Tuning the Thermochemistry and Reactivity of a Series of Cu-Based 4H+/4e- Electron-Coupled-Proton Buffers.

Electron-coupled-proton buffers (ECPBs) store and deliver protons and electrons in a reversible fashion. We have recently reported an ECPB based on Cu and a redox-active ligand that promoted 4H+/4e- reversible transformations (J. Am. Chem. Soc. 2022, 144, 16905). Herein, we report a series of Cu-based ECPBs in which the ability of these to accept and/or donate H• equivalents can be tuned via ligand modification. The thermochemistry of the 4H+/4e- ECPB equilibrium was determined using open-circuit potential measurements. The reactivity of the ECPBs against proton-coupled electron transfer (PCET) reagents was also analyzed, and the results obtained were rationalized based on the thermochemical parameters. Experimental and computational analysis of the thermochemistry of the H+/e- transfers involved in the 4H+/4e- ECPB transformations found substantial differences between the stepwise (namely, BDFE1, BDFE2, BDFE3, and BDFE4) and average bond dissociation free energy values (BDFEavg.). Our analysis suggests that this "redox unleveling" is critical to promoting the disproportionation and ligand-exchange reactions involved in the 4H+/4e- ECPB equilibria. The difference in BDFEavg. within the series of Cu-based ECPBs was found to arise from a substantial change in the redox potential (E1/2) upon modification of the ligand scaffold, which is not fully compensated for by a change in the acidity/basicity (pKa), suggesting "thermochemical decompensation".

Investigating and Quantifying Molecular Complexity Using Assembly Theory and Spectroscopy.

Current approaches to evaluate molecular complexity use algorithmic complexity, rooted in computer science, and thus are not experimentally measurable. Directly evaluating molecular complexity could be used to study directed vs undirected processes in the creation of molecules, with potential applications in drug discovery, the origin of life, and artificial life. Assembly theory has been developed to quantify the complexity of a molecule by finding the shortest path to construct the molecule from building blocks, revealing its molecular assembly index (MA). In this study, we present an approach to rapidly infer the MA of molecules from spectroscopic measurements. We demonstrate that the MA can be experimentally measured by using three independent techniques: nuclear magnetic resonance (NMR), tandem mass spectrometry (MS/MS), and infrared spectroscopy (IR). By identifying and analyzing the number of absorbances in IR spectra, carbon resonances in NMR, or molecular fragments in tandem MS, the MA of an unknown molecule can be reliably estimated. This represents the first experimentally quantifiable approach to determining molecular assembly. This paves the way to use experimental techniques to explore the evolution of complex molecules as well as a unique marker of where an evolutionary process has been operating.

Torsion Effects Beyond the δ Bond and the Role of π Metal-Ligand Interactions.

Previous studies on bimetallic paddlewheel compounds have established a direct correlation between metal-metal distance and ligand torsion angles, leading to the rule that higher torsion results in longer metal-metal bond distances. Here, the new discovery based on diarylformamidinate Ru25⁺ paddlewheel compounds [Ru2Cl(DArF)4] that show an opposite behavior is reported: higher torsions lead to shorter metal-metal distances. This discovery challenges the assumption that internal rotation solely impacts the δ bond. By combining experimental and theoretical techniques, it is demostrated that this trend is associated with previously overlooked π metal-ligand interactions. These π metal-ligand interactions are a direct consequence of the paddlewheel structure and the conjugated nature of the bidentate ligands. This findings offer far-reaching insights into the influence of equatorial ligands and their π-conjugation characteristics on the electronic properties of paddlewheel complexes. That this effect is not exclusive of diruthenium compounds but also occurs in other bimetallic cores such as ditungsten or dirhodium is demonstrated, and with other ligands showing allyl type conjugation. These results provide a novel approach for fine-tuning the properties of these compounds with significant implications for materials design.

A tale of two topological isomers: Uptuning [FeIV(O)(Me4cyclam)]2+ for olefin epoxidation.

