Showing papers on "Transition state published in 2018"

Solvent-enabled control of reactivity for liquid-phase reactions of biomass-derived compounds

Abstract: The use of organic solvents in biomass conversion reactions can lead to high rates and improved selectivities. Here, we elucidate the effects of organic solvent mixtures with water on the kinetics of acid-catalysed dehydration reactions of relevance to biomass conversion. Based on results from reaction kinetics studies, combined with classical and ab initio molecular dynamics simulations, we show that the rates of acid-catalysed reactions in the liquid phase can be enhanced by altering the extents of solvation of the initial and transition states of these catalytic processes. The extent of these effects increases as the number of vicinal hydroxyl or oxygen-containing groups in the reactant increases, moving from an alcohol (butanol), to a diol (1,2-propanediol), to a carbohydrate (fructose). We demonstrate that the understanding of these solvation effects can be employed to optimize the rate and selectivity for production of the biomass platform molecule hydroxymethylfurfural from fructose.

Asymmetric phosphoric acid–catalyzed four-component Ugi reaction

Abstract: INTRODUCTION The four-component Ugi reaction (Ugi-4CR) assembles peptide-like α-acylaminoamides through one-pot reaction of a carbonyl compound, an amine, an acid, and an isocyanide Ugi-4CR is well suited for diversity-oriented synthesis applicable in drug discovery, as it facilitates rapid access to diverse libraries of biologically important molecules The high step economy and atom efficiency of the reaction, as well as its convergent nature, foster its wide use in the synthesis of heterocyclic scaffolds, natural products, macrocycles, polymers, and other target molecules Despite these practical advantages, the long-standing stereochemical challenges of the Ugi reaction have yet to be fully addressed Consequently, access to chiral Ugi products for drug candidate exploration is hindered RATIONALE The chiral phosphoric acid (CPA) framework was targeted as a catalyst for asymmetric Ugi-4CR The heightened acidity of CPAs over carboxylic acids is perceived to accelerate the kinetics of the enantioselective Ugi reaction so as to outcompete the background reaction Also, self-assembled heterodimerization between the CPA and carboxylic acid brings about a dual effect: enhanced acidity of the catalyst and nucleophilicity of the carboxylic acid Both of these favor the catalytic enantioselective Ugi-4CR A myriad of well-established or custom CPAs with well-defined chiral pockets could be readily applied, potentially leading to complete stereocontrol A CPA that could suppress the Passerini and other side reactions would enable rapid imine formation and its preferential activation over the carbonyl group RESULTS A catalytic asymmetric Ugi-4CR was accomplished with 1,1′-spirobiindane-7,7′-diol (SPINOL)–derived CPA4 and CPA6 as organocatalysts The reaction exhibited broad substrate compatibility and good to excellent enantioselectivity [up to 99% enantiomeric excess (ee)] Activation of the imine might be accomplished by CPA–carboxylic acid heterodimer catalysis via a bifunctional activation mode, which was supported by experiments (carboxylic acids with varying pKa values and steric properties yielded products with a range of ee values) and density functional theory (DFT) calculations (lowest energy among all the considered activation modes) The calculated free energy profile for the catalytic Ugi reaction gave three CPA-combined key transition states, which highlighted the bifunctional property of the CPA In the favored enantio-determining transition states, the aryl groups fit into the pocket formed by the two substituents (cyclohexyl rings) of the catalyst, revealing the importance of noncovalent interactions in controlling the stereochemical outcome of this reaction CONCLUSION This operationally simple one-pot enantioselective Ugi-4CR harnesses inherent benefits of multicomponent reaction and organocatalysis to access up to 86 enantioenriched α-acylaminoamides, which are otherwise challenging to obtain via conventional methods, from four achiral building blocks in excellent yields and enantioselectivities DFT calculations gave a detailed catalytic mechanism, especially with respect to activation modes and enantio-determining transition states Because amide functionality constitutes the defining primary linkage in proteins, we foresee multiple uses of this asymmetric four-component Ugi protocol for the synthesis of chiral peptides and components of natural products We also anticipate that this work will initiate the further development of asymmetric multicomponent chemistry

The Emergence of Anion−π Catalysis

Abstract: The objective of this Account is to summarize the first five years of anion-π catalysis. The general idea of anion-π catalysis is to stabilize anionic transition states on aromatic surfaces. This is complementary to the stabilization of cationic transition states on aromatic surfaces, a mode of action that occurs in nature and is increasingly used in chemistry. Anion-π catalysis, however, rarely occurs in nature and has been unexplored in chemistry. Probably because the attraction of anions to π surfaces as such is counterintuitive, anion-π interactions in general are much younger than cation-π interactions and remain under-recognized until today. Anion-π catalysis has emerged from early findings that anion-π interactions can mediate the transport of anions across lipid bilayer membranes. With this evidence for stabilization in the ground state secured, there was no reason to believe that anion-π interactions could not also stabilize anionic transition states. As an attractive reaction to develop anion-π catalysis, the addition of malonic acid half thioesters to enolate acceptors was selected. This choice was also made because without enzymes decarboxylation is preferred and anion-π interactions promised to catalyze selectively the disfavored but relevant enolate addition. Concerning anion-π catalysts, we started with naphthalene diimides (NDIs) because their intrinsic quadrupole moment is highly positive. The NDI scaffold was used to address questions such as the positioning of substrates on the catalytic π surface or the dependence of activity on the π acidity of this π surface. With the basics in place, the next milestone was the creation of anion-π enzymes, that is, enzymes that operate with an interaction rarely used in biology, at least on intrinsically π-acidic or highly polarizable aromatic amino-acid side chains. Electric-field-assisted anion-π catalysis addresses topics such as heterogeneous catalysis on electrodes and remote control of activity by voltage. On π-stacked foldamers, anion-(π) n-π catalysis was discovered. Fullerenes emerged as the scaffold of choice to explore contributions from polarizability. On fullerenes, anionic transition states are stabilized by large macrodipoles that appear only in response to their presence. With this growing collection of anion-π catalysts, several reactions beyond enolate addition have been explored so far. Initial efforts focused on asymmetric anion-π catalysis. Increasing enantioselectivity with increasing π acidity of the active π surface has been exemplified for enamine and iminium chemistry and for anion-π transaminase mimics. However, the delocalized nature of anion-π interactions calls for the stabilization of charge displacements over longer distances. The first step in this direction was the formation of cyclohexane rings with five stereogenic centers from achiral acyclic substrates on π-acidic surfaces. Moreover, the intrinsically disfavored exo transition state of anionic Diels-Alder reactions is stabilized selectively on π-acidic surfaces; endo products and otherwise preferred Michael addition products are completely suppressed. Taken together, we hope that these results on catalyst design and reaction scope will establish anion-π catalysis as a general principle in catalysis in the broadest sense.

A Universal Approach To Determine the Free Energy Diagram of an Electrocatalytic Reaction

Abstract: Extended Tafel plots at various temperatures for an electrocatalyzed reaction and (possibly) its reversed reaction on single-crystalline model electrodes allow for constructing the (essential part of the) free energy surface, in particular the free energies of the transition states (TS). Free energies of the reaction intermediates (RIs) including the chemical nature of active surface sites (S) are hardly accessible to experiment and need therefore to be taken from constrained ab initio thermodynamics calculations. The compact compilation of experimental kinetic data in the form of a free energy diagram enables a critical assessment and validation of theoretical free energy landscapes based on first-principles kinetics. For three prototypical electrocatalyzed reactions, namely the chlorine evolution reaction (CER) and oxygen evolution reaction (OER) over RuO2(110) as well as hydrogen evolution reaction (HER) on Pt(111), we exemplify this universal approach and discuss potential benefits for theoretical mod...

Synthesis of reaction‐adapted zeolites as methanol-to-olefins catalysts with mimics of reaction intermediates as organic structure‐directing agents

Abstract: Catalysis with enzymes and zeolites have in common the presence of well-defined single active sites and pockets/cavities where the reaction transition states can be stabilized by longer-range interactions. We show here that for a complex reaction, such as the conversion of methanol-to-olefins (MTO), it is possible to synthesize reaction-adapted zeolites by using mimics of the key molecular species involved in the MTO mechanism. Effort has focused on the intermediates of the paring mechanism because the paring is less favoured energetically than the side-chain route. All the organic structure-directing agents based on intermediate mimics crystallize cage-based small-pore zeolitic materials, all of them capable of performing the MTO reaction. Among the zeolites obtained, RTH favours the whole reaction steps following the paring route and gives the highest propylene/ethylene ratio compared to traditional CHA-related zeolites (3.07 and 0.86, respectively).

