Bridged Stilbenes: AIEgens Designed via a Simple Strategy to Control the Non-radiative Decay Pathway.

To broaden the application of aggregation-induced emission (AIE) luminogens (AIEgens), the design of novel small-molecular dyes that exhibit high fluorescence quantum yield (Φfl ) in the solid state is required. Considering that the mechanism of AIE can be rationalized based on steric avoidance of non-radiative decay pathways, a series of bridged stilbenes was designed, and their non-radiative decay pathways were investigated theoretically. Bridged stilbenes with short alkyl chains exhibited a strong fluorescence emission in solution and in the solid state, while bridged stilbenes with long alkyl chains exhibited AIE. Based on this theoretical prediction, we developed the bridged stilbenes BPST[7] and DPB[7], which demonstrate excellent AIE behavior.

Molecular design strategy of fluorogenic probes based on quantum chemical prediction of intramolecular spirocyclization.

Fluorogenic probes are essential tools for real-time visualization of dynamic intracellular processes in living cells, but so far, their design has been largely dependent on trial-and-error methods. Here we propose a quantum chemical calculation-based method for rational prediction of the fluorescence properties of hydroxymethyl rhodamine (HMR)-based fluorogenic probes. Our computational analysis of the intramolecular spirocyclization reaction, which switches the fluorescence properties of HMR derivatives, reveals that consideration of the explicit water molecules is essential for accurate estimation of the free energy difference between the open (fluorescent) and closed (non-fluorescent) forms. We show that this approach can predict the open-closed equilibrium (pKcycl values) of unknown HMR derivatives in aqueous media. We validate this pKcycl prediction methodology by designing red and yellow fluorogenic peptidase probes that are highly activated by γ-glutamyltranspeptidase, without the need for prior synthesis of multiple candidates.

Roles of Closed- and Open-Loop Conformations in Large-Scale Structural Transitions of l-Lactate Dehydrogenase.

The mechanism of l-lactate generation from pyruvate by l-lactate dehydrogenase (LDH) from the rabbit muscle was studied theoretically by the multistructural microiteration (MSM) method combined with the quantum mechanics/molecular mechanics (QM/MM)-ONIOM method, where the MSM method describes the MM environment as a weighted average of multiple different structures that are fully relaxed during geometry optimization or a reaction path calculation for the QM part. The results showed that the substrate binding and product states were stabilized only in the open-loop conformation of LDH and the reaction occurred in the closed-loop conformation. In other words, before and after the chemical reaction, a large-scale structural transition from the open-loop conformation to the closed-loop conformation and vice versa occurred. The closed-loop conformation stabilized the transition state of the reaction. In contrast, the open-loop conformation stabilized the substrate binding and final states. In other words, the closed- to open-loop transition at the substrate binding state urges capture of the substrate molecule, the subsequent open- to closed-loop transition promotes the product generation, and the final closed- to open-loop transition at the final state prevents the reverse reaction going back to the substrate binding state. It is thus suggested that the exchange of stability between the closed- and open-loop conformations at different states promotes the catalytic cycle.

An Unexpected Ireland-Claisen Rearrangement Cascade During the Synthesis of the Tricyclic Core of Curcusone C: Mechanistic Elucidation by Trial-and-Error and Automatic Artificial Force-Induced Reaction (AFIR) Computations.

In the course of a total synthesis effort directed toward the natural product curcusone C, the Stoltz group discovered an unexpected thermal rearrangement of a divinylcyclopropane to the product of a formal Cope/1,3-sigmatropic shift sequence. Since the involvement of a thermally forbidden 1,3-shift seemed unlikely, theoretical studies involving two approaches, the "trial-and-error" testing of various conceivable mechanisms (Houk group) and an "automatic" approach using the Maeda-Morokuma AFIR method (Morokuma group) were applied to explore the mechanism. Eventually, both approaches converged on a cascade mechanism shown to have some partial literature precedent: Cope rearrangement/1,5-sigmatropic silyl shift/Claisen rearrangement/retro-Claisen rearrangement/1,5-sigmatropic silyl shift, comprising a quintet of five sequential thermally allowed pericyclic rearrangements.

