Metal-free Synthesis of 3-Arylquinolin-2-ones from Acrylic. Experimental and Computational Study

Transcription

1 Metal-free Synthesis of 3-Arylquinolin-2-ones from Acrylic Amides via a Highly Regio-selective 1,2-Aryl Migration: An Experimental and Computational Study Le Liu,,ǁ Tonghuan Zhang,,ǁ Yun-Fang Yang, Daisy Zhang-Negrerie, Xinhao Zhang, Yunfei Du,*, Yun-Dong Wu,*, and Kang Zhao*, Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin , China Lab of Computational Chemistry and Drug Design, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen , China duyunfeier@tju.edu.cn; wuyd@pkusz.edu.cn; zhaokang@tju.edu.cn Supporting Information Page 1. Computational Data S2- S16 2. References S H-NMR and 13 C-NMR Spectra S18-S57 4. X-ray Structures and Data of 3g and 4g S58-S73

2 1. Computational Data 1.1 Computational details DFT calculations were performed with the Gaussian09 suite of programs. S1 Reactants, transition states (TSs), intermediates, and products were optimized at the hybrid density functional B3LYP S2 level of theory with basis set I (BSI): LANL2DZ S3 incorporating a relativistic pseudopotential (effective core potential, ECP) S4 for I and 6-31G(d) S5 basis set for the rest of the elements. Single point energy calculations were then conducted at the M06 S6 level of theory with basis set II (BSII): Stuttgart-Dresden basis set (SDD) S7 incorporating ECP for I and G(d,p) for other elements. The SMD solvent model with the parameters for dichloroethane (DCE) were employed to account for solvent effects. S8 All vibrational frequencies were computed at the B3LYP/BSI to verify the stationary points and provide the thermal corrections. Intrinsic reaction coordinate (IRC) S9 analyses were performed to confirm that a specific TS connects the two relevant minima. All energies presented are Gibbs free energies at 298K in DCE in kcal/mol unless otherwise stated. Geometries were illustrated using CYLVIEW drawings. S Computational study of other mechanisms 1) Pathway S1 S2

3 Figure S1. Free-energy profile (kcal/mol) of pathway S1 in DCE as solvent calculated at M06/ G(d,p).. In this pathway, the nucleophilic attack on the iodine center by the carbonyl oxygen of the amide moiety in S1-A affords 3-azatriene S1-B, which is tautomerized into oxonium intermediate S1-B'. Then a 4-endo-trig ring closure occurred in S1-B' to give a four-membered intermediate S1-C, which could be stabilized by the stacking interaction between the phenyl ring of the aniline and the cis phenyl ring of the acrylic acid moiety. Next, a concerted process including the 1,2-aryl shift, the electrophilic attack of the generated electron-deficient carbon center to the N-phenyl ring, and the breakage of the I-O bond occurs to convert S1-C to a bridged intermediate S1-D. Finally, two protons were removed from intermediate S1-D to give 3-arylquinolin-2-one S1-E. As we can S3

4 see from the computational results, this mechanism is not acceptable due to the extremely unstable intermediates. 2) Pathway S2 (6π-disrotatory mechanism) Figure S2. Free-energy profile (kcal/mol) of pathway S2 in DCE as solvent calculated at M06/ G(d,p).. In this mechanism, the carbonyl oxygen of the amide attacks the iodine center leads to intermediate S2-B followed by an intramolecular 1,5-iodonum migration giving intermediate S2-C. BF 3 induces an aza-triene which subcequently undergoes a 6π disrotatory annulation and S4

5 iodonum miration generating S2-E. Then, only the phenyl ring above the ring surface migrates to the neighboring position with the release of PhI to afford S2-F, thus resulting in the regioselectivity nature. Finally, deprotonation lead to the ultimate formation of the title compound. The big energy barrier for the 6π-disrotatory transition state S2-TS-DE shows that pathway S2 is a not preferred either. 6.3 Energies and coordinates Figure S3. Optimized transition state structures for the ring closure step and the 1,2-migration step with key parameters (bond length in angstroms). The aryl migration is facilitated by the resonance effect in the migrating phenyl group. 1,2-alkyl-migration is not feasible. The calculated free energy barrier for the methyl migration, via S5

