Revealing the Critical Role of Global Electron Density Transfer in the Reaction Rate of Polar Organic Reactions within Molecular Electron Density Theory.

The critical role of global electron density transfer (GEDT) in increasing the reaction rate of polar organic reactions has been studied within the framework of Molecular Electron Density Theory (MEDT). To this end, the series of the polar Diels-Alder (P-DA) reactions of cyclopentadiene with cyanoethylene derivatives, for which experimental kinetic data are available, have been chosen. A complete linear correlation between the computed activation Gibbs free energies and the GEDT taking place at the polar transition state structures (TSs) is found; the higher the GEDT at the TS, the lower the activation Gibbs free energy. An interacting quantum atoms energy partitioning analysis allows for establishing a complete linear correlation between the electronic stabilization of the electrophilic ethylene frameworks and the GEDT taking place at the polar TSs. This finding supports Parr's proposal for the definition of the electrophilicity ω index. The present MEDT study establishes the critical role of the GEDT in the acceleration of polar reactions, since the electronic stabilization of the electrophilic framework with the electron density gain is greater than the destabilization of the nucleophilic one, making a net favorable electronic contribution to the decrease in the activation energy.

A combined BET and IQA-REG study of the activation energy of non-polar zw-type [3+2] cycloaddition reactions.

A combined Bonding Evolution Theory (BET) and Interacting Quantum Atoms-Relative Energy Gradient (IQA-REG) study is carried out on a non-polar zw-type [3+2] cycloaddition (32CA) reaction. BET is the joint use of Catastrophe Theory and the topology of the Electron Localization Function (ELF) to characterise molecular mechanisms, while IQA is a quantum topological energy partitioning method and REG is a method to compute chemical insight at atomistic level, usually in connection with energy. This 32CA reaction involves the simplest nitrone with ethylene and has been studied here at B3LYP/6-311G(d,p) level within the context of Molecular Electron Density Theory (MEDT), which is based on the idea that changes in electron density, and not molecular orbital interactions, are responsible for chemical reactivity. We aim to determine the origin of the high activation energy of 32CA reactions involving zwitterionic three-atom-components. The BET study and IQA-REG method are applied to the overall activation energy path. While BET suggests that the barrier is mainly associated with the rupture of the nitrone CN double bond, IQA-REG indicates that it is mainly related to the rupture of the ethylene CC double bond. The present study shows that activation energies can be accurately and easily described by IQA-REG, and its complementary use with BET helps achieving a more detailed description of molecular mechanisms.

A Molecular Electron Density Theory Study of the Domino Reaction of N-Phenyl Iminoboranes with Benzaldehyde Yielding Fused Bicyclic Compounds.

The reaction of N-phenyl iminoborane with benzaldehyde yielding a fused aromatic compound, recently reported by Liu et al., has been studied within the Molecular Electron Density Theory (MEDT). Formation of the fused aromatic compound is a domino process that comprises three consecutive reactions: (i) formation of a weak molecular complex between the reagents; (ii) an intramolecular electrophilic attack of the activated carbonyl carbon of benzaldehyde on the ortho position of the N-phenyl substituent of iminoborane; and (iii) a formal 1,3-hydrogen shift yielding the final fused aromatic compound. The two last steps correspond to a Friedel-Crafts acylation reaction, the product of the second reaction being the tetrahedral intermediate of an electrophilic aromatic substitution reaction. However, the presence of the imino group adjacent to the aromatic ring strongly stabilizes the corresponding intermediate, being the reaction product when the ortho positions are occupied by t-butyl substituents. This domino reaction shows a great similitude with the Brønsted acid catalyzed Povarov reaction. Although N-phenyl iminoborane can experience a formal [2+2] cycloaddition reaction with benzaldehyde, its higher activation Gibbs free energy compared to the intramolecular electrophilic attack of the activated carbonyl carbon of benzaldehyde on the ortho position of the N-phenyl substituent, 6.6 kcal·mol-1, prevents the formation of the formal [2+2] cycloadduct. The present MEDT study provides a different vision of the molecular mechanism of these reactions based on the electron density.