Computational Design of Active Site Structures with Improved Transition-State Scaling for Ammonia Synthesis

Abstract: The Haber–Bosch process for the reduction of atmospheric nitrogen to ammonia is one of the most optimized heterogeneous catalytic reactions, but there are aspects of the industrial process that remain less than ideal. It has been shown that the activity of metal catalysts is limited by a Bronsted–Evans–Polanyi (BEP) scaling relationship between the reaction and transition-state energies for N2 dissociation, leading to a negligible production rate at ambient conditions and a modest rate under harsh conditions. In this study, we use density functional theory (DFT) calculations in conjunction with mean-field microkinetic modeling to study the rate of NH3 synthesis on model active sites that require the singly coordinated dissociative adsorption of N atoms onto transition metal atoms. Our results demonstrate that this ”on-top” binding of nitrogen exhibits significantly improved scaling behavior, which can be rationalized in terms of transition-state geometries and leads to considerably higher predicted activi...

A combined experimental and computational study on the reaction of fluoroarenes with Mg–Mg, Mg–Zn, Mg–Al and Al–Zn bonds

Abstract: Through a combined experimental and computational (DFT) approach, the reaction mechanism of the addition of fluoroarenes to Mg–Mg bonds has been determined as a concerted SNAr-like pathway in which one Mg centre acts as a nucleophile and the other an electrophile. The experimentally determined Gibbs activation energy for the addition of C6F6 to a Mg–Mg bond of a molecular complex, ΔG‡298 K(experiment) = 21.3 kcal mol−1 is modelled by DFT with the ωB97X functional, ΔG‡298 K(DFT) = 25.7 kcal mol−1. The transition state for C–F activation involves a polarisation of the Mg–Mg bond and significant negative charge localisation on the fluoroarene moiety. This transition state is augmented by stabilising closed-shell Mg⋯Fortho interactions that, in combination with the known trends in C–F and C–M bond strengths in fluoroarenes, provide an explanation for the experimentally determined preference for C–F bond activation to occur at sites flanked by ortho-fluorine atoms. The effect of modification of both the ligand coordination sphere and the nature and polarity of the M–M bond (M = Mg, Zn, Al) on C–F activation has been investigated. A series of highly novel β-diketiminate stabilised complexes containing Zn–Mg, Zn–Zn–Zn, Zn–Al and Mg–Al bonds has been prepared, including the first crystallographic characterisation of a Mg–Al bond. Reactions of these new M–M containing complexes with perfluoroarenes were conducted and modelled by DFT. C–F bond activation is dictated by the steric accessibility, and not the polarity, of the M–M bond. The more open coordination complexes lead to enhanced Mg⋯Fortho interactions which in turn lower the energy of the transition states for C–F bond activation.

Direct single-molecule dynamic detection of chemical reactions.

Abstract: Single-molecule detection can reveal time trajectories and reaction pathways of individual intermediates/transition states in chemical reactions and biological processes, which is of fundamental importance to elucidate their intrinsic mechanisms. We present a reliable, label-free single-molecule approach that allows us to directly explore the dynamic process of basic chemical reactions at the single-event level by using stable graphene-molecule single-molecule junctions. These junctions are constructed by covalently connecting a single molecule with a 9-fluorenone center to nanogapped graphene electrodes. For the first time, real-time single-molecule electrical measurements unambiguously show reproducible large-amplitude two-level fluctuations that are highly dependent on solvent environments in a nucleophilic addition reaction of hydroxylamine to a carbonyl group. Both theoretical simulations and ensemble experiments prove that this observation originates from the reversible transition between the reactant and a new intermediate state within a time scale of a few microseconds. These investigations open up a new route that is able to be immediately applied to probe fast single-molecule physics or biophysics with high time resolution, making an important contribution to broad fields beyond reaction chemistry.

