Chapter I: General Introduction
I- 7. Properties of helicenes:
Martin wrote at the end of his review in 1974:37 “it is our intimate conviction that further work on these unique molecules... should be highly rewarding in many fields of chemistry.”
Indeed, because of their non-planar dissymmetric backbone, helicenes present an intriguing variety of properties and applications from areas of chiroptical38 and photochromic materials.39 excellent self-assembly,40 in domains such as asymmetric catalysis,41 supramolecular chemistry42
36 Thongpanchang, T.; Paruch, K.; Katz, T. J.; Rheingold, A. L.; Lam, K.-C.; Liable-Sands, L. J. Org. Chem. 2000, 65, 1850-1856.
37 Martin, R.H., The helicenes, in Angew. Chem. 1974. p. 727-38.
38 Graule, S.; Rudolph, M.; Vanthuyne, N.; Autschbach, J.; Roussel, C.; Crassous, J.; Réau, R. J. Amer. Chem. Soc.
2009, 131, 3183-3185.
39 Furche, F.; Ahlrichs, R.; Wachsmann, C.; Weber, E.; Sobanski, A.; Vögtle, F.; Grimme, S. J. Am. Chem. Soc.
2000, 122, 1717-1724; Norsten, T. B.; Peters, A.; McDonald, R.; Wang, M. T.; Branda, N. R. J. Am. Chem. Soc.
2001, 123, 7447-7448; Verbiest, T.; Sioncke, S.; Persoons, A.; Vyklicky, L.; Katz, T. J. Angew. Chem. Int. Ed.
2002, 41, 3882-3884; Field, J. E.; Muller, G.; Riehl, J. P.; Venkataraman, D. J. Am. Chem. Soc. 2003, 125, 11808-11809; Wachsmann, C.; Weber, E.; Czugler, M.; Seichter, W. Eur. J. Org. Chem. 2003, 2863-2876; Champagne, B.;
Andre, J.-M.; Botek, E.; Licandro, E.; Maiorana, S.; Bossi, A.; Clays, K.; Persoons, A. ChemPhysChem. 2004, 5, 1438-1442; Lebon, F.; Longhi, G.; Gangemi, F.; Abbate, S.; Priess, J.; Juza, M.; Bazzini, C.; Caronna, T.; Mele, A.
J. Phys. Chem. A 2004, 108, 11752-11761.
40 Nuckolls, C.; Katz, T. J.; Castellanos, L. J. Amer. Chem. Soc. 1996, 118, 3767-3768. Dai, Y.; Katz, T. J. J. Org.
Chem. 1997, 62, 1274-1285. Nuckolls, C.; Katz, T. J. J. Amer. Chem. Soc. 1998, 120, 9541-9544.
molecular machines43 and material sciences44 have been reported and thoroughly studied by Katz and coworkers.45
Introduction of peripheral functional groups onto helicene skeletons have also been the focus of many other research groups46 since the functionalisation could account for many changes in their properties. The introduction of polar hydroxy groups and amines, carboxylates or diphosphines have given access to applications in catalysis,41 molecular recognition47 and DNA interaction.48 This last property will be detailed in chapter III. Katz and coworkers have mostly developed helicenebisquinones and these moieties have shown fascinating self-assembling properties. As a matter of fact, all these mentioned derivatives are neutral.
Nevertheless, most carbohelicenes have properties rather far from the compounds of study (vide infra, chapters II-V) and as such, details will not be further given. Emphasis will, on the other hand, be made on azahelicenes and quinacridinium derivatives in particular.
41 Reetz, M. T.; Beuttenmuller, E. W.; Goddard, R. Tetrahedron Lett. 1997, 38, 3211-3214. Terfort, A.; Gorls, H.;
Brunner, H. Synthesis 1997, 79-86. Reetz, M. T.; Sostmann, S. J. Organomet. Chem. 2000, 603, 105-109. Reetz, M.
T.; Sostmann, S. Tetrahedron 2001, 57, 2515-2520.
