Interplay of Tunneling, Two-State Reactivity, and Bell–Evans–Polanyi Effects in C–H Activation by Nonheme Fe(IV)O Oxidants

The study of C–H bond activation reactions by nonheme Fe^IVO species with nine hydrocarbons shows that the kinetic isotope effect (KIE) involves strong tunneling and is a signature of the reactive spin states. Theory reproduces the observed spike-like appearance of plots of KIE_exp against the C−H bond dissociation energy, and its origins are discussed. The experimentally observed Bell–Evans–Polanyi correlations, in the presence of strong tunneling, are reproduced, and the pattern is rationalized

Kinetic Isotope Effect Determination Probes the Spin of the Transition State, Its Stereochemistry, and Its Ligand Sphere in Hydrogen Abstraction Reactions of Oxoiron(IV) Complexes

ConspectusThis Account outlines interplay of theory and experiment in the quest to identify the reactive-spin-state in chemical reactions that possess a few spin-dependent routes. Metalloenzymes and synthetic models have forged in recent decades an area of increasing appeal, in which oxometal species bring about functionalization of hydrocarbons under mild conditions and via intriguing mechanisms that provide a glimpse of Nature’s designs to harness these reactions. Prominent among these are oxoiron­(IV) complexes, which are potent H-abstractors. One of the key properties of oxoirons is the presence of close-lying spin-states, which can mediate H-abstractions. As such, these complexes form a fascinating chapter of spin-state chemistry, in which chemical reactivity involves spin-state interchange, so-called two-state reactivity (TSR) and multistate reactivity (MSR).TSR and MSR pose mechanistic challenges. How can one determine the structure of the reactive transition state (TS) and its spin state for these mechanisms? Calculations can do it for us, but the challenge is to find experimental probes. There are, however, no clear kinetic signatures for the reactive-spin-state in such reactions. This is the paucity that our group has been trying to fill for sometime. Hence, it is timely to demonstrate how theory joins experiment in realizing this quest.This Account uses a set of the H-abstraction reactions of 24 synthetic oxoiron­(IV) complexes and 11 hydrocarbons, together undergoing H-abstraction reactions with TSR/MSR options, which provide experimentally determined kinetic isotope effect (KIE_exp) data. For this set, we demonstrate that comparing KIE_exp results with calculated tunneling-augmented KIE (KIE_TC) data leads to a clear identification of the reactive spin-state during H-abstraction reactions. In addition, generating KIE_exp data for a reaction of interest, and comparing these to KIE_TC values, provides the mechanistic chemist with a powerful capability to identify the reactive-TS in terms of not only its spin state but also its geometry and ligand-sphere constitution.Since tunneling “cuts through” barriers, it serves as a chemical selectivity factor. Thus, we show that in a family of oxoirons reacting with one hydrocarbon, the tunneling efficiency increases as the ligands become better electron donors. This generates counterintuitive-reactivity patterns, like antielectrophilic reactivity, and induces spin-state reactivity reversals because of differing steric demands of the corresponding ^2<i>S+</i>1TS species, etc. Finally, for the same series, the Account reaches intuitive understanding of tunneling trends. It is shown that the increase of ligand’s donicity results in electrostatic narrowing of the barrier, while the decrease of donicity and increase of bond-order asymmetry in the TS (inter alia due to Bell–Evans–Polanyi effects) broadens the barrier. Predictions are made that usage of powerful electron-donating ligands may train H-abstractors to activate the strongest C–H bond in a molecule. The concepts developed here are likely to be applicable to other oxometals in the d- and f-blocks

Nucleophilic Degradation of Fenitrothion Insecticide and Performance of Nucleophiles: A Computational Study

