Dynamical Origin of Rebound versus Dissociation Selectivity during Fe-Oxo-Mediated C-H Functionalization Reactions.

The mechanism of catalytic C-H functionalization of alkanes by Fe-oxo complexes is often suggested to involve a hydrogen atom transfer (HAT) step with the formation of a radical-pair intermediate followed by diverging pathways for radical rebound, dissociation, or desaturation. Recently, we showed that in some Fe-oxo reactions, the radical pair is a nonstatistical-type intermediate and dynamic effects control rebound versus dissociation pathway selectivity. However, the effect of the solvent cage on the stability and lifetime of the radical-pair intermediate has never been analyzed. Moreover, because of the extreme complexity of motion that occurs during dynamics trajectories, the underlying physical origin of pathway selectivity has not yet been determined. For the reaction between [(TQA_Cl)FeIVO]+ and cyclohexane, here, we report explicit solvent trajectories and machine learning analysis on transition-state sampled features (e.g., vibrational, velocity, and geometric) that identified the transferring hydrogen atom kinetic energy as the most important factor controlling rebound versus nonrebound dynamics trajectories, which provides an explanation for our previously proposed dynamic matching effect in fast rebound trajectories that bypass the radical-pair intermediate. Manual control of the reaction trajectories confirmed the importance of this feature and provides a mechanism to enhance or diminish selectivity for the rebound pathway. This led to a general catalyst design principle and proof-of-principle catalyst design that showcases how to control rebound versus dissociation reaction pathway selectivity.

Intramolecular Heteroatom and Styryl Diels-Alder Reactions, Asymmetric Cycloadditions of Chiral 3-Phenylallyl Maleic Esters.

Polycyclic aryl naphthalene and tetralin dihydro arylnaphthalene lactone lignans possess anticancer and antibiotic activity. Related furo[3,4-c]pyranones, typified by the sequester-terpenoid isobolivianine, show similar antiproliferative bioactivity. Efficient syntheses of compounds featuring these polycyclic cores have proven challenging due to low yields and poor stereoselectivity. We report the synthesis of chiral cinnamyl but-2-enanoates and 3,3-diphenylallyl-but-2-enoates 1 as new Diels-Alder substrates. These compounds undergo [4 + 2]-cycloadditions to give furo[3,4-c]pyranones 2 in good yield (70%) and diastereoselectivity (7:1), together with naphthyl 3 and dihydronaphthyl tetralins 4 as minor products. Molecular structures and stereochemistries of the major products were verified using X-ray diffraction. Density functional theory calculations revealed that the cycloaddition process involves a bispericyclic/ambimodal process where there is a single transition state that leads to both intramolecular styryl Diels-Alder (ISDA) 3, 4 and intramolecular hetero Diels-Alder (IHDA) cycloadducts 2. With the elevated temperature conditions after cycloaddition, the resulting ISDA cycloadduct either undergoes [3,3]-sigmatropic rearrangement to the more stable major IHDA product or aromatization leading to the phenyltetralin.

Machine Learning Models for Predicting Zirconocene Properties and Barriers.

Zr metallocenes have significant potential to be highly tunable polyethylene catalysts through modification of the aromatic ligand framework. Here we report the development of multiple machine learning models using a large library (>700 systems) of DFT-calculated zirconocene properties and barriers for ethylene polymerization. We show that very accurate machine learning models are possible for HOMO-LUMO gaps of precatalysts but the performance significantly depends on the machine learning algorithm and type of featurization, such as fingerprints, Coulomb matrices, smooth overlap of atomic positions, or persistence images. Surprisingly, the description of the bonding hapticity, the number of direct connections between Zr and the ligand aromatic carbons, only has a moderate influence on the performance of most models. Despite robust models for HOMO-LUMO gaps, these types of machine learning models based on structure connectivity type features perform poorly in predicting ethylene migratory insertion barrier heights. Therefore, we developed several relatively robust and accurate machine learning models for barrier heights that are based on quantum-chemical descriptors (QCDs). The quantitative accuracy of these models depends on which potential energy surface structure QCDs were harvested from. This revealed a Hammett-type principle to naturally emerge showing that QCDs from the π-coordination complexes provide much better descriptions of the transition states than other potential-energy structures. Feature importance analysis of the QCDs provides several fundamental principles that influence zirconocene catalyst reactivity.

