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

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, 35392 Giessen, Germany; prs@org.chemie.uni-giessen.de Contents General Information... S1 Design of experiments analysis... S2 Iodine activity of compounds 1 3... 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%, 0.353 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 (0.040 0.063 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 0.250 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

standard 90 250 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) = (33+13+38+39)/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 (%) 1 0.17 1.7 18 1.5 0.17 1.7 27 2 0.17 1.7 33 2 0.08 1.7 13 2 0.25 1.7 38 2 0.34 1.7 39 2 0.17 3.4 60 2 0.17 6.8 69 5 (equiv) yield (%) slope 4 (equiv) yield (%) slope dilution (ml) yield (%) slope 1.7 28 16 0.08 13 10 1 18 4.5 3.4 60 0.17 33 1.5 27 6.8 69 4.5 0.25 38 2.5 2 33 3 S2

dilution/4 yield (%) slope dilution/5 yield (%) slope 2/0.17 54 7.5 2/1.7 31 14.6 2/0.34 39 2/3.4 60 4/5 yield (%) slope 0.17/1.7 26 6 0.25/1.7 38 Table S2. Relative relations dilution/4 dilution/5 4/5 5 4 dilution 1.3 2.4 1.0 1.8 1.0 1.2 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, 0.006 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 1 8 2 o-no2c6h4co2h 9.0 69 3 NH4Cl 10.5 56 b 4 PhCO2H 11.1 63 a Yield determined by 1 H NMR with DMT as internal standard; b 3 h. S3

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 3.98. 10-9 1.99. 10-9 3-ITMH 3.16. 10-9 1.99. 10-9 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 I2 2 24 I2 o-no2c6h4co2h (0.36) 3 3 2 8 4 3 2 I2 (0.1) 13 a Yield determined by 1 H NMR with DMT as internal standard. S4

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, 0.0625 mmol, 0.17 equiv), o-nitrobenzoic acid (22.7 mg, 0.136 mmol, 0.36 equiv) was diluted in CH2Cl2 (2 ml) and stirred for 1 min at 25 C. Subsequently DIH (143 mg, 0.375 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 25 27 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, 0.0625 mmol, 0.17 equiv), o-nitrobenzoic acid (22.7 mg, 0.136 mmol, 0.36 equiv) was diluted in CH2Cl2 (2 ml) and stirred for 1 min at 25 C. Subsequently 3-ITMH (94%, 100 mg, 0.375 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 25 27 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

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, 0.454 mmol, 60%) as a colorless solid below rt (22 23 C), Rf = 0.24; m.p. at rt (Lit. 4 23 24 C); 1 H NMR (400 MHz, CDCl3): δ = 7.40 7.36 (m, 2 H), 7.32 7.21 (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, 0.235 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, 0.361 mmol, 48%) as a colorless solid, Rf = 0.27; m.p. 57 58 C; 1 H NMR (400 MHz, CDCl3): δ = 7.95 (dd, 1 H, J = 7.7, 1.2 Hz, CHCCO2CH3), 7.47 7.40 (m, 2 H, CH2CCHCHCH), 7.35 7.30 (m, 1 H, CHCHCCH2), 4.93 (s, 2 H, CH2), 3.95 (s, 3 H, CH3) ppm; 13 C NMR (100 MHz, CDCl3): δ = 167.2 (CO), 141.4 (CCH2), 132.8 (CHAr), 131.7 (CHCCO), 131.4 (CHAr), 128.4 (CCO), 128.1 (CHCHCCH2), 52.4 (CH3), 4.1 (CH2) ppm; HRMS (ESI) calculated for C9H9INaO2 ([M+Na] + ): 298.9545. Found: 298.9551; elemental analysis calcd (%) for C9H9IO2 (276.1): C 39.16, H 3.29. Found: C 39.41, H 3.25. According to P2. 5 The residue was purified by flash column chromatography (silica gel, hexane/etoac 24:1) giving 8 (53.5 mg, 0.194 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, 0.384 mmol, 51%) as a colorless solid, Rf = 0.22; m.p. 51 52 C (Lit. 6 52 53 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 = 166.6 (CO), 139.9 (CCH2), 133.3 (CHCHCCH2), 130.9 (CCO), 129.8 (CCHC), 129.1 (COCCHCH), 52.4 (CH3), 4.3 (CH2) ppm; HRMS (ESI) calculated for C9H9INaO2 ([M+Na] + ): 298.9545. Found: 298.9545; elemental analysis calcd (%) for C9H9O2 (276.1): C 39.16, H 3.29. Found: C 39.19, H 3.12. According to P2. 5 The residue was purified by flash column chromatography (silica gel, hexane/etoac 24:1) giving 9 (53.2 mg, 0.192 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, 0.485 mmol, 65%) as a colorless solid, Rf = 0.14; m.p. 72 73 C (Lit. 7b 73 74 C); 1 H S6

NMR (400 MHz, CDCl3): δ = 7.98 7.94 (m, 2 H), 7.45 7.41 (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, 0.228 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, 0.503 mmol, 67%) as a colorless oil, Rf = 0.26; 1 H NMR (400 MHz, CDCl3): δ = 7.44 7.38 (m, 1 H), 7.37 7.32 (m, 1 H), 7.24 7.18 (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, 0.224 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, 0.368 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), 7.27 7.20 (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, 0.207 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, 0.368 mmol, 49%) as a colorless solid, Rf = 0.31; m.p. 60 61 C (Lit. 4 61 62 C); 1 H NMR (400 MHz, CDCl3): δ = 7.34 7.30 (m, 2 H), 7.29 7.25 (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, 0.224 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, 0.266 mmol, 35%) as a colorless solid, Rf = 0.21; m.p. 140 142 C (Lit. 7b 140 144 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, 0.177 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, 0.517 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 = 150.5 (CCHI), 132.7 (CHAr), 127.5 (CHAr), 118.7 (CN), 111.6 (CCN), 28.3 (CH3), 22.5 (CH) ppm; HRMS (ESI) calculated for C9H8INNa ([M+Na] + ): 279.9594. Found: 279.9593; elemental analysis calcd (%) for C9H8IN (257.1): C 42.05, H 3.14, N 5.45. Found: C 42.09, H 3.18, N 5.50. S7

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, 0.208 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, 0.277 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 = 143.5 (q, J = 1.3 Hz), 130.1 (q, J = 33.6 Hz), 129.2, 126.0 (q, J = 3.8 Hz), 124.1 (q, J = 273.1 Hz), 3.31 ppm. According to P2. The residue was purified by flash column chromatography (silica gel, hexane) giving 16 (68.1 mg, 0.238 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, 0.459 mmol, 61%) as a colorless solid, Rf = 0.24; m.p. 127.4 C (Lit. 4 125 126 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, 0.253 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, 0.299 mmol, 40%) as a colorless solid, Rf = 0.23; m.p. 34 C (Lit. 12 34-35 C); 1 H NMR (400 MHz, CDCl3): δ = 7.38 7.32 (m, 2 H, CHAr), 7.02 6.95 (m, 2 H, CHAr), 4.44 (s, 2 H, CH2) ppm; 13 C NMR (100 MHz, CDCl3): δ = 162.3 (d, J = 247.6 Hz, CF), 135.3 (d, J = 3.4 Hz, CCH2), 130.6 (d, J = 8.3 Hz, CHCCH2I), 115.9 (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, 0.240 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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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 298.15 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 4.88 2.41 1.92 F 4.88 2.41 1.92 Cl 5.07 2.60 1.73 CO2Me 5.35 2.88 1.45 CF3 5.40 2.93 1.40 CN 5.59 3.12 1.21 NO2 5.81 3.34 0.99 S25

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 1.825 1.839 2.144 2.707 2.499 2.996 3.445 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 0.118216 0.127949 0.128893 0.081583-625.339664-625.211714-625.210770-625.258080 HAdi 0.237848 0.258442 0.259387 0.183958-1250.718037-1250.459595-1250.458650-1250.534079 3 0.153694 0.165734 0.166678 0.114026-505.455138-505.289404-505.288460-505.341112 4 0.119432 0.128890 0.129834 0.084568-588.277539-588.148649-588.147705-588.192971 5 0.128171 0.134364 0.135308 0.097678-271.597145-271.462782-271.461837-271.499467 6 0.118944 0.126169 0.127113 0.084415-282.383546-282.257378-282.256433-282.299131 7 0.107513 0.116246 0.117190 0.072770-587.644224-587.527978-587.527034-587.571454 20 0.114887 0.120556 0.121501 0.085218-270.943597-270.823041-270.822097-270.858379 21 0.149181 0.159459 0.160403 0.113584-493.963893-493.804435-493.803491-493.850310 22 0.164761 0.175230 0.176174 0.129182-494.700424-494.525193-494.524249-494.571242 A 0.236824 0.252892 0.253836 0.191854-859.260220-859.007328-859.006384-859.068366 TS1 0.231788 0.247229 0.248173 0.187797-859.233027-858.985799-858.984854-859.045231 B 0.269869 0.288721 0.289665 0.218573-776.411964-776.123244-776.122299-776.193391 TS2 0.270763 0.289493 0.290437 0.218429-776.400254-776.110761-776.109817-776.181825 C 0.271808 0.291028 0.291972 0.219522-776.410014-776.118986-776.118042-776.190492 D 0.279263 0.297350 0.298294 0.231430-765.621197-765.323847-765.322902-765.389766 TS3 0.277745 0.294623 0.295567 0.231943-765.619000-765.324377-765.323433-765.387057 a-e 0.273126 0.296713 0.297657 0.215305-1130.818736-1130.522023-1130.521079-1130.603431 a-e' 0.273208 0.296763 0.297707 0.215527-1130.817887-1130.521124-1130.520180-1130.602360 a-ts2 0.390683 0.420680 0.421624 0.322777-1401.778669-1401.357989-1401.357045-1401.455892 a-ts2' 0.390939 0.420583 0.421527 0.324832-1401.782494-1401.361911-1401.360967-1401.457662 a-f 0.391550 0.421879 0.422823 0.324471-1401.788945-1401.367067-1401.366122-1401.464474 a-g 0.399460 0.428483 0.429428 0.336765-1390.996595-1390.568111-1390.567167-1390.659830 a-ts3 0.398403 0.426242 0.427186 0.337926-1390.994944-1390.568702-1390.567758-1390.657019 2a-E 0.393585 0.427929 0.428874 0.323673-1756.205471-1755.777541-1755.776597-1755.881797 2a-E' 0.393236 0.427855 0.428799 0.319183-1756.190785-1755.762930-1755.761985-1755.871602 2a-TS2 0.510850 0.551584 0.552528 0.433242-2027.168019-2026.616436-2026.615491-2026.734777 2a-TS2 0.510321 0.551475 0.552420 0.425572-2027.151168-2026.599692-2026.598748-2026.725596 2a-F 0.512361 0.553495 0.554439 0.434232-2027.172160-2026.618665-2026.617721-2026.737928 2a-F' 0.511449 0.553078 0.554022 0.426590-2027.157842-2026.604764-2026.603819-2026.731252 2a-G 0.519684 0.560177 0.561122 0.439617-2016.369396-2015.809218-2015.808274-2015.929779 S26

2a-G' 0.518899 0.559234 0.560178 0.439605-2016.363534-2015.804300-2015.803356-2015.923929 2a-TS3 0.518683 0.558136 0.559080 0.442938-2016.365377-2015.807242-2015.806298-2015.922440 2a-TS3' 0.518443 0.557650 0.558594 0.441003-2016.361399-2015.803749-2015.802805-2015.920396 p-cl-c 6H 4CH 3 0.105402 0.112236 0.113180 0.073450-730.539031-730.426795-730.425851-730.465581 p-meo 2C- C 6H 4CH 3 0.130338 0.138745 0.139689 0.096256-459.527032-459.388287-459.387343-459.430777 p-f 3C- C 6H 4CH 3 0.119821 0.129055 0.129999 0.083350-607.983999-607.854944-607.854000-607.900650 p-nc-c 6H 4CH 3 0.113699 0.121108 0.122052 0.081249-363.189345-363.068238-363.067294-363.108096 p-o 2N- C 6H 4CH 3 0.117898 0.125968 0.126912 0.084021-475.448335-475.322367-475.321423-475.364314 p-f-c 6H 4CH 3 0.106739 0.113213 0.114157 0.075737-370.175002-370.061789-370.060845-370.099265 S27