Synthesis and Characterization of New Spirooxindoles Including Triazole and Benzimidazole Pharmacophores via [3+2] Cycloaddition Reaction: An MEDT Study of the Mechanism and Selectivity.

A new series of spirooxindoles based on benzimidazole, triazole, and isatin moieties were synthesized via a [3+2] cycloaddition reaction protocol in one step. The single X-ray crystal structure of the intermediate triazole-benzimidazole 4 was solved. The new chemical structures of these spirooxindole molecules have been achieved for the first time. The final synthesized chemical architecture has differently characterized electronic effects. An MEDT study of the key 32CA reaction between in situ generated azomethine ylide (AY) and chalcones explained the low reaction rates and the total selectivities observed. The supernucleophilic character of AY and the strong electrophilicity of chalcones favor these reactions through a highly polar two-stage one-step mechanism in which bond formation at the ß-conjugated carbon of the chalcones is more advanced. The present combined experimental and theoretical study reports the synthesis of new spirooxindoles with potential biological activities and fully characterizes the molecular mechanisms for their formation through the key 32CA reaction step.

Unveiling the high reactivity of experimental pseudodiradical azomethine ylides within molecular electron density theory.

The [3+2] cycloaddition (32CA) reactions of N-methyl azomethine ylide (AY) with styrene, benzaldehyde and methyl 2-formyl-benzoate (MFB) were studied within molecular electron density theory (MEDT), at the ωB97X-D/6-311G(d) computational level, in order to characterize the reactivity of an experimental pseudodiradical TAC for the first time. ELF topological analysis indicates that AY presents a pseudodiradical structure. Analysis of CDFT reactivity indices allows classifying AY as a supernucleophile; while styrene is classified as a moderate electrophile, benzaldehyde and MFB are classified as strong electrophiles. The 32CA reaction with MFB is the most favorable one with a relatively low activation Gibbs free energy of 6.9 kcal mol-1, being irreversible and completely endo stereo- and chemo-selective towards the carbonyl group, a behavior predicted by the analysis of the Parr functions. The bonding evolution theory (BET) study indicates that while the 32CA reaction of AY with styrene is characterized as a pdr-type 32CA reaction, the one involving benzaldehyde follows a pmr-type mechanism prompted by the presence of the carbonyl group. The present MEDT study describes in detail the tunable high reactivity of one of the few experimentally available pseudodiradical TACs, showing that the mechanism of 32CA reactions can be modified not only by changing the electronic structure of TACs through proper substitution but also by the nature of their opposing ethylene derivative.

A Molecular Electron Density Theory Study of the [3+2] Cycloaddition Reaction of an Azomethine Ylide with an Electrophilic Ethylene Linked to Triazole and Ferrocene Units.

The [3+2] cycloaddition (32CA) reaction of an azomethine ylide (AY) with an electrophilic ethylene linked to triazole and ferrocene units has been studied within the Molecular Electron Density Theory (MEDT) at the ωB97X-D/6-311G(d,p) level. The topology of the electron localization function (ELF) of this AY allows classifying it as a pseudo(mono)radical species characterized by the presence of two monosynaptic basins, integrating a total of 0.76 e, at the C1 carbon. While the ferrocene ethylene has a strong electrophilic character, the AY is a supernucleophile, suggesting that the corresponding 32CA reaction has a high polar character and a low activation energy. The most favorable ortho/endo reaction path presents an activation enthalpy of 8.7 kcal·mol-1, with the 32CA reaction being exergonic by -42.1 kcal·mol-1. This reaction presents a total endo stereoselectivity and a total ortho regioselectivity. Analysis of the global electron density transfer (GEDT) at the most favorable TS-on (0.23 e) accounts for the high polar character of this 32CA reaction, classified as forward electron density flux (FEDF). The formation of two intermolecular hydrogen bonds between the two interacting frameworks at the most favorable TS-on accounts for the unexpected ortho regioselectivity experimentally observed.

Understanding the Participation of Fluorinated Azomethine Ylides in Carbenoid-Type [3 + 2] Cycloaddition Reactions with Ynal Systems: A Molecular Electron Density Theory Study.

