Bifunctional iminophosphorane organocatalyst with additional hydrogen bonding: Calculations predict enhanced catalytic performance in a michael addition reaction

IF 2.7 4区生物学 Q2 BIOCHEMICAL RESEARCH METHODS Journal of molecular graphics & modelling Pub Date : 2024-03-16 DOI:10.1016/j.jmgm.2024.108760

Virginia C. Rufino, Josefredo R. Pliego Jr.

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Abstract

A new iminophosphorane-thiourea superbase was rationally designed and investigated as an organocatalyst for the enantioselective Michael addition reaction of nitromethane to 4-phenylbut-3-en-2-one. Starting from an iminophosphorane-thiourea organocatalyst structure already known, we have used theoretical calculations to determine the structures of transition states involved in the carbon-carbon bond formation step and carried out structural modifications to accelerate the reaction rate and to increase the enantioselectivity. The effective structural modification was adding a rigid hydroxyl group able to make an additional hydrogen bond to the transition state, producing a substantial decrease of the ΔG^‡ by 7 kcal mol⁻¹. The enantiomeric excess is predicted to be above of 97% using the reliable M06-2X and ωB97M − V functionals. The determination of the complete reaction mechanism and free energy profile was followed by a detailed microkinetic analysis. The present study points out a new direction for structural modifications on this kind of organocatalyst.

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具有额外氢键的双功能亚氨基磷烷有机催化剂：计算预测迈克尔加成反应中催化性能的提高

我们合理地设计并研究了一种新的亚氨基磷烷-硫脲超级碱作为有机催化剂，用于硝基甲烷与 4-苯基丁-3-烯-2-酮的对映选择性迈克尔加成反应。从已知的亚氨基磷烷-硫脲有机催化剂结构出发，我们利用理论计算确定了参与碳-碳键形成步骤的过渡态结构，并进行了结构改造以加快反应速率和提高对映选择性。有效的结构改造是在过渡态中加入一个能形成额外氢键的刚性羟基，从而使ΔG 值大幅降低了 7 kcal mol。使用可靠的 M06-2X 和 ωB97M-V 函数预测对映体过量率高于 97%。在确定完整的反应机理和自由能曲线之后，还进行了详细的微动力学分析。本研究为这类有机催化剂的结构改造指明了新的方向。

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来源期刊

Journal of molecular graphics & modelling 生物-计算机：跨学科应用

CiteScore

5.50

自引率

6.90%

发文量

216

审稿时长

35 days

期刊介绍： The Journal of Molecular Graphics and Modelling is devoted to the publication of papers on the uses of computers in theoretical investigations of molecular structure, function, interaction, and design. The scope of the journal includes all aspects of molecular modeling and computational chemistry, including, for instance, the study of molecular shape and properties, molecular simulations, protein and polymer engineering, drug design, materials design, structure-activity and structure-property relationships, database mining, and compound library design. As a primary research journal, JMGM seeks to bring new knowledge to the attention of our readers. As such, submissions to the journal need to not only report results, but must draw conclusions and explore implications of the work presented. Authors are strongly encouraged to bear this in mind when preparing manuscripts. Routine applications of standard modelling approaches, providing only very limited new scientific insight, will not meet our criteria for publication. Reproducibility of reported calculations is an important issue. Wherever possible, we urge authors to enhance their papers with Supplementary Data, for example, in QSAR studies machine-readable versions of molecular datasets or in the development of new force-field parameters versions of the topology and force field parameter files. Routine applications of existing methods that do not lead to genuinely new insight will not be considered.