METHODOLOGIES FOR SYNTHESIS, ANALYSIS, THEORETICAL MODELING AND KINETIC STUDIES

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Nucleophilic substitutions at phosphorus atom

As we saw in the previous section, the SN2@P are an important part of the synthesis on phosphorous chemistry, especially for phosphine oxides.39 This methodology for synthesis has been widely used since their first synthesis in 1952 up until now for the synthesis of SPO.14 Theoretical studies of nucleophilic substitutions at phosphorus can be found in literature since the 1980’s. But the majority of these studies are about halogenated phosphorous compounds,40, 41 trivalent phosphorus atoms,40 cyclic phosphorous intermediates,42, 43, 44 and sometimes phosphonium salts;45 all of which we do not talk about in this thesis. Nevertheless, those studies showed the importance of taking into account the empty 3d orbitals of the phosphorus, low in energy, that can participate as acceptor in some molecules. This implies the use of an extended orbital basis.
To our knowledge, the only theoretical studies about SN2@P for non-halogenated nor ionic phosphine oxides were made by Bickelhaupt et al. between 2006 and 2009 within their work about ionic compounds such as Cl- or MeO- reacting with neutral phosphine oxides.46, 47, 48, 49
We could here argue that using ions generally needs to take the solvent explicitly into account since it acts on their stabilization or destabilization. The absence of explicit solvatation makes this study not linkable to experiments. However, they are still useful do determine what acts on the shape of reactive pathways for SN2@P.
In 2006, Bickelhaupt & al. have published their first work about the energy barriers of SN2 at phosphine oxides, and the shape of the potential energy surfaces (PES) depending on substituents at phosphorus atom.46 Using theoretical chemistry at OLYP/TZ2P level in gas phase, they showed that electronic and steric effects of those substituents could act on reactivity, thus on the shape of PES. As a result, the modeling of a nucleophilic substitution with Cl- as a reactant and leaving group while changing the substituents on the phosphorus atoms between H, OMe or Cl gives three different shapes of PES, respectively with one, two or three wells.
Their deduction was that not only the energy, but even the shape of the PES depends on steric hindrance and electronic properties of substituents. The central barrier of SN2 is absent with Cl, but present with OMe because of the hindrance induced by methyls which destabilizes the pentacoordinated phosphorus atom. As a result, this conformation becomes a transition state for OMe substituents, while it is an intermediate for the less hindered H and Cl, making the profile of the PES with two wells for Cl, and one well for H. They also showed that the hindrance of OMe increases the energy barrier by 4 kJ.mol-1 (65 kJ.mol-1 for R = Cl to 69 kJ.mol-1 for R = OMe).
In 2007, Bickelhaupt et al. have worked on OH- reacting on diakylphosphinic acids P(O)R2OH to study the importance of conformations on the reaction profile.47 They observed that the reaction path which begins from the most stable conformer of reactant shows a reaction profile 5 kJ.mol-1 lower than the others, following the Hammond’s postulate which specifies that a TS following an intermediate is close to its structure and energy. As a result, a TS should be lower in energy if it comes from a less energetic conformation. This effect has been noted in this study, where a less stable conformer results in a higher TS. Consequently, going from a more energetic structure acts on the whole PES because the entire mechanism is based on this first conformation. Starting with the most stable conformer should lower the whole PES. This result was also presented in their study of 2009 with P(O)(OMe)2X.49 To conclude, this observation implies that diminishing the size of reactants in simulation can influence the energy profile, so the model used for theoretical studies has to be chosen very carefully.
In 2008, Bickelhaupt et al. have worked on the effect of solvation on SN2@P for diverse P(III) and P(V) species substituted by Cl-. To model the effect of solvent, chose as water, they have used the COnductor-like Screening Model of solvent (COSMO).48 They observed that transition states were lowered from 20 kJ.mol-1 for P(O)Cl3 to 37 kJ.mol-1 for P(O)(CH3)2Cl, which shows the influence of solvent on the whole PES.
The last study of Bickelhaupt et al. about SN2@P was in 2009 on the effect of substituents at phosphorus atom.49 They tested SN2 with Cl, OH and OMe as substituted groups onto the phosphorus atom, and showed that the PES shape was changing from two wells with the addition of Cl-, to three wells with MeO- and HO-. They conclude that the steric effect acts on the shape of PES not only for substituents on the phosphorus atom, but also on the reactant.
Those diverse studies show how important it is to consider every part of the system around the phosphorous compound: substituents, reactants and solvent; since each of those acts on the profile of the PES. To conclude, we need to be very careful while choosing the system of interest for our study.

