Rate-determining Transition State Research Articles

A DFT Mechanistic Study on the Aza-Aldol Reaction of Boron Aza-Enolates: Relative Stability of Six-Membered Transition State and Its Relevance to the Coordination Mode of the Leaving Group.

The mechanism of the aza-aldol reaction between boron aza-enolate and benzaldehyde is investigated by using density functional theory calculations. The result shows that the syn-E isomer is preferentially formed, consistent with experimental observations. The six-membered ring transition state (TS) with the boat form leads to the E isomer, while the more unstable chair TS does to the Z isomer. The preference of the syn isomer is determined by the interactions between the substituents of aza-enolate and benzaldehyde. Structural distortion and intrinsic reaction coordinate analyses of simplified model systems provide insights into the origin of the relative stability of the rate-determining TS with boat and chair forms. The boat TS is an early TS; thus, minimal structural distortions of the reactant are required to reach this TS. The Lewis pair interactions between the boron and imine groups during B-N elimination also influenced the relative stability of the TSs. This interaction involves the nitrogen lone pair in the boat TS, while the π(N═C) orbital is involved in the chair TS. The Lewis pair with the lone pair stabilizes the TS more than that with the π orbital. The boron aza-enolate with 9-BBN generates an ate complex and forms C-C bonds sequentially, whereas that with Bpin does not generate an ate complex and exhibits the concerted formation of B-O and C-C bonds. Thus, the higher electrophilicity of boron such as 9-BBN enhances the reactivity by facilitating the formation of the ate complex. A reaction design is proposed to reverse the syn/anti selectivity. Proof-of-concept DFT calculations suggested that the modification of the imine group would change the relative stability of the boat/chair TSs and give the anti-product.

Kinetic Studies of CO2 Insertion into Metal-Element σ-Bonds.

ConspectusDespite the plethora of metal catalyzed reactions for CO2 utilization that have been developed in academic laboratories, practical systems remain elusive. The understanding of the elementary steps in catalysis is a proven method to improve catalytic performance. In many catalytic cycles for CO2 utilization, the insertion of CO2 into a metal-element σ-bond, such as hydrides, alkyls, amides, or hydroxides, is a crucial step. However, despite the many demonstrations of CO2 insertion, there are a paucity of kinetic studies, and information about the reaction mechanism has been predominantly elucidated from computational investigations. In this Account, kinetic studies on CO2 insertion into late transition metal-element σ-bonds performed by my group are summarized, along with their implications for catalysis.A common pathway for CO2 insertion into a metal hydride involves a two-step mechanism. The first step is nucleophilic attack on CO2 by the hydride to generate an H-bound formate, followed by rearrangement to form an O-bound formate product. Kinetic studies on systems in which both the first and second steps are proposed to be rate-determining, known as inner-sphere and outer-sphere processes, respectively, show that insertion rates increase as (i) the ligand trans to the hydride becomes a stronger donor, (ii) the ancillary ligand becomes more electron-donating, and (iii) the Dimroth-Reichardt parameter of the solvent increases. However, the magnitude of these effects is generally smaller for inner-sphere processes because there is less buildup of charge in the key transition state. For similar reasons, the presence of Lewis acids only increases the rate of outer-sphere processes. These results suggest it may be possible to experimentally differentiate between inner- and outer-sphere processes.The insertion of CO2 into a metal-alkyl bond results in the formation of a C-C bond, which is important for the generation of fuels from CO2. For square planar Group 10 complexes, the presence of a strong donor ligand trans to the alkyl group is critical for kinetically promoting insertion. Further, the nucleophilicity of the alkyl ligand directly impacts the rate of CO2 insertion via an SE2 mechanism, as does the steric bulk of the complex, and the reaction solvent. In contrast to the relatively slow rates of insertion observed for metal alkyls, CO2 insertion is rapid for metal hydroxides and amides. Although kinetics trends could be determined for hydroxides, reactions with amides are too fast for quantitative studies.Overall, the rates of insertion correlate with the nucleophilicity of the element in the metal-element σ-bond, so amide > hydroxide > hydride > alkyl. Due to the related pathways for insertion, similar trends in ligand and solvent effects are observed for insertion into different metal-element σ-bonds. Thus, the same strategies can be used to control the rates of insertion across systems. Differences in the magnitude of solvent and ligand effects are caused by variation in the amount of charge build-up on the metal in the rate-determining transition state. Likely, given that CO2 is related to organic molecules such as aldehydes, ketones, and amides, the results described in this Account are general to a wider range of substrates.