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

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

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

Cartesian coordinates of all computed structures at the B3LYP-D3/6-31G(d,p) level of theory HA (C1) C 2.159002-1.673021 0.015247 C 0.771344-1.820582 0.024086 C -0.066528-0.701736 0.018815 C 0.530418 0.564298-0.014479 C 1.910295 0.727946-0.008010 C 2.729006-0.400493 0.006958 H 2.792649-2.553879 0.020820 H 0.323691-2.807337 0.051438 H 2.318369 1.730729-0.030246 H 3.807351-0.281953 0.002283 C -1.539617-0.890145 0.209283 O -2.211299-0.283437 1.010025 O -2.017730-1.890527-0.563308 H -2.959043-1.978349-0.335841 N -0.288680 1.779581-0.156512 O 0.136930 2.806446 0.367626 O -1.311123 1.692033-0.829877 HAdi (C2) C 5.207494-1.775896-1.272949 C 3.831217-1.603204-1.122298 C 3.321991-0.534023-0.379778 C 4.234311 0.341534 0.222472 C 5.606915 0.192078 0.068063 C 6.094943-0.875152-0.685280 H 5.583609-2.611253-1.854306 H 3.133402-2.286977-1.591429 H 6.268600 0.900077 0.551453 H 7.165773-1.004406-0.801877 C 1.846319-0.294210-0.376429 O 1.384854 0.839383-0.519591 O 1.138699-1.395334-0.291689 H 0.150641-1.185430-0.373100 N 3.777302 1.406541 1.131290 O 2.821646 1.153340 1.857870 O 4.420706 2.453750 1.132098 C -5.208383 1.775716-1.272192 C -3.832003 1.603426-1.122005 C -3.322196 0.534293-0.379820 C -4.234062-0.341744 0.222480 C -5.606752-0.192685 0.068531 C -6.095356 0.874582-0.684421 H -5.584941 2.611040-1.853308 H -3.134529 2.287410-1.591324 H -6.268101-0.901007 0.551920 H -7.166264 1.003497-0.800687 C -1.846522 0.294808-0.376833 O -1.384904-0.838894-0.518698 O -1.138976 1.396123-0.293678 H -0.150940 1.186053-0.374925 N -3.776566-1.406836 1.130992 O -2.821695-1.153033 1.858375 O -4.419067-2.454597 1.130857 3 (Cs) C -0.606500 1.238884-0.000168 C -0.667649-1.105649-0.000129 N 0.134426 0.014967-0.000177 O -0.331759-2.269044-0.000122 O -0.128883 2.353028-0.000070 I 2.193436-0.030359 0.000024 C -2.992120 1.846194 0.000062 H -2.533518 2.835302 0.000795 H -3.621213 1.745560-0.891089 H -3.621576 1.744390 0.890818 C -2.118972-0.580314-0.000015 C -2.828418-1.068700 1.269520 H -3.870118-0.734774 1.279219 H -2.810880-2.160391 1.298276 H -2.328452-0.686026 2.163283 C -2.828985-1.069100-1.269041 H -2.811592-2.160804-1.297420 H -3.870647-0.735037-1.278405 H -2.329369-0.686802-2.163160 N -1.922106 0.871868-0.000312 4 (Cs) C 2.884141 0.699963-0.005265 C 1.684081 1.423220 0.001680 C 0.501894 0.699697 0.003183 C 0.501893-0.699698 0.003181 C 1.684079-1.423224 0.001638 C 2.884140-0.699968-0.005288 H 3.830236 1.232000-0.011681 H 1.670164 2.507838 0.002277 H 1.670161-2.507841 0.002240 H 3.830234-1.232005-0.011710 S31

C -0.909376 1.185051 0.009966 O -1.347056 2.312430-0.016641 O -1.347066-2.312424-0.016657 N -1.672353 0.000004 0.081913 C -0.909377-1.185051 0.010091 O -3.029329-0.000004-0.142737 H -3.435557 0.000013 0.738656 5 (Cs) C -1.200227 1.205122 0.002240 C 0.194727 1.202408-0.009201 C 0.913010 0.000243-0.012043 C 0.195017-1.202252-0.009198 C -1.199807-1.205347 0.002238 C -1.903392-0.000162 0.008635 H -1.737860 2.148950 0.001831 H 0.735784 2.145299-0.017968 H 0.736360-2.144996-0.017983 H -1.737239-2.149290 0.001824 H -2.989233-0.000360 0.014282 C 2.422373 0.000106 0.009599 H 2.802786-0.012765 1.038684 H 2.829691-0.879453-0.498060 H 2.829504 0.891903-0.476235 6 (Cs) C 3.045856 1.208357-0.273760 C 1.787106 1.207865 0.322395 C 1.145153 0.000054 0.629738 C 1.787048-1.207817 0.322506 C 3.045796-1.208424-0.273650 C 3.678149-0.000062-0.573888 H 3.533912 2.150311-0.504478 H 1.291328 2.147692 0.549191 H 1.291221-2.147599 0.549385 H 3.533805-2.150423-0.504286 H 4.658959-0.000109-1.039442 C -0.188580 0.000119 1.278920 H -0.388651-0.894479 1.863502 H -0.388639 0.894826 1.863340 I -1.874247-0.000015-0.214543 7 (C2v) C 2.844262 0.699996-0.015549 C 1.643341 1.424360-0.002210 C 0.461804 0.700176 0.006708 C 0.461803-0.700175 0.006713 C 1.643336-1.44366-0.002185 C 2.844259-0.700007-0.015531 H 3.789689 1.232564-0.026574 H 1.633905 2.508928-0.001182 H 1.633893-2.508934-0.001139 H 3.789685-1.232578-0.026543 C -0.948167 1.181640 0.022312 O -1.392731 2.309823-0.006217 O -1.392744-2.309811-0.006235 N -1.710641 0.000005 0.096021 C -0.948169-1.181632 0.022295 O -3.075463-0.000009-0.081552 20 (C2v) C 1.132944 1.211727 0.000009 C -0.252266 1.218059 0.000051 C -0.994175 0.000005-0.000026 C -0.252276-1.218054 0.000046 C 1.132934-1.211732 0.000006 C 1.838410-0.000006-0.000050 H 1.675814 2.152544 0.000038 H -0.794859 2.159325 0.000163 H -0.794874-2.159316 0.000151 H 1.675796-2.152554 0.000033 H 2.923818-0.000011-0.000166 C -2.399850 0.000001-0.000069 H -2.960012-0.928432 0.000036 H -2.960001 0.928439-0.000058 21 (C1) C -1.317835 0.793794 0.143339 C 1.018189 1.000968 0.211866 N -0.187372 1.684350-0.374506 O 2.135209 1.471310 0.107234 O -2.479521 1.140673 0.126231 C -1.646795-1.640742-0.084146 H -2.682084-1.298800-0.084871 H -1.438820-2.264680-0.960094 H -1.508922-2.244949 0.822948 C 0.663206-0.495805-0.012502 C 1.230448-1.224784 1.222435 H 0.996877-2.295730 1.230794 H 2.317150-1.119308 1.248399 H 0.818124-0.782147 2.133430 C 1.229890-1.063225-1.312778 H 2.308076-0.882720-1.342011 H 1.039511-2.139166-1.328930 S32

