A Potent Halogen-Bonding Donor Motif for Anion Recognition and Anion Template Mechanical Bond Synthesis

Article abstract of DOI:10.1002/anie.201907625

The covalent attachment of electron deficient perfluoroaryl substituents to a bis-iodotriazole pyridinium group produces a remarkably potent halogen bonding donor motif for anion recognition in aqueous media. Such a motif also establishes halogen bonding anion templation as a highly efficient method for constructing a mechanically interlocked molecule in unprecedented near quantitative yield. The resulting bis-perfluoroaryl substituted iodotriazole pyridinium axle containing halogen bonding [2]rotaxane host exhibits exceptionally strong halide binding affinities in competitive 50 % water containing aqueous media, by a factor of at least three orders of magnitude greater in comparison to a hydrogen bonding rotaxane host analogue. These observations further champion and advance halogen bonding as a powerful tool for recognizing anions in aqueous media.

Full text of DOI:10.1002/anie.201907625

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Accepted Article
Title: A Potent Halogen-Bonding Donor Motif for Anion Recognition and
Anion Template Mechanical Bond Synthesis
Authors: Thanthapatra Bunchuay, Andrew Docker, Antonio J. Martinez-
Martinez, and Paul D. Beer
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201907625
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http://dx.doi.org/10.1002/ange.201907625