Promoting Vibrations and the Function of Enzymes. Emerging Theoretical and Experimental Convergence

Abstract: A complete understanding of enzyme catalysis requires knowledge of both transition state features and the detailed motions of atoms that cause reactant molecules to form and traverse the transition state. The seeming intractability of the problem arises from the femtosecond lifetime of chemical transition states, preventing most experimental access. Computational chemistry is admirably suited to short time scale analysis but can be misled by inappropriate starting points or by biased assumptions. Kinetic isotope effects provide an experimental approach to transition state structure and a method for obtaining transition state analogues but, alone, do not inform how that transition state is reached. Enzyme structures with transition state analogues provide computational starting points near the transition state geometry. These well-conditioned starting points, combined with the unbiased computational method of transition path sampling, provide realistic atomistic motions involved in transition state formati...

O–O Radical Coupling: From Detailed Mechanistic Understanding to Enhanced Water Oxidation Catalysis

Abstract: A deeper mechanistic understanding of the key O–O bond formation step of water oxidation by the [Ru(bda)(L)2] (bdaH2 = 2,2′-bipyridine-6,6′-dicarboxylic acid; L is a pyridine or isoquinoline derivative) family of catalysts is reached through harmonious experimental and computational studies of two series of modified catalysts with systematic variations in the axial ligands. The introduction of halogen and electron-donating substituents in [Ru(bda)(4-X-py)2] and [Ru(bda)(6-X-isq)2] (X is H, Cl, Br, and I for the pyridine series and H, F, Cl, Br, and OMe for the isoquinoline series) enhances the noncovalent interactions between the axial ligands in the transition state for the bimolecular O–O coupling, resulting in a lower activation barrier and faster catalysis. From detailed transition state calculations in combination with experimental kinetic studies, we find that the main contributor to the free energy of activation is entropy due to the highly organized transition states, which is contrary to other re...

Enzymatic Transition States and Drug Design

Abstract: Transition state theory teaches that chemically stable mimics of enzymatic transition states will bind tightly to their cognate enzymes. Kinetic isotope effects combined with computational quantum chemistry provides enzymatic transition state information with sufficient fidelity to design transition state analogues. Examples are selected from various stages of drug development to demonstrate the application of transition state theory, inhibitor design, physicochemical characterization of transition state analogues, and their progress in drug development.

Meisenheimer Complexes in SNAr Reactions: Intermediates or Transition States?

Abstract: Meisenheimer's missing! Anionic σ-complexes, best known as Meisenheimer complexes, have long been assumed to be intermediates in SN Ar reactions. New evidence now suggests that these intermediates may only be formed in select cases and that a concerted pathway is more common. These claims are supported by 12 C/13 C kinetic isotopes effects, determined using a new method based on 19 F NMR, and DFT calculations.

Excited-State Proton Transfer Mechanism of 2,6-Diazaindoles·(H2O)n (n = 2–4) Clusters

Abstract: This paper identified a new excited-state proton transfer (ESPT) mechanism for 2,6-diazaindoles (2,6-DAI) in aqueous (H2O) solution based on time-dependent density functional theory. The calculated results show that the excited-state three proton transfer reaction cannot occur because the 2,6-DAI with two water molecules do not form hydrogen bond wires; this finding was different from those reported in previous experiments (Chung et al. J. Am. Chem. Soc. 2017, 139, 6396–6402). 2,6-DAI with three water molecules form 2,6-DAI·(H2O)3 clusters, whereas 2,6-DAI with four water molecules form 2,6-DAI·(H2O)4 cluster. These clusters participate in the ESPT reaction. To determine the ESPT mechanism of 2,6-DAI·(H2O)3 and 2,6-DAI·(H2O)4 clusters, we constructed the potential energy curves of S1 and S0 states. The results confirmed the simultaneous presence of both 2,6-DAI·(H2O)3 and 2,6-DAI·(H2O)4 clusters and only one proton transfer pathway. By calculating the transition states of 2,6-DAI·(H2O)3 and 2,6-DAI·(H2O)4...

