Unraveling the Catalytic Mechanism of ß-Cyclodextrin in the Vitamin D Formation.

Previous experimental studies have shown that the isomerization reaction of previtamin D3 (PreD3) to vitamin D3 (VitD3) is accelerated 40-fold when it takes place within a ß-cyclodextrin dimer, in comparison to the reaction occurring in conventional isotropic solutions. In this study, we employ quantum mechanics-based molecular dynamics (MD) simulations and statistical multistructural variational transition state theory to unveil the origin of this acceleration. We find that the conformational landscape in the PreD3 isomerization is highly dependent on whether the system is encapsulated. In isotropic media, the triene moiety of the PreD3 exhibits a rich torsional flexibility. However, when encapsulated, such a flexibility is limited to a more confined conformational space. In both scenarios, our calculated rate constants are in close agreement with experimental results and allow us to identify the PreD3 flexibility restriction as the primary catalytic factor. These findings enhance our understanding of VitD3 isomerization and underscore the significance of MD and environmental factors in biochemical modeling.

Combined DFT and Kinetic Monte Carlo Study of UiO-66 Catalysts for γ-Valerolactone Production.

Zr-based metal-organic frameworks (MOFs) are excellent heterogeneous porous catalysts due to their thermal stability. Their tunability via node and linker modifications makes them amenable for theoretical studies on catalyst design. However, detailed benchmarks on MOF-based reaction mechanisms combined with kinetics analysis are still scarce. Thus, we here evaluate different computational models and density functional theory (DFT) methods followed by kinetic Monte Carlo studies for a case reaction relevant in biomass upgrading, i.e., the conversion of methyl levulinate to γ-valerolactone catalyzed by UiO-66. We show the impact of cluster versus periodic models, the importance of the DF of choice, and the direct comparison to experimental data via simulated kinetics data. Overall, we found that Perdew-Burke-Ernzerhof (PBE), a widely employed method in plane-wave periodic calculations, greatly overestimates reaction rates, while M06 with cluster models better fits the available experimental data and is recommended whenever possible.

Correction: An integrated protocol to study hydrogen abstraction reactions by atomic hydrogen in flexible molecules: application to butanol isomers.

Correction for 'An integrated protocol to study hydrogen abstraction reactions by atomic hydrogen in flexible molecules: application to butanol isomers' by David Ferro-Costas et al., Phys. Chem. Chem. Phys., 2022, DOI: 10.1039/d1cp03928h.

An integrated protocol to study hydrogen abstraction reactions by atomic hydrogen in flexible molecules: application to butanol isomers.

This work presents a protocol designed to study hydrogen abstraction reactions by atomic hydrogen in molecules with multiple conformations. The protocol starts with the search and location of the conformers of the equilibrium structures using the TorsiFlex program. By a simple modification of the starting geometry of reactants, a Python script generates the input for the hydrogen abstraction transition states. Initially, the search of the stationary points (reactants and transition states) is carried out at a low-level employing firstly a preconditioned search and secondly a random search. The low-level conformers were reoptimized using a higher level electronic structure method. This information allows the evaluation of the multistructural harmonic-oscillator partition functions, which are corrected for zero-point energy anharmonicity by the hybrid degeneracy-corrected second-order vibrational perturbation theory and for torsional anharmonicity by the multistructural torsional method, as implemented in the MsTor program. The structural information of the stationary points is used by Pilgrim to evaluate the multipath canonical variational transition state theory thermal rate constants with multidimensional small-curvature corrections for tunneling. Therefore, the thermal rate constants include variational (recrossing) and tunneling effects in addition to the effect of multiple conformations on the thermal rate constants. These features grant the applicability of the method to a wide range of temperatures. The method was applied to each of the hydrogen abstraction sites of the four isomers of butanol. The methodology employed allowed us to calculate the thermal rate constants in the temperature range of 250-2500 K and to accurately fit them to analytical expressions. The variety of abstraction sites shows that the protocol is robust and that it can be employed to study hydrogen abstraction reactions in molecules containing carbon and oxygen as heavy atoms.

