Anion Recognition in Water by Charge-Neutral Halogen and Chalcogen Bonding Foldamer Receptors

Article abstract of DOI:10.1021/jacs.9b00148

A novel strategy for the recognition of anions in water using charge-neutral σ-hole halogen and chalcogen bonding acyclic hosts is demonstrated for the first time. Exploiting the intrinsic hydrophobicity of halogen and chalcogen bond donor atoms integrated into a foldamer structural molecular framework containing hydrophilic functionalities, a series of water-soluble receptors was constructed for an anion recognition investigation. Isothermal titration calorimetry (ITC) binding studies with a range of anions revealed the receptors to display very strong and selective binding of large, weakly hydrated anions such as I^- and ReO₄^-. This is achieved through the formation of 2:1 host-guest stoichiometric complex assemblies, resulting in an encapsulated anion stabilized by cooperative, multidentate, convergent σ-hole donors, as shown by molecular dynamics simulations carried out in water. Importantly, the combination of multiple σ-hole-anion interactions and hydrophobic collapse results in I^- affinities in water that exceed all known σ-hole receptors, including cationic systems (β₂ up to 1.68 × 10¹¹ M^-2). Furthermore, the anion binding affinities and selectivity trends of the first example of an all-chalcogen bonding anion receptor in pure water are compared with halogen bonding and hydrogen bonding receptor analogues. These results further advance and establish halogen and chalcogen bond donor functions as new tools for overcoming the challenging goal of anion recognition in pure water.

Full text of DOI:10.1021/jacs.9b00148

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Article
Anion recognition in water by charge-neutral
halogen and chalcogen bonding foldamer receptors
Arseni Borissov, Igor Marques, Jason Y. C. Lim, Vítor Félix, Martin D. Smith, and Paul D Beer
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b00148 • Publication Date (Web): 07 Feb 2019
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Anion recognition in water by charge-neutral halogen and chalcogen
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†
‡
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‡
†
,†
Arseni Borissov, Igor Marques, Jason Y. C. Lim, Vítor Félix, Martin D. Smith, and Paul D. Beer*
†Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA,
U.K.
‡Department of Chemistry, CICECO - Aveiro Institute of Materials, University of Aveiro, 3810-193 Aveiro, Portugal
KEYWORDS Halogen bonding, chalcogen bonding, anion recognition, foldamer
ABSTRACT: A novel strategy for the recognition of anions in water using charge-neutral σ-hole halogen bonding and chal-
cogen bonding acyclic hosts is demonstrated for the first time. Exploiting the intrinsic hydrophobicity of halogen and chal-
cogen bond donor atoms integrated into a foldamer structural molecular framework containing hydrophilic functionalities,
a series of water-soluble receptors were constructed for anion recognition investigation. Isothermal titration calorimetry
(
ITC) binding studies with a range of anions revealed the receptors to display very strong and selective binding of large,
-
-
weakly hydrated anions such as I and ReO . This is achieved through the formation of 2:1 host-guest stoichiometric com-
4
plex assemblies, resulting in an encapsulated anion stabilized by cooperative, multidentate convergent σ-hole donors, as
shown by molecular dynamics simulations carried out in water. Importantly, the combination of multiple σ-hole-anion in-
-
teractions and hydrophobic collapse results in I affinities in water that exceed all known σ-hole receptors, including cation-
1
1
-2
ic systems (β up to 1.68 × 10 M ). Furthermore, the anion binding affinities and selectivity trends of the first example of
2
an all-chalcogen bonding anion receptor in pure water are compared with halogen bonding and hydrogen bonding receptor
analogues. These results further advance and establish halogen and chalcogen bond donor functions as new tools for over-
coming the challenging goal of anion recognition in pure water.
The applications of σ-hole interactions such as halogen
bonding (XB) and chalcogen bonding (ChB), the attractive
INTRODUCTION
One of the key challenges in modern anion supramolecular
chemistry is the recognition of anions in water, which
needs to be achieved for applications in biology,
healthcare, and environmental monitoring under aqueous
conditions to be realised. To date, an overwhelming major-
ity of reported abiotic anion receptors operate in organic
solvents, whose lower polarity compared with water facili-
tates anion coordination via non-covalent interactions
supramolecular interactions between heavy electron-
26,27
deficient Group 17/16 atoms and Lewis bases
are im-
portant recent developments in the field. Compared to HB,
these interactions are characterised by more stringent
directionality, greater hydrophobicity, and are less sensi-
2
8–30
tive to solvent and pH changes.
Recent advances in the
2
8,31
use of XB and ChB
include several types of anion recep-
self-assembled structures,
3
2–35
36–39
tors,
and transmem-
1
40–43
such as hydrogen bonding (HB) and anion-π interactions.
brane anion transporters.
