Conductometry for the characterization of ionic organometallic compounds 

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Implicit solvation – the PCM modelx

To take into account in a cost-effective way the effects due to solvation, the polarizable continuum model (PCM) has been employed in the calculations presented in this thesis. The main idea at the basis of this model is that the solvent can be described as a polarizable dielectric medium that surrounds the molecular system of interest. As a consequence, mainly the electrostatic contribution to the solvation energy is taken into account. Effects due to specific solute/solvent interaction (e.g. hydrogen bonding interactions) are not described by this model. The fundamental equation of the PCM model is Gauss’s law of classical electrostatics: M [ (r)(r)]  4 (r) (69) in which  is the electrostatic potential, M is the charge distribution of the solute and ()r is the dielectric permittivity. As regards the latter, a molecular cavity of appropriate shape is defined and is taken as 1 (the permittivity of vacuum) inside the cavity and equal to the dielectric constant of the solvent outside.
The electrostatic problem can be solved in terms of the potential  , which can be thought as the sum of the contribution due to the solute M  plus the contribution of a fictitious surface charge distribution located on the surface  of the molecular cavity.

Selected theoretical tools used in this thesis

We will present briefly in this section three interpretative theoretical tools we used in this thesis to obtain chemically-relevant information from electronic structure theory calculations, i.e. the computation of thermodynamic functions from the results of electronic structure calculations, the distortion-interaction models and charge partition schemes (population analysis).

Calculation of thermodynamic functions

Electronic structure method calculations yield electronic energy values, which cannot be directly compared to typical experimentally measured data. Standard statistical mechanics is used to compute the thermal contributions to thermodynamic functions with perfect gas formulae in the framework of the harmonic oscillator – rigid rotator model. We recall that the thermodynamic quantities can be expressed in terms of the canonical partition function Q . More in detail, the Helmoltz free energy A is the natural potential associated to the canonical ensemble and the internal energy U can be expressed easily in terms of the partition function.

Distortion-interaction analysis

The distortion-interaction analysis (DIA), also known as activation-strain analysis, developed independently by Houk and Bickelhaupt,[35–37] is a fragment-based approach that allows to separate the contribution to activation barriers due to structural deformations of the reactants and to the interaction of the deformed fragments. It can be performed only at the transition state or at multiple points of the reaction path connecting reagent and products (e.g. all along an intrinsic reaction coordinate calculation).
This model is most suited for a bimolecular reactions. The geometries of the reactants are first optimized separately and the sum of their energy is taken as zero. Then, the structure of the transition state is obtained and the activation energy barrier calculated. The geometries of the two reactants are then extracted from the transition state structure and their energies are obtained by single-point calculations. The energy difference between these fragments and that of the corresponding reactants is defined as the distortion energy of each reactant. The difference between the activation barrier and the total distortion energy defines the interaction energy, which is always negative. An illustration of this model is given graphically in Figure 4.

Early studies on the insertion of isocyanides in the C-Pd bond

The first studies concerning isocyanide insertion into the C-Pd bond were performed on isolated organopalladium complexes long before the development of the related catalytic reactions. This process was described as early as in 1969 by Otsuka[5] and in 1970 by Yamamoto and Yamazaki [6].
In his pioneering study, Otsuka reported that on adding MeI to the Pd(0) complex [Pd(CNtBu)2] at 0 °C oxidative addition took place, leading to the square planar trans-[MePd(CNtBu)2I]. Increasing the temperature to 11 °C resulted in insertion of one of the coordinated tBuNC in the CH3-Pd bond, giving a complex of stoichiometry [(MeC=NtBu)Pd(CNtBu)I], that is probably a dimer. The latter species was not stable enough to be isolated, but on adding a ligand L (L = tBuNC or PPh3), stable square-planar [(MeC=NtBu)PdL(CNtBu)I] complexes were obtained (Scheme 2).

Earlier mechanistic studies related to palladium-catalyzed imidoylative couplings

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The commonly proposed mechanism of imidoylative couplings involving halogenoarenes is outlined in Scheme 27. After oxidative addition of ArX to a palladium(0) complex, a σ- arylpalladium(II) intermediate is formed. Migratory insertion of RNC converts the latter into an imidoylpalladium(II) complex, that can undergo ligand exchange with the incoming nucleophile or transmetalation (in the case of organometallic nucleophiles). Finally, reductive elimination generates the coupling product and regenerates palladium(0).

