Synthesis and properties of functionalization cationic [4]helicenes and triangulenes

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Thesis

Reference

Synthesis and properties of functionalization cationic [4]helicenes and triangulenes

HERNANDEZ DELGADO, Irène

Abstract

This PhD was focused in the reactivity and the study of (chir)optical properties of DMQA and DAOTA scaffolds, and their derivatives. The late stage functionalization of the [4]helicene core by electrophilic aromatic substitution reactions and derivatization, provided a substrate scope of 26 derivatives, and includes the solid state analysis, electronic, absorption and emission properties of these compounds, and for some enantiopure adducts, the study of the electronic circular dichroism and circularly polarized luminescence. The solid state analysis, electronic, absorption and emission properties upon the introduction of the auxochrome substituents in DAOTA series was also studied. The oxidative dimerization of cationic [4]helicene derivatives was also described. Two features were particularly emphasized: (i) the homochiral recognition in the intermolecular coupling and (ii) the kinetic and themodynamic atroposelectivity around the novel Csp2-Csp2 bond.

HERNANDEZ DELGADO, Irène. Synthesis and properties of functionalization cationic [4]helicenes and triangulenes. Thèse de doctorat : Univ. Genève, 2017, no. Sc. 5163

DOI : 10.13097/archive-ouverte/unige:102557 URN : urn:nbn:ch:unige-1025571

Available at:

http://archive-ouverte.unige.ch/unige:102557

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

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Synthesis and Properties of Functionalized Cationic [4]Helicenes and Triangulenes

THÈSE

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

par

Irene HERNÁNDEZ DELGADO

de

Santa Cruz de Tenerife (Espagne)

GENÈVE

Centre d’impression de l’Université de Genève, ReproMail, Unimail 2017

UNIVERSITÉ DE GENÈVE

Section de chimie et biochimie Département de chimie organique

FACULTÉ DES SCIENCES

Professeur Jérôme Lacour

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A mis padres, mi hermano, mi primo Gonzalo, a mis tinerfeños, especialmente a Fito, y mis ginebrinos españoles.

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1 a) C. Herse, D. Bas, F. C. Krebs, T. Bürgi, J. Weber, T. Wesolowski, B. W. Laursen, J. Lacour, Angew. Chem. Int.

Ed. 2003, 42, 3162; b) J. Guin, C. Besnard, J. Lacour, Org. Lett. 2010, 12, 1748; ^cJ. Gouin, T. Bürgi, L. Guénée, J.

Lacour, Org. Lett. 2014, 16, 3800.

2 I. Hernández Delgado, S. Pascal, A. Wallabregue, R. Duwald, C. Besnard, L. Guénée, C. Nancoz, E. Vauthey, R.

C. Tovar, J. L. Lunkley, G. Muller, J. Lacour, Chem. Sci. 2016, 7, 4685.

3 a) E. M. Sánchez-Carnerero, F. Moreno, B. L. Maroto, A. R. Agarrabeitia, M. J. Ortiz, B. G. Vo, G. Muller, S. d. l.

Moya, J. Am. Chem. Soc. 2014, 136, 3346; b) E. M. Sánchez-Carnerero, A. R. Agarrabeitia, F. Moreno, B. L.

Maroto, G. Muller, M. J. Ortiz, S. de la Moya, Chem. –Eur. J. 2015, 21, 13488; ^cS. Zhang, Y. Wang, F. Meng, C.

Dai, Y. Cheng, C. Zhu, Chem. Commun. 2015, 51, 9014.

4 a) K. E. S. Phillips, T. J. Katz, S. Jockusch, A. J. Lovinger, N. J. Turro, J. Am. Chem. Soc. 2001, 123, 11899; b) J. E.

Field, G. Muller, J. P. Riehl, D. Venkataraman, J. Am. Chem. Soc. 2003, 125, 11808; c) R. Hassey, E. J. Swain, N. I.

Hammer, D. Venkataraman, M. D. Barnes, Science 2006, 314, 1437; d) T. Kaseyama, S. Furumi, X. Zhang, K.

Tanaka, M. Takeuchi, Angew. Chem. Int. Ed. 2011, 50, 3684; e) K. Nakamura, S. Furumi, M. Takeuchi, T. Shibuya, K. Tanaka, J. Am. Chem. Soc. 2014, 136, 5555.

Ré sumé

Dans le groupe du Professeur Jérôme Lacour, l’étude des [4]hélicènes cationiques représente un intérêt constant depuis cette dernière décennie. Les dimethoxyquinacridiniums (DMQAs) présentent une configuration hélicoïdale liée à la jonction de quatre cycles aromatiques en position ortho. La présence de groupements MeO à l’extrémité terminale du squelette hélicènique leur confère une grande stabilité configurationelle.¹ Ces composés étant de bons chromophores/fluorophores dans le domaine du rouge et du proche infra-rouge, cette thèse de doctorat a été consacrée à leur post-fonctionnalisation périphérique d’une part, et à l’étude de la modulation de leurs propriétés (chir)optiques et électroniques d’autre part (Schème 1).²

Schème 1. Fonctionnalisation du DMQA.

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Résumé

D’une manière générale, l’introduction de substituants électroattracteurs présente un déplacement hypsochromique des maxima d’absorption, tandis qu’à l’inverse, l’introduction de groupements électrodonneurs induit un déplacement bathochrome. L’étude du dichroïsme circulaire des dérivés nitro et aldéhyde ont montré des effets Cotton dans le domaine du visible. Des études en luminescence circulairement polarisée (CPL) ont été également été conduites, et ont montré des valeurs de glum similaires à celles de molécules organiques déjà rapportées,³ particulièrement dans le domaine du rouge.⁴ Ces résultats seront présentés dans le chapitre 2.

Dans un second temps, la fonctionnalisation du diazaoxatriangulene (DAOTA) a été réalisée (Schème 2). La même tendance dans la modulation des propriétés optiques a pu être observée que pour le DMQA. Ces résultats seront décrits dans le chapitre 3.

Schème 2. Fonctionnalisation du DAOTA.

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Résumé

Finalement, le chapitre 4 relate l’étude d’une réaction de couplage oxydant entre deux molécules de DMQA (Schème 3). Cette réaction a lieu avec une excellente diastéréosélectivité, ainsi qu’une reconnaissance homochirale quasi parfaite. La barrière d’interconversion entre les deux atropoisomères a été déterminée à partir d’analyses RMN à température variable, en collaboration avec Marion Pupier. L’absence de formation du diastereoisomer meso a été déterminée via une réaction de couplage oxydant entre deux composés énantiopures possédant des chaines latérales différentes. Cette étude a été suivie par spectrométrie de masse de haute résolution, en collaboration avec Prof. Gérard Hopfgartner.

Schème 3. Couplage oxidative de DMQA.

