Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India.
Phys Chem Chem Phys. 2021 Apr 22;23(15):9500-9511. doi: 10.1039/d1cp00412c.
Engineered heme enzymes such as myoglobin and cytochrome P450s metalloproteins are gaining widespread importance due to their efficiency in catalyzing non-natural reactions. In a recent strategy, the naturally occurring Fe metal in the heme unit was replaced with non-native metals such as Ir, Rh, Co, Cu, etc., and axial ligands to generate artificial metalloenzymes. Determining the best metal-ligand for a chemical transformation is not a trivial task. Here we demonstrate how computational approaches can be used in deciding the best metal-ligand combination which would be highly beneficial in designing new enzymes as well as small molecule catalysts. We have used Density Functional Theory (DFT) to shed light on the enhanced reactivity of an Ir system with varying axial ligands. We look at the insertion of a carbene group generated from diazo precursors via N2 extrusion into a C-H bond. For both Ir(Me) and Fe systems, the first step, i.e., N2 extrusion is the rate determining step. Strikingly, neither the better ligand overlap with 5d orbitals on Ir nor the electrophilicity on the carbene centre play a significant role. A comparison of Fe and Ir systems reveals that a lower distortion in the Ir(Me)-porphyrin on moving from the reactant to the transition state renders it catalytically more active. We notice that for both metal porphyrins, the free energy barriers are affected by axial ligand substitution. Further, for Fe porphyrin, the axial ligand also changes the preferred spin state. We show that for the carbene insertion into the C-H bond, Fe porphyrin systems undergo a stepwise HAT (hydrogen atom transfer) instead of a concerted hydride transfer process. Importantly, we find that the substitution of the axial Me ligand on Ir to imidazole or chloride, or without an axial substitution changes the rate determining step of the reaction. Therefore, an optimum ligand that can balance the barriers for both steps of the catalytic cycle is essential. We subsequently used the QM cluster approach to delineate the protein environment's role and mutations in improving the catalytic activity of the Ir(Me) system.
由于其在催化非天然反应方面的效率，工程血红素酶，如肌红蛋白和细胞色素 P450 金属蛋白，正变得越来越重要。在最近的一项策略中，血红素单元中天然存在的 Fe 金属被非天然金属（如 Ir、Rh、Co、Cu 等）和轴向配体取代，从而产生人工金属酶。确定用于化学转化的最佳金属-配体组合并非易事。在这里，我们展示了如何使用计算方法来确定最佳的金属-配体组合，这对于设计新酶和小分子催化剂将非常有益。我们使用密度泛函理论（DFT）来阐明具有不同轴向配体的 Ir 系统的增强反应性。我们着眼于通过 N2 挤出从重氮前体制备的卡宾基团插入 C-H 键。对于 Ir(Me)和 Fe 系统，第一步即 N2 挤出是速率决定步骤。引人注目的是，无论是 Ir 上 5d 轨道的更好配体重叠还是卡宾中心的亲电性都没有起到重要作用。Fe 和 Ir 系统的比较表明，从反应物到过渡态，Ir(Me)-卟啉的变形较小使其催化活性更高。我们注意到，对于两种金属卟啉，轴向配体的取代都会影响自由能势垒。此外，对于 Fe 卟啉，轴向配体也会改变首选自旋态。我们表明，对于 C-H 键的卡宾插入，Fe 卟啉体系经历逐步 HAT（氢原子转移）而不是协同氢化物转移过程。重要的是，我们发现 Ir 上轴向 Me 配体被咪唑或氯取代，或者没有轴向取代，会改变反应的速率决定步骤。因此，平衡催化循环两步的最佳配体是必不可少的。随后，我们使用 QM 簇方法来描绘蛋白质环境的作用以及突变在提高 Ir(Me)体系的催化活性方面的作用。