H 0.767363-0.601468-2.189762 N -0.801971-0.468368 0.030663 22 (Cs) C 1.326238-0.740936-0.000150 C -1.006117-0.987298-0.000111 N 0.209872-1.635738-0.000159 O -2.115516-1.472626-0.000104 O 2.493328-1.068559-0.000052 C 1.615956 1.703665 0.000080 H 2.656596 1.378521 0.000813 H 1.433817 2.314165-0.891071 H 1.432610 2.314372 0.890836 C -0.675335 0.520316 0.000003 C -1.252409 1.159707 1.269538 H -1.057754 2.236162 1.279237 H -2.332405 0.999378 1.298294 H -0.807565 0.714151 2.163301 C -1.252879 1.160217-1.269023 H -2.332907 1.000030-1.297402 H -1.058084 2.236652-1.278387 H -0.808455 0.714958-2.163142 N 0.790122 0.515288-0.000294 H 0.318958-2.629771-0.000062 A C 0.055480 2.550198-0.247198 C 1.211976 2.003560-0.808443 C 2.077316 1.206865-0.042739 C 1.748361 0.971755 1.297992 C 0.595605 1.514509 1.862446 C -0.256333 2.311466 1.090954 H -0.604870 3.162683-0.857372 H 0.357673 1.311206 2.905749 H -1.158056 2.733272 1.528759 C -1.050311-0.609566-0.913373 C -1.332197-0.855213 0.437842 C -2.503590-0.405330 1.024413 C -3.403986 0.302236 0.218230 C -3.126239 0.543804-1.134731 C -1.940516 0.088404-1.719350 C 0.265506-1.183236-1.267580 C -0.209368-1.595406 1.051658 H -2.705158-0.590751 2.073531 H -4.332914 0.667372 0.645804 H -3.841933 1.099602-1.732409 H -1.712361 0.275341-2.762240 O -0.043392-1.993644 2.175812 O 0.876531-1.195266-2.308155 N 0.737107-1.792642-0.032606 O 1.852200-2.366705 0.090382 H 2.400978 0.340168 1.903230 H 1.443267 2.186669-1.853531 C 3.307299 0.584319-0.657529 H 3.630446 1.147440-1.567449 H 4.153279 0.565758 0.078026 H 3.093178-0.475537-0.953729 TS1 C 0.375352 2.230469-1.210133 C 1.526318 1.453945-1.213616 C 2.128092 1.042820 0.000116 C 1.526471 1.453630 1.214028 C 0.375509 2.230164 1.210890 C -0.208632 2.620066 0.000466 H -0.078720 2.524263-2.151232 H -0.078441 2.523720 2.152123 H -1.119149 3.210528 0.000600 C -1.242446-0.778097-0.699454 C -1.242546-0.778398 0.699180 C -2.316940-0.283921 1.422039 C -3.406558 0.218894 0.700152 C -3.406455 0.219199-0.700310 C -2.316733-0.283305-1.422256 C 0.056879-1.318491-1.185457 C 0.056723-1.318973 1.185140 H -2.300570-0.284325 2.506618 H -4.264919 0.616982 1.232326 H -4.264738 0.617519-1.232437 H -2.300206-0.283242-2.506832 O 0.473520-1.445201 2.313936 O 0.473838-1.444254-2.314246 N 0.761554-1.654938-0.000182 O 2.018703-2.087103-0.000190 H 1.957731 1.121581 2.153001 H 1.957464 1.122142-2.152728 C 3.266436 0.145140-0.000067 H 3.856761 0.102472-0.914843 H 3.856749 0.102097 0.914697 H 2.689861-1.095561-0.000325 B C -2.341211-1.176445-0.292437 C -2.255107 1.105428 0.171002 S33

N -1.548515-0.072370 0.129267 O -1.865316 2.208320 0.494641 O -1.959191-2.323494-0.408916 I 0.478847-0.262583 0.640856 C -4.681903-1.509113-0.991770 H -4.300861-2.527748-1.071347 H -5.520188-1.496172-0.286003 H -5.044764-1.186548-1.974499 C -3.690216 0.762959-0.288001 C -4.008354 1.549024-1.566533 H -5.031006 1.347160-1.899118 H -3.908827 2.618738-1.369010 H -3.318100 1.275111-2.369045 C -4.673626 1.098962 0.840010 H -4.585121 2.157522 1.094596 H -5.703049 0.898160 0.528196 H -4.455198 0.504844 1.731534 N -3.593953-0.676430-0.531040 C 4.878069-0.662551-1.642978 C 4.234607-1.108528-0.501641 C 3.887892-0.201733 0.542611 C 4.222257 1.173297 0.368323 C 4.866018 1.606432-0.777800 C 5.198430 0.694970-1.790665 H 5.133614-1.366880-2.428605 H 3.977693-2.157632-0.389269 H 3.956021 1.878971 1.149598 H 5.111995 2.657394-0.894192 H 5.700562 1.040166-2.688792 C 3.217859-0.647290 1.701460 H 3.031852 0.028392 2.528886 H 3.041541-1.704029 1.868851 TS2 C -2.753265-1.177589-0.304065 C -2.327510 1.062018-0.190698 N -1.871037-0.137973-0.662390 O -1.733887 2.117975-0.063233 O -2.530245-2.370869-0.405704 I 0.702867-0.550430-0.217184 C -5.123934-1.348341 0.391175 H -4.863602-2.404135 0.304728 H -5.518541-1.158686 1.395728 H -5.905037-1.109811-0.341699 C -3.841185 0.868639 0.136704 C -4.669093 1.488153-0.999532 H -5.739392 1.363974-0.806081 H -4.452778 2.557098-1.071516 H -4.427004 1.015509-1.955013 C -4.183247 1.495457 1.488990 H -3.924271 2.556260 1.472003 H -5.252250 1.399516 1.703919 H -3.620022 1.012675 2.292080 N -3.917697-0.590561 0.157929 C 5.657872-0.768725 0.551054 C 4.357346-0.623437 1.025378 C 3.549981 0.435226 0.578203 C 4.069528 1.336892-0.364862 C 5.370058 1.190816-0.837978 C 6.167163 0.137542-0.382065 H 6.274700-1.587638 0.907742 H 3.957777-1.330892 1.746728 H 3.444992 2.149504-0.724866 H 5.763381 1.896762-1.562731 H 7.180907 0.023257-0.753193 C 2.172895 0.594447 1.088713 H 1.778477 1.605687 1.028507 H 2.005250 0.160019 2.071055 C C -1.987953-0.415024-1.117885 C -1.462291 0.738883 0.774599 N -0.948558 0.054090-0.282289 O -0.889225 1.116442 1.792458 O -1.871607-1.194470-2.046143 I 0.803775-1.945597 0.129540 C -4.384867 0.108577-1.454835 H -4.232242-0.632580-2.240306 H -5.217283-0.210141-0.817684 H -4.646026 1.069723-1.915542 C -2.947245 1.060034 0.456044 C -3.059055 2.550087 0.098836 H -4.094589 2.813043-0.138702 H -2.733320 3.156418 0.947794 H -2.430654 2.785929-0.764417 C -3.842558 0.695725 1.642352 H -3.514023 1.246612 2.526455 H -4.886320 0.953393 1.437155 H -3.782081-0.374696 1.856354 N -3.158637 0.187874-0.696424 C 4.533555 1.301797-0.795546 C 3.885862 0.355585-0.008089 C 2.604702 0.614507 0.503717 C 1.980044 1.836718 0.210745 S34