6 TS-DE-methyl, was 42.5 kcal/mol, which is prohibitively high. The result is consistent with the experimental observation with entry 18 in table 2. In addition, for the cinnamamide that bears no substitution on the nitrogen atom, the reaction resulted in a complex mixture, without desired product being isolated (Table 2, entry 5). This is also verified by computational analyses showing that the overall Gibbs free energy barrier for the 1,2-phenyl migration step, via TS-DE-NH, is about 76.9 kcal/mol, which is also extremely high. Table S2. Energies of all the intermediates and transition states in Figure 2. Number E+ZPE G (E+ZPE) G 3g A B Bʹ TS-BC TS-BCʹ C D TS-DE TS-DEʹ TS-DE-1ʹ E 4g Sub-methyl TS-DE-methyl Sub-NH TS-DE-NH S6

7 3g Cartesian coordinates (in Å) of related structures in Figure 2. C C C C C C C H C C H H H C H H H H N H C C H C H C H C C H O C C H H C C H H H C Cl C A C C C C C C C H C C H H H C H H H H N Cl C C H O H I H C C C H C S7

8 C C H H C C C H C C C H C H H H C O H C C C H F H F H F C O B C C C C C H C C C H H C H H H H H H N Cl C C H H H I H C C O C C C C C C C C C H H C C H H O C C H C H H S8

9 O H C F H F C F C H B C C C C C H C C C H H C H H H H H H N Cl C I H O H C H O C C C F C F C F C C C C H C C C H C C C H H H H O H C H H H C C C H TS-BC C C C C S9

10 C H C C C H H C H H H H H C N H C I H C H O H C C C C C C C C H C C C H H O C C H C C H H H H F O F C F H H C H C Cl TS-BC C C C C C H C C C H H C H H H H H C N H C I H C S10

11 H O H C C C C C C C C H C C C H H O C C H C C H H H H F O F C F H H C Cl C H C C C C H C C C H C C H H H H H C N H C I H C H O H C C C C C C C C H C C C H H O C C H C S11

12 C H H H H F O F C F H H C H C Cl C D C O C C C H C C C C H C H C H H N C C H H C H H H H C H C Cl C C C H C O C C H O C C H F C F H F H TS-DE C O C C C H C C S12

13 C C H C H C H H N C C H H C H H H H C C C H C O C C C O C C H F C F H F C H H Cl H TS-DE C H C C C C C C C C H H H C H H N C C H H H H C H H C O C C C O C C C F C F H F S13

14 C H H Cl C B H F H F O F C TS-DE-1 C H C C C C C C C C H H H C H H N C C H H H H H H Cl C C C H C O C C C O C C H F C F H F C B H F H F O F C E C H C C S14

15 C C C C C C C H H C H H C C H H H H N C C O C C C H C C H H C H H H C H H Cl g C H C H C H C C C C C C H C H H C C H H H C C H C H C Cl C O C N C C H H C H H H C H S15

16 Sub-methyl C C C O C C C H C H H C H H H H H H N C C H C H H H TS-DE-methyl C C C H C C C H C O H C H O H C N F C F H F H C H H C H C H O H Sub-NH C C C C C C C H C C H H H C S16

17 H H H H N O C C C H H H C H C H TS-DE-NH C C C H C H C O C C H H H C H H N O C C C O C C C F C F C F H H C H H H References [S1] Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, S17

18 O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, revision A.02; Gaussian, Inc.: Wallingford, CT, [S2] Becke, A. D. Density functional thermochemistry. III. The role of exact exchange. J. Chem. Phys. 1993, 98, [S3] Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 299. [S4] (a) Andrae, D.; Häußermann, U.; Dolg, M.; Stoll, H.; Preuß, H. Theor. Chim. Acta. 1990, 77, 123. (b) Weigend, F.; Ahlrichs, R. Phys. Chem. Chem. Phys. 2005, 7, [S5] Hehre, W. J.; Radom. L.; Schleyer. P. V. R.; Pople, J. A. Ab-Initio Molecular Orbital Theory; Wiley: New York, [S6] Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215. [S7] Bergner, A.; Dolg, M.; Küchle, W.; Stoll, H.; Preuss, H. Mol. Phys. 1993, 80, [S8] Marenich A. V.; Cramer C. J.; Truhlar D. G. J. Phys. Chem. B, 2009, 113, [S9] (a) Fukui, K. Acc. Chem. Res. 1981, 14, 363; (b) Fukui, K. J. Phys. Chem. 1970, 74, [S10] Legault, C. Y. CYL View, version 1.0 b; Université de Sherbrooke, Sherbrooke, Québec, Canada, 2009; S18