COSMO-based computer-aided molecular/mixture design: A focus on reaction solvents

Abstract: In this article, we investigate reaction solvent design using COSMO-RS thermodynamics in conjunction with computer-aided molecular design (CAMD) techniques. CAMD using COSMO-RS has the distinct advantage of being a method based in quantum chemistry, which allows for the incorporation of quantum-level information about transition states, reactive intermediates, and other important species directly into CAMD problems. This work encompasses three main additions to our previous framework for solvent design (Austin et al., Chem Eng Sci. 2017;159:93–105): (1) altering the group contribution method to estimate hydrogen-bonding and non-hydrogen-bonding σ-profiles; (2) ab initio modeling of strong solute/solvent interactions such as H-bonding or coordinate bonding; and (3) solving mixture design problems limited to common laboratory and industrial solvents. We apply this methodology to three diverse case studies: accelerating the reaction rate of a Menschutkin reaction, controlling the chemoselectivity of a lithiation reaction, and controlling the chemoselectivity of a nucleophilic aromatic substitution reaction. We report improved solvents/mixtures in all cases. © 2017 American Institute of Chemical Engineers AIChE J, 63: 104–122, 2018

Enantioselective Synthesis of N,S-Acetals by an Oxidative Pummerer-Type Transformation using Phase-Transfer Catalysis.

Abstract: Reported is the first enantioselective oxidative Pummerer-type transformation using phase-transfer catalysis to deliver enantioenriched sulfur-bearing heterocycles. This reaction includes the direct oxidation of sulfides to a thionium intermediate, followed by an asymmetric intramolecular nucleophilic addition to form chiral cyclic N,S-acetals with moderate to high enantioselectivites. Deuterium-labelling experiments were performed to identify the stereodiscrimination step of this process. Further analysis of the reaction transition states, by means of multidimensional correlations and DFT calculations, highlight the existence of a set of weak noncovalent interactions between the catalyst and substrate that govern the enantioselectivity of the reaction.

A paramedic treatment for modeling explicitly solvated chemical reaction mechanisms.

Abstract: We report a static quantum chemistry modeling treatment to study how solvent molecules affect chemical reaction mechanisms without dynamics simulations. This modeling scheme uses a global optimization procedure to identify low energy intermediate states with different numbers of explicit solvent molecules and then the growing string method to locate sequential transition states along a reaction pathway. Testing this approach on the acid-catalyzed Morita-Baylis-Hillman (MBH) reaction in methanol, we found a reaction mechanism that is consistent with both recent experiments and computationally intensive dynamics simulations with explicit solvation. In doing so, we explain unphysical pitfalls that obfuscate computational modeling that uses microsolvated reaction intermediates. This new paramedic approach can promisingly capture essential physical chemistry of the complicated and multistep MBH reaction mechanism, and the energy profiles found with this model appear reasonably insensitive to the level of theory used for energy calculations. Thus, it should be a useful and computationally cost-effective approach for modeling solvent mediated reaction mechanisms when dynamics simulations are not possible.

Influence of Multiple Conformations and Paths on Rate Constants and Product Branching Ratios. Thermal Decomposition of 1-Propanol Radicals.

Abstract: The potential energy surface involved in the thermal decomposition of 1-propanol radicals was investigated in detail using automated codes (tsscds2018 and Q2DTor). From the predicted elementary reactions, a relevant reaction network was constructed to study the decomposition at temperatures in the range 1000-2000 K. Specifically, this relevant network comprises 18 conformational reaction channels (CRCs), which in general exhibit a large wealth of conformers of reactants and transition states. Rate constants for all the CRCs were calculated using two approaches within the formulation of variational transition-state theory (VTST), as incorporated in the TheRa program. The simplest, one-well (1W) approach considers only the most stable conformer of the reactant and that of the transition state. In the second, more accurate approach, contributions from all the reactant and transition-state conformers are taken into account using the multipath (MP) formulation of VTST. In addition, kinetic Monte Carlo (KMC) simulations were performed to compute product branching ratios. The results show significant differences between the values of the rate constants calculated with the two VTST approaches. In addition, the KMC simulations carried out with the two sets of rate constants indicate that, depending on the radical considered as reactant, the 1W and the MP approaches may display different qualitative pictures of the whole decomposition process.