Table of contents :

General introduction
Chapter I – Experimental and Theoretical Methods for Mechanistic Studies
1. Experimental techniques
1.1. Nuclear Magnetic Resonance spectroscopy of heteronuclei
1.2. Conductometry for the characterization of ionic organometallic compounds
2. Theoretical background
2.1. Fundamentals of wave mechanics for a molecular system
2.2. The Born-Oppenheimer approximation
2.3. The variational principle
2.4. Slater determinants and the associated energy
2.5. The independent particle model and the Hartree-Fock equations
2.6. The limits of the Hartree-Fock approach, correlation energy
2.7. Fundamental ideas of DFT, the Hohenberg-Kohn theorems
2.8. The Kohn-Sham method
2.9. Approximating the exchange-correlation functional
2.10. Empirical dispersion corrections
2.11. Implicit solvation – the PCM model
2.12. Basis set and effective core potentials
3. Selected theoretical tools used in this thesis
3.1. Calculation of thermodynamic functions
3.2. Distortion-interaction analysis
3.3. Population analysis
4. References
CHAPTER II – Multiple Roles of Isocyanides in Palladium-Catalyzed Imidoylative Couplings: A Mechanistic Study
1. Context of the Study
1.1. Introduction
1.2. Early studies on the insertion of isocyanides in the C-Pd bond
1.3. Palladium catalyzed imidoylative couplings
1.4. Earlier mechanistic studies related to palladium-catalyzed imidoylative couplings
2. Results and discussion
2.1. Choice of the model reaction
2.2. Generation of Pd(0) from Pd(II) precursors
2.3. Oxidative addition to isocyanide-ligated palladium(0)
2.4. Characterization of the product of oxidative addition
2.5. Interaction of complex 1 with triphenylphosphine
2.6. Interaction of complex 1 with 1,2-bis-(diphenylphosphino)ethane (dppe)
2.7. C-O bond forming reductive elimination
2.8. Theoretical study of the catalytic cycle
2.9. Theoretical study of the C-O bond forming reductive elimination
3. Conclusions
4. Computational details
5. References
CHAPTER III – Palladium-Catalyzed Reductive Benzofuran Ring-Opening Indole Ring-Closure via β-Phenoxide Elimination
1. Context of the Study
1.1. Palladium-catalyzed reactions involving unfunctionalized heteroarenes
1.2. Palladium-catalyzed direct arylation and dearomative couplings of benzofurans
2. Results and discussion
2.1. First steps
2.2. Optimization of reaction conditions
2.3. Scope of the reaction
2.4. Going beyond the synthesis of indoles
2.5. Mechanistic studies
2.6. Proposed catalytic cycle
3. Conclusions
4. References
CHAPTER IV – Copper-Catalyzed Hydroamination of Allenes: Mechanistic Studies and Methodology Development
1. Context of the Study
1.1. Introduction
1.2. Thermodynamic aspects of the hydroamination of alkenes and allenes
1.3. A survey of the literature on the hydroamination of allenes
2. Results and discussion
2.1. Object of the study
2.2. Nature of the catalytically active species
2.3. Catalytic cycle and the origin of selectivity
2.4. From mechanistic insight to methodology development – hydroamination of allenamides
2.5. Application of the hydroamination to the synthesis of an API – P-3374
2.6. Mechanistic insight into the hydroamination of allenamides
2.7. Extension to allenyl ethers
2.8. Extension to N-allenylazoles
2.9. Mechanistic insight into the copper-catalyzed hydroamination of azoles
2.10. Extension to N-allenylsulfonamides
2.11. Mechanistic aspects of the copper-catalyzed hydroamination of N-allenylsulfonamides
3. Conclusions
4. Computational details
5. Bibliography
General conclusions and perspectives
Experimental sections
1. Experimental section of chapter II
1.1. General remarks
1.2. Synthesis and characterization of organometallic complexes
1.3. Synthesis of reference materials
1.4. X-Ray data for compound 1
2. Experimental section of chapter III
2.1. General remarks
2.2. General procedure A – Pd-catalyzed ring-opening of benzofuran derivatives
2.3. Synthesis of starting materials
2.4. General procedure B for the alkylation of compounds S3a-d
2.5. Synthesis of complex
3. Experimental section of chapter IV
3.1. General remarks
3.2. General procedure for the hydroamination of N-allenylamides
3.3. Pictet-Spengler-type cyclization of hydroamination products
3.4. Synthesis of substrates for mechanistic studies
3.5. General procedure for the isomerization of N-propargylamides, carbamates and ethers to N-allenylamides carbamates, and ethers
3.6. General procedure for the preparation of N-propargyl amides and carbamates
3.7. Study of the reaction between morpholine and Cu(OTf)2 – identification of the organic products
3.8. Hydroamination of N-allenylazoles
3.9. Synthesis of N-propargyl heteroarenes
3.10. Hydroamination of N-allenylsulfonamides
3.11. Synthesis of N-allenylsulfonamides
3.12. Synthesis of miscellaneous allenes
3.13. Synthesis of miscellaneous starting materials


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