Institute of Organic Chemistry, Justus-Liebig University, Heinrich-Buff-Ring 17, Giessen, Germany;

Transcript

1 Catalytic Halogen Bond Activation in the Benzylic C H Bond Iodination with Iodohydantoins Sascha H. Combe, Abolfazl Hosseini, Lijuan Song, Heike Hausmann and Peter R. Schreiner* Institute of Organic Chemistry, Justus-Liebig University, Heinrich-Buff-Ring 17, Giessen, Germany; prs@org.chemie.uni-giessen.de Contents General Information... S1 Design of experiments analysis... S2 Iodine activity of compounds S3 NMR study for the role of the acid... S3 NMR study for the role of I2... S4 Experimental details and spectral data... S5 Computations... S25 Cartesian coordinates of all computed structures at the B3LYP-D3/6-31G(d,p) level of theory... S31 References... S48 General Information All chemicals were purchased from TCI, Sigma Aldrich, and Alfa Aesar in reagent grade or better quality and used without further purification. All solvents were distilled before usage. 3-ITMH was synthesized with a purity of 94 98% determined by 1 H NMR. Yields for method P2 are related to the quality of 3-ITMH (94%, mmol of pure iodine containing compound). Analytical thin-layer chromatography (TLC) was performed on SIL G UV254 from Macherey Nagel with a fluorescence indicator. Visualization of the TLC plate was performed by UV (254 nm), 5% phosphomolybdic acid. Column chromatography was performed using Merck silica gel 60 ( mm) or Büchi Reveleris Silica columns (0.040 mm). Flash chromatography was performed for P2 with the Reveleris X2 of Grace. 1 H and 13 C spectra were measured with Bruker spectrometer Avance II 200 MHz (AV 200), Avance II 400 MHz (AV 400) and Avance III HD 600 MHz (AV 600), using the solvent peak as the internal standard. NMR assignments were evaluated by Attached Proton Test (APT), Heteronuclear Single Quantum Coherence (HSQC) and Heteronuclear Multiple Bond Correlation (HMBC). CDCl3 was filtered over K2CO3 to remove traces of HCl. Reaction progress was monitored by NMR or by GC-MS analyses with a Quadrupol- MS HP MSD 5971(EI) and HP 5890A GC equipped with a J & W Scientific fused silica GC column (30 m mm, 0.25 micron DB 5MS stationary phase: 5% phenyl and 95% methyl silicone) using He (4.6 grade) as carrier gas; T-program S1

2 standard C (10 C/min heating rate), injector and transfer line 250 C. The exact mass was measured with an ESI-MS Mikro-TOF of Bruker. For CHN Thermo FlashEA 1112 was used. The glasses of the hood were coated with an UV foil (dc-fix) to exclude UV light. Design of experiments analysis Exemplified calculations: Slope (5) = (60-28)/2 = 16 Yield (dilution/5 2:1.7) = ( )/4 = 31% The relative relation (Table S2) is referred to the lowest number 5 = 4.5/2.5 = 1.8 Dilution/5 = 14.6/6 = 2.4 Table S1. Screening analysis 1 dilution (ml) 4 (equiv) 5 (equiv) yield (%) (equiv) yield (%) slope 4 (equiv) yield (%) slope dilution (ml) yield (%) slope S2

3 dilution/4 yield (%) slope dilution/5 yield (%) slope 2/ / / / /5 yield (%) slope 0.17/ / Table S2. Relative relations dilution/4 dilution/5 4/5 5 4 dilution Iodine activity of compounds 1 3 Scheme S1. Comparison of the iodine activity in 1, 2 and 3 a a 1 H NMR yield; dimethyl terephthalate (DMT) (0.625 M, mmol) used as internal standard. NMR study for the role of the acid Table S3. Evaluation of the role of acid entry acid pka (DMSO) 6 (%) a o-no2c6h4co2h NH4Cl b 4 PhCO2H a Yield determined by 1 H NMR with DMT as internal standard; b 3 h. S3

4 Table S4. Self-diffusion coefficients for pure o-nitrobenzoic acid and 3-ITMH in CD2Cl2 and in the complex molecule D(m 2 /s) pure in CD2Cl2 in the complex in CD2Cl2 o- NO2C6H4CO2H ITMH Figure S1. DOSY NMR of 3-ITMH (3) and o-no2c6h4co2h NMR study for the role of I2 Table S5. Evaluation of the role of I2 entry t (h) iodine source cat. (equiv) 6 (%) a 1 15 I I2 o-no2c6h4co2h (0.36) I2 (0.1) 13 a Yield determined by 1 H NMR with DMT as internal standard. S4