42 Murguly, E., R. McDonald, and N.R. Branda, Org. Lett. 2000, 2, 3169-3172; Kitahara, Y. and K. Tanaka, Chem.
Commun 2002, 932-933; Tanaka, K., H. Osuga, and Y. Kitahara, J. Org. Chem. 2002, 67, 1795-1801.
43 Kelly, T. R.; Cai, X.; Damkaci, F.; Panicker, S. B.; Tu, B.; Bushell, S. M.; Cornella, I.; Piggott, M. J.; Salives, R.;
Cavero, M.; Zhao, Y.; Jasmin, S. J. Amer. Chem. Soc. 2006, 129, 376-386.
44 Dai, Y. J.; Katz, T. J. J. Org. Chem. 1997, 62, 1274-1285; Fox, J. M.; Lin, D.; Itakagi, Y.; Fujita, T. J. Org. Chem.
1998, 63, 2031-2038; Stone, M. T.; Fox, J. M.; Moore, J. S. In Org. Lett., 2004; Vol. 6, pp 3317-3320; Miyasaka, M.; Rajca, A.; Pink, M.; Rajca, S. Chem. Eur. J. 2004, 10, 6531-6539; Miyasaka, M.; Rajca, A.; Pink, M.; Rajca, S.
J. Am. Chem. Soc. 2005, 127, 13806-13807.
45 Katz, T.J. Angew. Chem. Int. Ed. 2000, 39, 1921-1923.
46 Dreher, S. D.; Paruch, K.; Katz, T. J. J. Org. Chem. 2000, 65, 806-814. Paruch, K.; Vyklicky, L.; Wang, D. Z.;
Katz, T. J.; Incarvito, C.; Zakharov, L.; Rheingold, A. L. J. Org. Chem. 2003, 68, 8539-8544. Fox, J. M.; Goldberg, N. R.; Katz, T. J. J. Org. Chem. 1998, 63, 7456-7462.
47 Owens, L.; Thilgen, C.; Diederich, F.; Knobler, C. B. Helv. Chim. Acta 1993, 76, 2757-2774. Wang, D. Z.; Katz, T. J. J. Org. Chem. 2005, 70, 8497-8502. Murguly, E.; McDonald, R.; Branda, N. R. Org. Lett. 2000, 2, 3169-3172.
Reetz, M. T.; Sostmann, S. Tetrahedron 2001, 57, 2515-2520.
48 Xu, Y.; Zhang, Y. X.; Sugiyama, H.; Umano, T.; Osuga, H.; Tanaka, K. J. Am. Chem. Soc. 2004, 126, 6566-6567.
Honzawa, S.; Okubo, H.; Anzai, S.; Yamaguchi, M.; Tsumoto, K.; Kumagai, I. Bioorg. Med. Chem. 2002, 10, 3213-3218.
12 | P a g e I-8. Synthesis and properties of azahelicenes
Azahelicenes,49 a subgroup of helicenes containing at least one sp2-hybridized nitrogen atom within the helicene framework, have more recently caught the attention of the scientific community.50 Their use in asymmetric catalysis,51 in metal complexation (for instance with Ag+)55, proton affinities, self-assembly is extremely interesting.
They have been mainly synthesized by the photochemical route52 as shown by Caronna53 who managed to obtain through this route very diverse monoaza and diaza helicenes B26 (Scheme I-5). The position of the nitrogen was varied in the end target by modifying the precursors.
Relatively few other routes have been used for this class of molecules.54
Scheme I-5: Photochemical approach to diverse mono and diaza derivatives B26
The interesting approach pioneered by Starý, Stará et al. to afford helicenes via metal catalyzed [2+2+2] cycloisomerisation reactions was successfully employed in the formation of 1,14-diaza[5]helicene B28 and 1- and 2-aza[6]helicene B29 from triyne key precursors B27 (Scheme
49 Recent review: Dumitrascu, F.;Dumitrescu, D. G.; Aron I. ARKIVOC 2010, 1-32.
50 Sato, K.; Arai, S. Heterohelicenes Containing Nitrogen Aromatics: Azahelicenes and Azoniahelicenes In Cyclophane Chemistry for the 21st Century Takemura, H., Ed., Research Signpost: Kerena, India, 2002, 173 – 197.
