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A Mechanism Study of a Novel Acid-Activatable Michael-Type Fluorescent Probe for Thiols
Yao Tong,Chun-guang Dai,Yi Ren,Shi-wei Luo*
Author NameAffiliationE-mail
Yao Tong Department of Chemistry, University of Science and Technology of China, Hefei 230026, China  
Chun-guang Dai Department of Chemistry, University of Science and Technology of China, Hefei 230026, China  
Yi Ren College of Chemistry and State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610064, China  
Shi-wei Luo* Department of Chemistry, University of Science and Technology of China, Hefei 230026, China luosw@ustc.edu.cn 
Abstract:
A Michael addition is usually taken as a base-catalysed reaction. However, our synthesized 2-(quinolin-2-ylmethylene) malonic acid (QMA) as a Michael-type thiol fluorescent probe is acid-active in its sensing reaction. In this work, based on theoretic calculation and experi-mental study on 7-hydroxy-2-(quinolin-2-ylmethylene) malonic acid, we demonstrated that QMA as a Michael acceptor is acid-activatable, i.e., it works only in solutions at pH<7, and the lower the pH of solutions is, the higher reactivity QMA has. In alkaline solution, the malonate QMA[-2H+]2- cannot react with both RS- and RSH. In contrast, 2-(quinolin-2-ylmethylene) malonic ester (QME), the ester of QMA, reveal a contrary pH effect on its sensing reaction, that is, it can sense thiols in alkaline solutions but not in acidic solutions, like a normal base-catalysed Michael addition. The values of activation enthalpies from theoretic calculation support the above sensing behavior of two probes under different pH conditions. In acidic solutions, the protonated QMA is more highly reactive towards elec-trophilic attack over its other ionized states in neutral and alkaline solutions, and so can react with lowly reactive RSH. In contrast, there is a big energy barrier in the interaction of QME with RSH (acidic solutions), and the reaction of QME with the highly reactive nucle-ophile RS- is a low activation energy process (in alkaline solutions). Theoretic calculation reveals that the sensing reaction of QMA undergoes a 1,4-addition process with neutral thiols (RSH), and a 1,2-addition pathway for the sensing reaction of QME with RS-. Therefore, the sensing reaction of QMA is an acid-catalysed Michael addition via a 1,4-addition, and a normal base-catalysed Michael addition via a 1,2-addition.
Key words:  Fluorescent probe, Thiols, Michael addition, DFT calculation, Transition state, Activation enthalpy
FundProject:
新颖的酸催化迈克尔型巯基荧光探针的机理
童遥,代春光,任译,罗时玮*
摘要:
迈克尔加成反应通常为碱催化的反应,但是在本工作体系当中,2-(2-乙烯基,7-羟基喹啉)丙二酸(QMA)能够被酸催化检测巯基. 从实验和理论计算证明了QMA探测巯基是,且溶液pH值越低,活 性越强. 在碱性溶液中,它的负离子形式QMA[-2H+]2-不能够与电离前或电离后的巯基反应. 与QMA相比,它的酯QME显示出相反的pH效应,这与一般的基于迈克尔加成的巯基荧光探针类似. DFT计算得到的活化焓支持上述两种探针的pH效应. 在酸性溶液中,质子化的QMA与中性和碱性溶液中的负离子形式相比更容易与亲核试剂发生加成,因此能够与低活性的未电离硫醇反应. 相反地,QME与未电离硫醇反应的能垒很高,与电离后的硫醇反应活化能很低. 理论计算研究显示QMA与未电离硫醇的反应为1,4-加成而QME与电离后的硫醇的反应为1,2-加成.
关键词:  荧光探针,硫醇,迈克尔加成,DFT计算,过渡态,活化焓
DOI:10.1063/1674-0068/28/cjcp1412217
分类号: