An Unexpected and Significantly Lower Hydrogen-Bond-Donating

Supporting Information Wiley-VCH 2012 69451 Weinheim, Germany

An Unexpected and Significantly Lower Hydrogen-Bond-Donating Capacity of Fluorohydrins Compared to Nonfluorinated Alcohols** Jrme Graton,* Zhong Wang, Anne-Marie Brossard, Daniela GonÅalves Monteiro, JeanYves Le Questel, and Bruno Linclau*

anie_201202059_sm_miscellaneous_information.pdf

Table of contents 1. Synthesis of the fluoroalcohols 1.1 Stereoselective synthesis of fluoroalcohols 2 and 3: reduction of fluoroketones 11 and 12 by L-Selectride (see Scheme 2) 1.2 NMR spectra of the crude product obtained from reduction of 11. 1.3 NMR spectra of the crude product obtained from reduction of 12. 1.4 Synthesis of fluorohydrins 1 and 4. 1.5 Synthesis of the 1,3-fluorohydrins 5 and 6 1.5.1 Synthesis of 6 1.5.2 Synthesis of 5 1.6 Synthesis of the 2,2-difluoroalcohols 7 and 8

2

2. Hydrogen bond acidity measurements

15

3. Quantum chemistry calculations 3.1 Conformational study 3.2 Hydrogen bond acidity characterisation

16 16 17

4. Copies of 1H, 13C, and 19F spectra 4.1 Fluorohydrin 1 4.2 Fluorohydrin 2 4.3 Fluorohydrin 3 4.4 Fluorohydrin 4 4.5 Fluorohydrin 5 4.6 Fluorohydrin 6 4.7 Difluorohydrin 7 4.8 Difluorohydrin 8 4.9 Allylic alcohol SI1 4.10 Iodofluorination product SI2 4.11 Mitsunobu product SI3

19 19 21 23 25 27 29 31 33 35 36 38

1

2 4 5 6 8 8 11 13

1. Synthesis of the fluoroalcohols 1.1 Stereoselective synthesis of fluoroalcohols 2 and 3: reduction of fluoroketones 11 and 12 by LSelectride (see Scheme 2):

Compound 2: To a solution of L-Selectride (4.36 ml, 1 M in THF, 4.36 mmol, 1.5 equiv.) in dry THF (4.4 mL) was added a solution of fluoroketone 111 (500 mg, 2.91 mmol, 1 equiv.) in THF (2.3 mL) at 78 °C. The temperature was maintained for 2 h, then stirred at room temperature overnight. On the following day, the reaction mixture was cooled to 0 °C and quenched with water (20 mL). After warmed to room temperature, NaOH (2 mL, 3 M) and H2O2 (2 mL, 30%) was added and stirred for another 2 h. The mixture was then extracted with diethyl ether (3 × 30 mL). The combined organic layer was washed with brine (40 mL) and water (40 mL), dried over MgSO4, filtered, evaporated. The crude was purified by flash chromatography to afford 2, 421 mg (colourless oil, 2.41 mmol, 83%).

IR 3598(br,w), 3429(br,w), 2956(s), 2868(m), 1483(w), 1381(m), 1363(m), 1248(m), 1128(m), 1040(m), 998(s) cm-1; 1H NMR (400 MHz, CDCl3)  4.50 (1H, dddd, J 47.1, 11.6, 4.8, 2.8 Hz, H2), 4.10–4.20 (1H, m, H1), 1.97–2.08 (2H, m, H6-eq + OH), 1.82–1.91 (1H, m, H3-eq), 1.64 (1H, ddd, J 24.0, 11.9, 8.7 Hz, H3-ax), 1.29–1.49 (3H, m, H5-eq + H6-ax + H5-ax), 1.02–1.11 (1H, m, H4), 0.89 (9H, s, H8) ppm; 1H{19F} NMR (400 MHz, CDCl3)  4.46–4.54 (1H, m, a coupling of 11.5 Hz can be observed, H2), 4.15 (1H, br. s., H1), 1.95–2.06 (2H, m, H6-eq + OH), 1.87 (1H, br. d, J 11.4 Hz, H3eq), 1.64 (1H, dd, J 24.0, 12.1 Hz, H3-ax), 1.29–1.49 (3H, m, H5-eq + H6-ax + H5-ax), 1.02–1.11 (1H, m, H4), 0.90 (9H, s, H8) ppm; 13C NMR (75 MHz, CDCl3)  94.7 (d, J 174.7 Hz, C2), 66.9 (d, J 17.7 Hz, C1), 46.0 (d, J 10.0 Hz, C4), 32.3 (C7), 29.6 (d, J 6.6 Hz, C6), 27.5 (C8), 26.9 (d, J 16.6 Hz, C3), 19.4 (C5) ppm; 19F NMR (282 MHz, CDCl3)  -179.8 (d, J 46.2 Hz) ppm; MS(ESI-) m/z 173.0 [M-H]-.

1

S. E. Denmark, Z. Wu, C. M. Crudden, H. Matsuhashi, J. Org. Chem. 1997, 62, 8288–8289. 2

The 19F NMR chemical shift, and JC1-3–F values correspond to the literature.2 Compound 3: To a solution of L-Selectride (35.7 ml, 1 M in THF, 35.7 mmol, 1.5 equiv.) in dry THF (35 mL) was added a solution of fluoroketone 121 (4.1 g, 23.8 mmol, 1 equiv.) in THF (20 mL) at -78 °C. The temperature was maintained for 2 h, then stirred at room temperature overnight. On the following day, the reaction mixture was cooled to 0 °C and quenched with water (80 mL). After warmed to room temperature, NaOH (20 mL, 3 M) and H2O2 (20 mL, 30%) was added and stirred for another 2 h. The mixture was then extracted with diethyl ether (3 × 150 mL). The combined organic layer was washed with brine (150 mL) and water (150 mL), dried over MgSO4, filtered, evaporated. The crude was purified by flash chromatography to afford 3, 3.61g (20.73 mmol, 87%).

mp 88–91 ºC (lit3 76 °C); IR 3256(m, br), 2936(s), 2869(m), 1474(s), 1385(m), 1362(m), 1270(m), 1080(m), 1012(s), 982(s) cm-1; 1H NMR (400 MHz, CDCl3)  4.68–5.02 (1H, m, J 51.5 can be observed, H2), 3.36–3.66 (1H, m, H1, simplifies to a ddd, J 28.9, 11.6, 2.7 Hz upon D2O exchange), 2.07–2.29 (1H, m, H3-eq), 1.86–1.98 (2H, m, -OH + H6-eq, integration decreases by 1 upon D2O exchange), 1.77–1.85 (1H, m, H5-eq, simplifies to a dquin, J 13.2, 3.4 upon D2O exchange), 1.51–1.67 (1H, m, H6-ax, simplifies to a qd, J 12.3, 2.5 Hz upon D2O exchange), 1.36–1.46 (1H, m, H4, simplifies to a tt, J 12.6, 2.8 upon D2O exchange), 1.13–1.35 (1H, m, H3-ax, simplifies to dddd, J 45.2, 14.3, 12.8, 1.5 Hz upon D2O exchange), 0.97–1.12 (1H, m, H5-ax), 0.88 (9H, s, H8) ppm; 1H{19F} NMR (400 MHz, CDCl3)  4.82–4.88 (1H, m, H2), 3.45–3.54 (1H, m, H1), 2.12–2.21 (1H, m, H3-eq), 1.86–1.97 (2H, m, OH + H6-eq), 1.76–1.84 (1H, m, simplifies to dquin, J 13.2, 3.3 Hz upon D2O exchange, H5-eq), 1.59 (1H, qd, J 12.5, 3.4 Hz, H6-ax), 1.35–1.45 (1H, m, simplifies to tt, J 12.6, 3.1 Hz upon D2O exchange, H4), 1.18–1.29 (1H, m, H3-ax), 0.99–1.11 (1H, qd, J 12.7, 3.4 Hz, H5-ax), 0.86 (9H, s, H8) ppm;

