(Thio)urea Organocatalyst Equilibrium Acidities in DMSO

Transcription

1 upporting Information (Thio)urea rganocatalyst Equilibrium Acidities in DM Gergely Jakab, Carlo Tancon, Zhiguo Zhang, Katharina M. Lippert, and Peter R. chreiner* Institute of rganic Chemistry, Justus-Liebig University Giessen, einrich-buff-ring 58, Giessen, Germany Table of contents General remarks... 2 ynthesis and characterization of indicators Cyanofluorene (C-F) Carbomethoxyfluorene (MeC-F) Phenylfluorene (Ph-F) i Propylthiofluorene ( i Pr-F) Phenylthiofluorene (Ph-F) Bromo-9-phenylthiofluorene (2-Br-Ph-F) Phenylsulfonylfluorene (Ph 2 -F) Bromo-9-phenylsulfonylfluorene (2-Br-Ph 2 -F) Ethylsulfonylfluorene (Et 2 -F) ynthesis and characterization of (thio)urea derivatives phenyl- -(3-trifluoromethylphyenyl)-thiourea (9) phenyl- -(3,5-bis(trifluoromethyl)phenyl)-urea (10)... 5 Thiourea pectrophotometric titrations... 7 Preparation of stock solutions... 7 Titration and evaluation... 8 Reliability of the measurements References Appendix

2 General remarks Quartz spectrophotometric cells equipped with septum caps were purchased from tarna; chemicals from Acros rganics, Alfa Aesar, Aldrich, Merck, or Fluka, and were used without purification, unless otherwise noted. Column chromatography was conducted using J.T. Baker silica gel ( mm) or, for flash column chromatography, Merck silica gel 60 ( mm), respectively. Argon was passed through concentrated sulfuric acid, CaCl 2 and P 2 5 columns to remove residual water. 1 and 13 C MR spectra were recorded on a Bruker AV400 spectrometer, using TM as the internal standard with chemical shifts given in ppm relative to TM or the respective solvent residual peaks. Infrared and Ultraviolet spectra were recorded on a Bruker IF25, and a ewlett-packard 8453 UV-Vis spectrometer, respectively. RM spectra were recorded on an LTQ rbitrap Discovery mass spectrometer (Thermo cientific Gmb, Bremen, Germany), or a Thermo Finnigan MAT 95 mass spectrometer. C-- analyses were performed on a Thermo Flash EA 1112 device. ynthesis and characterization of indicators 4-nitrophenol (pk a = 10.8; λ max = 436 nm; ε = ± 531 dm 3 mol 1 cm 1 ) and 4-chloro-2- nitroaniline (pk a = 18.9; λ max = 522 nm; ε = 8451 ± 130 dm 3 mol 1 cm 1 ) were obtained from commercial source, and were recrystallized from ethanol. The other indicators were synthesized according to the literature procedures, unless otherwise noted. C 9-Cyanofluorene (C-F). 1 The product was recrystallized twice from ethanol. IR (KBr) 3418, 3064, 3038, 2898, 2251, 2228, 1605, 1449 cm 1 ; 1 MR (400 Mz, CDCl 3 ) δ 7.79 (d, J = 7.6 z, 2), 7.72 (d, J = 7.5 z, 2), 7.50 (t, J = 7.4 z, 2), 7.42 (t, J = 7.4 z, 2), 4.93 (s, 1); RM (EI ) calc. for [M ]: , found: ; pka = 8.3; λ max = 446 nm; ε = 2006 ± 56 dm 3 mol 1 cm 1. CMe 9-Carbomethoxyfluorene (MeC-F). 2 The product was recrystallized from methanol. IR (KBr) 3447, 3050, 3002, 2952, 1732, 1449, 1434, 1277, 1199, 1142 cm 1 ; 1 MR (400 Mz, CDCl 3 ) δ 7.79 (d, J = 7.5 z, 2), 7.69 (d, J = 7.6 z, 2), 7.46 (t, J = 7.5 z, 2), 7.38 (td, 2

