Applications of the Conceptual Density Functional Theory Indices to Organic Chemistry Reactivity

Indexación: Web of ScienceTheoretical reactivity indices based on the conceptual Density Functional Theory (DFT) have become a powerful tool for the semiquantitative study of organic reactivity. A large number of reactivity indices have been proposed in the literature. Herein, global quantities like the electronic chemical potential μ, the electrophilicity ω and the nucleophilicity N indices, and local condensed indices like the electrophilic and nucleophilic Parr functions, as the most relevant indices for the study of organic reactivity, are discussed.http://www.mdpi.com/1420-3049/21/6/74

Unravelling [3+2] Cycloaddition Reactions through the Molecular Electron Density Theory

Después de la primera clasificación de las reacciones 32CA en reacciones de tipo zw y pr, establecidas en el año 2014, la estructura y reactividad de los TACs más importantes utilizados en las reacciones 32CA ha sido completamente caracterizado en base a la MEDT propuesta recientemente. Entre la gran cantidad de trabajo desarrollado a lo largo de la presente tesis doctoral, se han seleccionado y discutido ocho publicaciones representativas, que permitieron caracterizar dos nuevos tipos de reactividad y consolidar la reactividad original de tipo zw. Así, dependiendo de las cuatro estructuras electrónicas diferentes de los TACs, es decir, pseudodiradical, pseudoradical, carbenoide y zwitteriónica, las reacciones 32CA se han clasificado en reacciones de tipo pdr, pmr, cb y zw. Mientras que las reacciones 32CA de tipo pdr son las más rápidas, las reacciones de tipo zw son las más lentas. Las diferentes estructuras electrónicas en el estado fundamental de los reactivos explican esta tendencia de reactividad y revelan que la reactividad de los TACs carbenoides es diferente. Además, ningún TAC puede considerarse una estructura 1,2-zwitteriónica, tal y como se propone para los “1,3-dipolos”. El carácter polar de la reacción, medido por el valor de la GEDT calculado en la estructura del TS, afecta a los cuatro tipos de reactividad, de tal forma que cuanto más fuertes sean las interacciones nucleofílicas / electrofílicas que tienen lugar en el TS, más rápida es la reacción, e incluso puede cambiar el mecanismo molecular de acuerdo con las funciones de Parr definidas dentro de la CDFT. Esta racionalización basada en la MEDT de las reacciones 32CA esclarece las propuestas mecanísticas de Huisgen y Firestone establecidas en los años 60. Independientemente del tipo de reactividad y el carácter polar de la reacción, el análisis topológico de la ELF a lo largo de las reacciones 32CA que tienen lugar en un solo paso sugiere que los cambios de enlace no son “concertados” sino secuenciales, descartando así la clasificación de estas reacciones como “pericíclicas”. En la presente tesis doctoral, la teoría clásica de las reacciones 32CA, establecida en los años 60 del siglo pasado y que aún prevalece en la actualidad, es revisitada y reinterpretada en base a la MEDT. Se establece un nuevo y sólido modelo de reactividad para las reacciones 32CA, enfatizando que la visión actual de la química orgánica necesita replantearse en base al análisis de la densidad electrónica.After the first classification of [3+2] cycloaddition (32CA) reactions into zw-type and pr-type reactions, established in 2014, the structure and reactivity of the most important three-atom-components (TACs) used in 32CA reactions has been completely characterised within the recently proposed Molecular Electron Density Theory (MEDT). Among the huge amount of work developed along the present Ph.D thesis, eight representative publications have been selected and discussed herein, which allowed characterising two new reactivity types as well as consolidating the original zw-type reactivity. Thus, depending on the four different electronic structures of TACs, i.e. pseudodiradical, pseudoradical, carbenoid and zwitterionic, 32CA reactions have been classified into pdr-, pmr-, cb- and zw-type reactions. While pdr-type 32CA reactions are the fastest, zw-type reactions are the slowest. The different electronic structures at the ground state of the reagents account for this reactivity trend and reveal that the reactivity of carbenoid TACs is different. In addition, no TAC can be considered a 1,2-zwitterionic structure as proposed for “1,3-dipoles”. The polar character of the reaction, measured by the global electron density transfer value computed at the transition state structure (TS), affects the four reactivity types in such a manner that the stronger the nucleophilic/electrophilic interactions taking place at the TS, the faster the reaction, and may even change the molecular mechanism according to the Parr functions defined within Conceptual DFT. This MEDT rationalisation of 32CA reactions unravels classical Huisgen’s and Firestone’s mechanistic proposals established in the 60’s. Regardless of the reactivity type and polar character of the reaction, topological analysis of the electron localisation function along one-step 32CA reactions suggests that the bonding changes are not “concerted”, but sequential, thus ruling out the classification of these reactions as “pericyclic”. In the present thesis, the classical theory of 32CA reactions, established in the 60’s of the past century and still prevailing today, is revisited and reinterpreted based on MEDT. A solid new reactivity model for 32CA reactions is established, emphasising that the way that organic chemists conceive organic chemistry demands a contemporary revision aimed towards the analysis of electron density