Vibrational synchronization and its reaction pathway influence from an entropic intermediate in a dirhodium catalyzed allylic C-H activation/Cope rearrangement reaction.

In reactions with consecutive transition states without an intermediate, and an energy surface bifurcation, atomic motion generally determines product selectivity. Understanding this dynamic-based selectivity can be straightforward if there is extremely fast descent from the first transition state to a product. However, in cases where a nonstatistical roaming/entropic intermediate occurs prior to product formation the motion that influences selectivity can be difficult to identify. Here we report quasiclassical direct dynamics trajectories for the dirhodium catalyzed reaction between styryldiazoacetate and 1,4-cyclohexadiene and prior experiments by Davies showed competitive allylic C-H insertion and Cope products. Trajectories confirmed the proposed energy surface bifurcation and revealed that dirhodium vinylcarbenoid when reacting with 1,4-cyclohexadiene can induce either a dynamically concerted pathway or a dynamically stepwise pathway with a nonstatistical entropic tight ion-pair intermediate. In the dynamically stepwise reaction pathway C-H insertion versus Cope selectivity is highly influenced by whether or not vibrational synchronization occurs in the nonstatistical entropic intermediate. This vibrational synchronization highlights the possible need for an entropic intermediate to have organized transition state-like motion to proceed to a product.

Trajectory-Based Time-Resolved Mechanism for Benzene Reductive Elimination from Cyclopentadienyl Mo/W Phenyl Hydride Complexes.

Calculated potential energy structures and landscapes are very often used to define the sequence of reaction steps in an organometallic reaction mechanism and interpret kinetic isotope effect (KIE) measurements. Underlying most of this structure-to-mechanism translation is the use of statistical rate theories without consideration of atomic/molecular motion. Here we report direct dynamics simulations for an organometallic benzene reductive elimination reaction, where nonstatistical intermediates and dynamic-controlled pathways were identified. Specifically, we report single spin state as well as mixed spin state quasiclassical direct dynamics trajectories in the gas phase and explicit solvent for benzene reductive elimination from Mo and W bridged cyclopentadienyl phenyl hydride complexes ([Me2Si(C5Me4)2]M(H)(Ph), M = Mo and W). Different from the energy landscape mechanistic sequence, the dynamics trajectories revealed that after the benzene C-H bond forming transition state (often called reductive coupling), σ-coordination and π-coordination intermediates are either skipped or circumvented and that there is a direct pathway to forming a spin flipped solvent caged intermediate, which occurs in just a few hundred femtoseconds. Classical molecular dynamics simulations were then used to estimate the lifetime of the caged intermediate, which is between 200 and 400 picoseconds. This indicates that when the η2-π-coordination intermediate is formed, it occurs only after the first formation of the solvent-caged intermediate. This dynamic mechanism intriguingly suggests the possibility that the solvent-caged intermediate rather than a coordination intermediate is responsible (or partially responsible) for the inverse KIE value experimentally measured for W. Additionally, this dynamic mechanism prompted us to calculate the kH/kD KIE value for the C-H bonding forming transition states of Mo and W. Surprisingly, Mo gave a normal value, while W gave an inverse value, albeit small, due to a much later transition state position.

Nickel-Catalyzed Electrochemical Cross-Electrophile C(sp2)-C(sp3) Coupling via a NiII Aryl Amido Intermediate.

Cross-electrophile coupling (XEC) between aryl halides and alkyl halides is a streamlined approach for C(sp2)-C(sp3) bond construction, which is highly valuable in medicinal chemistry. Based on a key NiII aryl amido intermediate, we developed a highly selective and scalable Ni-catalyzed electrochemical XEC reaction between (hetero)aryl halides and primary and secondary alkyl halides. Experimental and computational mechanistic studies indicate that an amine secondary ligand slows down the oxidative addition process of the Ni-polypyridine catalyst to the aryl bromide and a NiII aryl amido intermediate is formed in-situ during the reaction process. The relatively slow oxidative addition is beneficial for enhancing the selectivity of the XEC reaction. The NiII aryl amido intermediate stabilizes the NiII-aryl species to prevent the aryl-aryl homo-coupling side reactions and acts as a catalyst to activate the alkyl bromide substrates. This electrosynthesis system provides a facile, practical, and scalable platform for the formation of (hetero)aryl-alkyl bonds using standard Ni catalysts under mild conditions. The mechanistic insights from this work could serve as a great foundation for future studies on Ni-catalyzed cross-couplings.

