Solvent Cavity Research Articles

Front Cover: Conformation Regulation of Trisresorcinarene Directed by Cavity Solvation (Chem. Eur. J. 63/2024)

Front Cover: Conformation Regulation of Trisresorcinarene Directed by Cavity Solvation (Chem. Eur. J. 63/2024)

How to Probe Hydrated Dielectrons Experimentally: Ab Initio Simulations of the Absorption Spectra of Aqueous Dielectrons, Electron Pairs, and Hydride.

In the radiation chemistry of water, two hydrated electrons (ehyd-) can react to form H2 and OH-. Experiments and simulations suggest that this reaction occurs through a mechanism involving colocalization of two ehyd-'s into the same solvent cavity, forming a hydrated dielectron intermediate, with aqueous hydride (H-) as a subintermediate. However, there has been no direct experimental observation of either or H-. Here, we present TD-DFT-based predictions for the absorption spectrum of open-shell-singlet and triplet ehyd- pairs, , and H-. We find that relative to ehyd-, triplet and open-shell singlet electron pairs show spectral shifts to the blue and red, respectively. Additionally, we find that absorbs even further to the red, and that H- has a charge-transfer-to-solvent-like transition at wavelengths several eV to the blue, providing a direct experimental handle with which to probe these species. We propose a three-pulse transient absorption experiment that should allow detection of and H-.

Conformation Regulation of Trisresorcinarene Directed by Cavity Solvation.

This compound is a synthetic macrocycle comprising three pivaloyl-protected resorcinarene units connected by six pentylene chains. We conducted a conformational study using 1H-NMR, X-ray diffraction (XRD), and computational analyses. The macrocycle adopts two conformers, one open, the other closed. The ratio of the open to closed forms depended on the solvent used. Only the open form existed in [D8]toluene, both forms coexisted in [D6]benzene, and the closed form was the major conformer in [D1]chloroform. The benzene-solvated open form observed in the solid state suggests that cavity solvation by solvent molecules directs the open form. The open form was the major or only conformer in [D10]o- and [D10]m-xylene and [D12]mesitylene, whereas the closed form was the major conformer in [D6]acetone. The open and closed forms were equally populated in [D10]p-xylene, suggesting that the size, shape, and dimensions of the solvent molecules most likely influenced the conformation of the protected trisresocinarene.

Sub-100-fs energy transfer in coenzyme NADH is a coherent process assisted by a charge-transfer state

Excitation energy transfer (EET) is a key photoinduced process in biological chromophoric assemblies. Here we investigate the factors which can drive EET into efficient ultrafast sub-ps regimes. We demonstrate how a coherent transport of electronic population could facilitate this in water solvated NADH coenzyme and uncover the role of an intermediate dark charge-transfer state. High temporal resolution ultrafast optical spectroscopy gives a 54±11 fs time constant for the EET process. Nonadiabatic quantum dynamical simulations computed through the time-evolution of multidimensional wavepackets suggest that the population transfer is mediated by photoexcited molecular vibrations due to strong coupling between the electronic states. The polar aqueous solvent environment leads to the active participation of a dark charge transfer state, accelerating the vibronically coherent EET process in favorably stacked conformers and solvent cavities. Our work demonstrates how the interplay of structural and environmental factors leads to diverse pathways for the EET process in flexible heterodimers and provides general insights relevant for coherent EET processes in stacked multichromophoric aggregates like DNA strands.

Easy to Use DFT Approach for Computational pKa Determination of Carboxylic Acids.

