Etude théorique de réactions de Heck intramoléculaires

Aromatic cyclic compound opening catalyzed by palladium has been recently observed by ENSTA team. That kind of reactivité for palladium has not been shown before and is in competition with the C-H activation. This work studies theses reactions from a theoretical point of view to better understand the mechanisms. We first look for the functional who gives the best description of the competition between the nitrogen/alkene complexation comparing more than sixty functionals with CCSD(T)/CBS calculation. We choose at last the GGA functional BP86.We then study the intramolecular Heck reaction starting from the N-allyl-2-iodo-aniline. We justified that the indole moiety was the major product and showed that the nitrogen plays no rôle in the regioselectivity.However, in some cases, the nitrogen inhibits the reaction by trapping the palladium complex. A theoretical study showed that the main factor for this inhibition was the population of nitrogen lone pair and not the hybridation of the benzylic carbon.Furan opening was then considered. Between all the mechanisms proposed, our theoretical study showed that the main way is the β-alkoxyelimination, potentially assisted by the trialkylamine present in the environment.Finally, we have studied the benzylfurfurylaniline opening. The mechanism is similar to the one observed for the furan opening until the regeneration of the palladium complex. Indeed, in that case, the base plays the rôle of a proton donor.L'ouverture de cycle aromatique catalysée par le palladium a été récemment observée par une équipe de l'ENSTA. Ce type de réactivité du palladium n’a jamais été observé auparavant et entre en compétition avec l’activation C-H classique. Ce travail de thèse a consisté à étudier ces réactions d'un point de vue théorique pour mieux en comprendre les mécanismes.Nous avons tout d'abord cherché la fonctionnelle permettant la meilleure description de la compétition entre la complexation azote/alcène en comparant plus de soixante fonctionnelles à des calculs CCSD(T)/CBS. Nous avons retenu la fonctionnelle GGA BP86.Nous avons ensuite étudié la réaction de Heck intramoléculaire à partir de la N-allyl-2-iodo-aniline. Nous avons justifié que l'indole soit le produit majoritairement obtenu, et montré que l'azote ne joue pas de rôle sur la régiosélectivité. Cependant, dans certains cas, l'azote inhibe la réaction en piégeant le complexe de palladium. Une étude théorique a montré que le facteur prépondérant de cette inhibition est la population électronique de l'azote et non l'hybridation du carbone benzylique.L'ouverture du furane a été ensuite considérée. Parmi tous les mécanismes proposés, notre étude théorique a montré que la voie principale est celle de la β-alkoxyelimination, potentiellement assistée par la trialkylamine présente dans le milieu.Enfin, nous avons étudié l'ouverture du benzylfurfurylaniline. Le mécanisme est similaire à celui observé pour l'ouverture du furane jusqu'à la régénération du complexe de palladium catalytique. En effet, dans le ce cas, la base azotée joue le rôle d'un donneur de proton

Theoretical study of intramolecular Heck reactions

L'ouverture de cycle aromatique catalysée par le palladium a été récemment observée par une équipe de l'ENSTA. Ce type de réactivité du palladium n’a jamais été observé auparavant et entre en compétition avec l’activation C-H classique. Ce travail de thèse a consisté à étudier ces réactions d'un point de vue théorique pour mieux en comprendre les mécanismes.Nous avons tout d'abord cherché la fonctionnelle permettant la meilleure description de la compétition entre la complexation azote/alcène en comparant plus de soixante fonctionnelles à des calculs CCSD(T)/CBS. Nous avons retenu la fonctionnelle GGA BP86.Nous avons ensuite étudié la réaction de Heck intramoléculaire à partir de la N-allyl-2-iodo-aniline. Nous avons justifié que l'indole soit le produit majoritairement obtenu, et montré que l'azote ne joue pas de rôle sur la régiosélectivité. Cependant, dans certains cas, l'azote inhibe la réaction en piégeant le complexe de palladium. Une étude théorique a montré que le facteur prépondérant de cette inhibition est la population électronique de l'azote et non l'hybridation du carbone benzylique.L'ouverture du furane a été ensuite considérée. Parmi tous les mécanismes proposés, notre étude théorique a montré que la voie principale est celle de la β-alkoxyelimination, potentiellement assistée par la trialkylamine présente dans le milieu.Enfin, nous avons étudié l'ouverture du benzylfurfurylaniline. Le mécanisme est similaire à celui observé pour l'ouverture du furane jusqu'à la régénération du complexe de palladium catalytique. En effet, dans le ce cas, la base azotée joue le rôle d'un donneur de proton.Aromatic cyclic compound opening catalyzed by palladium has been recently observed by ENSTA team. That kind of reactivité for palladium has not been shown before and is in competition with the C-H activation. This work studies theses reactions from a theoretical point of view to better understand the mechanisms. We first look for the functional who gives the best description of the competition between the nitrogen/alkene complexation comparing more than sixty functionals with CCSD(T)/CBS calculation. We choose at last the GGA functional BP86.We then study the intramolecular Heck reaction starting from the N-allyl-2-iodo-aniline. We justified that the indole moiety was the major product and showed that the nitrogen plays no rôle in the regioselectivity.However, in some cases, the nitrogen inhibits the reaction by trapping the palladium complex. A theoretical study showed that the main factor for this inhibition was the population of nitrogen lone pair and not the hybridation of the benzylic carbon.Furan opening was then considered. Between all the mechanisms proposed, our theoretical study showed that the main way is the β-alkoxyelimination, potentially assisted by the trialkylamine present in the environment.Finally, we have studied the benzylfurfurylaniline opening. The mechanism is similar to the one observed for the furan opening until the regeneration of the palladium complex. Indeed, in that case, the base plays the rôle of a proton donor

