The Simulation of Solvent Polarizabilities and Dipolarities with Polarizable Continuum Model.

The ability of polarizable continuum models (PCM) to simulate nonspecific solvent effects (dipolarity and polarizability) was evaluated by calculating the transition energies of 1,1,10,10-tetrabutyldecanonaene (ttbp9) and 2-N,N-dimethylamino-7-nitrofluorene (DMANF), basis of Catalán's polarizability (SP) and dipolarity (SdP) solvent scales, respectively. Time-dependent density-functional theory (TD-DFT) calculations were performed at different levels of theory, employing four basis sets in 10 different solvents, covering the full range of the normalized SP and SdP scales. Transition energies were calculated using linear response (LR) and corrected linear response (cLR2) schemes. Although these methods yielded variable mean absolute errors, the LR-PCM calculations reproduced medium polarizability and dipolarity trends. While calculated ttbp9 transition energies correlated with SP and Laurence's dispersion-induced (DI) scales, the DMANF transition energies correlated poorly with SdP or Laurence's ES dipolarity scales. This result agrees with the fact that DMANF solvatochromism is "contaminated" by solvent polarizability and HB acidity. The incorporation of SP or DI contributions led to much better (r2 > 0.95) correlations with the DMANF-calculated transitions. The results offer a clearer picture of the limitations of continuum models in simulating the behavior of solvatochromic dyes in solution by pointing out their poor performance when specific solvent effects, such as hydrogen-bond interactions, play a significant role in their solvatochromism.

Deafness causing neuroplastin missense variants fail to promote plasma membrane Ca2+-ATPase levels and Ca2+ transient regulation in brain neurons.

Hearing, the ability to sense sounds, and the processing of auditory information are important for perception of the world. Mice lacking expression of neuroplastin (Np), a type-1 transmembrane glycoprotein, display deafness, multiple cognitive deficiencies, and reduced expression of plasma membrane calcium (Ca2+) ATPases (PMCAs) in cochlear hair cells and brain neurons. In this study, we transferred the deafness causing missense mutations pitch (C315S) and audio-1 (I122N) into human Np (hNp) constructs and investigated their effects at the molecular and cellular levels. Computational molecular dynamics show that loss of the disulfide bridge in hNppitch causes structural destabilization of immunoglobulin-like domain (Ig) III and that the novel asparagine in hNpaudio-1 results in steric constraints and an additional N-glycosylation site in IgII. Additional N-glycosylation of hNpaudio-1 was confirmed by PNGaseF treatment. In comparison to hNpWT, transfection of hNppitch and hNpaudio-1 into HEK293T cells resulted in normal mRNA levels but reduced the Np protein levels and their cell surface expression due to proteasomal/lysosomal degradation. Furthermore, hNppitch and hNpaudio-1 failed to promote exogenous PMCA levels in HEK293T cells. In hippocampal neurons, expression of additional hNppitch or hNpaudio-1 was less efficient than hNpWT to elevate endogenous PMCA levels and to accelerate the restoration of basal Ca2+ levels after electrically evoked Ca2+ transients. We propose that mutations leading to pathological Np variants, as exemplified here by the deafness causing Np mutants, can affect Np-dependent Ca2+ regulatory mechanisms and may potentially cause intellectual and cognitive deficits in humans.

Photophysical Analysis of Aggregation-Induced Emission (AIE) Luminogens Based on Triphenylamine and Thiophene: Insights into Emission Behavior in Solution and PMMA Films.

Aggregation-Induced Emission (AIE) luminogens have garnered significant interest due to their distinctive applications in different applications. Among the diverse molecular architectures, those based on triphenylamine and thiophene hold prominence. However, a comprehensive understanding of the deactivation mechanism both in solution and films remains lacking. In this study, we synthesized and characterized spectroscopically two AIE luminogens: 5-(4-(bis(4-methoxyphenyl)amino)phenyl)thiophene-2-carbaldehyde (TTY) and 5'-(4-(bis(4-methoxyphenyl)amino)phenyl)-[2,2'-bithiophene]-5-carbaldehyde (TTO). Photophysical and theoretical analyses were conducted in both solution and PMMA films to understand the deactivation mechanism of TTY and TTO. In diluted solutions, the emission behavior of TTY and TTO is influenced by the solvent, and the deactivation of the excited state can occur via locally excited (LE) or twisted intramolecular charge transfer (TICT) state. In PMMA films, rotational and translational movements are constrained, necessitating emission solely from the LE state. Nevertheless, in the PMMA film, excimers-like structures form, resulting in the emergence of a longer wavelength band and a reduction in emission intensity. The zenith of emission intensity occurs when molecules are dispersed at higher concentrations within PMMA, effectively diminishing the likelihood of excimer-like formations. Luminescent Solar Concentrators (LSC) were fabricated to validate these findings, and the optical efficiency was studied at varying concentrations of luminogen and PMMA.

On the role of water in the hydrogen bond network in DESs: an ab initio molecular dynamics and quantum mechanical study on the urea-betaine system.