5 Experimental details and spectral data 1 H NMR activation study of (3): 3-ITMH (10.0 mg, 37.3 μmol, 1.0 equiv) and the related additives (see Figure 1) were placed in the NMR tube and diluted with CD2Cl2 (600 μl). The sample was shaken or sonicated for 30 s and measured after about 0.5 h at 25 C. DOSY experiment: 3-ITMH (10.0 mg, 37.3 μmol, 1.0 equiv) and o-nitrobenzoic acid (2.24 mg, 13.4 μmol, 0.36 equiv) were transferred to the NMR tube and diluted with CD2Cl2 (600 μl). The NMR tube was sonicated for about 30 s and then measured in a time range of 43 min. The 1 H DOSY spectra were carried out on a Bruker Avance III HD 600 MHz spectrometer equipped with a 5 mm broadband BBO Z-gradient probe. The temperature was set and controlled at 298 K with an air flow of 540 l h -1. For each experiment, 16 dummy scans and 24 scans were used, with a relaxation delay of 2 s and a diffusion delay of 50 ms. The shape of the gradients were sinusoidal, with a length of 1 ms, and the strength was varied in 32 increments (2-95%) in a linear ramp. All DOSY experiments were obtained with a longitudinal eddy-current delay (LED) bipolar gradient pulse pair and two spoil gradients pulse sequence (ledbpgp2s) in the standard Bruker pulse sequence library. All experiments were processed with standard Bruker 1D and 2D DOSY software. General procedure for the iodination with DIH (P1): In a 5 or 10 ml reaction vessel N-hydroxyphthalimide (10.2 mg, mmol, 0.17 equiv), o-nitrobenzoic acid (22.7 mg, mmol, 0.36 equiv) was diluted in CH2Cl2 (2 ml) and stirred for 1 min at 25 C. Subsequently DIH (143 mg, mmol, 1.0 equiv) and the substrate (2.50 mmol, 6.7 equiv) was added and the vessel was sealed. After an additional stirring for 3 h at C, the reaction mixture was diluted with EtOAc (20 ml), washed with sat. NaHCO3 (10 ml), Na2S2O3 (5%, 10 ml), dried over Na2SO4 and concentrated under reduced pressure. General procedure for the iodination with 3-ITMH (P2): In a 10 ml reaction vessel N-hydroxyphthalimide (10.2 mg, mmol, 0.17 equiv), o-nitrobenzoic acid (22.7 mg, mmol, 0.36 equiv) was diluted in CH2Cl2 (2 ml) and stirred for 1 min at 25 C. Subsequently 3-ITMH (94%, 100 mg, mmol, 1.0 equiv) and the substrate (4.50 mmol, 12.0 equiv) was added and the vessel was sealed. After an additional stirring for 3 h at C, the reaction mixture was diluted with CH2Cl2 (20 ml), washed with Na2S2O3 (5%, 10 ml) and the aqueous phase extracted with CH2Cl2 (2 x 10 ml). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. 1-ITMH (1): 2 According to Gandelman et al..3,5,5-trimethylhydantoin (860 mg, 6.05 mmol, 1 equiv). The residue was filtered (D4), washed with CH2Cl2 (2 x 10 ml) and dried over paraffin to afford 1 (1.57 g, 5.86 mmol, 96%) as a pale pink solid; 1 H NMR (400 MHz, CDCl3): δ = 3.09 (s, 3 H), 1.25 (s, 6 H) ppm. S5