Ab initio and density functional theory (DFT) calculations have been performed to understand the destruction chemistry of an important organophosphorus insecticide <i>O</i>,<i>O</i>-dimethyl <i>O</i>-(3-methyl-4-nitrophenyl) phosphorothioate, fenitrothion (<b>FN</b>), toward nucleophilic attack. Breaking of the P–OAr linkages through nucleophilic attack is considered to be the major degradation pathway for <b>FN</b>. One simple nucleophile, hydroxide (OH^–), and two different α-nucleophiles, hydroperoxide (OOH^–) and hydroxylamine anion (NH₂O^–), have been considered for this study. Nucleophilic attack at the two different centers, S_N2@P and S_N2@C, has been monitored, and the computed reaction energetics confirms that the S_N2@P reactions are favorable over the S_N2@C reactions for all the nucleophiles. All electronic structure calculations for the reaction are performed at DFT-B3LYP/6-31+G­(d) level of theory followed by a refinement of energy at ab initio MP2/6-311++G­(2d,2p) level. The effect of aqueous polarization on both the S_N2 reactions is taken into account employing the conductor-like screening model (COSMO) as well as polarization continuum model (PCM) at B3LYP/6-31+G­(d) level of theory. Relative performance of the two α-nucleophiles, OOH^– and NH₂O^–, at the P center has further been clarified using natural bond orbital (NBO), conceptual DFT, and atoms in molecules (AIM) approaches. The strength of the intermolecular hydrogen bonding in the transition states and topological properties of the electron density distribution for −X–H···S (X = O, N) intermolecular hydrogen bonds are the subject of NBO and AIM analysis, respectively. Our calculated reaction energetics and electronic properties suggest that the relative order of nucleophilicity for the nucleophiles is OOH^– > NH₂O^– > OH^– for the S_N2@P, whereas for the S_N2@C the order, which gets little altered, is NH₂O^– > OOH^– > OH^–

Aminolysis of a Model Nerve Agent: A Computational Reaction Mechanism Study of <i>O</i>,<i>S</i>‑Dimethyl Methylphosphonothiolate

The mechanism for the aminolysis of a model nerve agent, <i>O</i>,<i>S</i>-dimethyl methylphosphonothiolate, is investigated both at density functional level using M062X method with 6-311++G­(d,p) basis set and at ab initio level using the second-order Møller–Plesset perturbation theory (MP2) with the 6-311+G­(d,p) basis set. The catalytic role of an additional NH₃ and H₂O molecule is also examined. The solvent effects of acetonitrile, ethanol, and water are taken into account employing the conductor-like screening model (COSMO) at the single-point M062X/6-311++G­(d,p) level of theory. Two possible dissociation pathways, methanethiol and methyl alcohol dissociations, along with two different neutral mechanisms, a concerted one and a stepwise route through two neutral intermediates, for each pathway are investigated. Hyperconjugation stabilization that has an effect on the stability of generated transition states are investigated by natural bond order (NBO) approach. Additionally, quantum theory of atoms in molecules analysis is performed to evaluate the bond critical (BCP) properties and to quantify strength of different types of interactions. The calculated results predict that the reaction of <i>O</i>,<i>S</i>-dimethyl methylphosphonothiolate with NH₃ gives rise to parallel P–S and P–O bond cleavages, and in each cleavage the neutral stepwise route is always favorable than the concerted one. The mechanism of NH₃ and H₂O as catalyst is nearly similar, and they facilitate the shuttle of proton to accelerate the reaction. The steps involving the H₂O-mediated proton transfer are the most suitable ones. The first steps for the stepwise process, the formation of neutral intermediate, are the rate-determining step. It is observed that in the presence of catalyst the reaction in the stepwise path possesses almost half the activation energy of the uncatalyzed one. A bond-order analysis using Wiberg bond indexes obtained by NBO calculation predicts that usually all individual steps of the reactions occur in a concerted fashion showing equal progress along different reaction coordinates

Catalysis of Methyl Transfer Reactions by Oriented External Electric Fields: Are Gold–Thiolate Linkers Innocent?