TorsiFlex: an automatic generator of torsional conformers. Application to the twenty proteinogenic amino acids.

In this work, we introduce TorsiFlex, a user-friendly software written in Python 3 and designed to find all the torsional conformers of flexible acyclic molecules in an automatic fashion. For the mapping of the torsional potential energy surface, the algorithm implemented in TorsiFlex combines two searching strategies: preconditioned and stochastic. The former is a type of systematic search based on chemical knowledge and should be carried out before the stochastic (random) search. The algorithm applies several validation tests to accelerate the exploration of the torsional space. For instance, the optimized structures are stored and this information is used to prevent revisiting these points and their surroundings in future iterations. TorsiFlex operates with a dual-level strategy by which the initial search is carried out at an inexpensive electronic structure level of theory and the located conformers are reoptimized at a higher level. Additionally, the program takes advantage of conformational enantiomerism, when possible. As a case study, and in order to exemplify the effectiveness and capabilities of this program, we have employed TorsiFlex to locate the conformers of the twenty proteinogenic amino acids in their neutral canonical form. TorsiFlex has produced a number of conformers that roughly doubles the amount of the most complete work to date.

Chemical reactivity from the vibrational ground-state level. The role of the tunneling path in the tautomerization of urea and derivatives.

Recent developments of low-temperature techniques are providing valuable knowledge about chemical processes that manifest in the quantum regimen. The tunneling effect from the vibrational ground-state is the main mechanism of these reactions, which usually involves the motion or transfer of hydrogen atoms. Theoretical methods can enrich the information supplied by these experimental methods through an insightful analysis of the tunneling process. In this context, canonical variational transition state theory with multidimensional tunneling corrections (CVT/MT) can handle this type of reaction, and it has been applied to several systems within the small-curvature approximation for tunneling (SCT). This method is of proven reliability for polyatomic reactions occurring at room temperature and above, but no tests have been performed to check its performance when only the lowest energy level is populated. In this work, we compare SCT against the least-action tunneling (LAT) method to study the tautomerization and cis-trans interconversion reactions in the enol forms of urea, thiourea, and selenourea. To the best of our knowledge, this is the first time that the LAT method is applied to a polyatomic reaction occurring in the deep-tunneling region. The theoretical results indicate that the reaction mechanisms are controlled by tunneling. The SCT and LAT tautomerization reaction times are in good agreement with the experimental values; however, LAT seems superior to SCT for reactions (tautomerizations) that involve moderate reaction path curvature, whereas the opposite is true for reactions with small curvature (interconversions). These results led us to introduce and recommend the microcanonically optimized tunneling path that selects the tunneling probability as the maximum between the SCT and LAT tunneling probabilities.

A Combined Systematic-Stochastic Algorithm for the Conformational Search in Flexible Acyclic Molecules.

We propose an algorithm that is a combination of systematic variation of the torsions and Monte Carlo (or stochastic) search. It starts with a trial geometry in internal coordinates and with a set of preconditioned torsional angles, i.e., torsional angles at which minima are expected according to the chemical knowledge. Firstly, the optimization of those preconditioned geometries is carried out at a low electronic structure level, generating an initial set of conformers. Secondly, random points in the torsional space are generated outside the "area of influence" of the previously optimized minima (i.e., outside a hypercube about each minima). These random points are used to build the trial structure, which is optimized by an electronic structure software. The optimized structure may correspond to a new conformer (which would be stored) or to an already existing one. Initial torsional angles (and also final ones if a new conformer is found) are stored to prevent visiting the same region of the torsional space twice. The stochastic search can be repeated as many times as desired. Finally, the low-level geometries are recovered and used as the starting point for the high-level optimizations. The algorithm has been employed in the calculation of multi-structural quasi harmonic and multi-structural torsional anharmonic partition functions for a series of alcohols ranging from n-propanol to n-heptanol. It was also tested for the amino acid L-serine.

