The influence of stereochemistry on anion binding and transport

Article abstract of DOI:10.1080/10610278.2013.806809

Bis(thio)urea receptors (1-4) based on 1,2-bisaminocyclohexane are shown to function as transmembrane anion antiporters. The results show that cis-receptors have a greater propensity for anion transport than analogous trans-receptors. Stability constants using ¹H NMR techniques highlight the significance of stereoisomerism on anion binding in solution, as cis-receptors bind anions more strongly than trans-receptors.

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The influence of stereochemistry on anion binding and
transport
Louise E. Karagiannidis a , Jennifer R. Hiscock a & Philip A. Gale a
a School of Chemistry, University of Southampton , Southampton , SO17 1BJ , UK
Published online: 01 Jul 2013.
To cite this article: Louise E. Karagiannidis , Jennifer R. Hiscock & Philip A. Gale , Supramolecular Chemistry (2013): The
influence of stereochemistry on anion binding and transport, Supramolecular Chemistry, DOI: 10.1080/10610278.2013.806809
To link to this article: http://dx.doi.org/10.1080/10610278.2013.806809
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Supramolecular Chemistry, 2013
http://dx.doi.org/10.1080/10610278.2013.806809
The influence of stereochemistry on anion binding and transport
Louise E. Karagiannidis, Jennifer R. Hiscock and Philip A. Gale*
School of Chemistry, University of Southampton, Southampton SO17 1BJ, UK
(Received 1 May 2013; final version received 13 May 2013)
Bis(thio)urea receptors (1–4) based on 1,2-bisaminocyclohexane are shown to function as transmembrane anion antiporters.
The results show that cis-receptors have a greater propensity for anion transport than analogous trans-receptors. Stability
1
constants using H NMR techniques highlight the significance of stereoisomerism on anion binding in solution, as cis-
receptors bind anions more strongly than trans-receptors.
Keywords: anion; urea; thiourea; hydrogen bond; stereochemistry
Introduction
enantiomeric receptors when binding chiral guests, yet no
such effect is observed on binding achiral anions. In fact,
Odago et al. reported the use of a racemic mix of the
thiourea equivalent of this receptor for the optical sensing
of cyanide anions (7).
The transport of anions across lipid bilayers is important to
many biological processes (1), and is often mediated by
proteins embedded within the lipid bilayer of cells, which
form ion channels. Genetic mutation of these proteins can
cause them to malfunction, leading to various diseases,
including cystic fibrosis (2), cardiac disorders, epilepsy
and Bartter syndrome (3). For this reason, there is an ever-
growing interest in the development of synthetic small
molecules, which can bind or encapsulate ions for
transport across lipid bilayers. These ‘carriers’ have
potential to be developed as therapeutic replacements for
the malfunctioning proteins that form ion channels (1).
Previous work within the Gale group has developed
structurally simple transmembrane anion receptors based
on the ortho-phenylenediamine bis-urea scaffold, which
exhibit transport activity across 1-palmitoyl-2-oleoylpho-
sphatidylcholine (POPC) bilayers at receptor to lipid ratios
as low as 1:1,000,000 (4). These receptors have shown to
bind chloride anions with stability constants of ,10–
80 M21 and bicarbonate anions with stability constants of
roughly 800–4000 M21 (in DMSO-d6/0.5% water at
298 K). The addition of an electron-withdrawing group to
the central core or peripheral phenyl groups of such
receptors results in increased anion affinity due to the
increased acidity of the H-bond donor NZH groups. We
postulated that the halogenation of the central core phenyl
group in such receptors also increases the acidity of the
phenylene CZH groups, resulting in strengthened
intramolecular H-bonds and pre-organisation of the
receptors for binding anions (5).
To investigate the effect of stereochemistry on
anion binding and transport, a series of cis- and trans-
ortho-cyclohexanediamine-based bis-(thio)ureas with
bis-trifluoromethylphenyl side groups were synthesised
(Figure 1). These four receptors were investigated for their
ability to transport chloride and bicarbonate anions across
bilayers of POPC, as well as their binding affinity with a
variety of different anions. U-tube experiments were
carried out to help determine the mode of anion transport.
Nagasawa and co-workers have previously reported
urea 3 as a catalyst for the hetero-Michael addition
reaction between pyrrolidine and g-crotonolactone, in
which 3 exhibits a low chiral induction effect on the final
product (8). In addition, thiourea 4 was shown to catalyse
the aza-Henry reaction of a Boc-protected imine, again
with a slight asymmetric induction (9). Receptor 2 has also
been previously reported (10).