19 8. 1 H-NMR and 13 C-NMR Spectra S19

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59 9. X-ray Structure and Data of 3g and 4g X-ray crystallography of 3g (Thermal ellipsoids are shown at the 30% probability level) Table S3. Crystal data and structure refinement for 3g. Identification code 3g Empirical formula C 22 H 18 Cl N O Formula weight Temperature 113(2) K Wavelength A Crystal system, space group Orthorhombic, Pbca Unit cell dimensions a = (8) A alpha = 90 deg. b = (8) A beta = 90 deg. c = (9) A gamma = 90 deg. Volume 3505(3) A^3 Z, Calculated density 8, Mg/m^3 Absorption coefficient mm^-1 F(000) 1456 Crystal size 0.20 x 0.18 x 0.12 mm Theta range for data collection 2.33 to deg. Limiting indices -19<=h<=19, -18<=k<=19, -21<=l<=21 Reflections collected / unique / 4156 [R(int) = ] Completeness to theta = % Absorption correction Semi-empirical from equivalents Max. and min. transmission and Refinement method Full-matrix least-squares on F^2 Data / restraints / parameters 4156 / 0 / 227 Goodness-of-fit on F^ Final R indices [I>2sigma(I)] R1 = , wr2 = R indices (all data) R1 = , wr2 = Largest diff. peak and hole and e.a^-3 S59

60 Table S4. Atomic coordinates ( x 10^4) and equivalent isotropic displacement parameters (A^2 x 10^3) for 3g. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. x y z U(eq) Cl(1) 10557(1) 7705(1) 1870(1) 34(1) O(1) 5595(1) 10524(1) 3790(1) 30(1) N(1) 6591(1) 11045(1) 4736(1) 22(1) C(1) 8490(1) 8006(1) 3432(1) 24(1) C(2) 9168(1) 7621(1) 2955(1) 26(1) C(3) 9673(1) 8177(1) 2442(1) 25(1) C(4) 9520(1) 9101(1) 2388(1) 25(1) C(5) 8835(1) 9471(1) 2865(1) 24(1) C(6) 8312(1) 8936(1) 3394(1) 22(1) C(7) 7599(1) 9352(1) 3923(1) 21(1) C(8) 7520(1) 9027(1) 4799(1) 22(1) C(9) 6684(1) 8872(1) 5164(1) 27(1) C(10) 6616(1) 8590(1) 5989(1) 33(1) C(11) 7388(1) 8457(1) 6456(1) 33(1) C(12) 8227(1) 8611(1) 6103(1) 31(1) C(13) 8291(1) 8887(1) 5280(1) 25(1) C(14) 7083(1) 10015(1) 3613(1) 23(1) C(15) 6374(1) 10537(1) 4057(1) 23(1) C(16) 5838(1) 11448(1) 5198(1) 28(1) C(17) 7478(1) 11117(1) 5079(1) 21(1) C(18) 7610(1) 10971(1) 5928(1) 26(1) C(19) 8467(1) 11022(1) 6258(1) 29(1) C(20) 9197(1) 11200(1) 5752(1) 28(1) C(21) 9062(1) 11361(1) 4909(1) 27(1) C(22) 8205(1) 11334(1) 4576(1) 24(1) S60

61 Table S5. Bond lengths [A] and angles [deg] for 3g. Cl(1)-C(3) (16) O(1)-C(15) (17) N(1)-C(15) (18) N(1)-C(17) (18) N(1)-C(16) (18) C(1)-C(2) 1.385(2) C(1)-C(6) 1.396(2) C(1)-H(1) C(2)-C(3) 1.382(2) C(2)-H(2) C(3)-C(4) 1.383(2) C(4)-C(5) 1.384(2) C(4)-H(4) C(5)-C(6) 1.394(2) C(5)-H(5) C(6)-C(7) 1.488(2) C(7)-C(14) 1.337(2) C(7)-C(8) 1.487(2) C(8)-C(9) 1.392(2) C(8)-C(13) 1.396(2) C(9)-C(10) 1.389(2) C(9)-H(9) C(10)-C(11) 1.383(2) C(10)-H(10) C(11)-C(12) 1.387(2) C(11)-H(11) C(12)-C(13) 1.384(2) C(12)-H(12) C(13)-H(13) C(14)-C(15) 1.485(2) C(14)-H(14) C(16)-H(16A) C(16)-H(16B) C(16)-H(16C) C(17)-C(22) 1.385(2) C(17)-C(18) 1.392(2) C(18)-C(19) 1.380(2) C(18)-H(18) C(19)-C(20) 1.379(2) C(19)-H(19) C(20)-C(21) 1.387(2) C(20)-H(20) C(21)-C(22) 1.382(2) C(21)-H(21) C(22)-H(22) C(15)-N(1)-C(17) (11) C(15)-N(1)-C(16) (12) C(17)-N(1)-C(16) (12) C(2)-C(1)-C(6) (14) C(2)-C(1)-H(1) C(6)-C(1)-H(1) C(3)-C(2)-C(1) (14) C(3)-C(2)-H(2) C(1)-C(2)-H(2) C(2)-C(3)-C(4) (13) C(2)-C(3)-Cl(1) (12) S61