Role of Microsolvation and Quantum Effects in the Accurate Prediction of Kinetic Isotope Effects: The Case of Hydrogen Atom Abstraction in Ethanol by Atomic Hydrogen in Aqueous Solution.

Hydrogen abstraction from ethanol by atomic hydrogen in aqueous solution is studied using two theoretical approaches: the multipath variational transition state theory (MP-VTST) and a path-integral formalism in combination with free-energy perturbation and umbrella sampling (PI-FEP/UM). The performance of the models is compared to experimental values of H kinetic isotope effects (KIE). Solvation models used in this study ranged from purely implicit, via mixed-microsolvation treated quantum mechanically via the density functional theory (DFT) to fully explicit representation of the solvent, which was incorporated using a combined quantum mechanical-molecular mechanical (QM/MM) potential. The effects of the transition state conformation and the position of microsolvating water molecules interacting with the solute on the KIE are discussed. The KIEs are in good agreement with experiment when MP-VTST is used together with a model that includes microsolvation of the polar part of ethanol by five or six water molecules, emphasizing the importance of explicit solvation in KIE calculations. Both, MP-VTST and PI-FEP/UM enable detailed characterization of nuclear quantum effects accompanying the hydrogen atom transfer reaction in aqueous solution.

Influence of Multiple Conformations and Paths on Rate Constants and Product Branching Ratios. Thermal Decomposition of 1-Propanol Radicals.

The potential energy surface involved in the thermal decomposition of 1-propanol radicals was investigated in detail using automated codes (tsscds2018 and Q2DTor). From the predicted elementary reactions, a relevant reaction network was constructed to study the decomposition at temperatures in the range 1000-2000 K. Specifically, this relevant network comprises 18 conformational reaction channels (CRCs), which in general exhibit a large wealth of conformers of reactants and transition states. Rate constants for all the CRCs were calculated using two approaches within the formulation of variational transition-state theory (VTST), as incorporated in the TheRa program. The simplest, one-well (1W) approach considers only the most stable conformer of the reactant and that of the transition state. In the second, more accurate approach, contributions from all the reactant and transition-state conformers are taken into account using the multipath (MP) formulation of VTST. In addition, kinetic Monte Carlo (KMC) simulations were performed to compute product branching ratios. The results show significant differences between the values of the rate constants calculated with the two VTST approaches. In addition, the KMC simulations carried out with the two sets of rate constants indicate that, depending on the radical considered as reactant, the 1W and the MP approaches may display different qualitative pictures of the whole decomposition process.

How Electronic Excitation Can be Used to Inhibit Some Mechanisms Associated to Substituent Effects.

Despite the fact that transferability and chemistry go hand in hand, transferability studies in electronically excited states (EESs) are normally omitted, although these states are becoming extremely important in modern processes and applications. In this work, it is shown that this kind of studies can be used to understand how substituent effects can be modified in EESs. Thus, for example, the analysis of the carbonyl oxygen transferability in different HCO-R molecules allowed us to find that the nO→πCO* excitation can be used to break the π conjugation associated to the resonance substituent effect. Moreover, as a direct consequence, the oxygen transferability is enhanced in the first electronically excited state.

Excluding hyperconjugation from the Z conformational preference and investigating its origin: formic acid and beyond.

Carboxylic acids, esters, secondary amides, and related molecules share a thermodynamic preference for the Z arrangement of their X[double bond, length as m-dash]C-Y-R moiety. This conformational predisposition is known as the Z effect and its most common explanation invokes the hyperconjugation from a Y lone pair to the σCX* orbital. In this work, we present clear topological evidence that hyperconjugation is not responsible for the Z preference. Diverse tools defined within the quantum chemical topology framework (such as, for example, atomic and electron localization function populations or the interacting quantum atoms energy decomposition) were used to analyse the evolution of formic acid from the E conformer towards the Z conformation. The results highlight the important role of the π resonance in the barrier between conformers and they also indicate that the hyperconjugative interaction lacks a leading role. Concretely, in an X[double bond, length as m-dash]C-Y-R structure, the XR interaction seems to be the key to understanding the preference for the Z arrangement of the moiety. Interestingly, our proposed explanation can be extended to a wide range of molecules presenting the same conformational preference, such as proteins or peptide nucleic acids.