Oriented external electric fields (OEEFs) are potent effectors of chemical change and control. We show that the Menshutkin reaction, between substituted pyridines and methyl iodide, can be catalyzed/inhibited at will, by just flipping the orientation of the EEF (<i>F</i>_<i>Z</i>) along the “reaction axis” (<i>Z</i>), N---C---I. A theoretical analysis shows that catalysis/inhibition obey the Bell–Evans–Polanyi principle. Significant catalysis is predicted also for EEFs oriented off the reaction axis. Hence, the observation of catalysis can be scaled up and may not require orienting the reactants vis-à-vis the field. It is further predicted that EEFs can also catalyze the front-side nucleophilic displacement reaction, thus violating the Walden-inversion paradigm. Finally, we considered the impact of gold–thiolate linkers, used experimentally to deliver the EEF stimuli, on the Menshutkin reaction. A few linkers were tested and proved not to be innocent. In the presence of <i>F</i>_<i>Z</i>, the linkers participate in the electronic reorganization of the molecular system. In so doing, these linkers induce local electric fields, which map the effects of the EEF and induce catalysis/inhibition at will, as in the pristine reaction. However, as the EEF becomes more negative than −0.1 V/Å, an excited charge transfer state (CTS), which involves one-electron transfer from the 5p lone pair of iodine to an antibonding orbital of the gold cluster, crosses below the closed-shell state of the Menshutkin reaction and causes a mechanistic crossover. This CTS catalyzes nucleophilic displacement of iodine radical from the CH₃I^•+ radical cation. The above predictions and others discussed in the text are testable

Kinetics and Mechanism of the Tropospheric Oxidation of Vinyl Acetate Initiated by OH Radical: A Theoretical Study

Vinyl acetate [VA (CH₃COOC₂H₃)] is an important unsaturated and oxygenated volatile organic compound responsible for atmospheric pollution. In this work, possible reaction mechanisms for the degradation of OH-initiated atmospheric oxidation of VA are investigated. The potential energy surfaces (PESs) for the reaction of OH radical with VA in the presence of O₂ and NO have been studied using the M06-2X/6-311++G­(d,p) method. The initial addition reactions of more and less substituted ethylenic C-atoms of VA are treated separately, followed by a conventional transition state theory (TST) calculation for reaction rates. The direct H-abstraction mechanism and kinetics have also been studied. The initial OH addition occurs through a prereactive complex, and the calculated rate constants in the temperature range 250–350 K for both the addition reactions are found to have negative temperature dependence. The calculation indicates that the reaction proceeds predominantly via the addition of OH radical to the double bond rather than the direct abstraction of H-atoms in VA. IM1 [CH₃C­(O)­O^•CHCH₂OH] and IM2 [CH₃C­(O)­OCH­(OH)^•CH₂], the OH adduct complexes formed initially, react with ubiquitous O₂ followed by NO before their rearrangement. The formation of the prereactive complex plays an important role in reaction mechanism and kinetics. The calculated rate constant, <i>k</i>_298K = 1.61 × 10^–11 cm³ molecule^–1 s^–1, is well harmonized with the previous experimental data, <i>k</i>_298K = (2.48 ± 0.61) × 10^–11 cm³ molecule^–1 s^–1 (Blanco et al.) and <i>k</i>_298K = (2.3 ± 0.3) × 10^–11 cm³ molecule^–1 s^–1 (Picquet-Varrult et al.). Additionally, consistent and reliable enthalpies of formation at 298.15 K (Δ_f<i>H</i>°_298.15) have been computed for all the species involved in the title reaction using the composite CBS–QB3 method. The theoretical results confirm that the major products are formic acetic anhydride, acetic acid, and formaldehyde in the OH-initiated oxidation of VA in the presence of O₂ and NO, which are in excellent agreement with the experimental findings

Highly Sensitive and Selective Rhodamine-Based “Off–On” Reversible Chemosensor for Tin (Sn⁴⁺) and Imaging in Living Cells

A structurally characterized new oxo-chromene functionalized rhodamine derivative <b>L1</b> exhibits high selectivity toward Sn⁴⁺ by forming a 1:1 complex, among other biologically important metal ions, as studied by fluorescence, absorption, and HRMS spectroscopy. Complexing with Sn⁴⁺ triggers the formation of a highly fluorescent ring-open form which is pink in color. The sensor shows extremely high fluorescence enhancement upon complexation with Sn⁴⁺, and it can be used as a “naked-eye” sensor. DFT computational studies carried out in mimicking the formation of a 1:1 complex between <b>L1</b> and Sn⁴⁺ resulted in a nearly planar pentacoordinate Sn­(IV) complex. Studies reveal that the <i>in situ</i> prepared <b>L1</b>–Sn complex is selectively and fully reversible in presence of sulfide anions. Further, confocal microscopic studies confirmed that the receptor shows <i>in vitro</i> detection of Sn⁴⁺ ions in RAW cells