TMC-anti and TMC-syn, the two topological isomers of [FeIV(O)(TMC)(CH3CN)]2+ (TMC = 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane, or Me4cyclam), differ in the orientations of their FeIV=O units relative to the four methyl groups of the TMC ligand framework. The FeIV=O unit of TMC-anti points away from the four methyl groups, while that of TMC-syn is surrounded by the methyl groups, resulting in differences in their oxidative reactivities. TMC-syn reacts with HAT (hydrogen atom transfer) substrates at 1.3- to 3-fold faster rates than TMC-anti, but the reactivity difference increases dramatically in oxygen-atom transfer reactions. R2S substrates are oxidized into R2S=O products at rates 2-to-3 orders of magnitude faster by TMC-syn than TMC-anti. Even more remarkably, TMC-syn epoxidizes all the olefin substrates in this study, while TMC-anti reacts only with cis-cyclooctene but at a 100-fold slower rate. Comprehensive quantum chemical calculations have uncovered the key factors governing such reactivity differences found between these two topological isomers.

Generation of Ru(III)-hypochlorite with resemblance to the heme-dependent haloperoxidase enzyme.

The reaction of [(Me/BnTPEN)RuII(NCCH3)]2+ (BnTPEN = N1-benzyl-N1,N2,N2-tris(pyridine-2-ylmethyl)ethane-1,2-diamine and MeTPEN = N1-methyl-N1,N2,N2-tris(pyridine-2-ylmethyl)ethane-1,2-diamine) with mCPBA in the presence of chloride ions in CH3CN : H2O generated a novel (Me/BnTPEN)RuIII-OCl species at room temperature. This hypochlorite adduct could also be obtained by the direct reaction of NaOCl and HClO4 with (L)RuII complexes. The current study mimics the synthesis of a metal hypochlorite adduct in a similar fashion as in the heme-dependent haloperoxidase enzyme. As an electrophilic oxidant, the ruthenium hypochlorite adduct catalyzes hydrogen atom abstraction reactions of phenols and their derivatives.

The peptide bond rupture mechanism in the serine proteases: an in silico study based on sequential scale models.

Given the importance of serine proteases for biochemical processes, we have studied the peptide bond rupture mechanism using three sequential scale models as representations of the KLK5 enzyme (a protein overexpressed in ovarian cancer). The first model contains the basic functional groups of the residues that conform to the catalytic triad present in serine proteases; the second model contains some additional residues and, finally, the last representation includes all atoms of the KLK5 protein together with 10.000 explicit water molecules. This separation into three scale models allows us to separate the intrinsic reactivity of the catalytic triad from the process taking place in the enzyme. The methodologies employed in this work include full DFT calculations with a dielectric continuum in the first two models and a multi-level setup with a Quantum Mechanics/Molecular Mechanics (QM/MM) partition in the whole protein system. Our results show that the peptide-bond rupture mechanism is a stepwise process involving two proton transfer reactions. The rate-determining step is the second proton transfer from the imidazole group to the amidic nitrogen of the substrate. In addition, we find that the simplest model does not provide accurate results compared to the full protein system. This can be attributed to the electronic stabilization conferred by the residues around the reaction site. Interestingly, the energy profile obtained with the second scale model with additional residues shows the same trends as the full system and could therefore be considered an appropriate model system. It could be used for studying the peptide bond rupture mechanism in case full QM/MM calculations cannot be performed, or as a rapid tool for screening purposes.

Reductive Coupling of Nitric Oxide by Cu(I): Stepwise Formation of Mono- and Dinitrosyl Species En Route to a Cupric Hyponitrite Intermediate.