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

Effectiveness of an intervention for improving drug prescription in primary care patients with multimorbidity and polypharmacy:Study protocol of a cluster randomized clinical trial (Multi-PAP project)

This study was funded by the Fondo de Investigaciones Sanitarias ISCIII (Grant Numbers PI15/00276, PI15/00572, PI15/00996), REDISSEC (Project Numbers RD12/0001/0012, RD16/0001/0005), and the European Regional Development Fund ("A way to build Europe").Background: Multimorbidity is associated with negative effects both on people's health and on healthcare systems. A key problem linked to multimorbidity is polypharmacy, which in turn is associated with increased risk of partly preventable adverse effects, including mortality. The Ariadne principles describe a model of care based on a thorough assessment of diseases, treatments (and potential interactions), clinical status, context and preferences of patients with multimorbidity, with the aim of prioritizing and sharing realistic treatment goals that guide an individualized management. The aim of this study is to evaluate the effectiveness of a complex intervention that implements the Ariadne principles in a population of young-old patients with multimorbidity and polypharmacy. The intervention seeks to improve the appropriateness of prescribing in primary care (PC), as measured by the medication appropriateness index (MAI) score at 6 and 12months, as compared with usual care. Methods/Design: Design:pragmatic cluster randomized clinical trial. Unit of randomization: family physician (FP). Unit of analysis: patient. Scope: PC health centres in three autonomous communities: Aragon, Madrid, and Andalusia (Spain). Population: patients aged 65-74years with multimorbidity (≥3 chronic diseases) and polypharmacy (≥5 drugs prescribed in ≥3months). Sample size: n=400 (200 per study arm). Intervention: complex intervention based on the implementation of the Ariadne principles with two components: (1) FP training and (2) FP-patient interview. Outcomes: MAI score, health services use, quality of life (Euroqol 5D-5L), pharmacotherapy and adherence to treatment (Morisky-Green, Haynes-Sackett), and clinical and socio-demographic variables. Statistical analysis: primary outcome is the difference in MAI score between T0 and T1 and corresponding 95% confidence interval. Adjustment for confounding factors will be performed by multilevel analysis. All analyses will be carried out in accordance with the intention-to-treat principle. Discussion: It is essential to provide evidence concerning interventions on PC patients with polypharmacy and multimorbidity, conducted in the context of routine clinical practice, and involving young-old patients with significant potential for preventing negative health outcomes. Trial registration: Clinicaltrials.gov, NCT02866799Publisher PDFPeer reviewe

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

A useful classification of organic reactions based on the flux of the electron density

A useful classification of polar organic reactions in Forward Electron Density Flux (FEDF) and Reverse Electron Density Flux (REDF), based on the unambiguously analysis of the direction of the flux of the global electron density transfer (GEDT) at the transition state structures (TSs), has been recently proposed (RSC Adv. 2020, 10, 15394) within the Molecular Electron Density Theory. Further, non-polar reactions have been classified as Null Electron Density Flux (NEDF) (Eur. J. Org. Chem. 2020, 5938). This classification allows characterizing the nucleophilic/electrophilic species participating in polar reactions. Analysis of the electronic chemical potential µ, and the electrophilicity ω and nucleophilicity N indices, defined within Conceptual DFT, at the ground state (GS) of the reagents also permits to establish this classification of polar reactions

A Molecular Electron Density Theory Study of the Reactivity of Azomethine Imine in [3+2] Cycloaddition Reactions