In pKa computational determination, the challenge in exploring and fostering new methodologies and approaches goes in parallel with the amelioration of computational performances. In this paper a "ready to use methodology" has been compared to other strategies, such as the re-shaping in solvation cavity (Bondi radius re-shaping), wanting to assess its reliability in predicting the pKa of a broad list of carboxylic acids. Thus, the functionals B3LYP and CAM-B3LYP have been selected, using SMD as continuum solvation model. Exploiting our previous results, two water molecules were made explicit on the reaction centre. Data show that our model (CAM-B3LYP/2H2 O) is capable to accurately predict pKa, leading to mean absolute error (MAE) values lower than 0.5. Noteworthy, good results were achieved in computing the pKa of substituents bearing nitro and cyano groups. Focusing on B3LYP, eventually remarkable outputs were obtained only when Bondi correction was applied to the complex with two water molecules. Hence, massive outcomes were obtained in foreseeing the trichloro and trifluoro acetic acid pKa. These findings demonstrated that no complex level of theory nor external factor is required to accurately predict carboxylic acids pKa, with MAE well below 0.5 units.

Solvation thermodynamics from cavity shapes of amino acids.

According to common physical chemistry wisdom, the solvent cavities hosting a solute are tightly sewn around it, practically coinciding with its van der Waals surface. Solvation entropy is primarily determined by the surface and the volume of the cavity while enthalpy is determined by the solute-solvent interaction. In this work, we challenge this picture, demonstrating by molecular dynamics simulations that the cavities surrounding the 20 amino acids deviate significantly from the molecular surface. Strikingly, the shape of the cavity alone can be used to predict the solvation free energy, entropy, enthalpy, and hydrophobicity. Solute-solvent interactions involving the different chemical moieties of the amino acid, determine indirectly the cavity shape, and the properties of the branches but do not have to be taken explicitly into account in the prediction model.

Pseudopolymorphism of a luminescent anthracene‐pentiptycene π‐system: The persistent alkyl‐pentiptycene threading mode

AbstractUnderstanding the crystal packing behavior of a luminescent π‐conjugated system would facilitate the design of crystals of the desired luminescence properties. Crystal pseudopolymorphism provides a great opportunity for such a purpose and meanwhile for tuning the solid‐state luminescence properties of a molecular system via crystallization in different solvents. Herein, we report an example of structural modification that converts a polymorphic anthracene‐pentiptycene π‐system (1) into a pseudopolymorphic counterpart (2), which displays polymorph‐dependent fluorescence color and [4 + 4] photodimerization activity. The five pseudopolymorphs of 2 (crystal notation 2/Solvent, and Solvent = THF, Hex, CHCl3, DCM, and MeOH) have a common feature of forming one‐dimensional (1D) columnar alkyl‐pentiptycene threading mode. The subsequent packing of the 1D columns depends on the size of the included solvents, leading to two major types of pentiptycene‐based framework. One of the frameworks possesses 1D solvent channels that account for 14–18% of the unit cell volume, and the other type has small solvent cavities. A crystal with partial hexane inclusion (i.e., 2/Hex') is also obtained, which provides insights into the stability of the apohost structure. Intriguing solvent guest effects on the fluorescence properties of 2/Solvent are also noted.

Electrochemical Generation of Hot Electrons in Fully Aqueous Solutions at Tetrahedral Amorphous Carbon Thin Film Electrodes and Electrochemiluminescence Immunoassay of Serum Amyloid A

AbstractElectrochemistry of hot electrons in fully aqueous solutions at tetrahedral amorphous carbon thin film electrodes is discussed. The generation of these highly reducing chemical species was confirmed by normal pulse voltammetry and several electrochemiluminescent systems. Electron transfer into pre‐existing solvent cavities was observed at approximately −2.65 V vs. Ag/AgCl (sat.). Electrogenerated hot electrons were utilized as chemiluminescent mediators in heterogeneous sandwich immunoassay of Serum Amyloid A. The calibration curve was linear over four orders of magnitude and the detection limit was 85 ng L−1 that demonstrates the efficiency of hot electron generation at this electrode material.

Piecewise Multipole-Expansion Implicit Solvation for Arbitrarily Shaped Molecular Solutes.

