S Anion binding vs. sulfonamide deprotonation in functionalised ureas Claudia Caltagirone, Gareth W. Bates, Philip A. Gale* and Mark E. Light Supplementary information Experimental Section General remarks: All reactions were performed in oven-dried glassware under a slight positive pressure of nitrogen. H-NMR (3 MHz) and 3 C NMR (75 MHz) spectra were determined on a Bruker AV3 spectrometer. Chemical shifts for H NMR are reported in parts per million (ppm), calibrated to the residual solvent peak set, with coupling constants reported in Hertz (Hz). The following abbreviations are used for spin multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet and br = broad. Chemical shifts for 3 C NMR are reported in ppm, relative to the central line of a septet at δ = 39.52 ppm for deuterio-dimethylsulfoxide. Infrared (IR) spectra were recorded on a Mattson Satellite (ATR). FTIR are reported in wavenumbers (cm ). Elemental analysis were performed by Medac Ltd. All solvents and starting materials were purchased from commercial sources where available. NMR titrations were performed by adding aliquots of the putative anionic guest (as the TBA) salt (.5 M) in a solution of the receptor (.M) in CD 3 CN to a solution of the receptor (.M) except in the case of the repeat of the fluoride titration with receptor (presented at the end of the ESI). N-(2-(3-phenylureido)phenyl)benzenesulfonamide () To a solution of -(2- aminophenyl)-3-phenylurea (.3 g,.32 mmol) in dry DMF (3 ml) and Et 3 N (.4 ml) a solution of benzenesulfonyl chloride (.23 g,.32 mmol) in dry dichloromethane ( ml) was added dropwise. The solution was stirred at room temperature under N 2 atmosphere for 6 h. After that time the solvent was removed
S2 under reduced pressure and the residue was taken up in dichloromethane and washed with water (3 ml). The organic phase was dried over MgSO 4 and the solvent was removed under reduced pressure. The crude product (a brown solid) was purified by flash chromatography on silica using a mixture of dichloromethane/ethylacetate (8/2 v/v) as eluent to afford a white solid (.8 g,.49 mmol, 37% yield). M.p.= 63 C. H NMR (3 MHz, DMSO-d 6 ): δ = 9.54 (s, H, NH sulfonamide), 9,5 (s, H, NH urea), 8.28 (s, H, NH urea), 8. (d, J = 8.3 Hz, H, ArH), 7.72-7.47 (m, 7H, ArH), 7.3 (t, J = 7.9Hz, 2H, ArH), 7.6 (t, J = 7.6 Hz, H, ArH), 6.99 (t, J = 7.53 Hz, H, ArH), 6.76 (t, J = 7.53 Hz, H, ArH), 6.44 (d, J = 7.53 Hz, H, ArH). 3 C NMR (75 MHz, DMSO-d 6 ) = δ = 53. (CO), 4.2 (CH), 39.7 (C) 37.4(C), 33.4 (CH), 3.7 (C), 29.5 (CH), 29.3 (CH), 28. (CH), 27.6 (CH), 25.4 (C), 22.3 (CH), 2.4 (CH), 8.7 (CH); IR (film): ν = 657, 598, 545, 496, 446, 39, 24, 54, 9, 75 cm ; LRMS (ES ): m/z : 366.2 [M-H] ; Elemental analysis for C 9 H 7 N 3 O 3 S Calc (%): C = 62., H = 4.66, N =.44; Found (%): C = 62.9, H = 4.7, N =.49. N,N -(2,2 -carbonylbis(azanediyl)bis(2,-phenylene))dibenzenesulfonamide (2) To a solution of,3-bis(2-aminophenyl)urea (.2 g,.83 mmol) in dry DMF (3 ml) and Et 3 N (.2 ml) a solution of benzenesulfonyl chloride (.29 g,.65 mmol) in dry dichloromethane ( ml) was added dropwise. The solution was stirred at room temperature under N 2 atmosphere for 24 h. After that time the solvent was removed under reduced pressure and the residue was taken up in dichloromethane and washed with water (3 ml). The organic phase was dried over MgSO 4 and the solvent was removed under reduced pressure. The crude product (a pale yellow solid) was purified by flash chromatography on silica using a mixture of dichloromethane/ethylacetate (8/2 v/v) as eluent to afford a white solid (.7 g,.32
S3 mmol, 39% yield). M.p.= 76 C. H NMR (3 MHz, DMSO-d 6 ): δ = 9.52 (s, 2H, NH sulfonamide), 8.7 (s, 2H, NH urea), 7.74-7.7 (m, 6H, ArH), 7.65-7.52 (m, 6H, ArH), 7.7 (t, J = 8.28 Hz, 2H, ArH), 6.89 (t, J = 7.53 Hz, 2H, ArH), 6.73 (d, J = 7.7 Hz, 2H, ArH). 3 C NMR (75 MHz, DMSO-d 6 ): δ = 53.8 (CO), 4.3 (C) 36.4 (C), 33.9 (CH), 3. (CH), 28.2 (C), 28. (CH), 27.7 (CH), 27.2 (CH), 23.9 (CH), 23.2 (CH); IR (film): ν = 3342, 66, 595, 537, 496, 329, 298, 66, 53, 9, 732 cm. LRMS (ES ):m/z: 52 [M-H] ; Elemental Analysis for C 25 H 22 N 4 O 5 S 2 Calc (%): C = 57.46, H = 4.24, N =.72; Found (%): C = 57.44, H = 4.26, N =.73.