The electronic structure and the participation of the simplest azomethine imine (AI) in [3+2] cycloaddition (32CA) reactions have been analysed within the Molecular Electron Density Theory (MEDT) using Density Functional Theory (DFT) calculations at the MPWB1K/6-311G(d) level. Topological analysis of the electron localisation function reveals that AI has a pseudoradical structure, while the conceptual DFT reactivity indices characterises this three-atom-component (TAC) as a moderate electrophile and a good nucleophile. The non-polar 32CA reaction of AI with ethylene takes place through a one-step mechanism with moderate activation energy, 8.7 kcal·mol−1. A bonding evolution theory study indicates that this reaction takes place through a non-concerted [2n + 2τ] mechanism in which the C–C bond formation is clearly anticipated prior to the C–N one. On the other hand, the polar 32CA reaction of AI with dicyanoethylene takes place through a two-stage one-step mechanism. Now, the activation energy is only 0.4 kcal·mol−1, in complete agreement with the high polar character of the more favourable regioisomeric transition state structure. The current MEDT study makes it possible to extend Domingo’s classification of 32CA reactions to a new pseudo(mono)radical type (pmr-type) of reactivity

Unveiling the Chemistry of Higher-Order Cycloaddition Reactions within the Molecular Electron Density Theory

The higher-order cycloaddition (HOCA) reaction of tropone with cyclopentadiene (Cp) has been studied within the Molecular Electron Density Theory. The Electron Localization Function (ELF) analysis of the electronic structure of tropone and Cp characterizes the structural behaviors of the two conjugated unsaturated systems, while the conceptual DFT reactivity indices classify tropone as a strong electrophile and Cp as a strong nucleophile participating in polar cycloaddition reactions of reverse electron density flux. Eight competitive reaction paths have been characterized for this cycloaddition reaction. The most favorable one allowing the formation of the formal out [6 + 4] cycloadduct has an activation enthalpy of 16.2 kcal·mol−1, and the reaction is exothermic by −21.4 kcal·mol−1. This HOCA reaction, which takes place through a non-concerted two-stage one-step mechanism, presents high stereo-, pseudocyclic- and regioselectivities, explaining the exclusive formation of the experimental [6 + 4] cycloadduct. While the most favorable nucleophilic attack of Cp on most electrophilic C2 positions of tropone accounts for regioselectivities, the favorable electrostatic interactions present between the Cp framework and the negatively charged O8 oxygen of tropone account for the stereo- and pseudocyclic selectivities. Despite the symmetry of the two reagents, this HOCA reaction takes place via a highly asynchronous transition state structure as a consequence of the most favorable two-center interactions taking place between the electrophilic C2 center of tropone and the nucleophilic C9 center of Cp

A Molecular Electron Density Theory Study of the [3+2] Cycloaddition Reaction of Pseudo(mono)radical Azomethine Ylides with Phenyl Vinyl Sulphone

The [3+2] cycloaddition (32CA) reaction of an azomethine ylide (AY), derived from isatin and L-proline, with phenyl vinyl sulphone has been studied within Molecular Electron Density Theory (MEDT) at the ωB97X-D/6-311G(d,p) level. ELF topological analysis of AY classifies it as a pseudo(mono)radical species with two monosynaptic basins at the C1 carbon, integrating a total of 0.76 e. While vinyl sulphone has a strong electrophilic character, AY is a supernucleophile, suggesting a high polar character and low activation energy for the reaction. The nucleophilic Parr functions indicate that the pseudoradical C1 carbon is the most nucleophilic center. The 32CA reaction presents an activation Gibbs free energy of 13.1 kcal·mol−1 and is exergonic by −26.8 kcal·mol−1. This reaction presents high endo stereoselectivity and high meta regioselectivity. Analysis of the global electron density transfer (GEDT) at the most favorable meta/endo TS, 0.31 e, accounts for the high polar character of this 32CA reaction, classified by forward electron density flux (FEDF). A Bonding Evolution Theory (BET) study along the most favorable meta/endo reaction path characterizes this 32CA reaction, taking place through a non-concerted two-stage one-step mechanism, as a pseudo(mono)radical-type 32CA reaction, in agreement with the ELF analysis of the AY