s hard to enhance the mixing efficiency of the organic–
aqueous two phase reactions in batch reactor. Although extending the reaction time might
improve the yield, the quality and stability of the desired product could not be maintained.
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Furthermore, safety risks existed in the conventional scaleꢀup batch reaction for the synthesis of
peresters.
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Microfluidic system, the emerging platform for chemical synthesis, has been developing
rapidly in green chemistry.7 Compared to traditional chemical batch reactors, microfluidic
reactors possess thinner channels with dimensions of tens to hundreds of micrometres,8 which
could improve the efficiency of mass transfer and heat transfer between oil and water.9 Besides,
the state of mixing could be controlled by regulating temperature and the average flow rate
precisely.10 As a phase transfer catalyst, TBAI worked well in previous method for the synthesis
of tertꢀbutyl peresters. However, the cheaper KI could not be applicable to these reactions due to
the poor efficiency of the organic–aqueous two phase reactions in conventional batch reactor.
Traditional methods for the synthesis of tertꢀbutyl peresters required several to twenty hours to
react, while the microfluidic system merely consumed a little residence time and the product was
constantly collected, which might efficiently solved the potential safety problem. Herein, we
developed a novel organic–aqueous two phase route to tertꢀbutyl peresters via KIꢀcatalyzed
oxidative coupling of methyl arenes and TBHP in a microfluidic chip reactor (Scheme 1, eq.3).
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Scheme 1. Microfluidic synthesis of tertꢀbutyl peresters via KIꢀcatalyzed oxidative coupling of
methyl arenes and tertꢀbutyl hydroperoxide
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RESULTS AND DISCUSSION
Initially, a model reaction of toluene (1a) and TBHP (2) to form tertꢀbutyl peresters (3a) in a
microfluidic chip reactor was chosen as the model reaction to optimize reaction conditions by
examining a series of reaction parameters. And the results were summarized in Table 1. As
shown in Table 1, the microfluidic chip reactor is consisted of syringe pumps (A and B),
Controller (C) and Start unit (D). The volume of syringe and chip are 1 mL and 10 ꢁL,
respectively. The reaction time can be modulated by adjusting the flow rate of syringes. What’
more, the heating device of the chip fixed on Start unit (D) was controlled by Controller (C). The
use of microfluidic chip reactor provides a medium for our reaction, which is safe, efficient,
environmental friendly and with practical application. Firstly, a series of phase transfer catalysts,
such as TBAI (tetrabutylammonium iodide), TBAB (tetrabutylammonium bromide) and TBAC
(tetrabutylammonium chloride) were screened to investigate the reaction conditions (Table 1,
Table 1. Optimization of reaction conditionsa
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Entry
Catalyst
Time (s)
Yield (%)b
T (℃)
40
1
TBAI
TBAB
TBAC
NIS
KI
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<5
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RT
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KI
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KI
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KI
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14c
KI
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KI
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KI
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KI
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KI
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a Reaction conditions: Solution A: 1 mmol 1a in 6 mmol 2 (70% in H2O), pumping the organic
phase in syringe A (Titration of TBHP in the aqueous phase was only 0.062 mmol, which could
be ignored); Solution B: 0.2 mmol catalyst in 1 ml H2O; flow rate of syringe A = flow rate of
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b
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syringe B (ꢁL/min); the volume of chip reactor = 10 ꢁL. Isolated yield. the volume of chip
reactor = 5 ꢁL.
entry 1ꢀ3), but only the TBAI obtained the higher yield (Table 1, entry 1). The reaction
proceeded less efficiently in the presence of NIS (Table 1, entry 4). To our surprise, when we
took advantage of inexpensive KI as the catalyst, an excellent yield of 61% was obtained within
40 seconds (Table 1, entry 5). Furthermore, the temperature was also tested (Table 1, entry 6ꢀ8).
However, both raising the temperature to 60℃ and lowering the temperature to RT (room
temperature) failed to improve the yield. In order to improve the yield of the product 3a, the
residence time in chip reactor was screened (Table 1, entry 9ꢀ13). The range of corresponding
flow rate of syringe A and B were adjusted from 3.75 ꢁL/min to 10 ꢁL/min. And the optimal
residence time was 60 s (Table 1, entry 11). From the Table 1, it’s easy to find that further
extending residence time could not improve the yield efficiently. When a smaller volume (5 ꢁL)
of chip was utilized, a lower yield of desired product 3a was obtained (Table 1, entry 14). As
shown in Figure 1, a group of experiments in batch and chip were completed, respectively. As
the reaction time went on, the yield of 3a was capable to slightly increase in batch and the best
yield was just 40%. Meanwhile, a yield of 81% was obtained at the best reaction conditions in
chip, which was a great breakthrough. However, a longer residence time brings a smaller average
velocity in a fixed reactor and leads to weaker mass transfer in the continuous flow system,
which could explain the phenomenon that extending the residence time reduced the reaction
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yield. These results clearly indicated that the reaction with KI as the catalyst in chip reactor
performs better than that in batch because the microfluidic chip reactor could provide the
efficient mixing to enhance mass transfer and heat transfer between the aqueous phase and the
organic phase.
