Supporting Information - Wiley-VCH18 hours under a nitrogen atmosphere. The solution was then washed...

Supporting Information

© Copyright Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, 2007

S.1

Cooperative AND Ion-Pair Recognition by Heteroditopic Calix[4]diquinone

Receptors

Michael D. Lankshear, Ian M. Dudley, Kar-Man Chan, Andrew R. Cowley, Sérgio M. Santos, Vitor

Felix and Paul D. Beer.*

Inorganic Chemistry Laboratory

University of Oxford

South Parks Road

Oxford, OX1 3QR

Departamento de Química

CICECO, Universidade de Aveiro

3810-193, Aveiro, Portugal

S.2

S. - Supporting Information

1. Synthetic Procedures Thallium (III) trifluoroacetate.1 Note that caution should be exercised when handling thallium

derivatives due to their high toxicity. A suspension of Tl2O3 (5g) in TFA (25ml) was heated under

reflux in the absence of light for 92 hours. The resulting solution was cooled, then filtered and stored

in a light protected vessel until required.

The syntheses of compounds 1, 6, 9, 12 and 15 have been described previously.2

7 - 2-(2-(2-phthalimidoethoxy)ethoxy)ethanol tosylate.3 Compound S2 (10.71g, 0.03825mol) was

dissolved in pyridine (50ml) and cooled to 5oC. Tosyl chloride (14.58g, 0.0765mol) was added

portionwise, maintaining the temperature at 5oC, and the resulting mixture was then stirred at room

temperature, under a nitrogen atmosphere, for 18 hours, after which time the solution was poured

over a mixture of 20% HCl(aq) (25ml) and ice (~25g). This mixture was extracted with ethyl acetate

(3 x 200ml), with the organic extracts being combined and reduced in vacuo. Purification by silica

gel chromatography (hexane/EtOAc 3:2 v/v) gave the colourless oil 2 (10.64, 61%). 1H NMR

(300MHz, CDCl3) d: 2.41 (3H, s, CH3), 3.51 (4H, m, OCH2CH2O), 3.58 (2H, t, 3J = 4.8Hz,

OCH2CH2N), 3.66 (2H, t, 3J = 5.8Hz, CH2CH2OSO2), 3.84 (2H, t, 3J = 4.8Hz, CH2N), 4.06 (2H, t, 3J

= 5.8Hz, CH2OSO2), 7.30 (2H, d, 3J = 8.3Hz, TosH), 7.68 (2H, dd, 3J = 5.4Hz, 4J = 3.0Hz, PhthH),

7.74 (2H, d, 3J = 8.3Hz, TosH), 7.80 (2H, dd, 3J = 5.4Hz, 4J = 3.0Hz, PhthH). ESMS m/z: 456.11

[M + Na]+.

S.3

8 - 2-(2-(2-(2-phthalimidoethoxy)ethoxy)ethoxy)ethanol tosylate.3 Compound S4 (3.13g,

0.01mol), triethylamine (1.42ml, 0.01mol) and DMAP (cat.) were dissolved in CH2Cl2 (100ml), and

the resulting solution cooled to 5oC. Tosyl chloride (1.91g, 0.01mol) was then added portionwise,

maintaining the temperature at 5oC, then the reaction mixture was left to stir at room temperature for

18 hours under a nitrogen atmosphere. The solution was then washed consecutively with 1M HCl(aq)

(2 x 100ml), H2O (2 x 100ml) and brine (2 x 100ml) before being dried over MgSO4, filtered, and

the solvent removed in vacuo from the filtrate. Purification by silica gel chromatography (EtOAc)

gave the colourless oil 8 (3.01g, 98%). 1H NMR (300MHz, CDCl3) d: 2.43 (3H, s, CH3), 3.50 (4H,

m, CH2OCH2CH2OCH2CH2OCH2), 3.56 (2H, m, CH2OCH2CH2OS), 3.63 (4H, m, NCH2CH2OCH2,

CH2CH2OSO2), 3.71 (2H, t, 3J = 5.9Hz, CH2CH2N), 3.88 (2H, t, 3J = 5.9Hz, CH2N), 4.13 (2H, t, 3J =

4.8Hz, CH2OSO2), 7.33 (2H, d, 3J = 8.2Hz, TosH), 7.71 (2H, dd, 3J = 5.4Hz, 4J = 3.1Hz, PhthH),

7.78 (2H, d, 3J = 8.2Hz, TosH), 7.83 (2H, dd, 3J = 5.4Hz, 4J = 3.1Hz, PhthH). ESMS m/z: 500.13 [M

+ Na]+.

5-nitroisophthaloyl dichloride. A suspension of 5-nitroisophthalic acid (0.24g, 1.14mmol) was

heated under reflux in thionyl chloride (10ml, excess) for 18 hours, after which time a pale yellow

solution had formed. The excess thionyl chloride was removed in vacuo to give 5-nitroisophthaloyl

dichloride, which was immediately reacted on, being supposed to have formed in quantitative yield.

S1 - 2-(2-phthalimidoethoxy)ethanol.3 2-(2-aminoethoxy)-ethanol (10.5g, 0.1mol) and phthalic

anhydride (14.8g, 0.1mol) were dissolved in toluene (450ml) and the resulting solution placed in a

round bottomed flask fitted with a Dean-Stark apparatus. The solution was then heated under reflux

for 4 hours, with the H2O evolved from reaction periodically removed from the system. The reaction

S.4

mixture was allowed to cool, dried over MgSO4, filtered, then the solvent removed in vacuo to give

the pure, white phthalimide protected amine S1 as a white solid (23.5g, 100g). 1H NMR (300MHz,

CDCl3) d: 3.61 (2H, m, CH2CH2OH), 3.69 (2H, m, CH2OH), 3.75 (2H, t, 3J = 5.3Hz, OCH2CH2N),

3.91 (2H, t, 3J = 5.3Hz, CH2N), 7.73 (2H, m, PhthH), 7.85 (2H, m, PhthH). ESMS m/z: 236.0933

([M + H]+, C12H14NO4 requires 236.0923), 258.07 [M + Na]+, 493.16 [2M + Na]+.