Electro/Ni Dual-Catalyzed Decarboxylative C(sp3)-C(sp2) Cross-Coupling Reactions of Carboxylates and Aryl Bromide.

Paired redox-neutral electrolysis offers an attractive green platform for organic synthesis by avoiding sacrificial oxidants and reductants. Carboxylates are non-toxic, stable, inexpensive, and widely available, making them ideal nucleophiles for C-C cross-coupling reactions. Here, we report the electro/Ni dual-catalyzed redox-neutral decarboxylative C(sp3)-C(sp2) cross-coupling reactions of pristine carboxylates with aryl bromides. At a cathode, a NiII(Ar)(Br) intermediate is formed through the activation of Ar-Br bond by a NiI-bipyridine catalyst and subsequent reduction. At an anode, the carboxylates, including amino acid, benzyl carboxylic acid, and 2-phenoxy propionic acid, undergo oxidative decarboxylation to form carbon-based free radicals. The combination of NiII(Ar)(Br) intermediate and carbon radical results in the formation of C(sp3)-C(sp2) cross-coupling products. The adaptation of this electrosynthesis method to flow synthesis and valuable molecule synthesis was demonstrated. The reaction mechanism was systematically studied through electrochemical voltammetry and density functional theory (DFT) computational studies. The relationships between the electrochemical properties of carboxylates and the reaction selectivity were revealed. The electro/Ni dual-catalyzed cross-coupling reactions described herein expand the chemical space of paired electrochemical C(sp3)-C(sp2) cross-coupling and represent a promising method for the construction of the C(sp3)-C(sp2) bonds because of the ubiquitous carboxylate nucleophiles and the innate scalability and flexibility of electrochemical flow-synthesis technology.

Direct Dynamics Trajectories Demonstrate Dynamic Matching and Nonstatistical Radical Pair Intermediates during Fe-Oxo-Mediated C-H Functionalization Reactions.

The generally proposed mechanism for the reaction between non-heme Fe-oxo complexes and alkane C-H bonds involves a hydrogen atom transfer (HAT) reaction step with a radical pair intermediate that then has competitive radical rebound, dissociation, or desaturation pathways. Here, we report density functional theory-based quasiclassical direct dynamics trajectories that examine post-HAT reaction dynamics. Trajectories revealed that the radical pair intermediate can be a nonstatistical type intermediate without complete internal vibrational redistribution and post-HAT selectivity is generally determined by dynamic effects. Fast rebound trajectories occur through dynamic matching between the rotational motion of the newly formed Fe-OH bond and collision with the alkane radical, and all of this occurs through a nonsynchronous dynamically concerted process that circumvents the radical pair intermediate structure. For radical pair dissociation, trajectories proceeded to the radical pair intermediate for a very brief time, followed by complete dissociation. These trajectories provide a new viewpoint and model to understand the inherent reaction pathway selectivity for non-heme Fe-oxo-mediated C-H functionalization reactions.

Understanding Formation and Roles of NiII Aryl Amido and NiIII Aryl Amido Intermediates in Ni-Catalyzed Electrochemical Aryl Amination Reactions.

Ni-catalyzed electrochemical aryl amination (e-amination) is an attractive, emerging approach to building C-N bonds. Here, we report in-depth experimental and computational studies that examined the mechanism of Ni-catalyzed e-amination reactions. Key NiII-amine dibromide and NiII aryl amido intermediates were chemically synthesized and characterized. The combination of experiments and DFT calculations suggest (1) there is coordination of an amine to the NiII catalyst before the cathodic reduction and oxidative addition steps, (2) a stable NiII aryl amido intermediate is produced from the cathodic half-reaction, a critical step in controlling the selectivity between cross-coupling and undesired homo-coupling reaction pathways, (3) the diazabicycloundecene additive shifts the aryl halide oxidative addition mechanism from a NiI-based pathway to a Ni0-based pathway, and (4) redox-active bromide in the supporting electrolyte functions as a redox mediator to promote the oxidation of the stable NiII aryl amido intermediate to a NiIII aryl amido intermediate. Subsequently, the NiIII aryl amido intermediate undergoes facile reductive elimination to provide a C-N cross-coupling product at room temperature. Overall, our results provide new fundamental understandings about this e-amination reaction and guidance for further development of other Ni-catalyzed electrosynthetic reactions such as C-C and C-O cross-couplings.

