Solvent-Induced Red-Shifts for the Proton Stretch Vibrational Frequency in a Hydrogen-Bonded Complex. 1. A Valence Bond-Based Theoretical Approach

A theory is presented for the proton stretch vibrational frequency ν_AH for hydrogen (H−) bonded complexes of the acid dissociation type, that is, AH···B ⇔ A^–···HB⁺(but without complete proton transfer), in both polar and nonpolar solvents, with special attention given to the variation of ν_AH with the solvent’s dielectric constant ε. The theory involves a valence bond (VB) model for the complex’s electronic structure, quantization of the complex’s proton and H-bond motions, and a solvent coordinate accounting for nonequilibrium solvation. A general prediction is that ν_AH decreases with increasing ε largely due to increased solvent stabilization of the ionic VB structure A^–···HB⁺ relative to the neutral VB structure AH···B. Theoretical ν_AH versus 1/ε slope expressions are derived; these differ for polar and nonpolar solvents and allow analysis of the solvent dependence of ν_AH. The theory predicts that both polar and nonpolar slopes are determined by (i) a structure factor reflecting the complex’s size/geometry, (ii) the complex’s dipole moment in the ground vibrational state, and (iii) the dipole moment change in the transition, which especially reflects charge transfer and the solution phase proton potential shapes. The experimental proton frequency solvent dependence for several OH···O H-bonded complexes is successfully accounted for and analyzed with the theory

Dynamical Disorder in the DNA Hydration Shell

The reorientation and hydrogen-bond dynamics of water molecules within the hydration shell of a B-DNA dodecamer, which are of interest for many of its biochemical functions, are investigated via molecular dynamics simulations and an analytic jump model, which provide valuable new molecular level insights into these dynamics. Different sources of heterogeneity in the hydration shell dynamics are determined. First, a pronounced spatial heterogeneity is found at the DNA interface and explained via the jump model by the diversity in local DNA interfacial topographies and DNA–water H-bond interactions. While most of the hydration shell is moderately retarded with respect to the bulk, some water molecules confined in the narrow minor groove exhibit very slow dynamics. An additional source of heterogeneity is found to be caused by the DNA conformational fluctuations, which modulate the water dynamics. The groove widening aids the approach of, and the jump to, a new water H-bond partner. This temporal heterogeneity is especially strong in the minor groove, where groove width fluctuations occur on the same time scale as the water H-bond rearrangements, leading to a strong dynamical disorder. The usual simplifying assumption that hydration shell dynamics is much faster than DNA dynamics is thus not valid; our results show that biomolecular conformational fluctuations are essential to facilitate the water motions and accelerate the hydration dynamics in confined groove sites

Predicting Hydride Donor Strength via Quantum Chemical Calculations of Hydride Transfer Activation Free Energy

We propose a method to approximate the kinetic properties of hydride donor species by relating the nucleophilicity (<i>N</i>) of a hydride to the activation free energy <i>Δ<i>G</i></i>^⧧ of its corresponding hydride transfer reaction. <i>N</i> is a kinetic parameter related to the hydride transfer rate constant that quantifies a nucleophilic hydridic species’ tendency to donate. Our method estimates <i>N</i> using quantum chemical calculations to compute <i>Δ<i>G</i></i>^⧧ for hydride transfers from hydride donors to CO₂ in solution. A linear correlation for each class of hydrides is then established between experimentally determined <i>N</i> values and the computationally predicted <i>Δ<i>G</i></i>^⧧; this relationship can then be used to predict nucleophilicity for different hydride donors within each class. This approach is employed to determine <i>N</i> for four different classes of hydride donors: two organic (carbon-based and benzimidazole-based) and two inorganic (boron and silicon) hydride classes. We argue that silicon and boron hydrides are driven by the formation of the more stable Si–O or B–O bond. In contrast, the carbon-based hydrides considered herein are driven by the stability acquired upon rearomatization, a feature making these species of particular interest, because they both exhibit catalytic behavior and can be recycled

Dihydropteridine/Pteridine as a 2H⁺/2e^– Redox Mediator for the Reduction of CO₂ to Methanol: A Computational Study

