Thermodynamic Characterization of Halide-π Interactions in Solution using Two-wall Aryl extended Calix[4]pyrroles as Model System

Transcription

1 Supporting Information Thermodynamic Characterization of Halide-π Interactions in Solution using Two-wall Aryl extended Calix[4]pyrroles as Model System Louis Adriaenssens, Guzmán Gil-Ramírez, Antonio Frontera, David Quiñonero, Eduardo C. Escudero-Adan, and Pablo Ballester*,,& Institute of Chemical Research of Catalonia (ICIQ), Avda. Països Catalans 16, Tarragona, Spain Department de Quimica, Universitat de les Illes Balears, ctra. Valldemossa km 7.5, E-07122, Palma, Spain & Catalan Institution for Research and Advanced Studies (ICREA), Passeig Lluís Companys 23, Barcelona, Spain Contents 1. General information. S2 2. Synthesis S3 3. X-ray structures S15 several α,β isomers of calixpyrroles 3 S15 complex TMA Cl α,α-3a S15 4. Binding Studies. S16 Tabulated and plotted results S16-S19 Thermodynamics of iodide binding (van t Hoff plots) S20 1 H NMR study of chloride binding in chloroform S21 NMR Titrations S22 Example titrations S23 Iodide binding S24-S28 Bromide binding S29-S31 ITC Titrations S32 Chloride binding in acetonitrile S33 Bromide binding in acetonitrile S34 Chloride binding in acetone S35 Chloride binding in chloroform S36 5. References S37 S1

2 General Information and Instrumentation Calixpyrroles 2 1, 3b 2, 3d 3, 3f 4, 3g 2, 3h 5 and 3i 6 were all prepared as described in the literature. 4 -azidoacetophenone was prepared according to a literature procedure. 7 Reagents were obtained from commercial suppliers and used without further purification unless otherwise stated. All solvents were commercially obtained and used without further purification except pyrrole which was distilled and then stored in the freezer for further use. Routine 1 H NMR spectra were recorded on a Bruker Avance 300 (300 MHz for 1 H NMR), Bruker Avance 400 (400 MHz for 1 H NMR) or a Bruker Avance 500 (500 MHz for 1 H NMR) ultrashield spectrometer. The deuterated solvents (Aldrich) used are indicated in the experimental part; chemical shifts are given in ppm. For CDCl 3 the peaks were referenced relative to the solvent residual peak δh = 7.26 ppm and δc = 77.0 ppm. For CD 3 CN the peaks were referenced relative to the solvent residual peak δh = 1.94 ppm. All NMR J values are given in Hz and are uncorrected. High resolution mass spectra were obtained on a Bruker Autoflex MALDI-TOF Mass Spectrometer. Mass spectra were recorded on a Waters LCT Premier ESI-TOF spectrometer, on an Agilent 1100 LC/MSD ESI-Quadrupole or on a Waters GTC spectrometer. Flash column chromatography was performed with Silica gel Scharlab60. Crystal structure determination was carried out using a Bruker- Nonius diffractometer equipped with a APPEX 2 4K CCD area detector, a FR591 rotating anode with MoKα radiation, Montel mirrors as monochromator and a Kryoflex low temperature device (T = 100 K). Full sphere data collection omega and phi scans. Programs used: Data collection Apex2 V (Bruker-Nonius 2004), data reduction Saint + Version 6.22 (Bruker-Nonius 2001) and absorption correction SADABS V (2003). Crystal structure solution was achieved using direct methods as implemented in SHELXTL Version 6.10 (Sheldrick, Universität Göttingen (Germany), 2000) and visualized using XP program. Missing atoms were subsequently located from difference Fourier synthesis and added to the atom list. Least-squares refinement on F2 using all measured intensities was carried out using the program SHELXTL Version 6.10 (Sheldrick, Universität Göttingen (Germany), 2000). S2

3 Synthesis General synthesis of dipyromethanes 5b-i Trifluoroacetic acid (60 mmol, 3 equiv.) was added dropwise over 30 min to a stirred suspension or solution of the relevant acetophenone (20 mmol, 1 equiv) in pyrrole (30 ml, excess, 0.67 M soln.) cooled in an ice bath and under an atmosphere of argon. The reaction was allowed to come to RT and stirred 14 h at RT. The reaction was diluted with water (10 ml) and basified to ph 10 with 2M NaOH aq. During basification a cloudy precipitate forms. The reaction mixture is extracted with DCM. The organic extracts are combined, dried over Na 2 SO 4, filtered and concentrated under vacuum. The resultant residue should be left for an extended period of time (several hours) under high vacuum so that as much pyrrole as possible is removed. If this thorough evaporation is not performed residual pyrrole will complicate the subsequent chromatography. The crude brown residue was subjected to column chromatography on silica (see below for specific conditions) and the first eluting fraction was collected. 5-methyl-5-phenyl dipyrromethane 5b (21% yield) purification: silica chromatography (1:9 ethylacetate:hexane) followed by recrystallization from hexane. Rf = 0.35 (1:9 ethylacetate:hexane, silica plate) 1 H NMR (400 MHz, CDCl 3, 25 ºC) δ (ppm) 2.06 (s, 3H), 5.98 (ddd, J = 3.4, 2.7, 1.5, 2H), 6.18 (dt, J = 3.4, 2.7, 2H), 6.68 (td, J = 2.6, 1.6, 2H), (m, 2H), (m, 3H), 7.78 (s, 2H) 1 H NMR spectrum of this compound is in agreement with that reported in the literature. 8 5-methyl-5-(4 -bromophenyl) dipyrromethane 5c (21% yield) purification: silica chromatography (1:3 ethyl acetate:hexane) followed by recrystallization from ethanol/water. 1 H NMR (400 MHz, CD 3 CN, 25 ºC) δ (ppm) 1.96 (s, 3H), 5.79 (m, 2H), 6.02 (m, 2H), 6.65 (m, 2H), 6.95 (d, J = 8.7, 2H), 7.42 (d, J = 8.7, 2H), 8.74 (s, broad 2H) S3