62 C(4)-C(3)-Cl(1) (11) C(3)-C(4)-C(5) (13) C(3)-C(4)-H(4) C(5)-C(4)-H(4) C(4)-C(5)-C(6) (14) C(4)-C(5)-H(5) C(6)-C(5)-H(5) C(5)-C(6)-C(1) (13) C(5)-C(6)-C(7) (13) C(1)-C(6)-C(7) (13) C(14)-C(7)-C(8) (13) C(14)-C(7)-C(6) (13) C(8)-C(7)-C(6) (12) C(9)-C(8)-C(13) (14) C(9)-C(8)-C(7) (13) C(13)-C(8)-C(7) (13) C(10)-C(9)-C(8) (14) C(10)-C(9)-H(9) C(8)-C(9)-H(9) C(11)-C(10)-C(9) (14) C(11)-C(10)-H(10) C(9)-C(10)-H(10) C(10)-C(11)-C(12) (15) C(10)-C(11)-H(11) C(12)-C(11)-H(11) C(13)-C(12)-C(11) (14) C(13)-C(12)-H(12) C(11)-C(12)-H(12) C(12)-C(13)-C(8) (14) C(12)-C(13)-H(13) C(8)-C(13)-H(13) C(7)-C(14)-C(15) (14) C(7)-C(14)-H(14) C(15)-C(14)-H(14) O(1)-C(15)-N(1) (13) O(1)-C(15)-C(14) (13) N(1)-C(15)-C(14) (12) N(1)-C(16)-H(16A) N(1)-C(16)-H(16B) H(16A)-C(16)-H(16B) N(1)-C(16)-H(16C) H(16A)-C(16)-H(16C) H(16B)-C(16)-H(16C) C(22)-C(17)-C(18) (13) C(22)-C(17)-N(1) (13) C(18)-C(17)-N(1) (12) C(19)-C(18)-C(17) (13) C(19)-C(18)-H(18) C(17)-C(18)-H(18) C(20)-C(19)-C(18) (15) C(20)-C(19)-H(19) C(18)-C(19)-H(19) C(19)-C(20)-C(21) (14) C(19)-C(20)-H(20) C(21)-C(20)-H(20) C(22)-C(21)-C(20) (14) C(22)-C(21)-H(21) C(20)-C(21)-H(21) C(21)-C(22)-C(17) (14) S62

63 C(21)-C(22)-H(22) C(17)-C(22)-H(22) Symmetry transformations used to generate equivalent atoms: S63

64 Table S6. Anisotropic displacement parameters (A^2 x 10^3) for 3g. The anisotropic displacement factor exponent takes the form: -2 pi^2 [ h^2 a*^2 U h k a* b* U12 ] U11 U22 U33 U23 U13 U12 Cl(1) 32(1) 41(1) 30(1) -7(1) 5(1) 5(1) O(1) 24(1) 30(1) 37(1) -3(1) -8(1) 3(1) N(1) 20(1) 22(1) 25(1) -3(1) 0(1) 0(1) C(1) 26(1) 23(1) 23(1) -1(1) -1(1) -4(1) C(2) 31(1) 20(1) 26(1) -3(1) -3(1) -1(1) C(3) 24(1) 30(1) 21(1) -6(1) -1(1) 2(1) C(4) 26(1) 30(1) 19(1) 1(1) 0(1) -4(1) C(5) 28(1) 22(1) 22(1) 0(1) -3(1) 0(1) C(6) 22(1) 23(1) 20(1) -2(1) -2(1) -2(1) C(7) 21(1) 19(1) 23(1) -1(1) -1(1) -4(1) C(8) 25(1) 16(1) 24(1) -1(1) 1(1) 1(1) C(9) 25(1) 23(1) 33(1) 1(1) 1(1) -1(1) C(10) 34(1) 30(1) 34(1) 2(1) 10(1) -4(1) C(11) 44(1) 28(1) 26(1) 4(1) 6(1) 4(1) C(12) 36(1) 28(1) 27(1) 2(1) -3(1) 8(1) C(13) 25(1) 25(1) 26(1) 1(1) 2(1) 4(1) C(14) 25(1) 23(1) 22(1) 0(1) -2(1) -1(1) C(15) 24(1) 19(1) 26(1) 2(1) -2(1) 0(1) C(16) 24(1) 29(1) 33(1) -4(1) 3(1) 1(1) C(17) 20(1) 17(1) 26(1) -2(1) -1(1) 0(1) C(18) 27(1) 26(1) 24(1) -1(1) 3(1) -3(1) C(19) 32(1) 29(1) 25(1) -1(1) -4(1) -2(1) C(20) 25(1) 31(1) 30(1) 0(1) -5(1) -2(1) C(21) 23(1) 28(1) 29(1) 2(1) 0(1) -3(1) C(22) 25(1) 23(1) 23(1) 2(1) -1(1) -2(1) Table S7. Hydrogen coordinates ( x 10^4) and isotropic S64