The carbenoid-type (cb-type) 32CA reaction of 1,1-difluoroated azomethine ylide (DFAY) with phenylpropynal has been studied using the molecular electron density theory (MEDT). Electron localization function (ELF) characterizes DFAY as a carbenoid species participating in cb-type 32CA reactions. The supernucleophilic character of DFAY and the strong electrophilic character of the ynal cause this polar 32CA reaction to have an unappreciable barrier; the reaction, which is highly exothermic, presents total chemo- and regioselectivity. ELF topological analysis of the bonding changes along the reaction establishes its non-concerted two-stage one-step mechanism, in which the nucleophilic attack of the carbenoid carbon of DFAY on the electrophilic carbonyl carbon of the ynal characterizes the cb-type reactivity of this three-atom component (TAC). The presence of two fluorines at DFAY modifies the pseudodiradical structure and reactivity of the simplest azomethine ylide to that of a carbenoid TAC participating in cb-type 32CA reactions toward electrophilic ethylenes.

The catalytic effects of a thiazolium salt in the oxa-Diels-Alder reaction between benzaldehyde and Danishefsky's diene: a molecular electron density theory study.

The oxa-Diels-Alder (ODA) reaction of benzaldehyde with Danishefsky's diene in the presence of a [thiazolium][Cl] salt, as a model of an ionic liquid, has been studied within Molecular Electron Density Theory (MEDT) at the M06-2X/6-311G(d,p) computational level. The formation of two hydrogen bonds (HBs) between the thiazolium cation and the carbonyl oxygen of benzaldehyde modifies neither the electrophilic character of benzaldehyde nor its electronic structure substantially but accelerates the reaction considerably. This ODA reaction presents an activation energy of 4.5 kcal mol-1; the formation of the only observed dihydropyranone is strongly exothermic by -28.8 kcal mol-1. The presence of the [thiazolium][Cl] salt decreases the Gibbs free energy of activation of the ODA reaction between benzaldehyde and Danishefsky's diene by 5.9 kcal mol-1. This ODA reaction presents total para regioselectivity and high endo stereoselectivity. This ODA reaction takes place through a highly asynchronous polar transition state structure (TS) associated with a non-concerted two-stage one-step mechanism. ELF analysis of para/endo TSs associated with the ODA reactions in the absence and presence of the [thiazolium][Cl] salt shows that the formation of the HBs at the TSs does not modify their electronic structure substantially. This MEDT study makes it possible to conclude that the acceleration found in the ODA reaction of benzaldehyde with Danishefsky's diene in ILs is a consequence of an increase of the global electron density transfer at TS3-pn, resulting from HB formation, and the greater strength of the HBs at the polar TS3-pn compared to that at the benzaldehyde : [thiazolium][Cl] complex, and that the strength in the HB formed is more relevant that than an increase of the electrophilic character of the interaction between reagent.

Effects of Non-thermal Ultrasound on a Fibroblast Monolayer Culture: Influence of Pulse Number and Pulse Repetition Frequency.

Despite the use of therapeutic ultrasound in the treatment of soft tissue pathologies, there remains some controversy regarding its efficacy. In order to develop new treatment protocols, it is a common practice to carry out in vitro studies in cell cultures before conducting animal tests. The lack of reproducibility of the experimental results observed in the literature concerning in vitro experiments motivated us to establish a methodology for characterizing the acoustic field in culture plate wells. In this work, such acoustic fields are fully characterized in a real experimental configuration, with the transducer being placed in contact with the surface of a standard 12-well culture plate. To study the non-thermal effects of ultrasound on fibroblasts, two different treatment protocols are proposed: long pulse (200 cycles) signals, which give rise to a standing wave in the well with the presence of cavitation (ISPTP max = 19.25 W/cm2), and a short pulse (five cycles) of high acoustic pressure, which produces a number of echoes in the cavity (ISPTP = 33.1 W/cm2, with Pmax = 1.01 MPa). The influence of the acoustic intensity, the number of pulses, and the pulse repetition frequency was studied. We further analyzed the correlation of these acoustic parameters with cell viability, population, occupied surface, and cell morphology. Lytic effects when cavitation was present, as well as mechanotransduction reactions, were observed.