S4 Figure S H NMR spectrum of compound in DMSO-d 6. Figure S2 3 C NMR spectrum of compound in DMSO-d 6.
S5 Figure S3 H NMR spectrum of compound 2 in DMSO-d 6. Figure S4 3 C NMR spectrum of compound 2 in DMSO-d 6.
S6 NH resonance (ppm) 3 2.5 2 2 3 4 5 6 7 Equivalents of dihydrogen phosphate Figure S5 Shifts of the urea NH groups of compound upon addition of tetrabutylammonium dihydrogen phosphate in CD 3 CN.
S7 NH resonances (ppm) 3.5 3 2.5 2 2 3 4 5 6 7 Equivalents of benzoate Figure S6 Shifts of the urea NH groups of compound upon addition of tetrabutylammonium benzoate in CD 3 CN. NH resonance (ppm) 2 3 4 5 6 7 Equivalents of fluoride Figure S7 Shifts of the urea NH groups of compound 2 upon addition of tetrabutylammonium fluoride in CD 3 CN. Upon addition of fluoride to compound 2 both the urea NH groups behave in an equivalent fashion presumably due to exchange between the sulfonamide NHs. As there are now two sulfonamide NH groups, 4 equivs. of fluoride are required to deprotonate them and generate 2 HF 2 - ions. As both urea NH groups are adjacent to a deprotonated sulfonamide they reach a plateau at 4 equivs. F -
S8 NH resonance (ppm) 3 2.5 2 2 3 4 5 6 7 Equivalents of acetate Figure S8 Shifts of the urea NH groups of compound 2 upon addition of tetrabutylammonium acetate in CD 3 CN. NH resonance (ppm) 2.5 2 2 3 4 5 6 7 Equivalents of dihydrogen phosphate
S9 Figure S9 Shifts of the urea NH groups of compound 2 upon addition of tetrabutylammonium dihydrogen phosphate in CD 3 CN. Change in chemical shifts of urea NH resonance (ppm) 3 2.5 2 2 3 4 5 6 7 Equivalents of benzoate Figure S Shifts of the urea NH groups of compound 2 upon addition of tetrabutylammonium benzoate in CD 3 CN.
S NH resonance (ppm) 2 2 3 4 5 6 7 Equivalents of chloride Figure S Shifts of the urea NH groups of compound 2 upon addition of tetrabutylammonium chloride in CD 3 CN. Figure S2 H NMR spectrum of doubly deprotonated sulfonamide 2 in acetonitriled 3.
S Calculations by WinEQNMR Version.2 by Michael J. Hynes Program run at 5:22:25 on 8/2/27 IDEAL DATA FOR : COMPLEX USING CHEMICAL SHIFT (TEST.FIT) Reaction: M + L = ML FILE: TEST.FIT IDEAL DATA: K = 63.9; DELTA M = 2.; DELTA ML = 2. File prepared by M. J. Hynes, October 22 2 NO. A PARAMETER DELTA ERROR CONDITION DESCRIPTION 7.5567E+3 2.E- 5.27E+2 2.94E+ K 2 7.772E+ 2.E-.5E-2.7E+ SHIFT M 3 9.2279E+.E+ 3.32E-3 2.5E+ SHIFT ML RMS ERROR = 8.79E-3 MAX ERROR =.76E-2 AT OBS.NO. 3 RESIDUALS SQUARED =.6E-3 RFACTOR =.885 PERCENT Figure S3 NMR titration of compound vs. TBACl in CD 3 CN.
S2 Calculations by WinEQNMR Version.2 by Michael J. Hynes Program run at ::2 on 8/29/27 IDEAL DATA FOR : COMPLEX USING CHEMICAL SHIFT (TEST.FIT) Reaction: M + L = ML FILE: TEST.FIT IDEAL DATA: K = 63.9; DELTA M = 2.; DELTA ML = 2. File prepared by M. J. Hynes, October 22 2 NO. A PARAMETER DELTA ERROR CONDITION DESCRIPTION 2.9557E+4 2.E- 5.42E+3.6E+ K 2 7.844E+ 2.E- 4.47E-2.67E+ 3 9.34449E+.E+ 9.384E-3.28E+ SHIFT M SHIFT ML RMS ERROR = 3.5E-2 MAX ERROR = 8.45E-2 AT OBS.NO. 3 RESIDUALS SQUARED =.84E-2 RFACTOR =.3465 PERCENT Figure S4 NMR titration of compound 2 vs. TBACl in CD 3 CN.
S3 NH resonances (ppm) 4. 3.5 3. 2.5 2... 5 5 2 25 Equivalents of fluoride Figure S5 Shifts of the urea groups of compound upon addition of aliquots of tetrabutylammonium fluoride (.3 M) in a solution of the receptor (2.2 x -3 M) CD 3 CN to a solution of receptor (2.2 x -3 M). The urea NH adjacent to the sulfonamide reaches a plateau upon deprotonation due to intramolecular hydrogen bonding. The other urea is free to bind to added aliquots of fluoride and continues to shift downfield as the fluoride concentration increases.