Ambient Electroreductive Carboxylation of Unactivated Alkyl Chlorides and Polyvinyl Chloride (PVC) Upgrading.

Electrosynthesis of alkyl carboxylic acids upon activating stronger alkyl chlorides at low-energy cost is desired in producing carbon-rich feedstock. Carbon dioxide (CO2), a greenhouse gas, has been recognized as an ideal primary carbon source for those syntheses, and such events also mitigate the atmospheric CO2 level, which is already alarming. On the other hand, the promising upcycling of polyvinyl chloride to polyacrylate is a high energy-demanding carbon-chloride (C-Cl) bond activation process. Molecular catalysts that can efficiently perform such transformation under ambient reaction conditions are rarely known. Herein, we reveal a nickel (Ni)-pincer complex that catalyzes the electrochemical upgrading of polyvinyl chloride to polyacrylate in 95 % yield. The activities of such a Ni electrocatalyst bearing a redox-active ligand were also tested to convert diverse examples of unactivated alkyl chlorides to their corresponding carboxylic acid derivatives. Furthermore, electronic structure calculations revealed that CO2 binding occurs in a resting state to yield an η2-CO2 adduct and that the C-Cl bond activation step is the rate-determining transition state, which has an activation energy of 19.3 kcal/mol. A combination of electroanalytical methods, control experiments, and computational studies were also carried out to propose the mechanism of the electrochemical C-Cl activation process with the subsequent carboxylation step.

Mechanism and Origins of Enantioselectivity in the Nickel-catalyzed Asymmetric Synthesis of Silicon-Stereogenic Benzosiloles.

As important π-skeletons, benzosiloles often possess unique electronic and optical properties and have been widely used in semiconductor materials. Therefore, great attention has been drawn to the area of developing novel synthetic methods for various benzosiloles. However, the synthesis of enantioenriched silicon-stereogenic benzosiloles is still at an early stage and remains to be explored. Herein, we performed systematic density functional theory studies on the recently reported nickel-catalyzed asymmetric synthesis of silicon-stereogenic benosiloles, which was enabled by an enantioselective desymmetrization of (2-alkenyl)aryl-substituted silacyclobutanes. Our computational study shows that the reaction mechanism involves ligand exchange, oxidative addition, alkene insertion, and hydrogen-transfer coupled reductive-demetalation steps. The proposed transmetalation and β-hydride elimination mechanism was not found, which might be due to the unfavorable ring strain of the multicyclic intermediates. The novel hydrogen-transfer coupled reductive-demetalation mechanism was shown to be reasonable for the generation of the silicon-stereogenic benzosilole. Noncovalent interactions (including C-H···π and hydrogen bonding) in the rate-determining alkene insertion transition state account for the origins of the enantioselectivity. Our computational study sheds light on the detailed reaction mechanism and also provides insights for the development of novel approaches for synthesis of high-value silicon-stereogenic compounds.

Insights into the Mechanism of O(3P)-Mediated Oxidation of Alkenes through Kinetic Isotope Effects and Computational Modeling.

Photodeoxygenation of aryl sulfoxides, such as dibenzothiophene S-oxide (DBTO), produces atomic oxygen [O(3P)] in solution. The mechanism of alkene oxidation with O(3P) remains uncertain. To address this, the current study utilized kinetic isotope effects (KIEs) and computational approaches to study the reaction of O(3P) with styrene and its isotopologues. Notably, the 2° CH/D KIE at the internal and terminal carbons of the reactive π-bond was ∼1.00 and ∼0.87, respectively. These findings indicate a terminal addition of O(3P) to the π-bond, supporting a stepwise oxidation pathway. Both epoxide and aldehyde products go through the same rate-determining transition state and then diverge based on the intermediate conformation. The O-C-C-C dihedral angle (φ) on the triplet surface dictates the product distribution, where φ = 50° or 310° leads to epoxide formation and φ = 180° leads to aldehyde formation. Computational modeling suggests that the epoxide is formed through rapid ring closure upon intersystem crossing from the triplet to the singlet ground state. Similarly, the aldehyde is generated via a 1,2-H shift immediately following intersystem crossing. This study integrates experimental and computational methods to understand the O(3P)-mediated oxidation of alkenes, providing supporting evidence for a stepwise addition mechanism.