13

C NMR (101 MHz, CDCl3)  92.5 (d, J 171.3 Hz. C2), 71.3 (d, J 20.5 Hz,

C1), 40.2 (C4), 31.8 (C7), 31.0 (d, J 20.5 Hz, C3), 29.7 (d, J 2.9 Hz, C6), 27.4 (C8), 24.9 (C5) ppm; 19

F NMR (282 MHz, CDCl3)  -204.1 (dddd, J 51.0, 45.1, 29.0, 8.9 Hz) ppm; MS(ESI-) m/z 173.1 [M-

H]-. 2 3

P. R. Anizelli, D. C. Favaro, R. H. Contreras, C. F. Tormena, J. Phys. Chem. A 2011, 115, 5684–5692. P. Moreau, A. Casadevall, E. Casadevall, Bull Chem. Soc. Fr. 1969, 2013–2020. 3

The 19F NMR chemical shift, and JC1-3–F values correspond to the literature.2 In both cases, the 1H and 19F NMR spectrum of the crude product only shows one diastereoisomer: 1.2 NMR spectra of the crude product obtained from reduction of 11:

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1.4 Synthesis of fluorohydrins 1 and 4. General procedures for reduction of ketone using NaBH4 with EtOH in diethyl ether.2 To a solution of ketone (0.3 mmol-20 mmol, 1 equiv.) in anhydrous diethyl ether was added NaBH4 and several drops of ethanol. The resulting mixture was stirred overnight. The reaction was monitored by TLC. If completed, the reaction was stopped by quenching with water (6 mL/mmol), extracted with diethyl ether three times (14 mL/mmol), dried over MgSO4 and concentrated. The crude was purified by flash chromatography.

Ketone 11 (2.1 g, 12.2 mmol) was reduced according to the general procedures described above to afford 2 (400 mg, 2.30 mmol, 19%) as colourless oil and 4 (786 mg, 4.51 mmol, 37%) as white solid. Compound 4:

mp 48–52 ºC (lit3 47–48 °C); IR 3368(w, br), 2947(s), 2857(m), 1459(w), 1361(s), 1231(w), 1064(s), 1032(s), 977 (m) cm-1; 1H NMR (400 MHz, CDCl3)  4.17–4.38 (1H, m, a coupling of 51.9 can be observed, H2), 3.54–3.66 (1H, m, H1), 2.42 (1H, br. s, OH), 2.10–2.20 (1H, m, H3-eq), 1.99–2.09 (1H, m, H6-eq), 1.67–1.78 (1H, m, H5-eq), 0.99–1.35 (4H, m, H3-ax + H4 + H5-ax + H6-ax), 0.88 (9H, s, H8) ppm; 1H{19F} NMR (400 MHz, CDCl3)  4.23–4.33 (1H, m, H2), 3.55–3.65 (1H, m, H1), 2.42 (1H, br. s., OH), 2.10–2.19 (1H, m, H3-eq), 2.01–2.09 (1H, m, a coupling of 13.1 can be observed, H6eq), 1.69–1.78 (1H, m, a coupling of 12.6 Hz can be observed, H5-eq), 1.0–1.35 (4H, m, H6-ax + H3ax + H4 + H5-ax), 0.88 (9H, s, H8) ppm;

13

C NMR (101 MHz, CDCl3)  97.5 (d, J 174.2 Hz, C2), 73.7

(d, J 17.6 Hz, C1), 45.9 (d, J 8.8 Hz, C4), 32.2 (C7), 31.7 (d, J 17.6 Hz, C3), 31.0 (d, J 7.3 Hz, C6), 27.5 (C8), 24.7 (d, J 2.9 Hz, C5) ppm; 19F NMR (376.5 MHz, CDCl3)  -180.7 (m, a coupling of J 50.8 Hz can be observed) ppm; MS(ESI-) m/z 173.1 [M-H]-. The 19F NMR chemical shift, and JC1-3–F values correspond to the literature.2

6

Ketone 12 (10.44 mmol) was reduced according to the general procedures described above to afford 1 (249 mg, 1.43 mmol, 14%) and 3 (868 mg, 4.98 mmol, 48%) as white solid. Compound 1:

mp 69–70 ºC (lit3 61 °C); IR 3321(m, br), 2953(s), 2859(m), 1477(m), 1356(w), 1236(m), 1159(m), 1049(s), 1025(s), 988(s) cm-1; 1H NMR (400 MHz, CDCl3) δ 4.61–4.76 (1H, m, a coupling of 46.5 Hz can be observed, H2), 3.98 (1H, br. s, H1), 1.90–1.99 (1H, m, H3-eq), 1.72–1.88 (2H, m, H6-eq + H6ax), 1.25–1.63 (5H, m, H5-eq + H3-ax + H4 + -OH + H5-ax, integration decreases by 1 following D2O exchange), 0.87 (9H, s, H8) ppm; 1H{19F} NMR (400 MHz, CDCl3)  4.66–4.72 (1H, m, H2), 3.96– 4.00 (1H, br. s, H1), 1.95 (1H, br. d, J 14.7 Hz H3-eq), 1.73–1.88 (2H, m, H6-eq + H6-ax), 1.27–1.60 (5H, m, H5-eq + H3-ax + H4 + -OH + H5-ax), 0.87 (9H, s, H8) ppm;

13

C NMR (101 MHz, CDCl3) δ

91.0 (d, J 171.3 Hz, C2), 66.2 (d, J 29.3 Hz, C1), 40.8 (C4), 32.1 (C7), 28.6 (C6), 27.2 (C8), 27.1 (d, J 19.0 Hz, C3), 19.9 (C5) ppm; 19F NMR (282 MHz, CDCl3) δ -186.0 (t, J 45.1 Hz) ppm; MS(ESI-) m/z 173.0 [M-H]-. The 19F NMR chemical shift, and JC1-3–F values correspond to the literature.2

7

1.5 Synthesis of 1,3-fluorohydrins 5 and 6. 1.5.1 Synthesis of 6

Reduction of 4-t-butyl cyclohexanone to give SI1 To a solution of 4-(t-butyl)cyclohex-2-enone (5.30 g, 34.8 mmol) and CeCl3•7H2O (19.50 g, 52.2 mmol) in MeOH (85 mL) at 0 oC was added NaBH4 (1.58 g, 41.8 mmol). The reaction was stirred at RT for 1 h, and then quenched by the addition of H2O (50 mL) and concentrated. Addition of HCl (50 mL, 1M) was followed by dilution with EtOAc (80 mL) and extraction. The organic layer was further washed with H2O (20 mL), and brine (20 mL), dried over NaSO4 and concentrated in vacuo. The crude product (6.27 g) was purified by gradient column chromatography (7  10% acetone in petrol ether) to afford 2.99 g (56% yield) of pure product (light yellow coloured oil). 1

H NMR (400 MHz, CDCl3)  5.69–5.80 (2H, m, H2 + H3), 4.20 (1H, br. s., H1), 2.11–2.19

(1H, m, H6’), 1.87–1.94 (1H, m, H4), 1.77–1.84 (1H, m, H5’), 1.56 (1H, br. s., OH), 1.24– 1.44 (2H, m, H5’’ + H6’’), 0.87 (9H, s, H8) ppm. 13C NMR (101 MHz, CDCl3)  132.1 (C3), 131.3 (C2), 67.7 (C1), 45.9 (C4), 33.3 (C6), 32.8 (C7), 27.1 (C8), 22.8 (C5) ppm. 1