51 Takenaka, N.; Chen, J.; Captain, B.; Sarangthem, R. S.; Chandrakumar, A. J. Amer. Chem. Soc. 2010, 132, 4536-4537. Samal, M.; Mísek, J.; Stará, I. G.; Starý, I. Collect. Czech. Chem. Commun. 2009, 74, 1151.
52 Sato, K.; Okazaki, S.; Yamagishi, T.; Arai, S. J. Heterocyclic Chem 2004; 41, 443-447. Bazzini, C.; Brovelli, S.;
Caronna, T.; Gambarotti, C.; Giannone, M.; Macchi, P.; Meinardi, F.; Mele, A.; Panzeri, W.; Recupero, F.; Sironi, A.; Tubino, R. Eur. J. Org. Chem. 2005, 2005, 1247-1257.
53 Bazzini, C.; Brovelli, S; Caronna, T.; Gambarotti, C.; Giannone, M.; Macchi, P.; Meinardi, F.; Mele, A.; Panzeri, W.; Recupero, F.; Sironi, A.; Tubino, R. Eur. J. Org. Chem. 2005, 1247-1257. Caronna, T.; Fontana, F.; Longhi, G.;
Mele, A.; Sora, I. N.; Panzeri, W.; Viganò, L. Arkivoc, 2009, 145. Abbate, S.; Bazzini, C.; Caronna, T.; Fontana, F.;
Gambarotii, C.; Gangemi, F.; Longhi, G.; Mele, A.; Sora, I. N.; Panzeri, W. Tetrahedron 2006, 62, 139.
54 El Abed, R.; Ben Hassine, B.; Genet, J.-P.; Gorsane, M.; Marinetti, A. Eur. J. Org. Chem., 2004; 1517-1522.
I-6).55 The resolution of the monoaza derivatives was successful using chiral HPLC and their absolute configuration determined by comparing the CD spectra with the one known of hexahelicene.55 These compounds were shown to be useful for metal complexation.55
Scheme I-6: [2+2+2] cycloisomerisation to form 1- and 2-aza[6]helicene B29
Takenaka reported very recently the use of a Stille-Kelly reaction of dihalogenated cis-stilbene-type precursors to form azahelicene derivatives that were active as hydrogen bond donor catalysts (Scheme I-7).56 Another method was also recently published using a mixed catalyst of PtCl4 and InCl3 and a double C-H activation process which gave the desired molecule in 80 % yield (Equation I-1).57
55 Mísek, J.; Teplý, F.; Stará, I. G.; Tichý, M.; Saman, D.; Císarová, I.; Vojtísek, P.; Starý, I. Angew. Chem. Inter.
Ed. 2008, 47, 3188-3191.
56 Takenaka, N.; Chen, J.; Captain, B.; Sarangthem, R. S.; Chandrakumar, J. Amer. Chem. Soc. 2010, 132, 4536-4537.
57 Storch, J.; Cermák, J.; Karban, J.; Císarová, I.; Sýkora, J. J. Org. Chem. 2010, 75, 3137-3140.
14 | P a g e Scheme I-7: Radical-mediated cyclisation to afford azahelicene B31.
Equation I-1: Metal-catalyzed process for the synthesis of 2-aza[6]helicene B33.
A completely different type of azahelicene was recently reported by the group of Venkatamaran.
These derivatives of triphenylamine were constructed in the aim of developing well-ordered compounds for further use in material sciences,58 using a strategy initially demonstrated by Hellwinkel.59 The synthesis was modified and better yields were obtained.73
58 Field, J.E., T.J. Hill, and D. Venkataraman, Bridged triarylamines: A new class of heterohelicene. Abstracts of Papers, 224th ACS National Meeting, Boston, MA, United States, August 18-22, 2002, 2002: p. ORGN-483; Field, J.E. and D. Venkataraman, HeterotriangulenesStructure and Properties. Chemistry of Materials, 2002. 14(3): p.