A Comprehensive Experimental and Theoretical Study on the [{(η5-C5H5)2Zr[P(µ-PNEt2)2P(NEt2)2P]}]2O Crystalline System.

The structure of tetraphosphetane zirconium complex C52H100N8OP10Zr21 was determined by single crystal X-ray diffraction analysis. The crystal belongs to the monoclinic system, space group P21/c, with a = 19.6452(14), b = 17.8701(12), c = 20.7963(14)Å, α = γ = 90°, ß = 112.953(7)°, V = 6722.7(8)Å3, Z = 4. The electronic structure of the organometallic complex has been characterized within the framework of Quantum Chemical Topology. The topology of the Electron Localization Function (ELF) and the electron density according to the Quantum Theory of Atoms in Molecules (QTAIM) show no covalent bonds involving the Zr atom, but rather dative, coordinate interactions between the metal and the ligands. This is the first reported case of a Zr complex stabilized by an oxide anion, anionic cyclopentadienyl ligands and rare tetraphosphetane anions.

Unveiling the Ionic Diels-Alder Reactions within the Molecular Electron Density Theory.

The ionic Diels-Alder (I-DA) reactions of a series of six iminium cations with cyclopentadiene have been studied within the Molecular Electron Density Theory (MEDT). The superelectrophilic character of iminium cations, ω > 8.20 eV, accounts for the high reactivity of these species participating in I-DA reactions. The activation energies are found to be between 13 and 20 kcal·mol-1 lower in energy than those associated with the corresponding Diels-Alder (DA) reactions of neutral imines. These reactions are low endo selective as a consequence of the cationic character of the TSs, but highly regioselective. Solvents have poor effects on the relative energies, and an unappreciable effect on the geometries. In acetonitrile, the activation energies increase slightly as a consequence of the better solvation of the iminium cations than the cationic TSs. Electron localization function (ELF) topological analysis of the bonding changes along the I-DA reactions shows that they are very similar to those in polar DA reactions. The present MEDT study establishes that the global electron density transfer (GEDT) taking place at the TSs of I-DA reactions, and not steric (Pauli) repulsions such as have been recently proposed, are responsible for the features of these types of DA reactions.

The Participation of 3,3,3-Trichloro-1-nitroprop-1-ene in the [3 + 2] Cycloaddition Reaction with Selected Nitrile N-Oxides in the Light of the Experimental and MEDT Quantum Chemical Study.

The regioselective zw-type [3 + 2] cycloaddition (32CA) reactions of a series of aryl-substituted nitrile N-oxides (NOs) with trichloronitropropene (TNP) have been both experimentally and theoretically studied within the Molecular Electron Density Theory (MEDT). Zwitterionic NOs behave as moderate nucleophiles while TNP acts as a very strong electrophile in these polar 32CA reactions of forward electron density flux, which present moderate activation Gibbs free energies of 22.8-25.6 kcal·mol-1 and an exergonic character of 28.4 kcal·mol-1 that makes them irreversible and kinetically controlled. The most favorable reaction is that involving the most nucleophilic MeO-substituted NO. Despite Parr functions correctly predicting the experimental regioselectivity with the most favorable O-CCCl3 interaction, these reactions follow a two-stage one-step mechanism in which formation of the O-C(CCl3) bond takes place once the C-C(NO2) bond is already formed. The present MEDT concludes that the reactivity differences in the series of NOs come from their different nucleophilic activation and polar character of the reactions, rather than any mechanistic feature.

Factors associated with the number of drugs in darunavir/cobicistat regimens.

