We are pleased to introduce the collection Theoretical and Computational Chemistry Editor’s Pick 2021. This collection showcases well-received spontaneous articles from the past couple of years, which have been specially handpicked by our Chief Editors, Prof. Sam de Visser and Prof. Thomas Hofer.  The work presented here highlights the broad diversity of research performed across the section, and aims to put a spotlight on the main areas of interest. All research presented here displays strong advances in theory, experiment and methodology with applications to compelling problems.   This collection aims to further support Frontiers’ strong community by recognizing highly deserving authors.

The University of Manchester

University of Innsbruck

Frontiers in Chemistry

Theoretical and Computational Chemistry

Theoretical and Computational Chemistry Editor’s Pick 2021

A mild ruthenium(II)-catalyzed homocoupling of α-carbonyl sulfoxonium ylides was developed and the detailed mechanism was understood based on DFT calculations in the current report. The catalytic system utilizes the α-carbonyl sulfoxonium ylide as both the directing group for ortho-sp2 C-H activation and the acylmethylating reagent for C-C coupling. Various substituents are compatible in the transformation and a variety of isocoumarin derivatives were synthesized at room temperature without any protection. The theoretical results disclosed that the full catalytic cycle contains eight elementary steps, and in all the cationic Ru(II) monomer is involved as the catalytic active species. The acid additive is responsible for protonation of the ylide carbon prior to the intramolecular nucleophilic addition and C-C bond cleavage. Interestingly, the intermediacy of free acylmethylation intermediate or its enol isomer is not necessary for the transformation.

A mild ruthenium(II)-catalyzed homocoupling of α-carbonyl sulfoxonium ylides was developed and the detailed mechanism was understood based on DFT calculations in the current report. The catalytic system utilizes the α-carbonyl sulfoxonium ylide as both the directing group for ortho-sp2 C-H activation and the acylmethylating reagent for C-C coupling. Various substituents are compatible in the transformation and a variety of isocoumarin derivatives were synthesized at room temperature without any protection. The theoretical results disclosed that the full catalytic cycle contains eight elementary steps, and in all the cationic Ru(II) monomer is involved as the catalytic active species. The acid additive is responsible for protonation of the ylide carbon prior to the intramolecular nucleophilic addition and C-C bond cleavage. Interestingly, the intermediacy of free acylmethylation intermediate or its enol isomer is not necessary for the transformation.

Ruthenium(II)-Catalyzed Homocoupling of α-Carbonyl Sulfoxonium Ylides Under Mild Conditions: Methodology Development and Mechanistic DFT Study

Metal-iodosylarene complexes have been recently viewed as a second oxidant alongside of the well-known high-valent metal-oxo species. Extensive efforts have been exerted to unveil the structure-function relationship of various metal-iodosylarene complexes. In the present manuscript, density functional theoretical calculations were employed to investigate such relationship of a specific manganese-iodosylbenzene complex [MnIII(TBDAP)(PhIO)(OH)]2+ (1). Our results fit the experimental observations and revealed new mechanistic findings. 1 acts as a stepwise 1e+1e oxidant in sulfoxidation reactions. Surprisingly, C-H bond activation of 9,10-dihydroanthracene (DHA) by 1 proceeds via a novel ionic hydride transfer/proton transfer (HT/PT) mechanism. As a comparison to 1, the electrophilicity of an iodosylbenzene monomer PhIO was investigated. PhIO performs concerted 2e-oxidations both in sulfoxidation and C-H activation. Hydroxylation of DHA by PhIO was found to proceed via a novel ionic and concerted proton-transfer/hydroxyl-rebound mechanism involving 2e-oxidation to form a transient carbonium species.

Metal-iodosylarene complexes have been recently viewed as a second oxidant alongside of the well-known high-valent metal-oxo species. Extensive efforts have been exerted to unveil the structure-function relationship of various metal-iodosylarene complexes. In the present manuscript, density functional theoretical calculations were employed to investigate such relationship of a specific manganese-iodosylbenzene complex [MnIII(TBDAP)(PhIO)(OH)]2+ (1). Our results fit the experimental observations and revealed new mechanistic findings. 1 acts as a stepwise 1e+1e oxidant in sulfoxidation reactions. Surprisingly, C-H bond activation of 9,10-dihydroanthracene (DHA) by 1 proceeds via a novel ionic hydride transfer/proton transfer (HT/PT) mechanism. As a comparison to 1, the electrophilicity of an iodosylbenzene monomer PhIO was investigated. PhIO performs concerted 2e-oxidations both in sulfoxidation and C-H activation. Hydroxylation of DHA by PhIO was found to proceed via a novel ionic and concerted proton-transfer/hydroxyl-rebound mechanism involving 2e-oxidation to form a transient carbonium species.