C 2.632563 2.783262-0.575657 C 3.906009 2.517756-1.082318 H 5.525133 1.095168-1.186177 H 4.366630-0.594438 0.209857 H 0.993766 2.031036 0.617029 H 2.147045 3.729363-0.794396 H 4.410986 3.255813-1.698238 C 1.918448-0.367262 1.363188 H 1.088605 0.041668 1.935251 H 2.578043-1.003054 1.949529 D C 1.596198 0.510391-1.193586 C 1.231550 1.138433 0.939672 N 1.516225 1.605995-0.356204 O 0.894885 1.816671 1.893810 O 1.623997 0.532716-2.413855 C -2.923784-1.134882-1.047303 C -2.478760 0.163173-1.296573 C -1.988076 0.971685-0.259386 C -1.941378 0.434088 1.036858 C -2.387051-0.863638 1.289122 C -2.882280-1.653596 0.249268 H -3.305859-1.740575-1.863722 H -2.517601 0.562604-2.306380 H -1.546301 1.041729 1.844734 H -2.361264-1.253573 2.303016 H -3.235740-2.661146 0.446652 C -1.516311 2.372769-0.530934 H -1.631848 3.012680 0.346903 H -2.052214 2.818907-1.373603 H -0.443155 2.393958-0.785311 C 1.720548-0.788918-0.359651 N 1.378723-0.248757 0.948253 C 3.181524-1.269642-0.423103 H 3.313536-2.164187 0.193315 H 3.436325-1.519650-1.455544 H 3.863780-0.492642-0.068793 C 0.749899-1.872849-0.828194 H 0.953405-2.099492-1.877011 H 0.881625-2.789748-0.245483 H -0.284664-1.540627-0.737355 C 1.169156-1.036726 2.135573 H 1.082202-0.346091 2.975366 H 0.240251-1.613529 2.052340 H 2.004417-1.726105 2.296323 TS3 C 1.144936-0.281358-1.343105 C 1.228064 1.432723 0.143755 N 1.132666 1.097301-1.229976 O 0.997704 2.531308 0.621644 O 0.788150-0.943473-2.300417 C -2.870325-1.484680-0.121532 C -2.419950-0.537317-1.036721 C -1.961348 0.720591-0.602143 C -1.929326 0.985668 0.781545 C -2.373142 0.034430 1.695131 C -2.852548-1.200909 1.247200 H -3.230359-2.446734-0.472860 H -2.415697-0.763104-2.098533 H -1.535538 1.936705 1.125316 H -2.349849 0.255519 2.758052 H -3.204232-1.939966 1.960727 C -1.447878 1.713723-1.568014 H -1.546908 2.749873-1.239132 H -1.805202 1.569934-2.589593 H -0.277933 1.578589-1.648284 C 1.709857-0.875193-0.026799 N 1.611426 0.302259 0.832922 C 3.165768-1.310255-0.256723 H 3.597644-1.704180 0.668683 H 3.198529-2.097068-1.014615 H 3.773350-0.467746-0.597156 C 0.842748-2.035495 0.463268 H 0.781267-2.790889-0.322988 H 1.278015-2.496617 1.355557 H -0.167686-1.694768 0.695619 C 1.867454 0.310841 2.252689 H 1.780058 1.343482 2.592376 H 1.132137-0.303145 2.786363 H 2.871079-0.066105 2.478717 a-e' C 3.648407-0.896426-0.137981 C 2.352615 1.029976 0.034984 N 2.330907-0.322795-0.128415 O 1.415669 1.814678 0.084468 O 3.895760-2.074584-0.266141 I 0.609162-1.452209-0.264996 C 5.945126-0.029380 0.059353 H 6.143747-1.095430-0.053452 H 6.435420 0.513374-0.756011 H 6.361255 0.312016 1.013244 S35

C 3.829718 1.440937 0.151446 C 4.065590 2.084747 1.525030 H 5.106690 2.405511 1.622051 H 3.419019 2.958164 1.633516 H 3.838720 1.378000 2.327498 C 4.180744 2.401618-0.992645 H 3.536954 3.282240-0.939448 H 5.222532 2.724904-0.913257 H 4.036142 1.917905-1.962346 N 4.509510 0.150790 0.020287 C -5.506575 2.196537-0.576029 C -4.128241 2.204637-0.356428 C -3.455630 1.036141 0.008918 C -4.207266-0.138986 0.122304 C -5.583467-0.163040-0.073793 C -6.236218 1.016841-0.426748 H -6.011158 3.115331-0.857201 H -3.559248 3.122734-0.450109 H -6.115523-1.100439 0.033208 H -7.308172 1.008953-0.593423 C -2.014679 1.099795 0.429830 O -1.627792 0.621044 1.474678 O -1.265914 1.779344-0.437967 H -0.322238 1.759826-0.137990 N -3.545455-1.428605 0.364018 O -4.129344-2.247541 1.065450 O -2.472779-1.621954-0.210756 a-ts2 C -2.548040-2.439805-0.954390 C -2.345302-1.361287 1.032364 N -1.738311-2.223751 0.129160 O -1.780469-0.817139 1.998128 O -2.292244-3.004496-2.000188 I 0.794170-2.030237-0.026118 C -1.495849 5.724248-0.115764 C -1.846285 4.393420 0.108121 C -0.883876 3.380279 0.084569 C 0.434627 3.751010-0.204019 C 0.806702 5.076002-0.419433 C -0.167488 6.068963-0.371355 H -2.261293 6.493065-0.088340 H -2.874021 4.116167 0.313477 H 1.842852 5.301105-0.638729 H 0.108652 7.103194-0.546826 C -1.353216 1.991129 0.432830 O -2.364928 1.532440-0.068464 O -0.633069 1.420717 1.384997 H -1.059924 0.535740 1.639547 N 1.471237 2.732537-0.380653 O 2.636929 3.049601-0.142582 O 1.117823 1.626753-0.791510 C 5.722708-2.238216 0.400945 C 4.463893-2.038642 0.956006 C 3.659041-0.965553 0.529333 C 4.137558-0.103814-0.475210 C 5.399758-0.306527-1.024048 C 6.192917-1.373056-0.592063 H 6.339204-3.065095 0.739421 H 4.091585-2.711361 1.723697 H 3.518062 0.725552-0.796538 H 5.767626 0.368648-1.790365 H 7.175762-1.529918-1.026043 C 2.333662-0.743256 1.123240 H 1.913716 0.246862 0.983488 H 2.203393-1.120107 2.133701 N -3.658017-1.226532 0.705237 C -3.942720-1.841819-0.595561 C -4.337584-0.804033-1.650886 H -4.330490-1.277988-2.635031 H -5.343465-0.418187-1.455480 H -3.634599 0.031809-1.646458 C -4.963475-2.978125-0.488416 H -5.954258-2.582602-0.242050 H -5.024580-3.503191-1.444777 H -4.668363-3.690776 0.286253 C -4.539448-0.301224 1.382504 H -4.103758-0.085670 2.358379 H -4.630632 0.637000 0.826005 H -5.528667-0.748647 1.519066 a-ts2' C -3.308256-1.568029-1.042012 C -2.748553-0.356738 0.812332 N -2.282138-1.061646-0.216875 O -2.131234 0.159678 1.756603 O -3.149985-2.285878-2.013145 I 0.107266-1.921604-0.334659 C -5.764788-1.304510-1.183120 H -5.589905-1.985553-2.017267 H -6.494623-1.756035-0.501378 H -6.180883-0.366737-1.571462 C -4.283524-0.244823 0.643417 C -4.635693 1.223975 0.373666 S36

