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Synthesis and Applications of Highly Stable Non-Symmetrical Heterocyclic Carbenium Ions Cyril Nicolas Group of Prof. Jérôme Lacour Department of Organic.

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Presentation on theme: "Synthesis and Applications of Highly Stable Non-Symmetrical Heterocyclic Carbenium Ions Cyril Nicolas Group of Prof. Jérôme Lacour Department of Organic."— Presentation transcript:

1 Synthesis and Applications of Highly Stable Non-Symmetrical Heterocyclic Carbenium Ions Cyril Nicolas Group of Prof. Jérôme Lacour Department of Organic Chemistry April, 28 th 2008

2 Highly Stable Carbocations The higher the pK R+ value, the higher the stability of the cation Articles: J. Am. Chem. Soc. 1988, 110, 633 J. Am. Chem. Soc. 1977, 99, 4721 J. Am. Chem. Soc. 1971, 93, 4715 J. Chem. Soc. 1949, 1724 Diffenbach, R. A. Thame, N. G. J. C. Martin Komatsu, K. Phillips, J. N. Freedman, H. H Malachite GreenCrystal Violet Phillips, J. N. Fluoresceine

3 Laursen, B. W.; Krebs, F. C. Angew. Chem., Int. Ed. 2000, 39, 3432 Triazatriangulenium Cations and Derivatives - Synthesis

4 c M (CH 2 Cl 2 ) Light absorptionLight emission Triazatriangulenium Cations and Derivatives – Synthesis and Properties

5 J. Am. Chem. Soc. 1983, 105, 2889 Ito J. Org. Chem. 1999, 64, 5815 Triazatriangulenium Cations and Derivatives – Stability

6 C 2 -Symmetric [4]Helicenium - Synthesis and Configurational Stability X-ray : R = Pr From the X-ray of Laursen, B. W. and Krebs, F. C.

7 C 2 -Symmetric [4]Helicenium - Synthesis and Configurational Stability Angew. Chem. Int. Ed. 2003, 42, 3162 Resolution process: Ion pairing with enantiopure BINPHAT anion Ph.D thesis A. Londez, 2000.Ph.D thesis C. Herse, Org. Lett. 2000, 2, 4185 Configuration assignment (VCD spectroscopy)

8 Angew. Chem. Int. Ed. 2003, 42, 3162 t 1/2 = 13.4 min (196 °C) kJ.mol -1 C 2 -Symmetric [4]Helicenium - Synthesis and Configurational Stability Racemization Barrier (determined using CSP-HPLC after derivatization into neutral adducts)

9 Addition adducts

10 Addition adducts – New Resolution Method  [nm] --- (M)(M) 1 CD (CH 2 Cl 2, M) X-ray 1 racemic (SiO 2, Et 2 O) R = n Pr Angew. Chem. Int. Ed. 2005, 44, 1879 Ph.D thesis B. Laleu, 2006

11 2 (P)(P)  [nm] --- (M)(M) CD (CH 2 Cl 2, M) X-ray racemic (SiO 2, Et 2 O) 1 R = n Pr 2 Addition adducts – New Resolution Method Angew. Chem. Int. Ed. 2005, 44, 1879 Ph.D thesis B. Laleu, 2006

12 1 racemic (SiO 2, Et 2 O) 1 R = n Pr 2 Addition adducts – New Resolution Method Angew. Chem. Int. Ed. 2005, 44, 1879 Ph.D thesis B. Laleu, 2006

13 1 Pummerer rearrangement racemic (SiO 2, Et 2 O) 1 R = n Pr 2 Addition adducts – New Resolution Method Angew. Chem. Int. Ed. 2005, 44, 1879 Ph.D thesis B. Laleu, 2006

14 1 Pummerer rearrangement racemic (SiO 2, Et 2 O) 1 R = n Pr 2 Addition adducts – New Resolution Method Angew. Chem. Int. Ed. 2005, 44, 1879 Ph.D thesis B. Laleu, 2006

15 1 Pummerer fragmentation racemic (SiO 2, Et 2 O) 1 R = n Pr 2 Addition adducts – New Resolution Method Angew. Chem. Int. Ed. 2005, 44, 1879 Ph.D thesis B. Laleu, 2006

16 CD / UV  x 10 3 (M -1 ·cm -1 )  (M -1 ·cm -1 ) Addition adducts – New Resolution Method

17 (SiO 2, Et 2 O) Ratio: 30, 21.5, 35, 13.5% 35% 30% 21.5% 13.5% Addition adducts – New Resolution Method Ph.D thesis B. Laleu,

18 Triazatriangulenium Cations: Highly Stable Carbocations for Phase-transfer Catalysis  -Ketoester alkylation Aziridination of styrene Epoxidation of trans-chalcone Addition of Dichlorocarbene to Styrene Org. Lett. 2006, 8, 4343 Is it possible to use them as phase-transfer catalyst (PTC) ?