Theoretical Study on the Structural-Function Relationship of Manganese(III)-Iodosylarene Adducts

Pt nanoparticles (NPs) are often used as cocatalysts to enhance the photocatalytic hydrogen production catalyzed by the metal organic framework (MOF) materials. The catalytic efficiency of many Pt/MOF systems can be greatly improved when Pt NPs are used as cocatalysts. In this work, the Pt/20%-MIL-125-(SCH3)2 was chosen as the template material to understand the functional role of a Pt metal cocatalyst in the catalytic process. Experimentally, the catalytic activity of Pt/20%-MIL-125-(SCH3)2 is more than 100 times that of the system without the help of Pt NPs. Firstly, we proposed a searching algorithm, which is based on the combined Monte Carlo (MC) method and principal component analysis (PCA) algorithm, to find that the most probable adsorption site of the Pt13 nanocluster loaded on the (001) surface of 20%-MIL-125-(SCH3)2. Next, by using density functional theory (DFT) and time-dependent density functional theory (TDDFT) methods, we revealed that the accumulation of some positive charges on the Pt13 cluster and proton adsorbed on the Pt13 cluster, which can promote the separation of photogenerated electrons and holes, thus improving the photocatalytic efficiency. This work not only provides a method to obtain the adsorption configuration of metal clusters on various MOFs but also provides a new insight into increasing photocatalytic efficiency for H2 production in Pt/MOF systems.

Pt nanoparticles (NPs) are often used as cocatalysts to enhance the photocatalytic hydrogen production catalyzed by the metal organic framework (MOF) materials. The catalytic efficiency of many Pt/MOF systems can be greatly improved when Pt NPs are used as cocatalysts. In this work, the Pt/20%-MIL-125-(SCH3)2 was chosen as the template material to understand the functional role of a Pt metal cocatalyst in the catalytic process. Experimentally, the catalytic activity of Pt/20%-MIL-125-(SCH3)2 is more than 100 times that of the system without the help of Pt NPs. Firstly, we proposed a searching algorithm, which is based on the combined Monte Carlo (MC) method and principal component analysis (PCA) algorithm, to find that the most probable adsorption site of the Pt13 nanocluster loaded on the (001) surface of 20%-MIL-125-(SCH3)2. Next, by using density functional theory (DFT) and time-dependent density functional theory (TDDFT) methods, we revealed that the accumulation of some positive charges on the Pt13 cluster and proton adsorbed on the Pt13 cluster, which can promote the separation of photogenerated electrons and holes, thus improving the photocatalytic efficiency. This work not only provides a method to obtain the adsorption configuration of metal clusters on various MOFs but also provides a new insight into increasing photocatalytic efficiency for H2 production in Pt/MOF systems.

A Ti-MOF Decorated With a Pt Nanoparticle Cocatalyst for Efficient Photocatalytic H2 Evolution: A Theoretical Study

A new valence bond (VB)-based multireference density functional theory (MRDFT) method, named λ-DFVB, is presented in this paper. The method follows the idea of the hybrid multireference density functional method theory proposed by Sharkas et al. (<xref ref-type="bibr" rid="B67">2012</xref>). λ-DFVB combines the valence bond self-consistent field (VBSCF) method with Kohn–Sham density functional theory (KS-DFT) by decomposing the electron–electron interactions with a hybrid parameter λ. Different from the Toulouse's scheme, the hybrid parameter λ in λ-DFVB is variable, defined as a function of a multireference character of a molecular system. Furthermore, the EC correlation energy of a leading determinant is introduced to ensure size consistency at the dissociation limit. Satisfactory results of test calculations, including potential energy surfaces, bond dissociation energies, reaction barriers, and singlet–triplet energy gaps, show the potential capability of λ-DFVB for molecular systems with strong correlation.

A new valence bond (VB)-based multireference density functional theory (MRDFT) method, named λ-DFVB, is presented in this paper. The method follows the idea of the hybrid multireference density functional method theory proposed by <a href="fchem-07-00225-HTML.html#B67">Sharkas et al. (2012)</a>. λ-DFVB combines the valence bond self-consistent field (VBSCF) method with Kohn–Sham density functional theory (KS-DFT) by decomposing the electron–electron interactions with a hybrid parameter λ. Different from the Toulouse's scheme, the hybrid parameter λ in λ-DFVB is variable, defined as a function of a multireference character of a molecular system. Furthermore, the EC correlation energy of a leading determinant is introduced to ensure size consistency at the dissociation limit. Satisfactory results of test calculations, including potential energy surfaces, bond dissociation energies, reaction barriers, and singlet–triplet energy gaps, show the potential capability of λ-DFVB for molecular systems with strong correlation.