Synthesis of fluorescent polycarbonates with highly twisted N,N-bis(dialkylamino)anthracene AIE luminogens in the main chain.

A synthetic route to embed aggregation-induced-emission-(AIE)-active luminophores in polycarbonates (PCs) in various ratios is reported. The AIE-active monomer is based on the structure of 9,10-bis(piperidyl)anthracene. The obtained PCs display good film-forming properties, similar to those observed in poly(bisphenol A carbonate) (Ba-PC). The fluorescence quantum yield (Φ) of the PC with 5 mol% AIE-active monomer was 0.04 in solution and 0.53 in solid state. Moreover, this PC is also miscible with commercially available Ba-PC at any blending ratio. A combined analysis by scanning electron microscopy and differential scanning calorimetry did not indicate any clear phase separation. These results thus suggest that even engineering plastics like polycarbonates can be functionalized with AIE luminogens without adverse effects on their physical properties.

Computational study on the luminescence quantum yields of terbium complexes with 2,2'-bipyridine derivative ligands.

Terbium complexes are widely used as luminescent materials because of their bright green emission and sharp emission spectra and the independence of their emission wavelengths from the surrounding environment. The luminescence quantum yield (LQY), however, heavily depends on the surroundings, and an appropriate ligand design is indispensable. In this study, we focus on a Tb3+ complex coordinated by a 2,2'-bipyridine derivative ligand (L1), whose LQY is almost zero at room temperature [M. Hasegawa et al., New. J. Chem. 2014, 38, 1225] and compare it with a Tb3+ complex with a bipyridine ligand, which is widely used as a photo-antenna ligand. To discuss the LQYs of the complexes, we computed their energy profiles, i.e. the energetic and structural changes during the emission and quenching processes. The low LQY of the TbL1(NO3)2 complex was explained by the stability of the minimum energy crossing point between the potential energy surfaces of the ligand-centered lowest triplet state and the ground state, which was induced by the out-of-plane bending of the azomethine moiety. The most efficient way to improve the LQY by modification of the ligand is to replace the azomethine moieties by other functional groups, such as ether or reduced azomethine groups, whose minimum energy crossing points are unstable enough to reduce the rate of the quenching processes.

Exploring the full catalytic cycle of rhodium(i)-BINAP-catalysed isomerisation of allylic amines: a graph theory approach for path optimisation.

We explored the reaction mechanism of the cationic rhodium(i)-BINAP complex catalysed isomerisation of allylic amines using the artificial force induced reaction method with the global reaction route mapping strategy, which enabled us to search for various reaction paths without assumption of transition states. The entire reaction network was reproduced in the form of a graph, and reasonable paths were selected from the complicated network using Prim's algorithm. As a result, a new dissociative reaction mechanism was proposed. Our comprehensive reaction path search provided rationales for the E/Z and S/R selectivities of the stereoselective reaction.

DFT and AFIR Study on the Mechanism and the Origin of Enantioselectivity in Iron-Catalyzed Cross-Coupling Reactions.

