Hajime Hirao

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Organization: Nanyang Technological University , Singapore

Department: School of Physical and Mathematical Sciences

Title: (PhD)

TOPICS

Physical Chemistry

Inorganic Chemistry

Chemicals
References

To rebound or dissociate? This is the mechanistic question in C–H hydroxylation by heme and nonheme metal–oxo complexes

Co-reporter:Kyung-Bin Cho, Hajime Hirao, Sason Shaik and Wonwoo Nam

Chemical Society Reviews 2016 vol. 45(Issue 5) pp:1197-1210

Publication Date(Web):21 Dec 2015

DOI:10.1039/C5CS00566C

Enzymatic reactions that involve C–H bond activation of alkanes by high-valent iron–oxo species can be explained by the rebound mechanism (RM). Hydroxylation reactions of alkane substrates effected by the reactive compound I (Cpd I) species of cytochrome P450 enzymes are good examples. There was initially little doubt that the rebound paradigm could be carried over in the same form to the arena of synthetic nonheme high-valent iron–oxo or other metal–oxo complexes. However, the active reaction centres of these synthetic systems are not well-caged, in contrast to the active sites of enzymes; therefore, the relative importance of the radical dissociation pathway can become prominent. Indeed, accumulating experimental and theoretical evidence shows that introduction of the non-rebound mechanism (non-RM) is necessary to rationalise the different reactivity patterns observed for synthetic nonheme complexes. In this tutorial review, we discuss several specific examples involving the non-RM while making frequent comparisons to the RM, mainly from the perspective of computational chemistry. We also provide a technical guide to DFT calculations of RM and non-RM and to the interpretations of computational outcomes.

Al2O3 Surface Complexation for Photocatalytic Organic Transformations

Co-reporter:Wan Ru Leow, Wilson Kwok Hung Ng, Tai Peng, Xinfeng Liu, Bin Li, Wenxiong Shi, Yanwei Lum, Xiaotian Wang, Xianjun LangShuzhou Li, Nripan MathewsJoel W. Ager, Tze Chien Sum, Hajime Hirao, Xiaodong Chen

Journal of the American Chemical Society 2016 Volume 139(Issue 1) pp:269-276

Publication Date(Web):December 14, 2016

DOI:10.1021/jacs.6b09934

The use of sunlight to drive organic reactions constitutes a green and sustainable strategy for organic synthesis. Herein, we discovered that the earth-abundant aluminum oxide (Al2O3) though paradigmatically known to be an insulator could induce an immense increase in the selective photo-oxidation of different benzyl alcohols in the presence of a large variety of dyes and O2. This unique phenomenon is based on the surface complexation of benzyl alcohol (BnOH) with the Brønsted base sites on Al2O3, which reduces its oxidation potential and causes an upshift in its HOMO for electron abstraction by the dye. The surface complexation of O2 with Al2O3 also activates the adsorbed O2 for receiving electrons from the photoexcited dyes. This discovery brings forth a new understanding on utilizing surface complexation mechanisms between the reactants and earth abundant materials to effectively achieve a wider range of photoredox reactions.

Pd-Catalyzed Conversion of Alkynyl-λ3-iodanes to Alkenyl-λ3-iodanes via Stereoselective 1,2-Iodine(III) Shift/1,1-Hydrocarboxylation

Co-reporter:Junliang Wu; Xiaozhou Deng; Hajime Hirao;Naohiko Yoshikai

Journal of the American Chemical Society 2016 Volume 138(Issue 29) pp:9105-9108

Publication Date(Web):July 15, 2016

DOI:10.1021/jacs.6b06247

Alkynyl-λ3-iodanes have been established as alkynyl cation equivalents for the alkynylation of carbon- and heteroatom-based nucleophiles. Herein, we report an unprecedented reaction mode of this compound class, which features a Pd(II)-assisted 1,2-I(III) shift of an alkynylbenziodoxole. A Pd(II) catalyst mediates this shift and the subsequent interception of the transient vinylidene species with carboxylic acid (1,1-hydrocarboxylation). The product of this stereoselective rearrangement–addition reaction, β-oxyalkenylbenziodoxole, represents a novel and useful building block for further synthetic transformations.

Asymmetric Conjugate Addition of Organoboron Reagents to Common Enones Using Copper Catalysts

Co-reporter:Chunlin Wu; Guizhou Yue; Christian Duc-Trieu Nielsen; Kai Xu; Hajime Hirao;Jianrong (Steve) Zhou

Journal of the American Chemical Society 2016 Volume 138(Issue 3) pp:742-745

Publication Date(Web):January 12, 2016

DOI:10.1021/jacs.5b11441

Copper complexes of phosphoramidites efficiently catalyzed asymmetric addition of arylboron reagents to acyclic enones. Importantly, rare 1,4-insertion of arylcopper(I) was identified which led directly to O-bound copper enolates. The new mechanism is fundamentally different from classical oxidative addition/reductive elimination of organocopper(I) on enones.

Fluorescent Porous Organic Frameworks Containing Molecular Rotors for Size-Selective Recognition

Co-reporter:Jinqiao Dong, Anil Kumar Tummanapelli, Xu Li, Shaoming Ying, Hajime Hirao, and Dan Zhao

Chemistry of Materials 2016 Volume 28(Issue 21) pp:7889

Publication Date(Web):October 18, 2016

DOI:10.1021/acs.chemmater.6b03376

Fluorescent porous materials have been under intensive investigation recently, because of their wide applications in molecular recognition and chemical sensing. However, it is a great challenge to achieve size selectivity and sensing linearity for molecular recognition. Herein, we report a series of porous organic frameworks (POFs) containing flexible tetraphenylethylene (TPE) moieties as molecular rotors with responsive fluorescent behavior. These fluorescent POFs exhibit size-selective turn-on fluorescence for the effective chemical sensing of volatile organic compounds (VOCs), which can be attributed to the different degrees of motion restriction of flexible TPE rotors by various VOCs, leading to the partially freezing of rotors in more fluorescent conformations. Significantly, a linear aggregation-induced emission (AIE) relationship is observed between the fluorescent POFs and the VOCs over a wide range of concentrations, which is highly beneficial for quantitative sensing applications. The gas-phase detection of arene vapors using POFs is also proven with unprecedentedly high sensitivity, selectively, and recyclability. The mechanism of responsive fluorescence in POFs is further investigated using molecular simulations and density functional theory (DFT) calculations.

