Paul Fleurat-Lessard

Challenging 50 Years of Established Views on Ugi Reaction: A Theoretical Approach

The Ugi reaction is one of the most famous multicomponent couplings, and its efficiency is still explained by the original mechanism suggested by Ugi in the 60s. This article aims to present a thorough theoretical study of this reaction. It describes how the imine is activated and how the new stereogenic center is formed. Our calculations strongly suggest alternatives to some commonly accepted features, such as the reversibility of the intermediate steps, and temper the nature of the driving force of the reaction.

Evidences for the Key Role of Hydrogen Bonds in Nucleophilic Aromatic Substitution Reactions

The effect of hydrogen bonds on the fate of nucleophilic aromatic substitutions (S(N)Ar) has been studied in silico using a density functional theory approach in the condensed phase. The importance of these hydrogen bonds can explain the built-in solvation model of Bunnett concerning intermolecular processes between halogenonitrobenzenes and amines. It is also demonstrated that it can explain experimental results for a multicomponent reaction (the Ugi-Smiles coupling), involving an intramolecular S(N)Ar (the Smiles rearrangement) as the key step of the process. Modeling reveals that when an intramolecular hydrogen bond is present, it lowers the activation barrier of this step and enables the multicomponent reaction to proceed.

Multiscale Modeling of Chemistry in Water: Are We There Yet?

This paper critically evaluates the state of the art in combined quantum mechanical/molecular mechanical (QM/MM) approaches to the computational description of chemistry in water and supplies guidelines for the setup of customized multiscale simulations of aqueous processes. We differentiate between structural and dynamic performance, since some tasks, e.g., the reproduction of NMR or UV-vis spectra, require only structural accuracy, while others, i.e., reaction mechanisms, require accurate dynamic data as well. As a model system for aqueous solutions in general, the approaches were tested on a QM water cluster in an environment of MM water molecules. The key difficulty is the description of the possible diffusion of QM molecules into the MM region and vice versa. The flexible inner region ensemble separator (FIRES) approach constrains QM solvent molecules within an active (QM) region. Sorted adaptive partitioning (SAP), difference-based adaptive solvation (DAS), and buffered-force (BF) are all adaptive approaches that use a buffer zone in which solvent molecules gradually adapt from QM to MM (or vice versa). The costs of SAP and DAS are relatively high, while BF is fast but sacrifices conservation of both energy and momentum. Simulations in the limit of an infinitely small buffer zone, where DAS and SAP become equivalent, are discussed as well and referred to as ABRUPT. The best structural accuracy is obtained with DAS, BF, and ABRUPT, all three of similar quality. FIRES performs very well for dynamic properties localized deep within the QM region. By means of elimination DAS emerges as the best overall compromise between structural and dynamic performance. Eliminating the buffer zone (ABRUPT) improves efficiency and still leads to surprisingly good results. While none of the many new flavors are perfect, all together this new field already allows accurate description of a wide range of structural and dynamic properties of aqueous solutions.

Understanding the HIV-1 Protease Reactivity with DFT: What Do We Gain from Recent Functionals?

The modeling of HIV-1 plays a crucial role in the understanding of its reactivity and its interactions with specific drugs. In this work, we propose a medium sized model to test the ability of a variety of quantum chemistry approaches to provide reasonable geometric parameters and energetics for this system. Although our model is large enough to include the main polarizing groups of the active site, it is small enough to be used within full quantum studies up to the second order Møller-Plesset (MP2) level with extrapolations to coupled cluster CCSD(T) level. These high level calculations are used as reference to assess the ability of electronic structure methods (semiempirical and DFT) to provide accurate geometries and energies for the HIV-1 protease reaction. All semiempirical methods fail to describe the geometry of the protease active site. Within DFT, pure generalized gradient approximation (GGA) functionals have difficulty in reproducing the reaction energy and underestimate the barrier. Hybrid and/or meta GGA approaches do not yield a consistent improvement. The best results are obtained with hybrid GGA B3LYP or X3LYP and with hybrid meta GGA functionals with a fraction of exact exchange around 30-40%, such as M06, B1B95, or BMK functionals. On the basis of these results, we propose an accurate and computationally efficient strategy, employing quantum chemistry methods. This is applied here to study the protonation state of the reaction intermediate and could be easily used in further QM/MM studies.

A valence bond view of isocyanides' electronic structure

High level Valence Bond calculations support a predominantly carbenic electronic structure for isocyanides, with a secondary zwitterionic character, despite their linear geometry. This geometry results from the significant energetic stabilization due to nitrogen π lone pair donation. Results are not changed by substitution or solvation effects.

Substituent Effects in Ugi–Smiles Reactions

In a recent communication, we described the mechanism of the well-known Ugi-type reactions with a model system (J. Org. Chem. 2012, 77, 1361-1366). Herein, focusing on the Ugi-Smiles coupling, we study the effects of each of the four reactants on the energy profile to further explain the experimental results. The variations observed with different carbonyl compounds rely on their influence on the formation of the aryl-imidate, whereas the variations on the amine preferentially affect the Smiles rearrangement. The effect of substituents on the phenol derivative is seen upon both aryl-imidate formation and the rearrangement. The effect of the isocyanide substituents is less pronounced.

