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The role of benzoic acid in proline-catalyzed asymmetric michael addition: A density functional theory study

Authors

  • Hongwei Shi,

    1. Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
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  • Xiangui Huang,

    1. Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
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  • Guixia Liu,

    Corresponding author
    1. Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
    2. State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chongzhi Road, Shanghai 201203, China
    • Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
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    • Fax: (+86) 21 64253651

  • Kunqian Yu,

    1. State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chongzhi Road, Shanghai 201203, China
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  • Congying Xu,

    1. Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
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  • Weihua Li,

    1. Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
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  • Bubing Zeng,

    Corresponding author
    1. Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
    2. Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
    • Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
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  • Yun Tang

    Corresponding author
    1. Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
    • Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
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Abstract

In asymmetric Michael addition between ketones and nitroolefins catalyzed by L-proline, we observed that it was benzoic acid or its derivatives rather than other proton acid that could accelerate the reaction greatly, and different benzoic acid derivatives brought different yields. To explain the experimental phenomena, a density functional theory study was performed to elucidate the mechanism of proline-catalyzed asymmetric Michael addition with benzoic acid. The results of the theoretical calculation at the level of B3LYP/6-311+G(2df,p)//B3LYP/6-31G(d) demonstrated that benzoic acid played two major roles in the formation of nitroalkane: assisting proton transfer and activating the nitro group. In the stage of enamine formation from imine, the energy profiles of benzoic acid derivatives were also calculated to investigate the reasons why different benzoic acid derivatives caused different yields. The results demonstrated that the pKa value was the major factor for p-substituted benzoic acid derivatives to improve the yields, whereas for m/o-substituted benzoic acid derivatives, both pKa value and electronic and steric effects could significantly increase the yields. The calculated results would be very helpful for understanding the reaction mechanism of Michael addition and provide some insights into the selection of efficient additives for similar experiments. © 2012 Wiley Periodicals, Inc.

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