H NMR data match with literature data.4

Iodofluorination of SI1 to give SI2 To a solution of SI1 (2.17 g, 14.1 mmol) in DCM (20 mL) at -60 °C was added HF•py 70% (511 L) (plastic syringe), immediately followed by NIS (6.33 g, 28.1 mmol). The reaction mixture was left in the dry ice bath for 2 h, and then allowed to warm up to room temperature while stirring for 24 h. To the reaction mixture was added a 17% solution of aq. ammonia (20 mL), and then extracted with Et2O (3  50 mL). The ether phases were washed with a sat. aq. Na2S2O3 solution (30 mL), and with brine (50 mL). Following drying (MgSO4), the solvent was evaporated, and the resulting crude mixture purified by gradient column chromatography (5  10% acetone in petrol ether) and preparative HPLC (5% acetone in hexane). This results in 1.95 g (46%) of pure SI2 as a white solid. Other isomers were formed in much smaller amounts, but could not be obtained pure. 4

D. Young, W. Kitching, G. Wickham, Aust. J. Chem. 1984, 37, 1841–1862. 8

mp 73–75 ºC; IR (neat) 3274 (m, br), 2949 (s), 2869 (m), 1478 (m), 1361 (m), 1270 (m), 1081 (s), 1058 (s), 960 (s), 915 (s) cm-1; 1H NMR (400 MHz, CDCl3)  5.24 (1H, br. d, J 47.7 Hz, H3), 4.77– 4.84 (1H, m, H2), 2.95–3.04 (1H, m, H1), 2.07 (1H, ddd, J 40.9, 10.7, 4.4 Hz, H4), 1.78–1.85 (1H, br. d, J 12.85 Hz, H6-eq), 1.48–1.71 (4H, m, OH + 2H5 + H6-ax), 0.96 (9H, s, H8) ppm; 1H{19F} NMR (400 MHz, CDCl3) 5.23–5.27 (1H, m, H3), 4.78–4.82 (1H, m, H2), 2.95–3.03 (1H, m, H1), 2.04–2.11 (1H, m, H4), 1.78–1.85 (1H, m, H6-eq), 1.48–1.71 (4H, m, OH + 2H5 + H6-ax), 0.97 (9H, s, H8) ppm; 13

C NMR (101 MHz, CDCl3)  94.4 (d, J 178.6 Hz, C3), 66.7 (C1), 43.8 (d, J 23.4 Hz, C2), 43.1 (d, J

19.0 Hz, C4), 32.2 (C7), 31.8 (C6), 28.3 (C8), 20.1 (d, J 2.9 Hz, C5) ppm; 19F NMR (282 MHz, CDCl3)  -173.7 (1F, ddd, J 47.3, 38.7, 8.6 Hz) ppm; MS (EI) 173.2 (6, M+.-HI), 57.1 (100).

Reduction of SI2 to give 1,3-fluorohydrin 6 To a solution of SI2 (2.54 g, 8.46 mmol) in degassed benzene (147 mL) was added Bu3SnH (4.6 mL, 16.9 mmol) and AIBN (111 mg, 0.68 mmol). The mixture was heated to reflux for 3 h, after which the solvent was removed under vacuo. The residue was purified by gradient column chromatography (9%  15% acetone in petrol ether) to give 1.28 g (87%) of 6 as a white solid.

mp 65–70 oC; IR (neat) 3282 (m, br.), 2949 (s), 1481 (m), 1363 (s), 1063 (s), 734 (s) cm-1; 1H NMR (400 MHz, CDCl3)  5.12 (1H, d, J 48.8 Hz, H3), 3.91–4.01 (1H, m, H1), 2.31–2.41 (1H, m, H2-eq), 2.05–2.13 (1H, m, a coupling of 11.9 Hz can be observed, H6-eq), 1.75–1.65 (1H, m, H5-eq), 1.61 (1H, qd, J 13.1, 2.9 Hz), 1.56 (1H, d, J 4.3 Hz, OH), 1.36 (1H, dt, J 44.3, 12.4 Hz, H2-ax), 1.23–1.35 (1H, m, H6-ax), 1.06 (1H, ddd, J 40.3, 12.3, 3.4 Hz), 0.96 (9H, s, H8) ppm; 1H{19F} NMR (400 MHz, CDCl3)  5.13 (1H, br. s, H3), 3.92–4.01 (1H, m, simplifies to tt, J 11.2, 4.8 Hz upon D2O exchange, H1), 2.36 (1H, br. d, J 12.4 Hz, H2-eq), 2.06–2.13 (1H, m, a coupling of 12.1 Hz can be observed, H6eq), 1.66–1.75 (1H, m, H5-eq), 1.61 (1H, qd, J 13.1, 3.0 Hz, H5-ax), 1.52 (1H, br. s., OH), 1.35–1.41 9

(1H, m, H2-ax), 1.29 (1H, qd, J 12.3, 3.5 Hz, H6-ax), 1.01–1.09 (1H, m, H4), 0.96 (9H, s, H8) ppm; 13

C NMR (101 MHz, CDCl3)  91.2 (d, J 171.3 Hz, C3), 66.5 (C1), 50.0 (d, J 19.0 Hz, C4), 41.2 (d, J

20.5 Hz, C2), 35.5 (C6), 32.3 (C7), 28.5 (C8), 19.9 (d, J 2.9 Hz, C5) ppm;

19

F NMR (282 MHz,

CDCl3)  -193.0– -192.5 (m, a coupling of 8.6 Hz can be observed) ppm; MS (EI) 154.2 (1.4, M+.-HF), 57.2 (100).

10

1.5.2 Synthesis of 5

Mitsunobu reaction of 6 to give SI3 To a solution of 6 (1.16g, 6.66 mmol) in toluene (66 mL) was added triphenyl phosphine (3.49 g, 13.3 mmol) and chloroacetic acid (1.26 g, 13.3 mmol). The mixture was cooled to 0 °C, and after DEAD (2.09 mL, 13.3 mmol) was added dropwise, it was left stirring at room temperature for 18 h. The solvent was removed in vacuo, and the resulting mixture was directly purified by gradient column chromatography (2%  10% acetone in petrol ether). This gave 1.08 g of ester SI3 (65%) as a colourless oil.

IR (neat) 2952 (s), 1746 (s), 1368 (m), 1312 (s), 1194 (s), 1168 (s), 1081 (s) cm-1; 1H NMR (400 MHz, CDCl3)  ppm 4.96–5.14 (2H, m, H3 + H1), 4.08 (2H, s, H10), 2.37–2.48 (1H, m, H2-eq), 2.03–2.12 (1H, m, H6-eq), 1.82–1.94 (1H, m, H5-ax), 1.52–1.74 (3H, m, H2-ax, H5-eq, H6-ax), 1.09 (1H, br. dd, J 39.9, 11.4 Hz, H4), 0.98 (9H, s, H8) ppm; 1H{19F} NMR (400 MHz, CDCl3)  5.11 (1H, br. s, H1), 5.04 (1H, br. s, H3), 4.08 (2H, s, H10), 2.43 (1H, br. d, J 16.7, H2-eq), 2.04–2.12 (1H, m, a coupling of 14.0 Hz can be observed, H6-eq), 1.82–1.94 (1H, m, H5-ax), 1.52–1.69 (3H, m, H2-ax, H5-eq, H6-ax), 1.09 (1H, br. d, J 12.7 Hz, H4), 0.98 (9H, s, H8) ppm;

13

C NMR (101 MHz, CDCl3)  ppm 167.1 (C9),

88.8 (d, J 174.2 Hz, C3), 70.1 (C1), 50.1 (d, J 20.5 Hz, C4), 41.4 (C10), 34.9 (d, J 20.5 Hz, C2), 32.6 (C7), 30.4 (C6), 28.3 (C8), 16.1 (C5) ppm; coupling of 12.9 Hz can be observed) ppm.