4 5-methyl-5-(4 pyridyl) dipyrromethane 5d (35% yield) purification: silica chromatography (1:19 MeOH:CH 2 Cl 2 ) Rf = 0.5 (1:19 MeOH:CH 2 Cl 2, silica plate) or 0.25 (1:1 ethylacetate:hexane, silica plate) 1 H NMR (400 MHz, CD 3 CN, 25 ºC) δ (ppm) 2.03 (s, 3H), 5.96 (ddd, J = 3.4, 2.7, 1.5, 2H), 6.18 (dt, J = 3.4, 2.7, 2H), 6.71 (td, J = 2.7, 1.6, 2H), (m, 2H), 7.93 (bs, 2H), (m, 2H) 1 H NMR spectrum of this compound is in agreement with that reported in the literature. 9 5-methyl-5-(4 -azidophenyl) dipyrromethane 5e (65% yield) purification: silica chromatography (100% hexane 2:8 ethylacetate:hexane) Rf = 0.3 (1:9 ethylacetate:hexane, silica plate) 1 H NMR (400.1 MHz, CDCl 3 ) δ (ppm) 2.04 (s, 3H), 5.96 (ddd, J = 3.4, 2.7, 1.5, 2H), 6.18 (dt, J = 3.3, 2.6, 2H), 6.68 (td, J = 2.7, 1.5, 2H), 6.94 (d, J = 8.8, 2H), 7.10 (d, J = 8.8, 2H), 7.78 (broad s, 2H) 1 H NMR spectrum of this compound is in agreement with that reported in the literature. 2 5-methyl-5-(4 -nitrophenyl) dipyrromethane 5f (48% yield) purification: silica chromatography (1:9 ethylacetate:hexane 2:8 ethylacetate hexane) Rf = 0.35 (2:8 ethylacetate:hexane, silica plate) 1 H NMR (400 MHz, CDCl 3, 25 ºC) δ (ppm) 2.10 (s, 3H), 5.96 (ddd, J = 3.4, 2.7, 1.5, 2H), 6.21 (dt, J = 3.4, 2.7, 2H), 6.75 (td, J = 2.7, 1.5, 2H), 7.29 (d, J = 8.9, 2H), 7.87 (s, 2H), 8.13 (d, J = 8.9, 2H) 1 H NMR spectrum of this compound is in agreement with that reported in the literature. 4 5-methyl-5-(2,3,4,5,6 -pentafluorophenyl) dipyrromethane 5g (9% yield) purification: silica chromatography (1:9 ethylacetate:hexane to 3:7 ethylacetate hexane) Rf = 0.4 (16% ethylacetate in hexane, silica plate) 1 H NMR (300 MHz, CDCl 3, 25 ºC) δ (ppm) 2.23 (t, J = 2.5, 3H), 6.00 (ddd, J = 3.5, 2.7, 1.5, 2H), (m, 2H), 6.70 (td, J = 2.7, 1.6, 2H), 7.99 (broad s, 2H) 19 F{ 1 H} NMR (375 MHz, CDCl 3, 25 ºC) δ (ppm) to (m, 2F), (tt, J = 21.5, 2.9, 1F), to (m, 2F) All spectroscopic data for this compound is in agreement with that reported in the literature. 2 S4

5 5-methyl-5-(3,5 -dinitrophenyl) dipyrromethane 5h (51% yield) purification: silica chromatography (1:9 ethylacetate:hexane to 3:7 ethylacetate hexane) Rf = 0.25 (2:8 ethylacetate:hexane, silica plate) 1 H NMR (500 MHz, CDCl 3, 25 ºC) δ (ppm) 2.14 (s, 3H), 5.90 (ddd, J = 3.5, 2.7, 1.5, 2H), 6.22 (dt, J = 3.5, 2.7, 2H), 6.78 (td, J = 2.7, 1.5, 2H), 7.94 (s, 2H), 8.31 (d, J = 2.1, 2H), 8.92 (t, J = 2.1, 1H) 1 H NMR spectrum of this compound is in agreement with that reported in the literature. 5 5-methyl-5-(4 -hydroxyphenyl) dipyrromethane 5i (23% yield) purification: silica chromatography (1:9 DCM:EtOAc) 1 H NMR (400 MHz, CDCl 3, 25 ºC) δ (ppm) 2.04 (s, 3H), 5.98 (m, 2H), 6.19 (m, 2H), 6.69 (m, 2H), 6.75 (d, J = 8.8, 2H), 7.01 (d, J = 8.8, 2H), 7.79 (s, 2H) 1 H NMR spectrum of this compound is in agreement with that reported in the literature. 6 S5

6 Synthesis of α,α calix[4]pyrrole 3b. Trifluoroacetic acid (3.44 ml 45 mmol, 10 equiv.) was added dropwise to a solution of dipyrromethane 5b (1.00 g; 4.5 mmol, 1 equiv.) in acetone (HPLC grade, 30 ml) under argon atmosphere cooled in an ice bath. The mixture was allowed to come to RT and stirred for 14 hours. The reaction mixture was diluted with water (30 ml) and basified to ph 10 with 2M NaOH aq. During basification the reaction mixture turned cloudy. The reaction mixture was extracted with DCM (3 ). The DCM extracts were combined, dried over Na 2 SO 4, filtered and evaporated to give a dark brown colored residue. This residue was purified on Silica (100% hexane to 1:9 ethyl acetate:hexane) and the second eluting fraction was collected to give α,α calixpyrrole 3b. This was recrystallized from hot acetonitrile to give pure α,α calixpyrrole 3b (60 mg, 5%). α,α-calixpyrrole 3b Rf = 0.40 (1:9 ethylacetate:hexane, silica plate) N H NH HN H N 1 H-NMR (300 MHz, CDCl 3, 25 ºC) δ (ppm) 1.54 (s, 6H), 1.62 (s, 6H), 1.90 (s, 6H), 5.63 (t, J = 3.0, 4H), 5.92 (t, J = 3.0, 4H), (m, 4H), (m, 10H) 13 C{ 1 H} NMR (75 MHz, CDCl 3, 25 ºC) δ (ppm) 27.8 (CH 3 ), 27.9 (CH 3 ), 30.0 (CH 3 ), 35.1 (C), 44.7 (C), (CH), (CH), (CH), (CH), (CH), (C), (C), (C) All spectroscopic data for this compound is in agreement with that reported in the literature. 2 S6