Applications in aqueous so-
In water, recognition of anions is thwarted by their strong
hydration, resulting in an additional energetic barrier due
to desolvation during host-guest binding. Early examples
of anion binding in water were dominated by highly
charged polycationic receptors to enhance the electrostatic
lution are however extremely rare and based exclusively
on cationic receptors. These include the observation of
-
helicate complexes between I and iodopyridinium recep-
4
4,45
tors
as well as our work on achieving anion recognition
46–48
49
in water for XB
and aqueous-organic media for ChB
2–8
attraction with anions. More recent years have offered
using macrocyclic and mechanically interlocked hosts.
Most importantly, these σ-hole donor hosts often outper-
form HB host analogues in binding affinities and offer
greatly contrasting anion selectivity. Nonetheless, the re-
sulting anion affinities still pale in comparison to natural
biotic receptors.
alternative strategies, such as the formation of strong co-
ordinate bonds with Lewis acidic main group elements
9
,10
11–14
15–17
(e.g. Sb),
transition metals,
and lanthanides.
Counterintuitively, low charge or neutral receptors have
also recently been demonstrated to be capable of function-
1
8
ing in aqueous media. Notable rare examples that oper-
Herein, we present a novel strategy for aqueous anion
binding by σ-hole donor hosts, which capitalises on the
tendency of XB and ChB donor atoms (I/Te) to self-
assemble in water due to their intrinsic hydrophobicity.
Confinement of these hydrophobic functions within a
shielded core of a folded receptor can create a stabilised
1
9,20
ate in 100% water include cyclopeptide macrocycles,
2
1,22
23,24
bambus[6]urils,
biotin[6]urils,
and indolocarba-
zoles where hydrogen bonding and hydrophobic effects
contribute to the preferential recognition of weakly hy-
2
5
-
-
-
drated chaotropic anions (e.g. PF
6
, SCN , ClO
4
).
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anion binding cavity with multiple σ-holes directed in a ester-bound tri(ethylene glycol) groups to impart water
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convergent manner. This process, which drives the folding
of peptides into complex tertiary and quaternary struc-
tures, has successfully been exploited by Flood and co-
workers, who used a preorganised aryl-triazole HB folda-
solubility (Figure 1). Positioning of solubilising groups
ortho to the I/MeTe-triazoles sterically restricts the rela-
tive rotation of triazole and phenylene units. As the bulky I
or Te atoms cannot move past the ortho substituent, arms
of the receptor are preorganised towards a folded state
which is favourable for anion binding. The host molecules
are also clearly differentiated into a hydrophilic outer rim
and a hydrophobic interior to stabilise folded confor-
mations that contain a central cavity lined with σ-hole do-
nors. Groups at the termini of the receptor can be varied
(Scheme 1) to customise the binding and sensing proper-
-
-
mer receptor to bind Cl and H
2
PO
4
in 1:1 MeCN/H
2
O solu-
tion via C-H hydrogen bond donors in a dehydrated micro-
5
0,51
environment.
By combining the strict geometric con-
trol of σ-hole interactions with receptor folding via hydro-
phobic collapse, we present the first-ever series of charge-
neutral XB and ChB receptors (Figure 1) capable of very
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strong and highly selective I binding in pure water. Rein-
forced by the tendency of hydrophobic σ-hole donors to
ties.
For
instance,
the
appendage
of
-
converge, the resulting I affinities surpass all known cati-
4-aminonaphthaleneimide fluorophores to the XB receptor
scaffold enabled significant ‘turn on’ fluorescent I sensing
(vide infra).
-
-
onic XB receptors, even exceeding the I affinity of the nat-
+
-
+
52
ural Na /I symporter (NIS) protein in Na -bound form.
Furthermore, the first example of an all-ChB anion recep-
tor studied in pure water allows direct anion binding affin-
ity and selectivity trend comparison with XB and HB recep-
tor analogues.
The tetrakis(iodotriazole) framework of the XB receptors
1
a-d was assembled in a sequence of copper(I)-catalysed
azide-alkyne cycloaddition (CuAAC) reactions (Scheme
54
1). First, azide terminal synthon 5a,c,d was reacted with
bis(iodoethynyl) precursor 7 in a statistical reaction lead-
ing to the arm fragment 3. In the case of the azide 5b, the
steric bulk of its naphthaleneimide unit prevented it from
reacting with 7 under the usual CuAAC conditions. The
target iodotriazole 3b was instead synthesized from 5b
and 6 in a one-pot desilylation-cycloaddition-iodination
procedure (See ESI for details). In this method the cy-
cloaddition occurs between the azide and Cu alkynide, thus
circumventing the steric restrictions. Arm fragments 3a-d
were then joined with the bis(azide) core synthon 8. Final-
ly, the resulting precursors 4a-d were treated with the
primary amine 9. This provided the final products 1a-d via
amidation of the labile ethylparaben esters in 4a-d. Fol-
lowing TMS-deprotection of 6, a similar sequence of Cu-
AAC and amidation steps provided the HB analog 1a . In-
H
troduction of tri(ethylene glycol) amide groups in the last
step avoids the terminal iodination of alkynes in the vicini-
ty of amides, which tends to provide cyclized products in-
5
5,56
stead of the desired iodoalkynes.
Additionally, this alle-
viates the purification difficulties common for heavily PEG-
substituted compounds.