Size-Dependent Catalytic Activity of Palladium Nanoparticles Fabricated in Porous Organic Polymers for Alkene Hydrogenation at Room Temperature

Co-reporter:John Mondal, Quang Thang Trinh, Avijit Jana, Wilson Kwok Hung Ng, Parijat Borah, Hajime Hirao, and Yanli Zhao

ACS Applied Materials & Interfaces 2016 Volume 8(Issue 24) pp:15307-15319

Publication Date(Web):June 3, 2016

DOI:10.1021/acsami.6b03127

Ultrafine palladium nanoparticles (Pd NPs) with 8 and 3 nm sizes were effectively fabricated in triazine functionalized porous organic polymer (POP) TRIA that was developed by nonaqueous polymerization of 2,4,6-triallyoxy-1,3,5-triazine. The Pd NPs encapsulated POP (Pd-POP) was fully characterized using several techniques. Further studies revealed an excellent capability of Pd-POP for catalytic transfer hydrogenation of alkenes at room temperature with superior catalytic performance and high selectivity of desired products. Highly flammable H2 gas balloon at high pressure and temperature used in conventional hydrogenation reactions was not needed in the present synthetic system. Catalytic activity is strongly dependent on the size of encapsulated Pd NPs in the POP. The Pd-POP catalyst with Pd NPs of 8 nm in diameter exhibited higher catalytic activity for alkene hydrogenation as compared with the Pd-POP catalyst encapsulating 3 nm Pd NPs. Computational studies were undertaken to gain insights into different catalytic activities of these two Pd-POP catalysts. High reusability and stability as well as no Pd leaching of these Pd-POP catalysts make them highly applicable for hydrogenation reactions at room temperature.

Hydride Reduction by a Sodium HydrideIodide Composite

Co-reporter:Dr. Pei Chui Too;Guo Hao Chan;Dr. Ya Lin Tnay; Hajime Hirao; Shunsuke Chiba

Angewandte Chemie 2016 Volume 128( Issue 11) pp:3783-3787

Publication Date(Web):

DOI:10.1002/ange.201600305

Abstract

Sodium hydride (NaH) is widely used as a Brønsted base in chemical synthesis and reacts with various Brønsted acids, whereas it rarely behaves as a reducing reagent through delivery of the hydride to polar π electrophiles. This study presents a series of reduction reactions of nitriles, amides, and imines as enabled by NaH in the presence of LiI or NaI. This remarkably simple protocol endows NaH with unprecedented and unique hydride-donor chemical reactivity.

Hydride Reduction by a Sodium HydrideIodide Composite

Co-reporter:Dr. Pei Chui Too;Guo Hao Chan;Dr. Ya Lin Tnay; Hajime Hirao; Shunsuke Chiba

Angewandte Chemie International Edition 2016 Volume 55( Issue 11) pp:3719-3723

Publication Date(Web):

DOI:10.1002/anie.201600305

Abstract

Estrogen Formation via H-Abstraction from the O–H Bond of gem-Diol by Compound I in the Reaction of CYP19A1: Mechanistic Scenario Derived from Multiscale QM/MM Calculations

Co-reporter:Kai Xu, Yong Wang, and Hajime Hirao

ACS Catalysis 2015 Volume 5(Issue 7) pp:4175

Publication Date(Web):June 3, 2015

DOI:10.1021/acscatal.5b00510

Recent experiments suggested that, contrary to traditional belief, the third step of aromatase-catalyzed estrogen formation should be effected by compound I (Cpd I), rather than by ferric peroxide. We performed QM/MM calculations to address the question of how Cpd I drives the aromatization process. Surprisingly, the calculations show that the reaction begins with hydrogen abstraction from the O–H bond of a gem-diol substrate, which is followed by barrierless homolytic C–C bond cleavage and then 1β-H-abstraction. Proton-coupled electron transfer enables the cleavage of the strong O–H bond. Another product, carboxylic acid, can be formed from either the gem-diol or aldehyde.Keywords: aromatase; Cpd I; H-abstraction; PCET; QM/MM

Multiscale Model for a Metal–Organic Framework: High-Spin Rebound Mechanism in the Reaction of the Oxoiron(IV) Species of Fe-MOF-74

Co-reporter:Hajime Hirao, Wilson Kwok Hung Ng, Adhitya Mangala Putra Moeljadi, and Sareeya Bureekaew

ACS Catalysis 2015 Volume 5(Issue 6) pp:3287

Publication Date(Web):April 22, 2015

DOI:10.1021/acscatal.5b00475

We performed ONIOM QM/MM calculations to understand how ethane is hydroxylated and ethanol is converted to acetaldehyde by an oxoiron(IV) species generated within an iron-containing metal–organic framework called Fe-MOF-74. The calculations showed that the ethane hydroxylation proceeds via a high-spin rebound mechanism. The conversion of ethanol into acetaldehyde should occur more favorably via H-abstraction from the O–H bond than via C–H cleavage, although the O–H bond of ethanol is stronger than the C(1)–H bond. This trend can be rationalized by the effect of proton-coupled electron transfer, which stabilizes the transition state for O–H cleavage.Keywords: C−H activation; metal−organic framework; oxoiron(IV); PCET; QM/MM

Insight into Enzymatic Nitrile Reduction: QM/MM Study of the Catalytic Mechanism of QueF Nitrile Reductase

Co-reporter:António J. M. Ribeiro, Lifeng Yang, Maria J. Ramos, Pedro A. Fernandes, Zhao-Xun Liang, and Hajime Hirao

ACS Catalysis 2015 Volume 5(Issue 6) pp:3740

Publication Date(Web):May 11, 2015

DOI:10.1021/acscatal.5b00528

The NADPH-dependent QueF nitrile reductases catalyze the unprecedented four-electron reduction of nitrile to amine. QueF nitrile reductases can be found in the tRNA biosynthetic pathway of many bacteria and are potential antimicrobial drug targets. QueF enzymes have also attracted great attention as potential industrial biocatalysts for replacing the nitrile-reducing metal hydride catalysts used commonly in the chemical and pharmaceutical industries. Because of their narrow substrate specificity, engineering of the QueF enzymes to generate variants with altered or broadened substrate specificity is crucial for producing practically useful biocatalysts. A better understanding of the catalytic mechanism of the QueF enzymes would expedite rational inhibitor design and enzyme engineering. In this work, we probed the catalytic mechanism of the Vibrio cholerae QueF nitrile reductase by state of the art QM/MM calculations at the ONIOM(B3LYP/6-311+G(2d,2p):AMBER) level. The QM/MM computational results suggest that the nitrile to amine conversion proceeds through four major stages: (a) formation of a C–S covalent bond between the substrate and the catalytic cysteine residue to form the thioimidate intermediate, (b) hydride transfer from NADPH to the substrate to generate the thiohemiaminal intermediate, (c) cleavage of the C–S covalent bond to generate the imine intermediate, and (d) second hydride transfer from NADPH to the imine intermediate to generate the final amine product. The free energy barrier for the rate-limiting step, i.e. the second hydride transfer, was found to be 20.8 kcal/mol. The calculated barrier height and the catalytic residues identified as essential for nitrile reduction are in accordance with the currently available experimental data. The knowledge about the transition states, intermediates, and protein conformational changes along the reaction path will be valuable for the design of enzyme inhibitors as well as the engineering of QueF nitrile reductases.Keywords: biocatalyst; covalent intermediate; enzyme catalysis; nitrile reductase; transition state

Benzyne Formation in the Mechanism-Based Inactivation of Cytochrome P450 by 1-Aminobenzotriazole and N-Benzyl-1-Aminobenzotriazole: Computational Insights