λ-Density Functional Valence Bond: A Valence Bond-Based Multiconfigurational Density Functional Theory With a Single Variable Hybrid Parameter

Respiratory complex I performs the reduction of quinone (Q) to quinol (QH2) and pumps protons across the membrane. Structural data on complex I have provided spectacular insights into the electron and proton transfer paths, as well as into the long (~30 Å) and unique substrate binding channel. However, due to missing structural information on Q binding modes, it remains unclear how Q reduction drives long range (~20 nm) redox-coupled proton pumping in complex I. Here we applied multiscale computational approaches to study the dynamics and redox chemistry of Q and QH2. Based on tens of microseconds of atomistic molecular dynamics (MD) simulations of bacterial and mitochondrial complex I, we find that the dynamics of Q is remarkably rapid and it diffuses from the N2 binding site to another stable site near the entrance of the Q channel in microseconds. Analysis of simulation trajectories also reveal the presence of yet another Q binding site 25–30 Å from the N2 center, which is in remarkable agreement with the electron density observed in recent cryo electron microscopy structure of complex I from Yarrowia lipolytica. Quantum chemical computations on the two Q binding sites closer to the entrance of the Q tunnel reveal redox-coupled protonation reactions that may be important in driving the proton pump of complex I.

Respiratory complex I performs the reduction of quinone (Q) to quinol (QH2) and pumps protons across the membrane. Structural data on complex I have provided spectacular insights into the electron and proton transfer paths, as well as into the long (~30 Å) and unique substrate binding channel. However, due to missing structural information on Q binding modes, it remains unclear how Q reduction drives long range (~20 nm) redox-coupled proton pumping in complex I. Here we applied multiscale computational approaches to study the dynamics and redox chemistry of Q and QH2. Based on tens of microseconds of atomistic molecular dynamics (MD) simulations of bacterial and mitochondrial complex I, we find that the dynamics of Q is remarkably rapid and it diffuses from the N2 binding site to another stable site near the entrance of the Q channel in microseconds. Analysis of simulation trajectories also reveal the presence of yet another Q binding site 25–30 Å from the N2 center, which is in remarkable agreement with the electron density observed in recent cryo electron microscopy structure of complex I from Yarrowia lipolytica. Quantum chemical computations on the two Q binding sites closer to the entrance of the Q tunnel reveal redox-coupled protonation reactions that may be important in driving the proton pump of complex I.

Role of Second Quinone Binding Site in Proton Pumping by Respiratory Complex I

Halogen bonds have recently gained attention in life sciences and drug discovery. However, it can be difficult to harness their full potential, when newly introducing them into an established hit or lead structure by molecular design. A possible solution to overcome this problem is the use of halogen-enriched fragment libraries (HEFLibs), which consist of chemical probes that provide the opportunity to identify halogen bonds as one of the main features of the binding mode. Initially, we have suggested the HEFLibs concept when constructing a focused library for finding p53 mutant stabilizers. Herein, we broaden and extent this concept aiming for a general HEFLib comprising a huge diversity of binding motifs and, thus, increasing the applicability to various targets. Using the construction principle of feature trees, we represent each halogenated fragment by treating all simple to complex substituents as modifiers of the central (hetero)arylhalide. This approach allows us to focus on the proximal binding interface around the halogen bond and, thus, its integration into a network of interactions based on the fragment's binding motif. As a first illustrative example, we generated a library of 198 fragments that unifies a two-fold strategy: Besides achieving a diversity-optimized basis of the library, we have extended this “core” by structurally similar “satellite compounds” that exhibit quite different halogen bonding interfaces. Tuning effects, i.e., increasing the magnitude of the σ-hole, can have an essential influence on the strength of the halogen bond. We were able to implement this key feature into the diversity selection, based on the rapid and efficient prediction of the highest positive electrostatic potential on the electron isodensity surface, representing the σ-hole, by VmaxPred.

Halogen bonds have recently gained attention in life sciences and drug discovery. However, it can be difficult to harness their full potential, when newly introducing them into an established hit or lead structure by molecular design. A possible solution to overcome this problem is the use of halogen-enriched fragment libraries (HEFLibs), which consist of chemical probes that provide the opportunity to identify halogen bonds as one of the main features of the binding mode. Initially, we have suggested the HEFLibs concept when constructing a focused library for finding p53 mutant stabilizers. Herein, we broaden and extent this concept aiming for a general HEFLib comprising a huge diversity of binding motifs and, thus, increasing the applicability to various targets. Using the construction principle of feature trees, we represent each halogenated fragment by treating all simple to complex substituents as modifiers of the central (hetero)arylhalide. This approach allows us to focus on the proximal binding interface around the halogen bond and, thus, its integration into a network of interactions based on the fragment's binding motif. As a first illustrative example, we generated a library of 198 fragments that unifies a two-fold strategy: Besides achieving a diversity-optimized basis of the library, we have extended this “core” by structurally similar “satellite compounds” that exhibit quite different halogen bonding interfaces. Tuning effects, i.e., increasing the magnitude of the σ-hole, can have an essential influence on the strength of the halogen bond. We were able to implement this key feature into the diversity selection, based on the rapid and efficient prediction of the highest positive electrostatic potential on the electron isodensity surface, representing the σ-hole, by VmaxPred.

Embracing the Diversity of Halogen Bonding Motifs in Fragment-Based Drug Discovery—Construction of a Diversity-Optimized Halogen-Enriched Fragment Library