Transition-metal-mediated reductive coupling of nitric oxide (NO(g)) to nitrous oxide (N2O(g)) has significance across the fields of industrial chemistry, biochemistry, medicine, and environmental health. Herein, we elucidate a density functional theory (DFT)-supplemented mechanism of NO(g) reductive coupling at a copper-ion center, [(tmpa)CuI(MeCN)]+ (1) {tmpa = tris(2-pyridylmethyl)amine}. At -110 °C in EtOH (<-90 °C in MeOH), exposing 1 to NO(g) leads to a new binuclear hyponitrite intermediate [{(tmpa)CuII}2(µ-N2O22-)]2+ (2), exhibiting temperature-dependent irreversible isomerization to the previously characterized κ2-O,O'-trans-[(tmpa)2Cu2II(µ-N2O22-)]2+ (OOXray) complex. Complementary stopped-flow kinetic analysis of the reaction in MeOH reveals an initial mononitrosyl species [(tmpa)Cu(NO)]+ (1-(NO)) that binds a second NO molecule, forming a dinitrosyl species [(tmpa)CuII(NO)2] (1-(NO)2). The decay of 1-(NO)2 requires an available starting complex 1 to form a dicopper-dinitrosyl species hypothesized to be [{(tmpa)Cu}2(µ-NO)2]2+ (D) bearing a diamond-core motif, en route to the formation of hyponitrite intermediate 2. In contrast, exposing 1 to NO(g) in 2-MeTHF/THF (v/v 4:1) at <-80 °C leads to the newly observed transient metastable dinitrosyl species [(tmpa)CuII(NO)2] (1-(NO)2) prior to its disproportionation-mediated transformation to the nitrite product [(tmpa)CuII(NO2)]+. Our study furnishes a near-complete profile of NO(g) activation at a reduced Cu site with tripodal tetradentate ligation in two distinctly different solvents, aided by detailed spectroscopic characterization of metastable intermediates, including resonance Raman characterization of the new dinitrosyl and hyponitrite species detected.

A 4H+/4e- Electron-Coupled-Proton Buffer Based on a Mononuclear Cu Complex.

In this research article, we describe a 4H+/4e- electron-coupled-proton buffer (ECPB) based on Cu and a redox-active ligand. The protonated/reduced ECPB (complex 1: [Cu(8H+/14e-)]1+), consisting of CuI with 2 equiv of the ligand (catLH4: 1,1'-(4,5-dimethoxy-1,2-phenylene)bis(3-(tert-butyl)urea)), reacted with H+/e- acceptors such as O2 to generate the deprotonated/oxidized ECPB. The resulting compound, (complex 5: [Cu(4H+/10e-)]1+), was characterized by X-ray diffraction analysis, nuclear magnetic resonance (1H-NMR), and density functional theory, and it is electronically described as a cuprous bis(benzoquinonediimine) species. The stoichiometric 4H+/4e- reduction of 5 was carried out with H+/e- donors to generate 1 (CuI and 2 equiv of catLH4) and the corresponding oxidation products. The 1/5 ECPB system catalyzed the 4H+/4e- reduction of O2 to H2O and the dehydrogenation of organic substrates in a decoupled (oxidations and reductions are separated in time and space) and a coupled fashion (oxidations and reductions coincide in time and space). Mechanistic analysis revealed that upon reductive protonation of 5 and oxidative deprotonation of 1, fast disproportionation reactions regenerate complexes 5 and 1 in a stoichiometric fashion to maintain the ECPB equilibrium.

Synthesis of FeIII and FeIV Cyanide Complexes Using Hypervalent Iodine Reagents as Cyano-Transfer One-Electron Oxidants.

We disclose a new reactivity mode for electrophilic cyano λ3 -iodanes as group transfer one-electron oxidants to synthesize FeIII and FeIV cyanide complexes. The inherent thermal instability of high-valent FeIV compounds without π-donor ligands (such as oxido (O2- ), imido (RN2- ) or nitrido (N3- )) makes their isolation and structural characterization a very challenging task. We report the synthesis of an FeIV cyanide complex [(N3 N')FeCN] (4) by two consecutive single electron transfer (SET) processes from FeII precursor [(N3 N')FeLi(THF)] (1) with cyanobenziodoxolone (CBX). The FeIV complex can also be prepared by reaction of [(N3 N')FeIII ] (3) with CBX. In contrast, the oxidation of FeII with 1-cyano-3,3-dimethyl-3-(1H)-1,2-benziodoxole (CDBX) enables the preparation of FeIII cyanide complex [(N3 N')FeIII (CN)(Li)(THF)3 ] (2-LiTHF ). Complexes 4 and 2-LiTHF have been structurally characterized by single crystal X-ray diffraction and their electronic structure has been examined by Mössbauer, EPR spectroscopy, and computational analyses.