The water-soluble ChB anion receptor 2Te was derived
from bis(methyltellanylethynyl) precursor 11Te in two
5
7
CuAAC steps analogous to the synthesis of 1a-d (Scheme
). To prepare 11Te, a transmetallation between Ag al-
2
5
8
kynide and MeTeBr was performed, which formed 11Te
under very mild conditions and in high yield. To the best of
our knowledge this is an entirely new method to access
organotellanyl alkynes. In 2Te an all-ester scaffold was
used, replacing the amide linkers present in 1a-d with es-
ter groups. This was due to synthetic difficulties which
prevented clean amidation of ethylparaben esters in the
presence of 5-(methyltellanyl) triazoles as well as for-
mation of MeTe-alkynes in the vicinity of amides.
Figure 1. Structures of XB and ChB anion receptors described
in this work. Local dipoles of the triazole units and positions
of σ-holes are highlighted. Bottom: Preorganisation of recep-
tor arms by restricted intramolecular rotation.
RESULTS AND DISCUSSION
Receptor design and synthesis
Building upon our previous work on tetradentate iodotria-
5
3
zole XB receptors, we designed a foldamer structure con-
sisting of alternating 5-iodo- or 5-methyltellanyl triazoles
and 1,3-phenylene units, whilst carrying several amide- or
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Scheme 1. Synthesis of XB anion receptors 1a-d and the HB analog 1a
H
.
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Scheme 2. Synthesis of tri(ethylene glycol) ester-substituted bis(methyltellanylethynyl) and bis(iodoethynyl) pre-
cursors 11Te and 11 that allow to access the ChB anion receptor 2Te and its XB analog 2 via CuAAC sequences simi-
I
I
lar to that shown in Scheme 1.
To attain a precise comparison between ChB and XB anion
ty. Interestingly, their solubility sharply decreased with
increasing temperature. This effect can be attributed to the
transition of tri(ethylene glycol) chains from C-C gauche to
receptors, an all-ester XB compound 2 was also prepared
I
via an analogous route. As the all-ester backbone is less
59,60
hydrophilic than the ester-amide type present in 1a-d,
the
less
hydrophilic
anti
conformation.
receptors 2Te and 2 displayed much lower water solubili-
I
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Figure 2. Equilibria and thermodynamic signatures of stepwise 2:1 binding between 1a and I . The receptor model is shown with
truncated solubilising chains.
-
Table 1. Equilibria and thermodynamics of I binding by XB anion receptors 1a-d and 2
I
, ChB receptor 2Te, and HB
receptor 1a
H
as determined in water by ITC.
-1
-1
β
2
[M]-2
K
1
[M ]
K
2
[M ]
ΔH [kJ/mol]
−52.2 (1.0)
−38.3 (2.1)
−55.3 (0.9)
−52.5 (1.8)
−31.6 (2.3)
−34.6 (1.4)
−23.2 (0.1)
TΔS [kJ/mol]
1a
1.45 (0.04) × 1010
8.68 (2.18) × 109
1.68 (0.14) × 1011
7.47 (0.57) × 106
2.64 (0.05) × 107
7.28 (0.57) × 109
---a
3.16 (0.06) × 104
1.60 (0.37) × 104
4.77 (0.40) × 104
4.87 (0.52) × 103
3.67 (0.41) × 102
2.87 (0.08) × 102
3.88 (0.02) × 103
4.59 (0.16) × 105
5.54 (1.32) × 105
3.53 (0.24) × 106
1.54 (0.11) × 103
7.30 (1.00) × 104
2.54 (0.22) × 107
---a
5.9 (1.0)
18.4 (2.7)
8.8 (1.0)
1b
1c
1d
−13.3 (1.6)
10.1 (2.2)
20.8 (1.6)
2.7 (0.1)
2
Te
2
I
1a
H
-
Uncertainties are given in parentheses. All experiments were performed in unbuffered water and I was introduced as NaI. Titra-
a
tions were done at 298
K
for 1a-d and 1a
H
,
or at 293
K
for
2Te and
I
2 .
1:1 binding stoichiometry.
Anion binding studies
expected to augment the hydrophobicity of phenylene-
triazole backbone and favour aggregation in water. Molec-
ular dynamics simulation of 2:1 complex of 1a and I (vide
infra) shows this structure to be stable in aqueous solu-
tion. Further evidence for the 2:1 binding mode was ob-
tained by diffusion-ordered NMR (DOSY) which showed a
decrease in diffusion coefficients upon guest addition
where significant 2:1 binding was indicated by ITC (see
section S4, ESI for more details).
The anion binding properties of all receptors 1a-d, 1a
were investigated in water by ITC. All experiments
with 1a-d and 1a were performed at 298 K, while 2 and
Te were studied at 293 K due to their higher solubility at
lower temperature (See section S3, ESI for full details).