DFT investigation of the formation of linear aminols as the first step toward the induction of oxidatively generated interstrand cross-link DNA lesions

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Performance of recent density functionals to discriminate between olefin and nitrogen binding to palladium

International audienceIn the last decades, density functional theory has become unavoidable in theoretical studies of organometallic chemistry. Most of the recent functionals contain many parameters that are adjusted using carefully chosen reaction sets. However, these sets only contain a few entries involving late transition metal reaction, so that choosing a functional for such a study is difficult. In this work, the theoretical description of the oxidative addition of Pd(PH3)2 to 2-iodo-allyl-aniline was chosen as a representative reaction of palladium. The competitive binding of the palladium to the alkene or the nitrogen atom was used to assess the accuracy of ab initio methods (MP2, MP3, MP2.5, SCS-MP2, SCS-MP3) and 56 functionals ranging from local density approximation to the costly double-hybrid approaches (such as B2PLYP), against a CCSD(T)/CBS reference value. Model systems [(PH3)2ClPd(NH3)]+ and [(PH3)2ClPd(H2C=CH2)]+ were first considered: all functionals correctly predict that the azane complex is the most stable. However, some functionals overestimate its stability compared to the alkene complex. This is amplified in the 2-iodo-allyl-aniline study: SCS-MP3, B2PLYP as well as BP86, most of the meta-GGA (generalized gradient approximation), hybrid GGAs and hybrid meta-GGAs are predicting that oxidative addition proceeds directly. On the contrary, many functionals, among which B3LYP, M06-2X and most range-separated methods, wrongly predict that palladium first binds to the nitrogen atom before proceeding to the olefin insertion. Resorting to these functionals to study inorganic reactions with palladium might thus result in predicting wrong mechanisms

Density Functional Study of Indole Formation by an Intramolecular Heck Reaction

International audienceThe mechanism of an intramolecular palladium-catalyzed Heck–Mizoroki reaction to form indole derivatives was studied using density functional theory (DFT). Starting from the N-allyl-2-iodo-N-methylaniline, four routes were detailed: two lead to five-membered rings and two to six-membered rings. In agreement with previous studies, oxidative addition was found to be the rate-determining step with a rather small activation free enthalpy of 10.2 kcal/mol. The five-membered ring is both kinetically and thermodynamically favored: the activation barriers for the ring closure differ by more than 4 kcal/mol, and the obtained five-membered product is more stable than the six-membered product by 1 kcal/mol . Because of its aromatic character, indole is more stable than the other three products by more than 20 kcal/mol: in agreement with experiments, it is the main product of this reaction. This study also revealed that the nitrogen atom does not play any role in the indole formation, while it discriminates between the two six-membered ring

Stability of the Guanine Endoperoxide Intermediate: A Computational Challenge for Density Functional Theory