S2 - 2-(2-(2-phthalimidoethoxy)ethoxy)ethanol.3 2-(2-(2-chloroethoxy)ethoxy)ethanol (9g,

0.053mol) and potassium phthalimide (9.82g, 0.053mol) were suspended in anhydrous DMF (50ml)

and heated at 110°C for 5 hours under a nitrogen atmosphere. The reaction mixture was allowed to

cool to room temperature, filtered, and then concentrated in vacuo. The crude material was purified

by silica gel chromatography (hexane/EtOAc/MeOH 7:7:1 v/v/v) to give S2 as a colourless oil

(10.71g, 72%). 1H NMR (300MHz, CDCl3) d: 3.52 (2H, t, 3J = 5.0Hz, CH2CH2OH), 3.61 (2H, m,

CH2CH2OH), 3.65 (4H, m, OCH2CH2O), 3.74 (2H, t, 3J = 5.6Hz, NCH2CH2O), 3.90 (2H, t, 3J =

5.6Hz, NCH2CH2O), 7.71 (2H, dd, 3J = 5.4Hz, 4J = 3.1Hz, ArH), 7.84 (2H, dd, 3J = 5.4Hz, 4J =

3.1Hz, ArH). ESMS m/z: 302.10 [M + Na]+.

S3 - tetraethyleneglycol monotosylate.3 Tetraethyleneglycol (30g, 0.154mol), triethylamine (5.6ml,

0.04mol) and DMAP (cat.) were dissolved in CH2Cl2 (300ml). The reaction mixture was cooled to

5°C, then tosyl chloride (7.24g, 0.039mol) was added portionwise maintaining the temperature at

5°C, before being left to stir at room temperature under a nitrogen atmosphere for 18 hours. The

reaction mixture was washed consecutively with 1M HCl(aq) (2 x 150ml), H2O (2 x 150ml) and brine

(2 x 150ml) before being dried over MgSO4, filtered, and the solvent removed in vacuo from the

filtrate. Purification by silica gel chromatography (EtOAc) gave the colourless oil S3 (10.15g, 75%).

S.5

1H NMR (300MHz, CDCl3) d: 2.45 (3H, s, CH3), 3.60 (8H, m, CH2OCH2CH2OCH2CH2OCH2),

3.65 (4H, m, OCH2CH2OH & OCH2CH2OSO2), 3.69 (2H, t, 3J = 5.0Hz, CH2OSO2), 4.16 (2H, t, 3J =

4.7Hz, CH2OH), 7.34 (2H, d, 3J = 8.1Hz, TosH), 7.80 (2H, d, 3J = 8.1Hz, TosH). ESMS m/z:

371.11 [M + Na]+.

S4 - 2-(2-(2-(2-phthalimidoethoxy)ethoxy)ethoxy)ethanol.3 Compound S3 (10.15g, 0.029mol) and

potassium phthalimide (5.56g, 0.03mol) were suspended in anhydrous DMF (100ml) and heated at

110oC for 18 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool, then

concentrated in vacuo. The resulting crude product was then dissolved in ethyl acetate (100ml) and

washed with 1M HCl(aq) (2 x 150ml) and brine (100ml) before being dried over MgSO4, filtered,

and the solvent removed in vacuo from the filtrate. Purification by silica gel chromatography

(EtOAc) gave S4 as a white solid (4.29g, 45%). 1H NMR (300MHz, CDCl3) d: 3.55 (10H, m,

CH2OCH2CH2OCH2CH2OCH2CH2OH), 3.63 (2H, t, 3J = 5.0Hz, CH2OH), 3.68 (2H, t, 3J = 5.7Hz,

NCH2CH2O), 3.84 (2H, t, 3J = 5.7Hz, CH2N), 7.65 (2H, dd, 3J = 5.5Hz, 4J = 2.9Hz, PhthH), 7.79 (2H,

dd, 3J = 5.5Hz, 4J = 2.9Hz, PhthH). ESMS m/z: 346.12 [M + Na]+.

2. Selected Spectral Characterization

S.6

Figure S1 – 1H NMR spectrum of 1, solvent: CD3CN, 298K.

Figure S2 – 1H NMR spectrum of 2, solvent: CDCl3, 298K.


S.7




S.8




S.9




S.10


Figure S14 – 1H NMR spectrum of 16, solvent: acetone-d6, 298K.


S.11



Figure S18 – Illustration of positive ROE correlations of the isophthalamide unit of (a) 1 and (b)

1.NH4Cl with the quinone proton k. The traces shown above the proton spectra illustrate the

coupling interaction with this proton. The peaks marked with an asterisk clearly indicate the

proximal arrangement of the two aromatic regions, consistent with p-stacked species. Solvent:

CD3CN, 298K.

S.12

Figure S19 – 2D-ROESY spectrum of 5, indicating positive coupling interactions between the

isophthalamide unit and the calixarene aromatic protons. Solvent: CD2Cl2, 298K.

Peak Monitored

a b e j k CH3CN

1 11.07 10.97 - 10.94 - 44.57

1.NH4Cl 10.79 10.47 10.55 10.48 10.32 43.05

Table S1 – Averaged diffusion coefficients (m2s-1 x 10-10) for solutions of 1 and 1.NH4Cl,

monitoring different proton signals. The similarity of the coefficients obtained indicates that the two

species are of similar size. Solvent: CD3CN, 298K. For proton assignments see Figure 2. The self

consistency of these experiments was confirmed by the similarity of the solvent (acetonitrile)

diffusion rates in both solutions, as well as the invariance of the obtained diffusion constant as a

function of proton environment monitored.