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Abbréviations

Abbreviations

ADOTA: azadioxatriangulene

CATB: cethyltrimetylammonium bromide C-G: cytosine-guanine

CPL: circularly polarized luminescence CSP: chiral stationary phase

CT: charge transfer CV: cyclovoltametry d: doublet

DAOTA: diazaoxatriangulene dd: doublet of doublets DFT: density functional theory

DMCA: dimethoxychromenoacridinium DMCX: chromenoxanthene

DMF: N,N-dimethylformamide DMQA: dimethoxyquinacridinium dt: doublet of triplets

ECD: electronic circularly dichroism ee: enantiomeric excess

Equiv: equivalent(s)

ESI-MS: electrosptray ionization mass spectrometry

FLIM: fluorescence lifetime imaging GS: ground state

HFIP: 1,1,1,3,3,3-hexafluoroisopropanol HPLC: high performance liquid

chromatography

HR-MS: high resolution mass spectrometry IR: infrared

ln: napierian logarithm

m: multiplet

NBS: N-bromosuccinimide NCS: N-chlorosuccinimide NMP: N-methyl-2-pyrrolidone NMR: nuclear magnetic resonance NOESY: nuclear overhauser effect spectroscopy

PET: photoinduced electron transfer PIFA: [bis(trifluoroacetoxy)iodo]benzene PPA: polyphosphoric acid

ppm: part(s) per million

Pyr·HCl: pyridinium hydrochloride Rf: retardation factor

RMSD: root mean square deviation s: singulet

SET: single electron transfer

SNAr: nucleophilic aromatic substitution t: triplet

TAPA: (S)-(+)-2-(2,4,5,7-tetranitro-9- fluorenylideneaminooxy)proponic acid TATA: triazatriangulenium

td: triplet of doublets

TMPA: tetramethoxyacridinium TOTA: trioxatriangulene

TS: transition state UV: ultraviolet

VCD: vibrational circularly dichroism Vis: visible

VT-NMR: variable temperature NMR

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Abbreviations

Symbols

δ: chemical shift ε: extinction coefficient

λmax: absorption maximum wavelength λem: emission maximum wavelength Φ: quantum yield

ν: wavenumbers J: coupling constant τ: lifetime

density of charge

k: kinetic constant C0: initial concentration

[x]eq: concentration at the equilibrium Ea: activation energy

A: pre-exponential factor

h: Planck constant, 6.62x10^-34 m² kg / s R: 8.31 kg m² s^-2 K^-1 mol^-1

ΔG^‡: Gibbs free energy at the transition state ΔH^‡: enthalpy at the transition state

ΔS^‡: entropy at the transition state

Units

°C: degree(s) Celsius cal: calories

g: gram(s) h: hour(s) Hz: hertz K: Kelvin

kcal/mol: kcalories per mole kg: kilogram(s)

L: litre m: meter(s) M: moles per liter mg: milligram(s) MHz: megahertz min: minute (s) mL: mililiter(s) mmol: milimole(s) mol: mole(s) nm: nanomete(s) s: second(s) μL: microliter(s)

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Rémérciéménts

Les résultats rapportés dans cette thèse ont été obtenus dans le cadre d’un travail réalisé au sein du laboratoire du Prof. Jérôme Lacour, dans le département de chimie organique de l’Université de Genève, du 1er Juin 2013 au 19 Décembre 2017.

J’exprime toute ma gratitude au Prof. Jérôme Lacour pour m’avoir donné l’opportunité d’intégrer son groupe de recherche, pour ses enseignements et les innombrables connaissances chimiques qu’il m’a transmises avec tout son enthousiasme et son professionnalisme.

Je tiens aussi à remercier le Dr. Narcis Avarvari (Université d’Angers, France) et le Dr. Fabien Cougnon (Université de Genève, Suisse) d’avoir eu l’amabilité de bien vouloir juger ce travail de thèse.

Je désire ensuite remercier les équipes du service d’analyse : RMN (Marion Pupier et le Dr.

Damien Jeannerat), Mass (Harry Theraulaz, Eliane Sandmeier et Dr. Sophie Michalet) et ainsi que le service de cristallographie (Dr. Céline Besnard) pour leurs indispensable contributions et le Prof.

Gérard Hopfgartner (Université de Geneve) et Prof. Neso Sojic (Université de Bordeaux) pour leur collaborations dans les travaux de cette thése.

Je tiens ensuite à remercier Dr. Romain Duwald, Dr. Johann Bosson, Dr. Kota Ramakrishna et Dr. Simon Pascal pour la participation active à la correction de cette thèse.

Un remerciement particulier au Amalia, Antoine, Cecilia, Thierry, Florian, p’tit Jéjé, Romain, Simon, Maya, Pau, Alejandro, Lluc, Marion, Kenji, Marta, Julien, Dominic, Joël, Léo, Sté, Alvina et Marie-Louise pour tous les bons moments qu’on a passé ensemble depuis que je vous ai rencontré.

Il me reste à remercier mes collègues du laboratoire et du département, en particulier:

Alejandro, Aless, Alex, Francesco, Elodie, Léo, Jojo, Daniele, Séb, Pau, Pavol, Geraldine, Kota, Romain, Simon, Margaux, Johann, Sté, p’tit Jéjé, Shinya, Sandip, Mahesh, Sumit, Alvina, Manon, Andjela, Marie-Louise, Flo, Titi, Ceci, Maya, Kenji, Marion, Marta, Amalia, Julien, Dominic, Sonia, Mireille, Lluc, Eric, Simona, Jack, Takuya, Marcello, Daniela, Giulio, Ludo, Gustavo et David Alonso, pour avoir rendu chaque jour au laboratoire un peu spécial et ces quatre ans et demi inoubliables.

Enfin, un grand merci à tout ma famille, et en particulier à ma mère, mon père, mon frère et mon cousin Gonzalo, et mes amies de Tenerife qui ont été très présents pendant toute ma thèse, même dans la distance, et à ma deuxième famille ici à Genève, mes amies espagnoles, pour tout son soutien moral, les nombreux conseils et l’encouragement.

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List of compounds

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List of Compounds

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List of Compounds

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List of Compounds

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Table of Contents

Tablé of Conténts

C

HAPTER

1: G

ENERAL

I

NTRODUCTION ... 1

1.1 PREAMBLE ... 1

1.2 HELICAL CHIRALITY ... 2

1.3 NOMENCALTURE OF HELICENES ... 2

1.4 SYNTHESIS AND PROPERTIES OF CARBAHELICENES ... 3

1.5 CONFIGURATIONAL STABILITY AND RACEMIZATION BARRIER ... 7

1.6 RESOLUTION METHODS ... 8

1.7 APPLICATIONS OF CARBOHELICENES ... 12

1.8 SYNTHESIS OF AZAHELICENES ... 13

1.9 APPLICATIONS OF AZAHELICENES ... 16

1.10 HIGHLY STABLE CATIONIC AZA[4] AND [6]HELICENES AND TRIANGULENES DERIVATIVES ... 17

1.11 RESOLUTION OF [4]HELICENES ... 20

1.12 THEMODYNAMIC STABILITY OF CARBENIUM IONS ... 23

1.13 OPTICAL PROPERTIES ... 24

1.14 ELECTRONIC PROPERTIES ... 27

1.15 NEW CATIONIC HELICENES ... 31

C

HAPTER

2: F

UNCTIONALIZATION OF

C

ATIONIC

[4]H

ELICENES AND

S

TUDY OF THEIR

C

HIROPTICAL AND

E

LECTRONIC

P

ROPERTIES AND

S

OLID

S

TATE

S

TRUCTURES ... 36

2.1 INTRODUCTION ... 36

2.2 SYNTHESIS ... 38

2.3 SOLID STATE STRUCTURAL ANALYSIS... 42

2.5 ELECTRONIC ABSORPTION ... 49

2.6 FLUORESCENCE ... 52

2.7 ELECTRONIC CIRCULAR DICHROISM AND CIRCULARLY POLARIZED LUMINESCENCE ... 55

2.8 CONCLUSION ... 57

CHAPTER 3:FUNCTIONALIZATION OF CATIONIC DIAZAOXATRIANGULENES AND STUDY OF OPTICAL PROPERTIES AND SOLID STATE STRUCTURES ... 59