962-964.
59 Hellwinkel, D. and G. Aulmich, Modified tetrahelicene systems. II. 9,13b-Dihydro-5,5,9,9-tetramethyl-5H-naphth[3,2,1-de]anthracen-13b-ylium and -13b-ide salts. Chem. Ber., 1979. 112(7): p. 2602-8; Hellwinkel, D., G.
Aulmich, and W. Warth, Rearrangement reactions in intramolecular electrophilic cyclizations in the triphenylmethane series. Chem. Ber., 1980. 113(10): p. 3275-93; Hellwinkel, D., G. Aulmich, and M. Melan,
Ullmann coupling, followed by transformation of the ester functions into the acid chlorides which can undergo an in situ cyclization with SnCl4 afforded the azahelicenes B37. The conditions were carefully chosen to avoid chlorination of the helicene core. Interestingly, the nitrogen atom can be oxidized to a radical cation, a property that can be used for the study of charge transport and conductance in helicenes. The substituent at the top of the helicene is there to stabilize the radical cation formed. Such a theory was confirmed by cyclic voltammetry studies which showed a quasi reversible one-electron oxidation at the oxidation potentials of the heterohelicenes and no evidence of dimerisation which happens when the radical form is not stable enough in solution to exist as such.
The solid-state study showed the helical twist of these derivatives as well as the increasing overlap of the terminal rings when going from one compound to the higher analogue. Also, a zig-zag π-stacking is depicted, when they are in a racemic mixture. The interplanar angles between the terminal rings increase from 43.4 to 58.860 to 60.1 for the dinaphthyl one. One phenol derivative was resolved using the (1S)-camphanates derivatization methodology of Katz et al, as mentioned before.61
Scheme I-8: Synthesis of helicene-like molecules B37 by the method of Venkatamaran
Polycyclic compounds of the triangulene type. II. Threefold ortho-bridged triphenylmethane derivatives. Chem.
Ber., 1981. 114(1): p. 86-108.
60 A value very close to the one of hexahelicene, 58.5°.
61 Field, J.E., et al., Circularly Polarized Luminescence from Bridged Triarylamine Helicenes. J. Am. Chem. Soc., 2003. 125(39): p. 11808-11809.
16 | P a g e Cationic helicene-like molecules can form supramolecular interactions between each other and even with their corresponding counterion.62 Apart from these classes of derivatives where the nitrogen is in the center or inside the helicity, there are other compounds where the nitrogen atom is at the periphery of the twisted scaffold.
I-9. Highly Stable Azahelicenes: DMQA
Recently, thanks to the leading work of Laursen and Krebs, a variety of highly stable aza-bridged heterocyclic carbenium ions (B38 to B41) have been reported.63,64 These polycyclic moieties, shown in Figure I-7, display many interesting chemical and physical properties.63 These compounds have been considered as attractive synthetic targets for the development of novel and original synthetic,65 asymmetric,66 photochemical and topological applications.67
Conveniently, all these derivatives (B38 to B41) are easily prepared from a single chemical precursor that is the tris(2,6-dimethoxybenzene) methylium ion B42 (vide infra, Scheme I-9).
Consecutive nucleophilic aromatic substitution (SNAr) of the methoxy groups of B42 by primary amines affords efficiently and successively B39, B40 and B41. In fact, each introduction of a nitrogen bridge is more difficult than the previous one. It is thus possible to obtain separately the different products in which two, four, or six of the ortho-methoxy groups of 11 are substituted by a nitrogen atom and this can be controlled by the experimental conditions.63
62 Senechal-David, K.; Toupet, L.; Maury, O.; Le Bozec, H. Crystal Growth & Design 2006, 6, 1493-1496.
63 Laleu, B.; Mobian, P.; Herse, C.; Laursen, B. W.; Hopfgartner, G.; Bernardinelli, G.; Lacour, J. Angew. Chem., Int. Ed. Engl. 2005, 44, 1879-1883. Herse, C.; Bas, D.; Krebs, F. C.; Buergi, T.; Weber, J.; Wesolowski, T.;
Laursen, B. W.; Lacour, J. Angew. Chem., Int. Ed. Engl. 2003, 42, 3162-3166. Laursen, B. W. Ph. D. Thesis, Univ.