S.13

3. Titration Protocols and Selected Data

3.1 NMR Titrations All titrations were conducted on either an Oxford Instruments Venus 300 or Varian Unity Plus

500MHz spectrometer, at 298K. Sample volumes used were 500µl. A typical concentration for the

titrations was 1.5 x 10-3 moldm-3 concentrations (7.5 x 10-7 moles/sample). Where necessary, 1:1

mixtures of metal salt and receptor were prepared prior to the titration so that the 1:1 complex had

the above concentration. All salts were thoroughly dried before use; all anions were added as TBA

salts, Na and Li were added as the ClO4- salts, K and NH4 as the PF6 salts, and Rb and Cs as the

BPh4 salts, for solubility reasons. Aliquots of the anion or cation solutions were then added (10 x 2µl,

2 x 5µl, 2 x 10µl, 1 x 20µl & 1 x 30µl) so that ten equivalents of anion in total were used (total

volume added 100µl). Spectra were recorded after each addition, and the sample shaken thoroughly

before measurement.

The resulting titration data were analysed by the winEQNMR computer program5 to attempt binding

constant determination. Estimates for each binding constant, the limiting chemical shifts and the

complex stoichiometry were also added to the input file. The various parameters were refined by

non-linear least-squares analysis to achieve the best fit between observed chemical shifts and

calculated chemical shifts. The program plots the observed and calculated chemical shifts versus

guest concentration, which reveals the accuracy of the experimental data and the suitability of the

model. It also gives the best-fit values of the stability constants together with their errors. The

parameters were varied until the values for the stability constants converged, and inspection of the

theoretical binding isotherm with that obtained experimentally demonstrated that the model used was

appropriate.

S.14

Chloride Bromide Iodide

? d (ppm) K11 (M-1) ? d (ppm) K11 (M-1) ? d (ppm) K11 (M-1)

TBAPF6 0.01 -a 0.01 - a 0.01 - a

LiClO4 0.07 900 0.03 350 0.00 - a

NaClO4 0.37 6150 0.24 1250 0.06 210

KPF6 0.58 2850 0.33 1100 0.06 170

RbBPh4 0.51 1770 0.32 860 0.06 270

CsBPh4 0.50 2420 0.29 990 0.05 230

NH4PF6 0.70 7960 0.41 2020 0.07 240

Table S2 – Anion binding behaviour of 1.M+ in 2:98 D2O/CD3CN, at 298K. ? d(ppm) values

correspond to the change in chemical shift of the isophthalamide CH proton c on addition of one

equivalent of anion to the receptor:metal complex. WinEQNMR association constants derived from

monitoring c proton, errors < 10%. aInteraction too weak for association constant derivation.

S.15

Figure S20 – Examples of the dependences of the chemical shift of the amide proton (d) of receptors

on the concentration of added anion, in the presence and absence of cationic guest. (a) Interaction of

3 with bromide and iodide in the presence and absence of potassium, and (b) interaction of 4 with

bromide in the presence of various cations. Although the association constants calculated for this

latter interaction were >104 M-1 when both potassium and rubidium were present, it is readily

apparent from the shapes of the curves here than bromide binds more strongly in the presence of

rubidium. [Receptor]i = 0.0015moldm-3. Endpoint corresponds to the addition of ten equivalents of

anion.

S.16

3 4 5

Br- I- Br- I- Br- I-

None 0.12 -0.01 0.27 0.01 0.19 0.03

LiClO4 -a 0.02 0.29 0.04 0.25 0.03

NaClO4 0.77 0.18 0.92 0.18 0.88 0.19

KPF6 0.85 0.39 0.94 0.18 1.03 0.39

RbBPh4 0.93 0.17 1.06 0.21 1.10 0.34

CsBPh4 0.94 0.15 0.96 0.24 1.05 0.29

NH4PF6 0.53 0.20 0.70 0.13 0.45 0.22

Table S3 – Change in the chemical shift (ppm) of amide proton (d) of 3-5 induced on the addition of

one equivalent of TBA anion salt, in the presence and absence of one equivalent of the metal salt of

a non-coordinating anion. Solvent: acetone-d6, 298K. aDramatic peak broadening and disappearance

observed.

3 4 5

Br- I- Br- I- Br- I-

None 120 - 250 45 135 35

LiClO4 -a -a 260 -a 230 100

NaClO4 3490 395 4190 760 3790 435

KPF6 >104 475 >104 525 6700 1055

RbBPh4 >104 370 >104 950 8860 775

CsBPh4 >104 540 >104 1050 9750 760

NH4PF6 3060 1325 5150 700 3120 860

S.17

Table S4 – WinEQNMR-derived 1:1 association constants (M-1) for the association of 3-5 with

anions in the presence and absence of one equivalent of the metal salt of a non-coordinating anion.

Solvent: acetone-d6, 298K. Errors < 10%. aData not suitable for association constant determination.

3.2 UV-visible Titrations UV-visible experiments were conducted on a Perkin-Elmer Lamda 6 spectrophotometer, at 298K.

The sample volume was 3ml, typically of 1 x 10-4 moldm-3 concentration. Where necessary, 1:1

mixtures of receptor and co-analyte were pre-prepared. All salts were thoroughly dried before use;

all anions were added as TBA salts, all metals as PF6 salts except for Li and Na which were added as

the ClO4- salts for solubility reasons. Aliquots of the cation or anion solution (typically 0.03 moldm-

3) were then added (10 x 2µl, 2 x 5µl, 2 x 10µl, 1 x 20µl & 1 x 30µl) so that ten equivalents of

analyte in total were used. Spectra were recorded after each addition, and the sample mixed

thoroughly before each measurement.

The resulting titration data were analysed by the SPECFIT computer program6 to attempt binding

constant determination. The spectra together with the host and guest concentrations were read into

the program for every titration point and the complex stoichiometry and whether the components

species were coloured was entered. The parameters were refined by global analysis that uses

singular value decomposition and non-linear modelling by the Levenberg-Marquardt method. Using

the calculated stability constants, the program plots the predicted spectra of the component species

together with the observed and calculated absorption versus guest concentration at a given

wavelength, both of which reveal the accuracy of the experimental data and the suitability of the

model. The program also gives the best-fit values of the stability constants together with their errors.

The parameters were varied until the values for the stability constants converged.