Experimental
Synthesis
1,10-((1R,2S)-Cyclohexane-1,2-diyl)bis(3-(3,5-
bis(trifluoromethyl)phenyl)urea) (1)
3,5-Bis(trifluoromethyl)phenyl isocyanate (0.62 mL,
3.6 mmol) and cis-1,2-diaminocyclohexane (0.21 mL,
1.8 mmol) were dissolved in dichloromethane (DCM)
(40 mL) and stirred for 6.5 h at rt under a nitrogen
atmosphere. A white precipitate was isolated by filtration
in a 71% yield after washing with excess DCM. 1H NMR
(DMSO-d6, 300 MHz): d ¼ 1.30–1.75 (m, 8H), 3.91 (br s,
Fabbrizzi and co-workers investigated the binding of
enantiomeric forms R,R and S,S of an ortho-cyclohex-
anediamine-based bis-urea receptor with para-nitrophenyl
side groups to a variety of anions (6). They demonstrated
that a chiral discriminating effect does exist between
*Corresponding author. Email: philip.gale@soton.ac.uk
q 2013 The Author(s). Published by Taylor & Francis.
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2
L.E. Karagiannidis et al.
Figure 1. ortho-Cyclohexanediamine-based bis-(thio)ureas of 1–4.
2H), 6.40 (d, 2H, J ¼ 6.0 Hz), 7.52 (s, 2H), 7.99 (s, 4H),
9.16 (s, 2H). 13C{1H} NMR (DMSO-d6, 100 MHz):
d ¼ 21.7 (CH2), 28.6 (CH2), 48.7 (CH), 113.4 (Ar CH),
117.1 (Ar CH), 123.3 (q, CF3, J ¼ 270.9 Hz), 130.6 (q, Ar
CZCF3, J ¼ 32.2 Hz), 142.3 (Ar C), 154.4 (CvO).
19F{1H} NMR (DMSO-d6, 282 MHz): d ¼ 61.86. LR-MS
ES2 (m/z): 623 [M 2 H]2. HR-MS ESþ (m/z): Act.
647.1293 [M þ Na]þ. Calcd 647.1287 [M þ Na]þ, err.
(ppm) 20.9 m.p. (8C): 275.7–275.9.
(0.21 mL, 1.8 mmol) were dissolved in DCM (40 mL)
and stirred for 72 h at rt under a nitrogen atmosphere. A
white precipitate was isolated by filtration in a 96%
yield after washing with excess DCM. 1H NMR
(DMSO-d6, 300 MHz): d ¼ 1.30 (br s, 4H), 1.70 (br s,
2H), 1.87 (br s, 2H), 3.48 (br s, 2H), 6.24 (d, 2H,
J ¼ 8.29 Hz), 7.37 (s, 2H), 7.90 (s, 4H), 9.211 (s, 2H).
13C{1H} NMR (DMSO-d6, 75 MHz): d ¼ 24.6 (CH2),
32.2 (CH2), 53.7 (CH), 113.2 (Ar CH), 116.8 (Ar CH),
123.2 (q, CF3, J ¼ 271.3 Hz), 130.4 (q, Ar CZCF3,
J ¼ 31.9), 142.3 (Ar C), 155.0 (CvO). 19F{1H} NMR
(DMSO-d6, 282 MHz): d ¼ 61.72. LR-MS ESþ (m/z):
625 [M þ H]þ. HR-MS ESþ (m/z): Act. 647.1289
[M þ Na]þ. Calcd 647.1287 [M þ Na]þ, err. (ppm)
20.3 m.p. (8C): 305.3–305.5.
1,10-((1R,2S)-Cyclohexane-1,2-diyl)bis(3-(3,5-
bis(trifluoromethyl)phenyl)thiourea) (2)