The mechanism of the full catalytic cycle for Fe-chiral-bisphosphine-catalyzed cross-coupling reaction between alkyl halides and Grignard reagents (Nakamura and co-workers, J. Am. Chem. Soc. 2015, 137, 7128) was rationalized by using density functional theory (DFT) and multicomponent artificial force-induced reaction (MC-AFIR) methods. The computed mechanism consists of (a) C-Cl activation, (b) transmetalation, (c) C-Fe bond formation, and (d) C-C bond formation through reductive elimination. Our survey on the prereactant complexes suggested that formation of FeII(BenzP*)Ph2 and FeI(BenzP*)Ph complexes are thermodynamically feasible. FeI(BenzP*)Cl complex is the active intermediate for C-Cl activation. FeII(BenzP*)Ph2 complex can be formed if the concentration of Grignard reagent is high. However, it leads to biphenyl (byproduct) instead of the cross-coupling product. This explains why slow addition of Grignard reagent is critical for the cross-coupling reaction. The MC-AFIR method was used for systematic determination of transition states for C-Fe bond formation and C-C bond formation starting from the key intermediate FeII(BenzP*)PhCl. According to our detailed analysis, C-C bond formation is the selectivity-determining step. The computed enantiomeric ratio of 95:5 is in good agreement with the experimental ratio (90:10). Energy decomposition analysis suggested that the origin of the enantioselectivity is the deformation of Ph-ligand in Fe-complex, which is induced by the bulky tert-butyl group of BenzP* ligand. Our study provides important mechanistic insights for the cross-coupling reaction between alkyl halides and Grignard reagents and guides the design of efficient Fe-based catalysts for cross-coupling reactions.

Multistructural microiteration technique for geometry optimization and reaction path calculation in large systems.

We propose a multistructural microiteration (MSM) method for geometry optimization and reaction path calculation in large systems. MSM is a simple extension of the geometrical microiteration technique. In conventional microiteration, the structure of the non-reaction-center (surrounding) part is optimized by fixing atoms in the reaction-center part before displacements of the reaction-center atoms. In this method, the surrounding part is described as the weighted sum of multiple surrounding structures that are independently optimized. Then, geometric displacements of the reaction-center atoms are performed in the mean field generated by the weighted sum of the surrounding parts. MSM was combined with the QM/MM-ONIOM method and applied to chemical reactions in aqueous solution or enzyme. In all three cases, MSM gave lower reaction energy profiles than the QM/MM-ONIOM-microiteration method over the entire reaction paths with comparable computational costs. © 2017 Wiley Periodicals, Inc.

The K-Region in Pyrenes as a Key Position to Activate Aggregation-Induced Emission: Effects of Introducing Highly Twisted N,N-Dimethylamines.

A new design strategy to activate aggregation-induced emission (AIE) in pyrene chromophores is reported. In a previous report, we demonstrated that highly twisted N,N-dialkylamines of anthracene and naphthalene induce drastic AIE when these donors are introduced at appropriate positions to stabilize the S1/S0 minimum energy conical intersection (MECI). In the present study, this design strategy was applied to pyrene: the introduction of N,N-dimethylamine substituents at the 4,5-positions of pyrene, the so-called K-region, are likely to stabilize MECIs. To examine this hypothesis, four novel pyrene derivatives, which contain highly twisted N,N-dimethylamino groups at the 4- (4-Py), 4,5- (4,5-Py), 1- (1-Py), or 1,6-positions (1,6-Py) were tested. The nonradiative transitions of 4,5-Py are highly efficient (knr = 57.1 × 107 s-1), so that its fluorescence quantum yield in acetonitrile decreases to Φfl = 0.04. The solid-state fluorescence of 4,5-Py is efficient (Φfl = 0.49). In contrast, 1,6-Py features strong fluorescence (Φfl = 0.48) with a slow nonradiative transition (knr = 11.0 × 107 s-1) that is subject to severe quenching (Φfl = 0.03) in the solid state. These results underline that the chemistry of the pyrene K-region is intriguing, both from a photophysical perspective and with respect to materials science.

Organic linkers control the thermosensitivity of the emission intensities from Tb(iii) and Eu(iii) in a chameleon polymer.