11

19

F NMR (282 MHz, CDCl3)  -192.2– -191.7 (m, a

Methanolysis of SI3 to give 5 To a solution of SI3 (627 mg, 2.50 mmol) in MeOH (10 mL) was added K2CO3 (346 mg, 2.50 mmol), and left stirring for 3 h. A half-saturated aqueous NH4Cl solution (30 mL) was added, and the mixture was four times extracted with DCM (30 mL each). The combined DCM phases were washed with brine (50 mL), dried (MgSO4), and the solvent evaporated in vacuo. The residue was purified by column chromatography (5% acetone in petrol ether) to give 5 (281 mg, 65%) as a white solid.

mp 57–60 oC; IR (neat) 3299 (m, br.), 2940 (s), 2903 (m), 1360 (m), 1313 (m), 1102 (s), 1090 (s), 942 (s) cm-1; 1H NMR (400 MHz, CDCl3)  5.20 (1H, br. d, J 49.1 Hz, H3), 3.96–4.04 (1H, m, H1), 2.48 (1H, dd, J 12.1, 9.5 Hz, OH), 2.28–2.38 (1H, m, H2-eq), 1.99–2.08 (1H, m, a coupling of 13.6 Hz can be observed, H6-eq), 1.87 (1H, qd, J 13.3, 2.9 Hz, H5-ax), 1.46–1.74 (3H, m, H2-ax, H5-eq, H6-ax), 1.09 (1H, dd, J 42.3, 13.6 Hz, H4), 0.97 (9H, s, H8) ppm; 1H{19F} NMR (400 MHz, CDCl3)  5.17– 5.23 (1H, m, H3), 3.96–4.03 (1H, m, H1), 2.49 (1H, d, J 8.6 Hz, OH), 2.33 (1H, br. d, J 15.7 Hz, H2eq), 1.99–2.07 (1H, m, a coupling of 13.7 Hz can be observed, H6-eq), 1.87 (1H, qd, J 13.3, 2.9 Hz, H5-ax), 1.46–1.74 (3H, m, H2-ax + H5-eq + H6-ax), 1.10 (1H, br. t, J 11.5 Hz, H4), 0.97 (9H, s, H8) ppm;

13

C NMR (101 MHz, CDCl3)  92.6 (d, J 166.9 Hz, C3), 65.9 (C1), 50.4 (d, J 19.0 Hz, C4), 37.7

(d, J 19.0 Hz, C2), 33.2 (C6), 32.6 (C7), 28.3 (d, J 2.9 Hz, C8), 15.3 (d, J 2.9 Hz, C5) ppm; 19F NMR (282 MHz, CDCl3)  -189.3– -188.7 (m) ppm; MS (EI) 154.2 (3.7, M+.-HF), 57.2 (100).

12

1.6 Synthesis of 2,2-difluoroalcohols 7 and 8

To a solution of SI4 and SI51 (2.60 g, 13.67 mmol, 1 equiv.) in dry diethyl ether (100 mL, 7.5 mL/mmol) was added NaBH4 (1.03 g, 27.34 mmol, 2 equiv.) and several drops of ethanol. The reaction mixture was stirred overnight at room temperature and then monitored by TLC. Upon completion, the reaction mixture was quenched with water (100 mL) and extracted with diethyl ether (3 × 200 mL). The combined organic layer was washed with brine, dried over MgSO4 and concentrated. The resulting crude was purified by column chromatography and HPLC to afford 7 (236 mg, 2.00 mmol, 9%) and 8 (2.04 g, 10.61 mmol, 77%), both as a white solid. Difluorohydrin 7

mp 43–45 oC; IR 3415(m, br), 2960(s), 2869(m), 1371(m), 1238(m), 1137(m), 1088(s), 1063(s), 1032(s) cm-1; 1H NMR (400 MHz, CDCl3)  3.86–3.92 (1H, m, H1), 2.02–2.06 (1H, m, -OH), 1.92– 2.02 (2H, m, H3-eq + H6-eq), 1.78 (1H, ddt, J 36.6, 12.6, 4.2 Hz, H3-ax), 1.58–1.71 (1H, m, H6-ax), 1.47–1.57 (1H, m, H5-eq), 1.30–1.45 (2H, m, H4 + H5-ax), 0.90 (9H, s, H8) ppm; 1H{19F} NMR (400 MHz, CDCl3)  3.88–3.91 (1H, m, H1), 2.03 (1H, t, J 2.2 Hz, OH), 1.98–2.01 (1H, m, H3-eq), 1.94– 1.97 (1H, m, H6-eq), 1.73–1.82 (1H, m, H3-ax), 1.61–1.71 (1H, m, H6-ax), 1.48–1.57 (1H, m, H5-eq), 1.30–1.45 (2H, m, H4 + H5-ax), 0.90 (9H, s, H8) ppm;

13

C NMR (101 MHz, CDCl3)  124.2 (dd, J

245.9, 243.0 Hz, C2), 67.9 (dd, J 35.1, 23.4 Hz, C1), 44.3 (d, J 8.8 Hz, C4), 32.1 (C7), 30.4 (dd, J 23.4, 20.5 Hz, C3), 28.9 (d, J 5.9 Hz, C6), 27.3 (C8), 19.1 (C5); 19F NMR (282 MHz, CDCl3)  ppm -101.7 (d, J 247.1 Hz, Feq), -107.1– -105.9 (m, couplings of 247.2 and 36.5 Hz can be observed, Fax).

13

Difluorohydrin 8

mp 49–50 ºC; IR 3346(m, br), 2959(m), 2872(m), 1365(s), 1185(m), 1171(m), 1106(s), 1081(s), 941(s) cm-1; 1H NMR (300 MHz, CDCl3) δ 3.59–3.70 (1H, ddt, J 20.2, 12.0, 4.9 Hz, H1), 2.55 (1H, br. s., OH), 2.11–2.21 (1H, m, H3’), 1.99–2.07 (1H, m, H6’), 1.74–1.82 (1H, m, a coupling of 13.3 Hz can be observed, H5’), 1.29–1.52 (3H, m, H6’’ + H3’’ + H4), 1.01–1.13 (1H, m, H5’’), 0.87 (9H, s, H8) ppm; 1

H{19F} NMR (400 MHz, CDCl3)  3.65 (1H, dd, J 12.0, 5.3 Hz, H1), 2.55 (1H, br. s., OH), 2.11–2.21

(1H, m, H3’), 1.99–2.06 (1H, m, H6-eq), 1.74–1.82 (1H, m, H5’), 1.46 (1H, qd, J 13.2, 3.8 Hz, H6-ax), 1.32–1.42 (2H, m, H3’’ + H4), 1.00–1.13 (1H, m, H5’’), 0.86 (9H, s, H8) ppm;

13

C NMR (101 MHz,

CDCl3)  ppm 122.9 (t, J 244.4 Hz, C2), 71.8 (t, J 22.0 Hz, C1), 44.3 (d, J 7.3 Hz, C4), 34.5 (dd, J 24.9, 20.5 Hz, C3), 31.9 (C7), 30.7 (d, J 7.3 Hz, C6), 27.3 (C8), 24.4 (C5);

19

F NMR (282 MHz,

CDCl3) δ -103.6 (d, J 232.1 Hz, Feq), -122.0– -120.0 (m, a coupling of 232.1 Hz can be observed, Fax) ppm.

