Striking Difference between Succinimidomethyl and Phthalimidomethyl Radicals in Conjugate Addition to Alkylidenemalonate Initiated by Dimethylzinc

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1 Striking Difference between Succinimidomethyl and Phthalimidomethyl Radicals in Conjugate Addition to Alkylidenemalonate Initiated by Dimethylzinc Ken-ichi Yamada*, Yusuke Matsumoto, Shintaro Fujii, Takehito Konishi, Yosuke Yamaoka, and Kiyosei Takasu Graduate School of Pharmaceutical Sciences, Kyoto University Yoshida, Sakyo-ku, Kyoto , Japan Table of Contents Details of DFT Calclulations...S2 NMR Charts...S8 ORTEP Drawing of 8...S58 Reference...S59 S1

2 DFT Calculations. All the calculations were performed using Gaussian 09W program. 1 The geometry optimization and the frequency analyses were conducted at B3LYP/6-31+G(d) level of theory, while the energies and the natural population were calculated at B3LYP/ G(3df,3pd) level of theory. N-Methylsuccinimide: Zero-point vibrational energy (Joules/Mol) (Kcal/Mol) (Hartree/Particle) Zero-point correction = Thermal correction to Energy = Thermal correction to Enthalpy = Thermal correction to Gibbs Free Energy = Energies (RB3LYP) = Sum of electronic and thermal Enthalpies = Atomic Coordinates (Angstroms) Type X Y Z H C H H N C C C H H C H H O O S2

3 Succinimidomethyl: Zero-point vibrational energy Supporting Information (Joules/Mol) (Kcal/Mol) (Hartree/Particle) Zero-point correction = Thermal correction to Energy = Thermal correction to Enthalpy = Thermal correction to Gibbs Free Energy = Energies (UB3LYP) = Sum of electronic and thermal Enthalpies = Atomic Coordinates (Angstroms) Type No X Y Z N C C C C H H H H C H H O O S3

4 Summary of Natural Population Analysis of α Spin Orbitals Atomic Natural Population Type No Natural Charge Core Valence Rydberg Total N C C C C H H H H C H H O O Total Summary of Natural Population Analysis of β Spin Orbitals Atomic Natural Population Type No Natural Charge Core Valence Rydberg Total N C C C C H H H H C H H O O Total S4

5 N-Methylphthalimide: Zero-point vibrational energy Supporting Information (Joules/Mol) (Kcal/Mol) (Hartree/Particle) Zero-point correction = Thermal correction to Energy = Thermal correction to Enthalpy = Thermal correction to Gibbs Free Energy = Energies (RB3LYP) = Sum of electronic and thermal Enthalpies = Atomic Coordinates (Angstroms) Type X Y Z H C H H N C C O O C C C C C C H H H H S5

6 Phthalimidomethyl: Zero-point vibrational energy Supporting Information (Joules/Mol) (Kcal/Mol) (Hartree/Particle) Zero-point correction = Thermal correction to Energy = Thermal correction to Enthalpy = Thermal correction to Gibbs Free Energy = Energies (UB3LYP) = Sum of electronic and thermal Enthalpies = Atomic Coordinates (Angstroms) Type No X Y Z N C C C H H O O C C C C C C H H H H S6

7 Summary of Natural Population Analysis of α Spin Orbitals Atomic Natural Population Type No Natural Charge Core Valence Rydberg Total N C C C H H O O C C C C C C H H H H Total Summary of Natural Population Analysis of β Spin Orbitals Atomic Natural Population Type No Natural Charge Core Valence Rydberg Total N C C C H H O O C C C C C C H H H H Total S7