ITC experiments revealed binding in 2:1 receptor-anion
H
,
-
2
Te, 2
I
H
I
2
-
stoichiometry for 1a-d, 2
2), the same was observed in titrations of 1a and 2Te with
other anions (Table 2). In contrast, the HB receptor 1a
I
and 2Te with I (Table 1, Figure
-
The ITC binding data for all receptors with I in water are
collected in Table 1. XB receptors 1a-d displayed very high
I affinity, with 2:1 cumulative association constants (β
H
was found to bind exclusively in 1:1 stoichiometry. This
can be explained by the differences in steric bulk of HB and
-
2
)
1
1
-2
up to 1.68 × 10
magnitude higher than K
erence for 2:1 binding. In 1d K
M
in the case of 1c. K
in 1a-c, indicating a strong pref-
was of much lower magni-
2
was 1-2 orders of
H
σ-hole donor atoms. In the case of 1a , the anion guest can
1
be bound in the plane of the folded receptor backbone in a
6
1,62
2
similar fashion to the known triazolophane
mer
and folda-
tude, which is likely due to the large size of its termini ste-
rically disfavouring the formation of the 2:1 stoichiometric
6
3,64
examples. In XB and ChB receptors, the very large
size of convergent I or MeTe units sterically forces the co-
ordinated anion to be held above the plane of the receptor.
This results in a capped binding geometry as we have pre-
viously observed in the solid state structure of a tetraden-
complex. Although the all-ester XB receptor 2
similar β value to 1a, its binding was much more domi-
nated by K . This may be attributed to the all-ester outer
rim of 2 being relatively less hydrophilic than the mixed
ester-amide functionalities of 1a. This can be expected to
disfavour the folding of 2 into 1:1 binding conformation
I
displayed a
2
2
I
53
tate receptor NaI complex, which facilitates coordination
of a second receptor molecule to the anion. Additionally,
hydrophobic character of the σ-hole donor atoms can be
I
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but enhance the hydrophobic collapse into a 2:1 complex.
Additionally, higher entropic contribution in 2 and 2Te can
receptors and a size mismatch with I . Due to its inability to
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form 2:1 complex (see DOSY data in section S4, ESI), 1a
has much lower overall I affinity than any of the XB/ChB
receptors. Similarly to the σ-hole receptors, 1a displays
enthalpy-dominated binding, ostensibly due to the for-
mation of weak C-H hydrogen bonding interactions with
I
H
-
be explained by the release of water molecules weakly
interacting with their ester groups. It is especially note-
worthy that all σ-hole-donor receptors exhibit higher io-
H
+
-
dide binding affinity than the Na /I symporter protein
4
-1
-
-
(
NIS, K
a
= 4.46 × 10 M ) responsible for the uptake of I
the bound I akin to that observed by Flood and co-
5
0
into the follicular cells of the thyroid gland in the first step
workers.
5
2
of the thyroid hormone biosynthesis.
-
In all XB and ChB receptors I binding was mainly enthal-
py-driven with overall ΔH of 2:1 binding in the range of
30 to −55 kJ/mol and generally favourable but less domi-
nant entropic contributions. The strong exothermicity may
be attributed to two effects: the ability of the σ-hole donors
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to form strong XB/ChB interactions with I within the
largely dehydrated core of the host complex, as well as the
formation of HB interactions between the released water
molecules and the bulk solvent.
As shown in Figure 2 for 1a, the stepwise binding consists
of enthalpy-driven formation of 1:1 complex followed by
entropy-driven coordination of another receptor molecule.
In the first binding event this highly exothermic signature
is likely due to four strong halogen bonds being formed
-
while the capped complex geometry allows I to remain
significantly hydrated. In the second equilibrium formation
of new XB is probably less efficient (as shown by molecular
modelling, at least six out of the eight iodotriazoles in 2:1
complex form XB contacts). This binding event must there-
fore be driven by favourable entropy change associated
with nearly complete dehydration of I and partial dehy-
dration of the receptor molecules. Similar thermodynamic
signatures were observed for 2
-
Figure 3 Changes of 125Te chemical shifts of 2Te (5 mM in
CD CN, 298 °K, 158 MHz) titrated with tetrabutylammonium
iodide (TBAI).
I
and 2Te (Table S3-1).
3
Amongst 1a-d, the unusually low enthalpic contribution
seen for 1b is an indication that XB contacts from its outer
iodotriazoles are disrupted by the steric bulk of its naph-
thaleneimide termini. At the same time, restricted rotation
of these termini relative to the iodotriazoles is a likely ex-
-
The exceptionally strong I binding by 1a and 2Te prompt-
ed us to investigate their affinities towards a range of other
anions in water by ITC. As shown in Table 2, the σ-hole
receptors 1a and 2Te showed a general preference for
-
planation for the higher TΔS. In contrast, in 1d the I bind-
-
-
binding weakly hydrated anions such as SCN and ReO
:1 stoichiometry resulting from the hydrophobic collapse.
On the other hand, no measurable interaction was found
4
in
ing is unusually entropically disfavoured, which may be
attributed to the loss of additional degrees of freedom in
its exceptionally large termini.