Modulation of a µ-1,2-Peroxo Dicopper(II) Intermediate by Strong Interaction with Alkali Metal Ions.

The properties of metal/dioxygen species, which are key intermediates in oxidation catalysis, can be modulated by interaction with redox-inactive Lewis acids, but structural information about these adducts is scarce. Here we demonstrate that even mildly Lewis acidic alkali metal ions, which are typically viewed as innocent "spectators", bind strongly to a reactive cis-peroxo dicopper(II) intermediate. Unprecedented structural insight has now been obtained from X-ray crystallographic characterization of the "bare" CuII2(µ-η1:η1-O2) motif and its Li+, Na+, and K+ complexes. UV-vis, Raman, and electrochemical studies show that the binding persists in MeCN solution, growing stronger in proportion to the cation's Lewis acidity. The affinity for Li+ is surprisingly high (∼70 × 104 M-1), leading to Li+ extraction from its crown ether complex. Computational analysis indicates that the alkali ions influence the entire Cu-OO-Cu core, modulating the degree of charge transfer from copper to dioxygen. This induces significant changes in the electronic, magnetic, and electrochemical signatures of the Cu2O2 species. These findings have far-reaching implications for analyses of transient metal/dioxygen intermediates, which are often studied in situ, and they may be relevant to many (bio)chemical oxidation processes when considering the widespread presence of alkali cations in synthetic and natural environments.

A Pseudotetrahedral Terminal Oxoiron(IV) Complex: Mechanistic Promiscuity in C-H Bond Oxidation Reactions.

S=2 oxoiron(IV) species act as reactive intermediates in the catalytic cycle of nonheme iron oxygenases. The few available synthetic S=2 FeIV =O complexes known to date are often limited to trigonal bipyramidal and very rarely to octahedral geometries. Herein we describe the generation and characterization of an S=2 pseudotetrahedral FeIV =O complex 2 supported by the sterically demanding 1,4,7-tri-tert-butyl-1,4,7-triazacyclononane ligand. Complex 2 is a very potent oxidant in hydrogen atom abstraction (HAA) reactions with large non-classical deuterium kinetic isotope effects, suggesting hydrogen tunneling contributions. For sterically encumbered substrates, direct HAA is impeded and an alternative oxidative asynchronous proton-coupled electron transfer mechanism prevails, which is unique within the nonheme oxoiron community. The high reactivity and the similar spectroscopic parameters make 2 one of the best electronic and functional models for a biological oxoiron(IV) intermediate of taurine dioxygenase (TauD-J).

A Unified Framework for Understanding Nucleophilicity and Protophilicity in the SN 2/E2 Competition.

The concepts of nucleophilicity and protophilicity are fundamental and ubiquitous in chemistry. A case in point is bimolecular nucleophilic substitution (SN 2) and base-induced elimination (E2). A Lewis base acting as a strong nucleophile is needed for SN 2 reactions, whereas a Lewis base acting as a strong protophile (i.e., base) is required for E2 reactions. A complicating factor is, however, the fact that a good nucleophile is often a strong protophile. Nevertheless, a sound, physical model that explains, in a transparent manner, when an electron-rich Lewis base acts as a protophile or a nucleophile, which is not just phenomenological, is currently lacking in the literature. To address this fundamental question, the potential energy surfaces of the SN 2 and E2 reactions of X- +C2 H5 Y model systems with X, Y = F, Cl, Br, I, and At, are explored by using relativistic density functional theory at ZORA-OLYP/TZ2P. These explorations have yielded a consistent overview of reactivity trends over a wide range in reactivity and pathways. Activation strain analyses of these reactions reveal the factors that determine the shape of the potential energy surfaces and hence govern the propensity of the Lewis base to act as a nucleophile or protophile. The concepts of "characteristic distortivity" and "transition state acidity" of a reaction are introduced, which have the potential to enable chemists to better understand and design reactions for synthesis.