Pseudorotations of pentacoordinated phosphorous compounds

Description of a pentacoordinated phosphorus

As was described oin the previous section, SN2@P can go through a pentavalent phosphorous intermediate that bears 5 different substituents, and form a pentacoordinated compound with a triangle-based bi-pyramidal (TBP) geometry as shown in Figure 1-17. We can separate ligands depending on their position: apical ligands are the two at top vertices of the bi-pyramid (blue), and equatorial ligands the three at vertices of the triangle base (red).
Figure 1-17: Triangle based bi-pyramidal pentacoordinated phosphorus. Groups in apical position are in blue, groups in equatorial are in red. Isomers are named after their apical groups, the heaviest one by Cahn-Ingold-Prelog rules on top. The enantiomers are named with a prime.
To name the different isomers, we use Cahn-Ingold-Prelog (CIP) rules50 on substituent groups and numerate them from 1 to 5, 1 being the most important and 5 the least. (Figure 1-17) An isomer is named after the groups in apical position, putting the most important group up. As an example, the isomer with the ligands 1 and 2 in apical position will be named 12.
If both apical ligands and the three equatorial groups are different from each other, the isomer 12 has two enantiomers depending on the order of equatorial groups. In this case, the original molecule 12 is the isomer where equatorial ligands are clockwise. Its enantiomer, where equatorial ligands are in the opposite order, is named with a prime. An example can be seen in Figure 1-17 with the isomer 12, where equatorial ligands are clockwise respecting the CIP rule (3-4-5), and its enantiomer 12’ where equatorial groups in the opposite order (5-4-3).
The position of ligands in the TBP depends on their apicophilicity, i.e. their relative preference to be in apical position. It depends on several characteristics, the most important being their electronegativity, since the more electronegative groups favor the apical position because of their inductive effect. 3d orbitals from the phosphorus atom that acts as an acceptor, which tends to stabilize its positive polarization.51 For groups with an equivalent electronegativity, the more sterically hindered groups will prefer the equatorial position because the 120° angle gives them more space than the 90° angles of apical positions.52 Based on various observations, several apicophilicity scales have been made respecting those rules.

The Berry pseudorotations

TBP based phosphorous molecules are known for their ability to undergo reorganization of ligands around the phosphorus. In those cases, two equatorial ligands switch their positions with both apical ligands, while the remaining ligand does not move during the process as shown on the Figure 1-18.54
We can divide those mechanisms in three different kinds. The first two are regular mechanisms which do not need to break a bond: Berry pseudorotation and turnstile isomerization. Berry are known to be about five times lower in energy than turnstile according to previous studies, which makes the last mechanisms less probable than the first.55, 56, 57 Opposite to regular processes, irregular processes go through the breaking of a bond. It generally happens for cyclic phosphorous molecules which are not presented in this thesis. We thus hereby exclusively work on Berry pseudorotations.
Figure 1-18: The three possible isomerizations from 12 around each possible pivot in equatorial position: 3 (blue), 4 (red) and 5 (green). The color of each arrow is assorted to the color of the ligand acting as a pivot that remains in equatorial position during the isomerization
In Berry’s mechanisms shown in Figure 1-19, four of the ligands borne by the phosphorus atom rotate around the fifth one which stays unchanged as a pivot. Both apical ligands in blue have their angle go from 180° to 120°, while two equatorial ligands in red have their angle increase from 120° to 180°. Those two movements are coordinated so the transition state (TS) appears to be a squared base pyramid.
Figure 1-19: Berry pseudorotation from the pentacoordinated compound 12 to 45’ around the equatorial ligand 3 (pivot), 1 and 2 go from apical position to equatorial, 4 and 5 go from equatorial to apical.
We can represent the pseudorotations and the isomers they connect with a de Bruin diagram as shown in Figure 1-20.58 Technically, if all five ligands are different in such a pentacoordinated structure, there are 20 different ways of positioning them around the phosphorous center so it can undergo 30 different pseudorotations.
Figure 1-20 : Complete list of all 20 pentacoordinated intermediates that can be transformed into each other through pseudorotations in case all groups bound to the phosphorus center are different, and all 30 pseudorotations that bind them. The color of each line representing a pseudorotation is assorted to the color of the ligand acting as a pivot that remains in equatorial position during the pseudorotation.