2
-
-
-
-
2-
with ClO
3
, NO
3
, AcO , H
2
PO
4
, and SO . In 1a high selectiv-
ity for I (ΔHhyd = −325 kJ/mol) over SCN and ClO (ΔHhyd =
−310, −229 kJ/mol, respectively) indicates that shape
4
-
-
-
The ChB receptor 2Te displayed a similar binding pattern
4
65
to 2
mation of 2:1 complex by 2Te is disfavoured by the addi-
tional steric bulk of Te-bound CH groups. As the K and ΔH
, it follows that the XB and
I
albeit with much lower K
2
. This indicates that for-
and size complementarity effects are present. Particularly,
-
3
1
the isotropic spherical geometry of I likely allows maximal
values are similar in 2Te and 2
I
interactions with the highly-directional σ-holes. Chalcogen
-
-
ChB interactions with I must be of comparable strength
and enthalpically driven character. The involvement of
ChB in I coordination was confirmed by the large down-
bonding 2Te was also I selective, although the degree of
-
discrimination over SCN was less pronounced. This signif-
-
-
icant I selectivity is in contrast to the known macrocyclic
1
25
field changes in Te chemical shifts (Δδ) upon titration
with TBAI in CD CN (Figure 3). In this organic solvent, 2Te
formed a 1:1 binding complex with I (K
Combined with a smaller Δδ magnitude of outer Te atoms
relative to the inner Te donors this implies that in CD CN
there is no solvophobic effect to drive the folding and 2:1
association of 2Te. In water however, hydrophobic collapse
stabilises the 1:1 and especially 2:1 bound states, prevail-
receptors with hydrophobic C-H HB donor cavities. For
2
2
3
instance, Sindelar’s water-soluble bambus[6]uril prefer-
-
-1
-
-
23
a
= 96.8 ± 0.6 M ).
entially binds ClO over I , while Pittelkow’s biotin[6]uril
4
-
66
-
is selective for SCN . Likewise, in Gibb’s cavitand I bind-
3
ing is over an order of magnitude weaker than that of
-
-
ReO
role of σ-hole interactions in I recognition by 1a and 2Te
Further evidence of the influence of σ-holes can be seen in
comparison with 1a , which exhibits a weaker and less
selective anion binding ability. Being modestly selective for
4
and ClO
4
. Importantly, this highlights the overriding
-
.
-
ing over the weak solvation of I .
H
Behaviour of 1a is in stark contrast with its σ-hole coun-
terparts. Its 1:1 I binding constant is lower than K
indicating a significantly weaker interaction than in XB
H
-
-
1
of 1a-d,
I , it displays surprisingly high affinity for the more hydro-
philic Cl . Interestingly, ReO was bound strongly only by
-
-
4
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1
a and 2Te and not 1a
H
, possibly implying an intrinsic σ-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
hole preference for the oxoanion and better size comple-
mentarity with the XB/ChB anion binding site.
Table 2. Affinities of 1a, 2Te and 1a for a range of anions determined in water by ITC.
4
8,67,68
H
-2
a
-1
-1
Host
Guest
β
2
[M ]
K
1
[M ]
K
2
[M ]
ΔH [kJ/mol]
−52.2 (1.0)
TΔS [kJ/mol]
NaI
1.45 (0.04) × 1010
3.16 (0.06) × 104
4.59 (0.16) × 105
5.9 (1.0)
NaBr
NaCl
3.43 (0.50) × 106
wb
1.03 (0.13) × 103
wb
3.34 (0.45) × 103
wb
−25.6 (1.1)
wb
11.7 (1.4)
wb
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1a
NaReO
4
6.66 (0.67) × 108
3.40 (0.17) × 107
1.21 (0.14) × 105
2.64 (0.05) × 107
1.26 (0.70) × 103
wb
4.91 (0.22) × 104
5.38 (0.22) × 103
5.55 (0.74) × 101
1.35 (0.08) × 104
6.33 (0.55) × 103
2.19 (0.09) × 103
7.30 (1.00) × 104
6.94 (1.56) × 100
wb
−20.3 (0.5)
−31.0 (0.9)
−29.4 (3.2)
30.1 (0.3)
12.1 (0.8)
−0.4 (3.4)
NaSCN
NaClO
NaI
4
3.67 (0.41) × 102
1.69 (0.55) × 102
wb
−31.6 (2.3)
−13.9 (6.0)
wb
10.1 (2.2)
3.2 (6.8)
wb
NaBr
NaCl
2
Te
NaReO
4
1.58 (0.11) × 106
5.70 (0.25) × 106
wb
1.84 (0.18) × 102
4.92 (0.12) × 102
wb
8.67 (1.09) × 103
1.16 (0.05) × 104
wb
−25.4 (2.5)
−2.0 (0.5)
wb
9.4 (2.5)
35.9 (0.5)
wb
NaSCN
NaClO
NaI
4
3876 (21)
---b
−23.2 (0.1)
---b
−2.7 (0.1)
---b
NaBr
NaCl
3367 (983)
wb
−0.5 (0.1)
wb
19.7 (0.7)
wb
1a
H
NaReO
NaSCN
NaClO
4
346 (14)
−21.7 (0.5)
−23.3 (0.1)
−7.2 (0.6)
−4.5 (0.1)
4
2000 (14)
wb – weak binding (too weak to quantify). Uncertainties are given in parentheses. All experiments were done in unbuffered wa-
a
b
ter at 298 K for 1a and 1a or at 293 K for 2Te. Formation constants of 2:1 host-guest complex. No satisfactory 1:1 fit obtained,
possible complex binding equilibria.