3,5-Bis(trifluoromethyl)phenyl isothiocyanate (0.66 mL,
3.6 mmol) and cis-1,2-diaminocyclohexane (0.21 mL,
1.8 mmol) were dissolved in DCM (40 mL) and stirred for
6.5 h at rt under a nitrogen atmosphere. Awhite precipitate
was isolated by filtration in 78% yield after washing with
excess DCM. 1H NMR (DMSO-d6, 300 MHz): d ¼ 1.40–
1.85 (m, 8H), 4.69 (br s, 2H), 7.73 (br s, 2H), 7.99 (d, 2H,
J ¼ 6.0 Hz), 8.29 (br s, 4H), 10.13 (br s, 2H). 13C{1H}
NMR (DMSO-d6, 100 MHz): d ¼ 21.9 (CH2), 27.8 (CH2),
52.5 (CH), 116.2 (Ar CH), 121.7 (Ar CH), 125.0 (q, CF3,
J ¼ 272.49 Hz), 129.9 (q, Ar CZCF3, J ¼ 31.2 Hz), 141.7
(Ar C), 180.3 (CvO). 19F{1H} NMR (DMSO-d6,
282 MHz): d ¼ 61.45. LR-MS ES2 (m/z): 655 [M 2 H]2.
HR-MS ESþ (m/z): Act. 679.0832 [M þ Na]þ. Calcd
679.0830 [M þ Na]þ, err. (ppm) 20.3 m.p. (8C): 189.8–
189.9.
1,10-((1S,2S)-Cyclohexane-1,2-diyl)bis(3-(3,5-
bis(trifluoromethyl)phenyl)thiourea) (4)
3,5-Bis(trifluoromethyl)phenyl isothiocyanate (0.66 mL,
3.6 mmol) and (^) - trans - 1,2 - diaminocyclohexane
(0.21 mL, 1.8 mmol) were dissolved in DCM (40 mL)
and stirred for 72 h at rt under a nitrogen atmosphere. A
white solid was collected and triturated in DCM (40 mL)
at 408C for 2 h. The precipitate was isolated by filtration
in a 98% yield after washing with excess DCM. 1H NMR
(DMSO-d6, 300 MHz): d ¼ 1.30 (br s, 4H), 1.71 (br s,
2H), 2.18 (br s, 2H), 4.33 (br s, 2H), 7.70 (s, 2H), 8.17 (s,
6H), 10.14 (br s, 2H). 13C{1H} NMR (DMSO-d6,
75 MHz): d ¼ 24.2 (CH2), 31.2 (CH2), 56.8 (CH), 116.2
(Ar CH), 122.0 (Ar CH), 123.2 (q, CF3, J ¼ 271.4 Hz),
130.0 (q, Ar CZCF3, J ¼ 33.0 Hz), 141.6 (Ar C), 180.1
(CvO). 19F{1H} NMR (DMSO-d6, 282 MHz):
d ¼ 61.48. LR-MS ESþ (m/z): 657 [M þ H]þ. HR-MS
ESþ (m/z): Act. 679.0825 [M þ Na]þ. Calcd 679.0830
[M þ Na]þ, err. (ppm) +0.8 m.p. (8C): 199.9–200.1.
1,10-((1S,2S)-Cyclohexane-1,2-diyl)bis(3-(3,5-
bis(trifluoromethyl)phenyl)urea) (3)
3,5-Bis(trifluoromethyl)phenyl isocyanate (0.62 mL,
3.6 mmol) and (^)-trans-1,2-diaminocyclohexane

Supramolecular Chemistry
3
Results and discussion
repelling each other as well as steric restraints around the
binding site.
Anion-binding studies were carried out for receptors 1–4 to
determine their binding affinity and binding stoichiometry
on a range of different anions. Stability constants for the
interaction of receptors 1–4 with a variety of anions were
1
The H NMR titration data between the same set of
anions and receptor 2 were also fitted to a 1:2
receptor:anion-binding isotherm, with the exception of
the data for the titration with bicarbonate, which showed
only a small downfield shift in NZH resonance position
upon addition of anion. This suggested that only a very
weak binding event was taking place, hence it was only
possible to fit the data to a 1:1 receptor:anion-binding
isotherm. The remaining results for 2 show trends similar
to those observed for 1 with each of the receptor–anion
interactions (excluding that with sulphate) having a K1
value that is greater than the K2 value.
1
determined by fitting the data obtained from H NMR
titrations to binding isotherms, using WinEQNMR2 (11).
The stability constants were determined by following the
shift of NZH protons. In many cases, the resonance of the
more deshielded NZH protons (i.e. those closest to the
aromatic ring systems) was subject to peak broadening upon
addition of the guest anion. However, the downfield shift of
both NZH resonances at the beginning of the titrations does
indicate that all four NZH groups are involved in H-
bonding to the anions. Amendola et al. (6) showed that an
analogous cyclohexane-based bis-urea receptor binds a
hydrogen-bonded dihydrogen phosphate dimer in the solid
state, whereas Costero et al. (12) showed that cyclohexane-
based bis-thioureas bind dicarboxylate anions in a 1:2
receptor:anion ratio (by UV–vis in DMSO). The results of
the anion-binding studies are shown in Table 1.