Co-reporter:Pratanphorn Chuanprasit, Shu Hui Goh, and Hajime Hirao

ACS Catalysis 2015 Volume 5(Issue 5) pp:2952

Publication Date(Web):March 31, 2015

DOI:10.1021/acscatal.5b00423

Cytochrome P450 enzymes (P450s) are ubiquitously distributed heme enzymes that play catalytic roles in the essential oxidative biotransformation of a wide range of exogenous and endogenous organic compounds. Strong inhibition of P450s through mechanism-based inactivation (MBI) essentially should not occur, because it would affect important metabolic processes adversely. However, accumulated evidence shows that the MBI of a P450 is not a rare event. MBI can also be exploited for useful applications such as reaction phenotyping. Thus, MBI is clearly one of the major problems concerning P450s, but the reaction mechanisms underlying MBI are not very clear in many cases. In this work, we used density functional theory (DFT) calculations to understand how a metabolite (benzyne) is formed from two mechanism-based inactivators of P450s: 1-aminobenzotriazole (ABT) and N-benzyl-1-aminobenzotriazole (BBT). ABT has been widely used for reaction phenotyping. Our DFT calculations show that the formation of benzyne from ABT occurs via two sequential H-abstraction reactions from the exocyclic N–H bonds, similar to the reaction of 1,1-dimethylhydrazine (Hirao, H.; Chuanprasit, P.; Cheong, Y. Y.; Wang, X. Chem. Eur. J. 2013, 19, 7361–7369). The transition states for these H-abstractions are stabilized by a proton-coupled electron transfer effect. The formation of benzyne from BBT is also triggered by H-abstraction from the N–H bond. However, in this case, the second step is H-abstraction from a benzylic C–H bond. In addition, for the formation of benzyne from BBT, another catalytic cycle should be necessary. Our computational study therefore elucidates the difference in reaction mechanisms between ABT and BBT, providing new insights into the processes involved in the MBI caused by these compounds.Keywords: benzyne; cytochrome P450; density functional theory; mechanism-based inactivation; reaction mechanism

Selective photocatalytic C–C bond cleavage under ambient conditions with earth abundant vanadium complexes

Co-reporter:Sarifuddin Gazi, Wilson Kwok Hung Ng, Rakesh Ganguly, Adhitya Mangala Putra Moeljadi, Hajime Hirao and Han Sen Soo

Chemical Science 2015 vol. 6(Issue 12) pp:7130-7142

Publication Date(Web):14 Sep 2015

DOI:10.1039/C5SC02923F

Selective C–C bond cleavage under ambient conditions is a challenging chemical transformation that can be a valuable tool for organic syntheses and macromolecular disassembly. Herein, we show that base metal vanadium photocatalysts can harvest visible light to effect the chemoselective C–C bond cleavage of lignin model compounds under ambient conditions. Lignin, a major aromatic constituent of non-food biomass, is an inexpensive, accessible source of fine chemical feedstocks such as phenols and aryl ethers. However, existing lignin degradation technologies are harsh and indiscriminately degrade valuable functional groups to produce intractable mixtures. The selective, photocatalytic depolymerization of lignin remains underexplored. In the course of our studies on lignin model compounds, we have uncovered a new C–C activation reaction that takes place under exceptionally mild conditions with high conversions. We present our fundamental studies on representative lignin model compounds, with the aim of expanding and generalizing the substrate scope in the future. Visible light is employed in the presence of earth-abundant vanadium oxo catalysts under ambient conditions. Selective C–C bond cleavage leads to valuable and functionally rich fine chemicals such as substituted aryl aldehydes and formates. Isotope labeling experiments, product analyses, and intermediate radical trapping, together with density functional theory studies, suggest a unique pathway that involves a photogenerated T1 state during the C–C bond cleavage reactions. Our study demonstrates a sustainable approach to harvest sunlight for an unusual, selective bond activation, which can potentially be applied in organic transformations and biomass valorization.

Reversible [4 + 2] cycloaddition reaction of 1,3,2,5-diazadiborinine with ethylene

Co-reporter:Di Wu, Rakesh Ganguly, Yongxin Li, Sin Ni Hoo, Hajime Hirao and Rei Kinjo

Chemical Science 2015 vol. 6(Issue 12) pp:7150-7155

Publication Date(Web):15 Sep 2015

DOI:10.1039/C5SC03174E

Under ambient conditions, a [4 + 2] cycloaddition reaction of 1,3,2,5-diazadiborinine 1 with ethylene afforded a bicyclo[2.2.2] derivative 2, which was structurally characterized. The cyclization process was found to be reversible, and thus retro-[4 + 2] cycloaddition reproduced 1 quantitatively, concomitant with the release of ethylene. Compound 1 reacted regio-selectively and stereo-selectively with styrene derivatives and norbornene, respectively, and these processes were found to be reversible too. Computational studies determined the reaction pathways which were consistent with the regio-selectivity observed in the reaction of styrene, and the reaction was suggested to be essentially concerted but highly asynchronous.

Electronic and magnetic properties of C60–Fen–graphene intercalating nanostructures (n = 1–6) predicted from first-principles calculations

Co-reporter:Hung M. Le, Wilson K.H. Ng, Hajime Hirao

Chemical Physics Letters 2015 Volume 618() pp:127-131

Publication Date(Web):2 January 2015

DOI:10.1016/j.cplett.2014.10.051

•Multiple Fe atoms are employed to connect C60 to graphene.•The proposed nanostructures possess great structural stability.•Interesting magnetic moments and semi-metallicity are observed.Graphene and C60 can establish coordination bonds with transition metal atoms/clusters. Using first-principles modeling methods, we explore the C60–Fen–graphene intercalating nanostructures (n = 1–6), which may have potential applications in, e.g., spintronics. Twelve optimized configurations are found to possess good energetic stability (with binding energies of 4.22–20.54 eV). Eleven structures have different magnitudes of magnetism (2.00–12.75 μB/cell), whereas one is non-magnetic. The magnetism is highly correlated with the bonding orientations between Fe atoms and C60. Seven nanostructures possess good half metallicity (with the spin polarization effects >0.8), while the non-magnetic structure is found to be insulating.

An attempt to evaluate the effect of proton-coupled electron transfer on the H-abstraction step of the reaction between 1,1-dimethylhydrazine and cytochrome P450 compound I

Co-reporter:Hajime Hirao, Pratanphorn Chuanprasit

Chemical Physics Letters 2015 Volume 621() pp:188-192

Publication Date(Web):4 February 2015

DOI:10.1016/j.cplett.2014.12.027

Highlights

•: DFT calculations are performed for H-abstraction reactions of P450 compound I.
•: The effect of PCET in the reaction of 1,1-dimethylhydrazine is evaluated.
•: Valence-bond diagrams are used to gain insight into the reactivity.

Metal-Free -Bond Metathesis in 1,3,2-Diazaphospholene-Catalyzed Hydroboration of Carbonyl Compounds

Co-reporter:Che Chang Chong;Dr. Hajime Hirao;Dr. Rei Kinjo

Angewandte Chemie International Edition 2015 Volume 54( Issue 1) pp:190-194

Publication Date(Web):

DOI:10.1002/anie.201408760

Abstract

The first metal-free catalytic hydroboration of carbonyl derivatives has been developed in which a catalytic amount of 1,3,2-diazaphospholene effectively promotes a hydroboration reaction of aliphatic and aromatic aldehydes and ketones. The reaction mechanism involves the cleavage of both the PO bond of the alkoxyphosphine intermediate and the BH bond of pinacolborane as well as the formation of PH and BO bonds. Thus, the reaction proceeds through a non-metal σ-bond metathesis. Kinetic and computational studies suggest that the σ-bond metathesis occurred in a stepwise but nearly concerted manner.