8 1 H NMR (500 MHz, CDCl 3 ) of 5aa S8

9 13 C NMR (500 MHz, CDCl 3 ) of 5aa S9

10 1 H NMR (500 MHz, CDCl 3 ) of 5ba S10

11 13 C NMR (500 MHz, CDCl 3 ) of 5ba S11

12 1 H NMR (500 MHz, CDCl 3 ) of 5ca S12

13 13 C NMR (500 MHz, CDCl 3 ) of 5ca S13

14 1 H NMR (500 MHz, CDCl 3 ) of 5da S14

15 13 C NMR (500 MHz, CDCl 3 ) of 5da S15

16 1 H NMR (500 MHz, CDCl 3 ) of 5ea S16

17 13 C NMR (500 MHz, CDCl 3 ) of 5ea S17

18 1 H NMR (500 MHz, CDCl 3 ) of 5ab S18

19 13 C NMR (500 MHz, CDCl 3 ) of 5ab S19

20 1 H NMR (500 MHz, CDCl 3 ) of 5bb S20

21 13 C NMR (125 MHz, CDCl 3 ) of 5bb S21

22 1 H NMR (500 MHz, CDCl 3 ) of 5cb S22

23 13 C NMR (125 MHz, CDCl 3 ) of 5cb S23

24 1 H NMR (500 MHz, CDCl 3 ) of 5db S24

25 13 C NMR (125 MHz, CDCl 3 ) of 5db S25

26 1 H NMR (500 MHz, CDCl 3 ) of 5eb S26

27 13 C NMR (125 MHz, CDCl 3 ) of 5eb S27

28 1 H NMR (500 MHz, CDCl 3 ) of 6aa S28

29 13 C NMR (125 MHz, CDCl 3 ) of 6aa S29

30 1 H NMR (500 MHz, CDCl 3 ) of 7aa S30

31 13 C NMR (125 MHz, CDCl 3 ) of 7aa S31

32 1 H NMR (500 MHz, CDCl 3 ) of 7ab S32

33 13 C NMR (125 MHz, CDCl 3 ) of 7ab S33

34 1 H NMR (500 MHz, CDCl 3 ) of 7bb S34

35 13 C NMR (125 MHz, CDCl 3 ) of 7bb S35

36 1 H NMR (500 MHz, CDCl 3 ) of 7cb S36

37 13 C NMR (125 MHz, CDCl 3 ) of 7cb S37

38 1 H NMR (500 MHz, CDCl 3 ) of 7db S38

39 13 C NMR (125 MHz, CDCl 3 ) of 7db S39

40 1 H NMR (500 MHz, CDCl 3 ) of 7eb S40

41 13 C NMR (125 MHz, CDCl 3 ) of 7eb S41

42 1 H NMR (500 MHz, CDCl 3 ) of 7ac S42

43 13 C NMR (125 MHz, CDCl 3 ) of 7ac S43

44 1 H NMR (500 MHz, CDCl 3 ) of 7ad S44

45 13 C NMR (500 MHz, CDCl 3 ) of 7ad S45

46 1 H NMR (500 MHz, CDCl 3 ) of Methyl 3-(4-Chlorophenyl)-4-phthalimidobutanoate S46

47 13 C NMR (500 MHz, CDCl 3 ) of Methyl 3-(4-Chlorophenyl)-4-phthalimidobutanoate S47

48 1 H NMR (500 MHz, CDCl 3 ) of 3-(4-Chlorophenyl)-4-phthalimidobutanoic Acid S48

49 13 C NMR (500 MHz, CDCl 3 ) of 3-(4-Chlorophenyl)-4-phthalimidobutanoic Acid S49

50 1 H NMR (500 MHz, D 2 O) of Baclofen Hydrochloride Supporting Information S50

51 1 H NMR (500 MHz, CDCl 3 ) of Methyl 5-Methyl-3-(phthalimidomethyl)hexanoate S51

52 13 C NMR (500 MHz, CDCl 3 ) of Methyl 5-Methyl-3-(phthalimidomethyl)hexanoate S52

53 1 H NMR (500 MHz, CDCl 3 ) of 5-Methyl-3-(phthalimidomethyl)hexanoic Acid S53

54 13 C NMR (500 MHz, CDCl 3 ) of 5-Methyl-3-(phthalimidomethyl)hexanoic Acid S54

55 1 H NMR (500 MHz, D 2 O) of Pregabalin Hydrocholide Supporting Information S55

56 1 H NMR (500 MHz, CDCl 3 ) of 8 S56

57 13 C NMR (125 MHz, CDCl 3 ) of 8 S57

58 The X-ray diffraction experiment of 8 was conducted with Cu Kα radiation at 93 K. ORTEP drawing of 8 (50% probability). Crystal Parameters monoclinic, P2 1 /c a = (8), b = (9), c = 8.306(7) α = 90.0, β = (15), γ = 90.0 V = (17) Å 3, Z = 4, Dx = g/cm 3 Refinement Metrics Data Completeness = R = , wr2 = , S = See the separate CIF file for further details. S58

59 Reference (1) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, Jr., J. A.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.; Gaussian, Inc., Wallingford CT, S59