1
For H NMR titrations of receptors 3 and 4 with the
series of anions, it was not possible to fit all the data-sets
using WinEQNMR2. Some of the titrations showed peak
broadening and peak slitting of the NZH and aromatic
CZH peaks upon addition of the anions, which could be
attributed to secondary equilibria processes in solution. Of
the results that were fitted to a 1:2 or 1:1 receptor:anion-
binding isotherm, trends similar to those of 1 and 2 were
observed. For all 1:2 receptor:anion-binding interactions
investigated for receptors 3 and 4, the first stability
constant, K1, is greater than the second stability constant,
K2, indicating a decreased affinity of the receptors to bind
a second equivalent of anion.
Receptor 1 was found to bind all tested anionic guests
in a 1:2 receptor:anion stoichiometry. The first stability
constant associated with the binding of chloride, acetate
and benzoate is high (.104 M21), indicating a strong
affinity for the first equivalent on anion. For the remaining
anions (bicarbonate, hydrogen sulphate, dihydrogen
phosphate and sulphate) the calculated K1 values were in
a lower order of magnitude (.103 M21), but still indicate
a strong affinity for the anions. For each of the anions
mentioned (excluding sulphate), the second stability
constant is significantly lower than the first, showing the
decreased affinity of receptor 1 for a second equivalent of
anion. This is most likely a result of the charged anions
Receptors 1–4 were investigated for anion transport
properties using Hill analysis techniques (13). Chloride
efflux from POPC vesicles was monitored upon addition
of varying loadings of receptor, for both Cl2=NO32 and
Cl2=HCO23 antiport processes, using a chloride ion
selective electrode (ISE). Figure 2 shows the percentage of
chloride efflux upon addition of 2 mol% receptor with
Table 1. Stability constants K1 and K2 (M21) for receptors 1–4, measured in DMSO-d6/H2O 0.5% at 298 K.
Receptor 1a Receptor 2a Receptor 3a
Receptor 4a
Anion
K1
K2
K1
K2
K1
K2
K1
K2
e
f
e
f
Cl2
.104
5490
6090
.104
.104
2930
5280
70
200
20
3970
,10d
.104
.104
.104
7130
70
N/A
60
,10
1080c
,10
,10
40c
,10
50
b
HCO23
HSO24
,10d
N/A
f,g
f,g
CH3COO2
C6H5COO2
H2PO24
40
10c
.104
160
330
.104
70
110
.104
.104
50
.104
100
e
e
f,h
f,h
g,h
g,h
SO242
.104
.104
10
Notes: Guest anions were added as tetrabutylammonium salts, unless otherwise stated, and the stability constants were determined by 1H NMR titrations
following the NZH resonance found closest to the aromatic region of the spectra. All data-sets were fitted to a 1:2 receptor:anion-binding isotherm using
WinEQNMR2, unless otherwise indicated.
a Errors within 15% unless otherwise stated.
b Added as the tetraethylammonium salt.
c Error . 15%.
d Data fitted to a 1:1 binding isotherm.
e Titration curves slightly plateau at 1 equiv. of anion, so data cannot be fitted to a binding isotherm.
f Peak broadening upon addition of anionic guest.
g Peak hidden by aromatic CZH peaks.
h Peak splitting upon addition of anionic guest.

4
L.E. Karagiannidis et al.
respect to lipid for the Cl2=NO23 antiport test. It can be
seen that thioureas 2 and 4 have an increased transport
activity relative to the analogous ureas 1 and 3 (14) and
that interestingly the cis-receptors outperform the trans-
receptors.
The same trends are present in the Cl2=HCO32 antiport
results, with receptors 1 and 4 showing almost identical
transport activity (Figure 3).
Results of the Hill analyses are shown in Table 2.
The EC50 values for the Cl2=NO32 and Cl2=HCO23
tests show similar trends, indicating the thiourea receptors
to be more efficient antiporters than the analogous ureas
(14), and show the most active transporter to be receptor 2,
with an EC50 of 0.61 mol% for Cl2=NO32 antiport and
1.47 mol% for Cl2=HCO32 antiport. The Hill coefficient
values support a mobile carrier transport mechanism for all
receptors.
