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4 Modelisation

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Modelisation : Dr. Etienne Derat

1- Understanding the reactivity of unusual palladium species

  • 1.1- Deciphering the mechanism of the Catellani reaction

Of the Ortho Effect in Palladium/Norbornene-Catalyzed Reactions : A Theoretical InvestigationMaestri, G. ; Motti, E. ; Ca, Della, N. ; Malacria, M. ; Derat, E. ; Catellani, M. J. Am. Chem. Soc. 2011, 133, 8574–8585.

Mechanistic questions concerning palladium and
 norbornene catalyzed aryl—aryl coupling reactions are treated 
in this paper : how aryl halides react with the intermediate
palladacycles, formed by interaction of the two catalysts with an
aryl halide, and what is the rational explanation of the “ortho
 effect” (caused by an ortho substituent in the starting aryl
halide), which leads to aryl—aryl coupling with a second 
molecule of aryl halide rather than to aryl_norbornyl coupling.
Two possible pathways have been proposed, one involving aryl 
halide oxidative addition to the palladacycle, the other passing
through a palladium(II) transmetalation, also involving the 
palladacycle, as previously proposed by Cardenas and Echavarren. Our DFT calculations using M06 show that, in palladium- catalyzed reaction of aryl halides, not containing ortho substituents, and norbornene, the intermediate palladacycle formed has a good probability to undergo transmetalation, energetically favored over the oxidative addition leading to Pd(IV). The unselective sp2—sp2 and sp2—sp3 coupling, experimentally observed in this case, can be explained in the framework of the transmetalation pathway since the energetic difference between aryl attack onto the aryl or norbornyl carbon of the palladacycle intermediate is quite small. On the other hand, according to the experimentally observed “ortho effect”, selective aryl_aryl coupling only occurs in the reactions of ortho-substituted metallacycles. The present work offers the first possible rationalization of this finding. These in situ formed palladacycles containing an ortho substituent could more easily undergo oxidative addition of an aryl halide rather than reductive elimination from the transmetalation intermediate as a result of a steric clash in the transition state of the latter. The now energetically accessible Pd(IV) intermediate, featuring a Y-distorted trigonal bipyramidal structure, can account for the reported selective aryl_aryl coupling through a reductive elimination which is easier than aryl_norbornyl coupling. Thus, the steric effect represents the main factor that dictates the energetic convenience of the system to follow the Pd(IV) or the transmetalation pathway. Ortho substituents cause a higher energy transition state for reductive elimination from the transmetalation intermediate than for oxidative addition to the metallacycle palladium(II) and the pathway based on the latter predominates.

This paper allowed us to develop strategies to bypass the ortho effect and to publish the following paper in which computational analysis were conducted :

Palladium-Catalyzed Reaction of Aryl Iodides with ortho- Bromoanilines and Norbornene/Norbornadiene : Unexpected Formation of Dibenzoazepine Derivatives

 Ca, Della, N. ; Maestri, G. ; Malacria, M. ; Derat, E. ; Catellani, M. Angew. Chem. Int. Ed. 2011, 123, 12465–12469.

Exception to the ortho effect in palladium/norbornene catalysis Larraufie, M.-H. ; Maestri, G. ; Beaume, A. ; Derat, E. ; Ollivier, C. ; Fensterbank, L. ; Courillon, C. ; Lacote, E. ; Catellani, M. ; Malacria, M. Angew Chem Int Edit 2011, 50, 12461–12464.

  • 1.2- Introducing Pd(III) species for aryl coupling

Radical Pd(III)/Pd(I) reductive elimination in palladium sequences
Maestri, G. ; Malacria, M. ; Derat, É. Chem Commun 2013, 49, 10424–10426.

Open-shell mechanisms are often at work in catalytic sequences involving first-row transition metals while usually not considered in palladium chemistry. This computational study suggests their possible relevance in catalytic methods involving paramagnetic Pd(III) intermediates. Indeed C–C bond forming reductive elimination pre- viously thought to occur in Pd(IV) complexes has lower barriers in neutral, radical Pd(III) intermediates instead. These species could form upon addition on Pd(II) of an aryl radical generated via single electron transfer from a photo-active ruthenium complex (see picture) and have the perfect stereo- electronic arrangement to smoothly undergo the coupling process.

Regarding this palladium topic, we also wrote a review :

Understanding palladium complexes structures and reactivities : beyond classical point of view Derat, E. ; Maestri, G. WIREs Comput Mol Sci 2013, 3, 529–541.

2- CH Activation : computational analysis

  • 2.1- CH activation made simple with cobalt

C–H activation/functionalization catalyzed by simple, well-defined low valent cobalt complexes Fallon, B. J. ; Derat, E. ; Amatore, M. ; Aubert, C. ; Chemla, F. ; Ferreira, F. ; Pérez-Luna, A. ; Petit, M. J. Am. Chem. Soc. 2015, 150127152307002.

A facile C–H activation and functionalization of aromatic imines is presented using low-valent cobalt catalysts. Using Co(PMe3)4 as catalyst we have developed an efficient and simple protocol for the C–H/hydroarylation of alkynes with an anti selectivity. Deuterium-labeling experiments, DFT calculation coupled with the use of a well-defined catalyst have for the first time shed light on the elusive black box of cobalt catalyzed C−H functionalization.

