Synthesis and applications of highly stable non-symmetrical heterocyclic carbenium ions

Thesis

Reference

Synthesis and applications of highly stable non-symmetrical heterocyclic carbenium ions

NICOLAS, Cyril

Abstract

Les carbocations sont généralement des intermédiaires réactionnnels à très courte durée de vie, cherchant à redonner "in fine" une molécule stable. Durant plusieurs décennies, l'étude des carbocations a d'ailleurs été principalement vouée à l'isolation et à la caractérisation de telles espèces. Il existe cependant une autre classe de carbocations dite (hautement) stabilisée. Cette dernière est constituée d'espèces carbocationiques très stables pouvant même être manipulées dans des conditions de nucléophilies et basicités extrêmes. Ces

"carbocations" sont aussi réputés, notamment pour leurs propriétés physico chimiques, mais également et surtout pour leurs innombrables applications. Plus particulièrement, récemment une nouvelle variété de carbocations hétérocycliques hautement stabilisés à ponts oxygénés et azotés a été publiée: les Azatriangulénium. Le but de cette thèse a donc été non seulement d'introduire d'autres atomes que l'oxygène et l'azote à la périphérie de ces ions, mais aussi de trouver toute une multitude d'applications très intéressantes avec ces [...]

NICOLAS, Cyril. Synthesis and applications of highly stable non-symmetrical heterocyclic carbenium ions. Thèse de doctorat : Univ. Genève, 2008, no. Sc. 3974

URN : urn:nbn:ch:unige-21357

DOI : 10.13097/archive-ouverte/unige:2135

Available at:

http://archive-ouverte.unige.ch/unige:2135

Disclaimer: layout of this document may differ from the published version.

Synthesis and Applications of Highly Stable Non- Symmetrical Heterocyclic Carbenium Ions

THÈSE

présentée à la Faculté des sciences de l’Université de Genève pour obtenir le grade de Docteur ès sciences, mention chimique

par

Cyril NICOLAS

de

Carpentras (Vaucluse, France)

Thèse N° 3974

GENÈVE

Atelier de reproduction de la Section de physique

2008

Parts of this Ph.D. thesis have already been published:

1. "Catalytic Aerobic Photooxidation of Primary Benzylic Amines Using Hindered Acridinium Salts" Nicolas, C.; Herse, C.; Lacour, J. Tetrahedron Lett. 2005, 46, 4605.

2. "Triazatriangulenium Cations: Highly Stable Carbocations for Phase-Transfer Catalysis"

Nicolas, C.; Lacour, J. Org. Lett. 2006, 8, 4343.

3. "Synthesis, Resolution, and VCD Analysis of an Enantiopure Diazaoxatricornan Derivative" Mobian, P.; Nicolas, C.; Francotte, E.; Bürgi, T.; Lacour, J. J. Am. Chem.

Soc. 2008, 130, 6507.

à mes enfants ma femme et mes parents

Table of Contents

REMERCIEMENTS... I

RÉSUMÉ... IV

SUMMARY...VII

LIST OF ABBREVIATIONS...X

LIST OF UNITS... XIII

LIST OF SYMBOLS... XIV

CHAPTER I GENERAL INTRODUCTION... - 1 -

I-1PREAMBLE... -1-

I-2THE CARBOCATIONS:DEFINITION,NOMENCLATURE AND REACTIVITY... -1-

I-3CARBOCATIONS WITH SHORT-LIFETIMES... -4-

I-4HIGHLY STABLE CARBOCATIONS... -6-

I-4.1 Introduction... - 6 -

I-4.2 Background... - 7 -

I-4.3 Highly Stable Aza-bridged Heterocyclic Carbenium ions... - 10 -

I-4.3.1 Introduction... - 10 -

I-4.3.2 Reactivity... - 10 -

I-4.3.3 Synthesis... - 13 -

I-4.3.4 Chirality... - 14 -

I-4.3.4.i Chiral TMPA⁺ Cations... - 14 -

TABLE OF CONTENTS

I-4.3.4.ii DMQA⁺ Cations... - 16 -

I-4.3.4.ii.a Helicene-like molecules... - 16 -

I-4.3.4.ii.b Cationic helicenes... - 17 -

I-4.3.4.ii.c Resolution of DMQA⁺ cations by Ion Pairing Association... - 20 -

I-4.3.4.ii.d Resolution of DMQA⁺ cations by Covalent Bond Formation... - 21 -

I-4.3.5 Reaction Discovery and Methodology Development... - 22 -

I-4.3.5.i Unprecedented Pummerer Fragmentations... - 22 -

I-4.3.5.ii Stereoselective synthesis of topological objects: inherently chiral pseudo- rotaxanes... - 24 -

I-5CONCLUSION... -25-

CHAPTER II SULFUR-BRIDGED TRIANGULENIUM DERIVATIVES: TOWARDS NEAR- INFRARED ABSORBING DYES... - 26 -

II-1INTRODUCTION... -26-

II-1.1 Preamble... - 26 -

II-1.2 Rationale... - 28 -

II-2SYNTHESIS... -29-

II-2.1 Sulfur-bridged acridinium analog: a building block for the synthesis of extended thiotriangulenium ions.... - 29 -

II-2.2 Double-bridged molecules... - 31 -

II-2.3 Triple-bridged molecules... - 33 -

II-3X-RAY CRYSTAL STRUCTURE OF CARBINOL 14... -34-

II-4ELECTRONIC ABSORPTION SPECTRA... -35-

II-5CYCLIC VOLTAMMETRY... -38-

II-6CONCLUSION... -40-

CHAPTER III CATALYTIC AEROBIC PHOTOOXIDATION OF PRIMARY BENZYLIC AMINES USING HINDERED ACRIDINIUM SALTS... - 42 -

III-1INTRODUCTION... -42-

III-1.1 Nicotinamide Adenine Dinucleotide (NAD): A Fascinating Cofactor... - 42 -

III-1.2 Acridine and Acridinium Derivatives as Efficient NAD Mimics... - 44 -

III-1.2.1 Foreword... - 44 -

III-1.2.2 General Mechanism of the Hydride Transfer Reaction... - 45 -

III-1.2.3 Applications... - 46 -

III-2RESULTS AND DISCUSSION... -50-

III-2.1 Preamble... - 50 -

III-2.2 Discussion... - 52 -

III-2.3 Mechanistic Rationale... - 56 -

III-3CONCLUSION... -58-

III-4PERSPECTIVES... -58-

CHAPTER IV TRIAZATRIANGULENIUM DERIVATIVES: HIGHLY STABLE CARBOCATIONS FOR PHASE-TRANSFER CATALYSIS... - 61 -

Table of Contents

IV-1INTRODUCTION... -61-

IV-1.1 Importance of Chirality... - 61 -

IV-1.2 Organocatalysis... - 64 -

IV-1.2.1 Definition and Advantages... - 64 -

IV-1.2.2 History... - 65 -

IV-1.3 Phase-Transfer Catalysis (PTC)... - 66 -

IV-1.3.1 Introduction... - 66 -

IV-1.3.2 Principle... - 67 -

IV-1.3.3 Asymmetric Phase-Transfer Catalysis... - 68 -

IV-2TRIAZATRIANGULENIUM CATIONS:HIGHLY STABLE CARBOCATIONS FOR PHASE-TRANSFER CATALYSIS... -70-

IV-2.1 Introduction... - 70 -

IV-2.2 Catalysts preparation... - 70 -

IV-2.3 PTC Alkylation of Methyl-1-oxo-2-indanecarboxylate... - 72 -

IV-2.4 PTC Epoxidation of Trans-Chalcone... - 74 -

IV-2.5 PTC Addition of Dichlorocarbene to Styrene... - 75 -

IV-2.6 PTC Aziridination of Styrene by Chloramine-T / I2... - 77 -

IV-3[4]HETEROHELICENIUM CATIONS:A NEW APPROACH FOR ASYMMETRIC-PTC.... -78-

IV-3.1 Symmetrical Dimethoxyquinacridinium Salts as PT Catalysts... - 78 -

IV-3.1.1 Synthesis and Resolution... - 78 -

IV-3.1.2 "Asymmetric"-PTC alkylation of methyl-1-oxo-2-indanecarboxylate... - 81 -