3.2 SYNTHESIS ... 65

3.4 ELECTROCHEMICAL PROPERTIES ... 72

3.5 ELECTRONIC ABSORPTION ... 75

3.6 FLUORESCENCE ... 77

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Table of Contents

CHAPTER 4:OXIDATIVE COUPLING OF CATIONIC [4]HELICENES – QUASI EXLCUSIVE HOMOCHIRAL COUPLING AND EFFECTIVE KINETIC ATROPOSELECTIVITY ... 81

4.2 OXIDATIVE COUPLING ... 87

4.3 INTERCONVERSION BARRIER ... 97

4.4 HOMOCHIRAL RECOGNITION... 102

4.7 ELECTRONIC ABSORPTION AND ELECTRONIC CIRCULARLY DICHROISM ... 112

4.8 MECHANISM RATIONAL ... 115

CHAPTER 5:GENERAL CONCLUSION AND OUTLOOK ... 120

5.2 OUTLOOK ... 121

CHAPTER 6:EXPERIMENTAL PART ... 125

6.1 GENERAL REMARKS AND ANALYSIS CONDITIONS ... 125

6.2 EXPERIMENTAL PART OF CHAPTER 2 ... 127

6.2.1 SYNTHETIC PROTOCOLS AND CHARACTERIZATIONS ... 127

6.2.2X-RAY DIFFRACTION ... 144

6.2.3VOLTAMMETRIC CURVES. ... 154

6.2.4ECD AND OR DATA ... 155

6.3 EXPERIMENTAL PART OF CHAPTER 3 ... 156

6.3.2 X-RAY DIFFRACTION ... 162

6.4EXPERIMENTAL PART OF CHAPTER 4 ... 168

6.4.2 MATHEMATICAL TREATMENT FOR INTERCONVERSION BARRIER. ... 175

6.4.3 HOMOCHIRAL RECOGNITI ON. ... 175

6.4.4 X-RAY DIFFRACTION ... 179

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1 J. D. Watson, F. H. C. Crick, Nature 1953, 171, 737.

Chapter 1: General Introduction

1.1 Preamble

The purpose of this thesis will be to study and enhance the reactivity and the physico- chemical properties of cationic [4]helicenes and triangulenes. This introductory chapter will highlight the reactivity of helicenes from their synthesis to applications. Properties and applications of carbohelicenes, as well as that of aza-analogues, will be discussed.

The elucidation of the double-helix structure of DNA in 1953 (Figure 1.1), has shown the importance of helical secondary conformations for both structure and function in living systems.¹ Thanks to specific directional non-covalent interactions, and hydrogen bonds in DNA in particular, flexible molecules can be folded to stable dimeric helical conformations. In the case of rigid molecules, helical conformations can arise from the steric interactions or strain. Helicenes, which are molecules made of ortho-fused aromatic rings, belong to this type of compounds, adopting twisted helical conformations due to the steric repulsion of their terminal groups or substituents. These molecules are usually characterized by large specific optical rotation values and intense circular dichroism spectra.

Figure 1.1. B-DNA double-strand.

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Chapter 1: General Introduction

2 a) R. H. Martin, Angew. Chem. Int. Ed. 1974, 13, 649; b) W. H. Laarhoven, W. J. C. Prinsen, in Stereochemistry (Eds.: F. Vögtle, E. Weber), Springer Berlin Heidelberg, Berlin, Heidelberg, 1984, pp. 63; c) K. P. Meurer, F.

Vögtle, in Organic Chemistry, Springer Berlin Heidelberg, Berlin, Heidelberg, 1985, pp. 1; d) A. E. Rowan, R. J. M.

Nolte, Angew. Chem. Int. Ed. 1998, 37, 63; e) T. J. Katz, Angew. Chem. Int. Ed. 2000, 39, 1921; f) A. Urbano, Angew. Chem. Int. Ed. 2003, 42, 3986; g) Y. Shen, C. F. Chen, Chem. Rev. 2012, 112, 1463; h) M. Gingras, Chem.

Soc. Rev. 2013, 42, 968; i) M. Gingras, G. Felix, R. Peresutti, Chem. Soc. Rev. 2013, 42, 1007.

3 R. S. Cahn, C. Ingold, V. Prelog, Angew. Chem. Int. Ed. 1966, 5, 385.

4 M. S. Newman, D. Lednicer, J. Am. Chem. Soc. 1956, 78, 4765.

5 H. Wynberg, M. B. Groen, H. Schadenberg, J. Org. Chem. 1971, 36, 2797.

1.2 Helical chirality

In spite of the absence of stereogenic centers, helicenes are inherently chiral molecules due to their non planar molecular backbone.² They present a C2 axis perpendicular to the helical axis (Figure 1.2a). Based on the helicity rule proposed by Cahn, Ingold and Prelog in 1966, two enantiomers can be defined, one right-handed designated as “plus” and denoted with P configuration and another left-handed designated as “minus” and denoted with M configuration (Figure 1.2b).³

Figure 1.2.

a) Axis in a helicene

and b) representations of P and M enantiomers.

1.3 Nomencalture of Helicenes

The nomenclature of helicenes was first introduced by Newman and Lednicer in 1956, who simpliflied the IUPAC nomenclature by naming the phenantro[3,4-c]phenantrene as hexahelicene (1.1 in Figure 1.3).⁴ An alternative nomenclature for the greek prefix is to indicate the number of ortho-fused aromatic rings present in the compound (in square brackets) preceding the name

“helicene”, thus, [6]helicene for hexahelicene.^2a-c

The term heterohelicenes was first used by Wynberg (1.2 in Figure 1.3).⁵ For simplicity and clarity, they are named as [n]heterohelicene, hetero[n]helicene or [n]helicene. For nitrogen, oxygen and sulfur containing heterohelicenes, aza-, oxa- and thia- prefix are employed, respectively.

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6 J. Meisenheimer, K. Witte, Ber. Dtsch. Chem. Ges. 1903, 36, 4153.

7 a) R. Pschorr, Ber. Dtsch. Chem. Ges. 1896, 29, 496; b) J. J. Li, in Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications (Ed.: J. J. Li), Springer Berlin Heidelberg, Berlin, Heidelberg, 2009, pp.

450.

8 J. W. Cook, J. Chem. Soc. (Resumed) 1933, 1592.

9 W. Fuchs, F. Niszel, Ber. Dtsch. Chem. Ges. (A and B Series) 1927, 60, 209.

10 H. T. Bucherer, J. Prakt. Chem. 1904, 69, 49.

Figure 1.3. Nomenclature of helicenes.

1.4 Synthesis and Properties of Carbahelicenes

The first synthesis of helicenes was done by Meisenheimer and Witte in 1903 (1.3 and 1.4 in Figure 1.4).⁶ Formerly in 1918, Weitzenböck and Klingler reported the synthesis of [5]helicene 1.5 by a Pschorr reaction,⁷ followed by a double decarboxylation. However, yield was low due to the lack of the regioselectivity of the reaction. In 1933, Cook reported an improved synthesis of it and confirmed its structure by crystallizing its dicarboxylic analogue 1.6.⁸ Then, the first example of heterohelicene was reported by Fuchs and Niszel in 1927.⁹ Compound 1.7 was synthesized by double Bucherer reaction,¹⁰ starting from 2,7-hydroxinaphthalene and phenylhydrazine with sodium bisulfite.

Figure 1.4. Reported helicenes from 1903 to 1933.

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11 M. S. Newman, W. B. Lutz, D. Lednicer, J. Am. Chem. Soc. 1955, 77, 3420;

12 M. Flammang-Barbieux, J. Nasielski, R. H. Martin, Tetrahedron Lett. 1967, 8, 743.

13 a) R. H. Martin, G. Morren, J. J. Schurter, Tetrahedron Lett. 1969, 10, 3683; b) R. H. Martin, M. Baes, Tetrahedron 1975, 31, 2135.

14 a) H. Wynberg, M. B. Groen, Journal of the Chemical Society D: Chemical Communications 1969, 964; b) H.

Wynberg, M. B. Groen, G. Stulen, G. J. Visser, J. Am. Chem. Soc. 1970, 92, 7218.

15 a) H. Kagan, A. Moradpour, J. F. Nicoud, G. Balavoine, R. H. Martin, J. P. Cosyn, Tetrahedron Lett. 1971, 12, 2479; b) H. Kagan, A. Moradpour, J. F. Nicoud, G. Balavoine, G. Tsoucaris, J. Am. Chem. Soc. 1971, 93, 2353; c) A. Moradpour, H. Kagan, M. Baes, G. Morren, R. H. Martin, Tetrahedron 1975, 31, 2139.

Nevertheless, it was not until 1955 that the chemistry of helicenes started to be developed.

Newman and coworkers described the synthesis of [6]helicene 1.1 (Figure 1.3) and [4]helicene 1.8 (Figure 1.5) in 12 and 8 steps, respectively.^11,4 Resolution of 1.1 by formation of charge-transfer complex (CT complex) with 2-(2,4,5,7-tetranitro-9-fluorenylideneaminooxy)-propionic acid 1.9 (TAPA, Figure 1.5) was reported. It will be further detailed in section 1.6. In the case of 1.8, cinchonidine was used as resolving agent.¹² With efficient resolution methods in hand, a keen interest in the chiroptical properties of helicenes was noticed.

Figure 1.5. Synthesis of [6]helicene 1.1 and [4]helicene 1.8 and resolution by CT complex with TAPA 1.9, reported by Newman and coworkers in 1955 and 1956.

A third major event occurred in the chemistry of helicenes with the photochemical synthesis of [7]helicene 1.10, reported by Martin and coworkers in 1967 (Scheme 1.1). The stilbene precursor was formed in two steps with the subsequent photocyclization to yield helicene 1.10.¹² Thanks to the readily accessible synthesis of stilbene precursors (Wittig reactions), this new synthetic route became the standard methodology for the production of a large number of helicenes. For instances, Martin reported the synthesis of [13] and [14] helicenes.¹³ Wynberg extended this to heterohelicenes.^14,5 Kagan and corworkers reported the stereoselective synthesis of helicenes by employing circularly

polarized light.¹⁵

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16 a) W. H. Laarhoven, T. J. H. M. Cuppen, R. J. F. Nivard, Recueil des Travaux Chimiques des Pays-Bas 1968, 87, 687; b) W. H. Laarhoven, T. J. H. M. Cuppen, R. J. F. Nivard, Tetrahedron 1970, 26, 1069; c) W. H. Laarhoven, T.

J. H. M. Cuppen, Tetrahedron Lett. 1971, 12, 163

17 L. Liu, T. J. Katz, Tetrahedron Lett. 1991, 32, 6831.

18 L. Liu, B. Yang, T. J. Katz, M. K. Poindexter, J. Org. Chem. 1991, 56, 3769.

19 Q. Lefebvre, M. Jentsch, M. Rueping, Beilstein Journal of Organic Chemistry 2013, 9, 1883.

20 L. Liu, T. J. Katz, Tetrahedron Lett. 1990, 31, 3983.

Scheme 1.1. Synthesis of [7]helicene by oxidative photocyclization reported by Martin and coworkers in 1967.

To go further in the understanding of regioselectivity and mechanism, Laarhoven made important contributions by calculations of intermediates, stereochemistry and excited state.^16,2b

The main drawback of this synthetic pathway is the generation of different regioisomers, difficult to separate from the desired helicene products. Katz and coworkers controlled the regioselectivity by using a bromo-stilbene derivative.¹⁷ The high diluted conditions and low yields obtained were however limiting factors in the scale-up. Katz and coworkers employed the propylene oxide as scavenger of HI (generated in situ), together with catalytic amounts of iodine, increasing considerably the yields.¹⁸ Continuous flow photoreactor can be set up, but the optimization of the flow rates and irradiation times are major issues.¹⁹ Finally, the limited scope of stilbenes and the low functional group tolerance limit the application of this synthetic strategy.

Other synthetic routes were thus investigated. Katz and coworkers introduced another historical landmark in helicene chemistry in 1990 by introducing the use of Diels-Alder reactions in the synthesis of functionalized [5], [6] and higher helicenes. Electron rich p-divinylbenzene and 12 equiv of electron-poor p-benzoquinone were used to generate [5]helicene bisquinone 1.11 in gram- scale (Scheme 1.2).²⁰

Scheme 1.2. Diels-Alder approach reported by Katz and coworkers for synthesis of [5]helicenebisquinone.

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21 M. C. Carreño, R. Hernández-Sánchez, J. Mahugo, A. Urbano, J. Org. Chem. 1999, 64, 1387.

22 a) R. S. Huber, G. B. Jones, Tetrahedron Lett. 1994, 35, 2655; b) F. Dubois, M. Gingras, Tetrahedron Lett. 1998, 39, 5039; c) M. Gingras, F. Dubois, Tetrahedron Lett. 1999, 40, 1309.

23 a) A. Kina, H. Miki, Y.-H. Cho, T. Hayashi, Advanced Synthesis & Catalysis 2004, 346, 1728; b) S. Collins, J. Côté, Synthesis 2009, 2009, 1499; ^cM. Weimar, R. Correa da Costa, F.-H. Lee, M. J. Fuchter, Org. Lett. 2013, 15, 1706.

24 a) F. Teplý, I. G. Stará, I. Starý, A. Kollárovič, D. Šaman, L. Rulíšek, P. Fiedler, J. Am. Chem. Soc. 2002, 124, 9175; b) F. Teplý, I. G. Stará, I. Starý, A. Kollárovič, D. Luštinec, Z. Krausová, D. Šaman, P. Fiedler, Eur. J. Org.

Chem. 2007, 2007, 4244; c) P. Sehnal, I. G. Stará, D. Šaman, M. Tichý, J. Míšek, J. Cvačka, L. Rulíšek, J.

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e) Y. Kimura, N. Fukawa, Y. Miyauchi, K. Noguchi, K. Tanaka, Angew. Chem. Int. Ed. 2014, 53, 8480.

25 G. Pieters, A. Gaucher, D. Prim, J. Marrot, Chem. Commun. 2009, 4827.

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T. Nunn, D. R. Fenwick, Tetrahedron Lett. 2002, 43, 7345; c) D. C. Harrowven, I. L. Guy, L. Nanson, Angew.

Chem. Int. Ed. 2006, 45, 2242.

27 a) S. K. Collins, A. Grandbois, M. P. Vachon, J. Côté, Angew. Chem. Int. Ed. 2006, 45, 2923; b) A. Grandbois, S.

K. Collins, Chem. –Eur. J. 2008, 14, 9323.

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Nicholls, L. D. Schaaf, C. Farès, C. W. Lehmann, M. Alcarazo, J. Am. Chem. Soc. 2017, 139, 1428.