Nickel-Catalyzed Asymmetric Transfer Hydrogenation of Hydrazones and Other Ketimines

Co-reporter:Haiyan Xu;Dr. Peng Yang;Pratanphorn Chuanprasit;Dr. Hajime Hirao;Dr. Jianrong (Steve) Zhou

Angewandte Chemie 2015 Volume 127( Issue 17) pp:5201-5205

Publication Date(Web):

DOI:10.1002/ange.201501018

Abstract

We report the use of nickel catalysts for the catalytic transfer hydrogenation of hydrazones and other ketimines with formic acid. Strongly donating bisphosphines must be used to support the catalysts. As in enzymatic catalysis, attractive weak interactions may be important for stereochemical control by the nickel/binapine catalyst.

Metal-Free -Bond Metathesis in 1,3,2-Diazaphospholene-Catalyzed Hydroboration of Carbonyl Compounds

Co-reporter:Che Chang Chong;Dr. Hajime Hirao;Dr. Rei Kinjo

Angewandte Chemie 2015 Volume 127( Issue 1) pp:192-196

Publication Date(Web):

DOI:10.1002/ange.201408760

Abstract

Nickel-Catalyzed Asymmetric Transfer Hydrogenation of Hydrazones and Other Ketimines

Co-reporter:Haiyan Xu;Dr. Peng Yang;Pratanphorn Chuanprasit;Dr. Hajime Hirao;Dr. Jianrong (Steve) Zhou

Angewandte Chemie International Edition 2015 Volume 54( Issue 17) pp:5112-5116

Publication Date(Web):

DOI:10.1002/anie.201501018

Abstract

Measuring the Relative Hydrogen-Bonding Strengths of Alcohols in Aprotic Organic Solvents

Co-reporter:Malcolm E. Tessensohn;Melvyn Lee; Dr. Hajime Hirao; Dr. Richard D. Webster

ChemPhysChem 2015 Volume 16( Issue 1) pp:160-168

Publication Date(Web):

DOI:10.1002/cphc.201402693

Abstract

Voltammetric experiments with 9,10-anthraquinone and 1,4-benzoquinone performed under controlled moisture conditions indicate that the hydrogen-bond strengths of alcohols in aprotic organic solvents can be differentiated by the electrochemical parameter ΔE_p^red=|E_p^red(1)−E_p^red(2)|, which is the potential separation between the two one-electron reduction processes. This electrochemical parameter is inversely related to the strength of the interactions and can be used to differentiate between primary, secondary, tertiary alcohols, and even diols, as it is sensitive to both their steric and electronic properties. The results are highly reproducible across two solvents with substantially different hydrogen-bonding properties (CH₃CN and CH₂Cl₂) and are supported by density functional theory calculations. This indicates that the numerous solvent–alcohol interactions are less significant than the quinone–alcohol hydrogen-bonding interactions. The utility of ΔE_p^red was illustrated by comparisons between 1) 3,3,3-trifluoro-n-propanol and 1,3-difluoroisopropanol and 2) ethylene glycol and 2,2,2-trifluoroethanol.

Metal-Free σ-Bond Metathesis in Ammonia Activation by a Diazadiphosphapentalene

Co-reporter:Jingjing Cui ; Yongxin Li ; Rakesh Ganguly ; Anusiya Inthirarajah ; Hajime Hirao ;Rei Kinjo

Journal of the American Chemical Society 2014 Volume 136(Issue 48) pp:16764-16767

Publication Date(Web):November 12, 2014

DOI:10.1021/ja509963m

A diazadiphosphapentalene derivative 5 featuring a bent geometry with two phosphorus atoms at the bridgehead has been synthesized. Under mild conditions, compound 5 readily activated ammonia to afford 1-aza-2,3-diphospholene derivative 6 bearing an enamine group. The reaction is therefore viewed as a formal σ-bond metathesis between an N–H bond of ammonia and an endocyclic P–N bond of 5. Details of the reaction mechanism for ammonia activation as well as subsequent isomerization were explored by density functional theory calculations.

Tandem Insertion–Cyclization Reaction of Isocyanides in the Synthesis of 1,4-Diaryl-1H-imidazoles: Presence of N-Arylformimidate Intermediate

Co-reporter:Benjamin Pooi, Jeongbin Lee, Kyujin Choi, Hajime Hirao, and Soon Hyeok Hong

The Journal of Organic Chemistry 2014 Volume 79(Issue 19) pp:9231-9245

Publication Date(Web):September 4, 2014

DOI:10.1021/jo501652w

A straightforward and high-yielding synthesis of 1,4-diaryl-1H-imidazoles is reported. 1,4-Diaryl-1H-imidazoles have been difficult to access in ambient conditions, but our method utilizes two different facets of isocyanide reactivity to achieve it. The reaction is believed to involve (1) NHC–copper-catalyzed isocyanide insertion into alcohol to form an N-arylformimidate intermediate and (2) subsequent base-promoted cycloaddition with benzyl isocyanide derivatives. There is cooperation between these two processes through the deprotonation of benzyl isocyanide by KOtBu. The deprotonation gives tert-butyl alcohol and the benzyl isocyanide anion, which are used for the first and second steps of the reaction, respectively. Various control and kinetic experiments were carried out to gain an in-depth understanding of the reaction mechanism and isocyanide reactivity. The reaction mechanism determined by density functional theory calculations was consistent with the experimental data and provided detailed explanations for the reactivity trends.

Effect of Protein Environment within Cytochrome P450cam Evaluated Using a Polarizable-Embedding QM/MM Method

Co-reporter:Nandun M. Thellamurege and Hajime Hirao

The Journal of Physical Chemistry B 2014 Volume 118(Issue 8) pp:2084-2092

Publication Date(Web):February 2, 2014

DOI:10.1021/jp412538n

Metalloenzymes accommodate cofactors and substrates in their active sites, thereby exerting powerful catalytic effects. Understanding the key elements of the mechanism via which such binding is accomplished using a number of atoms in a protein is a fundamental challenge. To address this issue computationally, here we used mechanical-embedding (ME), electronic-embedding (EE), and polarizable-embedding (PE) hybrid quantum mechanics and molecular mechanics (QM/MM) methods and performed an energy decomposition analysis (EDA) of the nonbonding protein environmental effect in the “compound I” intermediate state of cytochrome P450cam. The B3LYP and AMBER99/QP302 methods were used to deal with the QM and MM subsystems, respectively, and the nonbonding interaction energy between these subsystems was decomposed into electrostatic, van der Waals, and polarization contributions. The PE-QM/MM calculation was performed using polarizable force fields that were capable of describing induced dipoles within the MM subsystem, which arose in response to the electric field generated by QM electron density, QM nuclei, and MM point charges. The present QM/MM EDA revealed that the electrostatic term constituted the largest stabilizing interaction between the QM and MM subsystems. When proper adjustment was made for the point charges of the MM atoms located at the QM–MM boundary, EE-QM/MM and PE-QM/MM calculations yielded similar QM electron density distributions, indicating that the MM polarization effect does not have a significant influence on the extent of QM polarization in this particular enzyme system.