IV-3.2 Unsymmetrical Catalysts... - 82 -

IV-3.2.1 Structural Requisite for the Chiral Discrimination of Prochiral Anions... - 82 -

IV-3.2.2 Synthetic methodology... - 84 -

IV-3.2.3 Synthesis of the racemic catalysts... - 85 -

IV-3.2.4 Resolution... - 86 -

IV-3.2.5 "Asymmetric"-PTC alkylation of methyl-1-oxo-2-indanecarboxylate... - 88 -

IV-4CONCLUSION... -89-

CHAPTER V SYNTHESIS, RESOLUTION AND VCD ANALYSIS OF THE FIRST ENANTIOPURE DIAZAOXATRICORNAN DERIVATIVE... - 91 -

V-1INTRODUCTION... -91-

V-1.1 Preamble... - 91 -

V-1.2 Fullerenes and Carbon Nanotubes... - 92 -

V-1.2.1 Definition... - 92 -

V-1.2.1.i Fullerenes... - 92 -

V-1.2.1.ii Carbon nanotubes... - 95 -

V-1.2.2 Reactivity... - 96 -

V-1.2.3 Chirality... - 97 -

V-1.3 Closed capped structures... - 98 -

V-2RESULTS AND DISCUSSION... -102-

V-2.1 Choice of a Target.... - 102 -

V-2.2 Synthesis and Basic Optical Properties... - 103 -

V-2.3 Chiral Stationary Phase Enantiomeric Chromatographic Separation.... - 104 -

V-2.4 Absolute Configuration Determination.... - 107 -

V-2.5 Other Chiral-bowl Shaped Derivatives... - 111 -

V-2.6 Towards a Large Scale Resolution / Synthesis of Enantiopure Bowl-shaped Molecules of Type 107... - 112 -

V-2.6.1 Methodology... - 112 -

V-2.6.2 Formation of the Two Diastereomers... - 114 -

V-2.6.3 Chiral Stationary Phase Chromatographic Separation of the Diastereomeric Sulfoxides.... - 115 -

V-2.6.4 Generation of the Enantiopure Bowls... - 117 -

V-3CONCLUSION... -118-

V-4PERSPECTIVES... -118-

CHAPTER VI GENERAL CONCLUSION... - 121 -

EXPERIMENTAL PART... - 124 -

APPENDIX... - 159 -

Remerciements

Les résultats rapportés dans ce manuscrit ont été obtenus dans le cadre d’un travail de thèse réalisé dans le Département de Chimie Organique de l’Université de Genève (Genève, suisse) sous la direction de Mr. le Prof. Jérôme Lacour. Je tiens particulièrement à lui exprimer toute ma gratitude pour la confiance et l’autonomie qu’il m’a accordé dans la réalisation de ce travail. Je voudrais aussi le remercier pour sa disponibilité, son soutien et pour l’enthousiasme et le professionnalisme avec lequel il m’a transmis ses connaissances et sa passion. Je ne saurais imaginer de meilleures conditions pour préparer une thèse de doctorat que celles qu’il m’a offertes.

Ma reconnaissance va également à Mr. Le Prof. Bo. W. Laursen, du Centre de Nano- Sciences de l’Université de Copenhague (Copenhague, Danemark) et Mr. le Prof. Alexandre Alexakis, du Département de Chimie Organique de l’Université de Genève (Genève, suisse), qui ont accepté de s’engager comme experts lors de la soutenance et qui, à ce titre, ont lu et jugé le contenu de cet ouvrage.

La réalisation de ce manuscrit n’aurait évidement pas été possible sans les compétences et la participation dans des domaines aussi variés que la physique, chimie physique et chimie organique de nombreux collaborateurs. Je voudrais par conséquent remercier le Prof. Bo. W.

Laursen et Thomas Just Sørensen du Centre de Nano-Sciences de l’Université de Copenhague (Copenhague, Danemark) pour notre fructueuse collaboration sur l’étude des cations hautement stabilisés, ainsi que le Dr. Damien Jeannerat, André Pinto, Jean-Paul Saulnier, Bruno Vitorge du service RMN du Département de Chimie Organique de l’Université de Genève (Genève, Suisse) et le Dr. Gérald Bernardinelli du laboratoire de cristallographie de l’école de physique (Université de Genève, Genève, Suisse) pour leur compétence et leur

disponibilité. Je voudrais aussi remercier le Dr. Eric Francotte de l’Institut Biomédical de Novartis (Bâle, suisse) et le Prof. Thomas Bürgi de l’Institut de Microtechnologie de l’Université de Neuchâtel (Neuchâtel, Suisse) qui ont respectivement résolu par HPLC préparative chirale et déterminé par spectroscopie de dichroïsme circulaire vibrationnelle la configuration absolue du dérivé tricornan ainsi que le Dr. Pierre Mobian ancien du groupe avec qui ce composé a été synthétisé.

Je suis aussi particulièrement reconnaissant envers les stagiaires et collégiens de la

"Science appelle les Jeunes" avec qui j’ai eu l’opportunité de travailler. C'est-à-dire Sandrine Perrothon, Benjamin Elias et Thomas Frossard.

J’exprime également toute ma gratitude aux Docteurs Francine Dreier et Didier Perret ainsi qu’à Mireille Heimendinger pour leur aide scientifique, relationnelle et administrative.

Je n’oublie pas le Dr. Alexandre Fürstenberg et le Prof. Eric Vauthey du Département de Chimie Physique de l’Université de Genève (Genève, Suisse), le Prof. Rainer Herges de l’Institut de Chimie Organique de l’Université de Kiel (Kiel, Allemagne), le Prof. Olaf Magnussen, Belinda Baisch, Ulrich Jung de l’Institut de Physique Expérimentale de l’Université de Kiel (Kiel, Allemagne) et enfin le Prof. Robert Deschenaux et Stéphane Frein de l’Institut de Chimie de l’Université de Neuchâtel avec lesquels nous collaborons actuellement. Leurs travaux n’ont par conséquent pas étés reportés dans le présent manuscrit.

Je voudrais aussi chaleureusement saluer toutes les personnes du laboratoire et de la Faculté des sciences qui ont contribué à faire de cette thèse une période inoubliable.

