Chalcogen Bond Mediated Enhancement of Cooperative Ion-Pair Recognition

Article abstract of DOI:10.1002/anie.202001125

A series of heteroditopic receptors containing halogen bond (XB) and unprecedented chalcogen bond (ChB) donors integrated into a 3,5-bis-triazole pyridine structure covalently linked to benzo-15-crown-5 ether motifs exhibit remarkable cooperative recognition of halide anions. Multi-nuclear ¹H, ¹³C, ¹²⁵Te and ¹⁹F NMR, ion pair binding investigations reveal sodium cation–benzo-crown ether binding dramatically enhances the recognition of bromide and iodide halide anions, with the chalcogen bonding heteroditopic receptor notably displaying the largest enhancement of halide binding strength of over two hundred-fold, in comparison to the halogen bonding and hydrogen bonding heteroditopic receptor analogues. DFT calculations suggest crown ether sodium cation complexation induces a polarisation of the sigma hole of ChB and XB heteroditopic receptor donors as a significant contribution to the origin of the unique cooperativity exhibited by these systems.

Full text of DOI:10.1002/anie.202001125

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Chalcogen Bond Mediated Enhancement of Cooperative Ion-Pair
Recognition
Authors: Thanthapatra Bunchuay, Andrew Docker, Utt Eiamprasert,
Panida Surawatanawong, Asha Brown, and Paul D. Beer
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202001125
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10.1002/anie.202001125
Angewandte Chemie International Edition
RESEARCH ARTICLE
Chalcogen Bond Mediated Enhancement of Cooperative Ion-Pair
Recognition
Thanthapatra Bunchuay,[a,b] Andrew Docker,[a] Utt Eiamprasert,[c] Panida Surawatanawong,[b] Asha
Brown, and Paul D. Beer*[a]
[a]
Dr. T. Bunchuay, A. Docker,Prof. P. D. Beer
Department of Chemistry, University of Oxford
Chemistry Research Laboratory
Mansfield Road, Oxford OX1 3TA
E-mail: paul.beer@chem.ox.ac.uk
Dr. T. Bunchuay (Current address),
Assoc. Prof. P. Surawatanawong
[c]
Dr. U. Eiamprasert
Department of Chemistry, Faculty of Science and
Technology , Rajamangala University of technology
Thanyaburi, Thanyaburi Pathum Thani 12110 (Thailand)
[b]
Faculty of Science, Mahidol University
272 Rama IV Road, Ratchathewi,
District Bangkok 10400 (Thailand)
Abstract: A series of heteroditopic receptors containing halogen
bond and unprecedented chalcogen bond donors integrated into
a 3,5-bis-triazole pyridine structure covalently linked to benzo-15-
crown-5 ether motifs exhibit remarkable cooperative recognition
covalently linked to an electron-withdrawing group and a Lewis
base, have been exploited in anion supramolecular chemistry. In
particular, XB receptors and more recently ChB hosts have been
shown to display contrasting and often superior anion binding
strength and selectivities in comparison to analogous HB receptor
analogues. Taking this into account, it is surprising that the
integration of sigma hole donors into heteroditopic structural host
framework design is rare. Indeed, to date, there are only three
examples of halogen bonding ion-pair receptors reported[15–17]
and to the best of our knowledge, the incorporation of a chalcogen
bond donor group into heteroditopic host structures for ion-pair
recognition is unprecedented.
1
of halide anions. Multi-nuclear H, 13C, 125Te and 19F NMR, ion
pair binding investigations reveal sodium cation – benzo-crown
ether binding dramatically enhances the recognition of bromide
and iodide halide anions, with the chalcogen bonding
heteroditopic receptor notably displaying the largest
enhancement of halide binding strength of over two hundred-fold,
in comparison to the halogen bonding and hydrogen bonding
heteroditopic receptor analogues. DFT calculations suggest
crown ether sodium cation complexation induces a polarization of
the sigma hole of ChB and XB heteroditopic receptor donors as a
significant contribution to the origin of the unique cooperativity
exhibited by these systems.