29 J. Ichikawa, M. Yokota, T. Kudo, S. Umezaki, Angew. Chem. Int. Ed. 2008, 47, 4870.

An enantioselective version of this approach was reported by Carreño and Urbano in 1999.²¹ They used an enantiopure sulfinyl 1,4-benzoquinone as dienophile to yield enantioenriched carbohelicenes in 22% yield and 88% ee, by tandem reaction of cycloaddition and pyrolytic sulfoxide elimination (Scheme 1.3).

Scheme 1.3. Enantionselective Diels-Alder approach reported by Carreño and Urbano for synthesis of [5]helicenebisquinone.

Many other non-photophysical methods have been reported as effective synthetic pathways towards helicenes, such as carbenoid couplings,²² cross-couplings,²³ cyclotrimerization of acetylenes,²⁴ electrophilic aromatic cyclizations,²⁵ radical cyclizations,²⁶ olefin methatesis,²⁷ cycloisomerization²⁸ and Friedel-Crafts type cyclization.²⁹

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30 C. Goedicke, H. Stegemeyer, Tetrahedron Lett. 1970, 11, 937.

31 R. H. Martin, M. J. Marchant, Tetrahedron 1974, 30, 347.

32 H. J. Lindner, Tetrahedron 1975, 31, 281.

33 S. Grimme, S. D. Peyerimhoff, Chemical Physics 1996, 204, 411.

1.5 Configurational Stability and Racemization Barrier

The first description of the racemization process of helicenes is dated from 1956 and was reported by Newman and Wise. However, it was not until 1970 that Goedicke and Stegemeyer measured for the first time the racemization barrier of [5]helicene 1.5 (24 kcal/mol, Figure 1.6, vide infra).^4,30 In this report, the monitoring of the thermal racemization was performed by electronic circular dichroism (ECD) in solution. Later on, Martin and coworkers proceeded in the same way for the determination of racemization barriers of [7], [8] and [9]helicenes, where they proposed a conformational pathway for the racemization.^2a,31 To go further, Lindner reported calculations of the transition state (TS) of [5], [6] and [7]helicenes, proposing that racemization occurs through an achiral CS TS (Scheme 1.4, ground state (GS) and TS for [5]helicene 1.5 are shown).³² In the case of helicenes longer than [9]helicene, the racemization process go through more than one TS, complicating the process.

Scheme 1.4. GS and CS-TS of [5]helicene.

The study of the TS of the racemization process of small helicenes, such as [4]helicene 1.12 (scheme 1.5) and dimethyl [3]helicene, was reported in 1996 by Grimme and Peyerimhoff.³³ A C2V TS was suggested for these type of helicenes, where the [3] or [4]helicene in the GS adopt the coplanar C2V-TS, with the subsequent transformation to M or P-configuration with equal probability, leading to racemization (Scheme 1.5 shows the GS and C2V-TS for [4]helicene 1.12).

Scheme 1.5. GS and C2V-TS of [4]helicene.

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The obtained racemization barriers for small helicenes passing through a C2V-TS were lower than 16 kcal/mol at 23 °C (Figure 1.6) and, as a consequence, enantiomers of these types of helicenes cannot be separated at 23 °C.³³ However, helicenes passing through a CS-TS, possessed higher values of racemization barriers (figure 1.6), such as 24 kcal/mol at 27 °C for [5]helicene 1.5, 36 kcal/mol at 27 °C for [6]helicene 1.1 and 42 kcal/mol at 27 °C for [7]helicene 1.10.^2a So, the larger the [n]helicene, the higher the barrier. Another possibility to increase the configurational stability is the introduction of terminal substituents. For instance, when terminal methyls are introduced in the [4]helicene (1.13), racemization barrier is increased from 16 kcal/mol to more than 24 kcal/mol.

Figure 1.6. Racemization barriers for selected helicenes.

1.6 Resolution methods

Different methods have been reported for the resolution of helicenes. Initial studies were based on selective crystallization of diastereomeric charge-transfer (CT) complexes. Indeed, the first resolution of an helicene was reported by Newman and Lednicer in 1955, by formation of a charge- transfer (CT) complex between [6]helicene 1.1 and TAPA reagent 1.9 (Figure 1.5, vide supra).^11,4 The [6]helicene acted as the donor and TAPA as electron-poor acceptor. (-)-(R)-TAPA was used to form the CT with the P enantiomer, and (+)-(S)-TAPA to crystallize the diastereomeric complex with the M- antipode.

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34 H. Okubo, M. Yamaguchi, C. Kabuto, J. Org. Chem. 1998, 63, 9500.

35 J. Míšek, F. Teplý, I. G. Stará, M. Tichý, D. Šaman, I. Císařová, P. Vojtíšek, I. Starý, Angew. Chem. Int. Ed. 2008, 47, 3188.

36 F. Mikes, G. Boshart, E. Gil-Av, Journal of the Chemical Society, Chemical Communications 1976, 99.

37 F. e. Mikes˛, G. Boshart, Journal of Chromatography A 1978, 149, 455.

38 C. H. Lochmüller, R. R. Ryall, Journal of Chromatography A 1978, 150, 511.

Then, other enantiopure moieties were used for resolution by selective crystallization of diastereomeric salts. For instance, Newman and Lednicer reported the resolution of 1,12- dimethylbenzo[c]-phenantren-5-acetic acid 1.8 (Figure 1.5, vide supra) by employing cinchonidine 1.14 as base (Figure 1.7).^30a Yamaguchi and coworkers used quinine 1.15 for separation of dimethylbenzo[c]-phenantren-5,8-dicarboxylate.³⁴ Starý and coworkers used (+)-O,O’-dibenzoyl-D- tartaric acid 1.16 (Figure 1.7) for the separation of 2-aza[6]helicene.³⁵

Figure 1.7. Chiral agents for resolution of helicenes.

In contrast, to overcome issues observed in crystallization, slurry-packed silica gel coated with 10-25% of (R)-(-)-TAPA 1.9 (figure 1.5, vide supra) were prepared by Mikes and Gil-Av, this chiral stationary phase (CSP) allowing the resolution of [6], [7], [9], [11] and [13]helicenes by chromatography.³⁶ (R)-(-)-TABA 1.17 (Figure 1.8) was used for the resolution of [5]helicenes, requiring ten recycling steps by HPLC. Other chiral agents were coated to slurry-packed silica gel, such as binaphthyl-2,2′-diyl hydrogen phosphate 1.18 (binaphthylphosporic acid, BPA) (Figure 1.8), which resulted in efficient separations of heterohelicene.³⁷ L-alanine 1.19 (Figure 1.8) was effective with 1-aza[6]helicene.³⁸

Figure 1.8. Chiral agents in coated columns for helicenes resolution.

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40 T. Thongpanchang, K. Paruch, T. J. Katz, A. L. Rheingold, K.-C. Lam, L. Liable-Sands, J. Org. Chem. 2000, 65, 1850.

41 J. E. Field, G. Muller, J. P. Riehl, D. Venkataraman, J. Am. Chem. Soc. 2003, 125, 11808.

42 J. F. Schneider, M. Nieger, K. Nättinen, B. Lewall, E. Niecke, K. H. Dötz, Eur. J. Org. Chem. 2005, 2005, 1541.

However, crystallization and HPLC methods³⁹ are either inappropriate for the separation of large amounts of enantiopure helicenes or not generally applicable. To solve these problems, chiral auxiliaries were covalently bond to helicenes, being the most effective and reliable method for resolution of helicenes nowadays. Yamaguchi and coworkers used the (1S)-(-)-2,10-camphorsultam 1.21 to form the corresponding diasatereomeric derivatives 1.22 with dimethylbenzo[c]-phenantren- 5,8-dicarboxylate 1.20 (Scheme 1.6), which were separated by silica gel chromatography, and then, reduction of P-1.22 diastereoisomer yields P-1.23 diol, from which the absolute configuration was determined.³⁴

Scheme 1.6. Diastereomeric separation by column chromatography, achieved by Yamaguchi and coworkers.

In this context, Katz and coworkers studied the influence in the resolution of 1.25 with (S)-camphanate moieties introduced in positions 1 or 4 of each terminal ends of the helicenol 1.24 (Scheme 1.7). They concluded that the camphanate reagent is necessary in position 1 in order to achieve an effective resolution.⁴⁰ Venkatamaran⁴¹ and Dötz⁴² also applied the same strategy for the resolution of heterohelicenes 1.26 and 1.27 (Figure 1.9), respectively.

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Scheme 1.7. Resolution of helicenes by introducing (S)-camphanate in position 1, reported by Katz and coworkers.

Figure 1.9. Resolution of heterohelicenes with (S)-camphanate reported by Ventakamaran and Dötz.

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43 a) C. Nuckolls, T. J. Katz, J. Am. Chem. Soc. 1998, 120, 9541; b) T. J. Katz, Angew. Chem. Int. Ed. 2000, 39, 1921; c) M. Stohr, S. Boz, M. Schar, M. T. Nguyen, C. A. Pignedoli, D. Passerone, W. B. Schweizer, C. Thilgen, T.

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Anger, H. Iida, T. Yamaguchi, K. Hayashi, D. Kumano, J. Crassous, N. Vanthuyne, C. Roussel, E. Yashima, Polym.

Chem. 2014, 5, 4909; f) T. Hirose, N. Ito, H. Kubo, T. Sato, K. Matsuda, J. Mater. Chem. C 2016, 4, 2811.

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Sostmann, Tetrahedron 2001, 57, 2515; c) I. Sato, R. Yamashima, K. Kadowaki, J. Yamamoto, T. Shibata, K. Soai, Angew. Chem. Int. Ed. 2001, 40, 1096; d) P. Aillard, A. Voituriez, A. Marinetti, Dalton Trans. 2014, 43, 15263; e) M. J. Narcis, N. Takenaka, Eur. J. Org. Chem. 2014, 2014, 21; f) C.-F. Chen, Y. Shen, in Helicene Chemistry: From Synthesis to Applications, Springer Berlin Heidelberg, Berlin, Heidelberg, 2017, pp. 187.

45 D. Z. Wang, T. J. Katz, J. Org. Chem. 2005, 70, 8497.

1.7 Applications of Carbohelicenes

The screwed rigid and usually fully aromatic backbone confers to helicenes a variety of interesting properties. Of importance are obviously the chiroptical properties. The π–electronic nature of regular helicenes are also important and can be enhanced by self-assembly for functional materials.⁴³ Katz and co-workers reported helical columnar liquid crystal,^43a presenting stronger chiroptical properties than that of isolated molecules. They observed this improvement in both solid materials and in aggregates in solution.

Carbohelicenes have also been used as ligands in asymmetric catalysis.⁴⁴ Reetz and coworkers reported the Rh-catalyzed asymmetric hydrogenation of itaconic acid ester 1.28, by employing enantiopure (P)-1.29 helicene, yielding 1.30 in 39% ee and 54% yield (Scheme 1.8).^44a

Scheme 1.8. Asymmetric hydrogenation reported by Reetz.

Katz and coworkers developed a [5]Helol derivative as a NMR chiral shift agent, to determine the enantiomeric compositions of a variety of alcohols, phenols, amines and carboxylic acids by

means of phosphorous (III) linkages.⁴⁵

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46 S. Honzawa, H. Okubo, S. Anzai, M. Yamaguchi, K. Tsumoto, I. Kumagai, Bioorg. Med. Chem. 2002, 10, 3213.

47 C. Bazzini, S. Brovelli, T. Caronna, C. Gambarotti, M. Giannone, P. Macchi, F. Meinardi, A. Mele, W. Panzeri, F.

Recupero, A. Sironi, R. Tubino, Eur. J. Org. Chem. 2005, 2005, 1247.

Biological applications have also been found. For instance, Yamaguchi and co-workers reported the interaction of [4]helicenediamine derivatives with B-DNA, showing that the binding constant of (P)-helicene is slightly larger than that of the M-enantiomer.⁴⁶

1.8 Synthesis of Azahelicenes

Azahelicenes have emerged as a very attractive subclass of helicenes with interesting properties conferred by the presence of nitrogen donor atoms.

Caronna and coworkers reported the synthesis of azahelicenes by photocyclization. They synthesized the aza or diaza[5]helicenes 1.35 by a two-step process of isomerization(1.34)- photocyclization, starting from the 1,2-diarylethylenes 1.33 (obtained by Wittig reaction between 1.31 and 1.32) (Scheme 1.9).⁴⁷ Products were obtained in good to excellent yields except for the 2- aza[5]helicene and 7-aza[5]helicene.

Scheme 1.9. Synthesis of mono or diazahelicenes by photocyclization, reported by Caronna and corworkers.

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48 J. Klívar, A. Jančařík, D. Šaman, R. Pohl, P. Fiedler, L. Bednárová, I. Starý, I. G. Stará, Chem. –Eur. J. 2016, 22, 14401.

A different approach was reported by Starý and coworkers, by using a metal-induced synthesis consisting in a [2+2+2] cycloisomerization with Co^I catalyst (Scheme 1.10).^35,48 The 1,14- diaza[5]helicene 1.41 was obtained in a four-step process, starting from the alkyne derivative 1.38.

This precursor was synthesized from the bromopyridine derivative 1.36 and the alkyne 1.37 in 81%

yield. Sonogashira coupling yielded the corresponding trialkyne 1.39 in 86%. The tetrahydrodiazahelicene 1.38 was obtained by cycloisomerization in presence of [CpCo(CO)2] (60%

yield). Subsequent oxidation with MnO2 produced 1.41 in 41% yield.

Scheme 1.10. [2+2+2] cycloisomerization reported by Starý and coworkers.

Further transition-metal promoted reactions were considered for the synthesis of azahelicenes. Takenaka and coworkers reported the synthesis of [5] and [6]azahelicene derivatives (Scheme 1.11). Precursor 1.46 was prepared in three steps. The benzoquinoline 1.44 was synthesized by Wittig reaction between the pyridine 1.42 and the phosphonium salt 1.43, followed by subsequent Stille-Kelly cross coupling reaction. Then, 1.44 was regioselectivetly brominated by C-H functionalization, yielding 1.45. Oxidation in two steps produced 1.46. A second sequence of Wittig and Stille-Kelly cross coupling reactions with 1.47-1.49 was performed to obtain azahelicenes 1.50- 1.51. The resolution was easily achieved by transforming the azahelicenes in the corresponding

N-oxides and separating the enantiomers by CSP-HPLC.

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Scheme 1.11. Synthesis of azahelicenes by Stille-Kelly cross coupling reported by Tanaka and coworkers. a) NaHMDS, DMF, 78%; b) [PdCl2(Ph3P)2], (Me3Sn-)2, PhMe, 77%; c) Pd(II) catalyst, NBS, CH3CN, 84%; d) benzoyl peroxide, NBS, PhH, 71%; e) 2-nitropropane, NaOEt, EtOH, DMF, 86%; f) NaHMDS, DMF, 79% for 1.45, 76% for 1.46, 62% for 1.47; g) [PdCl2(Ph3P)2], (Me3Sn-)2, PhMe, 70% for 1.48, 61% for 1.49, 55% for 1.50.

HMDS=1,1,1,3,3,3-hexamethyldisilazane; DMF=N,Ndimethylformamide; NBS=N-bromosuccinimide.

More recently, Fuchter and coworkers reported step-economic (three steps) and scalable synthesis of aza[6]helicene 1.51 (Scheme 1.12).^23c First, cross coupling between 1.53 and the boron derivative 1.54, produced a mixture of 1.57 and 1.58 in 65% yield. Alternatively, a cuprate derivative can be obtained in situ with 1.55, to react with 1.53, generating 1.57 (79%). Deprotection of 1.57, and then, cyclization with PtCl4 catalyst, yielded 1.51 in 65%. Substituted analogues of 1.51 were synthesized by introducing MeO in 1.53. Functionalized 1.51 was further derivatized.

Scheme 1.12. Synthesis of aza[6]helicene reported by Fuchter and coworkers.

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49 L. Kötzner, M. J. Webber, A. Martínez, C. De Fusco, B. List, Angew. Chem. Int. Ed. 2014, 53, 5202.

50 a) K. Tanaka, Y. Kitahara, H. Suzuki, H. Osuga, Y. Kawai, Tetrahedron Lett. 1996, 37, 5925; b) E. Murguly, R.

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51 R. Passeri, G. G. Aloisi, F. Elisei, L. Latterini, T. Caronna, F. Fontana, I. N. Sora, Photochem. Photobio. Sci. 2009, 8, 1574.

52 a) R. Hassey, E. J. Swain, N. I. Hammer, D. Venkataraman, M. D. Barnes, Science 2006; b) S. Graule, M.

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55 S. H. Chen, D. Katsis, A. W. Schmid, J. C. Mastrangelo, T. Tsutsui, T. N. Blanton, Nature 1999, 397, 506.

List and coworkers reported an organocatalytic and asymmetric strategy for azahelicenes by enantioselective Fischer indole synthesis (Scheme 1.13).⁴⁹ Starting from hydrazines of type 1.59 and ketones of type 1.60, with (S)-1.61 (catalyst) and amberlite CG50, azahelicenes of type 1.62 were obtained in 40-91% yields with enantioselectivities up to 92%.

Scheme 1.13. Organocatalityc asymmetric synthesis of azahelicenes reported by List and coworkers.

1.9 Applications of Azahelicenes

The introduction of donor nitrogen atoms in the molecular framework confers new electronic and (chir)optical properties to the helicene scaffolds. Applications in self-assembly,⁵⁰ asymmetric catalysis,^44d,44f biochemistry,⁵¹ circular dichroism,⁵² circular polarized luminescence,⁵³ display⁵⁴ and optical storage devices⁵⁵ have been reported. Branda and coworkers studied the pyridinone[7]helicene 1.63 (figure 1.10) as a self-assembled material. This azahelicene form enantiomerically pure dimers held together by two pairs of cooperative hydrogen bonds.^50b Latterini and coworkers reported the cationic aza[5]helicene 1.64 (Figure 1.10) as a DNA intercalator.⁵¹ They observed a counterion dependence in its interaction with DNA.

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56 J. C. Martin, R. G. Smith, J. Am. Chem. Soc. 1964, 86, 2252.

57 a)B. W. Laursen, F. C. Krebs, M. F. Nielsen, K. Bechgaard, J. B. Christensen, N. Harrit, J. Am. Chem. Soc. 1998, 120, 12255; b) B. W. Laursen, F. C. Krebs, M. F. Nielsen, K. Bechgaard, J. B. Christensen, N. Harrit, J. Am. Chem.

Soc. 1999, 121, 4728; c) B. W. Laursen, F. C. Krebs, Angew. Chem. Int. Ed. 2000, 39, 3432; d) B. W. Laursen, University of Copenhagen (Risø) 2001; e) B. W. Laursen, F. C. Krebs, Chem. –Eur. J. 2001, 7, 1773; f) C. Herse, D.

Bas, F. C. Krebs, T. Bürgi, J. Weber, T. Wesolowski, B. W. Laursen, J. Lacour, Angew. Chem. Int. Ed. 2003, 42, 3162; g) J. Bosson, J. Gouin, J. Lacour, Chem. Soc. Rev. 2014, 43, 2824.

Figure 1.10. Selected azahelicenes with applications in self-assembly (1.63) and biochemistry (1.64).

1.10 Highly Stable Cationic Aza[4] and [6]Helicenes and triangulenes derivatives

In 1964, Martin and Smith reported the synthesis of the tetrafluoroborate carbenium salt 1.65 (Figure 1.11) from the corresponding carbinol.⁵⁶ Then, 35 years after, Laursen and coworkers reported a series of azabridged heterocyclic carbenium ions (1.66-1.68), by treatment of 1.65 with the corresponding primary amines.⁵⁷

Figure 1.11. Carbenium salts reported by Martin (1.65) and Laursen (1.66-1.68).

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58 J. Guin, C. Besnard, J. Lacour, Org. Lett. 2010, 12, 1748.

59 a) J. Gouin, T. Bürgi, L. Guénée, J. Lacour, Org. Lett. 2014, 16, 3800; b) T. J. Sørensen, A. Ø. Madsen, B. W.

Laursen, Chem. –Eur. J. 2014, 20, 6391.

60 C. Nicolas, G. Bernardinelli, J. Lacour, Journal of Physical Organic Chemistry 2010, 23, 1049.

The tetramethoxyacridinium salt 1.66 (TMPA⁺) was obtained from 1.65 by addition of slight excess of amine (2.5 equivalents) in NMP (25 °C, 20 h) in 70-90% yield (scheme 1.14).

Dimethoxyquinacridinium salt 1.67 (DMQA⁺) was obtained stepwise or in one step from 1.65, employing a large excess of amine (25 equivalents) (NMP at 100-110 °C, 1 h, 50-80% yield).

Triazatriangulenium salt 1.68 (TATA⁺) was obtained from 1.65 with large excess of amine in NMP at 130-190 °C for 10-24 h.

TATA⁺ is obviously the triaza analogue of trioxatriangulene salt 1.69 (TOTA⁺), reported by Martin and Smith. The synthesis of TOTA⁺ is achieved by simple treatment of 1.65 with molten Pyr·HCl (170 °C) as solvent for 1 h (30%) (Scheme 1.14).⁵⁶ Following this procedure, Laursen and coworkers reported the fully ring-closed derivatives azadioxatriangulene salt 1.70 (ADOTA⁺) (53-80%) and diazaoxatriangulene salt 1.71 (DAOTA⁺) (85%), with oxygen bridges instead of nitrogens.^57e

Lacour and Laursen extended the scope of cationic [4]helicenes to chromenoxanthene (DMCX⁺) 1.72⁵⁸ and dimethoxychromenoacridinium (DMCA⁺) 1.73.⁵⁹ Compound 1.72 was isolated in 15% yield. The cationic compound was reduced with NaBH4 to perform the purification, as 1.69 was the major product in the crude mixture. Then, treatment with excess of iodine afforded 1.72.

Derivative DMCA⁺ 1.73 was obtained by heating 1.66 at 160 °C in NMP, with yields up to 45%. The thioaza analogue 1.75 was also reported by Lacour and coworkers.⁶⁰ Such cationic [4]helicene was obtained in 30% yield from the precursor 1.74 (synthesized in a six steps process in 47% yield), by heating at 160 °C in presence of aniline and 3 equivalents of benzoic acid.