Plus particulièrement : Renaud Bach, Andrei Badoiu, Samuel Constant, Guillaume Duvanel, Caroline Falciola, Héléna Goncalves-Farbos, Richard Frantz, Alexandre Fürstenberg, Stéphane Grass, Mireille Heimendinger, Christelle Herse, Marie Hutin, Benoît Laleu, Alexandre Martinez, Nathalie Mehanna, Pierre Mobian, Federico Mora, Sarah Mossé- Sulzer, Benjamin Le Droumaguet, Sandrine Perrothon, David Schultz, Simone Tortoioli, Jérôme Vachon, Bruno Vitorge et David Linder.

Remerciements

Enfin, je tiens à remercier ma famille pour leur soutien tout au long de ces années. Je pense tout particulièrement à ma femme et mes deux enfants, Sandra, Alexandre et Christopher.

Traditionnellement, les carbocations sont définis comme des intermédiaires de réactions à très courte durée de vie, cherchant à réagir avec toute espèce du milieu réactionnel pour redonner une molécule stable. Durant plusieurs décennies la chimie des carbéniums et carboniums a d’ailleurs été principalement vouée à l’isolation et à la caractérisation de ces ions.¹

De nos jours, tandis que cette activité reste forte, la recherche de carbocations pouvant résister à des conditions de nucléophilies et basicités extrêmes est émergeante. Ce domaine englobe entre autre les cations acridiniums, trityliums, tropyliums et xanthyliums. Ces "carbocations" sont réputés pour leurs propriétés physico-chimiques : l’absorption dans l’UV-Visible, la fluorescence …, mais aussi pour leurs innombrables applications. Par exemple, la fluorescéine est très utilisée dans les sciences biologiques et chimiques comme sonde fluorescente, indicateur pH- métrique, antibactérien (e.g., éosine), ou encore comme moyen de signalisation de secours.^2,3

1 Laali, K. K. Recent Developments in Carbocation and Onium Ion Chemistry; American Chemical Society: Washington, D. C., 2007. Olah, G. A.; Prakash, G. K. S. Carbocation Chemistry; John Wiley & Sons: Hoboken, N. J., 2004. McClelland, R. A.

Org. React. Mech. 2004, 249-276. Olah, G. A. J. Org. Chem. 2001, 66, 5943-5957 et références à l’intérieur.

2 Komatsu, K.; Nishinaga, T. Synlett 2005, 187-202. Ito, S.; Kawakami, J.; Tajiri, A.; Ryuzaki, D.; Morita, N.; Asao, T.;

Watanabe, M.; Harada, N. Bull. Chem. Soc. Jpn. 2005, 78, 2051-2065. Fukuzumi, S.; Kotani, H.; Ohkubo, K.; Ogo, S.;

Tkachenko, N. V.; Lemmetyinen, H. J. Am. Chem. Soc. 2004, 126, 1600-1601. Ito, S.; Kubo, T.; Kondo, M.; Kabuto, C.;

Morita, N.; Asao, T.; Fujimori, K.; Watanabe, M.; Harada, N.; Yasunami, M. Org. Biomol. Chem. 2003, 1, 2572-2580.

Fukuzumi, S. In Electron Transfer Chem; Balzani, V., Ed.; Wiley-VCH: Weinheim, 2001; Vol. 4, pp 3-67. Fukuzumi, S.;

Ohkubo, K.; Suenobu, T.; Kato, K.; Fujitsuka, M.; Ito, O. J. Am. Chem. Soc. 2001, 123, 8459-8467. Ito, S.; Kikuchi, S.;

Okujima, T.; Morita, N.; Asao, T. J. Org. Chem. 2001, 66, 2470-2479. Ito, S.; Morita, N.; Asao, T. Bull. Chem. Soc. Jpn. 2000, 73, 1865-1874. Ito, S.; Kikuchi, S.; Morita, N.; Asao, T. J. Org. Chem. 1999, 64, 5815-5821. Ito, S.; Kikuchi, S.; Morita, N.;

Asao, T. Bull. Chem. Soc. Jpn. 1999, 72, 839-849. Ito, S.; Kikuchi, S.; Kobayashi, H.; Morita, N.; Asao, T. J. Org. Chem. 1997, 62, 2423-2431. Ito, S.; Kikuchi, S.; Morita, N.; Asao, T. Chem. Lett. 1996, 175-176. Ito, S.; Morita, N.; Asao, T. Bull. Chem.

Soc. Jpn. 1995, 68, 1409-1436. Ito, S.; Fujita, M.; Morita, N.; Asao, T. Chem. Lett. 1995, 475-476. Ito, S.; Morita, N.; Asao, T.

Tetrahedron Lett. 1994, 35, 751-754. Ito, S.; Morita, N.; Asao, T. Tetrahedron Lett. 1994, 35, 3723-3726. Ito, S.; Morita, N.;

Asao, T. Tetrahedron Lett. 1992, 33, 3773-3774. Ito, S.; Morita, N.; Asao, T. Tetrahedron Lett. 1991, 32, 773-776. Komatsu, K.; Akamatsu, H.; Jinbu, Y.; Okamoto, K. J. Am. Chem. Soc. 1988, 110, 633-634. Komatsu, K.; Tomioka, I.; Okamoto, K.

Tetrahedron Lett. 1980, 21, 947-950 et références à l’intérieur.

3 Shchepinov, M.; Bernad, P. Trityl derivatives for enhancing mass spectrometry. 2006134379, 2006. Nair, V.; Thomas, S.;

Mathew, S. C.; Abhilash, K. G. Tetrahedron 2006, 62, 6731-6747. Chiron, J.; Galy, J.-P. Synthesis 2004, 313-325. Sliwa, W.

Curr. Org. Chem. 2003, 7, 995-1048. Shchepinov, M. S.; Korshun, V. A. Chem. Soc. Rev. 2003, 32, 170-180. Hunger, K.

Industrial Dyes: Chemistry, Properties, Applications; Hunger, Klaus ed.; Wiley-VCH: Weinheim, 2003. Kim, M.-h.; Kim, D.- y.; Moon, B.-s.; Park, J.-c.; Kim, Y.-h.; Seo, S.-j. Process for preparing peptide nucleic acid probe using polymeric photoacid generator. 2002122874, 2002. Mason, W. T. Fluorescent and Luminescent Probes for Biological Activity, Second Edition: A Practical Guide to Technology for Quantitative Real-Time Analysis; Academic: London, UK, 1999. Popescu, A.; Doyle, R. J.