H -5.713504 1.333165 0.216662 H -4.341604 1.830642 1.232963 H -4.097642 1.595255-0.500279 C -4.989849-0.783856 1.891058 H -4.668013-0.215835 2.766779 H -6.075435-0.686631 1.790152 H -4.747363-1.838608 2.047025 N -4.495476-1.098584-0.526845 C 0.752875 5.969325-0.278365 C -0.066235 4.850110-0.136090 C 0.474367 3.563559-0.055618 C 1.865913 3.444589-0.154514 C 2.702710 4.550864-0.279922 C 2.139489 5.822634-0.340357 H 0.307597 6.957358-0.335657 H -1.143880 4.950323-0.074935 H 3.772268 4.395726-0.348433 H 2.780883 6.690827-0.448501 C -0.496805 2.442456 0.215985 O -1.587719 2.418637-0.321906 O -0.076193 1.603641 1.154510 H -0.831811 0.966435 1.381373 N 2.500945 2.127485-0.224028 O 3.629761 2.006655 0.254500 O 1.882951 1.228498-0.793236 C 4.452393-4.113737 0.610334 C 3.301425-3.462948 1.039428 C 3.047669-2.134708 0.649763 C 3.964292-1.475151-0.189711 C 5.116507-2.130786-0.612314 C 5.361879-3.448804-0.218195 H 4.643979-5.136524 0.919275 H 2.588358-3.976529 1.678526 H 3.766746-0.450344-0.482505 H 5.826159-1.613350-1.250248 H 6.260341-3.957700-0.553876 C 1.840575-1.437588 1.115304 H 1.860431-0.355711 1.040652 H 1.430514-1.790786 2.057286 a-f C -2.818797-2.253460-0.611122 C -2.037542-1.204958 1.221176 N -1.759664-2.166219 0.260663 O -1.198169-0.731067 2.013347 O -2.868406-2.811926-1.690137 I 0.530284-1.888127-1.190499 C -0.924263 5.845782-0.343794 C -1.355794 4.551134-0.055728 C -0.447867 3.493452 0.034669 C 0.902203 3.777148-0.205721 C 1.354774 5.064788-0.477408 C 0.431954 6.106161-0.544484 H -1.647673 6.652264-0.406201 H -2.404846 4.337735 0.115708 H 2.411518 5.225538-0.651726 H 0.771776 7.112226-0.766131 C -0.989841 2.157336 0.466144 O -2.042253 1.725902 0.027203 O -0.263546 1.595847 1.420118 H -0.676019 0.709645 1.691036 N 1.890234 2.696518-0.280547 O 3.038358 2.938970 0.086387 O 1.514580 1.624505-0.754903 C 4.807386-3.160455 1.109995 C 3.452356-2.844657 1.110047 C 3.018851-1.576892 0.690989 C 3.965186-0.631168 0.264597 C 5.321353-0.950292 0.268843 C 5.744751-2.213070 0.688147 H 5.134975-4.141769 1.439232 H 2.718565-3.578660 1.431396 H 3.630578 0.349742-0.057136 H 6.048530-0.211564-0.053927 H 6.802337-2.459533 0.688700 C 1.587664-1.222155 0.723432 H 1.386161-0.157154 0.702000 H 0.974631-1.731466 1.461319 N -3.358543-0.888515 1.191275 C -4.020817-1.500273 0.035709 C -4.564143-0.452167-0.938875 H -4.850542-0.946295-1.869810 H -5.445805 0.043717-0.519993 H -3.803652 0.302860-1.149391 C -5.088182-2.518140 0.451180 H -5.943246-2.013092 0.912056 H -5.438109-3.057911-0.432263 H -4.679971-3.238851 1.164655 C -3.951236 0.118666 2.041776 H -3.284136 0.270013 2.891285 H -4.059157 1.067824 1.507327 H -4.927663-0.215553 2.404999 a-g S37