Multiple Roles of Isocyanides in Palladium‐Catalyzed Imidoylative Couplings: A Mechanistic Study

Kinetic, spectroscopic and computational studies examining a palladium-catalyzed imidoylative coupling highlight the dual role of isocyanides as both substrates and ligands for this class of transformations. The synthesis of secondary amides from aryl halides and water is presented as a case study. The kinetics of the oxidative addition of ArI with RNC-ligated Pd0 species have been studied and the resulting imidoyl complex [(ArC=NR)Pd(CNR)2 I] (Ar=4-F-C6 H4 , R=tBu) has been isolated and characterized by X-ray diffraction. The unprecedented ability of this RNC-ligated imidoyl-Pd complex to undergo reductive elimination at room temperature to give the amide in the presence of water and an F- /HF buffer is demonstrated. Its behavior in solution has also been characterized, revealing an unexpected strong tendency to give cationic complexes, and notably [(ArC=NR)Pd(CNR)3 ]+ with excess isocyanide and [(ArC=NR)Pd(PP^ )(CNR)]+ with bidentate phosphines (PP^ ). These species may be responsible for catalyst deactivation and side-reactions. Ab initio calculations performed at the DFT level allowed us to rationalize the multiple roles of RNC in the different steps of the catalytic cycle.

Proton Transfer in Aqueous Solution: Exploring the Boundaries of Adaptive QM/MM

In this chapter, we review the current state-of-the-art in quantum mechanical/molecular mechanical (QM/MM) simulations of reactions in aqueous solutions, and we discuss how proton transfer poses new challenges for its successful application. In the QM/MM description of an aqueous reaction, solvent molecules in the QM region are diffusive and need to be either constrained within the region, or their description (QM versus MM) needs to be updated as they diffuse away. The latter approach is known as adaptive QM/MM. We review several constrained and adaptive QM/MM methods, and classify them in a consistent manner. Most of the adaptive methods employ a transition region, where every solvent molecule can continuously change character (from QM to MM, and vice versa), temporarily becoming partially QM and partially MM. Where a conventional QM/MM scheme partitions a system into a set of QM and a set of MM atoms, an adaptive method employs multiple QM/MM partitions, to describe the fractional QM character. We distinguish two classes of adaptive methods: Discontinuous and continuous. The former methods use at most two QM/MM partitions, and cannot completely avoid discontinuities in the energy and the forces. The more recent continuous adaptive methods employ a larger number of QM/MM partitions for a given configuration. Comparing the performance of the methods for the description of solution chemistry, we find that in certain cases the low-cost constrained methods are sufficiently accurate. For more demanding purposes, the continuous adaptive schemes provide a good balance between dynamical and structural accuracy. Finally, we challenge the adaptive approach by applying it to the difficult topic of proton transfer and diffusion. We present new results, using a well-behaved continuous adaptive method (DAS) to describe an alkaline aqueous solution of methanol. Comparison with fully QM and fully MM simulations shows that the main discrepancies are rooted in the presence of a QM/MM boundary, and not in the adaptive scheme. An anomalous confinement of the hydroxide ion to the QM part of the system stems from the mismatch between QM and MM potentials, which affects the free diffusion of the ion. We also observe an increased water density inside the QM region, which originates from the different chemical potentials of the QM and MM water molecules. The high density results in locally enhanced proton transfer rates.

Energy extrapolation schemes for adaptive multi-scale molecular dynamics simulations

This paper evaluates simple schemes to extrapolate potential energy values using the set of energies and forces extracted from a molecular dynamics trajectory. In general, such a scheme affords the maximum amount of information about a molecular system at minimal computational cost. More specifically, schemes like this are very important in the field of adaptive multi-scale molecular dynamics simulations. In this field, often the computation of potential energy values at certain trajectory points is not required for the simulation itself, but solely for the a posteriori analysis of the simulation data. Extrapolating the values at these points from the available data can save considerable computational time. A set of extrapolation schemes are employed based on Taylor series and central finite difference approximations. The schemes are first tested on the trajectories of molecular systems of varying sizes, obtained at MM and QM level using velocity-Verlet integration with standard simulation time steps. Remarkably good accuracy was obtained with some of the approximations, while the failure of others can be explained in terms of the distinct features of a molecular dynamics trajectory. We have found that, for a Taylor expansion of the potential energy, both a first and a second order truncation exhibit errors that grow with system size. In contrast, the second order central finite difference approximation displays an accuracy that is independent of the size of the system, while giving a very good estimate of the energy, and costing as little as a first order truncation of the Taylor series. A fourth order central finite difference approximation requires more input data, which is not always available in adaptive multi-scale simulations. Furthermore, this approximation gives errors of similar magnitude or larger than its second order counterpart, at standard simulation time steps. This leads to the conclusion that a second order central finite difference approximation is the optimal choice for energy extrapolation from molecular dynamics trajectories. This finding is confirmed in a final application to the analysis of an adaptive multi-scale simulation.

A Density Functional Theory Study of the Nef-Isocyanide Reaction: Mechanism, Influence of Parameters and Scope

The Nef reaction between isocyanides and acyl chlorides is studied at the M06-2X/6-311+G(d,p) level of theory in toluene. After proving that the reaction follows a concerted mechanism instead of an addition-elimination path, we study the influences of the solvent, the isocyanide, the acyl moiety and the leaving group on the energy profile of the reaction. The calculated data can be rationalized with the pK(a) of the leaving group, or more generally with the population of the oxygen lone pairs of the acyl moiety.