14

2. H-bond acidity measurements Spectroscopic grade carbon tetrachloride was dried over freshly activated 4 Å molecular sieves. Owing to the observed weak stability with light, N-methylpyrrolidinone (NMP) 99.9+% was as well dried on 4 Å molecular sieves and stored in the dark. The synthesized c-hexanols were also carefully dried. Handling of the solutes and solvents was carried out in a glove box under dry atmosphere at room temperature. All these precautions allow the determination of the H-bond acidity of alcohols by avoiding the presence of water, a competitive H-bond donor and acceptor. Infrared spectra were recorded with a Fourier transform spectrometer Bruker Tensor 27 at a resolution of 1 cm-1. Before H-bond acidity measurements, we carried out the spectroscopic characterisation of the OH bond of each c-hexanol in CCl4 using infrasil quartz cell of 1 cm path length. A Peltier effect regulation thermostatted the temperature at 25°C ± 0.2°C. The stretching vibration OH, the half-width 1/2, the molar absorption coefficient OH, the frequency shift upon Hbond complexation with N-methylpyrrolidinone OH were determined for the synthesised compounds and are reported in Table S1. No fluorohydrin self-association was observed at the concentration employed. Measurements of H-bonding complexation were carried out following the standard procedure established for H-bond basicity measurements,5 and choosing NMP as the reference H-bond acceptor. For dilute ternary c-hexanol-NMP-CCl4 solutions, the absorbance decrease of the characterised OH absorption of c-hexanols was followed at 25°C, leading to pKAHY values, where A denotes for the studied c-hexanol and Y for the H-bond acceptor reference, NMP. Table S1. Spectroscopic characteristics of the stretching vibration OH of the studied c-hexanols. Entry

OH [a]

1/2 [a]

OH [b]

OHB [a]

OH [a]

9

3627

15

79

3454

173

10

3623

19

67

3445

178

1

3631

17

99

3417

214

2

3613

16

155

3419

194

3

3606

15

124

3415

191

4

3616

16

130

3419

197

5

3619

16

136

---

---

6

3626

17

80

3436

190

7

3618

17

148

3385

233

8

3612

21

115

3380

232

[a] in cm-1. [b] in L mol-1 cm-1.

5

C. Ouvrard, M. Berthelot, C. Laurence, J. Chem. Soc., Perkin Trans. 2 1999, 1357–1362.

15

3. Quantum chemistry calculations Theoretical calculations were performed using the Gaussian 096 program. 3.1 Conformational study. Owing to their excellent performance-to-cost ratio, DFT methods constitute very appealing approaches. In the present work, we selected the MPWB1K functional 7 which has been proven to surpass other functionals for energy-barrier prediction and non-bonded interactions7 associated to the 6-31+G(d,p) atomic basis set to perform our conformational investigations in the gas phase. The harmonic frequencies were computed analytically in order to characterise the stationary points and to estimate the thermodynamic corrections derived from the MPWB1K/6-31+G(d,p) energies. The relative population of each conformer (Table S2) was evaluated from the Gibbs energies considering a Boltzmann distribution according to relation (1): pi 

eGi / RT



n i 1

eGi / RT

(1)

The influence of bulk solvent effects (here carbon tetrachloride, as in the experiments) has been simulated through the Polarisable Continuum Model (PCM). 8 It appears that no fundamental differences are found between relative populations of conformers calculated in vacuo Table S1) or in CCl4 as solvent, although the chelated conformations are slightly less populated.

6

M. J. T. Frisch, 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., J. A.; 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, 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., RevA.02 ed., Gaussian, Inc., Wallingford CT, 2009. 7 Y. Zhao, D. G. Truhlar, J. Phys. Chem. A 2004, 108, 6908–6918. 8 J. Tomasi, B. Mennucci, R. Cammi, Chem. Rev. 2005, 105, 2999–3093.

16

Table S2. Relative populations of the 4-t-butyl c-hexanol derivatives in the gas phase and in CCl4. Electrostatic potential V(r) computed in vacuo for each conformer. Entry

Trans pi[a]

9

24.9% (25.5%)

gV(r)

[b]

pi[a]

g+ V(r)

[b]

pi[a]

0.3151

75.1% (74.5%) [d]

0.3194

[d]

[d]

0.3181

[d]

73.2% (68.9%)

V(r) [b]

10

26.8% (31.1%)

0.3167

1

12.5% (12.3%)

0.3277

54.4% (49.4%)

0.3315

33.0% (38.3%)

0.3328

2

0.2% (0.7%)

0.3238

1.3% (2.7%)

0.3280

98.4% (96.6%)

0.3124

3

97.5% (93.1%)

0.3104

0.9% (3.8%)

0.3248

1.6% (3.2%)

0.3250

4

0.7% (1.9%)

0.3244

1.2% (2.6%)

0.3258

98.1% (95.4%)

0.3131

[f]

5

99.7% ()

0.2914

0.3% ()

0.3206

6

16.4% ()

0.3224

47.0% ()

0.3228

36.6% ()

0.3228

7

0.2% (0.7%)

0.3340

2.0% (4.1%)

0.3374

97.8% (95.2%)

0.3260

8

43.4% (48.9%)

0.3181

0.5% (1.9%)

0.3317

56.1% (49.2%)

0.3202

[a] in vacuo (in CCl4). [b] in a.u..

3.2 H-bond acidity characterisation. Since the original works of Murray and Politzer,9,10 it has been consistently demonstrated that H-bond acidity and the electrostatic potential are rather well correlated, owing to the mainly electrostatic character of the H-bond interaction. Kenny has recently introduced and recommended 11 the V(r) descriptor for such correlations. V(r) is defined as the molecular electrostatic potential calculated at a distance, r = 0.55Å, from the donor hydrogen atom on the axis defined by the nuclei of the hydrogen atom and the atom to which it was bonded. The V(r) values were calculated on the OH hydrogen atom of studied c-hexanols, and weighted by the conformers Boltzmann populations. These results are indeed found to be strongly correlated to the experimental Hbond acidity as shown in the manuscript. Some of these compounds are likely to give intramolecular interactions between the OH group and the fluorine atom. Those interactions were characterised from electron densities computed at the critical points of the corresponding H-bond, within the framework of Atoms in Molecules (AIM) theory 12,13 as implemented in the AIM2000 program.14 A Natural Bond Orbital (NBO)15,16 analysis was also carried 9

J. S. Murray, P. Politzer, J. Chem. Res., Synop. 1992, 110–111. H. Hagelin, J. S. Murray, T. Brinck, M. Berthelot, P. Politzer, Can. J. Chem. 1995, 73, 483–488. 11 P. W. Kenny, J. Chem. Inf. Model. 2009, 49, 1234–1244. 12 R. F. W. Bader, Chem. Rev. 1991, 91, 893–928. 13 R. F. W. Bader, Atoms in Molecules: A Quantum Theory, Clarendon, Oxford, 1994. 14 F. W. Biegler-Koenig, J. Schonbohm, D. Bayles, J. Comput. Chem. 2001, 22, 545–559. 15 A. E. Reed, L. A. Curtiss, F. Weinhold, Chem. Rev. 1988, 88, 899–926. 10

17

out, considering the interaction energy, E(2)n*, between the occupied non-bonded orbital of the fluorine atom, nF, and the unoccupied anti-bonding orbital of the OH bond, *OH. Table S3. Estimation of the loss of H-bond acidity in fluorohydrins in which an FHO interaction can occur. Entry

Trans pKAHY(calc)

2

0.95

[a]

gG

[b]

+3.0

3 4

0.98

+2.4

1.32

+1.6

5 7 8

pKAHY(calc)

[a]

g+ G

[b]

1.10

+3.8

0.98

+2.7

1.02

+2.6

0.84

+5.6

1.44

+2.3

1.24

+2.2

pKAHY(calc) 0.99

[a]

G [b] +2.5

[a] pKAHY(calc) = 35.88V(r) -10.67. [b] G = -5.708 (pKAHY(exp) - pKAHY(calc)).

16

E. D. Glendening, A. E. Reed, J. E. Carpenter, F. Weinhold, Theoretical Chemistry Institute, University of Wisconsin, Madison.