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Figure 1. Comparison of yield in batch and chip
in batcha
in chipb
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time (s)
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a Reaction conditions in batch: 1 mmol 1a, 0.2 mmol KI, 6mmol 2 in 1mL H2O, 40℃. Reaction
b
conditions in chip: Solution A: 1 mmol 1a in 6 mmol 2 (70% in H2O), pumping the organic
phase in syringe A (Titration of TBHP in the aqueous phase was only 0.062 mmol, which could
be ignored); Solution B: 0.2 mmol KI in 1 mL H2O; flow rate of syringe A = flow rate of syringe
B (ꢁL/min); the volume of chip reactor = 10 ꢁL.
With the optimized conditions in hands, a variety of toluene derivatives 1 were chosen to react
with TBHP 2 to synthesize the homologous products 3 in a microfluidic chip reactor. The results
were summarized in Table 2. Generally, toluene derivatives 1 with different substitution patterns
(electronꢀwithdrawing or electroꢀdonating groups) proceeded smoothly with TBHP 2. In
particular, a series of substituents, such as alkyl, sulfide, halide and cyano groups at the paraꢀ,
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metaꢀ, and orthoꢀposition, provided the corresponding products in 55% to 83% yields (Table 2,
3bꢀ3m). Notably, heteroarenes including 2ꢀmethylthiophene and 2ꢀmethylthiophene were also
suitable for our method (Table 2, 3n-3o). What’s more, 1ꢀmethylnaphthalene and 2ꢀ
methylnaphthalene were tolerated under the optimized conditions and afforded the desired
products 3p and 3q in 80% and 82% yields, respectively.
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Table 2. Substrate scope of toluene derivativesa,b,c
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a Reaction conditions: Solution A: 1 mmol 1 in 6 mmol 2 (70% in H2O), pumping the organic
phase in syringe A; Solution B: 0.2 mmol KI in 1 mL H2O; flow ratea = flow rateb =5 ꢁL/min;
the volume of chip reactor = 10 ꢁL. b Isolated yield. c Process mass intensity (PMI) = (total mass
in a process or process step) / (mass of product).
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To explore the practical value of this method, a scaleꢀup continuous flow reactor was set up,
which is composed of two syringe pumps, a Tꢀpiece micromixer and a tube reactor (Scheme 2).
Reaction proceeded effectively in this continuous flow reactor system, and the product 3a was
successfully got in a good yield.
Scheme 2. A scaleꢀup continuous flow reactora
a Reaction conditions: Solution A: 10 mmol 1 in 60 mmol 2 (70% in H2O), pumping the organic
phase in syringe A; Solution B: 2 mmol KI in 15 mL H2O; flow ratea = flow rateb =0.5 mL/min;
the volume of tube reactor = 10 mL; T = 40℃.
Next, the mechanism of the method was investigated by some control experiments (Scheme 3).
The target product 3a was successfully obtained from Benzyl alcohol A and benzaldehyde B in
the optimized conditions, respectively (Scheme 3, eq.1 and 2). The product 3a was formed in
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trace in the presence of radical inhibitor (TEMPO) and the compound 4 was obtained in 85%
yield (Scheme 3, eq.3). It clearly demonstrated that an acyl radical is formed in this reaction
process.
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Scheme 3. Experiments on the study of mechanism
On the basis of results above and previous reports,3,11 a plausible mechanism for the synthesis
of tertꢀbutyl peresters was proposed as shown in Scheme 4. Firstly, toluene 1a is transformed to
benzyl alcohol A,11e which is further oxidized into benzaldehyde B in the presence TBHP.
Afterwards, acyl radical C was formed via the cleavage of aldehydic C−H bond in the presence
of tertꢀbutoxyl, which was generated in the TBHPꢀKI catalytic cycle. Finally, the acyl radical C
couples with tertꢀbutylperoxy radical to afford the desired product 3a.
Scheme 4. Plausible reaction mechanism
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CONCLUSION
In summary, we have developed a green and efficient KIꢀcatalyzed organic–aqueous two
phase reaction route to tertꢀbutyl peresters from methyl arenes in a microfluidic chip reactor,
which not only improved the yield drastically, but also overcome the poor mixing efficiency of
organic–aqueous two phase reaction in batch. Moreover, a series of peresters were obtained in
moderate to good yields from commercially available methyl arenes and TBHP. A scaleꢀup
continuous flow system was successfully applied to this method, which verified its great
practical application in synthetic chemistry. Further investigation on the craft enlargement
experiment and application of this method are ongoing in our laboratory.