Introduction
Charged species are ubiquitous, playing crucial roles in biology,
medical health care and in particular in the environment resulting
from polluting anthropogenic chemical industry activities. Cation
and anion binding affinities of monotopic receptor systems are
critically influenced by the nature of counterions. This has
stimulated an ever increasing interest in the construction of
heteroditopic receptors for ion-pair recognition, which are
designed to enhance the efficacy of charged guest recognition via
favourable intramolecular electrostatic interactions and
conformational allosteric cooperativity.[1–4] Such systems have
been demonstrated to facilitate the solubilisation of inorganic salts
in organic media,[5–8] to function as efficient extraction and
membrane transport reagents,[9,10] and to be capable of
recognising biologically relevant zwitterionic species.[11–13]
A heteroditopic receptor typically utilizes Lewis acidic groups and
most commonly, various hydrogen bond (HB) donor motifs for
recognition of anion guest species.[1,14] During the last decade or
so, the sigma hole bonding interactions halogen bonding (XB) and
chalcogen bonding (ChB) which are the attractive non-covalent
interactions between an electrophilic halogen or chalcogen atom
Figure 1. a) The series 1,2,3-triazole donors as the anion binding functionalities
b) Heteroditopic 1•XB, 1•ChB and 1•HB receptor molecules.
Herein, we report a series of heteroditopic receptors containing
halogen (1•XB), chalcogen (1•ChB), and hydrogen bond (1•HB)
donors integrated into a 3,5-bis-triazole pyridine structure for
anion recognition which is covalently linked to benzo-15-crown-5
ether motifs for sodium cation binding (Figure 1). Importantly, ion-
pair binding investigations reveal sodium cation - benzocrown
ether binding switches on the recognition of bromide and iodide
halide anions. Notably, the chalcogen bonding heteroditopic
receptor displays a remarkable enhancement of halide binding
strength of over two hundred-fold relative to XB and HB
analogues.
1
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RESEARCH ARTICLE
Scheme 1. Synthesis of: 1•XB and 1•HB via CuAAC reaction and 1•ChB via sequential SNAr reactions.
Results and Discussion
Solution binding studies
Synthesis of heteroditopic receptors
The ion-pair binding properties of 1•XB, 1•ChB and 1•HB ditopic
receptors were studied by 1H-NMR spectroscopic titration
experiments in 10% d6-DMSO-CDCl3 solvent media. To evaluate
quantitative analysis of ion-pair recognition, comparative titrations
were carried out in the presence and absence of sodium cations,
the complementary sized alkali metal cation for the benzo-15-
crown-5 binding motif. In addition to association constants for
The target HB and XB heteroditopic receptors were prepared via
high yielding copper(I)-catalysed azide-alkyne cycloaddition
(CuAAC) methodology (Scheme 1). 1•XB receptor was prepared
via reaction between two equivalents of 4-azido-benzo-15-crown-
5 (2) and 3,5-diiodoethynylpyridine (3)[18] in the presence of
[Cu(MeCN)4]PF6 and TBTA in a mixture of 1:1 THF/DCM at room
temperature. Recrystallisation from MeOH afforded 1•XB in 84%
yield. The HB analogue was synthesised from 3,5-
diethynylpyridine (4) in DCM under the same conditions and
purification method to afford 1•HB in 72% yield (Scheme 1) The
preparation of bis-methyltelluro-triazole containing ChB receptor
(1•ChB) proved to be much more challenging and was initially
attempted by a nucleophilic substitution reaction between in situ
generated lithium methyl telluride anion and 1•XB.[19] Under these
conditions, the bis-iodotriazole (1•XB) starting material was
dehalogenated to the bis-prototriazole analogue 1•HB with no
evidence of formation of the desired product. An alternative
synthetic approach was undertaken via the preparation of a bis-
fluorotriazole intermediate (5) which was more reactive towards
nucleophilic aromatic substitution.[20] The XB receptor (1•XB) was
reacted with KF in acetonitrile/water mixtures under microwave
irradiation, and the desired product (5) isolated as an orange solid
in 20% yield after chromatographic purification. An SNAr reaction
of in situ generated lithium methyl telluride from methylithium and
tellurium(0) powder with (5) afforded, as evidenced from ESI-MS
analysis, a mixture products including 1•ChB, 1•HB and the mixed
ChB/HB compound analogue. The target chalcogen bonding
heteroditopic receptor 1•ChB was successfully isolated in 15%
yield after preparative thin layer chromatographic purification. All
three heteroditopic receptors were characterized by 1H, 13C, 125Te
NMR (where relevant) and high resolution ESI-MS spectrometry.