H
All ITC experiments presented in Table 1 and Table 2 were
done in unbuffered water, as all anions of interest are pH-
independent at pH > 3. Likewise, the receptors do not con-
tain significantly acidic or basic functions; in particular, the
basicity of 1,2,3-triazoles is known to be very weak. Addi-
tional titrations done in buffered solutions (Table S3-2)
lowing the modelling approach reported in our previous
4
6,47,49,73–77
works.
The modelling details are thoroughly de-
scribed in Section S7 of the ESI.
The starting binding arrangements of 2:1 host-guest com-
plexes of 1a and 2Te were generated as follows: two recep-
tor molecules were superimposed with the formation of a
binding pocket, in which one iodide was inserted almost
equidistant from the eight convergent binding units. In
addition, initial binding arrangements A, B, and C, differing
in the relative spatial disposition of the central phenylene
rings of the two individual receptors (α phenyl rings) were
considered, as depicted in Figure 4. These three ideal bind-
ing arrangements are characterised by the ω torsion angle,
between the centroids of the α phenyl rings and the axis
defined by the centroids of the four triazole rings of each
receptor. In A and B the α phenyl rings of the two mono-
mers are face-to-face and opposite to each other, leading to
ω torsion angles of 0 and 180°, respectively, while the in-
termediate arrangement C has an ω angle of 90°. After-
wards, the A, B and C binding arrangements of 1a and 2Te
structures were subject to preliminary conformational
analyses at high temperature by MD simulations in the gas
phase, as detailed in ESI. For both host-guest systems,
three Molecular Mechanics (MM) energy minimised struc-
tures were selected and are shown in Figure 4 for 1a and
6
9
-
revealed almost unchanged I binding by 1c at pH 4 (citrate
11
buffer, β
= 2.88 (0.87) × 10 ). Small increases in affinity can be
attributed to ionic strength rather than pH effects. In pH 10
NaHCO /Na CO buffer the binding was slightly weakened
(β = 3.65 (0.12) × 10 ) which indicates possible competi-
tion from HCO
ence was observed in an experiment using CsI rather than
2
= 2.22 (0.33) × 10 ) and pH 7.5 (HEPES buffer,
11
β
2
3
2
3
1
0
2
-
-
3
or OH ions. Additionally, no cation influ-
1
1
NaI (β = 1.49 (0.25) × 10 ). This confirms the expected
lack of alkali metal binding sites in the receptor structure.
2
Computational studies
Further structural insights into the 2:1 host-iodide stoichi-
ometric complexes of 1a and 2Te in water were obtained
by molecular dynamics (MD) simulations, carried out using
the AMBER software package and the General AMBER
Force Field (GAFF).
force field bonding parameters were developed for the
tellurium centre. The multiple XB and ChB interactions
were described by resorting to extra points of charge fol-
70
7
1,72
In addition, for the 2Te receptor,
in Figure S7-1 for 2Te
.
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 4. Top: Sketches of binding arrangements A, B and C in 2:1 host-guest complexes showing ω torsion angle, defined by the
-
centroids of the α rings and of the four triazole binding units of each foldamer. Bottom: MM structures of the 2:1 complexes (1a)
in binding arrangements A, B and C. The XB and HB interactions are shown in purple and green dashed lines, respectively.
2
∙I
Table 3. Average number and dimensions of XB or ChB interactions for 2:1 host-guest complexes of 1a and 2Te in
a
binding arrangements A, B, C.
№ of XB/ChB bondsb
-
b
-
b
Host
Binding arrangement
I/Te⋯I distance (Å)
∠Ctrz–I/Te⋯I (°)
A
6.6 ± 0.6
6.0 ± 0.2
6.8 ± 0.4
6.5 ± 0.6
5.1 ± 0.6
5.4 ± 0.6
4.7 ± 0.5
5.1 ± 0.6
4.03 ± 0.15
3.95 ± 0.21
4.02 ± 0.19
4.00 ± 0.19
4.07 ± 0.15
4.10 ± 0.17
4.14 ± 0.17
4.11 ± 0.17
171.2 ± 5.9
172.6 ± 4.1
173.1 ± 3.6
172.3 ± 4.7
165.5 ± 5.6
163.7 ± 4.5
163.9 ± 4.2
164.3 ± 4.9
B
1a
C
A + B + C
A
B
C
2
Te
A + B + C
a
Values estimated from MD simulations in water in binding arrangements A, B, C (N = 600000) or their concatenated data (A + B
b
+
C; N = 1800000); XB and ChB interactions were accounted using distances shorter than 4.5 Å and angles wider than 150°.