The multipole-expansion (MPE) model is an implicit solvation model used to efficiently incorporate solvent effects in quantum chemistry. Even within the recent direct approach, the multipole basis used in MPE to express the dielectric response still solves the electrostatic problem inefficiently or not at all for solutes larger than approximately ten non-hydrogen atoms. In existing MPE parametrizations, the resulting systematic underestimation of the electrostatic solute-solvent interaction is presently compensated for by a systematic overestimation of nonelectrostatic attractive interactions. Even though the MPE model can thus reproduce experimental free energies of solvation of small molecules remarkably well, the inherent error cancellation makes it hard to assign physical meaning to the individual free-energy terms in the model, raising concerns about transferability. Here we resolve this issue by solving the electrostatic problem piecewise in 3D regions centered around all non-hydrogen nuclei of the solute, ensuring reliable convergence of the multipole series. The resulting method thus allows for a much improved reproduction of the dielectric response of a medium to a solute. Employing a reduced nonelectrostatic model with a single free parameter, in addition to the density isovalue defining the solvation cavity, our method yields free energies of solvation of neutral, anionic, and cationic solutes in water in good agreement with experiment.

O2 solvation cavity in voids of ionic liquids studied by the solvatochromic red shift of O2(1Δg) phosphorescence.

Phosphorescence spectroscopy of singlet oxygen [=O2(1Δg)] was applied to study the solvation properties of small solute molecule, O2, in ionic liquids. Unlike conventional molecular solvents, the spectral red shift of the O2(1Δg) phosphorescence in ionic liquids from the gas phase was found to depend not only on the refractive indexof solvents but also on the vdW volume of anions. This unusual spectral shift of the O2(1Δg) luminescence is interpreted by considering the size of solvation cavities in voids, which is estimated by analyzing the free volume in ionic liquids. These results suggest the potential of the O2(1Δg) phosphorescence spectral shift measurement in the study of molecular-scale voids in ionic liquids.

Calculating Entropies of Large Molecules in Aqueous Phase.

Entropy benchmarking of different sized molecules in aqueous phase is carried out for known solvation models, where we compare geometry and solvation cavity packing parameters, which allows us to improve the accuracy of the obtained entropy values using empirical corrections. A comparison of solvation entropy models is conducted for a benchmarking set of 56 molecules, showing how an accurate description of cavitation entropy and its hindrance on other entropy values is important for large-sized solute molecules. Finally, we compare reaction free energies with entropies calculated using the most accurate solvation model considered, where we demonstrate a significant improvement in the accuracy relative to experimental values.

Inter-Subunit Dynamics Controls Tunnel Formation During the Oxygenation Process in Hemocyanin Hexamers.

Hemocyanin from horseshoe crab in its active form is a homo-hexameric protein. It exists in open and closed conformations when transitioning between deoxygenated and oxygenated states. Here, we present a detailed dynamic atomistic investigation of the oxygenated and deoxygenated states of the hexameric hemocyanin using explicit solvent molecular dynamics simulations. We focus on the variation in solvent cavities and the formation of tunnels in the two conformational states. By employing principal component analysis and CVAE-based deep learning, we are able to differentiate between the dynamics of the deoxy- and oxygenated states of hemocyanin. Finally, our results identify the deoxygenated open conformation, which adopts a stable, closed conformation after the oxygenation process.

Ice in biomolecular cryocrystallography.

Diffraction data acquired from cryocooled protein crystals often include diffraction from ice. Analysis of ice diffraction from crystals of three proteins shows that the ice formed within solvent cavities during rapid cooling is comprised of a stacking-disordered mixture of hexagonal and cubic planes, with the cubic plane fraction increasing with increasing cryoprotectant concentration and increasing cooling rate. Building on the work of Thorn and coworkers [Thorn et al. (2017), Acta Cryst. D73, 729-727], a revised metric is defined for detecting ice from deposited protein structure-factor data, and this metric is validated using full-frame diffraction data from the Integrated Resource for Reproducibility in Macromolecular Crystallography. Using this revised metric and improved algorithms, an analysis of structure-factor data from a random sample of 89 827 PDB entries collected at cryogenic temperatures indicates that roughly 16% show evidence of ice contamination, and that this fraction increases with increasing solvent content and maximum solvent-cavity size. By examining the ice diffraction-peak positions at which structure-factor perturbations are observed, it is found that roughly 25% of crystals exhibit ice with primarily hexagonal character, indicating that inadequate cooling rates and/or cryoprotectant concentrations were used, while the remaining 75% show ice with a stacking-disordered or cubic character.