Exploring Cuneanes as Potential Benzene Isosteres and Energetic Materials: Scope and Mechanistic Investigations into Regioselective Rearrangements from Cubanes.

Cuneane is a strained hydrocarbon that can be accessed via metal-catalyzed isomerization of cubane. The carbon atoms of cuneane define a polyhedron of the C2v point group with six faces─two triangular, two quadrilateral, and two pentagonal. The rigidity, strain, and unique exit vectors of the cuneane skeleton make it a potential scaffold of interest for the synthesis of functional small molecules and materials. However, the limited previous synthetic efforts toward cuneanes have focused on monosubstituted or redundantly substituted systems such as permethylated, perfluorinated, and bis(hydroxymethylated) cuneanes. Such compounds, particularly rotationally symmetric redundantly substituted cuneanes, have limited potential as building blocks for the synthesis of complex molecules. Reliable, predictable, and selective syntheses of polysubstituted cuneanes bearing more complex substitution patterns would facilitate the study of this ring system in myriad applications. Herein, we report the regioselective, AgI-catalyzed isomerization of asymmetrically 1,4-disubstituted cubanes to cuneanes. In-depth DFT calculations provide a charge-controlled regioselectivity model, and direct dynamics simulations indicate that the nonclassical carbocation invoked is short-lived and dynamic effects augment the charge model.

Density functional theory and CCSD(T) evaluation of ionization potentials, redox potentials, and bond energies related to zirconocene polymerization catalysts.

Quantum-mechanical-based computational design of molecular catalysts requires accurate and fast electronic structure calculations to determine and predict properties of transition-metal complexes. For Zr-based molecular complexes related to polyethylene catalysis, previous evaluation of density functional theory (DFT) and wavefunction methods only examined oxides and halides or select reaction barrier heights. In this work, we evaluate the performance of DFT against experimental redox potentials and bond dissociation enthalpies (BDEs) for zirconocene complexes directly relevant to ethylene polymerization catalysis. We also examined the ability of DFT to compute the fourth atomic ionization potential of zirconium and the effect the basis set selection has on the ionization potential computed with CCSD(T). Generally, the atomic ionization potential and redox potentials are very well reproduced by DFT, but we discovered relatively large deviations of DFT-calculated BDEs compared to experiment. However, evaluation of BDEs with CCSD(T) suggests that experimental values should be revisited, and our CCSD(T) values should be taken as most accurate.

Mechanistic studies of Ni-catalyzed electrochemical homo-coupling reactions of aryl halides.

Ni-catalyzed electrochemical arylation is an attractive, emerging approach for molecular construction as it uses air-stable Ni catalysts and efficiently proceeds at room temperature. However, the homo-coupling of aryl halide substrates is one of the major side reactions. Herein, extensive experimental and computational studies were conducted to examine the mechanism of Ni-catalyzed electrochemical homo-coupling of aryl halides. The results indicate that an unstable NiII(Ar)Br intermediate formed through oxidative addition of the cathodically generated NiI species with aryl bromide and a consecutive chemical reduction step. For electron-rich aryl halides, homo-coupling reaction efficiency is limited by the oxidative addition step, which can be improved by negatively shifting the redox potential of the Ni-catalyst. DFT computational studies suggest a NiIII(Ar)Br2/NiII(Ar)Br ligand exchange pathway for the formation of a high-valent NiIII(Ar)2Br intermediate for reductive elimination and production of the biaryl product. This work reveals the reaction mechanism of Ni-catalyzed electrochemical homo-coupling of aryl halides, which may provide valuable information for developing cross-coupling reactions with high selectivity.

Directing-Group-Free Arene C(sp2)-H Amination Using Bulky Aminium Radicals and DFT Analysis of Regioselectivity.

A hydroxylamine-derived electrophilic aminating reagent produces a transient and bulky aminium radical intermediate upon in situ activation by either TMSOTf or TFA and a subsequent electron transfer from an iron(II) catalyst. Density functional theory calculations were used to examine the regioselectivity of arene C-H amination reactions on diversely substituted arenes. The calculations suggest a simple charge-controlled regioselectivity model that enables prediction of the major C(sp2)-H amination product.

ReaLigands: A Ligand Library Cultivated from Experiment and Intended for Molecular Computational Catalyst Design.

