Chiral Photochemistry • Crystals • Zeolites • Solution 1 Why Chiral Chemistry 2 3 Photochemistry in Water The beginnings of chiral organic photochemistry hν + Ph Ph Ph Ph Ph Ph Hammond, G. S. and Cole, R. S. Horner, L. and Klaus, J. J. Am. Chem. Soc. 1965, p-3256 Liebigs Ann. Chem., 1979, p-1232 H O R N* Ac ee = 6.7% COOR* ee = 4.0 % R* - Menthyl Ouannes, C. Beugelmans, R. and Roussi, G. Vondenhof, M. and Mattay, J. J. Am. Chem. Soc., 1973, p-8472 Chem. Ber., 1990, p-2457 O CN * ee = 3.0% CN ee = 3.5% Me H Faljoni, A. Zinner, K. and Weiss, R. G. Inoue, Y. Shimoyama, H. Yamasaki, N. and Tai, A. Tetrahedron lett., 1974, p-1127 Chem, lett., 1991, p-593 MeO * R*OOC COOR* OMe * * * MeO * R OOC COOR * ee = 2.3% R - Menthyl, Bornyl ee = 10.4 % As chiral solvents 5 h /Sens* ν + Z (R)-(–)-E (S)-(+)-E CO R* CO2R* 2 CO2R* R*O2C CO2R* CO2R* CO2R* R*O2C CO2R* R*O2C CO2R* Sens*: CO2R* CO2R* CO2R* R*O2C CO2R* CO2R* R*: O O O n O O Temperature Pressure 73% ee at -110°C in pentane Solvent 6 Chiral photochemistry in solution through covalent chiral auxiliary Chiral photochemistry in solution through templation H H CO H N HO2C 2 O COOH N COOH CO2H O H N O COOH H O N O N O O N O 8 Chiral photochemistry in solution through templation MeOOC MeOOC OMe MeO MeO COOMe hν H H + + N O toluene N O N O H H H In the absence of template; e.e.: 0 In the presenceof template; e.e.: 82% OMe Blocked H N O N O N O Free H H O N O N Template One mode of approach blocked 9 Chiral photochemistry in solution through templation N H O N O O N H H O N O O O N O O N O H N O H O N H hν O N O O NH + NH toluene, -50°C O O 30% 45% (87% ee) (84% ee) 10 O O O O R O R O R hv + 46% ee 11 hν (254 nm) + Sens.: (R)-(-) (S)-(+) O O NH O NH2 Sens.: 2 H H H3C H N N N N N N N N N N N N N NH2 N HO O O HO O O HO O O HO O HO O HO OH HO HO OH HO OH HO OH Calf Thymus DNA 18.8% ee 12 CO2H CO2H 25-100 mol% HO2C γ-CDs hν (λ>320 nm) CO2H CO2H CO2H CO2H HO2C CO2H HO2C CO2H anti-HT, 149 syn-HT, 150 anti-HH, 151 syn-HH, 152 41% ee 13 CO2H OH NH(CH2)2N O O O O Cu2+ 7 HO OH HO OH DA-γ-CD -OOC Cu2+ -OOC hν (λ>320 nm) CO H CO2H HO2C CO2H 2 CO2H CO H HO2C 2 CO2H syn-HT, 150 syn-HH, 152 anti-HT, 149 anti-HH, 151 70% ee 14 15% ee for syn HT amylose 38% ee for syn HT 15 37% ee for syn HT amylose + γ-cyclodextrin 58% ee for anti HH Photochemistry in Solid State Chiral crystallization Achiral molecule may crystallize in achiral space group. e.g., quartz, urea, maleic anhydride, fast enantiomerization R ambient temp S spontaneous chiral S R crystallization 100% 100% Chiral crystallization of achiral materials 17 The most common space groups of organic crystalline compounds based upon a survey of 29059 crystal structure determinations space group number percentage P21/c 10450 36.0 P-1 3986 13.7 P212121* 3359 11.6 P21* 1957 6.7 C2/c 1930 6.6 Pbca 1261 4.3 Pnma 548 1.9 Pna21 513 1.8 Pbcn 341 1.2 P1* 305 1.1 *Chiral space group. 18 Ph Ph HO OH hν Ph H O H Ph Ph HO OH Ph H O O O H C H C N H H O H 19 Chiral crystallization Achiral Chiral R R R R spontaneous hv chiral h hv ν crystallization R = COOi-Pr Solution e.e : 0% achiral chiral crystal Crystals e.e : 100% H O Me hν Ar * * Me Ar * * H HO optically active Ar = Cl Solution e.e : 0% materials with Crystals e.e : 82% permanent chirality Absolute asymmetric synthesis in i-Pr the chiral crystalline environment O Cl N hν I-Pr HO N O O i-Pr Solution e.e : 0% 20 Crystals e.e : 100% H O h Ar HO Me ν Me + Me Ar Ar H OH Solution e.e : 0% Ar = Cl Crystals e.e : 82% Note that the two prochiral hydrogens are not equidistant from the carbonyl chromophore. The molecule being present in a chiral 3.74 A° space group does not have another molecule that is mirror symmetric. 2.71 A° Since only one prochiral hydrogen would be abstracted only one cyclobutanol enantiomer would be formed. 