19 Triazatriangulenium Cations: Highly Stable Carbocations for Phase-transfer Catalysis  -Ketoester alkylation Aziridination of styrene Epoxidation of trans-chalcone Addition of Dichlorocarbene to Styrene O CO 2 Me catalyst (mol %) PhCH 2 Br O CO 2 Me Ph 50% KOH aq, 20 °C CH 2 Cl 2 entry catalyst yield (%) a mol % time (h) 55 R = n-prop 65 R = n-oct 0 TBAB b R = n-hex 50 R = (CH 2 ) 2 OH none c 3 5 R = n-oct a Yield measured by 1 H-NMR spectroscopy using mesit- -yleneasinternalreference. b TBAB= [ N + ( n Bu) 4 ] Br -. c 85% isolated yield. - Org. Lett. 2006, 8, 4343

20 Triazatriangulenium Cations: Highly Stable Carbocations for Phase-transfer Catalysis  -Ketoester alkylation Aziridination of styrene Epoxidation of trans-chalcone Addition of Dichlorocarbene to Styrene Org. Lett. 2006, 8, 4343

21 Triazatriangulenium Cations: Highly Stable Carbocations for Phase-transfer Catalysis Org. Lett. 2006, 8, 4343

22 Triazatriangulenium Cations: Highly Stable Carbocations for Phase-transfer Catalysis  -Ketoester alkylation Aziridination of styrene Epoxidation of trans-chalcone Addition of Dichlorocarbene to Styrene Org. Lett. 2006, 8, 4343

23 Phase-Transfer Catalysis with Enantiopure C 2 -Symmetric [4]Helicenium Ions

24 (M)-[3][BF 4 ](P)-[3][BF 4 ] Phase-Transfer Catalysis with Non-Symmetrical [4]Helicenium Ions

25 Geodesic Polyarenes and Carbon Nanotubes ( f,s C)-C 76 -D 2 Diederich, F. Agranat, Curl, Dresselhaus, Haddon, Hirsch, Kroto, Mehta, Paquette, Prakash, Rabideau, Scott, Siegel, Smalley C 60 Siegel, J. J. Org. Chem. 1992, 57, 61 Siegel, J. Mascal, M. Galow, T. H Rabideau, P. W J. Am. Chem. Soc. 2007, 129, J. Org. Chem. 2007, 72, 4323 J. Am. Chem. Soc. 2007, 128, 6870 J. Am. Chem. Soc. 1995, 117, 6410 Reviews: Chem. Rev. 2006, 106, 5049 Chem. Rev. 2006, 106, 4843 Chirality 2005, 17, 404 Chem. Rev. 2006, 106, 4868 Tetrahedron 1998, 54, 13325

26 Trioxatricornan – a Chiral Cup-Like Molecule

27 Synthesis and Resolution of a Chiral Cup-Like Molecule

28 Synthesis Synthesis and Resolution of a Chiral Cup-Like Molecule

29 Intensity (arb units) time (min) Chromatographic Resolution Daicel OJ-H (99.5/0.5 hex / i-PrOH), 0.5 mL/min In collaboration with E. Francotte (Novartis) 17.2 min 30.8 min [  ] 589 = ± 1.4 (c = 1 mg / 1 mL) [  ] 589 = ± 1.6 (c = 1 mg / 1 mL) (R) Enantiomer(S) Enantiomer ECD Spectra First eluted fraction (dextrogyre) Wavelength[nm] C = mol.l -1  Second eluted fraction (levogyre) Synthesis and Resolution of a Chiral Cup-Like Molecule

30 VCD spectra Wavenumber / cm  A -1.5e e e e-6 1.0e-5 1.5e-5 ECD Spectra First eluted fraction (dextrogyre) Wavelength[nm] C = mol.l -1  Second eluted fraction (levogyre) First eluted fraction (dextrogyre) Second eluted fraction (levogyre) (R) Enantiomer(S) Enantiomer Synthesis and Resolution of a Chiral Cup-Like Molecule In collaboration with T. Bürgi (Neuchâtel)

31 (S) Enantiomer In collaboration with T. Bürgi (Neuchâtel) 1, 2.91 kcal/mol2, 2.86 kcal/mol3, 0.0 kcal/mol 4, 1.70 kcal/mol 6, 2.30 kcal/mol 8, 1.66 kcal/mol9, 2.20 kcal/mol 5, not stable 7, not stable DFT (b3pw91, G(d,p)) possible conformers of enantiomer (S) Synthesis and Resolution of a Chiral Cup-Like Molecule