anion and ion-pair binding, cooperativity factors ( = KNa+/Knone
)
were determined for comparison of XB ChB and HB enhancement
of anion binding that results from cooperative binding of cation
and anion in the host. The 1H-NMR titration experiments of 1•XB
and 1•HB with TBA halide salts typically caused a downfield shift
of the internal pyridine and phenyl proton resonances in the
ditopic receptors. Additionally, the shift of the triazole proton in the
HB receptor also indicated its participation in the anion binding
event. Perturbation in the chemical shift of the internal pyridine
proton incumbent upon the anion binding cavity was observed
and monitored as a function of anion concentration. Very small
perturbations were observed in analogous halide titrations with
1•ChB. WinEQNMR2 analysis[21] of the titration data determined
1:1 stoichiometric association constants shown in Table 1.
Although the association constant values are modest, notably the
1•XB receptor displays stronger halide binding than the 1•HB and
1•ChB receptors, with no selectivity preference. Interestingly,
1•ChB host binds all the halides very weakly (Ka < 5 M-1)
compared to 1•XB and 1•HB analogues.
2
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10.1002/anie.202001125
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RESEARCH ARTICLE
Figure 2. Truncated 1H-NMR spectra of·XB receptor, 1•XB in the presence of 2 equivalents of NaPF6 with increasing equivalents of TBAI, and binding equilibrium
in 10% d6-DMSO in CDCl3 (500 MHz, T = 298K).
Table 1. Anion association constants Ka (M-1) for 1•XB, 1•ChB and 1•HB in the presence and absence of two equivalents of sodium cation in 10% d6-DMSO-
CDCl3.
Anion association constants Ka (M-1) for heteroditopic acyclic receptors[a]
1•XB
None
35
1•ChB
None[b]
<5
1•HB
None [b]
10
Anions[b]
Na+[c]
α[d]
Na+[c]
α[d]
_
Na+[c]
α[d]
_
Cl-
[e]
[e]
[e]
[e]
Br-
I-
5060
5660
40
127
162
1400
1080
<5
280
216
379
364
18
21
23
35
<5
16
[a] Association constants calculated using WinEQNMR2 software, errors (±) less than 10%. [b] Anions added as their TBA salts. [c] Titration conducted in the
presence of two equivalents of NaPF6. [d] The cooperativity factor (α) is given by α = {Ka(Na+)/ Ka(none)}. [e] It was not possible to determine an association constant
from the titration data suggesting complex equilibria and/or possible competing precipitation of sodium chloride.
much stronger halide binding compared to 1•HB analogue;
impressively over an order of magnitude greater with 1•XB.[22]
The addition of two equivalents of NaPF6 to 1H-NMR solutions
(10% d6-DMSO-CDCl3) of each heteroditopic host did not cause
any perturbations of the respective pyridyl host protons which
provided evidence for hexafluorophosphate anion not
participating in anion complexation. In all cases significant
downfield perturbations of the phenyl protons as well as the crown
ether methylene protons in the crown ether region was observed
indicative of sodium cation binding in each crown ether binding
site (Figure S1-3).
Importantly, Table 1 demonstrates that for each heteroditopic
receptor the association constant values for bromide and iodide
anions are increased dramatically in the presence of co-bound
sodium cations. The combination of favorable electrostatics and
the crown ether bound sodium cation inductively withdrawing
electron density from the respective XB, ChB and HB anion
recognition site via a conjugated through bond mechanism may
be responsible for the observed cooperativity of ion pair
binding.[23] It is noteworthy that the calculated cooperativity factors
( = KNa+/Knone ) are the greatest for 1•ChB, being at least over a
two hundred fold enhancement of halide binding strength,
followed by 1•XB over a hundred fold halide binding enhancement
which is an order of magnitude larger than 1•HB (Table 1). In
effect with the chalcogen bonding heteroditopic receptor 1•ChB,
the presence of crown ether co-bound sodium cations switches
on the recognition of bromide and iodide anions. The greatly
enhanced cooperativity of ion-pair recognition by the XB and ChB
receptors relative to the HB analogue may be rationalized by
increased polarisation of C—X (X = I and TeMe) via sodium
complexation in the conjugated heteroditopic receptors.
The 1H-NMR halide titrations were then repeated in the presence
of two equivalents of NaPF6. With all three heteroditopic receptors,
a significant downfield shift of the respective internal pyridine (a)
and phenyl proton (c,d,e) resonances was observed whilst the
signals associated with the crown ether protons remained
unchanged (Representative example for 1•XB shown in Figure 2).