6 3-ITMH (3): 2 1,5,5-trimethylhydantoin (1.91 g, 13.4 mmol, 1 equiv), PhI(OAc)2 (2.81 g, 8.70 mmol, 0.65 equiv) and I2 (2.41 g, 9.50 mmol, 0.71 equiv) was diluted in CH3CN (23 ml). After stirring for 18 h at rt the solvent was removed under reduced pressure, the residue diluted in CH3CN (23 ml) and stirred for 1 h. The solvent was removed under reduced pressure, the residue treated with CH2Cl2 (40 ml) and stirred for 0.5 h. Filtration (D4), washing with CH2Cl2 (2 x 10 ml) and drying over paraffin afforded 3 (3.13 g, 11.6 mmol, 85%) as a pale pink solid; 1 H NMR (400 MHz, CDCl3): δ = 2.95 (s, 3 H), 1.39 (s, 6 H) ppm; 13 C NMR (100 MHz, CDCl3): δ = 178.7, 154.4, 64.2, 26.1, 22.9 ppm; 1 H NMR (400 MHz, DMSO-d6): δ = 2.77 (s, 3 H), 1.22 (s, 6 H) ppm; 13 C NMR (100 MHz, DMSO-d6): δ = 179.9, 155.9, 62.6, 25.1, 22.1 ppm. Benzyl iodide (6): 3 According to (P1). The residue was purified by column chromatography (silica gel, hexane) to give the iodide 6 (99.0 mg, mmol, 60%) as a colorless solid below rt (22 23 C), Rf = 0.24; m.p. at rt (Lit C); 1 H NMR (400 MHz, CDCl3): δ = (m, 2 H), (m, 3 H), 4.46 (s, 2 H) ppm; 13 C NMR (100 MHz, CDCl3): δ = 139.5, 129.0, 128.9, 128.0, 5.8 ppm. According to P2. The residue was purified by flash column chromatography (silica gel, hexane), giving 6 (51.2 mg, mmol, 67%). Methyl 2-(iodomethyl)benzoate (8): According to (P1). The residue was purified by column chromatography (silica gel, hexane/et2o 9:1) to give the iodide 8 (99.6 mg, mmol, 48%) as a colorless solid, Rf = 0.27; m.p C; 1 H NMR (400 MHz, CDCl3): δ = 7.95 (dd, 1 H, J = 7.7, 1.2 Hz, CHCCO2CH3), (m, 2 H, CH2CCHCHCH), (m, 1 H, CHCHCCH2), 4.93 (s, 2 H, CH2), 3.95 (s, 3 H, CH3) ppm; 13 C NMR (100 MHz, CDCl3): δ = (CO), (CCH2), (CHAr), (CHCCO), (CHAr), (CCO), (CHCHCCH2), 52.4 (CH3), 4.1 (CH2) ppm; HRMS (ESI) calculated for C9H9INaO2 ([M+Na] + ): Found: ; elemental analysis calcd (%) for C9H9IO2 (276.1): C 39.16, H Found: C 39.41, H According to P2. 5 The residue was purified by flash column chromatography (silica gel, hexane/etoac 24:1) giving 8 (53.5 mg, mmol, 55%). Methyl 3-(iodomethyl)benzoate (9): According to (P1). The residue was purified by column chromatography (silica gel, hexane/et2o 9:1) to give the iodide 9 (106 mg, mmol, 51%) as a colorless solid, Rf = 0.22; m.p C (Lit C); 1 H NMR (400 MHz, CDCl3): δ = 8.04 (t, 1 H, J = 1.8 Hz, CH3O2CCCHCCH2I), 7.91 (dt, 1 H, J = 7.8, 1.4 Hz, CHCHCCO2CH3), 7.56 (dt, 1 H, J = 7.8, 1.6 Hz, CHCHCCH2I), 7.38 (t, 1 H, J = 7.7 Hz, CHCHCH), 4.47 (s, 2 H, CH2), 3.92 (s, 3 H, CH3) ppm; 13 C NMR (100 MHz, CDCl3): δ = (CO), (CCH2), (CHCHCCH2), (CCO), (CCHC), (COCCHCH), 52.4 (CH3), 4.3 (CH2) ppm; HRMS (ESI) calculated for C9H9INaO2 ([M+Na] + ): Found: ; elemental analysis calcd (%) for C9H9O2 (276.1): C 39.16, H Found: C 39.19, H According to P2. 5 The residue was purified by flash column chromatography (silica gel, hexane/etoac 24:1) giving 9 (53.2 mg, mmol, 55%). Methyl 4-(iodomethyl)benzoate (10): 7 According to (P1). The residue was purified by column chromatography (silica gel, hexane/et2o 9:1) to give the iodide 10 (134 mg, mmol, 65%) as a colorless solid, Rf = 0.14; m.p C (Lit. 7b C); 1 H S6