Density functional theory investigations on the mechanisms of homogeneous Sm complex catalyzed CO[formula omitted] cycloaddition with epoxides

Converting excess CO2 into chemically valuable products is a promising routine for sustainable development. Catalyzing epoxides and CO2 cycloaddition reactions homogeneously with rare-earth compounds is an emerging approach. The reaction efficiency can be understood by mechanism study. In this work, we report a detailed density functional theory investigation on a well-designed experimental Sm catalyst. We calibrate the ωB97XD exchange–correlation functional as the best candidate functional for this specific catalytic system. The energetic span of catalytic cycle is approximately 25 kcal mol−1. The rate-determining transition state is the one for ring-closure to generate the product. Two competing paths are revealed. Through both ionic and covalent metal–ligand interactions, the lowering of the epoxide substrate ring-opening step barrier is significant compared with the Sm compound free case. This work demonstrate the values for utilizing modern density functional theory to complement the understandings on the homogeneous rare-earth catalytic processes.

Catalytic oxidation of carbon monoxide over copper oxide with interfering gases involved for industrial buildings: An experimental and theoretical study

With the intention of thoroughly eliminating carbon monoxide (CO) from indoor environment, it is one of the most promising methods of converting it into carbon dioxide (CO2) via catalytic oxidation processes. Therefore, in this study, catalytic oxidation mechanisms of CO over copper oxide (CuO) with interfering gases involved are investigated via theoretical calculations and experimental verification, which mainly include basic catalytic oxidation processes over CuO, effects of different interfering gases and analyses of thermodynamic features. According to results, catalytic oxidation of CO over CuO can be performed in three different routes and rate-determining transition-state (TS) energy barriers vary a lot from route to route at high temperature owing to different thermal stability. In the meantime, SO2, H2O and NO are theoretically proved to affect catalytic oxidation of CO via competitive adsorption, high oxidizability and hydrogen bonds, which are accompanied with different sensitivities to changes of temperature or temperature power exponents. In experiments, it is found that impurity of lattice planes and small specific surface areas in CuO are key to restricting catalytic oxidation performances. What is more, some extra chemical reactions in experiments (e.g. SO2 + O2 + CuO → CuSO4, NO + O2 + CO → CO2 + NO) caused by interfering gases colossally affect catalytic oxidation performances of CuO. The whole study provides crucial information for indoor air purification in industrial buildings by using cheap adsorbents/catalysts.

Linear Free Energy Relationships and Transition State Analysis of CO2 Reduction Catalysts Bearing Second Coordination Spheres with Tunable Acidity.

In molecular catalysts, protic functional groups in the secondary coordination sphere (SCS) work in conjunction with an exogenous acid to relay protons to the active site of electrochemical CO2 reduction; however, it is not well understood how the acidity of the SCS and exogenous acid together determine the kinetics of catalytic turnover. To evaluate the relative contributions of proton transfer driving forces, we synthesized a series of modular iron tetraphenylporphyrin electrocatalysts bearing SCS amides of tunable pKa (17.6 to 20.0 in dimethyl sulfoxide (DMSO)) and employed phenols of variable acidity (15.3 to 19.1) as exogenous acids. This system allowed us to (1) evaluate contributions from proton transfer driving forces associated with either the SCS or exogenous acid and (2) obtain mechanistic insights into CO2 reduction as a function of pKa. A series of linear free-energy relationships show that kinetics become increasingly sensitive to variations in SCS pKa when more acidic exogenous acids are used (0.82 ≥ Brønsted α ≥ 0.13), as well as to variations in exogenous acid pKa when SCS acidity is increased (0.62 ≥ Brønsted α ≥ 0.32). An Eyring analysis suggests that the rate-determining transition state becomes more ordered with decreasing SCS acidity, which is consistent with the proposal that SCS acidity modulates charge accumulation and solvation at the rate-limiting transition state. Together, these insights enable the optimization of activation barriers as a function of both SCS and exogenous acid pKa and can further guide the rational design of electrocatalytic systems wherein contributions from all participants in a proton relay are considered.