3 J 1 = 7.5 z, J 2 = 1.2 z, 2), 4.92 (s, 1), 3.78 (s, 3); 13 C MR (100 Mz, CDCl 3 ) δ 171.5, 141.4, 140.7, 128.2, 127.4, 125.6, 120.1, 53.4, 52.6; RM (EI ) calc. for [M ]: , found: ; pk a = 10.35; λ max = 411 nm; ε = 3530 ± 73 dm 3 mol 1 cm 1. Ph 9-Phenylfluorene (Ph-F). 3 1 MR (400 Mz, CDCl 3 ) δ 7.72 (d, J = 7.6 z, 2), 7.30 (t, J = 7.3 z, 2), 7.24 (d, J = 7.3 z, 2), (m, 5), (m, 2), 4.97 (s, 1); 13 C MR (100 Mz, CDCl 3 ) δ 148.0, 141.7, 141.1, 128.7, 128.4, 127.4, 126.9, 125.4, 119.9, 54.5; RM (EI) calc.: , found: ; pk a = 17.9; λ max = 489 nm; ε = 2424 ± 22 dm 3 mol 1 cm i Propylthiofluorene ( i Pr-F). 4 A 10 ml flask was charged with iso-propylthiol (0.31 g, 4.1 mmol) and 3 ml TF under argon atmosphere. Aqueous a solution (3 ml, 10 w%) was added at 0 C, then the mixture was allowed to warm up to room temperature. 9-Bromofluorene (1.00 g, 4.1 mmol) was dissolved in 2 ml TF, and the solution was added in one portion. The biphasic system was stirred overnight at room temperature. The mixture was diluted with DCM, and was washed with a solution; the organic phase dried over a 2 4, and concentrated under reduced pressure. The crude product was purified by flash chromatography (hexanes); the obtained solid was recrystallized from methanol to yield 0.44 g (45%) of the pure product. 1 MR (400 Mz, CDCl 3 ) δ 7.73 (d, J = 7.1 z, 2), 7.70 (d, J = 7.4 z, 2), (m, 4), 4.94 (s, 1), 2.60 (hep, J = 6.8 z, 1), 0.99 (d, J = 6.8 z, 6); 13 C MR (100 Mz, CDCl 3 ) δ 145.5, 140.4, 127.8, 127.4, 125.4, 119.9, 48.7, 33.7, 24.4; RM (EI ) calc. for [M ]: , found: ; pk a = 16.9; λ max = 465 nm; ε = 1603 ± 16 dm 3 mol 1 cm 1. Ph 9-Phenylthiofluorene (Ph-F). 5 The product was recrystallized from methanol. 1 MR (400 Mz, CDCl 3 ) δ 7.54 (d, J = 7.3 z, 2), 7.47 (d, J = 7.5 z, 2), 7.25 (t, J = 7.3 z, 2), 7.20 (td, J 1 = 7.3 z, J 2 = 1.4 z, 2), (m, 2), (m, 3), 5.18 (s, 1); 13 C MR (100 Mz, CDCl 3 ) δ 144.4, 140.5, 133.3, 133.0, 128.5, 128.1, 127.7, 127.3, 125.4, 119.9, 51.8; RM (EI ) calc. for [M ]: , found: ; pk a = 15.4; λ max = 453 nm; ε = 1908 ± 45 dm 3 mol 1 cm 1. 3