Emergence of Function in P450-Proteins: A Combined Quantum Mechanical/Molecular Mechanical and Molecular Dynamics Study of the Reactive Species in the H₂O₂‑Dependent Cytochrome P450_SPα and Its Regio- and Enantioselective Hydroxylation of Fatty Acids

This work uses combined quantum mechanical/molecular mechanical and molecular dynamics simulations to investigate the mechanism and selectivity of H₂O₂-dependent hydroxylation of fatty acids by the P450_SPα class of enzymes. H₂O₂ is found to serve as the surrogate oxidant for generating the principal oxidant, Compound I (Cpd I), in a mechanism that involves homolytic O–O bond cleavage followed by H-abstraction from the Fe–OH moiety. Our results rule out a substrate-assisted heterolytic cleavage of H₂O₂ en route to Cpd I. We show, however, that substrate binding stabilizes the resultant Fe–H₂O₂ complex, which is crucial for the formation of Cpd I in the homolytic pathway. <i>A network of hydrogen bonds locks the HO· radical</i>, formed by the O–O homolysis, thus directing it to exclusively abstract the hydrogen atom from Fe–OH, thereby forming Cpd I, while preventing the autoxoidative reaction, with the porphyrin ligand, and the substrate oxidation. The so formed Cpd I subsequently hydroxylates fatty acids at their α-position with <i>S</i>-enantioselectivity. These selectivity patterns are controlled by the active site: substrate’s binding by Arg241 determines the α-regioselectivity, while the Pro242 residue locks the prochiral α-CH₂, thereby leading to hydroxylation of the <i>pro</i>-<i>S</i> C–H bond. Our study of the mutant Pro242Ala sheds light on potential modifications of the enzyme’s active site in order to modify reaction selectivity. Comparisons of P450_SPα to P450_BM3 and to P450_BSβ reveal that <i>function</i> has evolved <i>in these related metalloenzymes by strategically placing very few residues in the active site</i>

Installation of efficient quenching groups of a fluorescent probe for the specific detection of cysteine and homocysteine over glutathione in solution and imaging of living cells

<p>Herein, we report the synthesis and characterisation of a new fluorescent probe 4-(7-nitro-benzo[1,2,5]oxadiazol-4-yl)-benzaldehyde (<b>NBOB</b>) installed with quenching groups for highly selective and sensitive sensing of biothiols. The probe itself is non-fluorescent due to the presence of quenching groups and photoinduced electron transfer (PET) process. Thus, sensitivity of the probe towards thiols was significantly improved by quenching effects. <b>NBOB</b> has been shown to exhibit selective reactivity towards cysteine (Cys) and homocysteine (Hcy) over glutathione (GSH) under stoichiometric conditions. The response mechanism was proved by ¹H NMR, LCMS and theoretical calculation. The probe <b>NBOB</b> has been shown to react with Cys present in Vero cells by fluorescence microscopy.</p

Privileged Role of Thiolate as the Axial Ligand in Hydrogen Atom Transfer Reactions by Oxoiron(IV) Complexes in Shaping the Potential Energy Surface and Inducing Significant H‑Atom Tunneling

An H/D kinetic isotope effect (KIE) of 80 is found at −20 °C for the oxidation of 9,10-dihydro­anthracene by [Fe^IV(O)­(TMCS)]⁺, a complex supported by the tetramethylcyclam (TMC) macrocycle with a tethered thiolate. This KIE value approaches that previously predicted by DFT calculations. Other [Fe^IV(O)­(TMC)­(anion)] complexes exhibit values of 20, suggesting that the thiolate ligand of [Fe^IV(O)­(TMCS)]⁺ plays a unique role in facilitating tunneling. Calculations show that tunneling is most enhanced (a) when the bond asymmetry between C–H bond breaking and O–H bond formation in the transition state is minimized, and (b) when the electrostatic interactions in the O---H---C moiety are maximal. These two factorswhich peak for the best electron donor, the thiolate ligandafford a slim and narrow barrier through which the H-atom can tunnel most effectively