Computational catalyst design requires identification of a metal and ligand that together result in the desired reaction reactivity and/or selectivity. A major impediment to translating computational designs to experiments is evaluating ligands that are likely to be synthesized. Here, we provide a solution to this impediment with our ReaLigands library that contains >30,000 monodentate, bidentate (didentate), tridentate, and larger ligands cultivated by dismantling experimentally reported crystal structures. Individual ligands from mononuclear crystal structures were identified using a modified depth-first search algorithm and charge was assigned using a machine learning model based on quantum-chemical calculated features. In the library, ligands are sorted based on direct ligand-to-metal atomic connections and on denticity. Representative principal component analysis (PCA) and uniform manifold approximation and projection (UMAP) analyses were used to analyze several tridentate ligand categories, which revealed both the diversity of ligands and connections between ligand categories. We also demonstrated the utility of this library by implementing it with our building and optimization tools, which resulted in the very rapid generation of barriers for 750 bidentate ligands for Rh-hydride ethylene migratory insertion.

Aza-Quasi-Favorskii Reaction: Construction of Highly Substituted Aziridines through a Concerted Multibond Rearrangement Process.

A new molecular rearrangement, the aza-Quasi-Favorskii rearrangement, has been developed for the construction of highly substituted aziridines. Electron-deficient O-sulfonyl oximes react readily with α,α-disubstituted acetophenone-derived enolates to furnish highly substituted aziridines via this unprecedented domino process. In-depth computational studies reveal an asynchronous yet concerted nitrenoid-type rearrangement pathway.

Quasiclassical Direct Dynamics Trajectory Simulations of Organometallic Reactions.

Homogeneous metal-mediated organometallic reactions represent a very large and diverse reaction class. Density functional theory calculations are now routinely carried out and reported for analyzing organometallic mechanisms and reaction pathways. While density functional theory calculations are extremely powerful to understand the energy and structure of organometallic reactions, there are several assumptions in their use and interpretation to define reaction mechanisms and to analyze reaction selectivity. Almost always it is assumed that potential energy structures calculated with density functional theory adequately describe mechanisms and selectivity within the framework of statistical theories, for example, transition state theory and RRKM theory. However, these static structures and corresponding energy landscapes do not provide atomic motion information during reactions that could reveal nonstatistical intermediates without complete intramolecular vibrational redistribution and nonintrinsic reaction coordinate (non-IRC) pathways. While nonstatistical intermediates and non-IRC reaction pathways are now relatively well established for organic reactions, these dynamic effects have heretofore been highly underexplored in organometallic reactions. Through a series of quasiclassical density functional theory direct dynamics trajectory studies, my group has recently demonstrated that dynamic effects occur in a variety of fundamental organometallic reactions, especially bond activation reactions. For example, in the C-H activation reaction between methane and [Cp*(PMe3)IrIII(CH3)]+, while the density functional theory energy landscape showed a two-step oxidative cleavage and reductive coupling mechanism, trajectories revealed a mixture of this two-step mechanism and a dynamic one-step mechanism that skipped the [Cp*(PMe3)IrV(H)(CH3)2]+ intermediate. This study also showed that despite a methane σ-complex being located on the density functional theory surface before oxidative cleavage and after reductive coupling, this intermediate is always skipped and should not be considered an intermediate during reactive trajectories. For non-IRC reaction pathways, quasiclassical direct dynamics trajectories showed that for the isomerization of [Tp(NO)(PMe3)W(η2-benzene)] to [Tp(NO)(PMe3)W(H)(Ph)], there are many dynamic reaction pathway connections due to a relatively flat energy landscape and π coordination is not necessary for C-H bond activation through oxidative cleavage. Trajectories also showed that dynamic effects are important in selectivity for ethylene C-H activation versus π coordination in reaction with Cp(PMe3)2Re, and trajectories provide a more quantitative model of selectivity than transition state theory. Quasiclassical trajectories examining Au-catalyzed monoallylic diol cyclizations showed dynamic coupling of several reaction steps that include alkoxylation π bond addition, proton shuttling, and water elimination reaction steps. Overall, these studies highlight the need to use direct dynamics trajectory simulations to consider atomic motion during reactions to understand organometallic reaction mechanisms and selectivity.

Experimental Demonstration and Density Functional Theory Mechanistic Analysis of Arene C-H Bond Oxidation and Product Protection by Osmium Tetroxide in a Strongly Basic/Nucleophilic Solvent.

