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

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 606-8501, Japan E-mail: yamak@pharm.kyoto-u.ac.jp Table of Contents Details of DFT Calclulations...S2 NMR Charts...S8 ORTEP Drawing of 8...S58 Reference...S59 S1

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/6-311++G(3df,3pd) level of theory. N-Methylsuccinimide: Zero-point vibrational energy 315299.6 (Joules/Mol) 75.35841 (Kcal/Mol) 0.120091 (Hartree/Particle) Zero-point correction = Thermal correction to Energy = 0.126942 Thermal correction to Enthalpy = 0.127887 Thermal correction to Gibbs Free Energy = 0.088560 Energies (RB3LYP) = 400.130319131 Sum of electronic and thermal Enthalpies = 400.002432 Atomic Coordinates (Angstroms) Type X Y Z H 1.022959 2.467186 0.000000 C 0.002528 2.082192 0.000000 H 0.514494 2.430054 0.898946 H 0.514494 2.430054 0.898946 N 0.003998 0.625570 0.000000 C 0.002166 0.138760 1.166916 C 0.002166 0.138760 1.166916 C 0.000188 1.610831 0.768795 H 0.879019 2.094689 1.206303 H 0.881178 2.091809 1.205934 C 0.000188 1.610831 0.768795 H 0.879019 2.094689 1.206303 H 0.881178 2.091809 1.205934 O 0.004055 0.321924 2.292079 O 0.004055 0.321924 2.292079 S2

Succinimidomethyl: Zero-point vibrational energy Supporting Information 278187.8 (Joules/Mol) 66.48848 (Kcal/Mol) 0.105956 (Hartree/Particle) Zero-point correction = Thermal correction to Energy = 0.113309 Thermal correction to Enthalpy = 0.114253 Thermal correction to Gibbs Free Energy = 0.074236 Energies (UB3LYP) = 399.468415626 Sum of electronic and thermal Enthalpies = 399.354163 Atomic Coordinates (Angstroms) Type No X Y Z N 1 0.000000 0.000000 0.687190 C 2 0.000000 1.174819 0.098915 C 3 0.000000 0.768683 1.563885 C 4 0.000000 0.768683 1.563885 C 5 0.000000 1.174819 0.098915 H 6 0.879963 1.203166 2.050344 H 7 0.879963 1.203166 2.050344 H 8 0.879963 1.203166 2.050344 H 9 0.879963 1.203166 2.050344 C 10 0.000000 0.000000 2.062265 H 11 0.000000 0.958509 2.559253 H 12 0.000000 0.958509 2.559253 O 13 0.000000 2.295868 0.365785 O 14 0.000000 2.295868 0.365785 S3

Summary of Natural Population Analysis of α Spin Orbitals Atomic Natural Population Type No Natural Charge Core Valence Rydberg Total N 1 0.25665 0.99958 2.74359 0.01347 3.75665 C 2 0.33331 0.99967 1.64677 0.02025 2.66669 C 3 0.23560 0.99960 2.22737 0.00862 3.23560 C 4 0.23560 0.99960 2.22737 0.00862 3.23560 C 5 0.33331 0.99967 1.64677 0.02025 2.66669 H 6 0.11469 0.00000 0.38397 0.00134 0.38531 H 7 0.11469 0.00000 0.38397 0.00134 0.38531 H 8 0.11469 0.00000 0.38397 0.00134 0.38531 H 9 0.11469 0.00000 0.38397 0.00134 0.38531 C 10 0.49242 0.99969 2.47645 0.01628 3.49242 H 11 0.11095 0.00000 0.38690 0.00216 0.38905 H 12 0.11095 0.00000 0.38690 0.00216 0.38905 O 13 0.31351 0.99987 3.29791 0.01573 4.31351 O 14 0.31351 0.99987 3.29791 0.01573 4.31351 Total 0.50000 7.99756 21.87383 0.12862 30.0000 Summary of Natural Population Analysis of β Spin Orbitals Atomic Natural Population Type No Natural Charge Core Valence Rydberg Total N 1 0.26779 0.99958 2.75770 0.01051 3.76779 C 2 0.37752 0.99968 1.60350 0.01931 2.62248 C 3 0.23941 0.99960 2.23183 0.00798 3.23941 C 4 0.23941 0.99960 2.23183 0.00798 3.23941 C 5 0.37752 0.99968 1.60350 0.01931 2.62248 H 6 0.11945 0.00000 0.37933 0.00122 0.38055 H 7 0.11945 0.00000 0.37933 0.00122 0.38055 H 8 0.11945 0.00000 0.37933 0.00122 0.38055 H 9 0.11945 0.00000 0.37933 0.00122 0.38055 C 10 0.36559 0.99969 1.62546 0.00926 2.63441 H 11 0.08799 0.00000 0.41088 0.00114 0.41201 H 12 0.08799 0.00000 0.41088 0.00114 0.41201 O 13 0.26389 0.99987 3.24947 0.01454 4.26389 O 14 0.26389 0.99987 3.24947 0.01454 4.26389 Total 0.50000 7.99757 20.89184 0.11060 29.00000 S4

