Lung Wa Chung

The ONIOM Method and Its Applications

Lung Wa Chung,† W. M. C. Sameera,‡ Romain Ramozzi,‡ Alister J. Page, Miho Hatanaka,‡ Galina P. Petrova, Travis V. Harris,‡,⊥ Xin Li, Zhuofeng Ke, Fengyi Liu, Hai-Bei Li, Lina Ding, and Keiji Morokuma*,‡ †Department of Chemistry, South University of Science and Technology of China, Shenzhen 518055, China ‡Fukui Institute for Fundamental Chemistry, Kyoto University, 34-4 Takano Nishihiraki-cho, Sakyo, Kyoto 606-8103, Japan Newcastle Institute for Energy and Resources, The University of Newcastle, Callaghan 2308, Australia Faculty of Chemistry and Pharmacy, University of Sofia, Bulgaria Boulevard James Bourchier 1, 1164 Sofia, Bulgaria Department of Chemistry, State University of New York at Oswego, Oswego, New York 13126, United States State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, China Key Laboratory of Macromolecular Science of Shaanxi Province, School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi’an, Shaanxi 710119, China School of Ocean, Shandong University, Weihai 264209, China School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China

The ONIOM method: its foundation and applications to metalloenzymes and photobiology

The ONIOM (our Own N‐layer Integrated molecular Orbital molecular Mechanics) method is one of the most popular, successful, and easily‐to‐implement hybrid quantum mechanics/molecular mechanics (QM/MM) methods to treat complex molecular systems. Hybrid QM/MM methods take advantage of the high accuracy of QM methods and the low computational cost of MM methods. One key feature of the ONIOM method is a simple linear extrapolation procedure, which allows the ONIOM method to be further extended to two‐layer ONIOM(QM1:QM2), three‐layer ONIOM(QM1:QM2:MM), and, in principle, any n‐layer n‐level‐of‐theory methods. Such hierarchical features of the ONIOM method are unique among the hybrid QM/MM methods. This review article provides an overview of the theoretical foundation and recent development of the ONIOM method. Some of its recent applications to metalloenzymes and photobiology will also be highlighted. Prospective ONIOM development for more realistic simulations on the complex systems will be discussed finally.

Computational Organic Chemistry: Bridging Theory and Experiment in Establishing the Mechanisms of Chemical Reactions

Understanding the mechanisms of chemical reactions, especially catalysis, has been an important and active area of computational organic chemistry, and close collaborations between experimentalists and theorists represent a growing trend. This Perspective provides examples of such productive collaborations. The understanding of various reaction mechanisms and the insight gained from these studies are emphasized. The applications of various experimental techniques in elucidation of reaction details as well as the development of various computational techniques to meet the demand of emerging synthetic methods, e.g., C-H activation, organocatalysis, and single electron transfer, are presented along with some conventional developments of mechanistic aspects. Examples of applications are selected to demonstrate the advantages and limitations of these techniques. Some challenges in the mechanistic studies and predictions of reactions are also analyzed.

Ligand-Controlled Remarkable Regio- and Stereodivergence in Intermolecular Hydrosilylation of Internal Alkynes: Experimental and Theoretical Studies

The first highly efficient ligand-controlled regio- and stereodivergent intermolecular hydrosilylations of internal alkynes have been disclosed. Cationic ruthenium complexes [Cp*Ru(MeCN)3](+) and [CpRu(MeCN)3](+) have been demonstrated to catalyze intermolecular hydrosilylations of silyl alkynes to form a range of vinyldisilanes with excellent but opposite regio- and stereoselectivity, with the former being α anti addition and the latter β syn addition. The use of a silyl masking group not only provides sufficient steric bulk for high selectivity but also leads to versatile product derivatizations toward a variety of useful building blocks. DFT calculations suggest that the reactions proceed by a mechanism that involves oxidative hydrometalation, isomerization, and reductive silyl migration. The energetics of the transition states and intermediates varies dramatically with the catalyst ligand (Cp* and Cp). Theoretical studies combined with experimental evidence confirm that steric effect plays a critical role in governing the regio- and stereoselectivity, and the interplay between the substituent in the alkyne (e.g., silyl group) and the ligand ultimately determines the observed remarkable regio- and stereodivergence.

Density Functional Theory Study on a Missing Piece in Understanding of Heme Chemistry : The Reaction Mechanism for Indoleamine 2,3-Dioxygenase and Tryptophan 2,3-Dioxygenase

Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) are heme-containing dioxygenases and catalyze oxidative cleavage of the pyrrole ring of L-tryptophan. On the basis of three recent crystal structures of these heme-containing dioxygenases, two new mechanistic pathways were proposed by several groups. Both pathways start with electrophilic addition of the Fe(II)-bound dioxygen concerted with proton transfer (oxygen ene-type reaction), followed by either formation of a dioxetane intermediate or Criegee-type rearrangement. However, density functional theory (DFT) calculations do not support the proposed concerted oxygen ene-type and Criegee-type rearrangement pathways. On the basis of DFT calculations, we propose a new mechanism for dioxygen activation in these heme systems. The mechanism involves (a) direct electrophilic addition of the Fe(II)-bound oxygen to the C2 or C3 position of the indole in a closed-shell singlet state or (b) direct radical addition of the Fe(III)-superoxide to the C2 position of the indole in a triplet (or open-shell singlet) state. Then, a radical-recombination or nearly barrierless charge-recombination step from the resultant diradical or zwitterionic intermediates, respectively, proceeds to afford metastable dioxetane intermediates, followed by ring-opening of the dioxetanes. Alternatively, homolytic O-O bond cleavage from the diradical intermediate followed by oxo attack and facile C2-C3 bond cleavage could compete with the dioxetane formation pathway. Effects of ionization of the imidazole and negatively charged oxyporphyrin complex on the key dioxygen activation process are also studied.

Mechanism of efficient firefly bioluminescence via adiabatic transition state and seam of sloped conical intersection.

Firefly emission is a well-known efficient bioluminescence. However, the mystery of the efficient thermal generation of electronic excited states in firefly still remains unsolved, particularly at the atomic and molecular levels. We performed SA-CASSCF(12,12)/6-31G* and CASPT2(12,12)/6-31G*//SA-CASSCF(12,12)/6-31G* calculations to elucidate the reaction mechanism of bioluminescence from the firefly dioxetanone in the gas phase. Adiabatic transition state (TS) for the O-O bond cleavage and the minimum energy conical intersection (MECI) were located and characterized. The unique topology of MECI featuring a seam of a sloped conical intersection for the firefly dioxetanone, which was uncovered for the first time, emerges along the reaction pathway to provide a widely extended channel to diabatically access the excited-state from the ground state.

ONIOM Study on a Missing Piece in Our Understanding of Heme Chemistry: Bacterial Tryptophan 2,3-Dioxygenase with Dual Oxidants

Unique heme-containing tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) catalyze oxidative cleavage of the pyrrole ring of L-tryptophan (Trp). Although these two heme dioxygenases were discovered more than 40 years ago, their reaction mechanisms were still poorly understood. Encouraged by recent X-ray crystal structures, new mechanistic pathways were proposed. We performed ONIOM(B3LYP:Amber) calculations with explicit consideration of the protein environment to study various possible reaction mechanisms for bacterial TDO. The ONIOM calculations do not support the proposed mechanisms (via either formation of the dioxetane intermediate or Criegee-type rearrangement); a mechanism that is exceptional in the hemes emerges. It starts with (1) direct radical addition of a ferric-superoxide intermediate with C2 of the indole of Trp, followed by (2) ring-closure via homolytic O-O cleavage to give epoxide and ferryl-oxo (Cpd II) intermediates, (3) acid-catalyzed regiospecific ring-opening of the epoxide, (4) oxo-attack, and (5) finally C-C bond cleavage concerted with back proton transfer. The involvement of dual oxidants, ferric-superoxide and ferryl-oxo (Cpd II) intermediates, is proposed to be responsible for the dioxygenase reactivity in bacterial TDO. In particular, the not-well-recognized ferric-superoxide porphyrin intermediate is found to be capable of reacting with pi-systems via direct radical addition, an uncommon dioxygen activation in the hemes. The comparison between Xanthomonas campestris TDO and some heme as well non-heme oxygenases is also discussed.

