New insight into atomic-level interpretation of interactions in molecules and reacting systems.

We hereby introduce the atomic degree of interaction (DOI), a new concept rooted in the electron density-based independent gradient model (IGM). Capturing any manifestation of electron density sharing around an atom, including covalent and non-covalent situations, this index reflects the attachment strength of an atom to its molecular neighbourhood. It is shown to be very sensitive to the local chemical environment of the atom. No significant correlation could be found between the atomic DOI and various other atomic properties, making this index a specific source of information. However, examining the simple H2 + H reacting system, a strong connection has been established between this electron density-based index and the scalar reaction path curvature, the cornerstone of the benchmark unified reaction valley approach (URVA). We observe that reaction path curvature peaks appear when atoms experience an acceleration phase of electron density sharing during the reaction, detected by peaks of the DOI second derivative either in the forward or reverse direction. This new IGM-DOI tool is only in its early stages, but it opens the way to an atomic-level interpretation of reaction phases. More generally, the IGM-DOI tool may also serve as an atomic probe of electronic structure changes of a molecule under the influence of physicochemical perturbations.

Deciphering the Role of Noncovalent Interactions in the Conformations of Dibenzo-1,5-dichalcogenocines.

This work reports a combined experimental and theoretical study on the new dibenzo-1,5-ditellurocine 2-Te in order to get an overview on the parameters controlling conformational change and to explain the differences with sulfur and selenium analogues. The preference of the boat conformer over the chair one is revealed by DFT calculations. For 2-Te, a ΔG value of about 3 kJ/mol was calculated, close to the value measured by NMR (5 kJ/mol). However, DFT calculations with implicit solvation effects could not clearly establish the presence of an intramolecular Te…HC noncovalent interaction (NCI), as observed in the solid state. The Independent Gradient Model (IGM) methodology discloses an existent but probably not sufficiently discriminating Te…HC NCI. It also confirms that van der Waals interactions between phenyl rings is a source of stabilization of the boat conformer. Furthermore, electrostatic potential analysis suggests that chalcogen bonds between Te σ-holes and solvent might play an important role.

Mechanistic insights into Smiles rearrangement. Focus on π-π stacking interactions along the radical cascade.

The synthesis of new arene and heteroarene scaffolds of therapeutic interest has generated a renewed interest in the domino radical cyclisation-Smiles. In this work we present a detailed mechanistic investigation of the radical version of a cascade involving a desulfonative Smiles rearrangement on an aromatic ring bearing a sulfonamide linker. Competing routes have been explored to characterize the molecular mechanism of the studied reaction. The knowledge gained from previous experimental observations is explained through the energy profile obtained by means of quantum mechanical calculations. This study answers questions about the rate determining step and the type of mechanism involved (two-step or concerted). Supplementary rate constant calculations as well as quantum molecular dynamics support experimental observations. An IGM-δg analysis performed along the reaction path unveils and quantifies an intramolecular π-π stacking interaction accelerating the reaction. This novel post processing IGM-δg tool based on the electron density, turns out to be useful to monitor and quantify specific intramolecular weak interactions along a reaction path from wave functions. From this mechanistic investigation it turns out that Smiles rearrangement here takes place in two steps rather than in a direct intramolecular radical substitution. Furthermore, we show that chain length effects must be taken into account in the functionalization of new sulfonylated derivatives subjected to this radical cascade, given their influence in the reaction rate.

New Way for Probing Bond Strength.

The covalent chemical bond is intimately linked to electron sharing between atoms. The recent independent gradient model (IGM) and its δg descriptor provide a way to quantify locally this electron density interpenetration from wavefunction calculations. Each bond has its own IGM-δgpair signature. The present work establishes for the first time a strong link between this bond signature and the physically grounded bond force constant concept. Analyzing a large set of compounds and bonds, the intrinsic bond strength index (IBSI) emerges from the IGM formulation. Our study shows that the IBSI does not belong to the class of conventional bond orders (like Mulliken, Wiberg, Mayer, delocalization index, or electron localization function-ELF), but is rather a new complementary index, related to the bond strength. A fundamental outcome of this research is a novel index allowing to range all two-center chemical bonds by their intrinsic strength in molecular situation. We believe that the IBSI is a powerful and robust tool for interpretation accessible to a wide community of chemists (organic, inorganic chemistry, including transition-metal complexes and reaction mechanisms).

The Independent Gradient Model: A New Approach for Probing Strong and Weak Interactions in Molecules from Wave Function Calculations.

Extraction of the chemical interaction signature from local descriptors based on electron density (ED) is still a fruitful field of development in chemical interpretation. In a previous work that used promolecular ED (frozen ED), the new descriptor, δg , was defined. It represents the difference between a virtual upper limit of the ED gradient (∇ρIGM , IGM=independent gradient model) that represents a noninteracting system and the true ED gradient (∇ρ ). It can be seen as a measure of electron sharing brought by ED contragradience. A compelling feature of this model is to provide an automatic workflow that extracts the signature of interactions between selected groups of atoms. As with the noncovalent interaction (NCI) approach, it provides chemists with a visual understanding of the interactions present in chemical systems. ∇ρIGM is achieved simply by using absolute values upon summing the individual gradient contributions that make up the total ED gradient. Hereby, we extend this model to relaxed ED calculated from a wave function. To this end, we formulated gradient-based partitioning (GBP) to assess the contribution of each orbital to the total ED gradient. We highlight these new possibilities across two prototypical examples of organic chemistry: the unconventional hexamethylbenzene dication, with a hexa-coordinated carbon atom, and ß-thioaminoacrolein. It will be shown how a bond-by-bond picture can be obtained from a wave function, which opens the way to monitor specific interactions along reaction paths.

Development of the first model of a phosphorylated, ATP/Mg2+-containing B-Raf monomer by molecular dynamics simulations: a tool for structure-based design.

A model of phosphorylated and ATP-containing B-Raf protein kinase is needed as a tool for the structure-based design of new allosteric inhibitors, since no crystal structure of such a system has been resolved. Here, we present the development of such a model as well as a thorough analysis of its structural features. This model was prepared using a systematic molecular dynamics approach considering the presence or absence of both the phosphate group at the Thr599 site and the ATP molecule. Then, different structural features (i.e. DFG motif, Mg2+ binding loop, activation loop, phosphorylation site and αC-helix region) were analysed for each trajectory to validate the aimed 2pBRAF_ATP model. Moreover, the structure and activating interactions of this 2pBRAF_ATP model were found to be in agreement with previously reported information. Finally, the model was further validated by means of a molecular docking study with our previously developed lead compound I confirming that this ATP-containing, phosphorylated protein model is suitable for further structure-based design studies.

Accurately extracting the signature of intermolecular interactions present in the NCI plot of the reduced density gradient versus electron density.

An electron density (ED)-based methodology is developed for the automatic identification of intermolecular interactions using pro-molecular density. The expression of the ED gradient in terms of atomic components furnishes the basis for the Independent Gradient Model (IGM). This model leads to a density reference for non interacting atoms/fragments where the atomic densities are added whilst their interaction turns off. Founded on this ED reference function that features an exponential decay also in interference regions, IGM model provides a way to identify and quantify the net ED gradient attenuation due to interactions. Using an intra/inter uncoupling scheme, a descriptor (δginter) is then derived that uniquely defines intermolecular interaction regions. An attractive feature of the IGM methodology is to provide a workflow that automatically generates data composed solely of intermolecular interactions for drawing the corresponding 3D isosurface representations.

Metalation of pyridines with nBuLi-Li-aminoalkoxide mixed aggregates: The origin of chemoselectivity.

The reactivity of alkyllithium-lithium-aminoalkoxide unimetallic superbases has been investigated. These systems are used for deprotonative lithiation of pyridine derivatives in apolar non-coordinating media with excellent regio- and chemoselectivity, in deep contrast with alkyllithium. With the aim of getting a better understanding of the chemistry behind these promising reagents, we have carried out a joint experimental and theoretical study of the metalation of 2-chloropyridine with combinations of nBuLi and (S)-(-)-N-methyl-2-pyrrolidinylmethoxide (LiPM). Nucleophilic addition or alpha-lithiation has been observed, depending on conditions (solvent, temperature, stoichiometry), while ortho-metalation was not detected. Theoretical calculations using Density Functional Theory (B3LYP/6-31G(d) method) have then been carried out in gas phase at 195 K to characterize the relevant chemical species (reactive aggregates, transition structures) and estimate free energies of activation and relative reaction rates. Solvent effects in hexane have been neglected according to previous calculations. The effect of coordinating solvents such as THF has been qualitatively discussed. A major achievement of the present work has been to demonstrate that chemoselectivity crucially depends on aggregate type: dimers systematically lead to nucleophilic addition, while tetramers lead to alpha-lithiation. Besides, the calculations predict dimers to be more reactive than tetramers, yet they are much less stable, so that the observed selectivity results from the combination of both properties. A simple procedure to evaluate the basicity of an organlithium compound has been proposed. It has allowed us to show that the nBuLi-LiPM tetramer has a significantly larger basicity than its corresponding dimer, which is not at all the case for nBuLi aggregates, thus explaining differences in selectivity. Solvent and temperature effects on nBuLi-LiPM reactivity have been analyzed. By increasing the temperature in hexane, or changing the solvent from hexane to THF, dimer concentration is expected to rise, and likewise the weight of nucleophilic addition rises, in agreement with the experimental findings.

Structure of mixed alkyllithium/lithium alkoxide aggregates in ethereal solvents. Insights from combined QM/MM molecular dynamics simulations.

Mixed alkyllithium/lithium alkoxides aggregates are important species in synthetic organic chemistry, but their electronic and geometric properties have not been extensively studied yet. The main objective of this work was to analyze the structure of simple prototypical aggregates in a coordinating solvent with the help of elaborated theoretical chemistry calculations. Within this aim, we have carried out molecular dynamics simulations for MeOLi, (EtLi)(MeOLi), and (EtLi)(2)(MeOLi)(2) systems in dimethyl ether solution. We use a combined QM/MM (quantum mechanics/molecular mechanics) force field that allows an appropriate description of the aggregate structure and of its interactions with the solvent. In the simulations, the aggregates are described at the B3LYP/6-31G(d) level while the solvent is described using the classical OPLS potential. For completeness, the influence of the chemical environment on the C-O-Li bond structure has been analyzed in some detail. The discussion focuses on (1) the distinctive properties of the alkoxide C-O-Li bond pattern, (2) the coordination of solvent molecules to the aggregates (number, stability), and (3) the time fluctuations of main structural parameters (Li-C and Li-O distances). We also show that nonclassical C-H...O hydrogen bonds involving H atoms of the solvent methyl groups and the O atom of the alkoxide are formed in the solvated MeOLi monomer and (EtLi)(MeOLi) dimer. Owing to these specific interactions, the monomer exhibits a nonlinear C-O-Li bond in solution.

A theoretical study on nBuLi/lithium aminoalkoxide aggregation in hexane and THF.

Theoretical calculations on aggregation of nBuLi/lithium aminoalkoxide superbases, such as nBuLi/LiDMAE (LiDMAE = Me(2)N(CH(2))(2)OLi) and nBuLi/LiPM (LiPM = Li-N-methyl-2-pyrrolidine methoxide) in gas phase and solution are reported. The combination of equimolar amounts of each component in hexane induced unusual reactivity of the resulting superbase, which remains misunderstood. In order to elucidate the corresponding reaction mechanisms, it is imperative to get a deeper insight into the energetics of aggregation and the effect of the medium on equilibrium constants. In the present study, we compute and compare the stability of (nBuLi)(n), (LiPM)(n), and equimolecular mixed aggregates (nBuLi:LiPM)(n) in gas phase, hexane, and THF. Calculations have been carried out at the density functional theory level (B3LYP/6-31G(d)) using continuum and discrete continuum models of solvation. Higher-level calculations (MP2/aug-ccpVQZ) have been done in some cases for test purposes. Enthalpic and entropic contributions have been discussed and were shown to play an opposite role in hexane (or gas phase) and THF. The characteristics of LiPM and mixed nBuLi/LiPM solutions are found to be significantly different from those of nBuLi solutions. These calculations are in accordance with experimental data in both hexane and THF. Further comparison of theoretical and experimental results for gas-phase Li(+)-THF and Li(+)-DME complexes has enabled a discussion on computational errors for entropic contributions in THF. The value for the release of a THF solvent molecule is proposed to be DeltaS approximately 23 eu. These results provide new insights to the aggregation of organolithium compounds in solution and will be useful for the investigation of other systems.