Conflicting experimental results for the electrocatalytic reduction of CO₂ to CH₃OH on a glassy carbon electrode by the 6,7-dimethyl-4-hydroxy-2-mercaptopteridine have been recently reported [J. Am. Chem. Soc. 2014, 136, 14007−14010, J. Am. Chem. Soc. 2016, 138, 1017–1021]. In this connection, we have used computational chemistry to examine the issue of this molecule’s ability to act as a hydride donor to reduce CO₂. We first determined that the most thermodynamically stable tautomer of this aqueous compound is its oxothione form, termed here PTE. It is argued that this species electrochemically undergoes concerted 2H⁺/2e^– transfers to first form the kinetic product 5,8-dihydropteridine, followed by acid-catalyzed tautomerization to the thermodynamically more stable 7,8-dihydropteridine PTEH₂. While the overall conversion of CO₂ to CH₃OH by three successive hydride and proton transfers from this most stable tautomer is computed to be exergonic by 5.1 kcal/mol, we predict high activation free energies (Δ<i>G</i>^‡_HT) of 29.0 and 29.7 kcal/mol for the homogeneous reductions of CO₂ and its intermediary formic acid product by PTE/PTEH₂, respectively. These high barriers imply that PTE/PTEH₂ is unable, by this mechanism, to homogeneously reduce CO₂ on a time scale of hours at room temperature

Roles of the Lewis Acid and Base in the Chemical Reduction of CO₂ Catalyzed by Frustrated Lewis Pairs

We employ quantum chemical calculations to discover how frustrated Lewis pairs (FLP) catalyze the reduction of CO₂ by ammonia borane (AB); specifically, we examine how the Lewis acid (LA) and Lewis base (LB) of an FLP activate CO₂ for reduction. We find that the LA (trichloroaluminum, AlCl₃) alone catalyzes hydride transfer (HT) to CO₂ while the LB (trimesitylenephosphine, PMes₃) actually hinders HT; inclusion of the LB increases the HT barrier by ∼8 kcal/mol relative to the reaction catalyzed by LAs only. The LB hinders HT by donating its lone pair to the LUMO of CO₂, increasing the electron density on the C atom and thus lowering its hydride affinity. Although the LB hinders HT, it nonetheless plays a crucial role by stabilizing the active FLP·CO₂ complex relative to the LA dimer, free CO₂, and free LB. This greatly increases the concentration of the reactive complex in the form FLP·CO₂ and thus increases the rate of reaction. We expect that the principles we describe will aid in understanding other catalytic CO₂ reductions

Reduction of CO₂ to Methanol Catalyzed by a Biomimetic Organo-Hydride Produced from Pyridine

We use quantum chemical calculations to elucidate a viable mechanism for pyridine-catalyzed reduction of CO₂ to methanol involving homogeneous catalytic steps. The first phase of the catalytic cycle involves generation of the key catalytic agent, 1,2-dihydropyridine (<b>PyH</b>_<b>2</b>). First, pyridine (Py) undergoes a H⁺ transfer (PT) to form pyridinium (PyH⁺), followed by an e^– transfer (ET) to produce pyridinium radical (PyH⁰). Examples of systems to effect this ET to populate PyH⁺’s LUMO (<i>E</i>⁰_calc ∼ −1.3 V vs SCE) to form the solution phase PyH⁰ via highly reducing electrons include the photoelectrochemical p-GaP system (<i>E</i>_CBM ∼ −1.5 V vs SCE at pH 5) and the photochemical [Ru­(phen)₃]²⁺/ascorbate system. We predict that PyH⁰ undergoes further PT–ET steps to form the key closed-shell, dearomatized (<b>PyH</b>_<b>2</b>) species (with the PT capable of being assisted by a negatively biased cathode). Our proposed sequential PT–ET–PT–ET mechanism for transforming Py into <b>PyH</b>_<b>2</b> is analogous to that described in the formation of related dihydropyridines. Because it is driven by its proclivity to regain aromaticity, <b>PyH</b>_<b>2</b> is a potent recyclable organo-hydride donor that mimics important aspects of the role of NADPH in the formation of C–H bonds in the photosynthetic CO₂ reduction process. In particular, in the second phase of the catalytic cycle, which involves three separate reduction steps, we predict that the <b>PyH</b>_<b>2</b>/Py redox couple is kinetically and thermodynamically competent in catalytically effecting hydride and proton transfers (the latter often mediated by a proton relay chain) to CO₂ and its two succeeding intermediates, namely, formic acid and formaldehyde, to ultimately form CH₃OH. The hydride and proton transfers for the first of these reduction steps, the homogeneous reduction of CO₂, are sequential in nature (in which the formate to formic acid protonation can be assisted by a negatively biased cathode). In contrast, these transfers are coupled in each of the two subsequent homogeneous hydride and proton transfer steps to reduce formic acid and formaldehyde

Multistep Drug Intercalation: Molecular Dynamics and Free Energy Studies of the Binding of Daunomycin to DNA