BACKGROUND: Darunavir/cobicistat can be used as mono, dual, triple or more than triple therapy. OBJECTIVES: To assess factors associated with the number of drugs in darunavir/cobicistat regimens. METHODS: A nationwide retrospective cohort study of consecutive HIV-infected patients initiating darunavir/cobicistat in Spain from July 2015 to May 2017. Baseline characteristics, efficacy and safety at 48 weeks were compared according to the number of drugs used. RESULTS: There were 761 patients (75% men, 98% were antiretroviral-experienced, 32% had prior AIDS, 84% had HIV RNA <50 copies/mL and 88% had ≥200 CD4 cells/mm3) who initiated darunavir/cobicistat as mono (n=308, 40%), dual (n=173, 23%), triple (n=253, 33%) or four-drug (n=27, 4%) therapy. Relative to monotherapy, triple therapy was more common in men aged <50 years, with prior AIDS and darunavir plus ritonavir use, and with CD4 cells <200/mm3 and with detectable viral load at initiation of darunavir/cobicistat; dual therapy was more common with previous intravenous drug use, detectable viral load at initiation of darunavir/cobicistat and no prior darunavir plus ritonavir; and four-drug therapy was more common with prior AIDS and detectable viral load at initiation of darunavir/cobicistat. Monotherapy and dual therapy showed a trend to better virological responses than triple therapy. CD4 responses and adverse effects did not differ among regimens. DISCUSSION: Darunavir/cobicistat use in Spain has been tailored according to clinical characteristics of HIV-infected patients. Monotherapy and dual therapy have been common and preferentially addressed to older patients with a better HIV status, suggesting that health issues other than HIV infection may have been strong determinants of its prescription.

A molecular electron density theory study of the enhanced reactivity of aza aromatic compounds participating in Diels-Alder reactions.

The enhanced reactivity of a series of four aza aromatic compounds (AACs) participating in the Diels-Alder (DA) reactions with ethylene has been studied using Molecular Electron Density Theory (MEDT). The analysis of the electronic structure of these AACs allows establishing that the substitution of the C-H unity by the isoelectronic N: unity linearly decreases the ring electron density (RED) of these compounds and concomitantly decreases their aromatic character and increases their electrophilic character. These behaviours not only decrease drastically the activation energies of these DA reactions, but also increase the reaction energies when they are compared with the very unfavourable DA reaction between benzene and ethylene. Very good correlations between the NICS(0) values and the electrophilicity ω indices of these AACs with the RED values are found. The present MEDT study makes it possible to establish two empirical electron density unity (EDU) indices accounting for the contribution of the C and N unities, 2.77 and 2.19 e, respectively, for the RED, which is mainly responsible for the reactivity of these AACs. Comprehensive chemical concepts such as electron density, aromaticity and electrophilicity make it possible to explain the chemical reactivity of these AACs participating in DA reactions towards ethylene.

Unveiling the Lewis Acid Catalyzed Diels-Alder Reactions Through the Molecular Electron Density Theory.

The effects of metal-based Lewis acid (LA) catalysts on the reaction rate and regioselectivity in polar Diels-Alder (P-DA) reactions has been analyzed within the molecular electron density theory (MEDT). A clear linear correlation between the reduction of the activation energies and the increase of the polar character of the reactions measured by analysis of the global electron density transfer at the corresponding transition state structures (TS) is found, a behavior easily predictable by analysis of the electrophilicity ω and nucleophilicity N indices of the reagents. The presence of a strong electron-releasing group in the diene changes the mechanism of these P-DA reactions from a two-stage one-step to a two-step one via formation of a zwitterionic intermediate. However, this change in the reaction mechanism does not have any chemical relevance. This MEDT study makes it possible to establish that the more favorable nucleophilic/electrophilic interactions taking place at the TSs of LA catalyzed P-DA reactions are responsible for the high acceleration and complete regioselectivity experimentally observed.

Unveiling the Different Chemical Reactivity of Diphenyl Nitrilimine and Phenyl Nitrile Oxide in [3+2] Cycloaddition Reactions with (R)-Carvone through the Molecular Electron Density Theory.

The [3+2] cycloaddition (32CA) reactions of diphenyl nitrilimine and phenyl nitrile oxide with (R)-carvone have been studied within the Molecular Electron Density Theory (MEDT). Electron localisation function (ELF) analysis of these three-atom-components (TACs) permits its characterisation as carbenoid and zwitterionic TACs, thus having a different reactivity. The analysis of the conceptual Density Functional Theory ( DFT) indices accounts for the very low polar character of these 32CA reactions, while analysis of the DFT energies accounts for the opposite chemoselectivity experimentally observed. Topological analysis of the ELF along the single bond formation makes it possible to characterise the mechanisms of these 32CA reactions as cb- and zw-type. The present MEDT study supports the proposed classification of 32CA reactions into pdr-, pmr-, cb- and zw-type, thus asserting MEDT as the theory able to explain chemical reactivity in Organic Chemistry.