S.18

4. Crystallographic Data

4.1 Crystal Structure of 1 A single crystal having dimensions approximately 0.18 x 0.24 x 0.32 mm was mounted on a glass

fibre using perfluoropolyether oil and cooled rapidly to 150K in a stream of cold N2 using an Oxford

Cryosystems CRYOSTREAM unit. Diffraction data were measured using an Oxford Diffraction

Gemini CCD diffractometer (graphite-monochromated MoKa radiation, ? = 0.71073 Å). Intensity

data were processed using the Crysalis software package.7 The structure was solved in the space

group P1 using the direct-methods program SIR92,8 which located all non-hydrogen atoms.

Subsequent full-matrix least-squares refinement was carried out using the CRYSTALS program

suite.9

Figure S21 - ORTEP-3 thermal ellipsoid plot of the single crystal structure of 1 at 40% probability

S.19

Crystal identification ARC1262 Chemical formula C54H59N3O10

Formula weight 910.08 Temperature (K) 150 Wavelength (Å) 0.71073 Crystal system Triclinic Space group P1 a (Å) 10.0261(3) b (Å) 12.5372(4) c (Å) 20.4416(6) α (°) 102.137(3) β (°) 94.601(3) γ (°) 20.4416(6) Cell volume (Å3) 2442.24(14) Z 2 Calculated density (Mg/m3) 1.237 Absorption coefficient (mm-1) 0.085 F000 968 Crystal size (mm) 0.18 x 0.24 x 0.32 Description of crystal Yellow block Absorption correction Semi-empirical from equivalent reflections Transmission coefficients (min, max) 0.97, 0.98 θ range for data collection (°) 4.5 ≤ θ ≤ 28.0 Index ranges -13 ≤ h ≤ 13, -16 ≤ k ≤ 16, 0 ≤ l ≤ 27 Reflections measured 22001 Unique reflections 11760 Rint 0.030 Observed reflections (I > 3σ(I)) 5735 Refinement method Full-matrix least-squares on F Parameters refined 612 Weighting scheme Chebychev 3-term polynomial Goodness of fit 1.1318 R 0.0447 wR 0.0514 Residual electron density (min, max) (eÅ-3)

Table S5 – Crystal data and refinement details concerning 1.

4.2 – Crystal Structure of 1.NH4Cl A large single crystal was cut to give a fragment having dimensions approximately 0.30 x 0.46 x

0.46 mm. This was mounted on a glass fibre using perfluoropolyether oil and cooled rapidly to 150K

in a stream of cold N2 using an Oxford Cryosystems CRYOSTREAM unit. Diffraction data were

measured using an Enraf-Nonius KappaCCD diffractometer (graphite-monochromated MoKa

radiation, ? = 0.71073 Å). Intensity data were processed using the DENZO-SMN package.10

Examination of the systematic absences of the intensity data showed the space group to be either C

S.20

2/c or C c. The structure was solved in the space group C 2/c using the direct-methods program

SIR92,8 which located all non-hydrogen atoms of the macrocycle and the NH4+ and Cl- ions.

Subsequent full-matrix least-squares refinement was carried out using the CRYSTALS program

suite.9

Figure S22 - ORTEP-3 thermal ellipsoid plot of the single crystal structure of 1.NH4Cl at 40%

probability.

Donor H atom Acceptor Symmetry operator of

acceptor

D···A distance (Å)

N(1) H(1) Cl(1) 3.2889(19) N(2) H(2) Cl(1) 3.385(2) N(3) H(3) O(5) 2.995(2) N(3) H(4) O(10) 2.979(2) N(3) H(5) Cl(1) 3.243(2) N(3) H(6) Cl(1) 3/2-x, 1/2-y, 1-z 3.1625(19)

O(11) H(7) Cl(1) 3.226(2) O(11) H(8) O(8) 3/2-x, -1/2-y, 1-z 2.776(23)

Table S6 – Hydrogen bond distances in 1.NH4Cl.

S.21

Crystal identification ARC1525 Chemical formula C54H65ClN4O11

Formula weight 981.58 Temperature (K) 150 Wavelength (Å) 0.71073 Crystal system Monoclinic Space group C 2/c a (Å) 40.3940(3) b (Å) 12.8438(2) c (Å) 28.0190(3) α (°) 90 β (°) 133.0878(5) γ (°) 90 Cell volume (Å3) 10616.2(2) Z 8 Calculated density (Mg/m3) 1.228 Absorption coefficient (mm-1) 0.134 F000 4176 Crystal size (mm) 0.30 x 0.46 x 0.46 Description of crystal Yellow fragment Absorption correction Semi-empirical from equivalent reflections Transmission coefficients (min,max) 0.94, 0.96 θ range for data collection (°) 5.0 ≤ θ ≤ 27.5 Index ranges -52 ≤ h ≤ 38, 0 ≤ k ≤ 16, 0 ≤ l ≤ 36 Reflections measured 59202 Unique reflections 12607 Rint 0.055 Observed reflections (I > 2σ(I)) 7465 Refinement method Full-matrix least-squares on F Parameters refined 764 Weighting scheme Chebychev 3-term polynomial Goodness of fit 1.0962 R 0.0425 wR 0.0482 Residual electron density (min,max) (eÅ-3) -0.22, 0.40

Table S7 – Crystal data and refinement details concerning 1.NH4Cl.

4.3 – Crystal Structure of 2 A polycrystalline aggregate was cut to give a fragment having dimensions approximately 0.38 x 0.56

x 0.60 mm. This was mounted on a glass fibre using perfluoropolyether oil and cooled rapidly to

150K in a stream of cold N2 using an Oxford Cryosystems CRYOSTREAM unit. Diffraction data

were measured using an Oxford Diffraction Gemini CCD diffractometer (graphite-monochromated

MoKa radiation, ? = 0.71073 Å). Intensity data were processed using the Crysalis software package.7

Examination of the systematic absences of the intensity data showed the space group to be P 21/n.