7 Synthesis of α,α calix[4]pyrrole 3c. (Acetone that has been stored over 4Å molecular sieves for one night is used for this synthesis. It is passed through a syringe tip filter during addition to eliminate any particles of molecular sieves.) BF 3 OEt 2 (5.0 mmol, 1.1 equiv.) is added dropwise to a stirred solution of dipyromethane 5c (4.6 mmol, 1 equiv.) in acetone (125 ml) under Ar. The reaction stirs for 3 hours at RT and is then diluted with water (100 ml). The reaction mixture is evaporated under vacuum until it is judged that most of the acetone has been removed. The reaction mixture is basified to ph 7 with NaOH aq (2M) and extracted with DCM (3 ). The DCM extracts are combined, dried over MgSO 4 filtered and evaporated in vacuo. The resultant residue is purified on silica (2:8 ethylacetate:hexane). The second eluting fraction is mostly pure α,α-3c. Recrystalization from acetonitrile furnishes α,α-3c as a white solid (120 mg, 8%) α,α-calixpyrrole 3c Rf = 0.37 (1:9 ethylacetate:hexane, silica plate) 1 H-NMR (400 MHz, CD 2 Cl 2, 25 ºC) δ (ppm) 1.56 (s, 6H), 1.66 (s, 6H), 1.89 (s, 6H), 5.67 (dd, J = 3.5, 3.0, 4H), 5.96 (dd, J = 3.5, 3.0, 4H), 6.88 (d, J = 8.7, 4H), 7.33 (s, broad 4H), 7.39 (d, J = 8.7, 4H) HR-MS (ESI+ve) m/z calcd for C 38 H 39 N 4 79 Br 2 ([M + H] + ) , found S7

8 Synthesis of α,α calix[4]pyrrole 3d. Trifluoroacetic acid (0.04 ml 0.52 mmol, 1.2 equiv.) was added to a solution of dipyrromethane 5d (100 mg; 0.45 mmol, 1 equiv.) in acetone (3 ml) under argon atmosphere cooled in an ice bath. The mixture was allowed to come to RT and stirred for 14 hours. The reaction mixture was basified to ph 10 with 2M NaOH aq. During basification the reaction mixture turned cloudy. The reaction mixture was extracted with DCM (3 ). The DCM extracts were combined, dried over Na 2 SO 4, filtered and evaporated to give a dark brown colored residue. This residue was purified on Silica (100% hexane to 1:1 ethylacetate:hexane) and the second eluting fraction was collected to give pure α,α calixpyrrole 3d. α,α-calixpyrrole 3d N NH N H H N HN N Rf = 0.3 (5% MeOH in CH 2 Cl 2, silica plate) 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm) 1.55 (s, 6H), 1.63 (s, 6H), 1.88 (s, 6H), 5.62 (dd, J = 2.8, 3.3, 4H), 5.95 (dd, J = 2.8, 3.3, 4H), 6.90 (d, J = 6.2, 4H), 7.20 (broad s, 4H), 8.47 (d, J = 6.2, 4H) 1 H-NMR spectroscopic data for this compound is in agreement with that reported in the literature. 3 S8

9 Synthesis of α,α calix[4]pyrrole 3e. Trifluoroacetic acid (4.22 ml 55 mmol, 10 equiv.) was added dropwise to a solution of dipyrromethane 5e (1.53 g; 5.5 mmol, 1 equiv.) in acetone (HPLC grade, 37 ml) under argon atmosphere cooled in an ice bath. The mixture was allowed to come to RT and stirred for 14 hours. The reaction mixture was diluted with water (100 ml) and basified to ph 10 with 2M NaOH aq. The reaction mixture was extracted with DCM (3 ). The DCM extracts were combined, dried over Na 2 SO 4, filtered and evaporated to give a dark brown colored residue. This residue was purified on Silica (100% hexane to 3:17 ethyl acetate:hexane) and the second eluting fraction was collected to give α,α calixpyrrole 3e (184 mg, 10.5%). α,α-calixpyrrole 3e Rf = 0.37 (1:9 ethylacetate:hexane, silica plate) 1 H-NMR (300 MHz, CDCl 3, 25 ºC) δ (ppm) 1.54 (s, 6H), 1.62 (s, 6H), 1.88 (s, 6H), 5.62 (t, J = 3.0, 4H), 5.93 (t, J = 3.0, 4H), 6.89 (d, J = 8.7, 4H), 6.96 (d, J = 8.7, 4H), 7.19 (broad s, 4H) 13 C{ 1 H} NMR (75 MHz, CDCl 3, 25 ºC) δ (ppm) 27.7 (CH 3 ), 27.8 (CH 3 ), 30.1 (CH 3 ), 35.1 (C), 44.3 (C), (CH), (CH), (CH), (CH), (CH), (C), (C), (C) All spectroscopic data for this compound is in agreement with that reported in the literature. 2 S9

10 Synthesis of α,α calix[4]pyrrole 3f. Trifluoroacetic acid (3.35 ml 43.8 mmol, 10 equiv.) was added dropwise to a solution of dipyrromethane 5f (1.17 g; 4.38 mmol, 1 equiv.) in acetone (HPLC grade, 29 ml) under argon atmosphere cooled in an ice bath. The mixture was allowed to come to RT and stirred for 14 hours. The reaction mixture was diluted with water (30 ml) and basified to ph 10 with 2M NaOH aq. During basification the reaction mixture turned cloudy. The reaction mixture was extracted with DCM (3 ). The DCM extracts were combined, dried over Na 2 SO 4, filtered and evaporated to give a dark red colored residue. This residue was purified on Silica (100% hexane to 3:7 ethyl acetate:hexane) and the second eluting fraction was collected to give α,α calixpyrrole 3f. This was recrystallized from hot isopropanol to give pure α,α 3f (99.5 mg, 7%). α,α-calixpyrrole 3f Rf = 0.32 (2:8 ethylacetate:hexane, silica plate) 1 H-NMR (300 MHz, CDCl 3, 25 ºC) δ (ppm) 1.56 (s, 6H), 1.65 (s, 6H), 1.93 (s, 6H), 5.62 (t, J = 3.1, 4H), 5.98 (t, J = 3.0, 4H), 7.16 (d, J = 8.9, 4H), 7.23 (s, 4H), 8.10 (d, J = 8.8, 4H) 13 C{ 1 H} NMR (75 MHz, CDCl 3, 25 ºC) δ (ppm) 27.5 (CH 3 ), 27.8 (CH 3 ), 30.0 (CH 3 ), 35.2 (C), 45.0 (C), (CH), (CH), (CH), (CH), (C), (C), (C), (C) All the spectroscopic data of this compound is in agreement with that reported in the literature. 4 S10