Thermometers whose emission color gradually changes with temperature are called chameleon emitters. In this study, we discuss the mechanism of the thermosensitivity of the emission color of polymers that contain two lanthanides (Ln3+), e.g., [Tb0.99Eu0.01(hfa)3(linker)] n , where the Ln3+(hfa)3 complexes (hfa: hexafluoro acetylacetonato) are connected by a phosphine oxide "linker" molecule. First, the difference in the thermosensitivities of the emissions from Tb3+ and Eu3+ are discussed. With increasing temperature, the green-emission intensity from Tb3+ decreases whereas the red-emission intensity from Eu3+ does not change. This was found to originate from the different reaction barriers for the quenching of the Ln3+ excited state via the intersystem crossing (ISC) between the hfa-centered triplet state and the ground state. Next, the excitation energy transfer (EET) from Tb3+ to Eu3+ is discussed. Although the direct EET between Ln3+ atoms is negligible because of the long distance between them, stepwise EET is found to occur via the linker-centered triplet state with a reasonable barrier. Thus, we propose a new idea-thermosensitivity can be controlled by the linker as well as by the ligand (hfa). To confirm the role of the linker, four phosphine oxides were examined. The thermosensitivity dependence on the linker is validated via experimental measurements.

Trihydroborates and Dihydroboranes Bearing a Pentacoordinated Phosphorus Atom: Double Ring Expansion To Balance the Coordination States.

The first trihydroborate bearing a pentacoordinated phosphorus atom was synthesized as a new P-B bonded compound. Hydride abstraction of the trihydroborate gave an intermediary dihydroborane, which showed hydroboration reactivity and was trapped with pyridine whilst maintaining the P-B bond. The dihydroborane underwent a rearrangement, which involved a double ring expansion to compensate for the unbalanced coordination states of the phosphorus and boron atoms, to give a new fused bicyclic phosphine-boronate.

Theoretical Study of Addition Reactions of L4M(M = Rh, Ir) and L2M(M = Pd, Pt) to Li+@C60.

The addition reaction of M(Cl)(CO)(PPh3)2 (M = Rh, Ir) and M(PPh3)2 (M = Pd, Pt) fragments with X@C60 (X = 0, Li+) were characterized by density functional theory (DFT) and the artificial force-induced reaction (AFIR) method. The calculated free energy profiles suggested that the η2[6:6]-addition is the most favorable reaction, which is consistent with the experimental observations. In the presence of Li+ ion, the reaction is highly exothermic, leading to η2[6:6] product of L4IrLi+@C60. In contrast, an endothermic reaction was observed in the absence of a Li+ ion. The encapsulated Li+ ion can enhance the thermodynamic stability of the η2[6:6] product. The energy decomposition analysis showed that the interaction between metal fragment and X@C60 fragment is the key for the thermodynamic stability. Among the group IA and IIA metal cations, Be2+ encapsulation is the best candidate for the development of new fullerene-transition metal complexes, which will be useful for future potential applications such as solar cells, catalysts, and electronic devices.

Artificial Force Induced Reaction Method for Systematic Determination of Complex Reaction Mechanisms.

Nowadays, computational studies are very important for the elucidation of reaction mechanisms and selectivity of complex reactions. However, traditional computational methods usually require an estimated reaction path, mainly driven by limited experimental implications, intuition, and assumptions of stationary points. However, the artificial force induced reaction (AFIR) method in the global reaction route mapping (GRRM) strategy can be used for unbiased and automatic reaction path searches for complex reactions. In this account, we highlight applications of the AFIR method to a variety of reactions (organic, organometallic, enzymatic, and photochemical) of complex molecular systems. In addition, the AFIR method has been successfully used to rationalise the origin of stereo- and regioselectivity. The AFIR method can be applied from small to large molecular systems, and will be a very useful tool for the study of complex molecular problems in many areas of chemistry, biology, and material sciences.

Theoretical insight into the wavelength-dependent photodissociation mechanism of nitric acid.