The values for the ω angle in the gas-phase MM minimised
structures of 1a are 20.6° (A), 172.2° (B), and 69.6° (C),
while in 2Te this angle is 44.8° (A), 146.1° (B) and 95.4° (C).
Moreover, the seven peripheral PEG-side chains of each
monomer are folded around the capsule core and are con-
sequently hampering the eventual access of water mole-
cules to the binding pocket. Thus, iodide recognition was
also investigated stretching the PEG-side chains of 1a and
forded and appointed for subsequent MD simulations car-
ried out under periodic boundary conditions in cubic box-
es with 11500 TIP3P water molecules. The foldamer cap-
sules 1a and 2Te were simulated along three independent
runs of 100 ns each, leading to a total of (3 × 2 × 3 × 100 =)
1.8 μs of MD simulation for each host. Notably, along the
equilibration period the unfolded PEG-side chains have
refolded, adopting equivalent dispositions to the ones ob-
served in the gas-phase. Consequently, the sampling data
of six independent MD runs for the A, B and C binding ar-
rangements of 1a and 2Te are treated together.
2
Te in the three starting arrangements. Ultimately, two
alternative scenarios for the A, B, and C spatial disposi-
tions, with folded and unfolded PEG-side chains, were af-
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the capsular architecture (see Table S7-1). In agreement
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
with these synergetic non-covalent interactions, the three
binding arrangements preserve the initial orientations, as
indicated by the average ω torsion angles of 19.2 ± 9.1°,
175.0 ± 5.4°, and 73.3 ± 7.2° for A, B and C, respectively.
Concerning iodide binding by 2Te capsule, the anion is
shared by the eight MeTe binding units, with an average of
ca. 5 ChB interactions, regardless of the binding scenario.
Moreover, in spite of the similarity between the average
-
-
-
Te⋯I and I⋯I distances (see Table 3), the Ctrz-Te⋯I an-
-
gles are less linear than the Ctrz-I⋯I ones. In addition, the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
weaker ChB interactions are more often interrupted than
their sister XB ones within the 1a capsule. In spite of that,
the initial relative orientations between monomers in the
A, B and C binding arrangements are also preserved, with
corresponding ω angles of 43.7 ± 7.8°, 149.5 ± 5.1° and
8
9.9 ± 4.5°.
The number of water molecules residing in the capsule
binding cavity of 1a or 2Te was assessed within 5.0 Å from
the guest iodide, concatenating the sampling data of the
three binding arrangements. This sphere radius was se-
lected as it roughly corresponds to the outer limit of the
host binding cavity defined by the iodine or tellurium bind-
ing units. An average of 2 water molecules surrounded the
encapsulated anion in both 2:1 host-guest complexes,
-
while an MD simulation of free I shows that it is solvated
by approximately 20 water molecules within the same 5.0
Å cut-off. In line, the radial distribution function of the wa-
ter molecules around the iodide, presented in Figure S7-4,
clearly shows that the dimeric foldamer capsules of 1a and
2
Te partially shelter the hosted anion from the solvent
molecules at least within a 10 Å shell, as suggested by the
gas-phase MM structures (Figures 4 and S7-1) and MD
snapshots (Figures 5, S7-2 and S7-3). Moreover, along the
MD simulations the equatorial and axial holes of the dimer-
ic capsules are intermittently opened/closed by the flexi-
ble PEG-side chains, that act as lids, limiting the access of
the water molecules to the centre of the binding cavity.
This feature is clearly illustrated in Movie S1.
Figure 5. Representative MD snapshots of dimeric capsules of
a and 2Te, in binding arrangement A, with the iodide guest
establishing XB (purple dashed lines) or ChB (orange dashed
lines) interactions with the binding units of the two foldamer
entities, while being surrounded by a few water molecules.
1
Fluorescent anion sensing
Compounds 1b-d incorporate fluorophores in their termi-
ni, which are engineered to give fluorescent output upon
anion binding. Compounds 1b and 1c showed little to no
response upon titration with NaI (see ESI section S6). On
Noteworthy, the dimeric capsules of 1a and 2Te are main-
tained throughout the simulation time, with the iodide
guest kept inside of the binding pocket, as illustrated in
Figure 5 for binding arrangement A of both complexes.
Equivalent depictions are presented in Figures S7-2 and
S7-3 for the B and C scenarios of these dimeric receptor
iodide complexes. The numbers and average dimensions of
the XB and ChB interactions are summarised in Table 3.
the other hand, 1d equipped with well-known 4-amino-
78–80
1
2
,8-naphthalene imide fluorophores
displayed nearly
-fold enhancement of emission intensity (Figure 6). A
small hypsochromic shift of emission maximum from 564
nm to 558 nm was also observed. This significant ‘turn-on’
-
-
emission observed upon I addition is especially notewor-
Receptor 1a binds I with ca. 7 intermittent XB interactions
8
1
thy, as the ‘heavy atom effect’ associated with this anion
for arrangements A and C or 6 for arrangement B. These
results indicate that at least six of the eight putative XB
binding units recognize the iodide during the course of
simulation time. The dimensions of the XB interactions are
indistinguishable between binding arrangements, with
82
often results in dramatic fluorescence attenuation or
4
7,83
small changes in intensity.