4 Ph 2-Bromo-9-phenylthiofluorene (2-Br-Ph-F). 6 The product was recrystallized from diethyl-ether. 1 MR (400 Mz, CDCl 3 ) δ 7.67 (d, J = 1.3 z, 1), (m, 2), (m, Br 2), (m, 2), (m, 3), (m, 2), 5.21 (s, 1); 13 C MR (100 Mz, CDCl 3 ) δ 146.5, 144.1, 139.5, 139.4, 133.7, 132.2, 131.1, 128.7, 128.6, 128.2, 128.1, 127.7, 125.5, 121.2, 121.0, 120.0, 51.7; RM (EI ) calc. for [M ]: , found: ; pk a = 13.2; λ max = 456 nm; ε = 1796 ± 31 dm 3 mol 1 cm 1. Ph 9-Phenylsulfonylfluorene (Ph 2 -F). 7 9-Phenylthiofluorene (0.43 g, 1.6 mmol) was dissolved in 8 ml DCM. m- Chlorperbenzoicacid (0.60 g, 3.5 mmol) was added portionwise, and the mixture was stirred overnight at room temperature. The precipitate was filtered off, and the DCM solution was washed with aq. a 2 C 3 solution and water. The organic phase was separated, dried over Mg 4, and concentrated under vacuum. The crude material was recrystallized from ethanol to yield 0.17 g (35%) pure product as a white solid. 1 MR (400 Mz, CDCl 3 ) δ (m, 2), (m, 2), (m, 4), (m, 1), (m, 2), (m, 2), 5.34 (s, 1); 13 C MR (100 Mz, CDCl 3 ) δ 141.9, 135.5, 134.4, 133.3, 129.5, 129.1, 127.6, 127.2, 119.9, 71.3; RM (EI ) calc. for [M ]: , found: ; pk a = 11.55; λ max = 382 nm; ε = 7788 ± 181 dm 3 mol 1 cm 1. Ph Br 2-Bromo-9-phenylsulfonylfluorene (2-Br-Ph 2 -F). 2-Bromo-9-phenylthiofluorene was oxidized in a similar manner as described above (Ph 2 -F). The crude material was recrystallized from ethanol (yield = 35%). 1 MR (400 Mz, CDCl 3 ) δ (m, 1), (m, 1), (m, 1), (m, 3), (m, 2), (m, 4), 5.39 (s, 1); 13 C MR (100 Mz, CDCl 3 ) δ 140.8, 137.5, 135.4, 134.3, 133.6, 132.6, 130.3, 129.7, 129.2, 128.1, 127.9, 127.2, 121.2, 121.1, 120.0, 71.1; RM (EI ) calc. for [M ]: , found: ; pk a = 9.6; λ max = 410 nm; ε = 4580 ± 16 dm 3 mol 1 cm 1. 4

5 9-Ethylsulfonylfluorene (Et 2 -F). 4 9-Ethylthiofluorene was synthesized similarly to i Pr-F followed by an oxidation described above (Ph 2 -F). The crude material was recrystallized twice from ethanol (overall yield = 30%). IR (KBr) 3444, 3060, 2943, 2901, 1449, 1306, 1290, 1174, 1112 cm 1 ; 1 MR (400 Mz, CDCl 3 ) δ 7.98 (d, J = 7.6 z, 2), 7.78 (d, J = 7.6 z, 2), 7.51 (t, J = 7.6 z, 2), 7.40 (td, J 1 = 7.6 z, J 2 = 1.2 z, 2), 5.26 (s, 1), 2.19 (q, J = 7.5 z, 2), 0.92 (t, J = 7.5 z, 3); 13 C MR (100 Mz, CDCl 3 ) δ 141.5, 135.6, 129.8, 128.2, 127.2, 120.4, 69.9, 41.2, 5.2; RM (EI ) calc. for [M ]: , found: ; pk a = 12.30; λ max = 406 nm; ε = 2304 ± 46 dm 3 mol 1 cm 1. ynthesis and characterization of (thio)urea derivatives -phenyl- -(3-trifluoromethylphyenyl)-thiourea (9). Freshly distilled aniline (150 mg, 1.6 mmol) was dissolved in 2 ml dry TF and cooled to 0 C. Under argon atmosphere 3- trifluoromethylphenyl-isothiocyanate (327 mg, 1.6 mmol) was added and the resulting mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the crude material was purified by column chromatography (hexanes/ethyl acetate = 5/1) to yield 350 mg (73%) pure product as a white solid. 1 MR (400 Mz, CDCl 3 ) δ 8.46 (br s, 1), 8.02 (br s, 1), (m, 1), 7.65 (s, 1), (m, 4), (m, 3); 13 C MR (100 Mz, CDCl 3 ) δ 179.7, 138.3, 136.2, (q, J = 33.6 z), 130.2, 129.6, 128.4, 127.9, 125.5, (q, J = 272 z), (q, J = 3.8 z), (q, J = 3.8 z); RM (EI) calc.: , found: ; Elemental anal.: calc. (%) for C F 3 2 (296.31): C 56.75, 3.74, 9.45; found: C 56.79, 3.67, phenyl- -(3,5-bis(trifluoromethyl)phenyl)-urea (10). Freshly distilled aniline (111 mg, 1.2 mmol) was dissolved in 2 ml dry TF and cooled to 0 C. Under argon atmosphere 3,5- bis(trifluoromethyl)phenylisocyanate (300 mg, 1.2 mmol) was added and the resulting mixture was stirred overnight at room temperature. The solvent was 5