11 Synthesis of calix[4]pyrrole 3g (Acetone that has been stored over 4Å molecular sieves for one night is used for this synthesis. It is passed through a syringe tip filter during addition to eliminate any particles of molecular sieves.) BF 3 OEt 2 (75 μl, 0.59 mmol, 1.1 equiv.) is added dropwise to a stirred solution of dipyromethane 5g (174.6 mg, mmol, 1 equiv.) in acetone (13 ml) under Ar. The reaction stirs for 3 hours at RT and is then diluted with water (13 ml). The reaction mixture is evaporated under vacuum until it is judged that most of the acetone has been removed. The reaction mixture is basified to ph 10 with NaOH aq (2M) and extracted with DCM (3 ). The DCM extracts are combined, dried over Na 2 SO 4 filtered and evaporated in vacuo. The resultant residue is purified on silica (2:8 ethylacetate:hexane 4:6 ethylacetate:hexane). The second fraction to elute is pure α,α 3g, a white solid (45.2 mg, 23%) α,α-calixpyrrole 3g Rf = 0.55 (2:8 ethylacetate:hexane, silica plate) 1 H-NMR (300 MHz, CDCl 3, 25 ºC) δ (ppm) 1.52 (s, 6H), 1.60 (s, 6H), 2.10 (broad s, 6H), 5.72 (t, J = 3.0, 4H), 5.95 (t, J = 3.0, 4H), 7.24 (broad s, 4H) 13 C{ 1 H} NMR (75 MHz, CDCl 3, 25 ºC) δ (ppm) 26.1 (CH 3 ), 27.8 (CH 3 ), 30.0 (CH 3 ), 35.2 (C), 41.7 (C), (CH), (CH), (C), (C) (note that the signals for several carbon atoms cannot be seen due to excessive splitting with the fluorine atoms) 19 F{ 1 H} NMR (375 MHz, CDCl 3, 25 ºC) δ (ppm) (broad s, 4F), (t, J = 21.4, 2F), (td, J = 22.1, 6.7, 4F) All the spectroscopic data of this compound is in agreement with that reported in the literature. 2 S11

12 Synthesis of calix[4]pyrrole 3h. Trifluoroacetic acid (0.70 ml 9.2 mmol) was added dropwise to a solution of 3,5dinitrophenyl dipyrromethane 5h (0.30 g; 0.92 mmol) in acetone (HPLC grade, 6.5 ml) under argon atmosphere cooled in an ice bath. The mixture was stirred at room temperature for 14 hours during which time a red precipitate had formed in the reaction mixture. The reaction mixture was diluted with water (10 ml) and basified to ph 10 with 2M NaOH aq. During basification the reaction mixture turned cloudy. The reaction mixture was extracted with DCM (3 ). The DCM extracts were combined, dried over Na 2 SO 4, filtered and evaporated to give a dark red colored residue. This residue was purified on Silica (1:19 ethyl acetate:hexane to 4:6 ethyl acetate:hexane) to yield both isomers of the calix[4]pyrrole. The second eluting fraction is the α,α isomer 3h. which is recrystallized from hot acetonitrile to give pure α,α 3h (36.2 mg, 5%). α,α-calixpyrrole 5h Rf = 0.18 (2:8 ethylacetate:hexane, silica plate) 1 H-NMR (400 MHz, CDCl 3, 25 ºC) δ (ppm) 1.60 (s, 6H), 1.68 (s, 6H), 2.01 (s, 6H), 5.59 (t, J = 3.2, 4H), 6.01 (t, J = 3.0, 4H), 7.28 (s, 4H), 8.17 (d, J = 2.1, 4H), 8.91 (t, J = 2.1, 2H) 13 C{ 1 H} NMR (75 MHz, CDCl 3, 25 ºC) δ (ppm) 27.1 (CH 3 ), 27.6 (CH 3 ), 30.0 (CH 3 ), 35.3 (C), 45.0 (C), (CH), (CH), (CH), (CH), (C), (C), (C), (C) All spectroscopic data is in agreement with that reported in the literature. 5 The only notable difference lies in the number of protons assigned to the signal resonating at 8.91 ppm in the 1 H NMR of compound 3h. In the literature this signal has mistakenly been assigned 4 protons instead of 2 protons. S12

13 Synthesis of calix[4]pyrrole 3i. Trifluoroacetic acid (5.5 ml 71 mmol, 10 equiv.) was added dropwise to a solution of 4- hydroxy dipyrromethane 5i (1.80 g; 7.1 mmol) in acetone (HPLC grade, 50 ml) under argon atmosphere cooled in an ice bath. The mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water (100 ml) and basified to ph 7 with 2M KOH aq. The mixture was extracted with DCM (2 ). The DCM extracts were combined, dried over MgSO 4, filtered and evaporated to give a dark brown residue. This residue was purified on Silica (6% ethyl acetate in DCM) to yield both isomers of the calix[4]pyrrole. The second eluting fraction is the α,α isomer 3i which is collected to give pure α,α 3i (50 mg, 2.4%). α,α-calixpyrrole 3i 1 H-NMR (400 MHz, CDCl 3, 25 ºC) δ (ppm) 1.55 (s, 6H), 1.63 (s, 6H), 1.88 (s, 6H), 5.65 (dd, J = 3.5, 2.8, 4H), 5.94 (dd, J = 3.5, 2.8, 4H), 6.70 (d, J = 8.8, 4H), 6.86 (d, J = 8.8, 4H) 7.23 (s, broad 4H) 1 H NMR spectrum is in agreement with that reported in the literature. 6 S13