  • 2.2- CH activation hidden in a cobalt catalytic cycle

Hydrido-Cobalt Catalyst as a Selective Tool for the Dimerisation of Arylacetylenes : Scope and Theoretical Studies Ventre, S. ; Derat, E. ; Amatore, M. ; Aubert, C. ; Petit, M. Adv. Synth. Catal. 2013, 355, 2584–2590.

A simple hydrido-cobalt complex efficiently catalyses the highly regio- and stereoselective di- merisation of various terminal arylacetylenes under mild conditions. The corresponding (E)-1,4-enynes are obtained as sole isomers with good to excellent yields. DFT calculations revealed that the reaction proceeds via a C—H activation/hydrocobaltation pathway.

  • 2.3- Iron & Redox ligand : DFT calculations highlight the CH activation mechanism

Tandem C-H activation/arylation catalyzed by low-valent iron complexes with bisiminopyridine ligands Salanouve, E. ; Bouzemame, G. ; Blanchard, S. ; Derat, E. ; Murr, M. D.-E. ; Fensterbank, L. Chemistry Eur. J. 2014, 20, 4754–4761.

Tandem C-H activation/arylation between unactivated arenes and aryl halides catalyzed by iron complexes that bear redox-active non-innocent bisiminopyridine ligands is reported. Similar reactions catalyzed by first-row transition metals have been shown to involve substrate-based aryl radicals, whereas our catalytic system likely involves ligand-centered radicals. Preliminary mechanistic investigations based on spectroscopic and reactivity studies, in conjunction with DFT calculations, led us to propose that the reaction could proceed through an inner-sphere C-H activation pathway, which is rarely observed in the case of iron complexes. This bielectronic noble-metal-like behavior could be sustained by the redox-active non-innocent bisiminopyridine ligands.

3- Large system simulations

  • 3.1- CH activation catalyzed by hybrid polyoxometallates

Hybrid polyoxometalate palladacycles : DFT study and application to the Heck reaction Riflade, B. ; Oble, J. ; Chenneberg, L. ; Derat, E. ; Hasenknopf, B. ; Lacote, E. ; Thorimbert, S. Tetrahedron 2013, 69, 5772–5779.

The phosphovanadotungstate polyanion [P2W15V3O62]9_ is a powerful support to stabilize palladacycles conjugated to the inorganic framework via an organic ligand. The insertion can be directed toward sp2 or sp3 C-H insertion upon appropriate choice of the substitution pattern on the organic ligand. DFT modeling indicates that the strong withdrawing effect of the POM transmitted through the conjugated carbonyl was responsible for this easy insertion.

  • 3.2- Unusual supramolecular interactions in cyclodextrins

Solid-state hierarchical cyclodextrin-based supramolecular polymer constructed by primary, secondary, and tertiary azido interactions Ménand, M. ; de Beaumais, S. A. ; Chamoreau, L.-M. ; Derat, E. ; Blanchard, S. ; Zhang, Y. ; Bouteiller, L. ; Sollogoub, M. Angew. Chem. Int. Engl. 2014, 53, 7238–7242.

The crystallization of a di-azido-α-cyclodextrin revealed a polymeric self-assembly involving a variety of azido-type interactions. The crystal arrangement relies on the cooperativity of a primary azido inclusion, a secondary azido– azido interaction involving an unprecedented distribution of canonical forms, and a tertiary azido–groove interaction. The second azido group brings in a major contribution to the supramolecular structure illustrating the benefit of a difunc- tionalization for the generation of hierarchy. The azido-azido interaction was nicely interpretated using NBO and NCI methodologies,on top of full DFT optimization of cyclodextrin dimer.

  • 3.3- Exploring enzyme eactivity with QM/MM : AChE.

Fixation of the two Tabun isomers in acetylcholinesterase : a QM/MM study. Kwasnieski, O. ; Verdier, L. ; Malacria, M. ; Derat, E. J Phys Chem B 2009, 113, 10001–10007.

Dysfunction of acetylcholinesterase (AChE) due to inhibition by organophosphorus (OP) compounds is a major threat since AChE is a key enzyme in neurotransmission. To more rigorously design reactivation agents, it is of prime importance to understand the mechanism of inhibition of AChE by OP compounds. Tabun is one of the more potent nerve agents. It is produced as a mixture of two enantiomers, one of them (the levorotatory isomer) being 6.3 times more potent. Could it be that the inhibition mechanism is different for the two enantiomers ? To address this critical issue, we used a hybrid quantum mechanics/molecular mechanics (QM/MM) methodology. Calculations were performed using BP86 functional and TZVP basis set. Single points were also done with B3LYP and PBE0 functionals. We studied the four possible attacks of tabun on the oxygen of Ser203 using two crystallographic structures (PDB codes 2C0P and 3DL7) : (S) tabun with the cyano group syn to the oxygen of Ser203 and (R) tabun with the cyano group anti, corresponding to the experimental X-ray structure ; (S) tabun with the cyano group anti to the oxygen of Ser203 and (R) tabun with the cyano group syn, leading to a different isomer than was experimentally seen. We found that the most active enantiomer is (S) tabun with the cyano group syn to the oxygen of Ser203. Thus it seems that the cyano group does not leave anti to the oxygen of Ser203 due to repulsive polar interactions between cyanide and aromatic residues in the active site.