7 NMR (400 MHz, CDCl3): δ = (m, 2 H), (m, 2 H), 4.46 (s, 2 H), 3.91 (s, 3 H) ppm; 13 C-NMR (100 MHz, CDCl3): δ = 166.7, 144.5, 130.3, 129.7, 128.9, 52.3, 4.0 ppm. According to P2. 5 The residue was purified by flash column chromatography (silica gel, hexane/etoac 24:1) giving 10 (62.9 mg, mmol, 65%). 2-chlorobenzyl iodide (11): 8 According to (P1). The residue was purified by column chromatography (silica gel, hexane) to give the iodide 11 (127.0 mg, mmol, 67%) as a colorless oil, Rf = 0.26; 1 H NMR (400 MHz, CDCl3): δ = (m, 1 H), (m, 1 H), (m, 2 H), 4.53 (s, 2 H) ppm; 13 C NMR (100 MHz, CDCl3): δ = 136.9, 134.0, 130.8, 130.3, 129.6, 127.5, 2.5 ppm. According to P2. The residue was purified by flash column chromatography (silica gel, hexane) giving 11 (56.6 mg, mmol, 64%). 3-chlorobenzyl iodide (12): 9 According to (P1), here 23 h. The residue was purified by column chromatography (silica gel, hexane) to give the iodide 12 (93.0 mg, mmol, 49%) as a colorless oil, Rf = 0.29; 1 H NMR (400 MHz, CDCl3): δ = 7.37 (q, 1 H, J = 1.4 Hz), (m, 3 H), 4.39 (s, 2 H) ppm; 13 C NMR (100 MHz, CDCl3): δ = 141.4, 134.6, 130.2, 129.0, 128.2, 127.1, 3.74 ppm. According to P2. The residue was purified by flash column chromatography (silica gel, hexane) giving 12 (52.3 mg, mmol, 59%). 4-chlorobenzyl iodide (13): 9 According to (P1). The residue was purified by column chromatography (silica gel, hexane) to give the iodide 13 (92.9 mg, mmol, 49%) as a colorless solid, Rf = 0.31; m.p C (Lit C); 1 H NMR (400 MHz, CDCl3): δ = (m, 2 H), (m, 2 H), 4.43 (s, 2 H) ppm; 13 C NMR (100 MHz, CDCl3): δ = 138.0, 133.8, 130.2, 129.2, 4.3 ppm. According to P2. The residue was purified by flash column chromatography (silica gel, hexane) giving (56.6 mg, mmol, 64%). 4-(iodomethyl)benzonitrile (14): 7b According to (P1). The residue was purified by column chromatography (silica gel, hexane/etoac 9:1) to give the iodide 14 (64.6 mg, mmol, 35%) as a colorless solid, Rf = 0.21; m.p C (Lit. 7b C); 1 H NMR (400 MHz, CDCl3): δ = 7.59 (d, 2 H, J = 8.4 Hz), 7.46 (d, 2 H, J = 8.3 Hz), 4.44 (s, 2 H, CH2) ppm; 13 C NMR (100 MHz, CDCl3): δ = 144.8, 132.7, 129.6, 118.6, 111.7, 2.9 ppm. According to P2. The residue was purified by flash column chromatography (silica gel, hexane to hexane/etoac 19:1) giving 14 (43.1 g, mmol, 50%). 4-(iodoethyl)benzonitrile (15): According to (P1). The residue was purified by column chromatography (silica gel, hexane/etoac 9:1) to give the iodide 15 (133 mg, mmol, 69%) as a pale yellow oil, Rf = 0.18; 1 H NMR (400 MHz, CDCl3): δ = 7.60 (d, 2 H, J = 8.4 Hz, CHAr), 7.52 (d, 2 H, J = 8.4 Hz, CHAr), 5.33 (q, 1 H, J = 7.1 Hz, CH), 2.20 (d, 3 H, J = 7.1 Hz, CH3) ppm; 13 C NMR (100 MHz, CDCl3): δ = (CCHI), (CHAr), (CHAr), (CN), (CCN), 28.3 (CH3), 22.5 (CH) ppm; HRMS (ESI) calculated for C9H8INNa ([M+Na] + ): Found: ; elemental analysis calcd (%) for C9H8IN (257.1): C 42.05, H 3.14, N Found: C 42.09, H 3.18, N S7