Reactions that result in the oxy-functionalization of sp2 C-H bonds to give phenols are relatively rare. Here we report experiments and density functional theory (DFT) calculations that demonstrate selective C-H bond hydroxylation of nitroarenes to their corresponding mono-phenoxide as the exclusive product using OsO4 in a highly basic solvent mixture of water, hydroxide, and pyridine. DFT calculations using a mixed explicit/continuum solvent approach indicate that there is likely a mixture of OsO4-hydroxide/pyridine ground-state structures that have competitive reactivity and that the mechanism involves the nucleophilic addition of an anionic metal-oxo species to the arene followed by a hydride transfer process that is different from the standard [3 + 2] mechanism often invoked for the OsO4 oxidation of σ and π bonds. This work demonstrates the utility of using a strongly basic solvent for C-H bond oxidation reactions as this effectively converts any reactive phenolic product into the corresponding phenoxide, which is protected and essentially inert to further oxidation by the nucleophilic metal-oxo species.

Microwave- and Thermally Promoted Iminyl Radical Cyclizations: A Versatile Method for the Synthesis of Functionalized Pyrrolines.

A detailed study of iminyl radical cyclizations of O-aryloximes tethered to alkenes is reported. The reactions can be triggered by either microwave irradiation or conventional heating in an oil bath. A variety of radical traps can be employed, enabling C-C, C-N, C-O, C-S, or C-X bond formation and producing a diverse array of functionalized pyrrolines. Substrates containing an allylic sulfide furnish terminal alkenes by a tandem cyclization-thiyl radical ß-elimination pathway. Cyclizations of hydroxylated substrates exhibit moderate diastereoselectivity that in some cases can partially be attributed to intramolecular hydrogen bonding. Computational studies suggested a possible role for thermodynamics in controlling the stereochemistry of cyclizations. The reaction temperature can be lowered from 120 to 100 °C by employing O-(p-tert-butylphenyl)oximes instead of O-phenyloximes as substrates, and these second-generation iminyl radical precursors can be used in a one-pot oxime ether formation-cyclization that is promoted by conventional heating. The functionalized pyrrolines obtained from these reactions can be conveniently transformed in several different ways.

Demonstration of High-Throughput Building Block and Composition Analysis of Metal-Organic Frameworks.

Metal-organic frameworks (MOFs) are composed of inorganic metal-containing nodes and organic linker groups and are promising porous materials for a wide range of applications. More than 90 000 different MOFs have been synthesized with different inorganic nodes, organic linkers, and node-linker connectivity patterns. While databases have been created to catalog this enormous number of structures, they generally do not provide functionality to easily search, sort, and understand MOFs based on composition and building blocks. Because structure-property relationships are critical to identify, here we outline our new program MOFseek and demonstrate that it can perform high-throughput structure and composition analyses of MOF structures. This program enables the fast analysis of tens of thousands of MOFs in databases based on the local chemical environment. We demonstrate the unique capabilities of MOFseek by analyzing the CoRE MOF database of structures.

Mechanism and Kinetics of Copper Complexes Binding to the Influenza A M2 S31N and S31N/G34E Channels.

Copper(II) is known to bind in the influenza virus His37 cluster in the homotetrameric M2 proton channel and block the proton current needed for uncoating. Copper complexes based on iminodiacetate also block the M2 proton channel and show reduced cytotoxicity and zebrafish-embryo toxicity. In voltage-clamp oocyte studies using the ubiquitous amantadine-insensitive M2 S31N variant, the current block showed fast and slow phases, in contrast to the single phase found for amantadine block of wild-type M2. Here, we evaluate the mechanism of block by copper adamantyl iminodiacitate and copper cyclooctyl iminodiacitate complexes and address whether the complexes can coordinate with one or more of the His37 imidazoles. The current traces were fitted to parametrized master equations. The energetics of binding and the rate constants suggest that the first step is copper complex binding within the channel, and the slow step in the current block is the formation of a Cu-histidine coordination complex. Solution-phase isothermal titration calorimetry and density functional theory (DFT) calculations indicate that imidazole binds to the copper complexes. Structural optimization using DFT reveals that the complexes fit inside the channel and project the Cu(II) toward the His37 cluster, allowing one imidazole to form a coordination complex with Cu(II). Electrophysiology and DFT studies also show that the complexes block the G34E amantadine-resistant mutant despite some crowding in the binding site by the glutamates.