EXPERIMENTAL SECTION
1 mmol methyl arenes 1 were dissolved in 6 mmol TBHP 2 (70% in H2O) and the mixture is
divided into an organic phase and an aqueous phase. Titration of TBHP in the aqueous phase was
only 0.062 mmol, which could be ignored. Then the organic phase was pumped in syringe A. 0.2
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mmol KI was dissolved in 1 ml H2O, which was pumped in syringe B. The flow rate of syringe
A and syringe B were 5 ꢁL/min and the volume of chip reactor was 10 ꢁL. The temperature of
the chip was set in 40℃. The outflow of the reaction mixture was collected, then quenched with
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saturated Na2S2O3 solution (10 mL) and extracted with ethyl acetate (30 mL × 2). The organic
layer was dried over anhydrous sodium sulfate and solvent was removed under vacuum. And the
crude product was purified by flash chromatography on silica gel by gradient elution with ethyl
acetate in petroleum, affording the desired product 3 in good yields.
ASSOCIATED CONTENT
Supporting Information
Microfluidic chip reactor device, the scaleꢀup continuous flow system, experimental procedures
1
and full characterization of all compounds, spectral data, and H and 13C NMR spectra for all
1
13
products Copies of H and C NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: guok@njtech.edu.cn (K. Guo), fzcpu@163.com (Z. Fang), Tel +86 25 5813 9926, Fax
+86 25 5813 9935.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
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The research has been supported by the National Natural Science Foundation of China (Grant
No.21522604, U1463201 and 21402240); Natural Science Foundation of Jiangsu Province
(Grant No.BK20150031); Project Funded by the Priority Academic Program Development of
Jiangsu Higher Education Institutions (PAPD); The National Key Research and Development
Program of China (2016YFB0301500).
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S.; Majumder, L.; Prodhan, C.; Chaudhuri, K. Org. Biomol. Chem. 2017. (g) Funnell, T.; Tasaki,
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Table of Contents graphic:
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Scheme 1. Microfluidic synthesis of tert-butyl peresters via KI-catalyzed oxidative
coupling of methyl arenes and tert-butyl hydroperoxide
Table 1. Optimization of reaction conditionsa
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Entry
1
Catalyst
TBAI
TBAB
TBAC
NIS
KI
T (℃)
40
Time (s)
40
Yield (%)b
62
<5
<5
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RT
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KI
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KI
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KI
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KI
40
60
a Reaction conditions: Solution A: 1 mmol 1a in 6 mmol 2 (70% in H2O), pumping
the organic phase in syringe A (Titration of TBHP in the aqueous phase was only
0.062 mmol, which could be ignored); Solution B: 0.2 mmol catalyst in 1 ml H2O;
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flow rate of syringe A = flow rate of syringe B (μL/min); the volume of chip reactor =
10 μL. b Isolated yield. c the volume of chip reactor = 5 μL.
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Figure 1. Comparison of yield in batch and chip
in batcha
in chipb
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time (s)
time (h)
a Reaction conditions in batch: 1 mmol 1a, 0.2 mmol KI, 6mmol 2 in 1mL H2O, 40℃.
b Reaction conditions in chip: Solution A: 1 mmol 1a in 6 mmol 2 (70% in H2O),
pumping the organic phase in syringe A (Titration of TBHP in the aqueous phase was
only 0.062 mmol, which could be ignored); Solution B: 0.2 mmol KI in 1 mL H2O;
flow rate of syringe A = flow rate of syringe B (μL/min); the volume of chip reactor =
10 μL.
Table 2. Substrate scope of toluene derivativesa,b,c
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a
Reaction conditions: Solution A: 1 mmol 1 in 6 mmol 2 (70% in H2O), pumping
the organic phase in syringe A; Solution B: 0.2 mmol KI in 1 mL H2O; flow ratea =
flow rateb =5 μL/min; the volume of chip reactor = 10 μL. Isolated yield. c Process
b
mass intensity (PMI) = (total mass in a process or process step) / (mass of product).
Scheme 2. A scale-up continuous flow reactora
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a Reaction conditions: Solution A: 10 mmol 1 in 60 mmol 2 (70% in H2O), pumping
the organic phase in syringe A; Solution B: 2 mmol KI in 15 mL H2O; flow ratea =
flow rateb =0.5 mL/min; the volume of tube reactor = 10 mL; T = 40℃.
Scheme 3. Experiment on the study of mechanism
Scheme 4. Plausible reaction mechanism
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