65 displacement parameters (A^2 x 10^3) for 3g. x y z U(eq) H(1) H(2) H(4) H(5) H(9) H(10) H(11) H(12) H(13) H(14) H(16A) H(16B) H(16C) H(18) H(19) H(20) H(21) H(22) S65

66 Table S8. Torsion angles [deg] for 3g. C(6)-C(1)-C(2)-C(3) 0.4(2) C(1)-C(2)-C(3)-C(4) -0.3(2) C(1)-C(2)-C(3)-Cl(1) (11) C(2)-C(3)-C(4)-C(5) -0.1(2) Cl(1)-C(3)-C(4)-C(5) (11) C(3)-C(4)-C(5)-C(6) 0.5(2) C(4)-C(5)-C(6)-C(1) -0.4(2) C(4)-C(5)-C(6)-C(7) (12) C(2)-C(1)-C(6)-C(5) -0.1(2) C(2)-C(1)-C(6)-C(7) (13) C(5)-C(6)-C(7)-C(14) 39.8(2) C(1)-C(6)-C(7)-C(14) (14) C(5)-C(6)-C(7)-C(8) (14) C(1)-C(6)-C(7)-C(8) 40.59(19) C(14)-C(7)-C(8)-C(9) 44.1(2) C(6)-C(7)-C(8)-C(9) (14) C(14)-C(7)-C(8)-C(13) (15) C(6)-C(7)-C(8)-C(13) 42.77(19) C(13)-C(8)-C(9)-C(10) 0.4(2) C(7)-C(8)-C(9)-C(10) (13) C(8)-C(9)-C(10)-C(11) -0.3(2) C(9)-C(10)-C(11)-C(12) 0.5(2) C(10)-C(11)-C(12)-C(13) -0.8(2) C(11)-C(12)-C(13)-C(8) 1.0(2) C(9)-C(8)-C(13)-C(12) -0.8(2) C(7)-C(8)-C(13)-C(12) (13) C(8)-C(7)-C(14)-C(15) 0.6(2) C(6)-C(7)-C(14)-C(15) (13) C(17)-N(1)-C(15)-O(1) (13) C(16)-N(1)-C(15)-O(1) 9.2(2) C(17)-N(1)-C(15)-C(14) -0.5(2) C(16)-N(1)-C(15)-C(14) (13) C(7)-C(14)-C(15)-O(1) (16) C(7)-C(14)-C(15)-N(1) 60.9(2) C(15)-N(1)-C(17)-C(22) 51.1(2) C(16)-N(1)-C(17)-C(22) (15) C(15)-N(1)-C(17)-C(18) (15) C(16)-N(1)-C(17)-C(18) 42.96(19) C(22)-C(17)-C(18)-C(19) -1.5(2) N(1)-C(17)-C(18)-C(19) (13) C(17)-C(18)-C(19)-C(20) -1.2(2) C(18)-C(19)-C(20)-C(21) 2.3(2) C(19)-C(20)-C(21)-C(22) -0.7(2) C(20)-C(21)-C(22)-C(17) -2.0(2) C(18)-C(17)-C(22)-C(21) 3.1(2) N(1)-C(17)-C(22)-C(21) (13) Symmetry transformations used to generate equivalent atoms: Table S9. Hydrogen bonds for 3g [A and deg.]. D-H...A d(d-h) d(h...a) d(d...a) <(DHA) S66