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Aim of the thesis

As was described in the first part of this section, chiral phosphorous molecules have successfully been used as ligands within several asymmetric catalytic processes.9, 59 P-stereogenic ligands, in particular, have shown to be efficient60, 14, 61 and, among them, monodentate P-stereogenic secondary phosphine oxides are thought to be very promising.62, 19, 18, 63 During the past decades, our group has significantly contributed to the making of such ligands with the development of an enantioselective synthesis of P-stereogenic SPO from AlkHP via a SN2 mechanism with a Grignard reagent.
It has been noticed that the nature of the alkyl group of the alkoxide borne by the phosphorus atom acts on the enantiomeric excess at the end of the reaction: the less hindered it is, the lower the e.e.. They also noticed that this alkyl group acts on the stability of the enantiomer: the more hindered the alkyl, the more stable the enantiomer. It is a reasonable assumption to think that both of these phenomena are related. We then decided to study the effect of this alkyl group on SN2@P by alcohols and their derivatives at phosphinates using experimental and theoretical chemistry.
Previous researches done by Bickelhaupt et al. showed how important it is to take the entire environment of phosphorus atom in consideration if we want to correctly describe the behavior of phosphorous compound. Consequently, we need to pay attention not to simplify too much our system of reference by lowering the hindrance of substituents or modifying their electronegativity. We will also study pseudorotations which, in certain case, could participate to inversion of configuration through isomerization of TBP intermediates.
However, before we head to the choice of our system of interest, we first need to choose theoretical and experimental methodologies we will use in this study. In the next section, we present those methodologies used during this thesis, and explain why they have been chosen.
Afin d’étudier la réactivité des AlkHP, nous allons utiliser des méthodes de chimie théorique et expérimentale présentées dans cette section. Pour les études mécanistiques, nous avons choisi la théorie de la fonctionnelle de la densité (DFT) qui se base sur les théorèmes de Kohn-Sham, développés en 1965, selon lesquels la densité électronique d’un système permet de connaître toutes ses propriétés. Ce niveau théorique est plus rapide qu’en utilisant une méthode Hartree-Fock, puisqu’on ne considère plus les noyaux et électrons d’un système un par un, mais sa densité électronique et son évolution au fil de la réaction. Nous avons choisi d’utiliser la fonctionnelle M06-2X/6-31++G(d,p) qui a été optimisée pour les études énergétiques, géométriques, vibrationnelles et mécanistiques, associée au modèle de solvant SMD développé et testé avec cette fonctionnelle.
Pour tenir compte de l’effet de la température à laquelle les expériences sont menées, nous avons utilisé les fonctions de partition dans les approximations de la translation libre, de l’oscillateur harmonique et du rotateur rigide. Cela permet d’ajouter la prise en compte des états vibrationnels, rotationnels et translationnels du système.
La synthèse de l’hydrogéno-phénylphosphinate d’éthyle EtHP utilisé dans cette thèse est réalisée à partir de dichlorophénylphosphine PhPCl2 réagissant avec de l’éthanol. L’identité de la molécule synthétisée est ensuite confirmée par RMN du phosphore et du proton. A l’issue de la synthèse, on a noté la présence d’un second produit non-identifié qui semble être le phénylphosphonate de diéthyle d’après une analyse COSY-NMR. Cela n’a pas pu être confirmé car le produit n’a pas été isolé. La méthode de synthèse des EtHP n’étant pas énantiosélective, la séparation de deux énantiomères a été réalisée par Marion Jean via chromatographie chirale (Chiral HPLC). L’excès énantiomérique est déterminé via UV-visible après chromatographie chirale. Ces méthodes d’analyse pourront être utilisées dans le cadre d’études cinétiques.
Les études cinétiques seront réalisées de manière à obtenir des 1ers ordres apparents. Cela permettra d’extraire facilement les constantes de vitesse kapp et d’en déduire les enthalpies libres de transition.
Un 1er ordre est souvent relié à une réaction monomoléculaire, mais peut également correspondre à une réaction où l’un des réactifs voit sa concentration virtuelllement constante au fil du temps. Pour cela, plusieurs modèles cinétiques, chacun décrivant une réaction différente caractérisée par sa propre constante de vitesse, pourront être construit. Leurs enthalpie libres de transition seront fittées pour approcher celle mesurée expérimentalement. La comparaison entre les valeurs du modèle et de l’expérience permettra de déterminer la validité du la réaction modèle.
Le développement par Rémy Fortrie d’un programme d’ajustement de modèles cinétiques peut permettre, à terme, de prendre en compte la participation de plusieurs mécanismes dans un modèle, et de pondérer leur participation pour recouper les résultats expérimentaux et déduire les mécanismes en solution.

Methodologies for synthesis, analysis, theoretical modeling and kinetic studies 

In the first chapter, we explored the history of monophosphine oxides, their properties and applications. We presented the researches made in our team by Buono & al. where they showed the influence of the alkyl group borne by the phosphinate on its enantiostablity and reactivity (Figure 2-1).