32 In collaboration with T. Bürgi (Neuchâtel) DFT (b3pw91, G(d,p)) IR spectrum (S) Enantiomer VCD spectrum (S)-conformer 3 Wavenumber / cm  Boltzmann average DFT (b3pw91, G(d,p)) 85% Wavenumber / cm Boltzmann average  conformer 3 Synthesis and Resolution of a Chiral Cup-Like Molecule

33 IR spectrum Calculated structure (S enantiomer) DFT (b3pw91, G(d,p)) In collaboration with T. Bürgi (Neuchatel) exp From Second eluted (levogyre) fraction Conformer 3 (R) Enantiomer(S) Enantiomer Synthesis and Resolution of a Chiral Cup-Like Molecule

34 VCD spectrum DFT (b3pw91, G(d,p)) In collaboration with T. Bürgi (Neuchâtel) Calculated structure (S enantiomer) From Second eluted (levogyre) fraction exp Conformer 3 (R) Enantiomer(S) Enantiomer Synthesis and Resolution of a Chiral Cup-Like Molecule

35 (S) Enantiomer; [  ] 365 = -300 (c = 0.06 g / 100 mL) VCD spectrum DFT (b3pw91, G(d,p)) In collaboration with T. Bürgi (Neuchâtel) Calculated structure (S enantiomer) From Second eluted (levogyre) fraction exp [  ] 589 = ± 1.6 (c = 1 mg / 1 mL) Conformer 3 Synthesis and Resolution of a Chiral Cup-Like Molecule

36 What has been achieved TRIAZATRIANGULENIUM CATIONS  Synthesis: Facile  Highly Stable Toward Reactive Bases and Nucleophiles.  Efficient Phase-Transfer Catalysts CHIRAL CUP-LIKE MOLECULES  Synthesis: Straightforward, Versatile  Easy Separation of the Enantiomers by Preparative CSP-HPLC  Determination of the Absolute configuration by VCD Measurements

37 Acknowledgments Prof. Alexandre Alexakis and Bo. W. Laursen Prof. Jérôme Lacour Dr. Gérald Bernardinelli (X-Ray Structures) Dr. Damien Jeannerat, André Pinto, Jean-Paul Saulnier, Bruno Vitorge (NMR) Prof. Thomas Bürgi (DFT calculations) Dr Eric Francotte (HPLC analyses) Prof. Rainer Herges, Olaf Magnussen (Nanoparticles) Prof. Robert Deschenaux, Stéphane Frein (Liquid Crystals) Alexandre Fürstenberg, Prof. Eric Vauthey (DNA Intercalation) Sandrine Perrothon, Benjamin Elias, Thomas Frossard Members of the Lacour’s group (past and present) Christelle Herse Benoît Laleu Dr. Pierre Mobian Members of the Department of Organic Chemistry

38 Acknowledgments Nathalie Mehanna (Lacour group) Mylene Cargouet Swiss National Science Foundation (SNSF) Département de l’Instruction Publique (DIP) Société Académique de Genève My family, my wife, my two children

39 Schlegel diagrams vertice edges Euler's formula: f+v = e+2

40 Thilgen, C.; Diederich, F. Chem. Rev. 2006, 106, 5049

41 (SiO 2, Et 2 O) Ratio: 30, 21.5, 35, 13.5% 35% 30% 21.5% 13.5% Addition adducts – New Resolution Method Ph.D thesis B. Laleu, 2006

42  (M -1 ·cm -1 ) [  ] D = (c = 0.06, CH 2 Cl 2 ) [  ] D = (c = 0.06, CH 2 Cl 2 ) [  ] D = (c = 0.06, CH 2 Cl 2 ) [  ] D = (c = 0.06, CH 2 Cl 2 ) (M)(M) (P)(P) Ratio: 30, 21.5, 35, 13.5% (SiO 2, Et 2 O) 35% 30% 21.5% 13.5% CD (CH 2 Cl 2,10 -5 M) Wavelenght (nm) Addition adducts – New Resolution Method

43 Ratio: 30, 21.5, 35, 13.5% (SiO 2, Et 2 O) 35% 30% 21.5% 13.5% M, CH 2 Cl 2  (M -1 ·cm -1 ) Wavelenght (nm)  x 10 3 (M -1 ·cm -1 ) 0 CD / UV [  ] 435 = (c = 0. 6; CH 2 Cl 2 ) Addition adducts – New Resolution Method

44 Ratio: 30, 21.5, 35, 13.5% (SiO 2, Et 2 O) 35% 30% 21.5% 13.5% M, CH 2 Cl 2  (M -1 ·cm -1 ) Wavelenght (nm)  x 10 3 (M -1 ·cm -1 ) 0 CD / UV 43 [  ] 435 = (c = 0. 6; CH 2 Cl 2 ) Addition adducts – New Resolution Method


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