67 X-ray crystallography of 4g (Thermal ellipsoids are shown at the 30% probability level) Table S10 Crystal data and structure refinement for 4g. Identification code 4g Empirical formula C 22 H 16 ClNO Formula weight Temperature 113(2) K Wavelength A Crystal system, space group Triclinic, P-1 Unit cell dimensions a = 9.594(7) A alpha = 67.85(5) deg. b = 9.699(7) A beta = 65.73(4) deg. c = (6) A gamma = 70.29(5) deg. Volume 854.0(10) A^3 Z, Calculated density 2, Mg/m^3 Absorption coefficient mm^-1 F(000) 360 Crystal size 0.20 x 0.18 x 0.12 mm Theta range for data collection 2.09 to deg. Limiting indices -11<=h<=11, -11<=k<=11, -12<=l<=13 Reflections collected / unique 8534 / 3007 [R(int) = ] Completeness to theta = % Absorption correction Semi-empirical from equivalents Max. and min. transmission and Refinement method Full-matrix least-squares on F^2 Data / restraints / parameters 3007 / 0 / 227 Goodness-of-fit on F^ Final R indices [I>2sigma(I)] R 1 = , wr 2 = R indices (all data) R 1 = , wr2 = Largest diff. peak and hole and e.a^-3 S67

68 Table S11. Atomic coordinates ( x 10^4) and equivalent isotropic displacement parameters (A^2 x 10^3) for4g. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. x y z U(eq) Cl(1) -4782(1) 3860(1) 1568(1) 29(1) O(1) -3307(2) 2431(2) 7144(1) 26(1) N(1) -1037(2) 2167(2) 7504(2) 22(1) C(1) -1727(2) 1797(2) 3639(2) 23(1) C(2) -2593(2) 2094(2) 2794(2) 24(1) C(3) -3658(2) 3479(2) 2601(2) 22(1) C(4) -3866(2) 4565(2) 3227(2) 23(1) C(5) -3013(2) 4238(2) 4084(2) 22(1) C(6) -1929(2) 2852(2) 4301(2) 19(1) C(7) -997(2) 2550(2) 5198(2) 20(1) C(8) 588(2) 2392(2) 4707(2) 20(1) C(9) 1439(2) 2118(2) 5624(2) 20(1) C(10) 3073(2) 1960(2) 5165(2) 24(1) C(11) 3862(2) 1702(2) 6057(2) 26(1) C(12) 3010(2) 1612(2) 7436(2) 28(1) C(13) 1400(2) 1782(2) 7922(2) 25(1) C(14) 584(2) 2024(2) 7029(2) 21(1) C(15) -1886(2) 2391(2) 6665(2) 21(1) C(16) -1921(2) 2035(3) 8970(2) 31(1) C(17) 1445(2) 2521(2) 3211(2) 20(1) C(18) 1141(2) 3891(2) 2222(2) 25(1) C(19) 1874(2) 3994(2) 832(2) 30(1) C(20) 2915(3) 2731(3) 410(2) 33(1) C(21) 3210(2) 1359(2) 1387(2) 30(1) C(22) 2487(2) 1254(2) 2779(2) 25(1) S68

69 Table S12. Bond lengths [A] and angles [deg] for 4g. Cl(1)-C(3) 1.746(2) O(1)-C(15) 1.236(3) N(1)-C(15) 1.392(3) N(1)-C(14) 1.397(3) N(1)-C(16) 1.475(2) C(1)-C(2) 1.390(3) C(1)-C(6) 1.395(3) C(1)-H(1) C(2)-C(3) 1.390(3) C(2)-H(2) C(3)-C(4) 1.391(3) C(4)-C(5) 1.385(3) C(4)-H(4) C(5)-C(6) 1.402(3) C(5)-H(5) C(6)-C(7) 1.490(3) C(7)-C(8) 1.363(3) C(7)-C(15) 1.473(3) C(8)-C(9) 1.453(3) C(8)-C(17) 1.500(3) C(9)-C(10) 1.407(3) C(9)-C(14) 1.420(3) C(10)-C(11) 1.388(3) C(10)-H(10) C(11)-C(12) 1.395(3) C(11)-H(11) C(12)-C(13) 1.384(3) C(12)-H(12) C(13)-C(14) 1.412(3) C(13)-H(13) C(16)-H(16A) C(16)-H(16B) C(16)-H(16C) C(17)-C(18) 1.400(3) C(17)-C(22) 1.401(3) C(18)-C(19) 1.391(3) C(18)-H(18) C(19)-C(20) 1.394(3) C(19)-H(19) C(20)-C(21) 1.393(3) C(20)-H(20) C(21)-C(22) 1.392(3) C(21)-H(21) C(22)-H(22) C(15)-N(1)-C(14) (15) C(15)-N(1)-C(16) (16) C(14)-N(1)-C(16) (16) C(2)-C(1)-C(6) (17) C(2)-C(1)-H(1) C(6)-C(1)-H(1) C(1)-C(2)-C(3) (17) C(1)-C(2)-H(2) C(3)-C(2)-H(2) C(2)-C(3)-C(4) (18) C(2)-C(3)-Cl(1) (15) C(4)-C(3)-Cl(1) (15) C(5)-C(4)-C(3) (17) S69