A Concerted Transfer Hydrogenolysis: 1,3,2-Diazaphospholene-Catalyzed Hydrogenation of NN Bond with AmmoniaBorane

Co-reporter:Che Chang Chong;Dr. Hajime Hirao;Dr. Rei Kinjo

Angewandte Chemie International Edition 2014 Volume 53( Issue 13) pp:3342-3346

Publication Date(Web):

DOI:10.1002/anie.201400099

Abstract

1,3,2-diazaphospholenes catalyze metal-free transfer hydrogenation of a NN double bond using ammonia–borane under mild reaction conditions, thus allowing access to various hydrazine derivatives. Kinetic and computational studies revealed that the rate-determining step involves simultaneous breakage of the BH and NH bonds of ammonia–borane. The reaction is therefore viewed as a concerted type of hydrogenolysis.

CH and CF Interactions Lead to Structural Changes of N-Heterocyclic Carbene Palladium Complexes

Co-reporter:Xiangya Xu;Benjamin Pooi;Dr. Hajime Hirao;Dr. Soon Hyeok Hong

Angewandte Chemie International Edition 2014 Volume 53( Issue 5) pp:1283-1287

Publication Date(Web):

DOI:10.1002/anie.201309371

Abstract

The role of CH–π and CF–π interactions in determining the structure of N-heterocyclic carbene (NHC) palladium complexes were studied using ¹H NMR spectroscopy, X-ray crystallography, and DFT calculations. The CH–π interactions led to the formation of the cis-anti isomers in 1-aryl-3-isopropylimidazol-2-ylidene-based [(NHC)₂PdX₂] complexes, while CF–π interactions led to the exclusive formation of the cis-syn isomer of diiodobis(3-isopropyl-1-pentafluorophenylimidazol-2-ylidene) palladium(II).

Nanostructures of C60—Metal—Graphene (Metal = Ti, Cr, Mn, Fe, or Ni): A Spin-Polarized Density Functional Theory Study

Co-reporter:Hung M. Le ; Hajime Hirao ; Yoshiyuki Kawazoe ;Duc Nguyen-Manh

The Journal of Physical Chemistry C 2014 Volume 118(Issue 36) pp:21057-21065

Publication Date(Web):August 18, 2014

DOI:10.1021/jp5078888

We used plane-wave density functional theory (DFT) to investigate the properties of C60—M—graphene (C60—M—G) nanostructures (M = Ti, Cr, Mn, Fe, or Ni). The calculated binding energies suggested that C60 could be mounted on a metal–graphene surface with good bonding stability. The high-spin C60—Cr—G nanostructure was found to be more stable than the previously reported low-spin configuration. Also, C60—Ti was found to stand symmetrically upright on the graphene surface, while in the remaining four cases, the orientation of C60—M in the C60—M—G nanostructures were bent, and the geometry of each structure is somewhat different, depending on the identity of the bridging metal atom. The large geometric distortion of C60—M in the tilted C60—M—G nanostructures (with Cr, Fe, Mn, and Ni) is attributed to the spin polarization in the 3d orbitals and dispersion interactions between graphene and C60. Additional DFT calculations on smaller C60—M—benzene complexes with atomic-orbital (AO) basis sets provided consistent results on structural geometry and numbers of unpaired electrons. The DFT calculations using AO basis sets suggested that the C60–M unit was flexible with respect to the bending motion. The knowledge of metal-dependent geometric differences derived in this study may be useful in designing nanostructures for spintronic and electronic applications.

CH and CF Interactions Lead to Structural Changes of N-Heterocyclic Carbene Palladium Complexes

Co-reporter:Xiangya Xu;Benjamin Pooi;Dr. Hajime Hirao;Dr. Soon Hyeok Hong

Angewandte Chemie 2014 Volume 126( Issue 5) pp:1307-1311

Publication Date(Web):

DOI:10.1002/ange.201309371

Abstract

A Concerted Transfer Hydrogenolysis: 1,3,2-Diazaphospholene-Catalyzed Hydrogenation of NN Bond with AmmoniaBorane

Co-reporter:Che Chang Chong;Dr. Hajime Hirao;Dr. Rei Kinjo

Angewandte Chemie 2014 Volume 126( Issue 13) pp:3410-3414

Publication Date(Web):

DOI:10.1002/ange.201400099

Abstract

Gold-Catalyzed Cycloisomerization of 1,6-Diyne Carbonates and Esters to 2,4a-Dihydro-1H-fluorenes

Co-reporter:Weidong Rao ; Ming Joo Koh ; Dan Li ; Hajime Hirao ;Philip Wai Hong Chan

Journal of the American Chemical Society 2013 Volume 135(Issue 21) pp:7926-7932

Publication Date(Web):April 29, 2013

DOI:10.1021/ja4032727

A synthetic method to prepare 2,4a-dihydro-1H-fluorenes efficiently from gold(I)-catalyzed 1,2-acyloxy migration/cyclopropenation/Nazarov cyclization of 1,6-diyne carbonates and esters is described. The suggested reaction pathway provides rare examples of [2,3]-sigmatropic rearrangement in this class of compounds as well as the involvement of an in situ formed cyclopropene intermediate in gold catalysis. Experimental and ONIOM(QM:QM′) [our own n-layered integrated molecular orbital and molecular mechanics(quantum mechanics:quantum mechanics′)] computational studies based on the proposed Au carbenoid species provide insight into this unique selectivity.

Guanine binding to gold nanoparticles through nonbonding interactions

Co-reporter:Xi Zhang, Chang Q. Sun and Hajime Hirao

Physical Chemistry Chemical Physics 2013 vol. 15(Issue 44) pp:19284-19292

Publication Date(Web):11 Oct 2013

DOI:10.1039/C3CP52149D

Gold nanoparticles have been widely used as nanocarriers in gene delivery. However, the binding mechanism between gold nanoparticles and DNA bases remains a puzzle. We performed density functional theory calculations with and without dispersion correction on AuN (N = 13, 55, or 147) nanoparticles in high-symmetry cuboctahedral structures to understand the mechanism of their binding with guanine at the under-coordinated sites. Our study verified that: (i) negative charges transfer from the inner area to the surface of a nanoparticle as a result of the surface quantum trapping effect; and (ii) the valence states shift up toward the Fermi level, and thereby participate more actively in the binding to guanine. These effects are more prominent in a smaller nanoparticle, which has a larger surface-to-volume ratio. Additional fragment orbital analysis revealed that: (i) electron donation from the lone-pair orbital of N to the unoccupied orbital of the Au cluster occurs in all complexes; (ii) π back-donation occurs from the polarized Au dyz orbital to the N py-π* orbital when there is no Au⋯H–N hydrogen bond, and, (iii) depending on the configuration, Au⋯H–N hydrogen bonding can also exist, to which the Au occupied orbital and the H–N unoccupied orbital contribute.