Figure 3. Chloride efflux as a function of time, promoted by the
addition of receptors 1 and 2 (2 mol% with respect to lipid) from
unilamellar POPC vesicles containing 451 mM NaCl buffered to
pH 7.2 with 20 mM sodium phosphate salts. The vesicles were
dispersed in the external solution containing 150 mM Na2SO4
buffered to pH 7.2 with 20 mM sodium phosphate salts. The
receptor was loaded as a DMSO solution at 0 s, and a spike of
NaHCO3 (33 mM) added at 120 s. At the end of the experiment,
the vesicles were lysed to calibrate the ISE to 100% chloride
efflux. Each point represents the average of three repeats.
This trend in transport efficiency may be explained by
considering the spatial arrangements of the cis- versus
trans-receptors. The hydrogen bond donor NZH groups of
the cis-receptors (1 and 2) are more favourably orientated
in an axial–equatorial arrangement, to bind to a guest
molecule (Figure 4). They are closer together and in better
spatial agreement to direct four hydrogen bonds towards
the guest species than analogous trans-receptors (3 and 4).
This is especially true when compared with the axial–
axial conformer of the trans-receptor, where the two arms
of the receptor point in opposite directions. The difference
in spatial arrangement likely makes it more difficult for the
trans-receptors to shield the charged guest from the
lipophilic interior of the POPC bilayer. This makes it
more difficult for the trans-receptors to partition into the
phospholipid bilayer, resulting in decreased transport
efficiency with respect to that of the cis-receptors.
U-tube experiments, as described in the electronic
supplementary information (ESI), were used to probe the
mode of anion transport. The results of the U-tube
experiment show an increase in the chloride concentration
of the sodium nitrate receiver solutions over time, indicating
that all the receptors function as mobile carriers. The large
volume, and hence distance separation, of the two aqueous
Table 2. EC50 values of 1–4 for the release of chloride from
POPC vesicles in Cl2=NO32 and Cl2=HCO23 antiport systems at
270 and 390 s, respectively.
EC50a, 270 s
nb
EC50a, 390 s
nb
Receptor (Cl2=NO32) (Cl2=NO32) (Cl2=HCO32) (Cl2=HCO23 )
1
2
3
4
1.74
0.61
1.20
1.18
7.04
1.47
1.75
1.43
c
c
c
c
Figure 2. Chloride efflux as a function of time, promoted by the
addition of receptors 1–4 (2 mol% with respect to lipid) from
unilamellar POPC vesicles containing 489 mM NaCl buffered to
pH 7.2 with 5 mM sodium phosphate salts. The vesicles were
dispersed in 489 mM NaNO3 buffered to pH 7.2 with 5 mM
sodium phosphate salts. The receptor was loaded as a DMSO
solution at 0 s. At the end of the experiment, the vesicles were
lysed to calibrate the ISE to 100% chloride efflux. Each point
represents the average of three repeats.
3.48
1.90
9.24
1.08
a EC50, defined as the concentration (mol% carrier to lipid) required to
obtain 50% chloride efflux from inside the vesicles.
b Hill coefficient.
c Receptor 3 was virtually inactive and at 20 mol% receptor loading, with
respect to lipid, showed only 5.20% chloride efflux at 270 s for Cl2=NO32
antiport and 3.99% chloride efflux at 390 s for Cl2=HCO32. Consequently
the data obtained for this receptor was not fitted to the Hill equation.

Supramolecular Chemistry
Supplementary Information
5
Please see ESI for additional information on anion
transport studies using vesicles, mobility assays, anion
binding studies and for general experimental procedures.
Acknowledgement
The authors thank the EPSRC for a studentship (LEK).
References
(1) (a) Davis, J.T.; Okunola, O.; Quesada, R. Chem. Soc. Rev.
2010, 39, 3843–3862, (b) Busschaert, N.; Gale, P.A. Angew.
´
Chem. Int. Ed. 2013, 52, 1374–1382, (c) Gale, P.A.; Perez-
Tomas, R.; Quesada, R. Acc. Chem. Res. 2013. DOI:
´
10.1021/ar400019p
(2) Sheppard, D.N.; Rich, D.P.; Ostedgaard, L.S.; Gregory,
R.J.; Smith, A.E.; Welsh, M.J. Nature 1993, 362, 160–164.
(3) Ashcroft, F.M. Ion Channels and Disease; Academic Press:
San Diego, London, 2000.
(4) Moore, S.J.; Haynes, C.J.E.; Gonzalez, J.; Sutton, J.L.;
Brooks, S.J.; Light, M.E.; Herniman, J.; Langley, G.J.;
´
´
Soto-Cerrato, V.; Perez-Tomas, R.; Marques, I.; Costa, P.J.;
Felix, V.; Gale, P.A. Chem. Sci. 2013, 4, 103–117.