The main reason for the
fluorescence enhancement is most likely the restriction of
84
-
intramolecular motion upon I complex formation. Alt-
hough it is not clear why only 1d exhibited a response, this
may result from increased separation of its fluorophores
from the anion binding site, further reducing the quench-
ing influence of iodide guest.
-
-
C
trz–I⋯I (trz = triazole) angles roughly linear and I⋯I dis-
tances of ca. 4.0 Å, showing that the iodide guest is tightly
bonded to the capsule. In addition, up to 14 N-H⋯O and N-
H⋯Ntrz hydrogen bonds between receptor molecules were
intermittently observed, also assisting the maintenance of
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Synthetic procedures and characterization data for com-
1
2
3
4
5
6
7
8
9
pounds, details of ITC and NMR anion binding studies, compu-
tational methods. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*paul.beer@chem.ox.ac.uk
ORCID
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
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5
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5
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5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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9
0
1
2
3
4
5
6
7
8
9
0
Arseni Borissov: 0000-0002-5408-1534
Igor Marques: 0000-0003-4971-9932
Jason Y. C. Lim: 0000-0002-8020-1720
Vítor Félix: 0000-0001-9380-0418
Martin D. Smith: 0000-0002-8849-488X
Paul D. Beer: 0000-0003-0810-9716
Present Addresses
J. Y. C. Lim: Institute of Materials Engineering and Research
(IMRE), 2 Fusionopolis Way, Singapore 138634.
Figure 6. Luminescence spectra of 1d (100 µM in H
442 nm) titrated with 0 – 10 equivalents of NaI.
2
O, λex
=
Author Contributions
All authors have given approval to the final version of the
manuscript.
CONCLUSIONS
In summary, we have achieved exceptionally strong and
-
highly selective I binding in pure water using unprece-
dented charge-neutral, non-macrocyclic XB and ChB anion
receptors. Anion binding studies in combination with mo-
lecular dynamics simulations demonstrate the formation
Notes
The authors declare no competing financial interest.
-
-
of 2:1 receptor-I complexes where the I guest is held by
multiple convergent σ-hole interactions. The hydrophobic
nature of σ-hole donor atoms facilitates this folding and
dimeric aggregation of receptor molecules, concomitant
with expulsion of water from the anion’s hydration shell.
This self-assembly of multidentate anion binding sites sta-
ACKNOWLEDGMENT
A. B. is grateful to the EPSRC Centre for Doctoral Training in
Synthesis for Biology and Medicine (EP/L015838/1) for a
studentship, generously supported by AstraZeneca, Diamond
Light Source, Defence Science and Technology Laboratory,
Evotec, GlaxoSmithKline, Janssen, Novartis, Pfizer, Syngenta,
Takeda, UCB and Vertex.
J. Y. C. L. thanks the Agency for Science, Technology and Re-
search (A*STAR), Singapore, for postgraduate funding.
V. F. acknowledges support from project PTDC/QEQ-
SUP/4283/2014 (POCI-01-0145-FEDER-016895) and CICECO
– Aveiro Institute of Materials (UID/CTM/50011/2013), fi-
nanced by National Funds through the FCT/MEC and co-
financed by QREN-FEDER through COMPETE under the
PT2020 Partnership Agreement.
-
bilized by hydrophobic collapse results in extremely high I
-
affinity, exceeding that of the natural NIS I receptor by
several orders of magnitude. Additionally, the use of σ-hole
-
interactions leads to the unique selectivity for I over other
-
-
less hydrated anions (e.g. ClO , SCN ), which is in contrast
4
with macrocyclic receptors containing deep hydrophobic
cavities.
-
Binding of I was predominantly enthalpy-driven in all XB
and ChB receptors, highlighting the formation of the re-
spective σ-hole interactions. In the first example of a ChB
anion receptor studied in water, close similarity in the
properties of ChB and XB was found as can be inferred
I. M. is grateful for a post-doc grant under project pAGE (Cen-
tro-01-0145-FEDER-000003).
ABBREVIATIONS
ChB, chalcogen bonding; HB, hydrogen bonding; ITC, isother-
mal titration calorimetry; MD, molecular dynamics; MM, mo-
lecular mechanics; XB, halogen bonding.
from comparable K
1
and ΔH values in 2Te and 2
I
(Table 1).
In comparison with the HB analogue 1a
H
, XB and ChB re-
-
ceptors displayed overwhelmingly higher I affinity and
selectivity. Additionally, the introduction of fluorescent
terminal groups into the XB foldamer receptor design al-
-
REFERENCES
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emission enhancement upon binding. Hence the observa-
tions herein further champion and advance halogen and
chalcogen bonding as highly effective new tools for the
selective binding and sensing of anions in water. Im-
portantly, the strategy of utilising the hydrophobic charac-
ter of σ-hole donor atoms for self-assembly of anion bind-
ing cavities marks a paradigm shift in exploiting these in-
teractions for anion receptor design.
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(
(
(
(
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Complexes
of
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3
4
5
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
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