In terms of mechanism, the introduction of aza-bridges is done by means of subsequent nucleophilic aromatic substitutions (SNAr). For instance, in derivative 1.67, four nucleophilic aromatic substitutions occur for each closure. A first MeO is substituted by one nucleophilic amine in an intermolecular SNAr process. Then, an intramolecular (facilitated) nucleophilic attack on the second MeO occurs, yielding 1.66. This sequence is repeated with two other MeO groups to yield 1.67.

For each bridging nitrogen atom introduced, in the present case, the eletrophilic reactivity of the aza-product is decreased. Experimentally, it means increased amounts of amines and higher temperatures for the next SNAr reactions.

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Scheme 1.14. Synthesis of aza- and oxa-bridged heterocyclic carbenium ions. a) R¹NH2, NMP, 25 °C; 20 h, 70- 90%; b) R²NH2, NMP, 110 °C, 1 h, 50-80%; c) R¹NH2, NMP, 190 °C, 10-24 h; d) PyrHCl, 190 °C, 1 h; e) i. BBr3, CH2Cl2, ii. HBF4 (aq), iii. 100 °C (neat), iv. NaBH4, EtOH, v. I2, Et2O; f) RNH2, NMP, 160 °C (MW).

Scheme 1.15. Synthesis of cationic thioaza [4]helicene.

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61 a) J. Lacour, G. Bernardinelli, V. Russell, I. Dance, CrystEngComm 2002, 4, 165; b) J. Lacour, A. Londez, Journal of Organometallic Chemistry 2002, 643, 392; c) J. Lacour, L. Vial, C. Herse, Org. Lett. 2002, 4, 1351; d) L.

Pasquato, C. Herse, J. Lacour, Tetrahedron Lett. 2002, 43, 5517; e) C. Pasquini, V. Desvergnes-Breuil, J. J. Jodry, A. Dalla Cort, J. Lacour, Tetrahedron Lett. 2002, 43, 423.

1.11 Resolution of [4]Helicenes

The carbenium ion DMQA⁺ 1.67 has been extensively studied in Lacour’s group. When the synthesis and optical properties of DMQA⁺ 1.67 were first reported by Laursen and coworkers in 2000, it was presented as a planar carbenium ion (Figure 1.11, vide supra).^57c-e Then, 3 years later, Lacour and Laursen evidenced the occurrence of an helical conformation and assigned the absolute configuration of the separated enantiomer by X-Ray diffraction and vibrational circular dichroism (VCD) studies.^57f Clearly, this helical conformation/configuration is due to the strong steric repulsion of its terminal methoxy groups (Scheme 1.16).

The resolution of 1.67 was achieved by selective crystallization of diastereomeric salts, using the enantiopure anion hexacoordinated phosphorous-centered BINPHAT 1.76 as resolving agent (Scheme 1.16 only presents results obtained with the (Δ,S)-1.76 enantiomer).^61,57f Salts [1.67][(Δ,S)- 1.76] and [1.67][(Ʌ,R)-1.76] were obtained by mixing 1.67 with [Me2NH2][(Δ,S)-1.76] and [Me2NH2][(Ʌ,R)-1.76], respectively. Purification of diastereomeric salts was performed by column chromatography on basic alumina (96-97% yields). The salts were then separated by crystallization in benzene:tetrahydrofuran, affording crystals of [(+)-P-1.67][(Δ,S)-1.76] from [1.67][(Δ,S)-1.76] in 49:1 d.r. The corresponding enantiomer (+)-P-1.67 was obtained from [(+)-P-1.67][(Δ,S)-1.76] by treatment with KPF6 in dicholoromethane and water in excellent enantiomeric ratio (49:1). The racemization barrier was determined by heating the enantiomer (in solid state) and the ratio was determined on the leuco adduct (CH2CN on the centre) by HPLC. The value was found to be higher than 40 kcal·mol^-1 at 200 °C, being among the highest for such a small helicene.

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62 B. Laleu, P. Mobian, C. Herse, B. W. Laursen, G. Hopfgartner, G. Bernardinelli, J. Lacour, Angew. Chem. Int. Ed.

2005, 44, 1879.

63 B. Laleu, M. S. Machado, J. Lacour, Chem. Commun. 2006, 2786.

Scheme 1.16. Resolution of 1.67 by crystallization of diasatereomeric salts.

A more reliable (applicable to essentially all lipophilic side chains) and scalable (multigram scale) resolution method of 1.67 was reported in 2005 by Lacour and coworkers (Scheme 1.17).⁶² Enantiopure (+)-(R)-methyl-p-tolylsulfoxyde 1.77 was used as chiral auxiliary. After deprotonation of 1.77, the strongly nucleophilic carbanion reacts on the centre of the carbenium ion producing diastereoisomers (R,M)-1.78 and (R,P)-1.78. Both compounds were easily separated by column chromatography on silica gel (ΔRf ≈ 0.3). Then, by a Pummerer fragmentation, enantiomers (-)-M- 1.67 and (+)-P-1.67 were obtained in excellent yields (up to 94%) and enantiomeric excess (>98%).^62-

63

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64 G. Pieters, A. Gaucher, S. Marque, F. Maurel, P. Lesot, D. Prim, J. Org. Chem. 2010, 75, 2096.

Scheme 1.17. Resolution of DMQA⁺ 1.67 by addition of chiral sulfoxide auxiliary to the center, reported by Lacour.

The study was expanded to others [4]heterohelicenes: dioxa 1.72⁵⁸ and azaoxa 1.73⁵⁹ (Figure 1.12). The 1.72 derivative presents a racemization barrier of 27.7 kcal·mol^-1 at 20 °C and 33.3 kcal·mol^-1 for 1.73. These results suggest that the presence of nitrogen atoms in the core of the carbenium ion increase the configurational stability, probably due to the intrinsic rigidity brought by the bridging nitrogen atoms.⁶⁴

Figure 1.12. Racemization barriers for 1.72 and 1.73.

ΔG^‡ = 27.7 kcal/mol ΔG^‡ = 33.3 kcal/mol

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1.12 Themodynamic Stability of Carbenium Ions

The stability of carbenium cations is being described by pKR+ values, which is defined as the affinity of carbenium ion for hydroxide (Equation 1.1).^56,57c-e Experimentally, the conversion from a carbenium ion to its carbinol (leuco product) can be monitored by UV-Vis spectrometry and hence, the equilibrium position is determined readily. The comparison of pKR+ values for selected carbenium ions are shown in Figure 1.13. As a general trend, as oxygen atoms are substituted by nitrogen atoms, the stability increases (higher pKR+ values). For example, TOTA⁺ 1.69 and DMCA⁺ 1.73 displays pKR+ values of 9 and 13, respectively, while TATA⁺ 1.68 presents a pKR+ value of 23.7. Compounds 1.70, 1.67, 1.71 and 1.68 have values that are superior to 14, meaning that the species are so stable that they do not react with hydroxyde to form the corresponding carbinol. In these particular cases, special experimental conditions for the determination of pKR+ were required as they cannot be measured in aqueous solution. Thus, a DMSO/water/Me4NOH solvent system was used for controlling the strength of hydroxide ions and the basicity of the medium (quantified by acidity function Hx).

Equation 1.1. Equilibrium between the cationic species and the corresponding carbinol. Definition of pKR+.

Figure 1.13. pKR+ values of selected carbenium ions.