Biotech. Histochem. 1996, 71, 145-151. Sliwa, W. Heterocycles 1994, 38, 897-922. Duxbury, D. F. Chem. Rev. 1993, 93, 381- 433. Hutchings, M. G.; Allen, S.; Bone, D. J.; Burgess, A. N.; Carter, N.; Devonald, D. P.; Eaglesham, A.; Froggat, E. S.; Ryan,

RÉSUMÉ

Résumé

Récemment, Laursen et Krebs ont publié une variété de carbocations hétérocycliques hautement stabilisés à ponts oxygénés et azotés (pKR+ allant jusqu'à 24, e.g., 17 à 19, Figure 1).⁴

N OMeOMe

R¹

O O MeMe

17

N O

N O

Me Me

R² R¹

18

N

N R²

R¹

N

19 R³

Figure 1. Carbeniums hautement stabilisés de type TMPA⁺, DMQA⁺ et TATA⁺

Ces molécules sont très facilement synthétisables, (2, 3 étapes au maximum) et donnent lieu à toute une panoplie d’applications très intéressantes. Par exemple, des acridiniums chiraux du type 17 ayant des phénomènes de rotation lente peuvent être préparés en une étape seulement et 75% de rendement.⁵ De même, les composés 18 sont des [4]-hélicènes et ont la plus grande barrière de racémisation qui ait été mesurée pour un hélicène à ce jour.⁶ Ces derniers peuvent également être résolus et utilisés comme médiateurs chiraux pour la synthèse diastéréosélèctive de rotaxanes,⁷ leur stabilité exceptionnelle permettant aussi le développement de nouvelles réactions telles que la fragmentation de Pummerer…⁸

Au vu des propriétés particulières de ces composés, le travail de cette thèse a donc été, dans un premier temps, de chercher à changer leurs propriétés. De ce fait, il a été décidé d’introduire d’autres atomes que l’oxygène et l’azote à la périphérie de ces structures. Une série d’analogues soufrés a par conséquent été synthétisée et les propriétés physico-chimiques analysées par Spectrophotométrie et Voltampérométrie cyclique (Chapitre II).

T. G.; et al. Chimia 1991, 45, 285-287. Waring, D. R.; Hallas, G. The Chemistry and Application of Dyes; Plenum Press: New York, 1990. Drexhage, K. H. Dye Lasers; Springer: Berlin, Germany, 1990. Zollinger, H. Color Chemistry: Syntheses, Properties and Applications of Organic Dyes and Pigments; Wiley-VCH: Weinheim, 1987;.

4 Krebs, F. C. Tetrahedron Lett. 2003, 44, 17-21. Laursen, B. W. Ph. D. Thesis, Univ. Copenhagen 2001, RisØ-R-1275 (EN).

Laursen, B. W.; Krebs, F. C. Chem. Eur. J. 2001, 7, 1773-1783. Laursen, B. W.; Krebs, F. C. Angew. Chem., Int. Ed. Engl.

2000, 39, 3432-3434.

5 Laleu, B.; Herse, C.; Laursen, B. W.; Bernardinelli, G.; Lacour, J. J. Org. Chem. 2003, 68, 6304-6308.

6 Herse, C.; Bas, D.; Krebs, F. C.; Burgi, T.; Weber, J.; Wesolowski, T.; Laursen, B. W.; Lacour, J. Angew. Chem., Int. Ed. Engl.

2003, 42, 3162-3166.

7 Mobian, P.; Banerji, N.; Bernardinelli, G.; Lacour, J. Org. Biomol. Chem. 2006, 4, 224-231. Laleu, B.; Mobian, P.; Herse, C.;

Laursen, B. W.; Hopfgartner, G.; Bernardinelli, G.; Lacour, J. Angew. Chem., Int. Ed. Engl. 2005, 44, 1879-1883.

Dans un deuxième temps, d’autres applications utilisant les carbeniums 17 à 19 ont étés développés.

En outre, les acridiniums de types 17 se sont trouvés être de très bons analogues de la nicotine amide (NAD) et de ce fait ont catalysés efficacement la transformation d’amines activées en imines sous irradiation (Chapitre III).⁹ La très grande stabilité des cations 18 et 19 a également permis leur utilisation dans des réactions de transfert de phases, réactions au sein desquelles des conditions "extrêmes" de nucléophilie (e.g., HOO^–) et basicité (OH^–) sont rencontrées (Chapitre IV).¹⁰ Enfin, certaines des molécules synthétisées au cours des Chapitre II à IV ont été utilisées pour la préparation d’une coupe chirale énantiopure dont la chiralité vient uniquement de la dissymétrie intrinsèque du carbone central. Cette dernière n’a malheureusement pas révélé une chiralité moléculaire très importante (VCD et [α]D très faible). Ceci pourrait être, cependant, un atout majeur pour le design et la synthèse de molécules cryptochirales.

8 Laleu, B.; Machado, M. S.; Lacour, J. Chem. Commun. 2006, 2786-2788.

9 Nicolas, C.; Herse, C.; Lacour, J. Tetrahedron Lett. 2005, 46, 4605-4608.

10 Nicolas, C.; Lacour, J. Org. Lett. 2006, 8, 4343-4346.

Summary

Traditionally, carbocations are considered as general electrophiles reacting with strong bases and nucleophiles to form neutral adducts by addition, elimination or fragmentation reactions.¹ For many years, the carbenium and carbonium ion chemistry has thus been devoted to the characterization of highly reactive cationic species that could only be synthesized using strongly acidic reaction media.¹

However, nowadays, while this activity remains strong, a search for carbocations that could be highly stable under strongly basic conditions, to the contrary of the species just mentioned, is under focus.^2,3 These moieties are renowned for their outstanding intensity of color, their brilliant shades of purple, red, blue, green and low lightfastness on many substrates.³ Many of them are used as textile and laser dyes, fluorescent probes for clinical and biological purposes, as well as pH indicators, mass spectrometric tags, photoprotecting groups and DNA intercalators among many other applications.³

1 Laali, K. K. Recent Developments in Carbocation and Onium Ion Chemistry; American Chemical Society: Washington, D. C., 2007. Olah, G. A.; Prakash, G. K. S. Carbocation Chemistry; John Wiley & Sons: Hoboken, N. J., 2004. McClelland, R. A.

Org. React. Mech. 2004, 249-276. Olah, G. A. J. Org. Chem. 2001, 66, 5943-5957 and references cited therein.

2 Komatsu, K.; Nishinaga, T. Synlett 2005, 187-202. Ito, S.; Kawakami, J.; Tajiri, A.; Ryuzaki, D.; Morita, N.; Asao, T.;

Watanabe, M.; Harada, N. Bull. Chem. Soc. Jpn. 2005, 78, 2051-2065. Fukuzumi, S.; Kotani, H.; Ohkubo, K.; Ogo, S.;

Tkachenko, N. V.; Lemmetyinen, H. J. Am. Chem. Soc. 2004, 126, 1600-1601. Ito, S.; Kubo, T.; Kondo, M.; Kabuto, C.;

Morita, N.; Asao, T.; Fujimori, K.; Watanabe, M.; Harada, N.; Yasunami, M. Org. Biomol. Chem. 2003, 1, 2572-2580.

Fukuzumi, S. In Electron Transfer Chem; Balzani, V., Ed.; Wiley-VCH: Weinheim, 2001; Vol. 4, pp 3-67. Fukuzumi, S.;

Ohkubo, K.; Suenobu, T.; Kato, K.; Fujitsuka, M.; Ito, O. J. Am. Chem. Soc. 2001, 123, 8459-8467. Ito, S.; Kikuchi, S.;

Okujima, T.; Morita, N.; Asao, T. J. Org. Chem. 2001, 66, 2470-2479. Ito, S.; Morita, N.; Asao, T. Bull. Chem. Soc. Jpn. 2000, 73, 1865-1874. Ito, S.; Kikuchi, S.; Morita, N.; Asao, T. J. Org. Chem. 1999, 64, 5815-5821. Ito, S.; Kikuchi, S.; Morita, N.;

Asao, T. Bull. Chem. Soc. Jpn. 1999, 72, 839-849. Ito, S.; Kikuchi, S.; Kobayashi, H.; Morita, N.; Asao, T. J. Org. Chem. 1997, 62, 2423-2431. Ito, S.; Kikuchi, S.; Morita, N.; Asao, T. Chem. Lett. 1996, 175-176. Ito, S.; Morita, N.; Asao, T. Bull. Chem.

