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Synthesis of Calix[4]Pyrrolidine, Calix[M]Tetrahydrofuran[N]

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Synthesis of Calix[4]Pyrrolidine, Calix[M]Tetrahydrofuran[N] Synthesis of Calix[4]pyrrolidine, Calix[m]tetrahydrofuran[n]pyrrolidine (m+n=4) and Similar Macrocyclic Systems - Elucidation of the Hydrogenation Sequence and Factors Influencing the Stereoselectivity Thèse présentée à la faculté des Sciences de l’Université de Neuchâtel pour l’obtention du titre de Docteur ès Sciences par Guillaume JOURNOT Chimiste diplômé de l’Université de Haute Alsace Mai 2012 Ce travail a été effectué de septembre 2008 à avril 2012 à l’institut de Chimie de l’Université de Neuchâtel sous la direction du Prof. Reinhard Neier. Je tiens vraiment à le remercier pour m’avoir offert l’opportunité de travailler au sein d’un groupe de recherche si stimulant, sur un sujet de thèse extrêmement intéressant et fructueux, pour sa disponibilité et sa gentillesse. Merci pour la confiance que tu m’as accordé dès les premiers jours, pour la liberté d’action que tu m’as offerte et merci d’avoir toujours su me guider et me soutenir dans mes choix. Finalement, merci pour toutes les discussions que l’ont a partagées, plus intéressantes les unes que les autres, pour tes conseils si précieux… J’adresse mes sincères remerciements aux Prof. Andreas Pfaltz et Prof. Robert Deschenaux qui ont pris part à mon jury de thèse et pris le temps de lire et de corriger mon manuscrit. Je remercie particulièrement le Prof. Helen Stoekli-Evans pour les nombreuses structures au rayon X élucidées, pour sa patience et sa gentillesse. Je remercie également toutes les personnes avec lesquelles j’ai eu la chance de travailler sur mon projet, le Dr. Christophe Letondor, Dr. Andrea Gualandi, Dr. Frédéric Bruyneel, Dr Claudio Dalvit et Lionel Burri. Mes remerciements s’adressent également à tous les membres de notre groupe, Dr. Damien Thevenet, Dr. Anca Pordea, Dr. Christophe Letondor, Dr. Andrea Gualandi, Dr. Frédéric Bruyneel, Christian Invernizzi, Christelle Schenk, Inga Kholod-Zaitseva, Dr. Maria Kolympadi, Dr. Ana-Maria Buciumas, Bjorn Bastürk, Lionel Burri et Lucia Cerisoli. Je remercie les membres du service analytique facultaire : Dr. Armelle Vallat (spectrométrie de masse) et le Dr. Julien Furrer et Dr. Claudio Dalvit (spectroscopie RMN). Merci pour leur efficacité et leurs analyses indispensables à la chimie organique de synthèse. Je remercie particulièrement les personnes qui ont fait que ces années passées à Neuchâtel resterons gravé en moi : Saltimbanque, Larson le pervers, Bucheron l’Alsacien, l’Italien (le Mont Blanc…), Mr. Thevent (une faute ?), Mr Synthol dit José le beau gosse, Luyen, Chris, Cyril et Cyrille, Anne-Flore, Christelle, Anca, Khosrow, Mika, Pipo, Jordi, Ha. Merci votre amitié, pour tous ces moments passés au Cerf, au Cercle national (la fondue !!!!), les repas à Champreveyre, au resto Chinois, toutes les parties d’échecs, les tennis et surtout à la salle de fit… Je tiens à remercier tous mes potes de Mulhouse city, Georgy, Best, Yass, Jojo, Matt, Fan, Chris, Damien, Bo-gosse, Taylor, Couzin, Franki, Marco, Guigui… Je remercie les personnes qui m’ont fait découvrir la recherche et m’ont donnés la passion de la chimie, sans lesquelles je ne serai pas la actuellement : Prof. Céline Tarnus, Dr. Albert Defoin et Dr. Joseph Schoepfer. Mes pensées vont également à tous les autres doctorants, post-doc et membres du personnel. Ce travail a été soutenu financièrement par l’Etat de Neuchâtel. Un grand merci à ma famille pour m’avoir toujours soutenu dans mes choix et encouragé dans les moments difficiles, en particulier mes parents Gabrielle et Jacques, mes trois sœurs Anne, Claire et Sophie, et finalement Mathieu. Finalement, je remercie du fond du cœur mon ange, Julie, pour son amour et son soutien. A Julie, A mes parents, A mes sœurs, “A scientist in his laboratory is not a mere technician: he is also a child confronting natural phenomena that impress him as though they were fairy tales” (Marie Curie) Keywords: Calix[4]pyrrole, mesooctamethylporphyrinogen, hydrogenation, reduction, pyrrole, furan, heterocycle, macrocycle, ligand. Abbreviation: aq. : aqueous atm.: atmosphrere cat. : catalytic TLC : Thin layer chromatography GC: gas chromatography ESI : Electron Spray Ionization h : hour (s) min.: minute (s) HR-MS : High Resolution Mass Spectroscopy IR : infra-red ppm : parts per million NMR : Nuclear Magnetic Resonance Rf : retention factor rt: room temperature DI: diastereoselective induction SM: starting material PBG. Porphobilinogen Uro III: uroporphirinogen III PpIX: protoporphyrin IX NCP: N-confused porphyrins NCCP: N-confused calix[4]pyrrole IS: internal standard The abbreviations of chemical reagents have been written according to the description done by Daub et al.1 Summary: The first meso-octaalkylporphyrinogen (calix[4]pyrrole) was synthesized by Baeyer more than 120 years ago, mixing pyrrole and acetone in the presence of an acid. We have performed a thorough study of the catalytic hydrogenation of calix[4]pyrrole 1, by using common as well as novel heterogeneous catalysts based on transition metals (Pd, Rh, Ru) supported on solid matrices. Another investigation concerning the hydrogenation reaction was performed using twelve different macrocyclic substrates. Different factors were tested, which might influence the stereoselectivity during the hydrogenation process and therefore the number of diastereomers obtained. One of the macrocycles synthesized, offers interesting perspectives for the development of novel catalysts. In this context, we investigated the reactivity and the modification of this macrocycle. A thorough study of the nucleophilic properties and a kinetic study allow the discovery the factors that influence the reactivity of these macrocycles. Table of Contents CHAPTER 1 INTRODUCTON….......................................................................1 1. INTRODUCTION .......................................................................................................................... 1 2. «PIGMENTS OF LIFE» ................................................................................................................. 3 3. SYNTHETIC NITROGEN CONTAINING MACROCYCLES .................................................... 6 4. BRIDGED AZAMACROCYCLES ............................................................................................... 7 5. CALIX[4]PYRROLE ..................................................................................................................... 9 6. MOTIVATION ............................................................................................................................. 12 7. KNOWN HYDROGENATIONS OF HETEROCYCLIC CALIX[4]ARENES .......................... 13 8. HYDROGENATION OF CALIX[4]FURAN 6 ........................................................................... 15 9. THE STRUCTURES AND PROPERTIES OF THE CALIX[4]TETRAHYDROFURANS 7.... 18 10. HYDROGENATION OF CALIX[4]PYRROLE ......................................................................... 21 11. CONCLUSIONS .......................................................................................................................... 22 CHAPTER 2 SYNTHESIS OF CALIX[4]PYRROLIDINE…….....................25 1. INTRODUCTION ........................................................................................................................ 27 2. FIRST RESULTS ON HYDROGENATION OF CALIX[4]PYRROLE IN OUR GROUP (Valeria Blangy) .................................................................................................................................... 28 2.1. First success ........................................................................................................................... 28 2.2. First isolation of the totally reduced calix[4]pyrrolidine 13 .................................................. 30 2.3. Hydrogenation of the structurally different calix[4]pyrroles 14 and 15 ................................ 31 2.4. Complexation of calix[4]pyrrolidine (made Dr. Valeria Blangy) ......................................... 32 3. HYDROGENATION OF CALIX[4]PYRROLE ......................................................................... 35 3.1. Calibration curve for control of hydrogenation reactions ..................................................... 37 3.2. Results and discussion ........................................................................................................... 39 3.2.1. Screening of heterogeneous-catalyst ............................................................................. 40 3.2.2. Screening of the reaction media .................................................................................... 42 3.2.3. Degradation of calix[4]pyrrole ...................................................................................... 45 3.2.4. Final optimization .......................................................................................................... 52 3.3. Studies and discussion of the mechanism ............................................................................. 54 3.4. The X-ray structures of compound 12a and 12b and of the calix[4]pyrrolidine 13 .............. 57 3.4.1. Formal description of compound 12a and compound 13 .............................................. 57 3.4.2. Number of possible stereoisomers ................................................................................. 59 3.4.3. Discussion of the structures of calix[2]pyrrole[2]pyrrolidine 12a and 12b .................. 62 3.4.4. Discussion on the structure of calix[4]pyrrolidine 13 ................................................... 63 3.5. Correction
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