Revisiting the carbonyl n → π* electronic excitation through topological eyes: expanding, enriching and enhancing the chemical language using electron number distribution functions and domain averaged Fermi holes.

The theory of chemical bonding is underdeveloped in electronic excited states, even in small molecules. Fortunately, real space tools may be used to offer rich images of simple excitation processes, as is shown in this work. The statistics of electron populations, through a fruitful combination of electron distribution functions (EDFs) and domain averaged Fermi holes (DAFHs), was used to enlighten our chemical knowledge of a paradigmatic process: the n → π* excitation in formaldehyde. Interestingly, our results are perfectly compatible with an alternative perception of the electronic transition: the rotation of one averaged-electron in the oxygen lone pair. This topological model does not require inter-orbital jumps to explain the final electron distribution and, in our humble opinion, this fact makes it, to some extent, more realistic. Finally, other far-reaching conclusions emerge smoothly from our analysis: (i) the σ link may contribute less to the total bond order (as measured by the delocalization index) of a polar double bond than the π one; (ii) populating an antibonding orbital does not necessarily imply decreasing the bond order of its corresponding bond.

Revisiting Lewis dot structure weightings: a pair density perspective.

A method based on a real space partitioning to measure the importance of Lewis structures is proposed in this work. A matrix containing diverse QTAIM atomic and diatomic properties endowed with significance within a Lewis structure framework is expanded in terms of what we call Lewis-structure matrices. Each of these matrices flawlessly describes an individual resonance structure and its associated linear expansion coefficient (Q-ALE coefficient) indicates the importance or convenience of the given Lewis structure. These coefficients were inspected looking at their evolution in a series of usual chemical issues. Among all the results, we find of interest that σ resonance structures in systems with π electrons are more important than normally expected, which justifies why the qualitative predictions arising from the application of the resonance model and the quantitative results based on QTAIM properties are sometimes discrepant. Likewise, we observe that the variation of the dielectric constant of the medium affects the π resonance to a greater extent than it does the σ one. Other interesting results in this manuscript are connected to homolytic dissociation of diatomic molecules, periodic trends in hydrogen compounds, and polarization of aromatic systems as a consequence of their interaction with electric fields and with diverse ions.

Beyond the molecular orbital conception of electronically excited states through the quantum theory of atoms in molecules.

We show that the use of the quantum theory of atoms in molecules (QTAIM) in electronically excited states allows expanding the knowledge that the molecular orbital (MO) framework provides about electronic rearrangements. Despite that historical prejudice seemed to preclude the use of QTAIM beyond the electronic ground state, this paper evidences that QTAIM is versatile enough to deal with excited states. As an example, the paradigmatic n → π* electronic transition of formaldehyde is analyzed. Using QTAIM, an energy partition of excited state energies into atomic and diatomic energies is carried out for the first time. This partition shows that upon electronic excitation the atoms of the CO bond experience a stabilization in their net energies, accompanied by a destabilization in their interaction, a fact which is in accordance with the idea of populating an antibonding π* MO. The associated C-O bond elongation in the nπ* state does not involve a change in the π atomic populations - as one would expect from a π* orbital - but in the σ ones. Moreover, it is also found that the nπ* state is characterized by a weaker C-O interaction energy in comparison to that in the electronic ground state. In order to strengthen this interaction, the electron-electron repulsion between C and O is reduced via a symmetry-breaking of the electron density, causing the C pyramidalization. A topological analysis based on the Laplacian of the electron density and on the electron localization function (ELF) reveals that the n → π* transition can be visualized as a rotation of 90° of the oxygen lone pairs.