6 removed under reduced pressure and the crude material was recrystallized from a mixture of hexanes and ethyl acetate to yield 284 mg (69%) pure product as a fluffy white solid. 1 MR (400 Mz, d 6 -DM) δ 9.38 (s, 1), 8.98 (s, 1), 8.13 (s, 2), 7.63 (s, 1), 7.48 (d, J = 7.8 z, 2), 7.30 (t, J = 7.8 z, 2), 7.01 (t, J = 7.5 z, 1); 13 C MR (100 Mz, d 6 - DM) δ , 141.9, 139.0, (q, J = 30.5 z), 128.7, (q, J = 272 z), 122.5, 118.8, (d, J = 4.0 z), (q, J = 3.5 z); RM (EI) calc.: , found: ; Elemental anal.: calc. (%) for C F 6 2 (348.24): C 51.73, 2.89, 8.04; found: C 51.77, 2.87, Thiourea 20. ()-2-(3-((1R,2R)-2-((E)-(3,5-di-tertbutyl-2-hydroxybenzylidene)-amino)cyclohexyl)-thio ureido)-,-diethyl-3,3-dimethylbutanamide. aturated aqueous ac 3 (10 ml) was added to a solution of L-tert-leucine diethylamide 8 (600 mg, 3.22 t-bu t-bu mmol) in DCM (18 ml) at 0 C. The mixture was stirred for 30 minutes, then the stirring was stopped and thiophosgene (282 μl, 3.54 mmol) was added to the organic phase by syringe. The resulting orange mixture was stirred at 0 C for 1 h. DCM (30 ml) was added, and the organic phase separated. The aqueous phase was extracted with DCM (3 40 ml). The combined organic extracts were dried over Mg 4 and concentrated, yielding ()-2-isothiocyanato-,-diethyl-3,3-dimethylbutanamide as a solid, which was used without further purification. The crude isothiocyanate was dissolved in freshly distilled DCM (30 ml) and (R,R)-1,2-diaminocyclohexane (404.5 mg, 3.54 mmol) was added in one portion. The reaction mixture was allowed to stir at room temperature for 30 min and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (2 M solution of ammonia in methanol/dcm = 1/9) to afford the corresponding amine (776 mg, 2.26 mmol), which was subsequently dissolved in anhydrous methanol (10 ml). nce the solution became homogeneous, oven dried sodium sulphate (2.6 g) was added. In a separate flask, 3,5-di-tert-butyl-2-hydroxybenzaldehyde (503.8 mg, 2.26 mmol) was dissolved in anhydrous methanol (18 ml), then added at once. The reaction mixture was stirred for 90 min, than concentrated under reduced pressure. The solid was suspended in hexanes (60 ml); the precipitate was filtered off, and rinsed with hexanes (60 ml). The filtrate was concentrated to yield g (68%) of 20 as a bright yellow solid, mp = 131 C. The compound exists as a ~4 : 1 mixture of rotamers: 9 the major 6