70 C(5)-C(4)-H(4) C(3)-C(4)-H(4) C(4)-C(5)-C(6) (17) C(4)-C(5)-H(5) C(6)-C(5)-H(5) C(1)-C(6)-C(5) (17) C(1)-C(6)-C(7) (16) C(5)-C(6)-C(7) (16) C(8)-C(7)-C(15) (17) C(8)-C(7)-C(6) (16) C(15)-C(7)-C(6) (16) C(7)-C(8)-C(9) (17) C(7)-C(8)-C(17) (17) C(9)-C(8)-C(17) (16) C(10)-C(9)-C(14) (17) C(10)-C(9)-C(8) (17) C(14)-C(9)-C(8) (17) C(11)-C(10)-C(9) (18) C(11)-C(10)-H(10) C(9)-C(10)-H(10) C(10)-C(11)-C(12) (18) C(10)-C(11)-H(11) C(12)-C(11)-H(11) C(13)-C(12)-C(11) (18) C(13)-C(12)-H(12) C(11)-C(12)-H(12) C(12)-C(13)-C(14) (18) C(12)-C(13)-H(13) C(14)-C(13)-H(13) N(1)-C(14)-C(13) (17) N(1)-C(14)-C(9) (17) C(13)-C(14)-C(9) (18) O(1)-C(15)-N(1) (17) O(1)-C(15)-C(7) (17) N(1)-C(15)-C(7) (16) N(1)-C(16)-H(16A) N(1)-C(16)-H(16B) H(16A)-C(16)-H(16B) N(1)-C(16)-H(16C) H(16A)-C(16)-H(16C) H(16B)-C(16)-H(16C) C(18)-C(17)-C(22) (18) C(18)-C(17)-C(8) (17) C(22)-C(17)-C(8) (17) C(19)-C(18)-C(17) (19) C(19)-C(18)-H(18) C(17)-C(18)-H(18) C(18)-C(19)-C(20) (19) C(18)-C(19)-H(19) C(20)-C(19)-H(19) C(21)-C(20)-C(19) (19) C(21)-C(20)-H(20) C(19)-C(20)-H(20) C(22)-C(21)-C(20) (19) C(22)-C(21)-H(21) C(20)-C(21)-H(21) C(21)-C(22)-C(17) (19) C(21)-C(22)-H(22) C(17)-C(22)-H(22) S70

71 Symmetry transformations used to generate equivalent atoms: S71

72 Table S13. Anisotropic displacement parameters (A^2 x 10^3) for 4g. The anisotropic displacement factor exponent takes the form: -2 pi^2 [ h^2 a*^2 U h k a* b* U12 ] U11 U22 U33 U23 U13 U12 Cl(1) 24(1) 44(1) 21(1) -7(1) -9(1) -11(1) O(1) 19(1) 31(1) 24(1) -8(1) -2(1) -4(1) N(1) 22(1) 27(1) 17(1) -9(1) -4(1) -5(1) C(1) 19(1) 24(1) 23(1) -7(1) -5(1) -4(1) C(2) 23(1) 28(1) 22(1) -10(1) -4(1) -9(1) C(3) 17(1) 32(1) 15(1) -5(1) -3(1) -8(1) C(4) 18(1) 27(1) 18(1) -6(1) -2(1) -3(1) C(5) 19(1) 25(1) 19(1) -8(1) -2(1) -5(1) C(6) 16(1) 24(1) 15(1) -5(1) -1(1) -6(1) C(7) 21(1) 19(1) 18(1) -6(1) -5(1) -4(1) C(8) 22(1) 19(1) 18(1) -7(1) -6(1) -4(1) C(9) 23(1) 19(1) 19(1) -7(1) -7(1) -5(1) C(10) 24(1) 27(1) 22(1) -8(1) -7(1) -7(1) C(11) 24(1) 29(1) 30(1) -9(1) -10(1) -7(1) C(12) 36(1) 28(1) 30(1) -9(1) -18(1) -6(1) C(13) 31(1) 26(1) 20(1) -9(1) -9(1) -5(1) C(14) 24(1) 20(1) 21(1) -8(1) -6(1) -4(1) C(15) 22(1) 20(1) 21(1) -8(1) -6(1) -2(1) C(16) 31(1) 44(1) 17(1) -11(1) -2(1) -8(1) C(17) 18(1) 28(1) 18(1) -7(1) -5(1) -8(1) C(18) 23(1) 28(1) 24(1) -6(1) -7(1) -9(1) C(19) 35(1) 37(1) 20(1) -2(1) -9(1) -18(1) C(20) 40(1) 45(1) 19(1) -14(1) -1(1) -21(1) C(21) 29(1) 37(1) 27(1) -18(1) -2(1) -9(1) C(22) 23(1) 30(1) 23(1) -10(1) -5(1) -7(1) Table S14. Hydrogen coordinates ( x 10^4) and isotropic displacement parameters (A^2 x 10^3) for 4g. x y z U(eq) H(1) H(2) H(4) H(5) H(10) H(11) H(12) H(13) H(16A) H(16B) H(16C) H(18) H(19) H(20) H(21) H(22) S72

