Density functional theory (DFT) modelling at the
PBE1PBE/6-311G** level of theory showed that out of four
aryl groups, only three participate in the anion–p interactions
of the TMACl complex of calix[4]arene 1 (Figure 3b, S21),
resulting in a binding energy of ꢃ58.3 kcalmolꢃ1.[23] For the
meta-isomer 2, DFT models confirmed the reinforcement of
the binding energy (ꢃ70.9 kcalmolꢃ1) with the formation of
two halogen bonds, whereas the other two iodoarene donors
rest nearby to, we speculated, possibly increase probability
effects and inertness of the complex (Figure S21). In the
absence of perfluorinated iodoarenes, the two halogen bonds
of the TMACl complex of calix[4]arene 5 were maintained
(Figure S22). However, the binding energy clearly decreased
to ꢃ59.7 kcalmolꢃ1, which correlates with the observed regain
in the transport activity with 5.
All pertinent control experiments confirmed that calix[4]-
arenes 1–6 act as counterion-activated anion transporters with
operational halogen bonds and anion–p interactions. Namely,
external anion exchange produced changes in transport
activity, and revealed a general selectivity for chloride ions
(Figure S4). This responsiveness to external anion exchange
indicated that weak anion binding occurs and matters for
transport in all cases.[1,17] The nonconformity to the Hofmeis-
ter topology suggested that the cost of at least partial anion
desolvation is compensated by binding.[17] Inability to trans-
port 5(6)-carboxyfluorescein (CF) excluded the occurrence of
nonspecific leakage through larger defects in the membrane
(Figure 2c ꢀ , S6).
In summary, the absolute transport activity of calix[4]ar-
ene transporters was about as modest as expected from
literature.[2,3] However, the calix[4]arene scaffold was very
useful to orchestrate transport with halogen bonds and anion–
p interactions. Best transport activity was obtained for anion
binding at the focal point of four pentafluorobenzyl p acids,
thus demonstrating that the functional relevance of anion–p
interactions is general, independent of the structural motif
involved. Direct substitution of these p acids by halogen-bond
donors did not afford active anion transporters, whereas
anion binding was clearly detectable. Thermodynamic and
kinetic destabilization of this too efficient binder by weaken-
ing of the strength and the proximity of the halogen-bond
donors, respectively, provided rational approaches to active
anion transporters. These remarkably consistent results con-
firm synthetic transporters as unique systems to explore the
functional relevance of weak interactions that are otherwise
difficult to detect. This is the first time anion transport in lipid
bilayers has been achieved with halogen bonds.
Figure 3. Too strong binding hinders transport: a) Part of the 19F NMR
spectra in dry [D6]acetone of the least active transporter 2 and a,a,a-
trifluorotoluene (ꢃ63.72 ppm) in the presence of increasing concen-
trations of TBACl (0–500 mm, bottom to top). b) DFT-optimized
(PBE1PBE/6-311G**) TMACl complex of the most active transporter 1;
TBACl binding by 1 was not detectable by 19F NMR spectroscopy in dry
[D6]acetone (ball-and-stick representation: C: cyan; H: white; O: red;
N: blue; Cl ion: green; F: magenta).
Kinetic destabilization was envisioned by moving the
halogen-bond donors from meta-position in 2 to para-position
in 4.[22] This constitutional isomerization should increase the
distance between halogen-bond donors and move the active
site to the periphery of the complex (Figure 1). Consistent
with mainly kinetic complex destabilization, TBACl binding
by para-isomer 4 remained detectable in 19F NMR titrations
(KD = 13.3 ꢀ 0.6 mm for TBACl in dry [D6]acetone, Fig-
ure S7–S9), whereas transport activity increased 15 times to
[21]
*
an EC50 = 68 mm (Figure 1, 2 , S1).
Reduced proximity of the halogen-bond donors in para-
isomer 4 further caused an increase from the usual n ꢂ 1 to a
*
Hill coefficient n ꢂ 2 (Figure 1, 2 ). This change can suggest
that, with peripheral active sites, two calix[4]arenes are
required to sufficiently surround and transport one chloride/
hydroxide ion, whereas the number of proximal halogen-bond
donors in meta-isomers is already sufficient in 1:1 com-
plexes.[20] Job plots of 19F NMR titrations in dry [D6]acetone
supported the 1:1 stoichiometry of complexes with meta-
isomers such as 2, whereas in acetone, para-isomers 4 could
bind around two chloride ions (Figure S9b). This inversion of
stoichiometry with para-isomers 4 provided compelling
evidence that binding of TBACl in acetone and transport of
TMACl across lipid bilayers must be compared with highest
caution.[7,21,23]
Replacement of one or two haloaryl substituents in the
too efficient binder 2 with one or two methoxy groups to
reduce the number of halogen-bond donors did not afford
active transporters.[16,S5] This persistent inactivity was mean-
ingful because neither power nor proximity of the individual
halogen-bond donors are significantly changed by this
modification. Moreover, the essential cation-binding site
could possibly be perturbed by the appearance of stable
calix[4]arene isomers.[12,13] Detectability of TMA-independ-
ent chloride ion binding by homologues of 2 without one or
two haloaryl substituents by 19F NMR spectroscopy in dry
[D6]acetone confirmed that reduction in multivalency is
insufficient to significantly reduce the thermodynamic stabil-
ity of the halogen-bond chloride complexes.[S5]
Received: July 15, 2011
Revised: September 20, 2011
Published online: October 13, 2011
Keywords: anions · anion transport · anion–p interactions ·
.
halogen bonds
[1] a) R. E. Dawson, A. Hennig, D. P. Weimann, D. Emery, S.
Gabutti, J. Montenegro, V. Ravikumar, M. Mayor, J. Mareda,
ˇ
Mꢁsek, A. Vargas Jentzsch, S. Sakurai, D. Emery, J. Mareda, S.
Angew. Chem. Int. Ed. 2011, 50, 11675 –11678
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim