STUDY ON THE RATE ACCELERATION OF THE BAYLIS-HILLMAN
REACTION WITHIN MICROREACTORS
Li Qi 1 *, Jun Yang 2, Juan Qiao 1, Huimin Ma 1 and Yi Chen 1
1
Institute of Chemistry, Chinese Academy of Sciences, No.2 Zhongguancun beiyijie, Beijing 100190, China
2
Graduate School, Chinese Academy of Sciences, Beijing 100049, China
ABSTRACT
The representative Baylis-Hillman (B-H) reaction of cyclopent-2-enone coupled with 4-nitrobenzaldehyde in the
presence of imidazole was accelerated by using electric field as well as temperature manipulation in microreactors. The
electric field was used to promote B-H reaction for the first time, the rate was approximately 4.0-fold to 5.2-fold than
carried out in conventional vessels.
KEYWORDS: Baylis-Hillman reaction, Microreactor, Rate acceleration, Imidazole
INTRODUCTION
Although the B-H reaction has an extensive application due to the inherent merits, the bottleneck is the slow reaction
rate and it will take some days to accomplish (1). For accelerating the reaction rate, many physical and chemical
strategies have been employed (2). In recent years, it has been found that organocatalysis as an effective strategy could
promote B-H reaction successfully. Especially, the medicine intermediate of imidazole displayed the excellent
performance (3).
Meanwhile, miniaturized reactors as a synthetic tools used in bio/chemical reactions have appeared for a long time.
Compared to the conventional vessels, the downscaled dimension leads to some important properties which have a
fundamental effect on the reactions. With the help of high specific surface areas and small dimension, mass and heat
transport are greatly enhanced. Meanwhile, minimal energy and reagent are consumed. In Scheme 1, the considerable
rate acceleration of B-H reaction was described involving cyclopent-2-enone and 4-nitrobenzaldehyde catalysed by
imidazole in microreactors.
Scheme1: The model reaction of Baylis-Hillman.
RESULTS AND DISCUSSION
Meanwhile, miniaturized reactors as a synthetic tools used in bio/chemical reactions have appeared for a long time.
Compared to the conventional vessels, the downscaled dimension leads to some important properties which have a
fundamental effect on the reactions. With the help of high specific surface areas and small dimension, mass and heat
transport are greatly enhanced. Meanwhile, minimal energy and reagent are consumed. In Scheme 1, the considerable rate
acceleration of B-H reaction was described involving cyclopent-2-enone and 4-nitrobenzaldehyde catalysed by imidazole in
microreactors.
The microreactors in this study were home-fabricated by standard photolithography and wet etching with the channel
dimension of 150 m in width, 60 m in depth and 70 cm in length. The schematic structure of the microreactor is illustrated
in Figure 1. The final products containing reactants were diluted by water and determined by capillary micellar
electrokinetic chromatography. The comparison of the conversion between microreactors and vials were described in Figure
2. Surprisingly, the conversion increased dramatically with the temperature increasing, which is corresponding to
approximately 4.0-fold of rate acceleration compared to the conversion gotten in vials (Figure 3).
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14th International Conference on
Miniaturized Systems for Chemistry and Life Sciences
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a
b
Figure 1: The structure of the microreactors
(a: used for temperature and pressure experiment; b: used for electric field experiment).
Figure 2: Comparison of conversions for the reaction carried out in vials and in microreactors.
Figure 3: The effect of temperature on conversion (after reacted in 30 min at each temperature value).
The process of B-H reaction refers to form six-membered transition state via covalent bond (Figure 4). No matter what
pathway the reaction experienced, the six-membered or four-membered rings of transition zwitterions always appeared.
Thus, we presume that if there is some kind of method that induces the transition zwitterions to generate and convert fastly,
the reaction rate will be accelerated. In this study, we readily found that the electric field applied in the reaction solution can
realize the hypothesis (Figure 5).
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Figure 4: The proposed mechanism of B-H reaction with and without existence of protic solvent.
Figure 5: The effect of electric field on the conversion at different voltage value in 30 min.
CONCLUSION
Based on microreactors, the rate of B-H reaction was accelerated for 4.0-fold to 5.2-fold than in vials via the flexible
manipulation of temperature, pressure and voltage. This reaction presents a sensitive responding to temperature and the
conversion reaches the peak value of 59.7% at 90ć. Unlike the temperature, the pressure almost has no obvious effect
on this reaction even at the utmost pressure of 5.0 MPa that the microreactor could sustain. However, electric field as a
robust and “green” approach was firstly used to accelerate the B-H reaction and display the satisfactory performance, to
enlarge this methodology in B-H reaction. It is meaningful to get a thorough understanding of mechanism and screen the
scope of substrate in further study.
ACKNOWLEDGEMENTS
The authors gratefully acknowledge the financial support from Ministry of Science and Technology of China (No.
2007CB714504), NSFC (No. 20875091 and No. 20935005) and Chinese Academy of Sciences.
REFERENCES
[1] D. Basavaiah, K.V. Rao and R. J. Reddy, The Baylis-Hillman reaction: a novel source of attraction, opportunities,
and challenges in synthetic chemistry, Chem. Soc. Rev. 36, 1581 (2007).
[2] V.K. Aggarwal, D.K. Dean, A. Mereu and R. Williams, Rate acceleration of the Baylis-Hillman reaction in polar
solvents (water and formamide). Dominant role of hydrogen bonding, not hydrophobic effects, is implicated, J.
Org. Chem. 67, 510 (2002).
[3] S.Z. Luo, B. L. Zhang, J. Q. He, A. Janczuk, P. G. Wang and J. P. Cheng, Aqueous Baylis-Hillman reactions of
cyclopent-2-enone using imidazole as catalyst, Tetrahedron Lett. 43, 7369 (2002).
CONTACT
* Li Qi, Tel: +86-10-82627290, Fax: +86-10-61559373; [email protected]
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