Soc. Jpn. 1995, 68, 1409-1436. Ito, S.; Fujita, M.; Morita, N.; Asao, T. Chem. Lett. 1995, 475-476. Ito, S.; Morita, N.; Asao, T.

Tetrahedron Lett. 1994, 35, 751-754. Ito, S.; Morita, N.; Asao, T. Tetrahedron Lett. 1994, 35, 3723-3726. Ito, S.; Morita, N.;

Asao, T. Tetrahedron Lett. 1992, 33, 3773-3774. Ito, S.; Morita, N.; Asao, T. Tetrahedron Lett. 1991, 32, 773-776. Komatsu, K.; Akamatsu, H.; Jinbu, Y.; Okamoto, K. J. Am. Chem. Soc. 1988, 110, 633-634. Komatsu, K.; Tomioka, I.; Okamoto, K.

Tetrahedron Lett. 1980, 21, 947-950 and references cited therein.

3 Shchepinov, M.; Bernad, P. Trityl derivatives for enhancing mass spectrometry. 2006134379, 2006. Nair, V.; Thomas, S.;

Mathew, S. C.; Abhilash, K. G. Tetrahedron 2006, 62, 6731-6747. Chiron, J.; Galy, J.-P. Synthesis 2004, 313-325. Sliwa, W.

Curr. Org. Chem. 2003, 7, 995-1048. Shchepinov, M. S.; Korshun, V. A. Chem. Soc. Rev. 2003, 32, 170-180. Hunger, K.

Industrial Dyes: Chemistry, Properties, Applications; Hunger, Klaus ed.; Wiley-VCH: Weinheim, 2003. Kim, M.-h.; Kim, D.- y.; Moon, B.-s.; Park, J.-c.; Kim, Y.-h.; Seo, S.-j. Process for preparing peptide nucleic acid probe using polymeric photoacid generator. 2002122874, 2002. Mason, W. T. Fluorescent and Luminescent Probes for Biological Activity, Second Edition: A Practical Guide to Technology for Quantitative Real-Time Analysis; Academic: London, UK, 1999. Popescu, A.; Doyle, R. J.

Biotech. Histochem. 1996, 71, 145-151. Sliwa, W. Heterocycles 1994, 38, 897-922. Duxbury, D. F. Chem. Rev. 1993, 93, 381- 433. Hutchings, M. G.; Allen, S.; Bone, D. J.; Burgess, A. N.; Carter, N.; Devonald, D. P.; Eaglesham, A.; Froggat, E. S.; Ryan, T. G.; et al. Chimia 1991, 45, 285-287. Waring, D. R.; Hallas, G. The Chemistry and Application of Dyes; Plenum Press: New York, 1990. Drexhage, K. H. Dye Lasers; Springer: Berlin, Germany, 1990. Zollinger, H. Color Chemistry: Syntheses, Properties and Applications of Organic Dyes and Pigments; Wiley-VCH: Weinheim, 1987;.

SUMMARY

Recently, a variety of nitrogen- and oxa-bridged heterocyclic carbenium ions of this highly stable class of compounds has been reported (e.g., pKR+ up to 24).⁴ Interestingly, all these polycyclic derivatives (17-19), shown in Figure 1, are simply prepared from a single chemical precursor, the tris(2,6-dimethoxybenzene)methylium ion 11. Sequences of nucleophilic aromatic substitution of the methoxy groups of 11 by primary amines lead successively to the effective formation of tetramethoxyphenylacridinium (TMPA⁺), dimethoxyquinacridinium (DMQA⁺) and triazatriangulenium (TATA⁺) cations (see 17, 18 and 19 respectively).

N OMeOMe

R¹

O O MeMe

17 OMe

O O

OMe

MeO OMe

MeMe

11

N O

N O

Me Me

R² R¹

18

N

N R²

R¹

N

19 R³ R¹NH₂

R²NH2 R³NH₂

Figure 1. Stepwise synthesis of highly stable carbenium ions of the TMPA⁺, DMQA⁺ and TATA⁺ families

More importantly, these moieties are attractive synthetic targets that display many interesting chemical and physical properties which can in turn, be used for the development of novel and original synthetic, asymmetric and topological applications.

For instance, triphenylmethylium 11, has been used for the construction of hindered chiral acridinium cations of type 17 that display interesting restricted rotational issues.⁵ Quinacridiniums of type 18 are cationic [4]-helicene derivatives that present the highest measured barrier of racemization for a helicene derivative and can be used

4 Krebs, F. C. Tetrahedron Lett. 2003, 44, 17-21. Laursen, B. W. Ph. D. Thesis, Univ. Copenhagen 2001, RisØ-R-1275 (EN).

Laursen, B. W.; Krebs, F. C. Chem. Eur. J. 2001, 7, 1773-1783. Laursen, B. W.; Krebs, F. C. Angew. Chem., Int. Ed. Engl.

2000, 39, 3432-3434.

Summary

as "template" for the stereoselective construction of interesting topological objects such as inherently chiral rotaxanes.^6,7 Furthermore, the super stability of derivatives 18 and 19 allows the observation of unknown chemical pathways, such as the Pummerer fragmentation.⁸ Finally, these cations are effective dyes and applications using their optical properties have been (are) considered.^4,9

In this respect, the aim of this Ph.D has thus been to extend even more the scope of the family of TMPA⁺, DMQA⁺ and TATA⁺ cations. First, it was decided to introduce other atoms that nitrogen and oxygen at the periphery of the interesting carbenium ions and sulfur in particular. As such, a series of novel sulfur-bridged heterocyclic carbocations of the acridinium and triangulenium family have been synthesized (see Chapter II). After that, it was decided to look for synthetic applications of the known cationic derivatives of type 17 to 19. Thus, TMPA⁺ cations 17 were used as effective catalysts for the photooxidation of benzylamines into benzylimines, making them interesting NAD⁺ analogues (Chapter III).¹⁰ The extremely high chemical stability of DMQA⁺ and TATA⁺ cations has allowed further their use as phase-transfer catalysts in strongly nucleophilic (e.g., OOH^–, enolates) and basic (e.g., OH^–) media (Chapter IV).¹¹ At last, some of the derivatives prepared for the new projects were used in a rather different research area and a new type of chiral non- racemic bowl-shaped molecule was generated (see Chapter V).

5 Laleu, B.; Herse, C.; Laursen, B. W.; Bernardinelli, G.; Lacour, J. J. Org. Chem. 2003, 68, 6304-6308.

6 Herse, C.; Bas, D.; Krebs, F. C.; Burgi, T.; Weber, J.; Wesolowski, T.; Laursen, B. W.; Lacour, J. Angew. Chem., Int. Ed. Engl.

2003, 42, 3162-3166.