8 According to P2 but without acid. 5 The residue was purified by flash column chromatography (silica gel, hexane/etoac 24:1) giving 15 (53.5 g, mmol, 59%). 4-(Trifluoromethyl)benzyl iodide (16): 10 According to (P1), 19 h. The residue was purified by column chromatography (silica gel, hexane/etoac 9:1) to give the iodide 16 (79.2 mg, mmol, 37%) as a colorless solid, Rf = 0.36; m.p. 44 C; 1 H NMR (400 MHz, CDCl3): δ = 7.56 (d, 2 H, J = 8.1 Hz), 7.48 (m, 2 H, J = 8.1 Hz), 4.46 (s, 2 H) ppm; 13 C NMR (100 MHz, CDCl3): δ = (q, J = 1.3 Hz), (q, J = 33.6 Hz), 129.2, (q, J = 3.8 Hz), (q, J = Hz), 3.31 ppm. According to P2. The residue was purified by flash column chromatography (silica gel, hexane) giving 16 (68.1 mg, mmol, 68%). 4-Nitrobenzyl iodide (17): 11 According to (P1), 22 h. The residue was purified by column chromatography (silica gel, hexane/etoac 9:1) to give the iodide 17 (121 mg, mmol, 61%) as a colorless solid, Rf = 0.24; m.p C (Lit C); 1 H NMR (400 MHz, CDCl3): δ = 8.16 (d, 2 H, J = 8.7 Hz), 7.52 (m, 2 H, J = 8.7 Hz), 4.48 (s, 2 H,) ppm; 13 C NMR (100 MHz, CDCl3): δ = 147.4, 146.9, 129.7, 124.3, 2.2 ppm. According to P2. 5 The residue was purified by flash column chromatography (silica gel, hexane/etoac 24:1) giving 17 (66.5 mg, mmol, 72%). 4-Fluorobenzyl iodide (18): According to (P1). The residue was purified by column chromatography (silica gel, hexane) to give the iodide 18 (70.6 mg, mmol, 40%) as a colorless solid, Rf = 0.23; m.p. 34 C (Lit C); 1 H NMR (400 MHz, CDCl3): δ = (m, 2 H, CHAr), (m, 2 H, CHAr), 4.44 (s, 2 H, CH2) ppm; 13 C NMR (100 MHz, CDCl3): δ = (d, J = Hz, CF), (d, J = 3.4 Hz, CCH2), (d, J = 8.3 Hz, CHCCH2I), (d, J = 21.7 Hz, CHCF), 4.7 (CH2) ppm. According to P2. The residue was purified by flash column chromatography (silica gel, hexane) giving 18 (56.7 mg, mmol, 68%). 3,5,5-trimethylhydantoin (23): 2 5,5-dimethylhydantoin (1.00 g, 7.80 mmol, 1 equiv) and K2CO3 (50%, 1.10 g, 7.80 mmol, 1 equiv) in EtOH (6 ml) was stirred for 0.5 h at rt. MeI (1.11 g, 7.80 mmol, 1 equiv) was added dropwise and the mixture stirred for additional 2 h at rt. Then the temperature was increased to 60 C and the mixture was stirred for 3 h. The solvent was evaporated under reduced pressure and the residue dissolved in H2O (4 ml). Extraction with CHCl3 (3 x 4 ml), drying over Na2SO4 and evaporation of the solvent at reduced pressure afforded 23 (876 mg, 6.15 mmol, 79%) as a white solid. 1 H NMR (400 MHz, CDCl3): δ = 5.45 (bs, 1 H), 3.02 (s, 3 H), 1.44 (s, 6 H) ppm; 13 C NMR (100 MHz, CDCl3): δ = 177.6, 156.9, 59.1, 25.2, 24.8 ppm. S8

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25 Computations General All calculations were performed by using Gaussian 09 programs. 13 Geometry optimization of all stationary points in the gas phase was conducted by B3LYP method. 14 The 6-31G (d, p) basis set was employed for H, C, N, O and Cl atoms, while the Lanl2dz basis set (augmented with f functions) and ECP were used for I. 15 Frequency calculation was performed for each optimized structure to verify the stationary points as either minima or saddle point at the same level of theory. Empirical dispersion corrections (D3-BJ) were included to treat non-covalent interactions. 16 The zero-point energy and free energy corrections were also derived from the vibration frequency calculations. Solvent effect (solvent = DCM) was included by single-point energy calculation using PCM model at the same level of theory. 17 The reported free energies (in kcal mol -1, at K and 1 atm), which were obtained from the abovementioned single-point PCM calculations combined with the gas-phase free-energy correction, are mainly used for our discussion unless stated otherwise. Frontier Molecular Theory (FMO) analysis was carried out to evaluate the gap between SOMO of the tolyl radicals and HOMO(LUMO) of the iodine reagent. 18 Table S6. LUMO SOMO and SOMO HOMO energies (B3LYP/6-31G**) in ev R E (SOMO) ΔE (LUMO SOMO) ΔE (SOMO-HOMO) H F Cl CO2Me CF CN NO S25