On the nature of organic electron density transfer complexes within molecular electron density theory.

The structural features of a series of organic molecular complexes formed between the strong electrophilic tetracyanoethylene and twelve benzene derivatives with increased nucleophilic character, herein called Electron Density Transfer Complexes (EDTCs), have been studied using Molecular Electron Density Theory. The favourable nucleophilic/electrophilic interactions, which favour the global electron density transfer (GEDT) towards the electrophile, are responsible for the formation of these species. Molecular complexes presenting a GEDT above 0.05e are classified as EDTCs. Analysis of the Parr functions of the separated reagents and the topological analysis of the electron density of the EDTCs allow the understanding of the subtle changes in the electronic structure of this significant class of molecular complexes, and consequently, their physical properties.

Are one-step aromatic nucleophilic substitutions of non-activated benzenes concerted processes?

Aromatic nucleophilic substitution (SNAr) reactions of non-electrophilically activated benzenes have been studied within the Molecular Electron Density Theory (MEDT) at the B3LYP/6-311+G(d) computational level. These reactions, taking place through a one-step mechanism, present a high activation Gibbs free energy, ΔG≠ = 31.0 kcal mol-1, which decreases to 22.1 kcal mol-1 in the intramolecular process. A topological analysis of the electron localisation function along the reaction paths permits establishing the non-concerted nature of these SNAr reactions. A series of unstable structures, with similar electronic structures to those of Meisenheimer intermediates, are characterised. The present MEDT study makes it possible to establish that even these one-step SNAr reactions involving only two single bonds are non-concerted processes.

Unveiling the high reactivity of cyclohexynes in [3 + 2] cycloaddition reactions through the molecular electron density theory.

[3 + 2] cycloaddition (32CA) reactions of cyclohexyne, a cyclic strained acetylene, with methyl azide and methoxycarbonyl diazomethane have been studied within the Molecular Electron Density Theory (MEDT) at the MPWB1K/6-311G(d) computational level. These 32CA reactions, which take place through a one-step mechanism involving highly asynchronous transition state structures, proceed with relatively low activation enthalpies of 6.0 and 4.3 kcal mol-1, respectively, both reactions being strongly exothermic. The reactions are initiated by the creation of a pseudoradical center at one of the two acetylenic carbons of cyclohexyne with a very low energy cost, 1.0 kcal mol-1, which promotes the easy formation of the first C-N(C) single bond in the adjacent acetylenic carbon. This scenario is completely different from that of the 32CA reaction involving non-strained but-2-yne; thus, strain in cyclohexyne triggers a high reactivity as a consequence of its unusual electronic structure at the ground state. Finally, the experimental regioselectivity of the 32CA reactions involving 3-alkoxy-cyclohexyne derivatives is correctly explained within MEDT.

A Molecular Electron Density Theory Study of the Synthesis of Spirobipyrazolines through the Domino Reaction of Nitrilimines with Allenoates.

The reaction of diphenyl nitrilimine (NI) with methyl 1-methyl-allenoate yielding a spirobipyrazoline has been studied within molecular electron density theory (MEDT) at the MPWB1K/6-311G(d) computational level in dichloromethane. This reaction is a domino process that comprises two consecutive 32CA reactions with the formation of a pyrazoline intermediate. Analysis of the relative Gibbs free energies indicates that both 32CA reactions are highly regioselective, the first one being also completely chemoselective, in agreement with the experimental outcomes. The geometries of the TSs indicate that they are associated to asynchronous bond formation processes in which the shorter distance involves the C1 carbon of diphenyl NI. Despite the zwitterionic structure of diphenyl NI, the appearance of a pseudoradical structure at the beginning of the reaction path, with a very low energy cost, suggests that the 32CA reaction between diphenyl NI, a strong nucleophile, and the allenoate, a moderate electrophile, should be mechanistically considered on the borderline between pmr-type and cb-type 32CA reactions, somewhat closer to the latter.