Spin-resolved charge displacement analysis as an intuitive tool for the evaluation of cPCET and HAT scenarios.

We introduce here the spin-resolved version of the charge displacement function, which is applied to two competing pathways of proton-coupled electron transfer in oxidation catalysis (hydrogen-atom transfer, concerted proton-coupled electron transfer). The difference in charge displacement between the two mechanisms is directly observable and can be translated to electron flow using this new analysis tool.

Effect of Alkali Metal Cations on Length and Strength of Hydrogen Bonds in DNA Base Pairs.

For many years, non-covalently bonded complexes of nucleobases have attracted considerable interest. However, there is a lack of information about the nature of hydrogen bonding between nucleobases when the bonding is affected by metal coordination to one of the nucleobases, and how the individual hydrogen bonds and aromaticity of nucleobases respond to the presence of the metal cation. Here we report a DFT computational study of nucleobase pairs interacting with alkali metal cations. The metal cations contribute to the stabilization of the base pairs to varying degrees depending on their position. The energy decomposition analysis revealed that the nature of bonding between nucleobases does not change much upon metal coordination. The effect of the cations on individual hydrogen bonds were described by changes in VDD charges on frontier atoms, H-bond length, bond energy from NBO analysis, and the delocalization index from QTAIM calculations. The aromaticity changes were determined by a HOMA index.

Stoichiometric Formation of an Oxoiron(IV) Complex by a Soluble Methane Monooxygenase Type Activation of O2 at an Iron(II)-Cyclam Center.

In soluble methane monooxygenase enzymes (sMMO), dioxygen (O2) is activated at a diiron(II) center to form an oxodiiron(IV) intermediate Q that performs the challenging oxidation of methane to methanol. An analogous mechanism of O2 activation at mono- or dinuclear iron centers is rare in the synthetic chemistry. Herein, we report a mononuclear non-heme iron(II)-cyclam complex, 1-trans, that activates O2 to form the corresponding iron(IV)-oxo complex, 2-trans, via a mechanism reminiscent of the O2 activation process in sMMO. The conversion of 1-trans to 2-trans proceeds via the intermediate formation of an iron(III)-superoxide species 3, which could be trapped and spectroscopically characterized at -50 °C. Surprisingly, 3 is a stronger oxygen atom transfer (OAT) agent than 2-trans; 3 performs OAT to 1-trans or PPh3 to yield 2-trans quantitatively. Furthermore, 2-trans oxidizes the aromatic C-H bonds of 2,6-di-tert-butylphenol, which, together with the strong OAT ability of 3, represents new domains of oxoiron(IV) and superoxoiron(III) reactivities.

Sc3+-Promoted O-O Bond Cleavage of a (µ-1,2-Peroxo)diiron(III) Species Formed from an Iron(II) Precursor and O2 to Generate a Complex with an FeIV2(µ-O)2 Core.

Soluble methane monooxygenase (sMMO) carries out methane oxidation at 4 °C and under ambient pressure in a catalytic cycle involving the formation of a peroxodiiron(III) intermediate (P) from the oxygenation of the diiron(II) enzyme and its subsequent conversion to Q, the diiron(IV) oxidant that hydroxylates methane. Synthetic diiron(IV) complexes that can serve as models for Q are rare and have not been generated by a reaction sequence analogous to that of sMMO. In this work, we show that [FeII(Me3NTB)(CH3CN)](CF3SO3)2 (Me3NTB = tris((1-methyl-1H-benzo[d]imidazol-2-yl)methyl)amine) (1) reacts with O2 in the presence of base, generating a (µ-1,2-peroxo)diiron(III) adduct with a low O-O stretching frequency of 825 cm-1 and a short Fe···Fe distance of 3.07 Å. Even more interesting is the observation that the peroxodiiron(III) complex undergoes O-O bond cleavage upon treatment with the Lewis acid Sc3+ and transforms into a bis(µ-oxo)diiron(IV) complex, thus providing a synthetic precedent for the analogous conversion of P to Q in the catalytic cycle of sMMO.