Dynamical Mechanism May Avoid High-Oxidation State Ir(V)-H Intermediate and Coordination Complex in Alkane and Arene C-H Activation by Cationic Ir(III) Phosphine.

Abstract: Organometallic reaction mechanisms are assumed to be appropriately described by minimum energy pathways mapped out by density functional theory calculations. For the two-step oxidative addition/reductive elimination mechanism for C–H activation of methane and benzene by cationic Cp*(PMe3)IrIII(CH3), we report quasiclassical direct dynamics simulations that demonstrate the IrV–H intermediate is bypassed in a significant amount of productive trajectories initiated from vibrationally averaged velocity distributions of oxidative addition transition states. This organometallic dynamical mechanism is akin to the σ-bond metathesis pathway but occurs on the oxidative addition/reductive elimination energy surface and blurs the line between two- and one-step mechanisms. Quasiclassical trajectories also reveal that the momentum of crossing the reductive elimination structure always induces complete alkane and arene dissociation from the Ir metal center, skipping weak C–H σ and π coordination complexes. This suggests...

Transition states of spin-forbidden reactions.

Abstract: Spin–orbit coupling plays an important role in determining the mechanisms and kinetics of spin-forbidden reactions and many reactions exhibiting two-state reactivity. Spin–orbit coupling can allow the system to change its spin state, especially when potential energy surfaces (PESs) of two spin states approach each other. Here, we introduce a convenient new approximation method for locating stationary points on the lowest mixed-spin potential energy surface along a reaction pathway by using density functional calculations. The mixing of different spin states is achieved by introducing the spin–orbit coupling into the electronic Hamiltonian using a pre-defined coupling constant. Two examples are given using the new methodology: (a) a CO association reaction with the coordinatively unsaturated Fe(CO)4 complex and (b) an α-H elimination reaction of a model complex containing W. We computed a Gibbs free energy of activation of 2.8 kcal mol−1 for the CO association reaction, which is reasonably consistent with the experimentally measured reaction rate. For the H elimination reaction, the spin change occurs at a relatively low energy, and the present treatment allows one conclude that kinetics of the reaction can be reasonably well described without spin–orbit coupling.

Role of Ligand-Driven Conformational Changes in Enzyme Catalysis: Modeling the Reactivity of the Catalytic Cage of Triosephosphate Isomerase

Abstract: We have previously performed empirical valence bond calculations of the kinetic activation barriers, Δ G‡calc, for the deprotonation of complexes between TIM and the whole substrate glyceraldehyde-3-phosphate (GAP, Kulkarni et al. J. Am. Chem. Soc. 2017 , 139 , 10514 - 10525 ). We now extend this work to also study the deprotonation of the substrate pieces glycolaldehyde (GA) and GA·HPi [HPi = phosphite dianion]. Our combined calculations provide activation barriers, Δ G‡calc, for the TIM-catalyzed deprotonation of GAP (12.9 ± 0.8 kcal·mol-1), of the substrate piece GA (15.0 ± 2.4 kcal·mol-1), and of the pieces GA·HPi (15.5 ± 3.5 kcal·mol-1). The effect of bound dianion on Δ G‡calc is small (≤2.6 kcal·mol-1), in comparison to the much larger 12.0 and 5.8 kcal·mol-1 intrinsic phosphodianion and phosphite dianion binding energy utilized to stabilize the transition states for TIM-catalyzed deprotonation of GAP and GA·HPi, respectively. This shows that the dianion binding energy is essentially fully expressed at our protein model for the Michaelis complex, where it is utilized to drive an activating change in enzyme conformation. The results represent an example of the synergistic use of results from experiments and calculations to advance our understanding of enzymatic reaction mechanisms.

Visualization of the Intrinsic Reaction Coordinate and Global Reaction Route Map by Classical Multidimensional Scaling.

Abstract: A classical multidimensional scaling (CMDS) method is employed to visualize an intrinsic reaction coordinate (IRC) and a global reaction route map consisting of the equilibrium minima and transition state structures connected by the IRC network As demonstrations, the method was applied to the IRCs of the intramolecular proton transfer in malonaldehyde and the SN2 reaction of OH– + CH3F → CH3OH + F–, which are both well described by two principal coordinates Next, the method was applied to the global reaction route map of the Au5 cluster; the resulting map shows appropriate positions of five minima and 14 transition states in a reduced 2- or 3-dimensional coordinate space successfully

QM-Mechanism-Based Hierarchical High-Throughput in Silico Screening Catalyst Design for Ammonia Synthesis.