Pd-Catalyzed Copolymerization of Methyl Acrylate with Carbon Monoxide: Structures, Properties and Mechanistic Aspects toward Ligand Design

Full details are provided for the alternating copolymerization of acrylic esters with carbon monoxide (CO) catalyzed by palladium species bearing a phosphine-sulfonate bidentate ligand. The copolymer of methyl acrylate (MA) and CO had complete regioregularity with stereocenters that slowly epimerize in the presence of methanol. In the presence of ethylene, terpolymers of MA/ethylene/CO were also prepared. The glass transition temperatures of the co- and terpolymers were higher than that of the ethylene/CO copolymer. Both experimental and theoretical investigations were performed to clarify the superior nature of the palladium phosphine-sulfonate system compared to an unsuccessful conventional palladium diphosphine system: (i) The reversible insertion of CO was directly observed with the isolated alkylpalladium complexes, [{o-((o-MeOC(6)H(4))(2)P)C(6)H(4)SO(3)}PdCH(CO(2)Me)CH(2)COMe], whereas it was not observed with the corresponding complex bearing 1,2-bis(diphenylphosphino)ethane (DPPE). (ii) The transition state of the subsequent MA insertion, the rate-determining step of the catalytic cycle, was lower in energy in the phosphine-sulfonate system than in the DPPE system. This stabilization could be attributed to the less hindered sulfonate moiety as well as the stronger back-donation from palladium to the electron-deficient olefin, which is located trans to the sulfonate.

Highly efficient and practical resolution of 1,1'-spirobiindane-7,7'-diol by inclusion crystallization with N-benzylcinchonidinium chloride

Abstract The chiral spirobiindane ligand, 1,1′-spirobiindane-7,7′-diol has been resolved efficiently by inclusion complexation with commercially available N-benzylcinchonidinium chloride. The resolved complex was studied by X-ray crystallography in order to characterize the intermolecular interactions and recognition nature.

New Mechanistic Insights on the Selectivity of Transition-Metal-Catalyzed Organic Reactions: The Role of Computational Chemistry

With new advances in theoretical methods and increased computational power, applications of computational chemistry are becoming practical and routine in many fields of chemistry. In organic chemistry, computational chemistry plays an indispensable role in elucidating reaction mechanisms and the origins of various selectivities, such as chemo-, regio-, and stereoselectivities. Consequently, mechanistic understanding improves synthesis and assists in the rational design of new catalysts. In this Account, we present some of our recent works to illustrate how computational chemistry provides new mechanistic insights for improvement of the selectivities of several organic reactions. These examples include not only explanations for the existing experimental observations, but also predictions which were subsequently verified experimentally. This Account consists of three sections discuss three different kinds of selectivities. The first section discusses the regio- and stereoselectivities of hydrosilylations of alkynes, mainly catalyzed by [Cp*Ru(MeCN)3](+) or [CpRu(MeCN)3](+). Calculations suggest a new mechanism that involves a key ruthenacyclopropene intermediate. This mechanism not only explains the unusual Markovnikov regio-selectivity and anti-addition stereoselectivity observed by Trost and co-workers, but also motivated further experimental investigations. New intriguing experimental observations and further theoretical studies led to an extension of the reaction mechanism. The second section includes three cases of meta-selective C-H activation of aryl compounds. In the case of Cu-catalyzed selective meta-C-H activation of aniline, a new mechanism that involves a Cu(III)-Ar-mediated Heck-like transition state, in which the Ar group acts as an electrophile, was proposed. This mechanism predicted a higher reactivity for more electron-deficient Ar groups, which was supported by experiments. For two template-mediated, meta-selective C-H bond activations catalyzed by Pd(II), different mechanisms were derived for the two templates. One involves a dimeric Pd-Pd or Pd-Ag active catalyst, and the other involves a monomeric Pd catalyst, in which a monoprotected amino acid coordinates in a bidentate fashion and serves as an internal base for C-H activation. The third section discusses a desymmetry strategy in asymmetric synthesis. The construction of rigid skeletons is critical for these catalysts to distinguish two prochiral groups. Overall, fruitful collaborations between computational and experimental chemists have provided new and comprehensive mechanistic understanding and insights into these useful reactions.