7 Mobian, P.; Banerji, N.; Bernardinelli, G.; Lacour, J. Org. Biomol. Chem. 2006, 4, 224-231. Laleu, B.; Mobian, P.; Herse, C.;

Laursen, B. W.; Hopfgartner, G.; Bernardinelli, G.; Lacour, J. Angew. Chem., Int. Ed. Engl. 2005, 44, 1879-1883.

8 Laleu, B.; Machado, M. S.; Lacour, J. Chem. Commun. 2006, 2786-2788.

9 Dileesh, S.; Gopidas, K. R. J. Photochem. Photobiol., A 2004, 162, 115-120. Laursen, B. W.; Krebs, F. C.; Nielsen, M. F.;

Bechgaard, K.; Christensen, J. B.; Harrit, N. J. Am. Chem. Soc. 1998, 120, 12255-12263.

10 Nicolas, C.; Herse, C.; Lacour, J. Tetrahedron Lett. 2005, 46, 4605-4608.

11 Nicolas, C.; Lacour, J. Org. Lett. 2006, 8, 4343-4346.

A: acceptor molecule AcCoA: acetyl coenzyme A ADOTA⁺: azadioxatriangulenium ADP: adenosine di-phosphate Al: aluminum

AlCl3: aluminium trichloride Al2O3: alumina

aq.: aqueous (lat) meaning in water aqueous: see aq. (lat)

ATP: adenosine tri-phosphate Bn: benzyl

br: broadened BuBr: bromobutane BuCN: cyanobutane C: carbon

c: concentration c: cyclo

CD: circular dichroism

CD2Cl2: deuterated dichloromethane CDCl3: deuterated chloroform CD3CN: deuterated acetonitrile

CF3SO3H: trifluoromethanesulfonic acid CH2Cl2: dichloromethane

CHCl3: chloroform CH3CN: actetonitrile c-hex: cyclo hexyl Cl: chlorine CN^–: cyanide

CNTs: carbon nanotubes

COSY: correlation spectroscopy CSP: chiral stationary phase CV: crystal violet

D: donor molecule d: doublet

d: dextrogyre

DAOTA⁺: diazaoxatriangulenium DBT: dibenzothiophene

dd: doublet of doublet

DDQ: 2,3-dichloro-5,6-dicyano-1,4- benzoquinone

d.e.: diastereomeric excess DFT: density functional theory DHP: dihydropyridine

DMBT: dimethyl dibenzothiophene DMF: N,N-dimethylformamide DMQA⁺: dimethoxyquinacridinium DMSO: dimethylsulfoxide

D2O: deuterated water d.r.: diastereomeric ratio Dr.: Doctor

ECD: electronic circular dichroism ee: enantiomeric excess

e.g.,: exempli gratia (lat) = as an example eq.: equivalent

equiv.: equivalent e.r.: enantiomeric ratio ES: electrospray

ESI: electrospray ionization

LIST OF ABBREVIATIONS

List of abbreviations

ETIC: electron transfer initiated cyclization

Et2O: diethyl ether EtOAc: ethyl acetate EtOH: ethanol F : fluorine

FeCl3: iron trichloride FSO3H: fluorosulfonic acid Ga : gallium

Glc: glucose H: hydrogen H⁺: proton

HBF4: tetrafluoroboric acid HCl: hydrochloric acid Hex: hexyl

HF: hydrogen fluoride H2O: water

H2O2: hydrogen peroxide HPLC: high-performance liq.

chromatography

HOMO: highest occupied molecular orbital

HRMS: high resolution mass spectrometer

hνννν: light

i.e., id est (lat) meaning that is In: Indium

INDOR: internal nuclear double resonance

in situ: (lat) in the place IPR: isolated pentagon rule

iPr: isopropyl

iPr2O: diisopropyl ether IR: infrared

K: potassium

KOH: potassium hydroxide L: length

l: levogyre lat: latin

LCDs: liquid crystalline dendrimers LCI: N-isopropylcyclohexylamide LDA: lithium diisopropyl amide Li: lithium

LUMO: lowest occupied molecular orbital

M: metal m: multiplet maj: major Me: methyl MeO: methoxy MeOH: methanol min: minor

M.p.: melting point MS: mass spectrometry

MWNTs: multi-walled carbon nanotubes N: nitrogen

Na: sodium

NaCl: sodium chloride

NaHCO3: sodium hydrogenocarbonate Na2SO4: sodium sulfate

NAD: nicotinamide adenine dinucleotide NADH: reduced NAD

NIR: near infrared

NMP: N-methyl-2-pyrrolidinone NMQ: N-methyl quinolinium NMR: nuclear Magnetic Resonance NO2: nitro

NOX: NADPH-Oxidase O: oxygen

O2: dioxygen

3O2: triplet dioxygen O2

–: superoxide Oct: octyl

OH^–: hydroxide ion OOH^–: hydroperoxide ion o-tol: ortho tolyl

P: phosphorus Ph: phenyl PhMe: toluene

PMN: polymorphonuclear neutrophils ppm: part per million

Pr: propyl Prof.: professor PT: phase-transfer

PTC: phase-transfer catalysis p-tol: para tolyl

Pyr: pyruvate

Q⁺: quaternary ammonium q: quartet

rac: racemic

Rf: retardation factor rt: room temperature RX: alkyl halide S: sulfur

s: singlet

SbCl3: antimony trichloride SbCl5: antimony pentachloride SiMe3: trimethylsilyl

SiO2: silicagel

SNAr: aromatic nucleophilic substitution SnCl4: tin tetrachloride

t: triplet T: temperature

TATA⁺: triazatriangulenium

TBAB: tetrabutylammonium bromide

tBu: tert-butyl

TCA: tricarboxylic acid cycle td: triplet of doublet

THF: tetrahydrofuran

TLC: thin layer chromatography TOF: time of flight

TOTA⁺: trioxatriangulenium U.S. : United States

UV: ultraviolet

VCD : vibrational circular dichroism via : (lat) way or path

vide infra : (lat) meaning see below vide supra : (lat) meaning see above VIS : visible

VT : variable temperature vs. : versus (lat) meaning against 18-C-6: 18-Crown-6

List of units

Å: Angstrom

°C: degree Celsius cal: calorie cm: centimeter εεεε: M^-1.cm^-1 g: gram h: hour Hz: Hertz J: joule K: Kelvin

Kcal: kilocalories KJ: kilojoules M: molarity Mhz: megahertz min: minute mL: milliliter µµµµl: microliter mmol: millimole µµµµmol: micromole mol: mole

mol %: moles percent mol.l^-1: moles per liter nm: nanometer mg: milligram s: second W: Watt

°: degree

%: percent

LIST OF UNITS

[αααα]X

Y: optical rotation at X nm and Y °C C1: point group of symmetry

C3: point group of symmetry D2: point group of symmetry

∆∆∆∆: reflux

δδδδ: chemical shift

∆∆∆∆G°: Gibbs free energy

∆∆∆∆G^≠≠≠≠: free energy of activation

∆∆∆∆H^≠≠≠≠: enthalpy of activation

∆∆∆∆S^≠≠≠≠: entropy of activation εεεε: extinction coefficient J: coupling constant λλλλ: wavelength o: ortho p: para

pKR+: measure of the stability of carbeniums

sp: linear hybridization sp²: trigonal hybridization sp³: tetrahedral hybridization t1/2: half life

tR: retention time

X*: excited molecule (X) X^•: radical specie

Ø: diameter 2^nd: second

LIST OF SYMBOLS

Chapter I. General Introduction

I-1 Preamble

The preparation of complex molecules (drugs, insecticides, herbicides, textiles, plastics, paints, fuels among others) starting from safe and inexpensive materials or procedures should constitute one of the main goal of our chemical science. In this respect, among all the noteworthy organic reactions that can be used many clean reactions proceed via carbocationic intermediates and simple reactions pathways.¹

The aim of this chapter is not to give an exhaustive list of all carbocations previously synthesized and characterized and all applications that have been reported in the literature so far using such moieties, but to constitute a brief survey of the field, trying to show to the reader how varied this field of chemistry can be. The "state of the art" on the exceptional class of triangulenium cations and derivatives will be however more particularly detailed as this family of compounds is at the heart of this Ph.D.