18

4. Copies of 1H, 13C, and 19F NMR spectra (in numerical order) 4.1 Fluorohydrin 1 H NMR (400 MHz) 0.87

1

JY1911SBG2.010.ESP

0.13

0.12

0.11

0.10

Normalized Intensity

0.09

0.08

0.07

0.06

1.58

0.05

5.32

1.37 1.33 1.30

1.44 1.41

1.00 2.00

1.94

4.62

4.74

7.27

0.02

3.97

0.03

1.79

0.04

0.01

0 0.91 7.0

6.5

6.0

5.5

5.0

4.5


3.5

3.0

2.5

2.0

1.5

9.00 1.0

19

H{ F} NMR (400 MHz) 0.87

1

0.91

0.30

0.20

0.15

1.42 1.39 1.31

1.53

1.78

1.97 1.93

3.98

0.05

4.69

1.45

0.10

7.27


0.25

0 0.88 7.0

6.5

6.0

5.5

5.0

194.5


0.93 1.92 3.5

3.0

2.5

2.0

5.05 1.5

9.32 1.0

13

C NMR (101 MHz) M07(d)

JY1911SBG2.011.esp

M05(s) M06(s)

27.22

J(M07)=19.03 Hz

77.31 77.00 76.68

M08(s)

M01(d)

95

90

85

80

75

70

65

19.86 27.01

32.06

66.35 66.06

M04(s)

60

55 50 Chemical Shift (ppm)

45

40

35

30

25

20

15

10

-186.03

F NMR (282 MHz) -186.03

19

M02(d)

90.19

91.88

J(M01)=171.25 Hz

28.59

40.75

M03(s)

1.00 0.95 0.90

-185.87

-186.19

0.85 0.80 0.75 0.70

-185.87 -186.19

0.60 0.55 0.50 1.00

0.45

-185.50 -185.55 -185.60 -185.65 -185.70 -185.75 -185.80 -185.85 -185.90 -185.95 -186.00 -186.05 -186.10 -186.15 -186.20 -186.25 -186.30 -186.35 -186.40 -186.45 -186.50 -186.55 -186.60 Chemical Shift (ppm)

0.40 0.35 0.30 0.25 0.20 0.15

-179.89 -180.06


0.65

0.10 0.05 0 -0.05

0.03 1.00 0

-10

-20

-30

-40

-50

-60

-70

-80

-90

-100

20

-110 -120 -130 -140 Chemical Shift (ppm)

-150

-160

-170

-180

-190

-200

-210

-220

-230

-240

-250

4.2 Fluorohydrin 2 H NMR (400 MHz) 0.89

1

AP1311SBG7.001.ESP

0.19 0.18 0.17 0.16 0.15 0.14 0.13


0.12 0.11 0.10 0.09 0.08

0.06

1.35

1.99

0.07

1.37

0.05

1.06

1.86

0.02

4.58 4.53 4.46 4.42

7.27

4.15

0.03

1.44

1.65

0.04

0.01 0 0.88 7.5

6.5

6.0

5.5

5.0

4.5


1.83 0.94 3.5

3.0

2.5

2.0

1.05

2.97

1.03 9.00

1.5

1.0

19

H{ F} NMR (400 MHz) 0.90

1

7.0

0.45

0.40

0.35

0.25

0.20

0.15

1.07

1.38

1.63

1.86

2.02

0.05

4.52 4.49

4.15

1.35

1.97

0.10

7.27


0.30

0 0.85 7.0

6.5

6.0

5.5

5.0

4.5

21


0.97 3.5

3.0

2.5

2.0

1.09

2.85 1.5

0.86 9.00 1.0

13

C NMR (75 MHz) M06(s)

JY0611ZW2.012.ESP

M08(s)

M05(d)

105

100

95

85

80

75

70 65 60 Chemical Shift (ppm)

55

50

45

2040.55 2023.96

2238.47 2231.84 2439.71

3477.97 3468.02

5060.24 5042.55

5843.08 5811.02 5778.95

90

M07(d)

M03(d)

40

35

30

25

20

15

10

F NMR (282 MHz)

-179.77

-179.93

1.00

-179.77 -179.93

19

110

M02(d)

7058.26

7232.96

J(M01)=174.70 Hz

115

1465.58

M04(s) M01(d)

0.95 0.90 0.85 0.80 0.75 0.70


0.65 0.60 0.96

0.55

-179.45

-179.50

-179.55

-179.60

-179.65

-179.70

-179.75

-179.80

-179.85 -179.90 Chemical Shift (ppm)

-179.95

-180.00

-180.05

-180.10

-180.15

-180.20

-180.25 -180.30

0.50 0.45 0.40 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0 0.96 0

-10

-20

-30

-40

-50

-60

-70

-80

-90

-100

22


-150

-160

-170

-180

-190

-200

-210

-220

-230

-240

-250


1

JY0811SBG11.010.ESP

0.30


0.25

0.20

0.15

1.04

1.41

1.29 1.18

1.80

3.53 3.46

1.58

2.17

4.79

4.92

0.05

7.27

1.91

0.10

0 1.00 7.5

7.0

6.5

6.0

5.5

5.0

4.5


4.5


3.5

1.20 3.0

2.5

2.00 1.05 1.06 1.03 1.24 1.14 9.86 2.0

1.5

1.0

0.5

19

H{ F} NMR (400 MHz) 0.86

1

0.99

0.40

0.35

0.30

0.20

0.15

1.07 1.04

1.22

1.41

1.61 1.58

1.92 1.89 1.82 1.79

0.05

3.49

4.86 4.84

2.17

0.10

7.27


0.25

0 0.83 7.0

6.5

6.0

5.5

5.0

0.78

23

3.5

1.04 3.0

2.5

1.02 2.0

0.95 0.91 0.88 0.93 9.00 1.5

1.0

13


JY0811SBG11.011.001.1R.ESP

7779.38 7747.18 7714.98

2754.59

J(M06)=2.93 Hz

M05(d)

M03(s)

7161.71 7180.74 90

85

80

75

70

65


50

45

40

35

30

25

20

15

-203.85

1.00

-203.75 -203.85

F NMR (282 MHz)

-203.75

19

95

9224.03

9393.81 100

M04(s)

3199.55 3132.22 3111.73 2991.71 2988.78

J(M02)=20.49 Hz

J(M01)=171.25 Hz

M06(d)

4039.70

M02(d)

M01(d)

2505.77

M08(s)

0.95

-203.91

-204.01

-203.91

-203.88

-203.78

-203.94

-204.04

0.75

-203.70

-203.60

-203.56

0.80

-203.67

0.85

-203.83

-203.72

0.90

-203.56 -204.04

0.70


0.65 0.60 0.55 0.50 0.45 1.00

0.40 -203.40

-203.45

-203.50

-203.55

-203.60

-203.65

-203.70

-203.75 -203.80 -203.85 Chemical Shift (ppm)

-203.90

-203.95

-204.00

-204.05

-204.10

-204.15

-204.20

0.35 0.30 0.25 0.20 0.15 0.10 0.05 0 1.00 0

-10

-20

-30

-40

-50

-60

-70

-80

-90

-100

24


-150

-160

-170

-180

-190

-200

-210

-220

-230

-240

-250


1

0.19 0.18 0.17 0.16 0.15 0.14


0.13 0.12 0.11 0.10 0.09 0.08

2.44

0.07 0.06 0.05

1.75 1.72

2.15 2.05

3.60

4.34

0.02

4.21

7.27

0.03

1.26 1.16 1.07

0.04

0.01 0 1.00 7.0

6.5

6.0

5.5

5.0

4.5


3.5

0.98 3.0

1.17 1.00

2.5

1.11

2.0

4.42 1.5

9.43 1.0

19

H{ F} NMR (400 MHz) 0.88

1

0.99

0.25

0.15

1.75 1.72

0.99

1.03

2.15

2.04

3.60

4.28

0.05

1.08

1.28 1.22 1.19

2.42

0.10

7.27


0.20

0 0.85 7.0

6.5

6.0

5.5

5.0

4.5

25


0.88 3.5

0.77 3.0

2.5

2.0

4.03 1.5

9.00 1.0

13


AP0411NJB2.011.001.1R.ESP

77.32 77.00 76.68

27.49

J(M06)=17.56 Hz

M05(d) M08(d)