Palladium-Catalyzed Hydrosilylation of Unactivated Alkenes and Conjugated Dienes with Tertiary Silanes Controlled by Hemilabile Hybrid P,O Ligand.

Novel P,O-type ligands, N-disulfonyl bicyclic bridgehead phosphorus triamides, were synthesized and utilized in Pd-catalyzed hydrosilylation involving tertiary silanes, unactivated alkenes, and conjugated dienes. The ligand displayed a remarkable level of reactivity for alkene hydrosilylation with tertiary silanes and its use resulted in a significant improvement in the regioselectivity of diene hydrosilylation towards 1,2-hydrosilylation. X-ray crystallographic analysis confirmed the bidentate nature of the ligand, with coordination of phosphorus and oxygen. Control experiments provided evidence for the formation of Pd0 species and the reversibility of Pd-H insertion in the reaction mechanism. Density functional theory (DFT) computations supported the importance of the hemilabile P,O ligand in stabilizing both the rate-determining transition state of Pd-H insertion and the transition state of reductive elimination that determines the regioselectivity.

Metal-free catalysis on the reactions of nitric acid with aliphatic aldehydes: A new potential source of organic nitrates

The photochemical reaction of peroxy radical (RO2·) and NO has been identified by field and forest studies as important source of organic nitrates (RONO2) in the atmosphere. However, this traditional pathway is not sufficient to explain the high concentration of RONO2. Hence, a new source of the tropospheric RONO2 from the dark reactions of nitric acid (HNO3) with aliphatic aldehydes (C1–C5) under catalysis is provided and examined for the first time by high-level quantum chemistry. The findings show that the reaction between HCHO and HNO3, which produces HOCH2ONO2, can be catalyzed by a series of metal-free catalysts (NH3, CH3NH2, CH3NHCH3, H2O, HNO3, H2SO4, HCOOH, HOOCCOOH). At 296 K, the effective rate constant for the bimolecular HNO3–HCHO reaction under the catalysis of CH3NH2 or CH3NHCH3 can be sufficiently accelerated by 5–8 order of magnitudes through this new loss pathway for HNO3 or HCHO to become competitive with the conventional loss pathway for their photochemical reactions with ·OH radical. Significantly, this new HOCH2ONO2 formation pathway from the dark reaction of HCHO with CH3NH3+NO3−/(CH3)2NH + NO3− was more favorable than the recognized source of RO2· with NO. Efficient catalysis performance of CH3NH2 and CH3NHCH3 is mainly attributed to their excellent proton receptivity capacity by activating the O–H bond of HNO3 to form stable organic nitrates (CH3NH3+NO3− and (CH3)2NH + NO3−) in the rate-determining step transition states. In the case of only considering the barrier, H2SO4 is the best catalyst among the investigated inorganic and organic acids, and dicarboxylic acid (HOOCCOOH) is stronger than monocarboxylic acid HCOOH in facilitating the RONO2 formation reaction. These new findings deepen our understanding on the unexpected source of organic nitrate and loss pathway of HNO3 or HCHO under catalysis in highly polluted regions.

Theoretical Study on the Copper-Catalyzed ortho-Selective C-H Functionalization of Naphthols with α-Phenyl-α-Diazoesters.

The aromatic C(sp2)-H functionalization of unprotected naphthols with α-phenyl-α-diazoesters under mild conditions catalyzed by CuCl and CuCl2 exhibits high efficiency and unique ortho-selectivity. In this study, the combination of density functional theory (DFT) calculations and experiments is employed to investigate the mechanism of C-H functionalization, which reveals the fundamental origin of the site-selectivity. It explains that CuCl-catalyzed ortho-selective C-H functionlization is due to the bimetallic carbene, which differs from the reaction catalyzed by CuCl2 via monometallic carbene. The results demonstrate the function of favourable H-bond interactions on the site- and chemo-selectivity of reaction through stabilizing the rate-determining transition states in proton (1,3)-migration.

Palladium-catalyzed generation of CO from formic acid for alkoxycarbonylation of internal alkenes involves a PTSA-assisted NH-Pd mechanism: a DFT mechanistic study.