14 Synthesis of calix[4]pyrrole 3a. Cs 2 CO 3 (0.23 g, 0.7 mmol, 5.5 equiv) and MeI (0.03 ml, 0.49 mmol, 3.8 equiv) were added to a solution of 4-hydroxyphenyl calixpyrrole 3i (75 mg, 0.13 mmol, 1 equiv) in dry DMF (5.0 ml) and the reaction mixture was stirred in a sealed tube under argon at C for 5h. Then the reaction was cooled to room temperature and poured in 15 ml of distilled water. The mixture was filtered to obtain compound 3a as a white precipitate (50 mg, 63%). α,α-calixpyrrole 3a 1 H-NMR (400 MHz, CDCl 3, 25 ºC) δ (ppm) 1.56 (s, 6H), 1.66 (s, 6H), 1.89 (s, 6H), 3.79 (s, 6H), 5.66 (dd, J = 3.7, 2.9, 4H), 5.95 (dd, J = 3.7, 2.9, 4H), 6.79 (d, J = 8.9, 4H), 6.89 (d, J = 8.9, 4H) 7.32 (s, broad 4H) HR-MS (ESI+ve) m/z calcd for C 40 H 45 N 4 O 2 ([M + H] + ) , found S14

15 X-ray structures Figure S1 X-ray structures of a) α,β-3c, b) α,β-3h and c) α,β-3g calix[4]pyrroles all in 1,2 alternate conformation. The two wall α,β-3 calixpyrroles are depicted in stick representation and the two hydrogen bonded acetonitrile molecules as CPK models. Figure S2 a) X-ray structure of the Cl α,α-3a complex. b) expansion (side and top views) of the region relevant to the chloride-π interaction; important geometrical parameters between the Cl and the aromatic ring are indicated. c) Partial packing of the X-ray structure of TMA Cl α,α-3a. S15

16 Binding Studies Binding (K a, ΔGG and ΔΔG) ) in acetonitrile Table S1. Association constants (K a, M -1 ) and free energies of complexation (ΔG, kcal mol -1 ) measured in MeCN at 298 K for the inclusion complexes of the three halide anions with the receptor series α,α-33 and the reference octamethyl calix[4] pyrrole 2, a statistically corrected free energy values calculated for the anion-π interactions (ΔΔG, kcal mol -1 ) halide chloride bromide iodide receptor 2 (Me) 3a (OMe) 3b (H) 3c (Br) 3d (Py) 3e (N 3) 3f (NO 2) 3g (C 6 F 5 ) 3h (di-no 2 ) esp n/a K a c c c c 553 c 1790 ΔG ΔΔG d n/a K a c 0.8 b 2.8 b 2.3 c 1.4 b 4.7 c 32.3 c 39.5 c ΔG ΔΔGG n/a K a 12.6 b 18.2 b 33.5 b 892 e 380 b ΔG ΔΔG d n/a [a] ITC titration experiments were repeated at least twice and the reported K a is the mean of the values obtained from the fit of the integrated heat data to a 1:1 binding model. NMR titration experiments were also repeated at least twice and the reported K a is the mean of the values obtained from the fit of the chemical shift changes observed for the proton signals to a 1.1 binding model. Errors for ΔG are assumed to be in the region of ±20%. [b] Determined by NMR spectroscopic titration [c] Determined by ITC [d] ΔΔG = (ΔGG X - 3 ΔG X - 2)/2.[e] Data from the titration of α,α-3g with TBAI failed to fit well to a 1:1 model and gave significantly different to expected values (see Figure S14). Figure S3 Experimental values for the anion-π interaction derived from the binding of chloride ( ), bromide ( ), or iodide ( ) with two-wall calix[4]pyrroles α,α-3 plotted against the ESP values calculated at the centroid of the aromatic walls. S16

17 Thermodynamic components of binding (ΔH and TΔS) in different solvents Table S2. Experimental values for the enthalpic (ΔH, kcal/mol) and entropic (TΔS, kcal/mol, 298 K) components of the free energy of binding for the complexes of chloride, bromide and iodide with two-wall calix[4]pyrroles α,α-3. a chloride (MeCN) bromide (MeCN) iodide (MeCN) chloride (acetone) chloride (CHCl 3) receptorr 2 (Me) 3a (OMe) 3b (H) 3c (Br) 3d (py) 3e (N 3 ) 3g (NO 2 ) 3h (F 5) 3i (di-no 2 ) ESP n/a ΔH TΔS ΔH TΔS ΔH TΔS ΔH TΔS ΔH TΔS [a] the values presented are the mean of those obtained from at least two ITC titration experiments with the exception of those for the binding of iodide that were obtained from a single variable temperature 1 H NMR titration. Errors for ΔH and TΔS are assumed to be in the region of ±20% Figure S4 Experimental values for the enthalpic (lower, circles, ΔH, kcal/mol) and entropic (upper, diamonds, 298 K, kcal/mol) components of the free energy of binding for the complexes of chloride in acetone (lime),chloride in acetonitrile (green), bromide in acetonitrile (burgandy) and iodide in acetonitrile (purple) with two-wall calix[4]pyrroles α,α-33 plotted against the ESP values at the center of the respective meso-aromatic rings. S17

18 Table S3. Association constant values (K a, M -1 ) measured in chloroform at 298 K and free energies of binding (ΔG, kcal/mol) for the inclusion complexes of MTOACl with the receptor series α,α-3 and the reference octamethyl calix[4]pyrrole 2, corresponding enthalpic (ΔH, kcal/mol) and entropic (TΔS, kcal/mol, 298 K) components, statistically corrected free energy values calculated for the chloride-π interactions (ΔΔG, kcal/mol). a receptor ESP K a 10 3 ΔG ΔH TΔS ΔΔG b 2 n/a n/a 3b(H) e(N 3) g(NO 2) h(F 5) i(di-NO 2 ) [a] the values presented are the mean of those obtained from at least two ITC titration experiments. Errors are assumed to be in the region of ±20%. [b] ΔΔG = (ΔG X - 3 MTOA ΔG X - 2 MTOA )/2. Figure S5 Experimental values for the enthalpic (lower, circles, ΔH, kcal/mol) and entropic (upper, diamonds, 298 K, kcal/mol) components of the free energy of binding for the complexes of chloride in CHCl 3 (blue) and chloride in acetonitrile (green) with twowall calix[4]pyrroles α,α-3 plotted against the ESP values at the center of the respective meso-aromatic rings. S18