Some interaction-related thermodynamic properties of aqueous tetramethylenediethylenetetramine (drug teotropine) solutions: Effect of the solvent H/D isotope substitution and temperature

The molar enthalpies of dissolution of 1,3,6,8-tetraazatricyclo[4.4.1.13,8]dodecane or TMDETA (tetramethylenediethylenetetramine: the teotropine pharmaceutical) in ordinary (H2O) and heavy (D2O) water were measured calorimetrically at T = (278.15, 288.15, 298.15, 308.15, and 318.15) K and p = 0.1 MPa. The standard molar enthalpies and heat capacities of TMDETA dissolution/hydration, along with D2O–H2O solvent isotope effects (IEs) in these quantities, were computed. Solution enthalpies and corresponding IEs were found to be negative, decreasing in magnitude as the temperature is rising. It was concluded that hydrophobic effects are the predominant part in the TMDETA hydration and they are enhanced in D2O and weakened going from TMDETA to its lower-molecular aminal derivative, hexamethylenetetramine (HMTA) being the known drug urotropine. Unlike the aqueous HMTA, the “dualistic” character of TMDETA hydration is less dependent on the initial structure state of a solvent isotopologue. The results of analyzing the contributions to the solvation enthalpy within the scope of Scaled Particle Theory showed that IEs in the enthalpy of TMDETA – water interaction and the solvent cavity formation is almost cancelling each other at T > 288.15 K.

Evaluation of solvate and co-crystal screening methods for CL-20 containing energetic materials

ABSTRACT The difficulty synthesizing new co-crystals has made the development of efficient methods for screening co-formers a high priority. Co-crystals have been realized as a new generation of materials with tuneable solubility, stability, and performance. Energetic co-formers have exceptionally weak intermolecular interactions making selection of co-crystallization method and parameters critical to forming a true co-crystal. COSMO-RS calculations coupled with the COSMOtherm software suite were used to screen common solvents and co-formers for CL-20. The predicted favorable solvates and co-crystal formers were compared to experimentally confirmed solvates and co-crystals to assess the accuracy of the COSMO method for CL-20-based materials. It was found that screening solvents using excess enthalpy and solvent cavity volume were able to predict experimentally confirmed CL-20 solvates. Co-crystal formation was difficult to predict using the COSMO method, highlighting the importance of entropy and solid-state interactions. The selection of good solvents is perhaps the best method for maximizing entropy. Understanding the dependence on entropy for energetic-energetic cocrystal formation coupled with an accurate method for screening co-crystal formation allows for intelligent design of co-crystallization methods.

Accounting for the Central Role of Interfacial Water in Protein-Ligand Binding Free Energy Calculations.

Rigorous binding free energy methods in drug discovery are growing in popularity because of a combination of methodological advances, improvements in computer hardware, and workflow automation. These calculations typically use molecular dynamics (MD) to sample from the Boltzmann distribution of conformational states. However, when part or all of the binding sites is inaccessible to the bulk solvent, the time needed for water molecules to equilibrate between bulk solvent and the binding site can be well beyond what is practical with standard MD. This sampling limitation is problematic in relative binding free energy calculations, which compute the reversible work of converting ligand 1 to ligand 2 within the binding site. Thus, if ligand 1 is smaller and/or more polar than ligand 2, the perturbation may allow additional water molecules to occupy a region of the binding site. However, this change in hydration may not be captured by standard MD simulations and may therefore lead to errors in the computed free energy. We recently developed a hybrid Monte Carlo/MD (MC/MD) method, which speeds up the equilibration of water between bulk solvent and buried cavities, while sampling from the intended distribution of states. Here, we report on the use of this approach in the context of alchemical binding free energy calculations. We find that using MC/MD markedly improves the accuracy of the calculations and also reduces hysteresis between the forward and reverse perturbations, relative to matched calculations using only MD with or without the crystallographic water molecules. The present method is available for use in AMBER simulation software.