I-2 The Carbocations: Definition, Nomenclature and Reactivity

A carbocation (or carbenium) is an ion with a "positively-charged" carbon atom which typically adopts a sp² hybridization at the cationic carbon center, in other words a trigonal planar molecular geometry.

1 Laali, K. K. Recent Developments in Carbocation and Onium Ion Chemistry; American Chemical Society: Washington, D. C., 2007. Olah, G. A.; Prakash, G. K. S. Carbocation Chemistry; John Wiley & Sons: Hoboken, N. J., 2004. McClelland, R. A.

Org. React. Mech. 2004, 249-276. Prakash, G. K. S.; Reddy, V. P. In Carbocation Chemistry; Olah, G. A. P., G. K. Surya., Ed.;

John Wiley & Sons: Hoboken, N. J., 2004; pp 73-101. Olah, G. A. J. Org. Chem. 2001, 66, 5943-5957.

Chapter I

GENERAL INTRODUCTION

p-orbital

(a) (b) (c) (d)

Figure I-1. The different forms of activated carbons: (a) carbanion, (b) free radical, (c) carbocation and (d) carbene.

The charged carbon atom is a "sextet", i.e., it has only six electrons in its outer valence shell instead of the eight valence electrons that ensures maximum stability (octet rule). The p-orbital or LUMO (lowest unoccupied molecular orbital) that is not utilized in the hybrids and which is perpendicular to the plane containing the substituents is empty and bears in the lewis description the positive charge since it represents the orbital available to accept electrons (see Figure I-1 and Figure I-2).¹

Figure I-2. Wire mesh surface representation of the reactive p-orbital (LUMO). This is where the nucleophile will attack.

As a consequence of this lewis acidity, carbocations are most often very reactive, seeking to fill the octet of valence electrons as well as regain a neutral charge. They react with various nucleophiles and/or alternatively, lose a proton (H⁺) or fragment to generate a π-bond.²

2 There is an other class of carbocations which is stable in air and can be handled without any precaution. Although "less known" it is very captivating. It will be reviewed later (see § I-4).

Chapter I. General Introduction

One of the key issues in this chemistry is actually the stability of the carbenium species translated into quantitative terms by the pKR+ value.³ It is a thermodynamic parameter that expresses the affinity of a carbocation towards hydroxide ions. It reports the equilibrium constant for the acid-base reaction that converts a carbenium ion into the corresponding carbinol (vide infra Equation I-1). In fact, the higher the pKR+ the more the carbocation is unreactive towards nucleophilic attack. In other words, it means that a carbocation of which the pKR+ value is 9.05 would be 50%

converted into its carbinol at pH 9.05 and thus is quite stable under slightly basic conditions.

pK_R+ = H_x + log R₃C⁺

R3COH R₃C⁺+ H₂O R₃COH+H⁺

Equation I-1. Definition of the pKR+ value (Hx = acidity function characteristic for the solvent system used and the carbenium ion/carbinol couple studied). R = any radical specie.

There are basically three types of carbocations: Those that are stabilized by resonance (either through lone pair electrons on adjacent atoms or through conjugated pi-bonding electrons), those that are stabilized by positive σ-induction of an adjacent electropositive substituent and those that are stabilized by hyperconjugation (i.e., alkyl carbocations). The latest can be classified in three classes (e.g., primary, secondary, or tertiary) depending on respectively one, two or three carbon atoms bonded to the ionized carbon. Their stability increases with the number of alkyl groups bonded to the charge-bearing carbon.¹

R R'' R'

R H

R'

R H

H

H H

H

> > >

III^aire II^aire I^aire methyl cation

least stable

Figure I-3. Order of stability of alkyl carbenium ions: tertiary (III) are more stable than secondary (II), which are more stable than primary (I) and methyl cation respectively.

3 Mayr, H.; Ofial, A. R. In Carbocation Chemistry; Olah, G. A. P., G. K. Surya., Ed.; John Wiley & Sons: Hoboken, N. J, 2004;

pp 331-358. Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66-77.

Thus, tertiary carbocations are more stable (and form more readily) than secondary and primary carbocations respectively. Methyl carbocations, which are devoid of alkyl chains in β position to the cationic charge, are to the contrary highly unstable (Figure I-3).

I-3 Carbocations with Short-lifetimes

For many years the chemistry of carbocations has thus been mainly devoted towards the development of highly reactive cationic species that could be only characterized in powerful acidic reaction media.¹

The history dates back to 1899 when J. Steglitz, while studying salts of imido ethers, stated first the idea of possible ionic hydrocarbon species.⁴ After that, several observations related to the presence of carbocationic intermediates were reported, but one of the most significant and original "assumption" was raised by H. Meerwein and van Emster in the 1920s. While exploring the Wagner rearrangement of camphene hydrochloride 1 to isobornyl chloride 2, they detected that the rate of the reaction increased with the dielectric constant of the solvent. They also observed that dry HCl, as well as certain Lewis acids such as SbCl3, SnCl4, SbCl5, FeCl3 and AlCl3

accelerated considerably the rearrangement.⁵

Cl Cl

Cl^-

Cl^- Cl^-

1 2

Scheme I-1. Meerwein rearrangement of camphene hydrochloride 1 to isobornyl chloride 2.

Meerwein concluded that the isomerization did not proceed by way of migration of the chlorine atom but by a rearrangement of a cationic intermediate (Scheme I-1).

Hence, the so-called Wagner-Meerwein rearrangement was born. Furthermore, he also postulated that positively charged ionic carbon compounds might be intermediates to

4 Stieglitz, J. Amer. Chem J. 1899, 21, 101-111.

Chapter I. General Introduction

the course of reactions that start from nonionic substrates and lead to nonionic covalent products. This significant interpretation was however greeted with much skepticism as no direct observation and interpretation of such species could be performed with high-performance apparatus until the late 1950s.

It was at that time that professor George A. Olah started to work in this fascinating field. Through a series of brilliant experiments he managed to solve this debated problem. He created methods as to prepare persistent (long-lived) carbocations in high concentrations, making then possible the study of their structure, stability and reactions with simple spectroscopic methods (e.g., INDOR - internuclear double resonance).¹ Thus, by mixing superacids with special solvents (i.e., Lewis acids), he convincely proved the existence of two groups of "carbocations".⁶ The trivalent ones (i.e., the real carbocations, see before), in which the positive carbon atoms are surrounded by three atoms and the hypervalent ones which are surrounded by five atoms and called carbonium.