The structure was solved using the direct-methods program SIR92,8 which located all non-hydrogen

S.22

atoms of the macrocycle. Subsequent full-matrix least-squares refinement was carried out using the

CRYSTALS program suite.9

Figure S23 - ORTEP-3 thermal ellipsoid plot of the single crystal structure of 2 at 40% probability

S.23

Crystal identification ARC1247 Chemical formula C56H67N3O14S2

Formula weight 1070.28 Temperature (K) 150 Wavelength (Å) 0.71073 Crystal system Monoclinic Space group P 21/n a (Å) 11.5329(2) b (Å) 21.4996(6) c (Å) 21.8990(5) α (°) 90 β (°) 95.5490(6) γ (°) 90 Cell volume (Å3) 5404.5(2) Z 4 Calculated density (Mg/m3) 1.315 Absorption coefficient (mm-1) 0.168 F000 2272 Crystal size (mm) 0.38 x 0.56 x 0.60 Description of crystal Yellow fragment Absorption correction Semi-empirical from equivalent reflections Transmission coefficients (min, max) 0.90, 0.94 θ range for data collection (°) 5.0 ≤ θ ≤ 27.5 Index ranges -14 ≤ h ≤ 14, 0 ≤ k ≤ 27, 0 ≤ l ≤ 28 Reflections measured 45283 Unique reflections 12378 Rint 0.012 Observed reflections (I > 3σ(I)) 7772 Refinement method Full-matrix least-squares on F Parameters refined 721 Weighting scheme Chebychev 3-term polynomial Goodness of fit 1.1392 R 0.0352 wR 0.0420 Residual electron density (min, max) (eÅ-3) -0.37, 0.26

Table S8 – Crystal data and refinement details concerning 2.

5. Computational Methods

5.1 Experimental Molecular modeling simulations were carried out with the SANDER module within the Amber9

software package,11 with ammonium and receptor atom parameters from the GAFF force field.12 The

van der waals parameters for alkali cations were Åqvist,13 available from the parm99 force field

whereas halide anions were described with OPLS parameters given in ref. 14 except for chloride,

which was described with ones taken from ref. 15. The acetonitrile and acetone solvent molecules

were described with explicit full atom models using partial charges and atomic force field

S.24

parameters from references 16 and 17 respectively. Partial charges for the receptor and ammonium

atoms were calculated at the HF/6-31G* level using a RESP methodology. The ion pair electrostatic

neutrality was achieved assigning atomic charges of +1 for cations and -1 for anions.

The starting models of 1 were the crystal structure of free receptor for conformational analyses and

1.NH4Cl complex for molecular dynamics simulations. The structures of 3 and 5 were constructed

by addition of the necessary polyether units to both loops of 1 and optimized in the universal Force

Field18 within the Cerius2 software.19 Subsequently the three starting models were transferred to

Gaussian0320 for charge calculations, as described above.

Conformational analysis for receptors 1, 3, and 5 were performed in gas-phase through quenched

molecular dynamics methods. The starting models were minimized by molecular mechanics and

submitted to a 2ns molecular dynamics run at 2000K, using a 1 fs time step. A total of 20000

structures were saved, which were further minimized by molecular mechanics, through 1000 steps of

the steepest descent method, followed by the conjugate gradient method until a convergence

criterion of 0.0001 kcal mol-1 was achieved.

Subsequent conformational analyses were repeated for 1 with ion pairs KCl and NH4Cl and for 3

and 5 with ion pair KBr. Each ion pair was inserted into the macrocyclic cavity, between the

calix[4]diquinone and isophthalamide moieties, with the anion pointing to the N-H binding sites. No

bond or angle terms between the ion pair and the receptor binding sites were included in the

simulations. Hence, the attractive interactions between the ion pair and the oxygen donors and amide

N-H groups were primarily electrostatic.

For the lowest energy structures of 3.KBr and 5.KBr complexes, found in conformational analyses

(cone type 1), RESP charges for the macrocycle were recalculated in the absence of the ion pair,

which were used in all subsequent molecular dynamics simulations in solution. The structures of the

S.25

remaining complexes were obtained by substitution of the enclosed KX ion-pairs as required (see

Tables S9 to S12). Solvent cubic boxes of CH3CN16 and CH3COCH3,17 used to solvate the

complexes and the isolated ion pairs, were equilibrated previously at 300 K and 1 atm. The 1.MX

complexes were solvated with 752 acetonitrile molecules while 3.MX and 5.MX complexes were

solvated with 580 and 600 molecules of acetone, respectively. The systems were equilibrated, under

periodic boundary conditions, according to the following multistage protocol. Firstly, the solvent

molecules were minimized by molecular mechanics via 1000 steps of steepest descent method

followed by 5000 steps of conjugate gradient, with positional restrains of 500 kcal mol-1 Å-2 applied

to the solutes, in order to remove bad contacts between these molecules. Next, the restrains were

removed and the entire system allowed to relax. Secondly, the systems were heated until 300 K, with

a NVT ensemble over 50 ps. Finally, the systems were submitted to 150 ps molecular dynamics

runs, at an average pressure of 1 atm and 300 K. At the end of this NPT simulation, the density of

the cubic boxes were in agreement with the experimental densities of the pure solvents (acetonitrile

or acetone), and remained almost constant for, at least, the final 50 ps of the simulation. The final

equilibrated acetone and acetonitrile cubic boxes were typically 42 Å in size. The SHAKE21

algorithm was employed to constrain all hydrogen involving bonds, thus allowing the usage of 2 fs

time steps. The particle mesh Ewald method was used to describe the long-range electrostatic

interactions, while the non-bonded van der Waals interactions were restrained to a 12 Å cut-off. The

temperatures of the systems were controlled through the Langevin thermostat, using a collision

frequency of 1.0 ps-1.

The estimation of relative binding energies, via thermodynamic integration methods, requires the

calculation of solvation free energies of the single ion pairs in solution. So, smaller systems were

prepared consisting on an ion-pair in 266 or 369 molecules of acetone or acetonitrile, respectively.

S.26

Further these systems were equilibrated adopting an equivalent protocol to that used for complexes

simulations, leading to equilibrated cubic boxes of 32 Å in size for both solvents.