Atomic-scale molecular dynamics and free energy calculations in explicit aqueous solvent are used to study the complex mechanism by which a molecule can intercalate between successive base pairs of the DNA double helix. We have analyzed the intercalation pathway for the anticancer drug daunomycin using two different methods: metadynamics and umbrella sampling. The resulting free energy pathways are found to be consistent with one another and point, within an equilibrium free energy context, to a three-step process. Daunomycin initially binds in the minor groove of DNA. An activated step then leads to rotation of the drug, coupled with DNA deformation that opens a wedge between the base pairs, bends DNA toward the major groove, and forms a metastable intermediate that resembles structures seen within the interfaces between DNA and minor-groove-binding proteins. Finally, crossing a small free energy barrier leads to further rotation of daunomycin and full intercalation of the drug, reestablishing stacking with the flanking base pairs and straightening the double helix

Reaction Mechanism for Direct Proton Transfer from Carbonic Acid to a Strong Base in Aqueous Solution I: Acid and Base Coordinate and Charge Dynamics

Protonation by carbonic acid H₂CO₃ of the strong base methylamine CH₃NH₂ in a neutral contact pair in aqueous solution is followed via Car–Parrinello molecular dynamics simulations. Proton transfer (PT) occurs to form an aqueous solvent-stabilized contact ion pair within 100 fs, a fast time scale associated with the compression of the acid–base hydrogen-bond (H-bond), a key reaction coordinate. This rapid barrierless PT is consistent with the carbonic acid-protonated base p<i>K</i>_a difference that considerably favors the PT, and supports the view of intact carbonic acid as potentially important proton donor in assorted biological and environmental contexts. The charge redistribution within the H-bonded complex during PT supports a Mulliken picture of charge transfer from the nitrogen base to carbonic acid without altering the transferring hydrogen’s charge from approximately midway between that of a hydrogen atom and that of a proton

Reaction Mechanism for Direct Proton Transfer from Carbonic Acid to a Strong Base in Aqueous Solution II: Solvent Coordinate-Dependent Reaction Path

The protonation of methylamine base CH₃NH₂ by carbonic acid H₂CO₃ within a hydrogen (H)-bonded complex in aqueous solution was studied via Car–Parrinello dynamics in the preceding paper (Daschakraborty, S.; Kiefer, P. M.; Miller, Y.; Motro, Y.; Pines, D.; Pines, E.; Hynes, J. T. <i>J. Phys. Chem. B</i> <b>2016</b>, DOI: 10.1021/acs.jpcb.5b12742). Here some important further details of the reaction path are presented, with specific emphasis on the water solvent’s role. The overall reaction is barrierless and very rapid, on an ∼100 fs time scale, with the proton transfer (PT) event itself being very sudden (<10 fs). This transfer is preceded by the acid–base H-bond’s compression, while the water solvent changes little until the actual PT occurrence; this results from the very strong driving force for the reaction, as indicated by the very favorable acid-protonated base Δp<i>K</i>_a difference. Further solvent rearrangement follows immediately the sudden PT’s production of an incipient contact ion pair, stabilizing it by establishment of equilibrium solvation. The solvent water’s short time scale ∼120 fs response to the incipient ion pair formation is primarily associated with librational modes and H-bond compression of water molecules around the carboxylate anion and the protonated base. This is consistent with this stabilization involving significant increase in H-bonding of hydration shell waters to the negatively charged carboxylate group oxygens’ (especially the former H₂CO₃ donor oxygen) and the nitrogen of the positively charged protonated base’s NH₃⁺

Benzimidazoles as Metal-Free and Recyclable Hydrides for CO2 Reduction to Formate

We report a novel metal-free chemical reduction of CO2 by a recyclable benzimidazole-based organo-hydride, whose choice was guided by quantum chemical calculations. Notably, benzimidazole-based hydride donors rival the hydride-donating abilities of noble metal-based hydrides such as [Ru(tpy)(bpy)H]+ and [Pt(depe)2H]+. Chemical CO2 reduction to the formate anion (HCOO) was carried out in the absence of biological enzymes, a sacrificial Lewis acid, or a base to activate the substrate or reductant. 13CO2 experiments confirmed the formation of H13COO by CO2 reduction with the formate product characterized by 1H-NMR and 13C-NMR spectroscopies, and ESI-MS. The highest formate yield of 66% was obtained in the presence of potassium tetrafluoroborate under mild conditions. The likely role of exogenous salt additives in this reaction is to stabilize and shift the equilibrium towards the ionic products. After CO2 reduction, the benzimidazole-based hydride donor was quantitatively oxidized to its aromatic benzimidazolium cation, establishing its recyclability. In addition, we electrochemically reduced the benzimidazolium cation to its organo-hydride form in quantitative yield, demonstrating its potential for electrocatalytic CO2 reduction. These results serve as a proof of concept for the electrocatalytic reduction of CO2 by sustainable, recyclable and metal-free organo-hydrides