Table of contents :

CHAPTER 1:
PRESENTATION OF ALKYL HYDROGENO-PHENYLPHOSPHINATES
1.1 FROM ASYMMETRIC CATALYSIS TO HYDROGENO-PHOSPHINE OXIDES
1.1.1 Organophosphorous compounds in asymmetric catalysis
1.1.2 Description of secondary phosphine oxides
1.2 SYNTHESIS OF SECONDARY PHOSPHINE OXIDES
1.3 NUCLEOPHILIC SUBSTITUTIONS AT PHOSPHORUS ATOM
1.4 PSEUDOROTATIONS OF PENTACOORDINATED PHOSPHOROUS COMPOUNDS
1.4.1 Description of a pentacoordinated phosphorus
1.4.2 The Berry pseudorotations
1.5 AIM OF THE THESIS
CHAPTER 2:
METHODOLOGIES FOR SYNTHESIS, ANALYSIS, THEORETICAL MODELING AND KINETIC STUDIES
2.1 INTRODUCTION
2.2 THEORETICAL CHEMISTRY
2.2.1 The Schrödinger Equation
2.2.2 Density Functional Theory
2.2.3 Implicit solvation
2.2.4 Effect of the temperature
2.3 SYNTHESIS OF ALKYL HYDROGENO-PHENYLPHOPHINATES
2.4 ANALYSIS METHODS AND QUANTIFICATION
2.4.1 Nuclear magnetic resonance
2.4.2 Chiral high performance liquid chromatography
2.5 KINETICS
2.5.1 Reaction rate and transition standard Gibbs free energy
2.5.2 A case of study: the racemization of ethyl phenylphosphinate
2.6 CONCLUSION
CHAPTER 3:
SYSTEM OF INTEREST AND EQUILIBRIUM IN SOLUTION
3.1 INTRODUCTION
3.1.1 Context
3.1.2 Choice of the system
3.2 CONFORMATION OF THE METHYL HYDROGENO-PHENYLPHOSPHINATE
3.3 PROTOTROPIC EQUILIBRIUM
3.4 ACIDOBASICITY SCALE
3.4.1 How to build an acidobasicity scale
3.4.2 Determination of the pKa of the compounds of interest
3.5 METHOXIDE AND PHOSPHONIDE
3.5.1 Deprotonation of phosphinate by an alkoxide
3.5.2 Inversion of configuration of a phosphinide
3.6 CONCLUSION
CHAPTER 4:
TRANSESTERIFICATION MECHANISM OF METHANOL ON ALKYL HYDROGENOPHENYLPHOSPHINATE
4.1 INTRODUCTION
4.1.1 Context
4.1.2 Methodology
4.2 ADDITION OF METHANOL ONTO THE PHOSPHORUS ATOM
4.2.1 Possible approaches of methanol onto phosphinate
4.2.2 A study of the 6 mechanisms for SN2
4.3 INFLUENCE OF THE PENTACOORDINATED INTERMEDIATE ON THE GLOBAL MECHANISM
4.3.1 Further evolution on the pentacoordinated intermediate
4.3.2 Berry pseudorotations of the pentacoordinated intermediate
4.4 KINETIC STUDY
4.4.1 Experimental measurements
4.4.2 Observations
4.4.3 Discussion
4.4.4 Kinetic adjustment
4.5 RELIABILITY OF SIMULATIONS
4.6 CONCLUSION
CHAPTER 5:
EFFECT OF BASIC CATALYSIS ON THE TRANSESTERIFICATION MECHANISM OF ALKYL HYDROGENOPHENYLPHOSPHINATES BY ALCOHOL
5.1 INTRODUCTION
5.1.1 Context
5.1.2 Methodology
5.2 EXPERIMENTAL STUDY: KINETIC OF ENANTIOMERIZATION
5.2.1 Observations
5.2.2 Kinetic modeling
5.3 EQUILIBRIUM OF THE SYSTEM IN BASIC CONDITIONS
5.3.1 Tautomerism and coordination of TMA
5.3.2 Deprotonation of reactants
5.3.3 Conclusion
5.4 ADDITION MECHANISM IN BASIC CONDITIONS
5.4.1 Addition on phosphinous acid form
5.4.2 With one equivalent of TMA
5.4.3 With 2 equivalents of TMA
5.4.4 Deprotonated phosphinate
5.4.5 The mysterious catalyst
5.4.6 Conclusion
5.5 CONCLUSION
CHAPTER 6:
EFFECT OF THE HINDRANCE ON THE ENANTIOSTABILITY OF ALKYL HYDROGENOPHENYLPHOSPHINATES
6.1 INTRODUCTION
6.1.1 Context
6.1.2 Methodology
6.2 INFLUENCE OF THE ALKYL GROUP ON SN2@P IN NEUTRAL CONDITIONS
6.3 KINETIC STUDY IN BASIC CONDITIONS USING 31P-CPD NMR
6.3.1 Choice of the system
6.3.2 Observations
6.4 EARLY CONCLUSION
GENERAL CONCLUSION

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