This implies that halide anion binding occurs within the respective
bis-triazole cleft of the heteroditopic receptor and not simply via
direct electrostatic association with the benzo crown ether bound
sodium cations. Monitoring the internal pyridine proton (a) of each
receptor, association constants were determined from the titration
data using WinEQNMR2 (Table 1). In the case of bromide and
iodide, the sigma hole type receptors (1•XB and 1•ChB) display
3
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RESEARCH ARTICLE
Further evidence for the participation of halogen bonding in 1•XB
ion-pair recognition was also observed by a comparison of 13C-
NMR spectra of 1•XB in the presence of two equivalents of NaPF6,
and two equivalents of NaI (Figure S4). The chemical shift of the
quaternary carbon of the bis- iodotriazole motif was significantly
perturbed upfield with NaI (Δδ = -2.22 ppm). Iodide anion
complexation was also confirmed by the upfield shift of internal
pyridine carbon (Δδ = -1.45 ppm) which indicates the halide anion
being located in the bis-iodotriazole XB binding cleft of the
receptor. Analogous experiments with 1•ChB were carried out to
provide evidence for chalcogen bond formation, probed by 125Te
NMR spectroscopy, between the bis-methyltelluro triazole motif
and iodide. The 125Te nucleus, despite its low natural abundance,
is highly sensitive to changes in chemical environment as well as
Computational DFT studies
Having demonstrated the unique ion-pair recognition properties of
1•ChB and 1•XB, DFT calculations were performed to gain insight
into the electronic structures of the sigma hole mediated
heteroditopic receptors and importantly the perturbation of that
structure upon Na+ complexation.[28] A survey of the calculated
binding energies of the free and sodium complexed receptors,
summarized in Table 2, show good agreement to the
experimentally observed trend to the association constants
obtained from 1H NMR titration experiments. As anticipated from
increased electrostatic interactions towards the anionic iodide
guest, the dicationic complexes [1•ChB+2Na]2+ and [1•XB+2Na]2+
show dramatically enhanced I- association energies relative to the
1•ChB and 1•XB .Indeed, further evidence for the strengthening
of the sigma hole-iodide interaction was suggested by the TeI
and the II distances in [1•ChB+2Na+I]+ and [1•XB+2Na+I]+
which are shorter than the corresponding distances in [1•ChB+I]-
and [1•XB+I] - by about 0.1 Å (Table S3). From the molecular
electrostatic potential (ESP) plots, the maximum ESPs at Te and
I are 0.060 and 0.061 au, for 1•ChB and 1•XB respectively (Figure
3). Upon sodium cation complexation, the maximum ESPs for
[1•ChB+2Na]2+ and [1•XB+2Na]2+ become significantly more
positive (0.188 and 0.152 au, respectively). That is the maximum
ESPs in [1•ChB+2Na]2+ and [1•XB+2Na]2+ are higher than those
in 1•ChB and 1•XB. These computational results allude to the
source of the remarkable cooperativity of bromide and iodide
halide binding exhibited by the sodium cation benzocrown ether
complexed ChB and XB heteroditopic receptors. The
cooperativity factor (α) for both 1•ChB and 1•XB can be
rationalized from the increase in the calculated binding energies
with halide, which is related to the increase in the magnitude of
the bound cation induced polarization.
non-covalent interaction formation in solution.[24,25]
A
complexation experiment with two equivalents of NaPF6 revealed
an upfield perturbation due to crown ether sodium cation
complexation. By contrast addition of two equivalents of NaI
resulted in a downfield shift indicative of iodide ChB anion
recognition (Figure S5).
The genuine participation of halogen bonding or chalcogen
bonding, as opposed to electrostatic contribution was confirmed
by a series of control experiments using the pyridine-bis-
fluorotriazole crown ether host (5) as a model in this study. The
fluorotriazole derivative serves as a non-halogen bond donor
group,[26] where anion coordination is only viably governed by
electrostatic interactions. From qualitative 1H-NMR spectroscopic
experiments, the sodium complexed fluorotriazole receptor (5)
receptor did not display any proton resonance perturbations upon
addition of 5 equivalents of iodide anion indicating no anion
binding to this receptor (Figure S6b).[27] Moreover, the 19F-NMR
spectrum also indicates no perturbation of fluorine atom in fluoro
triazole group by iodide anion (Figure S6c). From this experiment,
this indicates that the sodium complexed bis-triazole receptors do
not assist cooperative ion-pair binding via simple direct
electrostatic interaction between the cations and anion.
a)
1•ChB
[1•ChB+2Na]2+
b)
1•XB
[1•XB+2Na]2+
Figure 3. Electrostatic potential plots (ESPs) were mapped over electron density surfaces with isodensity of 0.004 au with the color scale from 0.05 to 0.26
au for 1•ChB and 1•XB and their sodium complexes.