CH₄ + H⁺ CH₅⁺ CH5+ CH₃⁺ + H₂ CH3+ + 3 CH4 (CH3)3C⁺ + 3 H2

Figure I-4. Conversion of methane into tert-butyl carbocation under superacid activation.

He found also that the superacids are so strong that they can donate a proton to simple saturated hydrocarbons. These just generated penta-coordinated carbonium ions can then undergo further reactions such as, for example, the phenomenal conversion of methane into tertiary-butyl carbocation under treatment with FSO3H- SbF5 at 140 °C (Figure I-4).⁷

Thus, over the years outstanding chemists such as C. K. Ingold⁸ who performed stereochemical and kinetic studies about carbenium intermediates (e.g., S_N1 and E1

5 Meerwein, H.; Van Emster, K.; Joussen, J. Ber. Dtsch. Chem. Ges. 1922, 55B, 2500-2528.

6 The term superacid was originally coined by James Bryant Conant in 1927 to describe acids that were stronger than 100%

sulfuric acid, which has an acid dissociation constant of -3.00. Commercially available superacids include fluorosulfonic acid (FSO3H) and trifluoromethanesulfonic acid (CF3SO3H), both of which are about a thousand times stronger than pure sulfuric acid. The strongest superacids, namely the one discovered by Olah, and which foiled him the Nobel prize in 1994, are prepared by the combination of a strong Lewis acid and a strong Brønsted acid (as for example antimony pentafluoride (SbF5) and FSO3H the combination of which is called "magic acid" or hydrogen fluoride (HF) and SbF5 which is the stongest superacid system.

7 This phenomenon has contributed to the discovery and the development of petrochemistry.

8 Ingold, C. K. In Structure and Mechanism in Organic Chemistry; Cornell Univ. Press: Ithaca, N.Y., 1953; p 828 and references cited therein.

reactions), F. C. Whitmore⁹ who generalized the concept to several other organic reactions, H. Meerwein, P. D. Bartlett, C. D. Nenitzescu, S. Winstein, D. J. Cram, M.

J. S Dewar, J. D. Roberts, P. v. R. Schleyer, G. H. Mc Lafferty among others and finally leading investigator George A. Olah slowly brought to maturity this fundamental concept, which constitutes today the field of modern carbocationic chemistry.^1,10

I-4 Highly Stable Carbocations

I-4.1 Introduction

However, today, while the just mentioned reactivity studies remain strong, a search for carbocations that would be, to the contrary highly stable under strongly basic and nucleophilic conditions is going on.^11,12 It is the field of highly stable carbocations. It includes essentially all the carbocationic moieties which can be stored and handled without any strenuous precautions (e.g., inert atmosphere, dry media…).

In short, all entities of which the pKR+ is higher than – 6.6, the pKR+ value of the trityl cation (Ph3C⁺) 3, are concerned. These moieties, which are attractive synthetic targets

9 Whitmore, F. C. J. Am. Chem. Soc. 1932, 54, 3274-3283. Whitmore, F. C. Chem. Eng. News 1948, 26, 668-674. Whitmore, F.

C. Organic Chemistry; Dover Pubs: New york, N.Y., 1961;

10 Bethell, D.; Gold, V. Carbonium Ions, an Introduction; Academic Press, London: New York, N.Y., 1967. Olah, G. A.;

Schleyer, P. v. R.; Wiley-Interscience: New York, N.Y., 1976; Vols. I-V. Vogel, P. Carbocation chemistry; Elsevier:

Amsterdam, 1985; and reviews therein.

11 Nicolas, C.; Herse, C.; Lacour, J. Tetrahedron Lett. 2005, 46, 4605-4608. Komatsu, K.; Nishinaga, T. Synlett 2005, 187-202.

Ito, S.; Kawakami, J.; Tajiri, A.; Ryuzaki, D.; Morita, N.; Asao, T.; Watanabe, M.; Harada, N. Bull. Chem. Soc. Jpn. 2005, 78, 2051-2065. Fukuzumi, S.; Kotani, H.; Ohkubo, K.; Ogo, S.; Tkachenko, N. V.; Lemmetyinen, H. J. Am. Chem. Soc. 2004, 126, 1600-1601. Ito, S.; Kubo, T.; Kondo, M.; Kabuto, C.; Morita, N.; Asao, T.; Fujimori, K.; Watanabe, M.; Harada, N.; Yasunami, M. Org. Biomol. Chem. 2003, 1, 2572-2580. Fukuzumi, S.; Ohkubo, K.; Suenobu, T.; Kato, K.; Fujitsuka, M.; Ito, O. J. Am.

Chem. Soc. 2001, 123, 8459-8467. Fukuzumi, S. In Electron Transfer Chem; Balzani, V., Ed.; Wiley-VCH: Weinheim, 2001;

Vol. 4, pp 3-67. Ito, S.; Morita, N.; Asao, T. Bull. Chem. Soc. Jpn. 2000, 73, 1865-1874. Ito, S.; Kikuchi, S.; Morita, N.; Asao, T. J. Org. Chem. 1999, 64, 5815-5821. Ito, S.; Kikuchi, S.; Morita, N.; Asao, T. Bull. Chem. Soc. Jpn. 1999, 72, 839-849. Ito, S.; Kikuchi, S.; Kobayashi, H.; Morita, N.; Asao, T. J. Org. Chem. 1997, 62, 2423-2431. Ito, S.; Kikuchi, S.; Morita, N.; Asao, T. Chem. Lett. 1996, 175-176. Ito, S.; Morita, N.; Asao, T. Bull. Chem. Soc. Jpn. 1995, 68, 1409-1436. Ito, S.; Morita, N.; Asao, T. Bull. Chem. Soc. Jpn. 1995, 68, 2639-2648. Ito, S.; Fujita, M.; Morita, N.; Asao, T. Chem. Lett. 1995, 475-476. Ito, S.;

Fujita, M.; Morita, N.; Asao, t. Bull. Chem. Soc. Jpn. 1995, 68, 3611-3620. Ito, S.; Morita, N.; Asao, T. Tetrahedron Lett. 1994, 35, 751-754. Ito, S.; Morita, N.; Asao, T. Tetrahedron Lett. 1994, 35, 3723-3726. Ito, S.; Morita, N.; Asao, T. Tetrahedron Lett.

1992, 33, 3773-3774. Ito, S.; Morita, N.; Asao, T. Tetrahedron Lett. 1991, 32, 773-776. Komatsu, K.; Akamatsu, H.; Jinbu, Y.;

Okamoto, K. J. Am. Chem. Soc. 1988, 110, 633-634. Komatsu, K.; Tomioka, I.; Okamoto, K. Tetrahedron Lett. 1980, 21, 947- 950.

12 Shchepinov, M.; Bernad, P. Trityl derivatives for enhancing mass spectrometry. 2006134379, 2006. Nair, V.; Thomas, S.;

Mathew, S. C.; Abhilash, K. G. Tetrahedron 2006, 62, 6731-6747. Chiron, J.; Galy, J.-P. Synthesis 2004, 313-325. Sliwa, W.

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