Copenhagen 2001, RisØ-R-1275 (EN). Laursen, B. W. Triangulenium salts. Risoe Natl. Lab., Roskilde, Den., 2001.
Laursen, B. W.; Krebs, F. C. Angew. Chem., Int. Ed. Engl. 2000, 39, 3432-3434. Laursen, B. W.; Krebs, F. C.;
Nielsen, M. F.; Bechgaard, K.; Christensen, J. B.; Harrit, N. J. Am. Chem. Soc. 1999, 121, 4728. Laursen, B. W.;
Krebs, F. C.; Nielsen, M. F.; Bechgaard, K.; Christensen, J. B.; Harrit, N. J. Am. Chem. Soc. 1998, 120, 12255-12263.
64 Interestingly B39, B40 and B41 are among the most stable carbocations of the literature (pKR+ of 19.4 for B39 and 24.3 for B40).
65 Nicolas, C.; Lacour, J. Org. Lett. 2006, 8, 4343-4346.
66 Villani, C.; Laleu, B.; Mobian, P.; Lacour, J. Chirality 2007, 19, 601-606.
67 Herse, C.; Bas, D.; Krebs, F. C.; Bürgi, T.; Weber, J.; Wesolowski, T.; Laursen, B. W.; Lacour, J. Angew. Chem.
Int. Ed. 2003, 42, 3162-3166. Laleu, B.; Herse, C.; Laursen, B. W.; Bernardinelli, G.; Lacour, J. J. Org. Chem. 2003, 68, 6304-6308. Laleu, B.; Mobian, P.; Herse, C.; Laursen, B. W.; Hopfgartner, G.; Bernardinelli, G.; Lacour, J.
Angew. Chem. Int. Ed. 2005, 44, 1879-1883. Nicolas, C.; Herse, C.; Lacour, J. Tetrahedron Lett. 2005, 46, 4605-4608. Laleu, B.; Machado, M. S.; Lacour, J. Chem. Commun. 2006, 2786-2788. Mobian, P.; Banerji, N.;
Bernardinelli, G.; Lacour, J. Org. Biomol. Chem. 2006, 4, 224-231. Baisch, B.; Raffa, D.; Jung, U.; Magnussen, O.
M.; Nicolas, C.; Lacour, J.; Kubitschke, J.; Herges, R. J. Am. Chem. Soc. 2009, 131, 442-443. Mobian, P.; Nicolas, C.; Francotte, E.; Bürgi, T.; Lacour, J. J. Am. Chem. Soc. 2008, 130, 6507-6514.
Figure I-7. Highly stable heterocyclic carbenium ions B38 to B41 (R = n-alkyl).
More specifically, in term of synthesis, the reaction at room temperature (20 °C) of the readily available B42 with alkylamines in slight excess (2.5 equiv.) and NMP as polar solvent gives tetramethoxyphenylacridinium salts B38 (TMPA+) in excellent yields after 20 hours (70-90%). For the formation of the double nitrogen bridged dimethoxyquinacridinium (DMQA+) salts B39 the reactions proceeds also in NMP, but much faster (~ 1 hour) with more elevated temperatures (80 - 110 °C) and a large excess of amines (25 equiv.). The DMQA+ cations B39 are usually obtained in moderate to good yields (50 to 80%). The triply nitrogen-bridged triazatriangulenium (TATA+) salts B40 require even higher temperatures and longer reaction times and are formed after heating to 130-190 °C. In this case, reactions cannot be achieved with low boiling point amines except with the addition of benzoic acid to the reaction mixture allowing the reflux temperature to be raised. Finally, partially bridged B39 can be converted into another fully ring-closed derivative, this time with an oxygen bridge instead of a nitrogen. The diazaoxa-triangulenium salts (DAOTA+, B41) are obtained by intramolecular ring closure upon heating with molten PyrH+Cl- (~ 200 °C) as solvent or LiI as reagent.