4
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10.1002/anie.202001125
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RESEARCH ARTICLE
Conclusion
Table 2. Relative free energies (in kcalmol-1) for the binding of an iodide to
the sigma hole type receptors 1•ChB and 1•XB.
In conclusion, a series of novel heteroditopic receptors were
synthesized, each containing benzo-15-crown-5 ether cation
binding groups covalently attached to 3,5-bis-iodine, tellurium-
and proton-functionalised-triazole pyridine anion binding motifs
providing respective XB, unprecedented ChB and HB ion-pair
receptors. 1H, 13C, 125Te and 19F NMR spectroscopy, ESI-MS and
X-ray crystallography ion-pair binding studies demonstrate the
cooperative recognition of bromide and iodide halide anions via
concomitant sodium cation crown ether complexation of the
respective heteroditopic receptor. This can be rationalized by
favorable electrostatics combined with the crown ether bound
sodium cation facilitating an inductive withdrawal of electron
density from the respective XB, ChB and HB anion recognition
site. Importantly, determined cooperativity factors reveal the ChB
heteroditopic receptor exhibits a remarkable and the largest
enhancement of halide binding strength of over two hundred-fold,
in comparison to the XB and HB heteroditopic receptors. In effect,
sodium cation – benzo-crown ether binding by 1•ChB switches on
the recognition of bromide and iodide halide anions. DFT
calculations suggest crown ether sodium cation complexation
results in a polarization of the ChB and XB heteroditopic receptor
donors as a significant contribution to the origin of the unique
cooperativity exhibited by these systems. These observations
provide evidence for a new mechanism of cooperativity for ion-
pair recognition unique to the mediation of sigma hole interactions
via co-bound cation recognition illustrating an exciting opportunity
for their exploitation in future ion-pair host design.
Reaction[a]
1•ChB + I− → [1•ChB+I] -
ΔG (kcalmol-1)
−4.65
[1•ChB+2Na]2+→ [1•ChB+2Na+I]+
1•XB + I− → [1•XB+I] -
−19.94
−3.92
[1•XB+2Na]2+→ [1•XB+2Na+I]+
−22.23
[a] Optimization and single-point calculations were performed in CHCl3
solvent
Solid state structure determination
Further insight into the ion-pair binding behaviour of the ditopic
host systems was provided by solid state characterisation of the
sodium iodide complex of the hydrogen-bonding receptor 1•HB.
Crystals of the complex 1•HB•2NaI suitable for X-ray structural
determination were grown by slow evaporation of
a
chloroform:acetonitrile 9:1 solution of the receptor 1•HB•2NaPF6
containing two molar equivalents of tetrabutylammonium iodide
(Figure 4). The cations are coordinated by the five oxygen atoms
from the crown ether host, with Na+—O distances ranging from
2.302(10) Å to 2.477(10) Å and their coordination spheres are
completed by additional interactions with water solvate molecules
and iodide anions. The triazole bound iodide anion is
encapsulated within each of the 3,5-bis-triazole pyridine anion-
binding clefts via an array of CH···I- hydrogen bonding
interactions. [29,30]
Acknowledgements
T.B. thanks the Development and Promotion of Science and
Technology Talents (DPST) Project Thailand for a student
scholarship.
Keywords: Chalcogen Bonding • Halogen Bonding •
Cooperativity • Ion-pair receptors• Heteroditopic Receptors.
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6
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Entry for the Table of Contents
Halogen bond and chalcogen bond ion-pair heteroditopic receptors exhibit remarkable cooperative recognition of halide anions via
sodium cation – benzo-crown ether binding. The chalcogen bonding receptor displays the largest enhancement of halide binding
strength of over two hundred-fold. DFT calculations suggest sodium cation crown ether complexation induces a polarisation of the
ChB and XB donor atoms as the source of cooperativity.
7
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