DFT calculations have been performed to find the mechanism of the alkyloxycarbonylation of an internal alkene with HCOOH catalyzed by a palladium complex with P,N hemilabile ligands. Four different cycles have been explored in detail, and a plausible catalytic cycle involves the decomposition of HCOOH/HCOOMe to CO, internal alkene isomerization, terminal alkene insertion, CO migratory insertion and methanolysis. It is shown that decomposition and isomerization processes involve a cooperative P,N hemilabile ligand and Pd(0) (NH-Pd) rather than the Pd(II) hydride (Pd-H) mechanism. Intriguingly, the simultaneous presence of PTSA acts as a hydrogen shuttle (H-shuttle), assisting CO generation and methanolysis. With such a mechanism, the rate-determining transition state corresponds to internal alkene isomerization, which is consistent with the experimental observation that isomerization was the slow step in this process. The back-bonding between palladium and olefin and rapid hydrogen transfer in the presence of a PTSA H-shuttle are responsible for the moderate barriers. In addition, a careful study of the solvent effect indicates that polar solvents, which are capable of hydrogen bonding, can promote the catalytic reactions. Mechanistic insights gained by this theoretical study have not only rationalized the experimental observations well but also have implications for new reaction development.

On the Effect of Iodide and Acids in the Metolachlor Process

Iridium-catalyzed asymmetric imine hydrogenation is the key step in the industrial syntheses of dextromethorphan and metolachlor. Nevertheless, the mechanism of this reaction relying on ferrocenyldiphosphine ligands remains unclear. Through computational studies, we propose a mechanism that is in line with all experimental observations including the enantioselectivity. The calculated mechanism reveals the interplay of potentially three rate-determining transition states, namely, the migratory insertion, amido-ligand protonation, and heterolytic H2-activation. Most salient, the mechanism rationalizes the “magic iodide effect” in combination with proton co-catalysis, which improve the reaction rate as well as enantioselectivity. Acid additives accelerate both the protonation- and H2-splitting steps. Iodide further facilitates the protonation and potentially the H2-activation. Thus, these additives prevent that other elementary steps within the catalytic cycle compromise the enantioselectivity control exerted by the migratory insertion step.

Theoretical study on Rh(III)-catalyzed reaction of allenylsilanes with N-methoxybenzamides

The reaction mechanism of the Rh(III)-catalyzed C−H functionalization of N-methoxybenzamides with allenes have been computationally investigated by employing density functional theory (DFT) calculations. Two reaction mechanisms have been calculated. The reaction mechanism involving β‒H elimination first followed by protonation is calculated to be preferred to the one in which protonation occurs first followed by β‒H elimination. The catalytic cycle consists of seven major processes: N‒H deprotonation, C‒H activation, alkene insertion, β‒H elimination and, N‒H bond-forming reductive elimination, MeOH elimination, and N‒H bond-forming oxidative addition. The C(sp2)‒H activation is the rate-determining transition state with a free energy barrier of 19.5 kcal/mol. The electronic effect could account for the observed regioselectivity. In addition, the reaction mechanisms for the formation of other side products have been calculated and compared.

Structure, reactivity and catalytic properties of manganese-hydride amidate complexes.

The high efficiency of widely applied Noyori-type hydrogenation catalysts arises from the N-H moiety coordinated to a metal centre, which stabilizes rate-determining transition states through hydrogen-bonding interactions. It was proposed that a higher efficiency could be achieved by substituting an N-M' group (M' = alkali metals) for the N-H moiety using a large excess of metal alkoxides (M'OR); however, such a metal-hydride amidate intermediate has not yet been isolated. Here we present the synthesis, isolation and reactivity of a metal-hydride amidate complex (HMn-NLi). Kinetic studies show that the rate of hydride transfer from HMn-NLi to a ketone is 24-fold higher than that of the corresponding amino metal-hydride complex (HMn-NH). Moreover, the hydrogenation of N-alkyl-substituted aldimines was realized using HMn-NLi as the active catalyst, whereas HMn-NH is much less effective. These results highlight the superiority of M/NM' bifunctional catalysis over the classic M/NH bifunctional catalysis for hydrogenation reactions.

