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D:\Data Files\Thèse\Rédaction\0 THÈSE Pour obtenir le diplôme de doctorat Spécialité Physique Préparée au sein de l’Université De Rouen Normandie Contribution to Chiral Discrimination in the Solid State & Access to Pure Enantiomer via Crystallization Présentée et soutenue par François-Xavier GENDRON Thèse soutenue publiquement le 29 Juin 2018 devant le jury composé de M. Richard M. KELLOGG Prof. University of Groningen Rapporteur M. Jean-Jacques COUNIOUX Prof. University of Lyon I Rapporteur Mme. Christine MARTIN Dr. University of Caen Examinateur M. Gérard COQUEREL Prof. University of Rouen Directeur de thèse Thèse dirigée par Gérard COQUEREL, professeur des universités au laboratoire Sciences et Méthodes Séparatives (EA 3233 SMS) A la pépite Agathe, arrivée au début de la fin. & A ma famille, qui m’a accompagné depuis 6 ans & A mon grand-père André, parti à la fin du début. “Don’t the great tales never end?” “No, they never end as tales,” said Frodo, “but the people in them come, and go when their part’s ended. Our part will end later – or sooner.” J. R. R. Tolkien, The Two Towers “If more of us valued food and cheer and song above hoarded gold, it would be a merrier world.” J. R. R Tolkien, The Hobbit Remerciements Remerciements Bien que cette thèse ait été rédigée dans la langue de Shakespeare, j’ai souhaité ici retourner à ma langue maternelle, celle de Molière, et ce afin de pouvoir pleinement y exprimer mes intentions. Mes tout premiers remerciements sont pour le Professeur Gérard Coquerel pour, le temps d’une pause lors d’un cours, avoir reçu, lu et finalement accepté ma demande de stage. Ce fut le 1er pas d’un voyage de 6 ans à vos côtés. I would like to thank the members of the jury committee for accepting the review of my thesis and for their questions and comments during the defense: Prof. Richard M. Kellogg, Prof. Jean- Jacques Counioux and Dr. Christine Martin. Thanks also to the Prof. Reiko Kuroda to be the source of the last chapter of this thesis. 5 ans et 3 mois se sont donc écoulés depuis mes 1ers pas au sein du laboratoire. Comme pour toute thèse, des hauts et des bas sont venus « enrichir » cette expérience. Je remercie les différents permanents du laboratoire pour leurs aides, scientifique ou non, et en particulier lors de ces derniers mois : Clément Brandel, Morgane Sanselme, Nicolas Couvrat, Yohann Cartigny, Gabin Gbabobe, Valérie Dupray et Samuel Petit pour l’équipe Crist, ainsi que Pascal Cardinael et Valérie Peulon-Agasse pour l’équipe Chro. Beaucoup d’autres membres du laboratoire SMS sont également à remercier, et ce pour différentes raisons. La précédente gestionnaire Ghislaine Chevalier (pour ton aide administrative) et l’actuelle, Lucie Dautréaux (pour mes erreurs administratives résiduelles) ainsi que Marie Vaccaro et Céline Bensakoun (mes camarades du Pays de Caux) et Françoise Ringot (Framboise). 7 Remerciements La 1ère génération de doctorants que j’ai connue : Julien Mahieux (encadrement du 1er stage), Simon Clevers (Loulou), J.C Debray & Florent Simon (mon 1er surnom au labo : FootX). La 2ème génération : Emilie Bobo (je léguerai notre place à une âme digne), Benjamin Schammé (quand tu veux pour le full), Mélanie Mignot (la Folle Mignot), Quentin Viel (mon 2ème surnom au labo : ChouppFx) et Aurélien Curat. Une autre génération avec Lina Yuan (quand même) et Antoine Burel (Bibu). Arrive enfin ma génération avec Bienvenu Atawa et Clément De Saint JoreS, mon tour est passé et vous êtes les prochains !!! Les générations suivantes : Manon Schindler (Super SchinMan !!), CORE Project Lina Harfouch, Alyou Mbodjy &Ryusei Oketani, Kangli Li et enfin Chloé Sainlaud. Et les stagiaires : Manon Poupard (PoupaMan !!), Maxime Charpentier, Aurélien Lemercier & Marine Hoquante. Mon cousin Valentin Aubert (3ème surnom évité : Gendron Beurre), Béranger Cardinot et Mélanie Canu. Je tiens également à remercier un autre groupe qui se fait connaître sous le nom de « Les Dignes Fils de Gégé », nom que je n’approuve pas, pour leurs « soutiens » et leurs « compréhensions » tout au long de ma thèse : Antonin, Hervé, Charlotte, Aurélie & Ségolène. A partir de maintenant, je fais les fins de soirées avec vous. Enfin je souhaite remercier ma famille. Les discussions ne sont pas l’un de nos points forts, et j’en suis un digne représentant, mais il n’empêche que vous avez toujours été là pour moi et cette thèse vous est dédié à vous : Papa, Maman, Aurélie & Camille & Agathe, Quentin & Camille, Mamie et tout le monde. F.x 8 Remerciements 9 Contribution to Chiral Discrimination in the Solid State & Access to Pure Enantiomer via Crystallization Table of contents Laboratoire SMS, Université de Rouen Normandie François-Xavier Gendron 29/06/2018 Table of contents Remerciements p.7 Table of content p.11 General introduction p.19 