International audienceThe addition of singlet molecular oxygen 1O2 onto guanine is a most important and deleterious reaction in biological damage. We assess the efficiency of density functional theory for evaluating the respective stabilities of two intermediates that can form upon 1O2 addition: a charge-separated adduct with a peroxide anion at the C8 position of guanine, and the corresponding cyclic endoperoxide across the 4,8-bond, of the imidazole ring. The reference post Hartree–Fock SCS-MP3/aug-cc-pVTZ//MP2/DZP++ level of theory provides an unambiguous assignment in favor of the endoperoxide intermediate, based on implicitly solvated structures, by −8.0 kcal·mol–1. This value is taken as the reference for a systematic and extended benchmarck performed on 58 exchange--correlation functionals. While B3LYP remains commonly used for studying oxidative DNA lesions, we prove that the stability of the peroxide anion is overestimated by this functional, but also by other commonly used exchange-correlation functionals. The significant error (ca. +3 kcal·mol–1 over a representative set of 58 functionals) arises from overdelocalization but also from the description of the dynamic correlation by the density functional. The significantly improved performance of several recently proposed functionals, including range-separated hybrids such as LC-BLYP, is outlined. We believe that our results will be of great help to further studies on the versatile chemistry of singlet oxygen-induced DNA damage, where complex reaction mechanisms are required to be depicted at a quantum level

An intensive GPU-­-based screening of complexa9on energies towards Lanthanides-­-driven crystallogenesis

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Modélisation de structures d'ADN endommagé : un microscope computationnel

National audienceLa modélisation moléculaire permet la compréhension des phénomènes chimiques à l'échelle atomique. De nos jours, les approches multi-échelles (Prix Nobel de Chimie 2013) sont largement utilisées dans l'étude des mécanismes de formation des lésions de l'ADN [1]. Connaître ce type de réaction est d'importance capitale pour décrire la génération de tels dommages, et dans une plus longue perspective, créer de nouveaux médicaments. La modélisation moléculaire peut apporter des informations permettant de rationaliser et caractériser les phénomènes qui prennent place au sein de la double hélice d'ADN, quand cette dernière est la cible d'agents mutagènes engendrant la modification chimique des nucléobases, à l'origine du vieillissement des cellules, de leur apoptose, ou de leur dégénérescence.Nous nous appuyons sur cet outil dans le but de modéliser les déformations structurales de l'ADN endommagé, et comprendre de quelle manière les lésions peuvent impacter la structure de la double-hélice. Les simulations de dynamique moléculaire nous permettent d'étudier le comportement dynamique de différents systèmes endommagés, et de rationnaliser leur formation par analyse structurale. Nous avons dans ce cadre étudié plusieurs systèmes, comme les mécanismes de formation de la 8-oxoguanine [2], les liaisons inter-brins très cytotoxiques [3], et les dommages induits par rayonnements UV sur les thymines et cytosines [4]. Nos études sont conduites au sein du Labex PRIMES.[1] E. Dumont et al., Front. Chem., Vol. 3, 43, 2015.[2] E. Dumont et al., Nucl. Acids Res., Vol. 44, 56-62, 2016.[3] N. A. Price et al., J. Am. Chem. Soc., Vol. 136, 3483-3490, 2014.[4] E. Bignon et al., Chem. Eur. J., Vol. 21, 32, 11509-16, 2015

Singlet Oxygen Attack on Guanine: Reactivity and Structural Signature within the B-DNA Helix

International audienceOxidatively generated DNA lesions are numerous and versatile, and have been the subject of intensive research since the discovery of 8-oxoguanine in 1984. Even for this prototypical lesion, the precise mechanism of formation remains elusive due to the inherent difficulties in characterizing high-energy intermediates. We have probed the stability of the guanine endoperoxide in B-DNA as a key intermediate and determined a unique activation free energy of around 6 kcal mol−1 for the formation of the first C−O covalent bond upon the attack of singlet molecular oxygen (1O2) on the central guanine of a solvated 13 base-pair poly(dG-dC), described by means of quantum mechanics/molecular mechanics (QM/MM) simulations. The B-helix remains stable upon oxidation in spite of the bulky character of the guanine endoperoxide. Our modeling study has revealed the nature of the versatile 1O2 attack in terms of free energy and shows a sensitivity to electrostatics and solvation as it involves a charge-separated intermediate

From Benzofurans to Indoles: Palladium-Catalyzed Reductive Ring-Opening and Closure via β-Phenoxide Elimination

International audienceBenzofurans can undergo ring-opening by a palladium-catalyzed process resulting in C−O bond breaking. Benzofuran-tethered 2-iodoanilines give synthetically interesting 2-(3-indolylmethyl)phenols in an overall reductive process. Mechanistic studies suggest that this unusual reaction proceeds by carbopalladation of benzofuran giving a 3-palladated 2,3-dihydrobenzofuran intermediate, which then fragments by an uncommon trans-elimination of the phenoxide group β to the metal. In this transformation, N,N-diisopropylethylamine (DIPEA) acts as a base and as a reducing agent: it regenerates palladium(0) from palladium(II), thus allowing catalytic turnover