M06(d)

45.94 45.85

96.64

73.78 73.61

M03(d)

98.36

90

85

80

75

70


55

50

45

40

35

30

25

20

F NMR (282 MHz)

-188.14

-188.29

-188.14 -188.29

19

95

31.57 31.06 30.99

M02(d)

32.19 31.74

J(M01)=174.18 Hz

100

J(M08)=2.93 Hz

M04(s)

24.69

M01(d)

1.00 0.95 0.90 0.85 0.80 0.75 0.70


0.65 0.60 0.55 0.50 0.45

0.97 -187.70

-187.75

-187.80

-187.85

-187.90

-187.95

-188.00

-188.05

-188.10

0.40


-188.30

-188.35

-188.40

-188.45

-188.50

-188.55

-188.60

-188.65

-188.70

0.35 0.30 0.25 0.20 0.15 0.10 0.05 0 0.97 0

-10

-20

-30

-40

-50

-60

-70

-80

-90

-100

26


-150

-160

-170

-180

-190

-200

-210

-220

-230

-240

-250


1

JA2612SBG3.010 AXOH AXF.ESP

0.25


0.20

0.15

1.13

1.71

1.86

2.02

2.48

2.33

4.00

7.27

5.26

0.05

5.14

1.55

0.10

0 0.95 7.0

6.5

6.0

5.5

5.0

4.5


0.92 0.97 3.5

3.0

2.5

0.98 1.02 2.0

3.22

10.00

1.5

1.0

19

H{ F} NMR (400 MHz)

0.97

1

0.91

0.25

0.15

2.50 2.48 2.34 2.30

2.05 2.01 1.89 1.85

0.94

0.87

0.94 0.97

0.98 1.01

1.10

4.00

0.05

5.22 5.19

1.55

0.10

7.27


0.20

0

7.0

6.5

6.0

5.5

5.0

4.5

27


3.5

3.0

2.5

2.0

2.96 1.5

9.00 1.0

C NMR (101 MHz) 28.29

13

JA2612SBG3.011 AXOH AXF.ESP 1.0

0.9

33.23

0.6

0.5

37.59

32.61

37.78

50.45 50.26

93.47

0.3

15.28 15.25

0.4 91.81


0.7

65.86

77.32 77.00 76.68

0.8

0.2

0.1

0 100

90

85

80

75

70

65

60


45

40

35

30

25

20

15

10

5

-189.09

F NMR (282 MHz)

-189.09

19

95

1.00

-188.94

0.95 0.90

-189.04

-189.22

-188.87

-188.81 -188.72


0.65

-189.26

0.70

0.60

-189.30

-188.98

-188.77

0.80 0.75

-189.13

0.85

0.55 0.50 0.45

1.00 -188.55

-188.60

-188.65

-188.70

-188.75

-188.80

-188.85

-188.90

0.40


-189.10

-189.15

-189.20

-189.25

-189.30

-189.35

-189.40

-189.45

0.35 0.30 0.25 0.20 0.15 0.10 0.05 0 1.00 0

-10

-20

-30

-40

-50

-60

-70

-80

-90

-100

28


-150

-160

-170

-180

-190

-200

-210

-220

-230

-240

-250


1

JA2612SBG1 68-1C EQOH AXF.010.ESP

0.25


0.20

0.15

1.31

1.56

0.10

1.42

1.12 1.02

1.70

2.08

2.35

3.97

5.06

7.27

5.18

0.05

0 0.83 7.0

6.5

6.0

5.5

5.0

4.5

H{19F} NMR (400 MHz)


0.91 3.5

3.0

2.5

0.90

3.00

2.0

2.00 1.5

9.74 1.0

0.96

1

0.85

0.30

0.20

0.15

1.07

0.99

1.36 1.31

1.00

1.69 1.63

3.97

2.11 2.08

0.05

2.38 2.34

5.13

1.52

0.10

7.27


0.25

0 0.92 7.0

6.5

6.0

5.5

0.93 5.0

4.5

29


3.5

3.0

2.5

2.0

2.34 0.88 2.02 1.5

9.36 1.0

C NMR (101 MHz) 28.53

13

JA2612SBG1 68-1C EQOH AXF.011.ESP 1.0

0.8

0.6

0.2

32.34

41.06

50.06 49.87

92.07

0.3

41.26

0.4

19.91 19.88

66.47

0.5

90.37


0.7

35.51

77.32 77.00 76.68

0.9

0.1

0 100

90

85

80

75

70

65


50

45

40

35

30

25

20

15

-192.67

F NMR (282 MHz) -192.67

19

95

1.00

-192.82

0.95 0.90

-192.50

-192.97

-192.53

0.80 0.75

-193.00

0.85

0.70


0.65 0.60 0.55 0.50 1.00

0.45

-192.40

-192.45

-192.50

-192.55

-192.60

-192.65


-192.80

-192.85

-192.90

-192.95

-193.00

-193.05

0.40 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0 1.00 0

-10

-20

-30

-40

-50

-60

-70

-80

-90

-100

30


-150

-160

-170

-180

-190

-200

-210

-220

-230

-240

-250

4.7 Difluorohydrin 7 H NMR (400 MHz) 0.90

1

0.19 0.18 0.17 0.16 0.15 0.14


0.13 0.12 0.11 0.10 0.09 0.08 0.07 0.06

1.52

1.82 1.73 1.65

3.89

0.03 0.02

1.38

2.04 1.95

0.04

7.27

0.05

0.01 0 0.87 7.0

6.0

5.5

5.0

4.5


5.0

4.5


1.87 3.5

3.0

3.5

3.0

2.5

1.95

2.0

0.92 1.81 1.5

9.00 1.0

H{19F} NMR (400 MHz) 0.90

1

6.5

0.16 0.15 0.14 0.13 0.12

0.10 0.09 0.08 0.07 0.06

1.52

1.78

0.02

1.65

0.03

1.38

1.95

3.90

0.04

2.03

0.05

7.27


0.11

0.01 0 1.00 7.0

6.5

6.0

5.5

31

1.21 1.03 2.5

2.0

1.10 2.12 1.5

9.85 1.0

C NMR (101 MHz) 27.28

13

130

124.15

32.06 30.56 30.36 28.95

68.17 67.94 67.82 67.60 120

115

110

105

100

95

90

85

80


65

60

55

50

45

40

35

30

25

20

15

-102.13

F NMR (282 MHz) -102.13

19

125

121.73

126.59

44.30 44.21

19.07

77.31 77.00 76.68

DC0111CQF3.011.esp

-101.25

1.00 0.95 0.90

-101.25

0.85 0.80 0.75 0.70 1.00 -100.0

-100.5

-101.0

-101.5

-102.0 Chemical Shift (ppm)