Ground and excited state dipole moments of 1-methylindole from thermochromic shifts in absorption and emission spectra

The permanent dipole moments of 1-methylindole in its ground and lowest excited singlet ππ*-state have been determined using the method of thermochromic shifts of the absorption and fluorescence spectra and compared to ab initio calculated dipole moments. While ab initio theory predicts an excited state dipole moment, which nearly equals that of the ground state, the thermochromic shifts give an excited state dipole moment, which is about 2 Debye larger than that of the ground state. Perturbation of the excited state through the large electric field strength of the solvent cavity leads to strong mixing with the next excited singlet state, which has a considerably larger dipole moment. This perturbation is analyzed using the method described by Lombardi [John R. Lombardi J. Phys. Chem. A 1998, 102, 2817–2823]. The perturbing state could be identified as 1La-state, which is the second adiabatic state in the gas phase, but the lowest state in a polar surrounding.

The hydrophobic effect: is water afraid, or just not that interested?

Our understanding of the hydrophobic effect has advanced greatly since 1990, with the help of experimental, theoretical, and computer simulation results. The key hydrophobic signature of positive ∆C°P and negative ∆S° at room temperature has been interpreted in light of the importance of solvent cavity creation, solvent-excluded volume, and solute–water intermolecular forces, along with some unusual thermodynamic properties of pure water. Application of the hydrophobic effect to the hydration of small nonpolar solutes, protein folding stability, and protein–ligand binding is discussed in detail in this review, with an emphasis on thermodynamic analyses and interpretations.

GIAO 13C NMR Calculation with Sorted Training Sets Improves Accuracy and Reliability for Structural Assignation.

GIAO 13C NMR calculation plays important roles in structural assignment for small organic molecules. Especially, higher accuracy and confidence are required for the structural assignation of complex organic molecules. In this GIAO 13C NMR calculation strategy, carbons were sorted according to their type of hybridization, radii of solvation cavity, or solvent interactions. The calculated shielding tensors of carbons in each sorted training set were linear-regressed with experimental data separately, and the obtained linear parameters were used to convert calculated shielding tensors into calculated chemical shifts. This approach shows significantly improved accuracy, especially for sp2 carbons, compared to conventional GIAO 13C NMR calculation protocols. A statistic-based probability algorithm was proposed to quantify the reliability of structural assignation. With empirical linear parameters for three commonly used NMR solvents as well as an easy-to-use script and a spreadsheet, this 13C NMR calculation protocol provides a useful tool for structural validation or assignation of ambiguous organic structures.

Potential main group amine borane-based chemical hydrogen storage molecular systems

The thermodynamics as a function of the temperature for the decomposition of the substituted amine boranes X(NH2BH3)3 and X(BH2NH3)3 for X = N and P and E(NH2BH3)4 and E(BH2NH3)4 for E = C and Si were predicted using composite correlated molecular orbital G3(MP2) theory. The relative stabilities of isomers were explained using bond dissociation energies. Equilibrium concentrations of products with respect to temperature were determined using Gibbs free energy minimization. The activation energy for loss of the first H2 was calculated at the G3(MP2)B3 level and is larger than the respective bond dissociation energy to lose terminal BH3 or NH3 via dative bond cleavage. Dipole moments and polarizabilities were calculated at the DFT/B3LYP level and boiling points were calculated at the DFT/BP/COSMO-RS level. Planar fits were developed for the boiling points of N(BH2NH3)3, P(BH2NH3)3, C(BH2NH3)4, and Si(BH2NH3)4 dehydrogenation products using dipole moment, polarizability, and solvent cavity surface area.