Abstract: We propose and test a hierarchical high-throughput screening (HHTS) approach to catalyst design for complex catalytic reaction systems that is based on quantum mechanics (QM) derived full reaction networks with QM rate constants but simplified to examine only the reaction steps likely to be rate determining. We illustrate this approach by applying it to determine the optimum dopants (our of 35 candidates) to improve the turnover frequency (TOF) for the Fe-based Haber–Bosch ammonia synthesis process. We start from the QM-based free-energy reaction network for this reaction over Fe(111), which contains the 26 most important surface configurations and 17 transition states at operating conditions of temperature and pressure, from which we select the key reaction steps that might become rate determining for the alloy. These are arranged hierarchically by decreasing free-energy reaction barriers. We then extract from the full reaction network, a reduced set of reaction rates required to quickly predict the effect of the catalyst changes on each barrier. This allows us to test new candidates with only 1% of the effort for a full calculation. Thus, we were able to quickly screen 34 candidate dopants to select a small subset (Rh, Pt, Pd, Cu) that satisfy all criteria, including stability. Then from these four candidates expected to increase the TOF for NH3 production, we selected the best candidate (Rh) for a more complete free-energy and kinetic analysis (10 times the effort for HHTS but still 10% of the effort for a complete analysis of the full reaction network). We predict that Rh doping of Fe will increase the TOF for NH_3 synthesis by a factor of ∼3.3 times compared to Fe(111), in excellent agreement with our HHTS predictions, validating this approach.

Reaction coordinates and transition states in enzymatic catalysis

Abstract: Enzymatic reactions are complex chemical processes taking place in complex dynamic environments. Theoretical characterization of these reactions requires the determination of the reaction coordinate and the transition state ensemble. This is not an easy task because many degrees of freedom may be involved in principle. We present recent efforts to find good enzymatic reaction coordinates and the implications of these findings in the interpretation of enzymatic efficiency. In particular, we analyze different strategies based on the use of minimum free energy paths and direct localization of the dividing surface on multidimensional free energy surfaces. Another strategy is based on the generation of reactive trajectories, using the transition path sampling method, from which transition state configurations can be harvested. Most of the applications carried out until now coincide to stress the change in the nature of the reaction coordinate, in terms of the participation of the chemical and environmental degrees of freedom, as the reaction advances. The degrees of freedom of the chemical system are dominant at the transition state while environmental participation can be more important at early or late stages of the process. For further resources related to this article, please visit the WIREs website.

Chiral Brønsted acid-catalyzed intramolecular SN2′ reaction for enantioselective construction of a quaternary stereogenic center

Abstract: An enantioselective intramolecular anti-SN2′ cyclization reaction for the construction of a quaternary stereogenic center was accomplished through the activation of the leaving group using a binaphthol-derived phosphoramide as the chiral Bronsted acid catalyst. The present allylic substitution reaction is beneficial not only for the regioselective nucleophilic substitution at the multi-substituted site of the double bond but also for controlling the stereochemical outcome because of using a geometrically defined double bond. Indeed, the reaction afforded synthetically useful amino alcohol derivatives having a tetra-substituted carbon center in a highly enantioselective manner in most cases, in which the modification of the sulfonamide unit of the phosphoramide catalyst was demonstrated to improve the enantioselectivity. Experimental and theoretical elucidation of the reaction mechanism suggested that the reaction proceeds through a synchronous anti-SN2′ pathway, although NMR monitoring of the reaction indicated the formation of the phosphorimidate ester via the SN2 reaction of the catalyst with the substrate, which results in catalyst deactivation. Further theoretical studies of the origin of the stereochemical outcome at the generated quaternary stereogenic center were performed. Structural analysis of the transition states at the enantio-determining step revealed that the distinct discrimination of the substituents attached to the geometrically defined double bond is achieved by the anthryl and sulfonamide substituents of the catalyst through the three-point hydrogen bonding interactions and the T-shaped C–H⋯π interactions.