(5) Brooks, S.J.; Edwards, P.R.; Gale, P.A.; Light, M.E. New
J. Chem. 2006, 30, 65–70, See also: Brooks, S.J.; Gale,
P.A.; Light, M.E. Chem. Commun. 2005, 4696–4698.
(6) Amendola, V.; Boiocchi, M.; Esteban-Gomez, D.; Fab-
brizzi, L.; Monzani, E. Org. Biomol. Chem. 2005, 3, 2632–
2639.
Figure 4. Axial–equatorial conformation of 2, axial–axial
conformation of 4 and equatorial–equatorial conformation of 4.
Structure was generated using Spartan’10 for Macintosh (PM3
molecular dynamics energy minimisation) (15). Spheres have
been resized for clarity.
(7) Odago, M.O.; Colabello, D.M.; Lees, A.J. Tetrahedron
2010, 66, 7465–7471.
(8) Sohtome, Y.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K.
Chem. Pharm. Bull. 2004, 54, 477–480.
(9) Rampalakos, C.; Wulff, W.D. Adv. Synth. Catal. 2008, 350,
1785–1790.
phases of the U-tube experiment ensures that channel
formationacrossthespanoftheorganicphaseisnotpossible,
hence a channel mechanism of transport is not conceivable.
(10) This compound has previously been reported in a patent:
Hamilton, G.S.; Belyakov, S.; Vaal, M.; Wei, L.; Wu, Y.-Q.;
Steiner, J.P., 2002. WO 2002044126.
(11) Hynes, M.J. J. Chem. Soc., Dalton Trans. 1993, 311–312.
´
(12) Costero, A.M.; Colera, M.; Gavin˜a, P.; Gil, S.; Llaosa, U.
Tetrahedron 2008, 64, 7252–7257.
(13) Hill, A.V. Biochem. J. 1913, 7, 471–480; Bhosale, S.;
Matile, S. Chirality 2006, 18, 849–856.
(14) We have previously noted enhanced transmembrane anion
transport by thiourea compounds relative to analogous
ureas: (a) Moore, S.J.; Wenzel, M.; Light, M.E.; Morley, R.;
Conclusions
The cis-receptors 1 and 2 have a greater activity as anion
antiporters than the corresponding trans-receptors 3 and 4.
The evidence presented supports our previous findings that
thioureas are more effective functional group motifs than
ureas for promoting anion antiport across lipid bilayers,
possibly due to the increased lipophilicity of sulphur atoms
as compared with oxygen atoms (16). In addition, the
difference in transport efficiency between cis- and trans-
stereoisomers can be rationalised with respect to their
differing ability to shield hydrophilic receptor regions and
anionic guests from the lipophilic interior of phospholipid
membranes. Anion-binding investigations were able to
highlight the significance of stereoisomerism on anion
binding in solution, as the cis-receptors interact with anions
more favourably than the trans-receptors, and show how a
lack of conformational isomers in cis-receptors allows for
less complex binding equilibria.
´
Bradberry, S.J.; Gomez-Iglesias, P.; Soto-Cerrato, V.;
´
´
Perez-Tomas, R.; Gale, P.A. Chem. Sci. 2012, 3, 2501–
2508, (b) Andrews, N.J.; Haynes, C.J.E.; Light, M.E.;
Moore, S.J.; Tong, C.C.; Davis, A.P.; Harrell, W.A.; Gale,
P.A. Chem. Sci. 2011, 2, 256–260, (c) Busschaert, N.;
´
Wenzel, M.; Light, M.E.; Iglesias-Hernandez, P.; Perez-
Tomas, R.; Gale, P.A.J. Am. Chem. Soc. 2011, 133, 14136–
´
´
14148, (d) Busschaert, N.; Gale, P.A.; Haynes, C.J.E.;
Light, M.E.; Moore, S.J.; Tong, C.C.; Davis, J.T.; Harrell,
Jr., W.A. Chem. Commun. 2010, 46, 6252–6254.
(15) Spartan’10; Wavefunction Inc.: Irvine, CA, 2010.
(16) Bu¨hlmann, P.; Nishizawa, S.; Xiao, K.P.; Umezawa, Y.
Tetrahedron 1997, 53, 1647–1654.

6
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Louise E. Karagiannidis, Jennifer R. Hiscock and Philip A. Gale
The influence of stereochemistry on anion binding and transport
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