26 Table S7. Global electrophilicity index of different tolyl radicals in ev at the B3LYP/6-31G(g,d) level of theory 19 R H F Cl CO2Me CF3 CN NO2 ω Table S8. Absolute energies in au at the B3LYP-D3/6-31G(d,p) level of theory Structures ZPVE ΔE ΔH ΔG HF E H G HA HAdi A TS B TS C D TS a-e a-e' a-ts a-ts2' a-f a-g a-ts a-E a-E' a-TS a-TS a-F a-F' a-G S26

27 2a-G' a-TS a-TS3' p-cl-c 6H 4CH p-meo 2C- C 6H 4CH p-f 3C- C 6H 4CH p-nc-c 6H 4CH p-o 2N- C 6H 4CH p-f-c 6H 4CH S27

28 Scheme S2. Generation of benzyl radical 20 (energies in kcal mol -1 ) Scheme S3. Generation of benzyl iodide without acid (energies in kcal mol -1 ) S28

29 Scheme S4. Reaction catalyzed by one acid molecule (energies in kcal mol -1 ) S29

30 Scheme S5. Reaction catalyzed by two acid molecules (energies in kcal mol -1 ) S30

31 Cartesian coordinates of all computed structures at the B3LYP-D3/6-31G(d,p) level of theory HA (C1) C C C C C C H H H H C O O H N O O HAdi (C2) C C C C C C H H H H C O O H N O O C C C C C C H H H H C O O H N O O (Cs) C C N O O I C H H H C C H H H C H H H N (Cs) C C C C C C H H H H S31

32 C O O N C O H (Cs) C C C C C C H H H H H C H H H (Cs) C C C C C C H H H H H C H H I (C2v) C C C C C C H H H H C O O N C O (C2v) C C C C C C H H H H H C H H (C1) C C N O O C H H H C C H H H C H H S32

33 H N (Cs) C C N O O C H H H C C H H H C H H H N H A C C C C C C H H H C C C C C C C C H H H H O O N O H H C H H H TS1 C C C C C C H H H C C C C C C C C H H H H O O N O H H C H H H B C C S33

34 N O O I C H H H C C H H H C H H H N C C C C C C H H H H H C H H TS2 C C N O O I C H H H C C H H H C H H H N C C C C C C H H H H H C H H C C C N O O I C H H H C C H H H C H H H N C C C C S34

35 C C H H H H H C H H D C C N O O C C C C C C H H H H H C H H H C N C H H H C H H H C H H H TS3 C C N O O C C C C C C H H H H H C H H H C N C H H H C H H H C H H H a-e' C C N O O I C H H H S35

36 C C H H H C H H H N C C C C C C H H H H C O O H N O O a-ts2 C C N O O I C C C C C C H H H H C O O H N O O C C C C C C H H H H H C H H N C C H H H C H H H C H H H a-ts2' C C N O O I C H H H C C S36

37 H H H C H H H N C C C C C C H H H H C O O H N O O C C C C C C H H H H H C H H a-f C C N O O I C C C C C C H H H H C O O H N O O C C C C C C H H H H H C H H N C C H H H C H H H C H H H a-g S37

38 C C N O O C C C C C C H H H H C O O H N O O C C C C C C H H H H H C H H H C N C H H H C H H H C H H H a-ts3 C C N O O C C C C C C H H H H C O O H N O O C C C C C C H H H H H C H H H C N C H S38

39 H H C H H H C H H H a-E C C N O O I C H H H C C H H H C H H H N C C C C C C H H H H C O O H N O O C C C C C C H H H H C O O H N O O a-E' C C N O O I C C C C C C H H H H C O O H N O O N C C S39

40 H H H C H H H C H H H C C C C C C H H H H C O O H N O O a-TS2 C C N O O I C H H H C C H H H C H H H N C C C C C C H H H H C O O H N O O C C C C C C H H H H C O O H N O O C C C C C C H H H H S40

41 H C H H a-TS2' C C N O O I C C C C C C H H H H C O O H N O O C C C C C C H H H H H C H H N C C H H H C H H H C H H H C C C C C C H H H H C O O H N O O a-F C C N O O I C H H H C C H H H C H H S41