In order to obtain an insight into the binding interaction between the ion pairs and the receptors,

molecular dynamics collection runs of 2 ns were carried out with the above equilibrated systems.

Snapshots of the simulations were recorded every 0.2 ps, resulting in trajectory files containing

10000 frames, which were subsequently analyzed by the ptraj module of the AMBER9 package.11

27

5.2 Coordination Numbers

Figure S24 – Graphical representation of coordination numbers of 1.MX complexes (blue) in

acetonitrile and 3.MX (red) and 5.MX (green) complexes in acetone: a) coordination number

given by donors of the receptor and by halide anion; b) coordination number of the solvent

molecules; c) Overall coordination of the cation.

5.3 Free Energy Calculations The relative binding affinities of the macrocycles to the ion-pairs (? ? Gbinding) were

calculated from the relative free energies obtained for isolated ion-pairs (solvation free energy

– ? Gsolvation) and ion pair complexes (interaction free energy – ? Ginteraction), in solution of

28

acetonitrile or acetone, via thermodynamic integration methods and standard thermodynamic

cycles. With this purpose, a selected ion (Y) of the ion-pair, in the presence of the counter-ion,

was mutated into another (Z), by coupling its Hamiltonian to a mutation variable (λ), which

spanned from 0 to 1 along the transformation Y ? Z. This type of transformation was

performed independently for a selected ion of an ion pair in “free” and receptor bounded states,

and the corresponding free energy difference calculated, by the thermodynamic integration

method, using the following equation (eq. 1):

1

0( 1) ( 0)

VG G G d

λ

λλ

λ λ λλ

=

=

∂∆ = = − = =

∂∫ (1),

where G and V stand for the free and potential energy, respectively.

The above integral can be estimated by a trapezoidal integration scheme when the integral is

evaluated at a large number of discrete values of ? (typically 21 windows) or alternatively

through a Gaussian quadrature method, as defined in the AMBER9 manual, using selected ?

values and adequate weights. The first analytical method was adopted for evaluation of the

integral associated to the majority of the performed mutations, with exception of the NH4+ ?

K+ mutations, in which the second method was employed. Thus, generally, a perturbation

calculation was divided into 21 windows (?=0, 0.05, 0.10, …, 1). Each window consisted on a

molecular dynamics simulation, divided into a 20 ps equilibration step followed by a data

collection step of 100 ps, both carried out at 300 K and 1 atm using the previously equilibrated

systems. The SHAKE algorithm was used on all hydrogen involving bonds, allowing the usage

of a 2 fs time step. The NH4+ ? K+ mutations involve the annihilating of the ammonium

hydrogen atoms. In order to performer these particular mutations, it was necessary to remove

the SHAKE algorithm from the N-H bonds of the ammonium cation, and to consequently

change the time step from 2 to 1 fs. The length of these simulations was maintained and, in

29

order to reduce computation time, the integral evaluation (eq. 1) was limited to 12 windows,

with ? ranging from 0.00922 to 0.99078. This transformation was performed using a single

perturbation methodology in two consecutive steps. In the first one, the charges of the

ammonium were changed and, in the second, the van der Waals parameters were altered. The

free energy values for these particular mutations were calculated by means of the Gaussian

quadrature method.

The relative free energy of binding ? ? Gbinding was finally computed from (eq. 2):

intBinding solvation eractionG G G∆∆ = ∆ − ∆ (2).

The total error (Err?G) associated to the relative free energies (? G) of a single mutation was

determined according to:

( )( )1 2

2/G i i

i

Err dV dλσ λ∆ = ∆ ∑ (3),

in which ? ?i is the width of the simulation window i, and s (dV/d?i) is the estimated error in

window i obtained through block averaging.22 All further errors (associated to relative free

energies of binding) were calculated according to the principle of uncertainty propagation.

30

Figure S25. Standard thermodynamic cycle used to calculate relative free energies (? Gcalc)

from the directly obtained values (? G). Here, M1, M2 and M3 are different cations and X and Y

different anions of an ion pair. As can be seen, two independent ? G values are obtained for

each mutation and, for M2X? M2Y, a third value is calculated.

1

Table S9 – Differences in Free Energies of solvation (? Gsol), Free Energies of Interaction (? Gint) and Free Energies of Binding (? ? Gbinding), in kcal/mol, of the cations of the ion-pair to 1, in acetonitrile, and to 3 and 5, in acetone, as directly obtained from the simulations.

Mutation ? Gsola

(acetonitrile) ? Gsol

a (acetone) ? Gint(1)a ? Gint(3)a,b ? Gint(5)a,b ? ? Gbinding(1)a,b ? ? Gbinding(3)a,b ? ? Gbinding(5)a,b

LiCl ? NaCl 23.39 ± 0.04 21.37 ± 0.05 -2.02 ± 0.06

NaCl ? KCl 16.22 ± 0.03 16.72 ± 0.03 0.5 ± 0.04

KCl ? RbCl 5.44 ± 0.01 5.88 ± 0.01 0.45 ± 0.01

RbCl ? CsCl 8.01 ± 0.01 8.29 ± 0.02 0.28 ± 0.02

NH4Cl ? KCl 2.25 ± 0.02 4.37 ± 0.03 2.13 ± 0.04

LiBr ? NaBr 22.68 ± 0.04 24.88 ± 0.04 20.88 ± 0.04 21.13 ± 0.05 20.79 ± 0.06 20.82 ± 0.05

-1.8 ± 0.06 -3.75 ± 0.07 -4.09 ± 0.07 -4.07 ± 0.07

NaBr ? KBr 15.83 ± 0.03 17.36 ± 0.03 16.19 ± 0.03 16.51 ± 0.04 17.16 ± 0.04 0.37 ± 0.04 -0.85 ± 0.05 -0.2 ± 0.05

KBr ? RbBr 5.34 ± 0.01 5.74 ± 0.01 5.62 ± 0.01 5.76 ± 0.01 5.65 ± 0.01 0.28 ± 0.01 0.01 ± 0.02 -0.1 ± 0.02