-102.5

-103.0

-103.5

-104.0

-106.00 -106.01 -106.03

0.50

0.40

-106.87 -106.89 -106.91

0.45

0.35

-107.00 -107.02 -107.04

0.55

-106.13 -106.14 -106.16

-106.16

0.60

-107.04


0.65

0.30 0.25 1.00 -105.8

-105.9

-106.0

-106.1

-106.2

-106.3

-106.4

0.20


-106.7

-106.8

-106.9

-107.0

-107.1

-107.2

0.15 0.10 0.05 0 1.00 0

-10

-20

-30

-40

-50

-60

-70

-80

-90

-100

32


-150

-160

-170

-180

-190

-200

-210

-220

-230

-240

-250

4.8 Difluorohydrin 8 H NMR (400 MHz) 0.86

1

0.19 0.18 0.17 0.16 0.15 0.14


0.13 0.12 0.11 0.10 0.09 0.08 0.07 0.06

1.40 1.35

0.05

1.09 1.05

1.47

2.01

1.80 1.76

3.69 3.60

7.27

0.02

2.55

0.03

2.18 2.15

0.04

0.01 0 1.00 7.0

6.0

5.5

5.0

4.5


4.5


1.01 3.5

3.0

3.5

3.0

2.5

1.06 1.04

1.05

2.0

3.15 1.5

1.11

9.32

1.0

H{19F} NMR (400 MHz) 0.86

1

6.5

0.20


0.15

1.39 1.36

0.10

0.98

1.09 1.05

1.80 1.76

1.04 0.98

1.48

2.17 2.15 2.05 2.01

7.27

2.55

3.67 3.62

0.05

0 0.94 7.0

6.5

6.0

5.5

5.0

33

0.92 2.5

2.0

3.00 1.5

1.02 1.0

8.92

C NMR (101 MHz) 27.31

13

125

115

110

105

100

95

90

85


65

60

55

50

45

24.35

34.70 34.45 34.24 31.90

44.31

72.02 71.81 71.59

122.84

120

40

35

30

25

F NMR (282 MHz) -103.21 -104.03

19

120.42

125.27

44.24

30.74 30.67

77.32 77.00 76.68

OC2411CD4.011.001.1r.esp

-103.21

-104.03

1.00 0.95 0.90 0.85 0.80 0.75 0.70 0.65 -102.9

-103.0

-103.1

-103.2

-103.3

-103.4

-103.5


-103.8

-103.9

-104.0

-104.1

-104.2

-104.3

-104.4

0.55 0.50

-121.51 -121.54

-121.57

-121.43

-121.46

-120.75

-121.40

-120.64

-120.72

-121.37

0.30

-120.67

0.35

-120.50

-121.51

0.40

-120.55

0.45

-120.58

-120.64


1.08

0.60

0.25 0.20 1.00 -120.3

-120.4

-120.5

-120.6

-120.7

-120.8

-120.9

0.15


-121.2

-121.3

-121.4

-121.5

-121.6

-121.7

0.10 0.05 0 1.08 0

-10

-20

-30

-40

-50

-60

-70

-80

-90

-100

34

1.00 -110 -120 -130 -140 Chemical Shift (ppm)

-150

-160

-170

-180

-190

-200

-210

-220

-230

-240

-250

4.9 Allylic alcohol SI1 H NMR (400 MHz) 0.87

1

0.25


0.20

0.15

1.90 1.80

7.27

4.20

2.14

0.05

1.34

1.56

5.76 5.73

0.10

0 1.91 7.0

6.0

0.93 5.5

5.0

4.5

1.06


3.5

3.0

2.5

2.10

0.95

2.0

2.11

9.00

1.5

1.0

C NMR (101 MHz) 27.12

13

6.5

0.55

0.50

0.45

33.26 77.32 77.00

0.35

0.25

22.77

45.91

67.59

132.09

76.68

0.30

0.20

131.23 0.15

32.78


0.40

0.10

0.05

0 130

125

120

115

110

105

100

95

90

85

35


65

60

55

50

45

40

35

30

25

20

4.10 Iodofluorination product SI2 H NMR (400 MHz) 0.97

1

FE0212CQF5.010 70H.ESP

0.20

1.67 1.64

0.10

1.58 1.56 1.49 1.55 1.53 1.52

1.83 1.80 2.02

2.14

2.99

4.81 4.79

5.18

5.30

0.05

7.27


0.15

0 0.97 7.0

6.0

5.5

0.91 5.0

0.94 4.5


3.5

3.0

1.09 2.5

1.07

2.0

4.00

8.92

1.5

1.0

H{19F} NMR (400 MHz) 0.97

1

6.5

0.115 0.110 0.105 0.100 0.095 0.090 0.085 0.080 0.075

0.065 0.060 0.055

0.045

1.68 1.66

0.050

7.27

0.040 0.035

0.010

0.98

0.92

1.06

1.55 1.52

0.015

1.80

5.23

0.020

2.09 2.07

0.025

2.99

4.80

1.59

0.030

5.26


0.070

0.005 0 1.00 7.0

6.5

6.0

5.5

0.97 5.0

4.5

36


3.5

3.0

2.5

2.0

1.88 1.5

9.67 1.0

28.34

C NMR (101 MHz) 77.32 77.00 76.69

13

0.70

0.65

31.87

0.60

0.55

0.50

66.69

0.40

0.35

20.10


0.45

95.30

0.20

32.19

93.53

42.99

0.25

20.13

43.93 43.18

0.30

0.15

0.10

0.05

0

95

90

85

80

75

70

65


50

45

40

35

30

25

20

F NMR (282 MHz)

-173.68

-173.68

19

1.00 0.95

-173.82

-173.65

-173.55

0.85

-173.71

0.90

-173.87

-173.52

0.80 0.75 0.70


0.65 0.60 0.55 1.00 -173.45

0.50

-173.50

-173.55

-173.60

-173.65

-173.70 Chemical Shift (ppm)

-173.75

-173.80

-173.85

-173.90

-173.95

0.45 0.40 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0 1.00 0

-10

-20

-30

-40

-50

-60

-70

-80

-90

-100

37


-150

-160

-170

-180

-190

-200

-210

-220

-230

-240

-250

4.11 Mitsunobu product SI3 H NMR (400 MHz) 0.98

1

JA2612SBG2.010 AXOP AXF.ESP

0.30

0.20

0.15

1.57


4.08

0.25

1.13 1.06

1.69

2.10

2.43

4.98

0.05

1.86

5.11

7.27

0.10

0 1.89 7.0

6.0

5.5

1.80

5.0

4.5


0.94 3.5

3.0

2.5

0.94 1.02 2.0

3.58

10.00 1.5

1.0

19

H{ F} NMR (400 MHz) 0.98

1

6.5

4.08

0.25

0.15

2.10 2.06

1.90 1.86

0.96

0.96

0.98

1.11 1.08

2.45 2.40

0.05

5.11 5.04

1.57

0.10

7.27


0.20

0 1.91 7.0

6.5

6.0

5.5

1.76

5.0

4.5

38


3.5

3.0

2.5

2.0

3.28 1.5

9.00 1.0

C NMR (101 MHz) 77.32 77.00 76.68

13

0.70

0.65

28.33

0.60

0.55

0.50

0.40

0.35

30.37


0.45

0.30

35.02 34.82 32.63

89.67 87.92 167.07

49.96

0.15

0.10

50.16

0.20

16.10

41.35

70.12

0.25

0.05

0 168

152

144

136

128

120

112

104


72

64

56

48

40

32

24

16

8

F NMR (282 MHz)

-192.03

1.00

-191.89

-191.86

-191.86 -192.03

19

160

-192.15

-192.06

-191.68

0.85

-191.72

0.90

-192.19

-191.98

0.95

0.80 0.75 0.70


0.65 0.60 0.55 0.50 0.45 1.00

0.40

-191.50

-191.55

-191.60

-191.65

-191.70

-191.75

-191.80

-191.85


-192.05

-192.10

-192.15

-192.20

-192.25

-192.30

-192.35

-192.40

0.35 0.30 0.25 0.20 0.15 0.10 0.05 0 -0.05

1.00 0

-10

-20

-30

-40

-50

-60

-70

-80

-90

-100

39


-150

-160

-170

-180

-190

-200

-210

-220

-230

-240

-250