Computational NMR Spectra of o-Benzyne and Stable Guests and Their Hemicarceplexes.

The incarceration of o-benzyne and 27 other guest molecules within hemicarcerand 1, as reported experimentally by Warmuth, and Cram and co-workers, has been studied by density functional theory (DFT). The 1 H NMR chemical shifts, rotational mobility, and conformational preference of the guests within the supramolecular cage were determined, which showed intriguing correlations of the chemical shifts with structural parameters of the host-guest system. Furthermore, based on the computed chemical shifts reassignments of some NMR signals are proposed. This affects, in particular, the putative characterization of the volatile benzyne molecule inside a hemicarcerand, for which our CCSD(T) and KT2 results indicate that the experimentally observed signals are most likely not resulting from an isolated o-benzyne within the supramolecular host. Instead, it is shown that the guest reacted with an aromatic ring of the host, and this adduct is responsible for the experimentally observed signals.

Lewis versus Brønsted Acid Activation of a Mn(IV) Catalyst for Alkene Oxidation.

Lewis acid (LA) activation by coordination to metal oxido species has emerged as a new strategy in catalytic oxidations. Despite the many reports of enhancement of performance in oxidation catalysis, direct evidence for LA-catalyst interactions under catalytically relevant conditions is lacking. Here, we show, using the oxidation of alkenes with H2O2 and the catalyst [Mn2(µ-O)3(tmtacn)2](PF6)2 (1), that Lewis acids commonly used to enhance catalytic activity, e.g., Sc(OTf)3, in fact undergo hydrolysis with adventitious water to release a strong Brønsted acid. The formation of Brønsted acids in situ is demonstrated using a combination of resonance Raman, UV/vis absorption spectroscopy, cyclic voltammetry, isotope labeling, and DFT calculations. The involvement of Brønsted acids in LA enhanced systems shown here holds implications for the conclusions reached in regard to the relevance of direct LA-metal oxido interactions under catalytic conditions.

Directed Hydroxylation of sp2 and sp3 C-H Bonds Using Stoichiometric Amounts of Cu and H2O2.

The use of copper for C-H bond functionalization, compared to other metals, is relatively unexplored. Herein, we report a synthetic protocol for the regioselective hydroxylation of sp2 and sp3 C-H bonds using a directing group, stoichiometric amounts of Cu and H2O2. A wide array of aromatic ketones and aldehydes are oxidized in the carbonyl γ-position with remarkable yields. We also expanded this methodology to hydroxylate the ß-position of alkylic ketones. Spectroscopic characterization, kinetics, and density functional theory calculations point toward the involvement of a mononuclear LCuII(OOH) species, which oxidizes the aromatic sp2 C-H bonds via a concerted heterolytic O-O bond cleavage with concomitant electrophilic attack on the arene system.

Four-component relativistic 31P NMR calculations for trans-platinum(ii) complexes: importance of the solvent and dynamics in spectral simulations.

We report a combined experimental-theoretical study on the 31P NMR chemical shift for a number of trans-platinum(ii) complexes. Validity and reliability of the 31P NMR chemical shift calculations are examined by comparing with the experimental data. A successful computational protocol for the accurate prediction of the 31P NMR chemical shifts was established for trans-[PtCl2(dma)PPh3] (dma = dimethylamine) complexes. The reliability of the computed values is shown to be critically dependent on the level of relativistic effects (two-component vs. four component), choice of density functionals, dynamical averaging, and solvation effects. Snapshots obtained from ab initio molecular dynamics simulations were used to identify those solvent molecules which show the largest interactions with the platinum complex, through inspection by using the non-covalent interaction program. We observe satisfactory accuracy from the full four-component matrix Dirac-Kohn-Sham method (mDKS) based on the Dirac-Coulomb Hamiltonian, in conjunction with the KT2 density functional, and dynamical averaging with explicit solvent molecules.