RbBr ? CsBr 7.94 ± 0.01 8.4 ± 0.01 8.26 ± 0.02 8.88 ± 0.02 9.85 ± 0.02 9.54 ± 0.02 0.32 ± 0.02 0.48 ± 0.02 1.45 ± 0.03

1.14 ± 0.02

NH4Br ? KBr 1.73 ± 0.03 3.23 ± 0.03 3.58 ± 0.03 4.41 ± 0.03 4.88 ± 0.03 1.84 ± 0.04 1.18 ± 0.04 1.65 ± 0.04

LiI ? NaI 19.19 ± 0.04 21.2 ± 0.04 17.12 ± 0.03 17.85 ± 0.04 18.41 ± 0.05 -2.07 ± 0.05 -3.36 ± 0.06 -2.79 ± 0.06

NaI ? KI 13.81 ± 0.02 15.96 ± 0.03 15.39 ± 0.03 15.13 ± 0.03 15.67 ± 0.04 1.57 ± 0.03 -0.84 ± 0.04 -0.3 ± 0.05

KI ? RbI 5.17 ± 0.01 5.14 ± 0.01 4.94 ± 0.01 5.19 ± 0.01 5.24 ± 0.01 5.5 ± 0.01 -0.23 ± 0.01 0.05 ± 0.01

0.09 ± 0.01 0.36 ± 0.01

RbI ? CsI 7.2 ± 0.01 7.65 ± 0.01 7.62 ± 0.01 7.93 ± 0.02 7.75 ± 0.02 8.93 ± 0.02 0.43 ± 0.02 0.28 ± 0.02

0.10 ± 0.02 1.28 ± 0.02 1.19 ± 0.02

NH4I ? KI -0.19 ± 0.03 1.35 ± 0.03 1.64 ± 0.03 2.78 ± 0.03 2.63 ± 0.03 1.83 ± 0.04 1.42 ± 0.04 1.28 ± 0.04

a)A positive value means that the solvation, interaction or binding of the first cation of the mutation is preferred; Values are presented along with the associated standard error. b) Values in bold correspond to the reverse mutation of that indicated. Experimental data not shown.

2

Table S10 – Differences in Free Energies of solvation (? Gsol), Free Energies of Interaction (? Gint) and Free Energies of Binding (? ? Gbinding) , in kcal/mol, of the anions of the ion-pair to 1, in acetonitrile, and to 3 and 5, in acetone, as directly obtained from the simulations.

Mutation ? Gsola


a (acetone) ? Gint(1)a ? Gint(3)a,b ? Gint(5)a,b ? ? Gbinding(1)a,b ? ? Gbinding(3)a,b ? ? Gbinding(5)a,b

LiCl ? LiBr 2.005 ± 0.003 2.51 ± 0.004 0.505 ± 0.005

NaCl ? NaBr 1.409 ± 0.002 1.93 ± 0.003 0.521 ± 0.004

KCl ? KBr 1.055 ± 0.002 1.512 ± 0.003 0.457 ± 0.003

RbCl ? RbBr 0.957 ± 0.002 1.429 ± 0.002 0.472 ± 0.003

CsCl ? CsBr 0.849 ± 0.002 1.406 ± 0.002 0.557 ± 0.003

NH4Cl ? NH4Br 1.634 ± 0.003 2.108 ± 0.003 0.474 ± 0.004

LiBr ? LiI 14.84 ± 0.03 14.33 ± 0.03 18.79 ± 0.04 18.75 ± 0.05 18.54 ± 0.04 17.51 ± 0.05 3.95 ± 0.05 4.42 ± 0.05

4.20 ± 0.05 3.18 ± 0.05

NaBr ? NaI 11.3 ± 0.02 10.56 ± 0.02 15.41 ± 0.03 14.75 ± 0.04 14.06 ± 0.04 4.11 ± 0.04 4.19 ± 0.04 3.5 ± 0.04

KBr ? KI 9.26 ± 0.02 8.59 ± 0.02 12.97 ± 0.03 13.03 ± 0.03 12.3 ± 0.03 3.71 ± 0.04 4.44 ± 0.04 3.72 ± 0.04

RbBr ? RbI 8.68 ± 0.02 7.97 ± 0.02 12.28 ± 0.03 12.44 ± 0.03 12 ± 0.03 3.61 ± 0.04 4.47 ± 0.04 4.03 ± 0.04

CsBr ? CsI 7.95 ± 0.02 7.18 ± 0.02 10.61 ± 0.03 11.52 ± 0.03 10.89 ± 0.03 2.66 ± 0.03 4.34 ± 0.04 3.71 ± 0.04

NH4Br ? NH4I 11.09 ± 0.03 10.37 ± 0.03 14.65 ± 0.04 12.58 ± 0.04 13.57 ± 0.04 3.56 ± 0.05 2.2 ± 0.05 3.2 ± 0.05

a,b) Details as given in Table S9.

3

Table S11 – Differences in Free Energies of solvation (? Gsol), Free Energies of Interaction (? Gint) and Free Energies of Binding (? ? Gbinding) , in kcal/mol, of the cations of the ion-pair to 1, in acetonitrile, and to 3 and 5, in acetone, computed from MD simulations and standard thermodynamic cycles.