Photodissociation pathways of HNO3 involving the four lowest electronic singlet states (S0, S1, S2 and S3) were studied by the MS-CAS(12e,8o)PT2/6-31+G* method. All critical points, i.e. minima, transition states and minimum energy conical intersections, were explored systematically by the global reaction route mapping (GRRM) strategy utilizing the anharmonic downward distortion following (ADDF) method. Some key structures were also optimized at the MS-CAS(16e,12o)PT2/aug-cc-pVDZ level. Based on structures and relative energies of these critical points, we discussed the wavelength-dependent photodissociation mechanism of HNO3 in detail. The OH(X(2)Π) dissociation was found to occur through four pathways on the S1, S2, and S3 surfaces depending on the excitation energy, and one of the four pathways was shown to undergo the excited state roaming mechanism. The experimental appearance energy of the O((1)D) dissociation channel at 538.8 kJ mol(-1) was attributed to a conical intersection between the S2 and S3 surfaces. It has been shown experimentally that the O((1)D) channel was dominant at the higher excitation energy. In this study, its mechanistic reason was explained by the shape of the S3 surface and locations of important critical points.

Highly Twisted N,N-Dialkylamines as a Design Strategy to Tune Simple Aromatic Hydrocarbons as Steric Environment-Sensitive Fluorophores.

The steric-environment sensitivity of fluorescence of 9,10-bis(N,N-dialkylamino)anthracenes (BDAAs) was studied experimentally and theoretically. A new design strategy to tune simple aromatic hydrocarbons as efficient aggregation-induced emission (AIE) luminogens and molecular rotors is proposed. For a variety of BDAAs, prominent Stokes shifts and efficient solid-state fluorescence were observed. Calculations on BDAA-methyl suggested that in the ground state (S0) conformations, the pyramidal amine groups are highly twisted, so that their lone-pair orbitals cannot conjugate with the anthracene π orbitals. Fluorescence takes place from the S1 minima, in which one or both amine groups are planarized. The stability of the S1 excited state minima as well as destabilization of the S0 state is the origin of large Stokes shift. Experimental measurement of the nonadiabatic transition rate suggests that para disubstitution by dialkylamino (or strongly electron-donating) groups is a key for fast internal conversion. Minimum energy conical intersection (MECI) between S1 and S0 states was found to have a Dewar-benzene like structure. Although this can be reached efficiently in liquid phase for fast internal conversion, a large amplitude motion is required to reach this MECI, which is prohibited in the solid state and caused efficient AIE. This strategy is used to find experimentally that naphthalene analogues are also efficient AIE luminogens. The flexibility of alkyl chains on amino groups is also found to be important for allowed charge-transfer transition. Thus, three points [(1) highly twisted N,N-dialkylamines, (2) substitution at the para positions, (3) with flexible alkyl groups] were proposed for activation of small aromatic hydrocarbons.

Artificial Force Induced Reaction (AFIR) Method for Exploring Quantum Chemical Potential Energy Surfaces.

In this account, a technical overview of the artificial force induced reaction (AFIR) method is presented. The AFIR method is one of the automated reaction-path search methods developed by the authors, and has been applied extensively to a variety of chemical reactions, such as organocatalysis, organometallic catalysis, and photoreactions. There are two modes in the AFIR method, i.e., a multicomponent mode and a single-component mode. The former has been applied to bimolecular and multicomponent reactions and the latter to unimolecular isomerization and dissociation reactions. Five numerical examples are presented for an Aldol reaction, a Claisen rearrangement, a Co-catalyzed hydroformylation, a fullerene structure search, and a nonradiative decay path search in an electronically excited naphthalene molecule. Finally, possible applications of the AFIR method are discussed.

Computational SN 2-Type Mechanism for the Difluoromethylation of Lithium Enolate with Fluoroform through Bimetallic C-F Bond Dual Activation.