19 Chloride binding (K a, ΔG and ΔΔG) in chloroform and acetonitrile Table S4. Association constants (K a, M -1 ) and free energies of complexation (ΔG, kcal mol -1 ) measured in MeCN or chloroform at 298 K for the inclusion complexes of chloride with the receptor series α,α-3 and the reference octamethyl calix[4]pyrrole 2, a statistically corrected free energy values calculated for the anion-π interactions (ΔΔG, kcal mol -1 ) chloroform acetonitrile receptor esp K a 10 3 ΔG ΔΔG b K a 10 3 ΔG ΔΔG b 2 (Me) n/a n/a n/a 3b (H) e (N 3 ) f (NO 2) g (C 6F 5) h (di-no 2 ) [a] ITC titration experiments were repeated at least twice and the reported K a is the mean of the values obtained from the fit of the integrated heat data to a 1:1 binding model. Errors for ΔG are assumed to be in the region of ±20%. [b] ΔΔG = (ΔG X - 3 ΔG X - 2 )/2 Figure S6 Experimental values for the anion-π interaction in chloroform (blue) or acetonitrile (green) derived from the binding of chloride with two-wall calix[4]pyrroles α,α- 3 plotted against the ESP values calculated at the centroid of the aromatic walls. S19

20 Thermodynamics of iodide binding (van t Hoff plots) Due to the low stability of the Iodide complexes I 3 and the generally low solubility of calixpyrroles 3 in acetonitrile, the enthalpic and entropic components of the free energy of binding for complexes I 33 could not be reliably determined using ITC. To gain an idea of whether the same general trends that were seen for the Cl 3 and Br 3 complexes in acetonitrile persisted for the I 3 complexes, we performed variable temperature 1 H NMR titrations and then inserted the obtained values into the van t Hoff equation. Specifically, α,α-3f, 3g & 3h (around 1 mm in CD 3 CN) were titrated with TBA I. By cooling and heating the sample within the NMR spectrometer, each point during the titration was analysed by 1 H NMR at three different temperatures between 253 K and 318 K. After the titration, a binding constantt was determined for the complex I 3 at each of the different temperatures. Then by plotting the natural log of the binding constant against the inverse of the temperature, ΔH and ΔSS could be extracted from the slope and y intercept of the linear regression line using the integrated van t Hoff equation (equation 1). As can be seen in Figure S4, the same trends persisted for the complexes of receptors 3 with Cl, Br and I. Table S5. Binding constants and the natural log of those binding constants for the complexes I 3 in CD 3 3CN at different temperatures. 3f (NO 2 ) 3g (C 6 F 5 ) 3h (di-no 2 ) T (K) /T Ka (M -1 ) Ln(Ka) Ka (M -1 ) Ln(Ka) Ka (M ) Ln(Ka) [a] the values presented were determined by 1H NMR titrations. Errors for Ka are assumed to be in the region of ±20% (1) ln K a = ΔH RT + ΔS R Table S6. Values for the enthalpic and entropic components of binding (ΔH and ΔS) for the complexes I 3 determined using the integrated van t Hoff equation (equation 1). receptor 3f 3g 3h ΔH (kcal/mol) ΔS (kcal/mol) Figure S7 Plot of ln K a vs. 1/T for the complexes of iodide with 3f (purple) 3g (red) and 3h (green). The equations shown define the linear regression lines and were used to determinee ΔH and ΔSS for the different binding processes using the slope, y intercept and the integrated vant Hoff equation (equation 1). S20

21 1 H NMR study of chloride binding in chloroform Figure S8 Selected regions of the 1 H NMR spectra acquired for the titration of α,α-3f (NO 2 ) with MTOACl in CDCl 3 solution at 298 K. [α,α-3f] = 2.2 mm. Primed symbols indicate proton signals for the bound receptor. Arrows are used to allocate this set of proton signals in the slow chemical exchange. The addition of less than 1 equiv. of MTOACl induced the appearance of a new set of proton signals alongside the signals belonging to the free receptor. We assigned the new set of signals to protons of the bound receptor in the inclusion complex Cl α,α- 3f TMOA +. The addition of 1 equivalent of MTOACl gave rise to the observation of a single set of sharp proton signals corresponding to the receptor in the bound state. The addition of more than 1 equivalent of MTOACl did not induce additional changes to the proton signals of the receptor. Upon chloride binding, the proton signal of the pyrrole NHs (H a ) was shifted significantly downfield (Δδ = 4 ppm) while the signals corresponding to the protons of the aromatic walls (H d&e ) moved upfield (Δδ = -0.1 for H e and -0.3 ppm for H d ). The downfield shift experienced by the signal belonging to the NHs is consistent with the formation of four hydrogen bonds with the chloride anion. The upfield shift registered for the aromatic protons constitutes clear evidence for the interaction of the chloride ion with the face of the π-system and not with the CH groups via CH Cl hydrogen bonds. The movement in opposite directions of the β-pyrrolic protons H b&c is representative of the conformational change of the calixpyrrole from 1,3 alterate to cone. 10 All in all, the binding induced changes in the 1 H NMR spectrum suggest a binding geometry in which the calix[4]pyrrole core of the receptor adopts the cone conformation and forms four hydrogen bonds between the pyrrole NHs and the bound chloride. The bound chloride is sandwiched in the cleft defined by the two axially oriented meso-phenyl groups. S21