7 rotamer is donated by *. 1 MR (400 Mz, CDCl 3 ) δ (br s, 1, *), (br s, 1, ), 9.88 (s, 1, C=), 8.40 (s, 1, C=*), 7.59 (d, J = 2.4 z, 1, Ar), 7.35 (d, J = 2.3 z, 1, Ar*), 7.07 (d, J = 2.3 z, 1, Ar*), 6.47 (br s, 1, *), 6.14 (br s, 1, *), 5.49 (d, J = 9.35, 1, C(C 3 )*), 3.83 (br s, 1, C cycl.*), (m, 2, C 2 C 3 *), (m, 1, C 2 C 3 *), 3.13 (br s, 1, C cycl.*), (m, 1, C 2 C3*), 2.17 (s, 1, C 2 cycl.*), (m, 4, C 2 cycl.*), (m, 3, C 2 cycl.*), 1.41 (s, 9, C(C 3 ) 3 *), 1.32 (s, 9, C(C 3 ) 3 ), 1.28 (s, 9, C(C 3 ) 3 *), 1.23 (t, J = 7.1 z, 3, C 2 C 3 ), 1.08 (t, J = 7.1 z, 3, C 2 C 3 ), 0.89 (s, 9, C(C 3 ) 3 *); 13 C MR (100 Mz, CDCl 3 ) δ 197.4, 181.2, 170.7, 166.2, 159.1, 158.0, 141.6, 140.0, 137.6, 136.5, 131.9, 127.9, 127.1, 126.3, 117.8, 60.3, 56.8, 42.9, 40.1, 36.3, 35.0, 34.3, 34.1, 33.4, 31.5, 31.3, 31.0, 29.5, 29.3, 26.7, 26.6, 24.2, 23.6, 14.6, 12.8; RM (EI+) calc. for [M+]: , found: ; Elemental anal.: calc. (%) for C (558.86): C 68.77, 9.74, 10.02; found: C 68.52, 9.82, pectrophotometric titrations Preparation of stock solutions 10 DM: The commercial solvent was stored over Al 2 3 for 24h. Then approximately 100 ml was transferred to a distillation device under argon atmosphere. The system was evacuated and flushed with argon repeatedly, followed by the addition of triphenylmethane (5 10 mg). odiumamide was added portionwise until the solution turned deep red. The system was evacuated again, and the ammonia gas trapped with liquid nitrogen. When the gas evolution ceased, the distillation was started by elevating the oil bath temperature to 55 C (10 4 mbar). After collecting 10 ml fore fraction, the dry DM was received in a chlenk-tube, and kept under argon. The fresh solvent was used within 24 hours. Water content was determined by Karl-Fischer method prior to each titration, and was found to be in a range of 7 25 ppm. K-dimsyl base: 800 mg K (25 35 w% dispersion in mineral oil) was added to a schlenk-tube under argon, and was washed several times with pentane. The most of the solvent was removed with a syringe, and the remaining solid was dried in vacuum. With vigorous stirring 20 ml dry 7

8 DM was added to the tube and the solid was dissolved in a slightly exothermic reaction. The system was evacuated, and was flushed with argon, when de gas evolution ceased. The base solution (c = mmol/g) was stored under argon in a chlenk-tube covered with aluminum foil and used for several days. Catalyst and indicator solutions: The desired compound was added to a previously weighted oven dried flask, and the precise amount determined. The flask was sealed with septum and weighted again, then flushed with argon. Dry DM was added, the accurate amount determined gravimetrically. After the solid was dissolved argon was bubbled through the stock solution, which was kept under this protective atmosphere throughout the whole titration. The solutions were prepared prior to use, and were discarded after. Titration and evaluation 10 The spectrophotometric cell (d = 1 cm, quartz) was equipped with a stirring bar, sealed with a septum cap, and weighted. The cell was charged with freshly distilled DM and weighted again. Argon was bubbled through the liquid and calculated amount of the base solution was added, the cell weighted again. Then the first UV spectrum was recorded to determine the base line, and the titration was started. everal aliquots (15 20 μl) of the indicator stock solution was added, the weight of the cell and the UV spectrum recorded after each step, until no further increase of the absorbance value at a chosen wavelength was observed. The absorbance value and the concentration of the indicator in the cell corresponded according to Lambert-Beer s law, a typical example demonstrated below (Figure 1). The slope of the linear fit gave the molar extinction coefficient, and was determined in every titration. At this stage the K-dimsyl base in the cell was consumed completely and the solution contained only the two species of the indicator. The concentration of the deprotonated form could be calculated directly from the absorbance value: c Ind = A λ /ε (1) The overall amount of the two species was known, which led to the concentration of the protonated form: c Ind = c 0 c Ind (2) 8