N-Methylphthalimide: Zero-point vibrational energy Supporting Information 377912.8 (Joules/Mol) 90.32332 (Kcal/Mol) 0.143939 (Hartree/Particle) Zero-point correction = Thermal correction to Energy = 0.152789 Thermal correction to Enthalpy = 0.153734 Thermal correction to Gibbs Free Energy = 0.109737 Energies (RB3LYP) = 552.599192866 Sum of electronic and thermal Enthalpies = 552.445459 Atomic Coordinates (Angstroms) Type X Y Z H 3.513035 1.032334 0.000000 C 3.130194 0.006025 0.000000 H 3.483065 0.506272 0.896944 H 3.483065 0.506272 0.896944 N 1.676377 0.006303 0.000000 C 0.892526 0.001207 1.164377 C 0.892526 0.001207 1.164377 O 1.325979 0.001565 2.301403 O 1.325979 0.001565 2.301403 C 0.527382 0.000328 0.698783 C 2.912376 0.001842 0.700979 C 1.710438 0.000246 1.425031 C 0.527382 0.000328 0.698783 C 1.710438 0.000246 1.425031 C 2.912376 0.001842 0.700979 H 1.700131 0.000048 2.511034 H 1.700131 0.000048 2.511034 H 3.859165 0.003333 1.234310 H 3.859165 0.003333 1.234310 S5

Phthalimidomethyl: Zero-point vibrational energy Supporting Information 340753.6 (Joules/Mol) 81.44207 (Kcal/Mol) 0.129786 (Hartree/Particle) Zero-point correction = Thermal correction to Energy = 0.139123 Thermal correction to Enthalpy = 0.140067 Thermal correction to Gibbs Free Energy = 0.095495 Energies (UB3LYP) = 551.939278473 Sum of electronic and thermal Enthalpies = 551.799211 Atomic Coordinates (Angstroms) Type No X Y Z N 1 0.000000 0.000000 1.734061 C 2 0.000000 1.173694 0.929719 C 3 0.000000 1.173694 0.929719 C 4 0.000000 0.000000 3.104807 H 5 0.000000 0.957468 3.603886 H 6 0.000000 0.957468 3.603886 O 7 0.000000 2.306206 1.369247 O 8 0.000000 2.306206 1.369247 C 9 0.000000 0.699829 0.479850 C 10 0.000000 0.700296 2.866183 C 11 0.000000 0.699829 0.479850 C 12 0.000000 1.424943 1.663016 C 13 0.000000 0.700296 2.866183 C 14 0.000000 1.424943 1.663016 H 15 0.000000 2.510791 1.653054 H 16 0.000000 1.234269 3.812459 H 17 0.000000 2.510791 1.653054 H 18 0.000000 1.234269 3.812459 S6

Summary of Natural Population Analysis of α Spin Orbitals Atomic Natural Population Type No Natural Charge Core Valence Rydberg Total N 1 0.25775 0.99961 2.74547 0.01267 3.75775 C 2 0.32688 0.99961 1.65329 0.02022 2.67312 C 3 0.32670 0.99961 1.65346 0.02023 2.67330 C 4 0.48458 0.99968 2.46856 0.01634 3.48458 H 5 0.11048 0.00000 0.38734 0.00218 0.38952 H 6 0.11049 0.00000 0.38734 0.00217 0.38951 O 7 0.29608 0.99987 3.28127 0.01494 4.29608 O 8 0.29602 0.99987 3.28121 0.01494 4.29602 C 9 0.05705 0.99941 2.04661 0.01103 3.05705 C 10 0.09961 0.99958 2.09097 0.00906 3.09961 C 11 0.05446 0.99941 2.04444 0.01061 3.05446 C 12 0.08822 0.99942 2.07789 0.01090 3.08822 C 13 0.10284 0.99958 2.09372 0.00953 3.10284 C 14 0.09374 0.99951 2.08468 0.00954 3.09374 H 15 0.11773 0.00000 0.38077 0.00150 0.38227 H 16 0.11009 0.00000 0.38895 0.00095 0.38991 H 17 0.11785 0.00000 0.38065 0.00150 0.38215 H 18 0.11016 0.00000 0.38885 0.00099 0.38984 Total 0.49996 11.99518 29.83547 0.16931 41.99996 Summary of Natural Population Analysis of β Spin Orbitals Atomic Natural Population Type No Natural Charge Core Valence Rydberg Total N 1 0.25437 0.99961 2.74498 0.00978 3.75437 C 2 0.36515 0.99961 1.61577 0.01947 2.63485 C 3 0.36497 0.99961 1.61594 0.01948 2.63503 C 4 0.34811 0.99968 1.64310 0.00910 2.65189 H 5 0.08820 0.00000 0.41070 0.00110 0.41180 H 6 0.08820 0.00000 0.41070 0.00110 0.41180 O 7 0.25863 0.99987 3.24481 0.01394 4.25863 O 8 0.25856 0.99987 3.24475 0.01394 4.25856 C 9 0.05859 0.99941 2.04863 0.01054 3.05859 C 10 0.08474 0.99958 2.07625 0.00890 3.08474 C 11 0.05599 0.99941 2.04646 0.01012 3.05599 C 12 0.07207 0.99942 2.06200 0.01065 3.07207 C 13 0.08796 0.99958 2.07901 0.00937 3.08796 C 14 0.07760 0.99951 2.06880 0.00928 3.07760 H 15 0.11725 0.00000 0.38124 0.00150 0.38275 H 16 0.10961 0.00000 0.38947 0.00092 0.39039 H 17 0.11738 0.00000 0.38112 0.00150 0.38262 H 18 0.10967 0.00000 0.38936 0.00096 0.39033 Total 0.50004 11.99519 28.85311 0.15166 40.99996 S7

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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 = 13.361(8), b = 11.884(9), c = 8.306(7) α = 90.0, β = 90.210(15), γ = 90.0 V = 1318.8(17) Å 3, Z = 4, Dx = 1.424 g/cm 3 Refinement Metrics Data Completeness = 0.993 R = 0.0345, wr2 = 0.0936, S = 1.111 See the separate CIF file for further details. S58

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, 2004. S59