We herein report an ab initio molecular dynamics study on a natural DES composed of urea and betaine in a 3 : 2 ratio, as a test case for evaluating the water effect. The article deals with a theoretical study using both ab initio molecular dynamics and quantum chemistry computations in order to unravel the role of water in the nanostructure of a urea-betaine mixture. Preliminary molecular dynamics outcomes (both radial and spatial distribution functions) suggest that water promotes the association between urea and betaine by increasing the hydrogen bond network and precluding the aggregation of urea molecules. In other words, the presence of water allows a less restrictive hydrogen bond network, presenting a regimen where the strong hydrogen bond interactions are replaced by a wide variety of weaker hydrogen bond interactions. On the other hand, in a water free DES there is a regimen where strong urea-betaine interactions are dominant. It is shown that second order perturbation theory energy analysis provides cogent insights into charge spreading and hydrogen bond patterns. A vibrational analysis (both IR and power spectrum) over the ab initio molecular dynamics trajectories in the water free DES as well as in the urea-betaine-water systems reveals that our results are consistent with the second order perturbation theory analysis and with the hydrogen bond network pattern.

Unraveling the Selectivity Patterns in Phosphine-Catalyzed Annulations of Azomethine Imines and Allenoates.

The mechanism and selectivity of phosphine-catalyzed [3 + 2] and [3 + 3] annulations of azomethine imines and allenoates have been computationally studied. Exploration of the potential energy surface reveals that the cyclization step is a key step controlling the selectivity of the process. This contrasts with previous studies on related transformations where the initial nucleophilic addition involving the activated allenoate was found to exclusively control the regioselectivity of the transformation. Among the possible reaction pathways, the energetically low-lying reaction channel involves an intramolecular Michael addition leading to the experimentally observed [3 + 2] product. The factors controlling the observed regioselectivity have been quantitatively rationalized by means of state-of-the-art computational methods, namely, the activation strain model of reactivity in combination with the energy decomposition analysis.

Meisenheimer complexes as hidden intermediates in the aza-SNAr mechanism.

In this work we report a computational study about the aza-SNAr mechanism in fluorine- and chlorine-containing azines with the aim to unravel the physical factors that determine the reactivity patterns in these heterocycles towards propylamine. The nature of the reaction intermediate was analyzed in terms of its electronic structure based on a topological analysis framework in some non-stationary points along the reaction coordinate. The mechanistic dichotomy of a concerted or a stepwise pathway is interpreted in terms of the qualitative Diabatic Model of Intermediate Stabilization (DMIS) approach, providing a general mechanistic picture for the SNAr process involving both activated benzenes and nitrogen-containing heterocycles. With the information collected, a unified vision of the Meisenheimer complexes as transition state, hidden intermediate or real intermediate was proposed.

Theoretical insights into the E1cB/E2 mechanistic dichotomy of elimination reactions.

E1cB and E2 eliminations have been described as competing mechanisms that can even share a common pathway when the E1cB/E2 borderline mechanism operates. A suitable case study evincing such a mechanistic dichotomy corresponds to the elimination reaction of ß-phenylmercaptoethyl phenolate, since its mechanism has been thought to be an E2 elimination. Nonetheless, according to the computational assessment of the substituents on the leaving group, we demonstrate that the reaction proceeds via a borderline E1cB mechanism. Stabilization of the carbanion was provided not only by substituent effects tuning the nucleofugality of the leaving group, but also by a base, since distortion/interaction-activation strain and Natural Bond Order (NBO) analyses suggest a stabilizing interaction between the base and Cß of the E1cB intermediate. In order to gain insights into these results in a more general context, we have rationalized them with a qualitative picture of the E1cB/E2 mechanistic dichotomy using simple relationships between diabatic parabolas modeling the potential wells of reactants, intermediates, and products. In this Diabatic Model of Intermediate Stabilization (DMIS), the borderline E1cB mechanism for the elimination reaction of ß-phenylmercaptoethyl phenolate was discussed in terms of bonding and dynamic stepwise processes. The conceptual model presented herein should be useful for the analysis of any reaction comprising competing one- and two-step mechanisms.

How Meaningful Is the Halogen Bonding in 1-Ethyl-3-methyl Imidazolium-Based Ionic Liquids for CO2 Capture?

We report on several parameters that can be used to describe the 1-ethyl-3-methyl-4,5-(X2)imidazolium cations (where X = H, Br, and I) within the Canongia-Lopez and Padua Force Field (CL&P) framework. Geometrical parameters like intramolecular distances and radial distribution functions are close to the experimental structure. Density values obtained with our force field are within the expected ones from CL&P calculations in related systems. This information is used to simulate through molecular dynamics the solubilization of CO2 by these ILs. For pure ILs, the addition of halides in position 4 and 5 promotes an enhanced hydrogen bond interaction at position 2 with the oxygen atoms in the anion. It is found that CO2 should be in the interstices of the anion-cation 3D network with longer distances than those found in other reports at ab initio levels, suggesting that halogen bond, if present, may be not the driving force interaction in these systems. Therefore, it seems that CO2 interacts linearly via an oxygen atom with the cation and with the anion through a π-stacking or hydrogen-bonded fashions. Solvation enthalpies compare well with the experimental data, thereby suggesting that halogenated ILs dissolve more efficiently in CO2 than C2C1Im+ derivatives. This result suggests that halogenated ILs can be considered as reliable candidates for CO2 capture.