Each step introducing a new nitrogen atom continually decreases the reactivity of the resulting products; this is mainly due on one hand, to the increased planarity of these structures that facilitates electron resonance delocalization of the central charge and also because nitrogen atoms are much better electron-donating groups than oxygen atoms thus stabilizing more and more the central electron poor carbon. The structural modifications due to the introduction of the aza-bridges induce a lowering of the gap between filled and empty molecular orbitals of the molecules (in other words between the HOMO and LUMO) which is also the reason behind their bright and beautiful colors. Indeed, these molecules (B38 to B41) are dyes, ranging from red orange (B38), green (B39) to pink (B40-41) and B39-41 are highly fluorescent when submitted
18 | P a g e to UV / Vis light. This latter property will be extensively used in the course of this Ph.D (Chapters II-IV).
Thus, by virtue of its stepwise and irreversible nature, this process provides a powerful tool for the synthesis of a large variety of derivatives which can be accessible by simple structural variations of the nitrogen residues. It is worth mentioning that the nature of the substituent introduced first, is more amenable to structural changes than the others as the stronger electrophilicity of the methoxy-substituted ortho positions of cation B42 allows the nucleophilic additions of a variety of less nucleophilic amines and aromatic anilines in particular as shown by Krebs63,68 and in the Ph.D. of Cyril Nicolas of the group.63,69
Scheme I-9: Stepwise synthesis of highly stable aza- and oxa-bridged heterocyclic carbenium ions: (a) R1NH2, NMP, 25°C, 20 h; (b) R2NH2, NMP, 110°C, 1h; (c) R3NH2, NMP, 190°C, 10-24 h; (d) LiI, NMP,
190 °C or PyrH+Cl-, 190 °C, 1h.
In the recent years, our group became highly interested in the particular family of quinacridinium ions or DMQA B39 – for their explicit and interestingly helical chirality in particular. In fact, due to a strong steric repulsion between the MeO substituents (at positions 1
68 Krebs, F. C. Tetrahedron Lett. 2003, 44, 17-21.
69 Nicolas, C. Ph.D. Thesis, Univ. Geneva 2008, 3974 (EN).
and 13), these compounds display a helical conformation which was confirmed by the X-ray diffraction analysis of the tetraphenyl borate salt of 5,9-di-n-propyl-1,13-dimethoxyquinacridinium cation 1a (see chapter II). A very slow interconversion between the two helical forms was noticed. A racemization barrier of ca. 40 kcal.mol-1 was determined for B39 at 200 °C – one amongst the highest for helicenes (vide supra, § I-5). This molecule is therefore part of the few [4]helicene-like molecules that were proven to be configurationally stable. Some of them are shown in Figure I-8.70,71,72,73 Very recently, our group has been able to synthesize the dioxa- B49 and the thioaza- B50 analogues of cation B39.74
Figure I-8: Configurationally stable [4]helicenes (B39, B45 to B48) and R-DMQA+ B49-50 thia and oxo-derivatives (P enantiomers arbitrarily depicted).
This survey has for now mostly detailed the knowledge in the group and the synthetic state-of-the-art in the literature prior to this Ph.D. To further extend the scope of the applications of the DMQA+ family of cations, it was thus decided to try to introduce different side-chains on the nitrogen-atoms – ones carrying polar functional groups in particular. This chemistry led to interesting observations while trying to resolve the corresponding [4]helicenes which are reported in Chapter II. We decided to look for biological applications of these derivatives – something that the group had never done so far to any large extent. Together with the group of
70 Newman, M. S.; Wise, R. M. J. Am. Chem. Soc. 1956, 78, 450-454.
71 Saiki, Y.; Sugiura, H.; Nakamura, K.; Yamaguchi, M.; Hoshi, T.; Anzai, J. J. Am. Chem. Soc. 2003, 125, 9268-9269. Saiki, Y.; Nakamura, K.; Nigorikawa, Y.; Yamaguchi, M. Angew. Chem., Int. Ed. Engl. 2003, 42, 5190-5192.