Chapter 1 - Thermodynamics, Crystallogenesis & Chirality Introduction p.27 Part.I Thermodynamics & Heterogeneous Equilibria p.27 I Thermodynamic phase and states of the matter …………………………………………………………………………………………… p.27 II Phase equilibria ……………………………………………………………………………………………………………………………………………… p.28 II.1 Energy of a system ……………………………………………………………………………………………………………………………………….. p.28 II.2 Equilibrium and stability ………………………………………………………………………………………………………………………………. p.29 II.3 Variance ……………………………………………………………………………………………………………………………………………………….. p.30 III Phase diagram ……………………………………………………………………………………………………………………………………………… p.30 III.1 Unary phase diagram ………………………………………………………………………………………………………………………………….. p.30 III.2 Binary phase diagram ………………………………………………………………………………………………………………………………….. p.32 III.3 Ternary phase diagram ……………………………………………………………………………………………………………………………….. p.38 III.4 Quaternary phase diagram ………………………………………………………………………………………………………………………….. p.42 III.5 Hereafter …………………………………………………………………………………………………………………………………………………….. p.45 Part.II Crystals p.45 I Crystallography ………………………………………………………………………………………………………………………………………………. p.45 I.1 The group theory ………………………………………………………………………………………………………………………………………….. p.46 I.1.1 Repetition motif ………………………………………………………………………………………………………………………………………. p.46 I.1.2 Asymmetric unit ………………………………………………………………………………………………………………………………………. p.46 I.1.3 Point group ……………………………………………………………………………………………………………………………………………… p.46 I.1.4 The unit cell ………………………………………………………………………………………………………………………………………………p.47 I.1.5 Modes ……………………………………………………………………………………………………………………………………………………… p.48 I.1.6 Space group …………………………………………………………………………………………………………………………………………….. p.50 I.2 Organic crystals …………………………………………………………………………………………………………………………………………….. p.50 I.2.1 Crystallographic data ……………………………………………………………………………………………………………………………….. p.50 I.2.2 Interactions in organic crystals ………………………………………………………………………………………………………………… p.51 I.2.3 Polymorphism of organic compounds ……………………………………………………………………………………………………… p.51 I.2.4 Nomenclature of organic crystals ……………………………………………………………………………………………………………..p.52 II Crystal genesis ……………………………………………………………………………………………………………………………………………….. p.52 II.1 Precipitation ………………………………………………………………………………………………………………………………………………… p52 II.1.1 Supersaturation ………………………………………………………………………………………………………………………………………. p.52 13 Table of contents II.1.2 Nucleation ………………………………………………………………………………………………………………………………………………. p.53 II.1.2.1 Primary nucleation & CNT …………………………………………………………………………………………………………………. p.53 II.1.2.2 Secondary nucleation ………………………………………………………………………………………………………………………… p.55 II.1.3 Growth ……………………………………………………………………………………………………………………………………………………. p.55 II.1.4 Ostwald ripening …………………………………………………………………………………………………………………………………….. p.56 II.2 Defect in crystals ………………………………………………………………………………………………………………………………………….. p.56 II.2.1 Powdered sample …………………………………………………………………………………………………………………………………… p.57 II.2.2 Single crystal …………………………………………………………………………………………………………………………………………… p.57 Part.III Chirality p.58 I Definition …………………………………………………………………………………………………………………………………………………………. p.58 I.1 History …………………………………………………………………………………………………………………………………………………………… p.58 I.2 Chirality around us ………………………………………………………………………………………………………………………………………… p.59 II Properties of chiral system …………………………………………………………………………………………………………………………… p.60 II.1 Properties …………………………………………………………………………………………………………………………………………………….. p.60 II.2 Nomenclature & types of chirality ……………………………………………………………………………………………………………….. p.61 II.2.1 Polarimetry …………………………………………………………………………………………………………………………………………….. p.61 II.2.2 Asymmetric atom & Enantiomery …………………………………………………………………………………………………………… p.61 II.2.3 Several asymmetric atoms & Diasteromery ……………………………………………………………………………………………. p.62 II.2.4 Blocked configuration & Atropisomery …………………………………………………………………………………………………… p.62 II.2.5 Spatial arrangement & Supramolecular chirality …………………………………………………………………………………….. p.63 III Thermodynamic of chiral system ……………………………………………………………………………………………………………….. p.63 III.1 The 3 extreme cases ……………………………………………………………………………………………………………………………………. p.64 III.1.1 Racemic compound ……………………………………………………………………………………………………………………………….. p.64 III.1.2 Conglomerate ………………………………………………………………………………………………………………………………………… p.65 III.1.3 Solid solution …………………………………………………………………………………………………………………………………………. p.65 III.2 Intermediate cases ……………………………………………………………………………………………………………………………………… p.66 III.3 Crystallography of chiral compounds ………………………………………………………………………………………………………….. p.67 IV Access to pure enantiomer …………………………………………………………………………………………………………………………… p.68 IV.1 Overview …………………………………………………………………………………………………………………………………………………….. p.68 IV.1 Resolution via crystallization ………………………………………………………………………………………………………………………. p.69 IV.2.1
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