Lewis Acidity/Basicity Changes in Imidazolium Based Ionic Liquids Brought About by Impurities.

We herein report on the effect that water molecules, present as impurities, in the vicinity of an ionic liquid model structure, may induce on the Lewis acidity/basicity patterns normally observed in these materials. Depending on the position and orientation of water, the Lewis acidity/basicity pattern changes from "normal distribution" (i.e., the basicity located at the anion moiety and the acidity located at the cation fragment) to "bifunctional distribution" (i.e., the acidity and basicity located at the cation moiety). In some specific cases, there appears a third Lewis acidity/basicity distribution, where water may bind both the cation and the anion of the ion pair; a response we tentatively call "amphoteric". These effects are clearly traced to the hydrogen bond formation ability of water to coordinate different regions of pure ionic liquids taken as references.

Regional electrophilic and nucleophilic Fukui functions efficiently highlight the Lewis acidic/basic regions in ionic liquids.

The origin of catalysis and selectivity induced by room temperature ionic liquids in several organic reactions has putatively been associated with the concept of cation effect (hydrogen bond donor ability of the ionic liquids) or anion effect (hydrogen bond accepting ability of the ionic liquids). We show that there may be cases where this a priori classification may not be correctly assigned. Cations may concentrate both Lewis acidity and basicity functions in one fragment of the ionic liquid: an effect we tentatively call bifunctional distribution of the molecular Lewis acidity/basicity. Bifunctionality on the cation is however anion dependent through electronic polarization effects. The molecular distribution of the Lewis acidity/basicity may simply be assessed by evaluating the regional Fukui function within a reference ion pair structure. The model is tested for a set of nine ionic liquids based on the 1-butyl-3-methylimidazolium cation commonly used as solvent to run organic reactions.

Hydrogen bond contribution to preferential solvation in S(N)Ar reactions.

Preferential solvation in aromatic nucleophilic substitution reactions is discussed using a kinetic study complemented with quantum chemical calculations. The model system is the reaction of a series of secondary alicyclic amines toward phenyl 2,4,6-trinitrophenyl ether in aqueous ethanol mixtures of different compositions. From solvent effect studies, it is found that only piperidine is sensitive to solvation effects, a result that may be traced to the polarity of the solvent composition in the ethanol/water mixture, which points to a specific electrophilic solvation in the aqueous phase.

Specific nucleophile-electrophile interactions in nucleophilic aromatic substitutions.

We herein report results obtained from an integrated experimental and theoretical study on aromatic nucleophilic substitution (S(N)Ar) reactions of a series of amines towards 1-fluoro-2,4-dinitrobenzene in water. Specific nucleophile-electrophile interactions in the title reactions have been kinetically evaluated. The whole series undergoes S(N)Ar reactions where the formation of the Meisenheimer complex is rate determining. Theoretical studies concerning specific interactions are discussed in detail. It is found that H-bonding effects along the intrinsic reaction coordinate profile promote the activation of both the electrophile and the nucleophile. Using these results, it is possible to establish a hierarchy of reactivity that is in agreement with the experimental data. Second order energy perturbation energy analysis highlights the strong interaction between the ortho-nitro group and the acidic hydrogen atom of the amine. The present study strongly suggests that any theoretical analysis must be performed at the activated transition state structure, because the static model developed around the reactant states hides most of the relevant specific interactions that characterize the aromatic substitution process.

Reactivity indices profile: a companion tool of the potential energy surface for the analysis of reaction mechanisms. Nucleophilic aromatic substitution reactions as test case.

We herein report on the usefulness of the reactivity indices profiles along a reaction coordinate. The model is tested to fully describe the reaction mechanism of the title reactions. Group nucleophilicity and electrophilicity profiles help describe the bond-breaking/bond-formation processes and the intramolecular electron density reorganization. The reactivity indices' profile analysis is consistently complemented with hydrogen bonding (HB) effects along the reaction coordinate: the final outcome of the reaction is determined by the stage at which the HB complex can be formed. Transition-state structures located for six reactions studied, including the charged nucleophile thiocyanate, show that the main stabilizing interaction is that formed between the hydrogen atom of the nucleophile and the o-NO(2) group. This result discards the role of HB interaction between the nucleophile and the leaving group previously proposed in the literature.

Are electrophilicity and electrofugality related concepts? A density functional theory study.

It is proposed that the electrofugality of a fragment within a molecule is determined by its group nucleophilicity. The variation of electrofugality should be tightly related to the electron releasing ability of the substituent attached to the electrofuge moiety. This contribution closes the set of relationships between philicity and fugality quantities: while nucleofugality appears related to the group electrophilicity of the leaving group, electrofugality is related to the group nucleophilicity of the permanent group.