9 Dilution effect was taken into account through the volume increase upon sample addition. We assumed that the dilute stock solutions had the same density as that of the pure DM. Five increments of the catalyst solution were added, the weight of the cell and the absorbance value recorded after each step. With an appropriate indicator a new acid-base equilibrium was established with each addition, causing a loss in the absorbance value at a chosen wavelength, as the indicator anion was reprotonated (Figure 2). The change could only be implemented by the catalyst (A) as proton source, so the following equations applied: A + Ind A + Ind (3) Δ[Ind] = Δ[A] (4) With the necessary concentration values in hand, the equilibrium constant of eq. 3 could be calculated, which led to the desired pk a value. Charges were omitted for clarity: [ Ind] [ [ A] [ ] A K eq = (5) Ind] pk a = pk Ind logk eq (6) 2-Br-9-Ph-F 1,6000 1, nm / AU 1,2000 1,0000 0,8000 0,6000 0,4000 y = 1828,9x + 0,0328 R 2 = 0,9999 0,2000 0, ,0001 0,0002 0,0003 0,0004 0,0005 0,0006 0,0007 0,0008 0,0009 Concentration / M Figure 1. A typical Lambert-Beer plot This way the titration provided 5 pk a values and the average of them was considered to be the result. In our selected example, the following values were obtained: 9

10 K eq pk a Four of them showed excellent agreement, so the first value was not taken into account, when the final pk a was calculated. mean st. dev. pk a Figure 2. Absorption spectra of 2-Br-9-Ph-F obtained during the second part of the titration 10

11 Reliability of the measurements In order to verify our method and manipulations, two model compounds were chosen for measurement with known pk a values. Four titrations (two runs with different indicators for each weak acid) were selected to demonstrate the close agreement between the obtained results and the literature values. compound indicator (pk a ) pk a value (lit.) st. dev. C PP (10.8) (11.0) C MeC-F (10.35) (11.0) 0.02 Et 2 -F (12.30) Br-9-Ph-F (13.2) (13.4) Furthermore, one catalyst was selected to be measured against three different indicators, to see how these parallel titrations correlate. These measurements were conducted from different benches of dry DM and stock solutions, thus considered independent. In this way, the standard deviation of the dataset below furnished the error of the pk a determination, while the average value gave the mean (pk a = ± 0.04). 11

12 compound indicator (pk a ) pk a value st. dev. Et -F (12.30) Et -F (12.30) Ph 2 -F (11.55) Ph -F (11.55) Br-9-Ph-F (13.2) The pk a values reported in this study were determined similarly to the example presented. At least two different indicators were used in parallel measurements in each case. References (1) ou, X.; Ge, Z.; Wang, T.; Guo, W.; Wu, J.; Cui, J.; Lai, C.; Li, R. Arch. Pharm. 344, (2) Krogh, E.; Wan, P. J. Am. Chem. oc. 1992, 114, (3) Ullmann, F.; von Wurstemberger, R. Chem. Ber. 1904, 37, (4) Bordwell, F. G.; Drucker, G. E.; McCollum, G. J. J. rg. Chem. 1982, 47, (5) Kice, J. L.; Lotey,. J. rg. Chem. 1988, 53, (6) Bordwell, F. G.; Clemens, A.. J. rg. Chem. 1982, 47, (7) Bavin, P. M. G. Can. J. Chem. 1960, 38, (8) Taylor, M..; Jacobsen, E.. J. Am. Chem. oc. 2004, 126, (9) Wenzel, A. G.; Jacobsen, E.. J. Am. Chem. oc. 2002, 124, (10) Matthews, W..; Bares, J. E.; Bartmess, J. E.; Bordwell, F. G.; Cornforth, F. J.; Drucker, G. E.; Margolin, Z.; McCallum, R. J.; McCollum, G. J.; Vanier,. R. J. Am. Chem. oc. 1975, 97,

13 Appendix 1 MR spectrum of 9: 9 13 C MR spectrum of 9: 9 13

14 1 MR spectrum of 10: C MR spectrum of 10: 10 14

15 1 MR spectra of 20: 20 t-bu t-bu 20 t-bu t-bu 15

16 20 t-bu t-bu 13 C MR spectrum of 20: 20 t-bu t-bu 16