C 4.161023-1.391224 0.319326 C 2.030612-1.128730 0.937253 N 3.311711-1.347108 1.408810 O 1.016971-1.019124 1.629881 O 5.376865-1.497271 0.368262 C -5.910820-1.546603 0.562638 C -4.563532-1.898018 0.652727 C -3.566753-1.011297 0.242699 C -3.967485 0.219421-0.288370 C -5.304431 0.596122-0.370231 C -6.282115-0.297842 0.060964 H -6.671680-2.247501 0.890515 H -4.264326-2.859414 1.055438 H -5.556823 1.564498-0.784643 H -7.329311-0.022946-0.006776 C -2.128397-1.396341 0.457403 O -1.684031-2.470712 0.095363 O -1.466357-0.462946 1.124061 H -0.504259-0.732543 1.268805 N -2.973073 1.127824-0.867081 O -3.168885 2.338281-0.758251 O -2.022959 0.620200-1.461310 C 1.541531 3.019925-1.097261 C 2.600147 2.725447-0.237249 C 2.367046 2.237934 1.058604 C 1.035436 2.075588 1.477134 C -0.022592 2.379725 0.627570 C 0.223694 2.844970-0.669510 H 1.745339 3.391104-2.097424 H 3.624216 2.886616-0.564661 H 0.836488 1.686400 2.470549 H -1.042887 2.238906 0.964191 H -0.612329 3.049751-1.328288 C 3.501891 1.882437 1.976554 H 3.378150 2.345446 2.961267 H 4.467264 2.191885 1.567371 H 3.546995 0.795703 2.151238 C 3.366947-1.325974-1.001895 N 2.047854-1.028869-0.454146 C 3.393853-2.708177-1.679818 H 2.789609-2.701131-2.591649 H 4.425036-2.953581-1.943671 H 3.008639-3.479213-1.007638 C 3.886889-0.231939-1.934566 H 4.940962-0.425506-2.144314 H 3.338692-0.226631-2.881146 H 3.788708 0.749226-1.468663 C 0.857728-0.783060-1.232001 H 0.107798-1.552847-1.016739 H 0.432386 0.192177-0.971048 H 1.109033-0.794943-2.291660 a-ts3 C -4.118585-0.776072-0.208651 C -2.020437-1.160001-0.925742 N -3.339780-0.945631-1.341902 O -1.041600-1.111451-1.679429 O -5.229932-0.286809-0.142687 C 5.961801-1.141279-0.674149 C 4.655277-1.598222-0.844253 C 3.572572-0.889174-0.318776 C 3.850129 0.273394 0.409840 C 5.146166 0.754082 0.576870 C 6.208267 0.039539 0.028393 H 6.787694-1.705705-1.094903 H 4.450091-2.507719-1.397819 H 5.301826 1.662225 1.145993 H 7.223327 0.398622 0.160881 C 2.189441-1.395495-0.628535 O 1.903832-2.574085-0.518170 O 1.396619-0.439482-1.085612 H 0.469729-0.789814-1.283317 N 2.779293 0.993658 1.107567 O 2.888197 2.217878 1.203750 O 1.862219 0.331330 1.586367 C -1.763646 2.864823 1.038117 C -2.668255 2.522945 0.036294 C -2.212496 2.116923-1.233670 C -0.824192 2.065822-1.464600 C 0.076437 2.408622-0.464747 C -0.386950 2.800062 0.794809 H -2.128866 3.178002 2.011862 H -3.737228 2.555828 0.227559 H -0.462413 1.726380-2.429754 H 1.140993 2.358272-0.655205 H 0.329447 3.033959 1.574478 C -3.161520 1.651310-2.266220 H -2.786359 1.754035-3.287265 H -4.166716 2.066698-2.165293 H -3.312982 0.512401-2.128982 C -3.337629-1.346140 1.005432 N -2.001696-1.427631 0.414330 C -3.903041-2.736317 1.340406 H -3.339954-3.189166 2.162250 S38

H -4.947341-2.640909 1.648169 H -3.849602-3.397595 0.471886 C -3.392210-0.407847 2.209147 H -4.436646-0.225374 2.471628 H -2.888747-0.854634 3.071854 H -2.914852 0.545725 1.977079 C -0.798629-1.769624 1.146987 H -0.125275-2.339422 0.503398 H -0.276750-0.868606 1.486960 H -1.063777-2.379123 2.013121 2a-E C -3.149054-0.543030-0.867662 C -2.742438-0.018230 1.350187 N -2.839399 0.476071 0.081907 O -2.419626 0.580117 2.366714 O -3.153514-0.379123-2.082570 I -2.306079 2.387664-0.473869 C -3.557066-2.952985-0.813404 H -4.308159-3.552222-0.292647 H -3.884290-2.777428-1.837885 H -2.598084-3.476377-0.834200 C -3.134776-1.499796 1.271311 C -4.381340-1.746046 2.129880 H -4.664218-2.801613 2.087733 H -4.166642-1.483843 3.168221 H -5.222635-1.142957 1.778487 C -1.940581-2.350434 1.725460 H -1.681023-2.077695 2.750987 H -2.204890-3.411229 1.705710 H -1.077192-2.188277 1.081430 N -3.424550-1.660535-0.162987 C 4.391502-0.281662 2.408224 C 2.997665-0.247580 2.421549 C 2.297307 0.630391 1.589939 C 3.038215 1.462828 0.746598 C 4.429525 1.435627 0.715760 C 5.109478 0.561570 1.558604 H 4.916527-0.968168 3.064804 H 2.436737-0.914038 3.065218 H 4.949599 2.104238 0.041909 H 6.194273 0.541499 1.552497 C 0.796722 0.560212 1.564921 O 0.167984 0.236106 0.577471 O 0.268243 0.818041 2.757289 H -0.716781 0.763346 2.678561 N 2.363567 2.449886-0.105747 O 1.274916 2.877258 0.269895 O 2.946798 2.808359-1.129856 C 3.620841-0.061403-2.420271 C 2.235086-0.154785-2.520903 C 1.523059-1.105945-1.781685 C 2.248063-1.945303-0.929383 C 3.627959-1.860871-0.808014 C 4.317595-0.916598-1.567502 H 4.150565 0.692391-2.991452 H 1.680896 0.518303-3.162567 H 4.149276-2.519170-0.122732 H 5.396089-0.843486-1.477492 C 0.039125-1.205849-1.872590 O -0.609402-2.025951-1.244360 O -0.492657-0.317370-2.710622 H -1.478219-0.375864-2.643614 N 1.589368-2.975350-0.099910 O 1.388924-4.064830-0.616307 O 1.369104-2.685702 1.075241 2a-E' C -0.339705 1.559769-0.930332 C 0.690780 1.610616 1.137432 N 0.054598 0.818298 0.147066 O 1.178389 1.174578 2.176446 O -0.920728 1.177683-1.935964 I -0.284300-1.200146 0.377386 C 7.362288 0.369130-0.902601 C 6.108950 0.812733-0.482331 C 5.127976-0.092656-0.069735 C 5.435007-1.457104-0.122179 C 6.685028-1.916532-0.524153 C 7.654468-0.995170-0.915081 H 8.111274 1.089326-1.215640 H 5.872089 1.870459-0.455971 H 6.869847-2.983407-0.541148 H 8.628699-1.345240-1.239680 C 3.845476 0.478839 0.460445 O 3.285182 1.414578-0.088738 O 3.472800-0.069469 1.606831 H 2.614765 0.342664 1.901213 N 4.406837-2.472738 0.152054 O 4.781983-3.538285 0.637157 O 3.252261-2.203780-0.169173 N 0.644965 2.890228 0.710787 C 0.091423 3.004501-0.648923 C 1.158707 3.421172-1.671550 S39