Mutation ? Gsola


a (acetone) ? Gint(1)a ? Gint(3)a ? Gint(5)a ? ? Gbinding(1)a ? ? Gbinding(3)a ? ? Gbinding(5)a

LiCl ? NaCl 23.33 ± 0.06 21.41 ± 0.06 -1.92 ± 0.09

NaCl ? KCl 16.2 ± 0.04 16.67 ± 0.05 0.47 ± 0.06

KCl ? RbCl 5.44 ± 0.01 5.79 ± 0.02 0.35 ± 0.02

RbCl ? CsCl 8.03 ± 0.02 8.29 ± 0.02 0.26 ± 0.03

NH4Cl ? KCl c 2.25 ± 0.02 4.37 ± 0.03 2.13 ± 0.04

LiBr ? NaBr 22.73 ± 0.08 24.93 ± 0.07 20.72 ± 0.09 21.49 ± 0.09 21.16 ± 0.11 -2.01 ± 0.12 -3.44 ± 0.11 -3.77 ± 0.13

NaBr ? KBr 15.85 ± 0.06 17.65 ± 0.05 16.77 ± 0.07 16.68 ± 0.07 17.29 ± 0.07 0.93 ± 0.09 -0.97 ± 0.09 -0.36 ± 0.09

KBr ? RbBr 5.48 ± 0.03 5.75 ± 0.03 5.68 ± 0.05 5.77 ± 0.05 5.73 ± 0.05 0.2 ± 0.06 0.01 ± 0.06 -0.02 ± 0.06

RbBr ? CsBr 7.92 ± 0.04 8.42 ± 0.03 8.61 ± 0.05 8.86 ± 0.05 9.81 ± 0.06 0.69 ± 0.06 0.45 ± 0.06 1.39 ± 0.07

NH4Br ? KBr c 1.73 ± 0.03 3.23 ± 0.03 3.58 ± 0.03 4.41 ± 0.03 4.88 ± 0.03 1.84 ± 0.04 1.18 ± 0.04 1.65 ± 0.04

LiI ? NaI 19.16 ± 0.07 21.15 ± 0.07 17.31 ± 0.08 17.48 ± 0.09 17.87 ± 0.10 -1.86 ± 0.1 -3.67 ± 0.11 -3.28 ± 0.12

NaI ? KI 13.8 ± 0.05 15.68 ± 0.05 14.57 ± 0.06 14.61 ± 0.08 15.54 ± 0.07 0.77 ± 0.08 -1.06 ± 0.09 -0.14 ± 0.09

KI ? RbI 4.97 ± 0.03 5.13 ± 0.03 4.94 ± 0.05 5.2 ± 0.05 5.42 ± 0.05 -0.03 ± 0.06 0.06 ± 0.06 0.29 ± 0.06

RbI ? CsI 7.2 ± 0.03 7.63 ± 0.03 7.1 ± 0.05 7.88 ± 0.06 8.84 ± 0.06 -0.1 ± 0.06 0.25 ± 0.06 1.21 ± 0.07

NH4I ? KI c -0.19 ± 0.03 1.35 ± 0.03 1.64 ± 0.03 2.78 ± 0.03 2.63 ± 0.03 1.83 ± 0.04 1.42 ± 0.04 1.28 ± 0.04

a) Details as given in Table S9; c) The indicated free energies are those directly obtained from simulations.

4

Table S12 – Differences in Free Energies of solvation (? Gsol), Free Energies of Interaction (? Gint) and Free Energies of Binding (? ? Gbinding) , in kcal/mol, of the anions of the ion-pair to 1, in acetonitrile, and to 3 and 5, in acetone, computed from MD simulations and standard thermodynamic cycles.

Mutation ? Gsola


a (acetone) ? Gint(1)a ? Gint(3)a ? Gint(5)a ? ? Gbinding(1)a ? ? Gbinding(3)a ? ? Gbinding(5)a

LiCl ? LiBr 2.06 ± 0.06 2.46 ± 0.06 0.4 ± 0.09

NaCl ? NaBr 1.38 ± 0.07 2 ± 0.08 0.61 ± 0.11

KCl ? KBr 1.04 ± 0.04 1.54 ± 0.05 0.49 ± 0.06

RbCl ? RbBr 0.95 ± 0.02 1.37 ± 0.03 0.43 ± 0.04

CsCl ? CsBr 0.87 ± 0.02 1.4 ± 0.02 0.53 ± 0.03

NH4Cl ? NH4Br c 1.634 ± 0.003 2.108 ± 0.003 0.474 ± 0.004

LiBr ? LiI 14.81 ± 0.07 14.28 ± 0.07 18.98 ± 0.08 18.44 ± 0.1 16.97 ± 0.1 4.17 ± 0.1 4.15 ± 0.12 2.69 ± 0.12

NaBr ? NaI 11.31 ± 0.08 10.4 ± 0.09 14.74 ± 0.09 14.87 ± 0.11 14.33 ± 0.11 3.43 ± 0.12 4.48 ± 0.14 3.93 ± 0.14

KBr ? KI 9.13 ± 0.05 8.77 ± 0.06 13.51 ± 0.07 13.13 ± 0.08 12.34 ± 0.08 4.38 ± 0.09 4.36 ± 0.1 3.57 ± 0.1

RbBr ? RbI 8.82 ± 0.04 7.96 ± 0.04 11.94 ± 0.06 12.46 ± 0.07 11.99 ± 0.07 3.12 ± 0.07 4.5 ± 0.08 4.03 ± 0.08

CsBr ? CsI 7.94 ± 0.03 7.2 ± 0.03 11.13 ± 0.05 11.5 ± 0.05 10.98 ± 0.05 3.19 ± 0.06 4.3 ± 0.06 3.78 ± 0.06

NH4Br ? NH4I c 11.09 ± 0.03 10.37 ± 0.03 14.65 ± 0.04 12.58 ± 0.04 13.57 ± 0.04 3.56 ± 0.05 2.2 ± 0.05 3.2 ± 0.05

a) Details as given in Table S9. c) The indicated free energies are those directly obtained from simulations.

5

6. Reference 21 from Main Article (Full Citation) Case, D. A.; Darden, T. A.; Cheatham, I., T. E.; Simmerling, C. L.; Wang, J.; Duke, R. E.; Luo, R.; Merz, K. M.; Pearlman, D. A.; Crowley, M.; Walker, R. C.; Zhang, W.; Wang, B.; S., H.; Roitberg, A.; Seabra, G.; Wong, K. F.; Paesani, F.; Wu, X.; Brozell, S.; Tsui, V.; Gohlke, H.; Yang, L.; Tan, C.; Mongan, J.; Hornak, V.; Cui, G.; Beroza, P.; Mathews, D. H.; Schafmeister, C.; Ross, W. S.; Kollman, P. A. AMBER9, University of California: San Francisco, 2006.

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