ONIOM (DFT:MM) Study of the Catalytic Mechanism of myo-Inositol Monophosphatase: Essential Role of Water in Enzyme Catalysis in the Two-Metal Mechanism

Co-reporter:Xiaoqing Wang and Hajime Hirao

The Journal of Physical Chemistry B 2013 Volume 117(Issue 3) pp:833-842

Publication Date(Web):December 26, 2012

DOI:10.1021/jp312483n

myo-Inositol monophosphatase (IMPase), a putative target of lithium therapy for bipolar disorder, is an enzyme that catalyzes the hydrolysis of myo-inositol-1-phosphate (Ins(1)P) into myo-inositol (MI) and inorganic phosphate. It is known that either two or three Mg2+ ions are used as cofactors in IMPase catalysis; however, the detailed catalytic mechanism and the specific number of Mg2+ ions required have long remained obscure. To obtain a clearer view of the IMPase reaction, we undertook extensive ONIOM hybrid quantum mechanics and molecular mechanics (QM/MM) calculations, to evaluate the reaction with either three or two Mg2+ ions. Our calculations show that the three-metal mechanism is energetically unfavorable; the initial inline attack of a hydroxide ion on the Ins(1)P substrate markedly destabilized the system without producing any stable transition state or intermediate. By contrast, for the two-metal mechanism, a favorable pathway was obtained from QM/MM calculations. In our proposed two-metal mechanism, the phosphoryl oxygen of the substrate acts as an acid–base catalyst, activating a water molecule in the first step, and the resultant hydroxide ion attacks the substrate in an inline fashion. A second water molecule, bound to a Mg2+ ion, was found to play an essential role in the final proton-transfer step that leads to the formation of an MI product; this is achieved by lowering the energy barrier by 2.5 kcal/mol compared with the barrier for the mechanism that does not use this water molecule. Our results should advance our understanding of the IMPase mechanism, and this could have profound implications for the treatment of disease in the central nervous system.

Electrochemical Properties of Phenols and Quinones in Organic Solvents are Strongly Influenced by Hydrogen-Bonding with Water

Co-reporter:Malcolm E. Tessensohn ; Hajime Hirao ;Richard D. Webster

The Journal of Physical Chemistry C 2013 Volume 117(Issue 2) pp:1081-1090

Publication Date(Web):December 20, 2012

DOI:10.1021/jp311007m

The electrochemical behavior of several phenols, quinones and hydroquinone in acetonitrile (CH3CN) with varying amounts of water were investigated to understand the effect of hydrogen-bonding on their voltammetric responses. Karl Fischer coulometric titrations were performed to obtain an accurate reading of the water concentrations. The solvent/electrolyte mixture was carefully dried using 3 Å molecular sieves to obtain an initial water content that was close to the substrate concentration (∼1 × 10–3 M), and higher water contents were then achieved via the addition from microliter syringes. It was found that small changes in what is often considered “trace” amounts of water were sufficient to substantially change the potential and in some cases the appearance of the voltammetric waves observed during the oxidation of the phenols/hydroquinones and reduction of the quinones. Density functional theory calculations were performed on the reduced/oxidized species in the presence of varying numbers of water molecules to better understand the hydrogen-bonding interactions at the molecular level. The results highlight the importance of accurately knowing the trace water content of organic solvents when used for voltammetric experiments.

Abnormal N-Heterocyclic Carbene Gold(I) Complexes: Synthesis, Structure, and Catalysis in Hydration of Alkynes

Co-reporter:Xiangya Xu, Seung Hyo Kim, Xi Zhang, Atanu Kumar Das, Hajime Hirao, and Soon Hyeok Hong

Organometallics 2013 Volume 32(Issue 1) pp:164-171

Publication Date(Web):December 24, 2012

DOI:10.1021/om3009603

Two abnormal N-heterocyclic carbene (aNHC) gold(I) complexes, [(aNHC)AuCl], were prepared from C2-protected imidazolium salts. The air-stable complexes chloro(1-isopropyl-3-methyl-2,4-diphenylimidazol-5-ylidene)gold(I) (5) and chloro(1,4-diisopropyl-3-methyl-2-phenylimidazol-5-ylidene)gold(I) (6) were synthesized via transmetalation using (SMe2)AuCl and the corresponding silver salt such as [(aNHC)AgI] or [(aNHC)2Ag][I] and were fully characterized by NMR and mass spectroscopy and by X-ray crystallography. To investigate the structure, bonding, and catalytic activity of the aNHC-based Au complexes in comparison with their traditional NHC analogues, the sterically similar NHC-based Au complexes chloro(1,3-diisopropylimidazol-2-ylidene)gold(I) (7) and chloro(3-isopropyl-1-phenylimidazol-2-ylidene)gold(I) (8) were prepared from 1,3-diisopropylimidazolium iodide (3) and 3-isopropyl-1-phenylimidazolium iodide (4), respectively. X-ray crystallography and density functional theory (DFT) calculations showed that the aNHC complexes have longer Au–Ccarbene bond distances than the NHC complexes. Furthermore, DFT calculations predicted that, despite their longer Au–Ccarbene distances, aNHC complexes have stronger binding energies. It is suggested on the basis of additional theoretical analyses that these counterintuitive trends can be rationalized by considering individual factors that comprise the molecular interaction. The efficient back-donation of electrons and the smaller overlap repulsion in NHC complexes render the Au–Ccarbene distance shorter, whereas the stronger Au–Ccarbene bonding in the aNHC-Au complexes is attributed to the greater electrostatic attraction and the higher electron-donating ability of the carbene lone pair orbital. Catalytic activities of the NHC-based Au complexes were also compared in the alkyne hydration. Traditional NHC-based Au complexes exhibited higher efficiency in the reaction.

Comparative computational analysis of binding energies between several divalent first-row transition metals (Cr2+, Mn2+, Fe2+, Co2+, Ni2+, and Cu2+) and ligands (porphine, corrin, and TMC)

Co-reporter:Serdaraly Myradalyyev, Taweetham Limpanuparb, Xiaoqing Wang, Hajime Hirao

Polyhedron 2013 Volume 52() pp:96-101

Publication Date(Web):22 March 2013

DOI:10.1016/j.poly.2012.11.018

B3LYP density functional theory calculations were performed to quantify the binding affinities of six divalent first-row transition metals (Cr2+, Mn2+, Fe2+, Co2+, Ni2+, and Cu2+) for three well-known macrocyclic ligands (porphine, corrin, and 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane [TMC]). Our calculations show that, as expected from the neutral, monoanionic, and dianionic characters of the TMC, corrin, and porphine ligands, respectively, the binding energy increases in the order TMC < corrin < porphine. This is because a more anionic ligand gives rise to greater electrostatic stabilization upon interaction with the metal cations. For all ligands, the binding energy increases in the order Mn2+ < Cr2+ ∼ Fe2+ < Co2+ < Ni2+ < Cu2+. Single occupation of all five d orbitals in the high-spin Mn2+ complexes does not afford large stabilization due to either ligand-to-metal or metal-to-ligand charge transfer, thereby resulting in the minimum binding energies observed for Mn2+ among the six different metal ions considered.Graphical abstractB3LYP density functional theory calculations were performed to quantify the binding affinities of six divalent first-row transition metals (Cr2+, Mn2+, Fe2+, Co2+, Ni2+, and Cu2+) for three well-known macrocyclic ligands (porphine, corrin, and 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane [TMC]).Highlights► Metal–ligand binding energy was calculated. ► Interactions between three ligands and six divalent metal ions were investigated. ► Different binding energies and spin-state preferences were observed.