72 Carreno, M. C.; Garcia-Cerrada, S.; Sanz-Cuesta, M. J.; Urbano, A. J. Org. Chem. 2003, 68, 4315-4321.
73 Field, J. E.; Hill, T. J.; Venkataraman, D. J. Org. Chem. 2003, 68, 6071-6078.
74 Guin, J.; Besnard, C.; Lacour, J. Org. Lett. 2010, 12, 1748-1751. Nicolas, C.; Bernardinelli, G.; Lacour, J. J. Phys.
Org. Chem. 2010, in press.
20 | P a g e Prof. Eric Vauthey (Department of Physical Chemistry, University of Geneva), studies on the interactions of these fluorescent derivatives with nucleic acids and within protein environments were started. Results are reported in Chapters III and IV. Finally, several other aspects of the chemistry of derivatives of type B39 and B40 were tackled which are briefly mentioned in Chapter V.
Chapter II: Resolution of cationic [4]helicenes through enantiopure sulfoxide addition
II-1 Preamble
Whenever a chiral molecule demonstrates its utility in a certain field, its accessibility in enantiomerically pure form by a simple procedure, is often essential.
In this chapter, we will deal with several conjugated derivatives of triaryl methanes as seen in Figure II-1, in particular, the chiral dimethoxyquinacridinium (DMQA) salts 1.1 Studies on the biological properties of DMQA structures will also be the focus of chapters III and IV.
Figure II-1: Chemical structure of the chiral DMQA salts 1 and other related derivatives 2-5
1 In chapter I, compounds 1, 2, 3, 4 and 5 were referred to as B39, B40, B38, B41 and B43 respectively.
22 | P a g e II-2 Historical Background
Following the work of Laursen and Krebs,2 on triazatriangulenium (TATA) salts 2 and their C2 -symmetric precursors DMQA salts 1, the Lacour’s group became interested in 2000, in the latter type of scaffolds, supposing that the repulsion of the terminal methoxy groups would force the molecule to adopt a helical conformation (Scheme II-1).
a: 2.5 eq. of amine R’NH2, NMP, RT, t = 20 h; b: 25 eq. of amine R’NH2, NMP, T = 110 °C, t = 1.5 h; c: ~50 eq. of amine R’NH2, NMP, T = 180 °C, t = 24 h.
Scheme II-1: Stepwise Nucleophilic Aromatic Substitution (SNAr) of methoxy groups of 6 by a primary amine leading to DMQA-1 and TATA-2 formation
In collaboration with Drs Laursen and Krebs from The Danish Polymer Centre, RISØ National Laboratory, Roskilde (Denmark), this was later confirmed by the X-ray structural analysis of samples of the tetrafluoroborate salt of the racemic dipropyl derivative rac-[(nPr)2 -DMQA-1a][BPh4] as depicted in figure II-2.
Figure II-2: General representation of the M and P enantiomers of helical DMQA with the X-ray crystal
structure for R = nPr
2 Laursen, B. W.; Krebs, F. C.; Nielsen, M. F.; Bechgaard, K.; Christensen, J. B.; Harrit, N. J. Am. Chem. Soc. 1998, 120, 12255-12263. Laursen, B. W.; Krebs, F. C. Angew. Chem. Int. Ed. 2000, 39, 3432-3434. Laursen, B. W. Ph.D.
Thesis, Univ. Copenhagen 2001, Ris∅-R-1275 (EN).