22 1 H NMR Titrations All titrations were carried out on a Bruker 500 MHz or 400 MHz spectrometer, at 298 K, in acetonitrile-d 3 (CD 3 CN). The association constant between receptors 2 and α,α- 3b-h and bromide or iodide was determined by monitoring the chemical shift changes of the proton signals corresponding to the receptors in the 1 H NMR spectrum (and in the case of α,α-3g the 19 F NMR spectrum as well) as incremental amounts of the guest were added. As many signals as possible were monitored but sometimes excessive broadening or peak overlap rendered a specific signal impossible to follow. The value of the association constant was calculated using the software HypNMR 11 which uses least-squares minimization to obtain globally optimized parameters. In all cases, except the binding of Iodide with receptor α,α-3g (Figure S14), the data fit well to a simple 1:1 binding model. Specifically, the association constants were determined using about 1-2 mm solutions of 2 and α,α-3b-h in CD 3 CN at 298 K, and adding aliquots of a solution of [Bu 4 N] + [X] -, approximately 10 to 100 times more concentrated, in the same solvent. In this manner, by using the aforementioned 1-2 mm solutions of 2 and α,α-3b-h to prepare the solutions of [Bu 4 N] + [X] - the concentration of the receptor was maintained constant throughout the titration. The association constant (K a ) for the binding process between receptors 2 and α,α-3b-h and bromide or iodide were determined by averaging the values from at least two titrations. S22

23 Iodide Binding Figure S9 Selected regions of the 1 H NMR spectra acquired for the titration of α,α-3h with TBAI in acetonitrile solution at 298 K. [α,α-3h] = 1.1 mm. * Impurity. Numbers with primes indicate the signals of complexed α,α-3h. Bromide binding Figure S10 Selected regions of the 1 H NMR spectra acquired for the titration of α,α-3h with TBABr in acetonitrile solution at 298 K. [α,α-3h] = 1.1 mm. Numbers with primes indicate the signals of complexed α,α-3h. S23

24 Octamethyl Calixpyrrole 2 iodide binding Figure S11 Binding data taken from the titration of calixpyrrole 2 with [Bu 4 N] + [I] -. panel A: 1 H NMR (400 MHz, CD 3 CN, 298 K) spectra of the starting point (2.9 mm 2) and end point (2.9 mm 2 with 61 equiv [Bu 4 N] + [I] - ) of the titration. Panel B: speciation of free calixpyrrole 2 and host guest complex I - 2 as a function of [Bu 4 N] + [I] - concentration. Panel C: fitting of the 1 H NMR data, experimental data points are red circles (H a ) and blue squares (H b ) the correspondingly colored lines represent the theoretical fitted data. S24

25 Calixpyrrole 3d iodide binding Figure S12 Binding data taken from the titration of calixpyrrole 3d with [Bu 4 N] + [I] -. Panel A: 1 H NMR (400 MHz, CD 3 CN, 298 K) spectra of the starting point (1.0 mm 3d) and end point (1.0 mm 3d with 1000 equiv [Bu 4 N] + [I] - ) of the titration. Panel B: speciation of free calixpyrrole 3d and host guest complex I - 3d as a function of [Bu 4 N] + [I] - concentration. Panel C: fitting of the 1 H NMR data, experimental data points are red triangles (H c ) and blue triangles (H b ) the correspondingly colored lines represent the theoretical fitted data. S25

26 Calixpyrrole 3f iodide binding Figure S13 Binding data taken from the titration of calixpyrrole 3f with [Bu 4 N] + [I] -. panel A: 1 H NMR (4000 MHz, CD 3 CN, 298 K) spectra of the starting point (0.86 mm 3f) and end point (0.86 mm 3f with 68 equiv [Bu 4 4N] + [I] - ) of the titration. Panel B: speciation of free calixpyrrole 3f and host guest complex I - 3f as a function of [Bu 4 N] + [I] - concentration. Panel C: fitting of the 1 H NMR data, experimental data points are red diamonds (H b ) and blue triangles (H c ) the correspondingly colored lines represent the theoretical fitted data. S26

27 Calixpyrrole 3g iodide binding Figure S14 Binding data taken from the titration of calixpyrrole 3g with [Bu 4 N] + [I] -. panel A: 1 H NMR (400 MHz, CD 3 CN, 298 K) and 19 F NMR (insets) spectra of the starting point (10 mm 3g) and endpoint (10 mm 3g with 2.1 equiv [Bu 4 N] + [I] - ) of the titration. Panel B: speciation of free calixpyrrole 3g and host guest complex I - 3g as a function of [Bu 4 4N] + [I] - concentration. Panel C: fitting of the NMR data, experimental data points are red triangles (F ortho ) and blue circles (H a ) the correspondingly colored lines represent the theoretical fitted data. S27

28 Calixpyrrole 3h iodide binding Figure S15 Binding data taken from the titration of calixpyrrole 3h with [Bu 4 N] + [I] -. panel A: 1 H NMR (400 MHz, CD 3 CN, 298 K) spectra of the starting point (3 mm 3h) and endpoint (3 mm 3h with 9. 5 equiv [Bu 4 N] + [I] - ) of the titration. Panel B: speciation of free calixpyrrole 3h and host guest complex I - 3h as a function of [Bu 4 N] + [I] - concentration. Panel C: fitting of the NMR data, experimental data points are red triangles (H c ) and blue circles (H a ) the correspondingly colored lines represent the theoretical fitted data. S28

29 Calixpyrrole 3b bromide binding Figure S16 Binding data taken from the titration of calixpyrrole 3b with [Bu 4 N] + [Br] -. panel A: 1 H NMR (400 MHz, CD 3 CN, 298 K) spectra of the starting point (1 mm 3b) and beyond the end point (1 mm 3b with 40 equiv [Bu 4 N] + [Br] - ) of the titration. Panel B: speciation of free calixpyrrole 3b and host guest complex Br - 3b as a function of [Bu 4 N] + [Br] - concentration. Panel C: fitting of the NMR data, experimental data points are red triangles (H c ) and blue circles (H a ) the correspondingly colored lines represent the theoretical fitted data. S29

30 Calixpyrrole 3c bromide binding Figure S17 Binding data taken from the titration of calixpyrrole 3c (1.3 mm) with [Bu 4 N] + [Br] -. Panel A: structure of α,α-3c with selected proton assignments: Panel B: speciation of free calixpyrrole 3c and host guest complex Br - 3c as a function of [Bu 4 N] + [Br] - concentration. Panel C: fitting of the NMR data, experimental data points are triangles (H d ) and squares (H c ) the lines represent the theoretical fitted data. S30