Cover Picture: How Is a Metabolic Intermediate Formed in the Mechanism-Based Inactivation of Cytochrome P450 by Using 1,1-Dimethylhydrazine: Hydrogen Abstraction or Nitrogen Oxidation? (Chem. Eur. J. 23/2013)

Co-reporter:Dr. Hajime Hirao;Pratanphorn Chuanprasit;Ying Yi Cheong ;Dr. Xiaoqing Wang

Chemistry - A European Journal 2013 Volume 19( Issue 23) pp:

Publication Date(Web):

DOI:10.1002/chem.201390081

How Is a Metabolic Intermediate Formed in the Mechanism-Based Inactivation of Cytochrome P450 by Using 1,1-Dimethylhydrazine: Hydrogen Abstraction or Nitrogen Oxidation?

Co-reporter:Dr. Hajime Hirao;Pratanphorn Chuanprasit;Ying Yi Cheong ;Dr. Xiaoqing Wang

Chemistry - A European Journal 2013 Volume 19( Issue 23) pp:7361-7369

Publication Date(Web):

DOI:10.1002/chem.201300689

Abstract

A precise understanding of the mechanism-based inactivation of cytochrome P450 enzymes (P450s) at the quantum mechanical level should allow more reliable predictions of drug–drug interactions than those currently available. Hydrazines are among the molecules that act as mechanism-based inactivators to terminate the function of P450s, which are essential heme enzymes responsible for drug metabolism in the human body. Despite its importance, the mechanism explaining how a metabolic intermediate (MI) is formed from hydrazine is not fully understood. We used density functional theory (DFT) calculations to compare four possible mechanisms underlying the reaction between 1,1-dimethylhydrazine (or unsymmetrical dimethylhydrazine, UDMH) and the reactive compound I (Cpd I) intermediate of P450. Our DFT calculations provided a clear view on how an aminonitrene-type MI is formed from UDMH. In the most favorable pathway, hydrogen is spontaneously abstracted from the N2 atom of UDMH by Cpd I, followed by a second hydrogen abstraction from the N2 atom by Cpd II. Nitrogen oxidation of nitrogen atoms and hydrogen abstraction from the CH bond of the methyl group were found to be less favorable than the hydrogen abstraction from the NH bond. We also found that the reaction of protonated UDMH with Cpd I is rather sluggish. The aminonitrene-type MI binds to the ferric heme more strongly than a water molecule. This is consistent with the notion that the catalytic cycle of P450 is impeded when such an MI is produced through the P450-catalyzed reaction.

Pivotal Role of Water in Terminating Enzymatic Function: A Density Functional Theory Study of the Mechanism-Based Inactivation of Cytochromes P450

Co-reporter:Hajime Hirao, Zhi Hao Cheong, and Xiaoqing Wang

The Journal of Physical Chemistry B 2012 Volume 116(Issue 27) pp:7787-7794

Publication Date(Web):May 23, 2012

DOI:10.1021/jp302592d

The importance of the mechanism-based inactivation (MBI) of enzymes, which has a variety of physiological effects and therapeutic implications, has been garnering appreciation. Density functional theory calculations were undertaken to gain a clear understanding of the MBI of a cytochrome P450 enzyme (CYP2B4) by tert-butylphenylacetylene (tBPA). The results of calculations suggest that, in accordance with previous proposals, the reaction proceeds via a ketene-type metabolic intermediate. Once an oxoiron(IV) porphyryn π-cation radical intermediate (compound I) of P450 is generated at the heme reaction site, ketene formation is facile, as the terminal acetylene of tBPA can form a C–O bond with the oxo unit of compound I with a relatively low reaction barrier (14.1 kcal/mol). Unexpectedly, it was found that the ketene-type intermediate was not very reactive. Its reaction with the hydroxyl group of a threonine (Thr302) to form an ester bond required a substantial barrier (38.2 kcal/mol). The high barrier disfavored the mechanism by which these species react directly. However, the introduction of a water molecule in the reaction center led to its active participation in the reaction. The water was capable of donating its proton to the tBPA molecule, while accepting the proton of threonine. This water-mediated mechanism lowered the reaction barrier for the formation of an ester bond by about 20 kcal/mol. Therefore, our study suggests that a water molecule, which can easily gain access to the threonine residue through the proton-relay channel, plays a critical role in enhancing the covalent modification of threonine by terminal acetylene compounds. Another type of MBI by acetylenes, N-alkylation of the heme prosthetic group, was less favorable than the threonine modification pathway.

ONIOM(DFT:MM) Study of 2-Hydroxyethylphosphonate Dioxygenase: What Determines the Destinies of Different Substrates?

Co-reporter:Hajime Hirao ;Keiji Morokuma

Journal of the American Chemical Society 2011 Volume 133(Issue 37) pp:14550-14553

Publication Date(Web):August 29, 2011

DOI:10.1021/ja206222f

Why can enzymes provide different products from only slightly different substrates? While the reaction of 2-hydroxyethylphosphonate (2-HEP) catalyzed by 2-hydroxyethylphosphonate dioxygenase (HEPD) yields hydroxymethylphosphonate and formic acid, the HEPD−catalyzed reaction of 1-HEP gives acetylphosphate. ONIOM(DFT:MM) was used to uncover the distinct reaction mechanisms for the different substrates. Calculations show that, in both reactions, similar radical intermediates are generated by the same process. After the formation of common radical intermediates, proton-coupled electron transfer (PCET) operates in the 1-HEP reaction, whereas in the 2-HEP reaction, it cannot occur and an alternative pathway sets in. Thus, the PCET plays a critical role in defining the fates of the substrates.