21 Essential Criteria for Asymmetric Photochemistry in the Crystalline State Molecules must crystallize in a chiral space group (non-centro symmetric form) Majority of achiral molecules crystallize in a non chiral space group (symmetric packing) O O % ee: 0 N % ee: 100 O OCH3 P21/n P212121 centrosymmetric non-centrosymmetric 22 Use of chiral hosts: Solid state photochemistry OMe Chiral hosts upon hν H3CO O Cl Cl N inclusion of an achiral (S,S)-(-)- Ph Ph N O Me molecule may induce OH OH Me e.e.: 100% chirality on the achiral molecule. O O OCH3 Cl Cl hν OMe (S,S)-(-) Ph Ph The above host-guest OH OH complexation would lead e.e.: 100% to diastereomeric (instead of OH CH3 CH3 enantiomeric) transition Cl Cl O N hν Ph (S,S)-(-) Ph Ph N states . O O Me OH OH Ph e.e.: 100% In solution no chiral induction is obtained. 23 Use of chiral hosts: Unimolecular reactions OH CH3 CH3 O O Ph OCH2CH3 O N hν OCH CH N hν 2 3 Ph O O Me e.e.: 100% e.e.: 100% 4.6 A° 2.8 A° 24 Use of chiral hosts: Bimolecular reactions hν No dimer O O Crystal Ph Ph OH hν O O O + + O O O O Crystal O OH O O O O Ph Ph 96% ee 1:1 complex hυ 3.6 A° 25 Most commonly occurring space groups 230 unique space groups of which only 65 are chiral space groups Chiral space groups (symmetry elements are rotational, translational and combinations of these) achiral space groups (symmetry elements are mirror, glide plane or center of inversion) Space Total no. % group of crystals Ionic Chiral Auxillary Approach P21/ c 10450 36.0 P!1 3986 13.7 P212121 3359 11.6 P21 1957 6.7 Reactive part Chiral auxliary C2/ c 1930 6.6 Pbca 1261 4.3 Pnma 548 1.9 Covalent Chiral Auxillary Approach Pna21 513 1.8 Pbcn 341 1.2 P1 305 1.1 Reactive part Chiral auxliary Chiral space group 26 Ionic chiral auxiliary approach: Solid state photochemistry The chiral auxiliary ensures that the reactant molecule crystallizes in a chiral space group. This would make the two diastereomeric reaction pathways to have different activation energies. 27 Ionic chiral auxiliary approach Ph COOCH COO H3N CH3 3 O HO hν Me Me CH N workup 2 2 ee 97% crystals Ph COOCH COO 3 O HO H3N CH 3 hν CH CH 3 3 CH2N2 workup crystals ee 80% COOCH3 O hν H CH N workup OH COO H2N 2 2 HOH C 2 (+)- ee 97% crystals The two prochiral hydrogens are distinguishable in the crystalline state. In solution no chiral induction is obtained. 28 Ph Ph COO COO H3N CH3 O H3N CH3 HO hν CH3 CH3 ee 80% 2.6 A° 3.6 A° 29 Covalent chiral auxiliary approach H O OH O hν O R* R* H N H H O H N N N Me R* O Br OMe % de 97 90 92 80 22 5 30 O O O NH NH O R S R O O R S O R P21 P21 C2 R S 3.2 A° 2.6 A° 3.7 A° 2.76 A° 2.86 A° 4.1 A° Trans CB Trans CB Trans CB % de 97 90 92 31 Asymmetric photoreactions within zeolites • Key is the cation binding to the included organic molecule. Confined space also imposes restrictions. • Details yet to be understood. 32 Asymmetric Photoreactions Within Zeolites 33 C hi r a l i n du ct o r a p p ro a c h A B C Chiral Inductor D E F A B C Achiral Reactant Chiral Inductor D E F 34 Enantioselective Electrocylization of Achiral Tropolones O O CH3 hυ hυ H H O O O O H3C H3C H H3CO H O O H3CO 35 Chiral Induction: Solution vs. Zeolite O O O hυ Ph O O O Ph + Ph ee = 0 % ee = 0 % e.e. 0% e.e. 68% e.e. 69% Hexane-methylene NaY NaY / (-)-Ephedrine NaY / (+)-Ephedrine chloride/(-)-Ephedrine Silica gel/(-)-Ephedrine 36 Chiral inductor approach A B C Achiral Reactant Chiral Inductor D E F A B Chiral auxiliary approach Achiral Reactant Covalent bond Chiral Auxiliary 37 Chiral Induction (Diastereoselectivity) Solution vs.Zeolite CH3 O CH3 O O O CH CH O CH3 h * 3 O 3 * υ CH3 + * d.e. = 0 % 53 % A Hexane NaY 38 Chiral inductor approach A B C Achiral Reactant Chiral Inductor D E F A B Chiral auxiliary approach Achiral Reactant Covalent bond Chiral Auxiliary Gumbo approach A B Reactant Chiral Auxiliary Chiral Inductor 39 Chiral induction within a chirally modified zeolite CH3 O CH3 O O O CH CH O CH3 h * 3 O 3 * υ CH3 + * d e 0 % d e 0 % 53 % A 90 % (A) Silica gel / (CH2Cl2 / hexane) NaY (-)-ephedrine / NaY (-)-ephedrine (-)-ephedrine 40 Asymmetric Photoreactions Within Zeolites • Chiral Induction Depends on • Nature of the Cation • Number of Cations (Si/Al ratio) • Water Content Cation is the Key 41 Chiral Induction Depends on the Nature Alkali Metal Ion CH3 CH H H 3 CH3 O N O N H H H O N H hν + Ph Ph Ph Ph Ph Ph (RR-isomer) (SS-isomer) Solution LiY NaY KY RbY CsY 2 (SS) 80 (SS) 28 (RR) 14 (RR) 5 (RR) 5 (RR) 42 Role of Cation-Carbonyl Dipolar Interaction Carboalkoxy vs Alkyl X X X hν + Ph Ph Ph Ph Ph Ph H H O N N H O COOMe H CH3 Zeolite % d.e.