The reaction mechanism for difluoromethylation of lithium enolates with fluoroform was analyzed computationally (DFT calculations with the artificial force induced reaction (AFIR) method and solvation model based on density (SMD) solvation model (THF)), showing an SN 2-type carbon-carbon bond formation; the "bimetallic" lithium enolate and lithium trifluoromethyl carbenoid exert the C-F bond "dual" activation, in contrast to the monometallic butterfly-shaped carbenoid in the Simmons-Smith reaction. Lithium enolates, generated by the reaction of 2 equiv. of lithium hexamethyldisilazide (rather than 1 or 3 equiv.) with the cheap difluoromethylating species fluoroform, are the most useful alkali metal intermediates for the synthesis of pharmaceutically important α-difluoromethylated carbonyl products.

Computational Catalysis Using the Artificial Force Induced Reaction Method.

The artificial force induced reaction (AFIR) method in the global reaction route mapping (GRRM) strategy is an automatic approach to explore all important reaction paths of complex reactions. Most traditional methods in computational catalysis require guess reaction paths. On the other hand, the AFIR approach locates local minima (LMs) and transition states (TSs) of reaction paths without a guess, and therefore finds unanticipated as well as anticipated reaction paths. The AFIR method has been applied for multicomponent organic reactions, such as the aldol reaction, Passerini reaction, Biginelli reaction, and phase-transfer catalysis. In the presence of several reactants, many equilibrium structures are possible, leading to a number of reaction pathways. The AFIR method in the GRRM strategy determines all of the important equilibrium structures and subsequent reaction paths systematically. As the AFIR search is fully automatic, exhaustive trial-and-error and guess-and-check processes by the user can be eliminated. At the same time, the AFIR search is systematic, and therefore a more accurate and comprehensive description of the reaction mechanism can be determined. The AFIR method has been used for the study of full catalytic cycles and reaction steps in transition metal catalysis, such as cobalt-catalyzed hydroformylation and iron-catalyzed carbon-carbon bond formation reactions in aqueous media. Some AFIR applications have targeted the selectivity-determining step of transition-metal-catalyzed asymmetric reactions, including stereoselective water-tolerant lanthanide Lewis acid-catalyzed Mukaiyama aldol reactions. In terms of establishing the selectivity of a reaction, systematic sampling of the transition states is critical. In this direction, AFIR is very useful for performing a systematic and automatic determination of TSs. In the presence of a comprehensive description of the transition states, the selectivity of the reaction can be calculated more accurately. For relatively large molecular systems, the computational cost of AFIR searches can be reduced by using the ONIOM(QM:QM) or ONIOM(QM:MM) methods. In common practice, density functional theory (DFT) with a relatively small basis set is used for the high-level calculation, while a semiempirical approach or a force field description is used for the low-level calculation. After approximate LMs and TSs are determined, standard computational methods (e.g., DFT with a large basis set) are used for the full molecular system to determine the true LMs and TSs and to rationalize the reaction mechanism and selectivity of the catalytic reaction. The examples in this Account evidence that the AFIR method is a powerful approach for accurate prediction of the reaction mechanisms and selectivities of complex catalytic reactions. Therefore, the AFIR approach in the GRRM strategy is very useful for computational catalysis.

Trimeric cluster of lithium amidoborane-the smallest unit for the modeling of hydrogen release mechanism.

A detailed first-principle DFT M06/6-311++G(d.p) study of dehydrogenation mechanism of trimeric cluster of lithium amidoborane is presented. The first step of the reaction is association of two LiNH2 BH3 molecules in the cluster. The dominant feature of the subsequent reaction pathway is activation of H atom of BH3 group by three Li atoms with formation of unique Li3 H moiety. This Li3 H moiety is destroyed prior to dehydrogenation in favor of formation of a triangular Li2 H moiety, which interacts with protic H atom of NH2 group. As a result of this interaction, Li2 H2 moiety is produced. It features N(-) H(+) H(-) group suited near the middle plane between two Li(+) in the transition state that leads to H2 release. The transition states of association and hydrogen release steps are similar in energy. It is concluded that the trimer, (LiNH2 BH3 )3 , is the smallest cluster that captures the essence of the hydrogen release reaction.