73 Table S16. Torsion angles [deg] for 4g C(6)-C(1)-C(2)-C(3) 0.8(3) C(1)-C(2)-C(3)-C(4) 0.3(3) C(1)-C(2)-C(3)-Cl(1) (13) C(2)-C(3)-C(4)-C(5) -1.5(3) Cl(1)-C(3)-C(4)-C(5) (13) C(3)-C(4)-C(5)-C(6) 1.5(3) C(2)-C(1)-C(6)-C(5) -0.8(3) C(2)-C(1)-C(6)-C(7) (15) C(4)-C(5)-C(6)-C(1) -0.3(3) C(4)-C(5)-C(6)-C(7) (15) C(1)-C(6)-C(7)-C(8) 64.0(2) C(5)-C(6)-C(7)-C(8) (2) C(1)-C(6)-C(7)-C(15) (19) C(5)-C(6)-C(7)-C(15) 66.8(2) C(15)-C(7)-C(8)-C(9) -2.4(3) C(6)-C(7)-C(8)-C(9) (15) C(15)-C(7)-C(8)-C(17) (15) C(6)-C(7)-C(8)-C(17) -0.2(3) C(7)-C(8)-C(9)-C(10) (16) C(17)-C(8)-C(9)-C(10) -0.1(3) C(7)-C(8)-C(9)-C(14) -0.2(2) C(17)-C(8)-C(9)-C(14) (15) C(14)-C(9)-C(10)-C(11) 0.6(3) C(8)-C(9)-C(10)-C(11) (16) C(9)-C(10)-C(11)-C(12) -0.7(3) C(10)-C(11)-C(12)-C(13) -0.2(3) C(11)-C(12)-C(13)-C(14) 1.1(3) C(15)-N(1)-C(14)-C(13) (15) C(16)-N(1)-C(14)-C(13) -1.1(3) C(15)-N(1)-C(14)-C(9) 0.4(3) C(16)-N(1)-C(14)-C(9) (16) C(12)-C(13)-C(14)-N(1) (16) C(12)-C(13)-C(14)-C(9) -1.1(3) C(10)-C(9)-C(14)-N(1) (15) C(8)-C(9)-C(14)-N(1) 1.2(2) C(10)-C(9)-C(14)-C(13) 0.3(3) C(8)-C(9)-C(14)-C(13) (15) C(14)-N(1)-C(15)-O(1) (16) C(16)-N(1)-C(15)-O(1) -2.1(2) C(14)-N(1)-C(15)-C(7) -2.9(2) C(16)-N(1)-C(15)-C(7) (15) C(8)-C(7)-C(15)-O(1) (17) C(6)-C(7)-C(15)-O(1) 3.4(2) C(8)-C(7)-C(15)-N(1) 3.8(2) C(6)-C(7)-C(15)-N(1) (14) C(7)-C(8)-C(17)-C(18) 62.9(2) C(9)-C(8)-C(17)-C(18) (2) C(7)-C(8)-C(17)-C(22) (2) C(9)-C(8)-C(17)-C(22) 67.4(2) C(22)-C(17)-C(18)-C(19) -0.5(3) C(8)-C(17)-C(18)-C(19) (16) C(17)-C(18)-C(19)-C(20) 0.2(3) C(18)-C(19)-C(20)-C(21) 0.6(3) C(19)-C(20)-C(21)-C(22) -1.0(3) C(20)-C(21)-C(22)-C(17) 0.7(3) C(18)-C(17)-C(22)-C(21) 0.1(3) C(8)-C(17)-C(22)-C(21) (17) S73

74 Symmetry transformations used to generate equivalent atoms: Table S17. Hydrogen bonds for 4g [A and deg.]. D-H...A d(d-h) d(h...a) d(d...a) <(DHA) S74