QM/MM Study of the Reaction Mechanism of Thermophilic Glucuronoyl Esterase for Biomass Treatment.

Hydrolysis of lignocellulosic biomass, composed of a lignin-carbohydrate-complex (LCC) matrix, is critical for producing bioethanol from glucose. However, current methods for LCC processing require costly and polluting processes. The fungal Thermothelomyces thermophila glucuronoyl esterase (TtGE) is a promising thermophilic enzyme that hydrolyses LCC ester bonds. This study describes the TtGE catalytic mechanism using QM/MM methods. Two nearly-degenerate rate-determining transition states were found, with barriers of 16 and 17 kcal ⋅ mol-1 , both with a zwitterionic nature that results from a proton interplay from His346 to either the Ser213-hydroxyl or the lignin leaving group and the rehybridisation of the ester moiety of the substrate to an alkoxide. An oxyanion hole, characteristic of esterases, was provided by the conserved Arg214 through its backbone and sidechain. Our work further suggests that a mutation of Glu267 to a non-negative residue will decrease the energetic barrier in ca. -5 kcal ⋅ mol-1 , improving the catalytic rate of TtGE.

Balanced nitrogen and hydrogen chemisorption by [RuH6] catalytic center favors low-temperature NH3 synthesis

Ammonia is a central vector in sustainable global growth, but the usage of fossil feedstocks and centralized Haber-Bosch synthesis conditions causes >1.4% of global anthropogenic CO 2 emissions. While nitrogenase enzymes convert atmospheric N 2 to ammonia at ambient conditions, even the most active manmade inorganic catalysts fail due to low activity and parasitic hydrogen evolution at low temperatures. Here, we show that the [RuH 6 ] catalytic center in ternary ruthenium complex hydrides (Li 4 RuH 6 ) activates N 2 preferentially and avoids hydrogen over-saturation at low temperatures and near ambient pressure by delicately balancing H 2 chemisorption and N 2 activation. The active [RuH 6 ] catalytic center is capable of achieving high yield at low temperatures via a shift in the rate-determining reaction intermediates and transition states, where the reaction orders in hydrogen and ammonia change dramatically. Temperature-dependent atomic-scale understanding of this unique mechanism is obtained with synchronized experimental and density functional theory investigations. • Atomic-scale study reveals how Li 4 RuH 6 catalyzes NH 3 at a low temperature • Li 4 RuH 6 inherently balances N 2 activation/H 2 chemisorption to avoid H poisoning • The reaction orders of hydrogen and ammonia change with a temperature change The NH 3 industry is energy intensive, fossil-fuel based, responsible for >2% of the world’s CO 2 emission, and awaits a green technology. Pan et al. study how Li 4 RuH 6 activates N 2 , preferentially avoids H poisoning, and produces NH 3 at low temperatures, potentially informing greener NH 3 synthesis design.

Toward rational design of supported vanadia catalysts of lignin conversion to phenol

In sustainable chemical engineering, catalytic upgrading of lignocellulosic biomass has recently gained attention for producing renewable platform chemicals. To achieve maximal biomass utilization, upgrading the underutilized lignin components is essential. Among various catalysts for lignin upgrading, supported vanadia (V2O5) catalysts are promising because of their cost-effectiveness and tunability of either dopant metals or catalyst supports. Here, computational studies are conducted to derive rational design guidelines of supported V2O5 catalysts for accomplishing the high catalytic activity of lignin upgrading to phenol, a key compound for producing bioplastics and biofuel blendstocks. Guaiacol was used as the model compound since it comprises the highest portion of depolymerized lignin. Computational mechanistic studies for the catalytic guaiacol conversion to phenol were performed for the V2O5 catalysts on Titania (TiO2) and silica (SiO2) to explain higher experimental phenol yields on V2O5/SiO2 than V2O5/TiO2. The hydrogen migration from the methoxy group to the aryl ring was identified as a rate-determining step, and the overall activation energies on the two catalysts were compared. A structural analysis was carried out for the catalysts and rate-determining transition states to gain further insights from mechanistic studies. It was concluded that the tilt angle of the aryl group in the hydrogen migration transition state is a key descriptor determining the catalytic activity of phenol formation. These features correlate well with activation energies and experimental phenol yields, indicating that they provide design guidelines for supported metal catalysts for lignin upgrading before experiments.