31 Calixpyrrole 3e bromide binding Figure S18 Binding data taken from the titration of calixpyrrole 3e with [Bu 4 N] + [Br] -. panel A: 1 H NMR (400 MHz, CD 3 CN, 298 K) spectra of the starting point (2.3 mm 3e) and the end point (2.3 mm 3e with 4 equiv [Bu 4 N] + [Br] - ) of the titration. Panel B: speciation of free calixpyrrole 3e and host guest complex Br - 3e as a functionn of [Bu 4 N] + [Br] - concentration. Panel C: fitting of the NMR data, experimental data points are red triangles (H b ) and blue circles (H c ) the correspondingly colored lines represent the theoretical fitted data. S31

32 ITC Titrations All titrations were carried out on a Microcal VP-ITC microcalorimeter, at 298 K, in acetonitrile or acetone as designated in the following pages. The association constant between receptors 2 and 3a-h and chloride or bromide was determined by monitoring the heat released by the system as incremental amounts of the guest were added. The values of the association constant K a and the enthalpy of binding ΔH were calculated using the Origin 7 software package which uses least-squares minimization to obtain globally optimized parameters as described in Wiseman et al. 12 In all cases the data fit well to a simple 1:1 binding model. Specifically, the association constants were determined using mm solutions of 2 and 3a-h in acetonitrile, acetone or chloroform at 298 K, and adding aliquots of a solution of [Bu 4 N] + [X] -, approximately 10 times more concentrated, in the same solvent. The association constant (Ka) and ΔH values for the binding process between receptors 2 and 3a-h and chloride or bromide were determined by averaging the values from at least two titrations. S32

33 Chloride binding in acetonitrile Figure S19 Top: Raw data for the ITC titration in acetonitrile of [Bu 4 N] + [Cl] into Calix[4]pyrrole receptors 2 and 3. Bottom: Binidng isotherm of the calorimetric titration data shown on top. The enthalpy of binding for each injection is plotted against the ratio guest/host in the cell. The continuous red line represents the least squares fit of the data to a 1:1 binding model. a) [3a] = 2.2 mm b) [3b] = 1.1 mm c) [3c] = 0.4 mm d) [3d] = 0.8 mm e) [3e] = 0.9 mm f) [3f] = 0.2 mm g) [3g] = 0.2 mm h) [3h] = 0.1 mm i) [2] = 0.6 mm S33

34 Bromide binding in acetonitrile Figure S20 Top: Raw data for the ITC titration in acetonitrile of [Bu 4 N] + [Br] into calix[4]pyrrole receptors 2 and 3. Bottom: Binding isotherm of the calorimetric titration data shown on top. The enthalpy of binding for each injection is plotted against the molar ratio guest/host in the cell. The continuous red line represents the least squares fit of the data to a 1:1 binding model. a) [3d] = 1.0 mm b) [3f] = 0.8 mm c) [3g] = 0.9 mm d) [3h] = 0.8 mm e) [2] = 2.8 mm. S34

35 Chloride binding in acetone Figure S21 Top: Raw data for the ITC titration in acetone of [Bu 4 N] + [Cl] into calix[4]pyrrole receptors 3. Bottom: Binding isotherm of the calorimetric titration data shown on top. The enthalpy of binding for each injection is plotted against the molar ratio guest/host in the cell. The continuous red line represents the least squaress fit of the data to a 1:1 binding model. a) [3e] = 0.3 mm b) [3f] = 0.1 mm c) [3h] = 0.1 mm. S35

36 Chloride binding in chloroform (Note that the quantities of titrant added per injection were not always constant and so what seem like abnormalities in the raw ITC data (μcal/sec) are present. As can be seen from the integrated data (kcal/mol) these spikes are actually in line with the rest of the data. These variations in the method of injection were necessary because some of the processes were so exothermic that the signal overran the range of the calorimeter s detector. In these cases the titrations were started with very small injections and then finished with larger injections.) Figure S22 Top: Raw data for the ITC titration in chloroform of [Me(Oct) 3 N] + [Cl] into calix[4]pyrrole receptors 3 and 2. Bottom: Binding isotherm of the calorimetric titration data shown on top. The enthalpy of binding for each injection is plotted against the molar ratio guest/host in the cell. The continuous red line represents the least squares fit of the data to a 1:1 binding model. a) [3b] = 6.51 mm b) [3e] = 1.72 mm c) [3f] = 0.59 mm. d) [3g] = 0.51 mm e) [3h] = 0.23 mm f) [2] = 0.66 mm. S36

37 References 1 P. Rothemund and C. L. Gage, J Am Chem Soc 1955, 77, L. Adriaenssens, C. Estarellas, A. Vargas-Jentzsch, M. Martinez-Belmonte, S. Matile and P. Ballester, J. Am. Chem. Soc. 2013, ASAP 3 P. Sokkalingam, D. S. Kim, H. Hwang, J. L. Sessler and C. H. Lee, Chem Sci 2012, 3, G. Bruno, G. Cafeo, F. H. Kohnke and F. Nicolo, Tetrahedron 2007, 63, J. S. Park, K. Y. Yoon, D. S. Kim, V. M. Lynch, C. W. Bielawski, K. P. Johnston and J. L. Sessler, Proc. Natl. Acad. Sci. U. S. A. 2011, 108, J. Yoo, I. W. Park, T. Y. Kim and C. H. Lee, Bull. Korean Chem. Soc. 2010, 31, K. Barral, A. D. Moorhouse and J. E. Moses, Org. Lett. 2007, 9, A. J. F. N. Sobral, N. G. C. L. Rebanda, M. da Silva, S. H. Lampreia and M. R. Silva, Tetrahedron Lett. 2003, 44, H. Maeda, M. Hasegawa and A. Ueda, Chem. Commun. 2007, X-ray structures suggest that when in the 1,3 alternate conformation H b is shielded by the meso-aromatic rings. Hence, in the 1 H NMR spectrum, the signal belonging to H b appears upfield with respect to the signal corresponding to H c. Upon binding, the conformational change to cone conformation moves H b away from the anisotropic current of the meso-aromatic ring and so the 1 H NMR signal corresponding to H b is shifted downfield past the signal for H c. 11 HypNMR 2008 Version Protonic Software. peter.gans@hyperquad.co.uk. 12 T. Wiseman, S. Williston, J. F. Brandts and L. N. Lin, Anal. Biochem. 1989, 179, S37