At that time, the majority of the [4]helicenes described in the literature, possessed essentially very low barriers of racemisation which prevented their resolution, we sought to verify if the same situation applied to this type of derivatives. To our greatest delight, these molecules presented extremely high configurational stability (ΔG≠rac = 41.3 kcal/mol or 172.8 kJ/mol; t1/2
183 h at 200 °C)3 which promised the isolation of each of the possible enantiomers at RT and their manipulation without any of the drawbacks observed with most of their previous analogs (Chapter I, § I-5).
II-2.1.Previous Studies and resolution attempts
This new family of cationic [4]helicenes can be accessed through a simple two-step process (Scheme II-1, vide supra), albeit in racemic form. Their resolution is therefore essential to isolate the corresponding enantiomers.
This was sought at first, through the association of the cation with BINPHAT (BT) anion 7, a C2 -symmetric chiral hexacoordinated phosphorus derivative well established in our group.4 Since the cationic molecule is chiral and presents both M and P-conformers, this powerful enantiopure anion, permitted the formation of diastereomeric ion pairs with a high lipophilicity (Figure II-3).
O
Figure II-3: Chemical structure of Δ-BT (7) and Δ-TT (8)
3 values notably higher than the ones observed with [6]helicene (154.3 kJ/mol; t1/2 = 13.4 min at 196 °C).
4 Lacour, J.; Ginglinger, C.; Grivet, C.; Bernardinelli, G. Angew. Chem. Int. Eng. Ed. 1997, 36, 608-610; Lacour, J.;
Londez, A.; Goujon-Ginglinger, C.; Buß, V.; Bernardinelli, G. Org. Lett. 2000, 2, 4185-4188; Lacour, J.; Vial, L.;
Herse, C. Org. Lett. 2002, 4, 1351-1354; Pasquato, L.; Herse, C.; Lacour, J. Tetrahedron Lett. 2002, 43, 5517-5520;
Hebbe, V.; Londez, A.; Goujon-Ginglinger, C.; Meyer, F.; Uziel, J.; Jugé, S.; Lacour, J. Tetrahedron Lett. 2003, 44, 2467-2471.
24 | P a g e Thus, a strong association was obtained between a solution of the cationic nPr2-DMQA in dichloromethane or acetone and the enantiopure BINPHAT salt ([Me2NH2][(Δ,S)-7] or [Me2NH2][(Λ,R)-7] in acetone. After filtration on basic alumina of the 1:1 mixture of diastereomers, the separation of one of the ion pairs was possible through a careful selective precipitation, in THF/benzene (1:3 v/v), leaving the second one in the mother liquor in an enantioenriched form. By switching to the other enantiomer of BT, the second/opposite configuration of the cation can be isolated.
Scheme II-2: Resolution example of rac-nPr2-DMQA 1a by association with (Δ, S)-7.
a) Resolution; b) ion metathesis with PF6 salts
As a general rule, association with the [Me2NH2][(Δ,S)-7] gives the [P-1][(Δ, S)-7] cation as an almost enantiopure precipitate (d.r. > 49:1). Its antipode is obtained thanks to the association with [Me2NH2][(Λ,R)-7] (Scheme II-2).5
Such a method based on solubility differences was deemed not applicable to all the derivatives and necessitated a large amount of solvents. It was therefore important to find an alternative more general and straightforward way.
5 Herse, C.; Bas, D.; Krebs, F. C.; Bürgi, T.; Weber, J.; Wesolowski, T.; Laursen, B. W.; Lacour, J. Angew. Chem.
Int. Ed. 2003, 42, 3162-3166.
II-2.2.Looking for a different approach
This was envisaged using the aptitude of these cationic derivatives to undergo a nucleophilic addition on their central carbon, affording neutral adducts that can then be separated through classical chromatography or HPLC.6
Scheme II-3: Nucleophilic addition on nPr2-DMQA+ 1a
For instance, alkyl, aromatic and propargylic lithium and magnesium reagents add to rac-nPr2
For instance, alkyl, aromatic and propargylic lithium and magnesium reagents add to rac-nPr2