Theoretical Study of the Mechanism of Oxoiron(IV) Formation from H2O2 and a Nonheme Iron(II) Complex: O–O Cleavage Involving Proton-Coupled Electron Transfer

Co-reporter:Hajime Hirao, Feifei Li, Lawrence Que Jr., and Keiji Morokuma

Inorganic Chemistry 2011 Volume 50(Issue 14) pp:6637-6648

Publication Date(Web):June 16, 2011

DOI:10.1021/ic200522r

It has recently been shown that the nonheme oxoiron(IV) species supported by the 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane ligand (TMC) can be generated in near-quantitative yield by reacting [FeII(TMC)(OTf)2] with a stoichiometric amount of H2O2 in CH3CN in the presence of 2,6-lutidine (Li, F.; England, J.; Que, L., Jr. J. Am. Chem. Soc. 2010, 132, 2134−2135). This finding has major implications for O–O bond cleavage events in both Fenton chemistry and nonheme iron enzymes. To understand the mechanism of this process, especially the intimate details of the O–O bond cleavage step, a series of density functional theory (DFT) calculations and analyses have been carried out. Two distinct reaction paths (A and B) were identified. Path A consists of two principal steps: (1) coordination of H2O2 to Fe(II) and (2) a combination of partial homolytic O–O bond cleavage and proton-coupled electron transfer (PCET). The latter combination renders the rate-limiting O–O cleavage effectively a heterolytic process. Path B proceeds via a simultaneous homolytic O–O bond cleavage of H2O2 and Fe–O bond formation. This is followed by H abstraction from the resultant Fe(III)–OH species by an •OH radical. Calculations suggest that path B is plausible in the absence of base. However, once 2,6-lutidine is added to the reacting system, the reaction barrier is lowered and more importantly the mechanistic path switches to path A, where 2,6-lutidine plays an essential role as an acid–base catalyst in a manner similar to how the distal histidine or glutamate residue assists in compound I formation in heme peroxidases. The reaction was found to proceed predominantly on the quintet spin state surface, and a transition to the triplet state, the experimentally known ground state for the TMC-oxoiron(IV) species, occurs in the last stage of the oxoiron(IV) formation process.

Computational Studies of Bacterial Resistance to β-Lactam Antibiotics: Mechanism of Covalent Inhibition of the Penicillin-Binding Protein 2a (PBP2a)

Co-reporter:Nguyen Hoa My, Hajime Hirao, Dang Ung Van, and Keiji Morokuma

Journal of Chemical Information and Modeling 2011 Volume 51(Issue 12) pp:3226-3234

Publication Date(Web):November 30, 2011

DOI:10.1021/ci2004175

β-Lactam resistance of methicillin-resistant Staphylococcus aureus (MRSA), a pathogenic bacterium that causes staph infections, represents a serious threat to public health. This arises primarily due to the inability of β-lactam antibiotics to inhibit the transpeptidase activity of penicillin-binding protein 2a (PBP2a). Effective inhibition of PBP2a to prevent the bacterial cell wall biosynthesis is of great importance for the treatment of a variety of clinically challenging infectious diseases caused by MRSA. To gain fundamental insights into the mode of covalent inhibition of the enzyme, we have carried out computational studies of the acylation reactions between small β-lactam molecules (methicilin and nitrocefin) and PBP2a using the B3LYP/6-31G* and ONIOM(B3LYP/6-31G*:AMBER) hybrid quantum mechanical/molecular mechanical methods. Our calculations show that the acylation involves two transition states and that methicilin and nitrocefin undergo acylation in slightly different manners. The acylation of nitrocefin is more facile, which is attributed to the larger release of ring strain and the larger resonance stabilization gained upon ring opening. We suggest that, in addition to the nonbonded interactions between the ligand and the protein, these quantum chemical factors, which are associated with efficiency of the acylation step, should be taken into account and carefully controlled in designing novel β-lactam inhibitors of PBP2a.

The Effects of Protein Environment and Dispersion on the Formation of Ferric-Superoxide Species in myo-Inositol Oxygenase (MIOX): A Combined ONIOM(DFT:MM) and Energy Decomposition Analysis

Co-reporter:Hajime Hirao

The Journal of Physical Chemistry B 2011 Volume 115(Issue 38) pp:11278-11285

Publication Date(Web):September 7, 2011

DOI:10.1021/jp2057173

The catalytic reaction of myo-inositol oxygenase, a nonheme diiron enzyme, is initiated by the binding of an O2 molecule to the ferrous center of a mixed-valence Fe(II)Fe(III) intermediate. This generates a (superoxo)Fe(III)Fe(III) reactive species that abstracts a hydrogen atom from the myo-inositol substrate. To understand the effects of protein environment and intracluster dispersion on this O2-binding process, we undertook a combined ONIOM(B3LYP:AMBER) and energy decomposition analysis. The interaction energy between the active site and the thousands of atoms present in the protein environment was decomposed into electrostatic, van der Waals (vdW) and polarization terms. These terms were further decomposed into contributions from individual amino acid residues. The dispersion effect, which is not adequately accounted for by the B3LYP method, was estimated in an empirical manner. The results show that the electrostatic, vdW, and polarization effects slightly enhance the O2 binding process. The dispersion effect enhances O2 binding more significantly than these effects. Despite these stabilizing effects, the entropy effect disfavors O2 binding, making the process almost thermoneutral.

Which DFT Functional Performs Well in the Calculation of Methylcobalamin? Comparison of the B3LYP and BP86 Functionals and Evaluation of the Impact of Empirical Dispersion Correction

Co-reporter:Hajime Hirao

The Journal of Physical Chemistry A 2011 Volume 115(Issue 33) pp:9308-9313

Publication Date(Web):August 2, 2011

DOI:10.1021/jp2052807

Controversy remains regarding the suitable density functionals for the calculation of vitamin B12 systems that contain cobalt. To identify the optimum functionals, geometry optimization calculations were performed on a full-size model of methylcobalamin (MeCbl) using the B3LYP, B3LYP-D, BP86, and BP86-D methods in conjunction with the 6-31G* basis set. Single-point energy evaluations were also performed with the 6-311+G(2d,p) basis set. Consistent with previous studies, the BP86-optimized geometry showed fairly good agreement with the experimental geometry. Various factors that may influence the homolytic bond dissociation energy (BDE) of the Co–C bond of MeCbl were systematically evaluated with these methods. Our analysis demonstrated that dispersion was the largest correction term that influenced the magnitude of BDE. Previous studies have shown that B3LYP significantly underestimates BDE, whereas BP86 gives BDE values that are fairly close to the experimental values (36–37 kcal/mol). The same trend in the relative magnitudes of the BDEs was observed in the present calculations. However, BP86 underestimated the BDE for a full model of MeCbl. When the amount of Hartree–Fock exchange in the B3LYP functional was reduced to 15% and the dispersion correction was made (i.e., B3LYP*-D), the calculated BDE was in good accord with experimental values. B3P86-D also performed well. A detailed analysis was undertaken to determine which atoms in cobalamin have large dispersion interactions with a methyl fragment of MeCbl.

Guanine binding to gold nanoparticles through nonbonding interactions

Co-reporter:Xi Zhang, Chang Q. Sun and Hajime Hirao

Physical Chemistry Chemical Physics 2013 - vol. 15(Issue 44) pp:NaN19292-19292

Publication Date(Web):2013/10/11

DOI:10.1039/C3CP52149D

Selective photocatalytic C–C bond cleavage under ambient conditions with earth abundant vanadium complexes

Co-reporter:Sarifuddin Gazi, Wilson Kwok Hung Ng, Rakesh Ganguly, Adhitya Mangala Putra Moeljadi, Hajime Hirao and Han Sen Soo

Chemical Science (2010-Present) 2015 - vol. 6(Issue 12) pp:NaN7142-7142

Publication Date(Web):2015/09/14

DOI:10.1039/C5SC02923F

To rebound or dissociate? This is the mechanistic question in C–H hydroxylation by heme and nonheme metal–oxo complexes

Co-reporter:Kyung-Bin Cho, Hajime Hirao, Sason Shaik and Wonwoo Nam