H 0.743815 3.325054-2.677397 H 1.442638 4.465602-1.512206 H 2.045566 2.791321-1.580538 C -1.141827 3.913798-0.683690 H -0.858740 4.940308-0.432952 H -1.566847 3.905345-1.689968 H -1.898795 3.556963 0.016469 C 1.457538 3.915980 1.336447 H 1.581430 3.652572 2.386744 H 2.444942 3.977674 0.867093 H 0.952366 4.881956 1.265370 C -7.301409 0.797142 0.812631 C -5.970689 1.093632 0.521131 C -5.112820 0.119414 0.003294 C -5.627476-1.169295-0.183796 C -6.957694-1.477447 0.082125 C -7.798903-0.486016 0.583394 H -7.950414 1.569648 1.212193 H -5.571878 2.089404 0.678576 H -7.305793-2.488675-0.088870 H -8.834806-0.721372 0.803991 C -3.731794 0.562054-0.382786 O -3.106559 1.373197 0.279002 O -3.335417 0.048609-1.541416 H -2.419529 0.372609-1.741355 N -4.757315-2.289404-0.575272 O -5.238645-3.144444-1.315385 O -3.630300-2.319728-0.088539 2a-TS2 C -3.749401 0.757530-0.545095 C -3.052336-0.236264 1.370471 N -2.942958 0.862305 0.598326 O -2.387271-0.546959 2.360155 O -3.699045 1.516467-1.518701 I -1.130776 2.373803 0.853554 C -5.341078-0.843181-1.494010 H -6.279580-1.272132-1.132442 H -5.560963-0.021660-2.176038 H -4.770108-1.605968-2.034466 C -4.220084-1.081769 0.812850 C -5.365134-1.099488 1.833640 H -6.206374-1.682763 1.446530 H -5.021524-1.557425 2.764324 H -5.711693-0.084433 2.044632 C -3.722128-2.494830 0.490486 H -3.328182-2.944830 1.404550 H -4.546911-3.114656 0.125690 H -2.930532-2.473770-0.257837 N -4.578975-0.307079-0.384772 C 2.816842-4.637631 1.221186 C 1.791086-3.732523 1.494399 C 2.023586-2.354439 1.464733 C 3.321451-1.922229 1.170008 C 4.352686-2.808003 0.877608 C 4.096374-4.177639 0.905809 H 2.612265-5.703105 1.243826 H 0.785240-4.077237 1.695464 H 5.336241-2.416752 0.647598 H 4.895314-4.879071 0.689133 C 0.863015-1.404602 1.548571 O 0.804183-0.397560 0.864455 O -0.066791-1.823052 2.391118 H -0.873694-1.238014 2.349735 N 3.667723-0.496165 1.196572 O 3.244072 0.179866 2.129166 O 4.401561-0.079880 0.298062 C 2.679443-0.157366-2.564746 C 1.343918 0.236216-2.578871 C 0.327796-0.678480-2.282247 C 0.700024-1.989241-1.970047 C 2.026404-2.395980-1.934288 C 3.022174-1.468850-2.237444 H 3.458253 0.562650-2.789535 H 1.067337 1.260932-2.793477 H 2.273457-3.415033-1.659522 H 4.063287-1.767811-2.197726 C -1.099945-0.259812-2.204714 O -1.974826-1.010274-1.798978 O -1.308430 0.993331-2.590322 H -2.238843 1.250046-2.329871 N -0.308351-3.020950-1.655821 O -0.832826-3.594889-2.598985 O -0.491340-3.277790-0.466977 C 3.288822 3.348840-1.334191 C 2.584433 2.702258-0.328001 C 1.818558 3.449369 0.593264 C 1.764198 4.854080 0.459028 C 2.465872 5.492870-0.554945 C 3.230765 4.742150-1.454550 H 3.894831 2.770849-2.024493 H 2.618972 1.624391-0.235302 H 1.168555 5.430908 1.161096 H 2.422650 6.573446-0.647520 S40

H 3.781514 5.242096-2.245384 C 1.099549 2.771425 1.654877 H 0.850909 3.363398 2.532084 H 1.393025 1.749043 1.865850 2a-TS2' C 0.535680-2.588923-0.735521 C -0.572086-2.344140 1.216709 N 0.133555-1.713765 0.201169 O -1.146530-1.766284 2.155833 O 1.169417-2.376165-1.773881 I 0.286976 0.801599 0.274671 C -7.336059-1.359253-0.836935 C -6.063540-1.747126-0.419529 C -5.047167-0.806597-0.230609 C -5.349578 0.532752-0.505869 C -6.618403 0.942250-0.906969 C -7.618286-0.012844-1.071819 H -8.108794-2.108813-0.973590 H -5.833526-2.787746-0.221272 H -6.794513 1.992885-1.101564 H -8.607469 0.294151-1.394397 C -3.747170-1.318952 0.330662 O -3.286946-2.387948-0.034074 O -3.256137-0.556900 1.294963 H -2.418132-0.994575 1.666250 N -4.306240 1.560700-0.471502 O -4.634324 2.697843-0.129542 O -3.174203 1.234586-0.824466 C 0.741586 5.628514 0.894974 C 0.431209 4.365232 1.383934 C -0.683225 3.663976 0.885331 C -1.471027 4.247466-0.124622 C -1.158094 5.514770-0.605015 C -0.052348 6.205591-0.101077 H 1.601816 6.163691 1.284204 H 1.051103 3.906686 2.149179 H -2.328728 3.703315-0.503832 H -1.775535 5.965996-1.375401 H 0.192359 7.191527-0.484357 C -1.019245 2.331145 1.403583 H -2.016600 1.972289 1.173918 H -0.722133 2.135730 2.430108 N -0.537174-3.686142 1.011260 C 0.083951-3.996692-0.285410 C -0.931461-4.551671-1.291880 H -0.471195-4.581417-2.282248 H -1.226057-5.568884-1.014828 H -1.822578-3.920929-1.324882 C 1.315901-4.892562-0.132717 H 1.026403-5.875191 0.253668 H 1.788481-5.024642-1.108855 H 2.041623-4.432152 0.540289 C -1.406917-4.592335 1.730942 H -1.617954-4.148398 2.703914 H -2.354036-4.743938 1.201311 H -0.908153-5.554644 1.875165 C 7.567479-1.249206 0.346508 C 6.236019-1.650443 0.250623 C 5.239601-0.761236-0.163131 C 5.625690 0.553312-0.451929 C 6.953030 0.965977-0.384211 C 7.929662 0.057589 0.018391 H 8.322299-1.959372 0.668662 H 5.937932-2.666428 0.483315 H 7.195663 1.992810-0.629088 H 8.965145 0.375067 0.084162 C 3.862677-1.338055-0.356848 O 3.445213-2.231910 0.358758 O 3.241459-0.843115-1.418562 H 2.393081-1.363339-1.582410 N 4.632767 1.598636-0.741088 O 4.926722 2.438151-1.589972 O 3.606842 1.597288-0.066464 2a-F C 3.787865-0.650924 0.102001 C 2.393244-0.552401-1.680534 N 2.889692 0.122172-0.639229 O 1.557407-0.171236-2.513664 O 4.295195-0.311810 1.177495 I 2.284706 2.493115 0.286000 C 4.599484-2.963617 0.103779 H 5.134027-3.576307-0.627264 H 5.308681-2.580127 0.837359 H 3.850659-3.570258 0.623185 C 3.079322-1.941788-1.707271 C 3.852072-2.098766-3.021518 H 4.347597-3.073991-3.055274 H 3.161427-2.028409-3.865232 H 4.611010-1.318236-3.119619 C 2.029499-3.045388-1.525644 H 1.315437-3.009089-2.351135 H 2.512939-4.026954-1.536996 S41