Local Charge Distributions, Electric Dipole Moments, and Local Electric Fields Influence Reactivity Patterns and Guide Regioselectivities in α-Ketoglutarate-Dependent Non-heme Iron Dioxygenases.

Non-heme iron dioxygenases catalyze vital processes for human health related to the biosynthesis of essential products and the biodegradation of toxic metabolites. Often the natural product biosyntheses by these non-heme iron dioxygenases is highly regio- and chemoselective, which are commonly assigned to tight substrate-binding and positioning. However, recent high-level computational modeling has shown that substrate-binding and positioning is only part of the story and long-range electrostatic interactions can play a major additional role.In this Account, we review and summarize computational viewpoints on the high regio- and chemoselectivity of α-ketoglutarate-dependent non-heme iron dioxygenases and how external perturbations affect the catalysis. In particular, studies from our groups have shown that often a regioselectivity in enzymes can be accomplished by stabilization of the rate-determining transition state for the reaction through external charges, electric dipole moments, or local electric field effects. Furthermore, bond dissociation energies in molecules are shown to be influenced by an electric field effect, and through targeting a specific bond in an electric field, this can lead to an unusually specific reaction. For instance, in the carbon-induced starvation protein, we studied two substrate-bound conformations and showed that regardless of what C-H bond of the substrate is closest to the iron(IV)-oxo oxidant, the lowest hydrogen atom abstraction barrier is always for the pro-S C2-H abstraction due to an induced dipole moment of the protein that weakens this bond. In another example of the hygromycin biosynthesis enzyme, an oxidative ring-closure reaction in the substrate forms an ortho-δ-ester ring. Calculations on this enzyme show that the selectivity is guided by a protonated lysine residue in the active site that, through its positive charge, triggers a low energy hydrogen atom abstraction barrier. A final set of examples in this Account discuss the viomycin biosynthesis enzyme and the 2-(trimethylammonio)ethylphosphonate dioxygenase (TmpA) enzyme. Both of these enzymes are shown to possess a significant local dipole moment and local electric field effect due to charged residues surrounding the substrate and oxidant binding pockets. The protein dipole moment and local electric field strength changes the C-H bond strengths of the substrate as compared to the gas-phase triggers the regioselectivity of substrate activation. In particular, we show that in the gas phase and in a protein environment C-H bond strengths are different due to local electric dipole moments and electric field strengths. These examples show that enzymes have an intricately designed structure that enables a chemical reaction under ambient conditions through the positioning of positively and negatively charged residues that influence and enhance reaction mechanisms. These computational insights create huge possibilities in bioengineering to apply local electric field and dipole moments in proteins to achieve an unusual selectivity and specificity and trigger a fit-for-purpose biocatalyst for unique biotransformations.

Selective Acid-Catalyzed Hydroarylation of Nonactivated Alkenes with Aniline Assisted by Hexafluoroisopropanol.

The catalytic hydroarylation of nonactivated alkenes with aniline is a reaction of high interest, aiming at providing C-functionalized aniline derivatives that are important precursors for the fabrication of polyurethanes. However, this reaction remains a longstanding goal of catalysis, as it requires one to simultaneously address two important goals: (1) the very low reactivity of nonactivated alkenes and (2) control of the hydroarylation/hydroamination selectivity. As a result, the hydroarylation of aniline is mostly restricted to activated alkenes (i.e., featuring ring strain, conjugation, or activation with electron-donating or -withdrawing groups). Here we show that the combination of bismuth triflate and hexafluoroisopropanol (HFIP) leads to the formation of highly active catalytic species capable of promoting the hydroarylation of various nonactivated alkenes, such as 1-octene, 1-heptene, and 1-undecene, among others, with aniline with high selectivity (71-92%). Through a combined experimental and computational investigation, we propose a reaction pathway where HFIP stabilizes the rate-determining transition state through a H-bond interaction with the triflate anion, thus assisting the acid catalyst in the hydroarylation of nonactivated alkenes. From a practical point of view, this work opens a catalytic access to C-functionalized aniline derivatives from two cheap and abundant feedstocks in a 100% atom-economical fashion.