Electronegativity estimator built on QTAIM-based domains of the bond electron density.

The electron localization function, natural localized molecular orbitals, and the quantum theory of atoms in molecules have been used all together to analyze the bond electron density (BED) distribution of different hydrogen-containing compounds through the definition of atomic contributions to the bonding regions. A function, gAH , obtained from those contributions is analyzed along the second and third periods of the periodic table. It exhibits periodic trends typically assigned to the electronegativity (χ), and it is also sensitive to hybridization variations. This function also shows an interesting S shape with different χ-scales, Allred-Rochow's being the one exhibiting the best monotonical increase with regard to the BED taken by each atom of the bond. Therefore, we think this χ can be actually related to the BED distribution.

Anomeric effect in halogenated methanols: a quantum theory of atoms in molecules study.

The quantum theory of atoms in molecules (QTAIM) has been used to analyze the gauche conformational preference of fluoromethanol and chloromethanol. The analysis of the total atomic population and localization and delocalization indices show trends that are not in line with the hyperconjugative explanation. Energy terms arising from the QTAIM partitioning have been obtained for fluoromethanol, revealing that (i) C-O interaction plays the most significant role in stabilizing the gauche rotamer and (ii) the summation of exchange terms (the only ones that could be related to hyperconjugation) has a smaller weight than electrostatic ones in the energy balance among gauche, anti, and syn conformations; however, they are far from being negligible.

Influence of the O-protonation in the O═C-O-Me Z preference. A QTAIM study.

One of the three O-protonations of methyl formate (MF) gives rise to a system where the Z preference is switched off and the E conformer becomes the most stable arrangement. The quantum theory of atoms in molecules scheme for splitting the physical space of a molecule into atomic subspaces has been employed to analyze this trend, as well as the effect of the protonation in MF. The most important changes in energy and electron density upon protonation do not take place when MF reorganizes its nuclei, but when the proton is introduced explicitly. The same trend is observed when the H attached to the carbonyl C is replaced by electron donating and withdrawing groups (CN, F, OH, CH(3), and CF(3)). The origin of the inversion in the conformational preference relies in the changes experienced by two interactions: (i) the methyl group with the proton and (ii) that between the atoms of the ether C-O bond.

Complementarity of QTAIM and ELF Partitions: Deeper Understanding of the Anomeric Effect.

In this work, fragments with chemical significance are defined inside QTAIM basins through the use of the ELF partition. In an ideal situation, core and monosynaptic ELF basins for an atom A (CA and VA, respectively) should belong exclusively to its atomic basin (CA, VA ∈ ΩA), while disynaptic ones ought to be divided between the atoms of the corresponding bond (for an A-B bond, VA-B ∈ ΩA ∪ ΩB). Several examples here analyzed verify this situation (within 0.01 au). This combined partitioning is also applied to the analysis of the conformational preference in diverse anomeric compounds. Results lead to an alternative interpretation, independent of hyperconjugative effects.

A QTAIM-based energy partitioning for understanding the physical origin of conformational preferences: application to the Z effect in O=C-X-R and related units.

A quantum theory of atoms in molecules-based energy partitioning was carried out for Z and E conformers of a series of O=C-X-R containing compounds. The results obtained for the simplest compound (formic acid) indicate that the attraction of the electron density within carbonyl oxygen by the nucleus of the acid hydrogen is the most important energy term for Z preference. This conclusion can be extended (mutatis mutandis) to larger carboxylic acids, esters, sulfur derivatives, secondary amides, and carbonyl isocyanates, and even explains the sequence of relative conformational energies in the HCXOH series (X = O, S, Se). In contrast, although the hyperconjugative model has been traditionally employed to explain this preference, we observe it is incompatible with: (i) relative values of diverse QTAIM atomic populations for the Z/E conformational equilibrium; (ii) conformational energies in the HCXOH series.