10.1002/anie.201907625
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COMMUNICATION
A Potent Halogen-Bonding Donor Motif for Anion Recognition
and Anion Template Mechanical Bond Synthesis
Thanthapatra Bunchuay, Andrew Docker, Antonio J. Martinez−Martinez, and Paul D. Beer*
Dedicated to Professor Jean-Marie Lehn on the occasion of his 80th birthday
Abstract: The covalent attachment of electron deficient perfluoroaryl
substituents to a bis-iodotriazole pyridinium group produces a
remarkably potent halogen bonding donor motif for anion recognition
in aqueous media. Such a motif also establishes halogen bonding
anion templation as a highly efficient method for constructing a
mechanically interlocked molecule in unprecedented near
quantitative yield. The resulting bis-perfluoroaryl substituted
iodotriazole pyridinium axle containing halogen bonding [2]rotaxane
host exhibits exceptionally strong halide binding affinities in
competitive 50% water containing aqueous media, by a factor of at
least three orders of magnitude greater in comparison to a hydrogen
bonding rotaxane host analogue. These observations further
champion and advance halogen bonding as a powerful tool for
recognising anions in aqueous media.
Originating from its exploitation in solid state crystal engineering
and in materials design, halogen bonding (XB), the highly
directional, attractive intermolecular non-covalent interaction
between an electrophilic halogen atom and a neutral or charged
Lewis base, has begun to emerge as a powerful complement to
the ubiquitous hydrogen bonding (HB) interactions for solution
phase applications in catalysis, medicinal chemistry, anion
transport, and anion recognition.[1–6] Regarding the latter, we and
others have demonstrated that XB hosts often display superior
anion affinities and contrasting selectivities in comparison to HB
host analogues.[7–11] However, examples of XB host systems
that function in competitive aqueous media remain extremely
rare due in part to the challenging syntheses of such
systems.[12,13] This is especially the case with elaborate XB
mechanically interlocked molecules (MIMs) which due to their
unique topological three-dimensional and highly preorganised
cavities are capable of aqueous anion recognition.[7,14,15] Herein
we report
a novel, remarkably potent electron deficient
perfluoroaryl substituted bis-iodotriazole pyridinium XB donor
motif (Figure 1a) which is demonstrated to dramatically
increase the strength of XB―anion interactions for
recognition in aqueous media and the efficacy for an
unprecedented near quantitative high yielding XB MIM
synthesis of a rotaxane 1∙PF6 (Figure 1b) using anion
templation.
Figure 1. a) Electron deficient perfluoroaryl substituted bis-iodotriazole
pyridinium XB donor motif and b) XB [2]rotaxane 1∙PF6.
[*]
Dr. T. Bunchuay, A. Docker, A. J. Martinez-Martinez, Department of
Chemistry, University of Oxford, Chemistry Research Laboratory
Mansfield Road, Oxford OX1 3TA (UK)
E-mail: paul.beer@chem.ox.ac.uk
Dr. T Bunchuay
Current Address: Faculty of Science Mahidol University, 272 Rama
IV Road, Ratchathewi District, Bangkok 10400 (Thailand)
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In order to investigate whether XB halide anion binding
potency could be tuned via the covalent attachment of suitable
electron withdrawing substituents, the synthesis of a series of
Single crystals suitable for X-ray diffraction studies were
obtained for the halide salts 5·Cl and 5·I. In both structures the
XB acyclic
receptors consisting of
a
3,5-bis-iodotriazole
acyclic receptor adopts
a
close triazole–I conformation
pyridinium motif functionalized with methylene linked benzylic
and ester groups, and aryl linked benzene and perfluorinated
benzene ester groups was undertaken initially. The
monocationic pyridinium XB receptors 2·PF6, 3·PF6, 4·PF6, and
5·PF6 (Figure 2) were prepared via copper(I)-catalysed azide-
alkyne cycloaddition (CuAAC) reactions between appropriate
azides and 3,5-diiodoethynylpyridine, subsequent methylation
with iodomethane and anion exchange. (The synthetic details
are described in the SI). The halide anion binding properties of
the XB acyclic receptors, studied by 1H-NMR titration
experiments in d6-DMSO, revealed chloride to form the strongest
complexes correlating with halide charge density (Table 1).
encapsulating the anion guest through strong halogen bond-
halide interactions (Figure 3, see SI for CCDC) as indicated by
triazole–I···X– interatomic distances significantly shorter than the
sum of the van der Waals radii (see Table 2).[17]
Figure 3. Structures of monocationic acyclic XB bis-iodotriazole pyridinium
receptors 5+ as the; a) chloride and b) iodide salt.
Table 2. XB bond lengths and percentage shortening of the sum of the van
der Waals radii (%VdW).[17]
Guest Anion
interatomic distances
(I···X–/Å)[a]
%vdW
Figure 2. Structures of monocationic acyclic XB bis-iodotriazole pyridinium
receptors as their hexafluorophosphate salts (PF6 ).
-
Cl-
I-
3.1419(6), 3.0079(6)
3.4010(3), 3.3522(3)
83%, 79%
81%, 80%
It is noteworthy that the largest association constant
magnitudes were observed with the perfluorinated arene
functionalized receptor 5·PF6 with all halides. This result
highlights the inductive effect of the electron withdrawing
perfluoroaryl spacer motifs polarising the iodine atoms of the bis-
iodotriazole XB donor groups facilitating strong XB-anion
interactions.
[a] Calculated errors given in parenthesis.
The XB donor bis-iodotriazole pyridinium structural motifs
of the acyclic receptors were integrated into a bis-permethylated
β-cyclodextrin stoppered axle component for respective XB
[2]rotaxane construction using a chloride anion template amide
condensation clipping rotaxanation reaction. Axles 6·Cl, 7·Cl,
8·Cl were each stirred with an equimolar amount of bis-amine
macrocycle precursor 10[18] and NEt3 in dry CH2Cl2 at 0oC,
whereupon addition of 3,5-bis-chlorocarbonyl pyridine 11
afforded, after purification by preparative thin layer silica gel
Table 1. Anion association constant (Ka/M-1) acyclic pyridinium bis-
iodotriazole receptors in d6-DMSO.[a]
[1]
Anion[a]
2·PF6
3·PF6
4·PF6
5·PF6
-
chromatography and anion exchange to their PF6 salts, the
target XB [2]rotaxanes 12·PF6, 13·PF6 and 1·PF6 in respective
isolated yields of 40%, 45% and 91% (Scheme 1). In contrast,
the combined effect of XB and perfluoroaryl group incorporation
in effective rotaxane formation was further highlighted by a
significantly lower 42% isolated yield of the HB rotaxane 14·PF6,
obtained from using perfluoroaryl HB 9·Cl axle as a template,
compared to the 91% yield of XB rotaxane 1·PF6.
Cl-
Br-
I-
387
238
146
403
206
62
429
277
98
1395
491
190
[a] Anions added as their TBA salts, values of Ka determined using the
WinEQNMR2 software[16] using a 1:1 host-guest binding model; errors (±)
less than 10%. d6-DMSO, T = 298 K.
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Scheme 1. [2]Rotaxane synthesis via chloride template amide condensation
Clearly the perfluorinated benzene functionalized XB axle
8·Cl acts as the most efficient anion template for rotaxane
synthesis as evidenced by the impressive 91% yield of
[2]rotaxane 1·PF6. By contrast, the axles containing the non-
fluorinated aromatic and alkyl spacers result in [2]rotaxane
formation in the typical yield range for the anion template
method of 40-60%.[7,15,18] Taking into account the chloride anion
association constant data shown in Table 1, where the acyclic
XB receptor 5·PF6
by virtue of the electron-withdrawing
perfluoroaryl spacer motifs forms the strongest association with
chloride, there is an obvious correlation of chloride anion
association strength with yield of rotaxane formation. Notably,
the observed > 90% yield for the preparation of [2]rotaxane
1·PF6 via this XB anion template clipping method matches the
highest yields obtained for MIM formation using metal cation , π-
[19–26]
donor-π-acceptor and hydrogen bond templates.
Figure 4 a) Perfluorinated and non-fluorinated [2]rotaxane host molecules b) Truncated 1H-NMR of 1·PF6 in D2O:d6-Acetone (1:1) upon addition of iodide anion as
its TBA salt. c) Anion Binding isotherm of 1·PF6, [host] = 1mM and [guest] = 50 mM (500MHz, 298K).
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10.1002/anie.201907625
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COMMUNICATION
Table 3. Anion association constant (Ka/M-1) for acyclic and [2]rotaxane hosts in D2O:d6-Acetone (1:1).[a]
Ka (M-1) in 1:1 D2O/d6-Acetone
Entry
Receptors
Chloride
Bromide
Iodide
Perfluorinated Hosts
>105
63
1
2
Monocationic XB Perfluoroaryl Rotaxane 1·PF6
Monocationic HB Perfluoroaryl Rotaxane 14·PF6
930
NBb
1727
NBb
Non-fluorinated Hosts
Monocationic XB Rotaxane 15·PF6
3
150
436
1036
a Anions added as TBA salts, errors (±) less than 10%, 1:1 association constants calculated using WinEqNMR2 software,2 monitoring the perturbation
of the internal pyridinium proton Ha (500MHz, 298K). b NB =No binding.
The halide anion recognition properties of XB
monocationic rotaxanes together with a HB rotaxane analogue
and axle were investigated using H-NMR titration experiments
in D2O:d6-acetone (1:1). With all XB rotaxanes the addition of
halide anion caused significant perturbations of interlocked
cavity proton resonances (Ha and H1) (Figure 5b). The downfield
shift of the axle component internal pyridinium proton (Ha) and
the upfield shift of the internal pyridine proton (H1) from the
iodotriazole axle component of 1·PF6, facilitating in particular the
amplified potency of XB donor – halide anion interactions.
1
In conclusion, the covalent attachment of electron deficient
perfluoroaryl substituents to a bis-iodotriazole pyridinium group
produces a powerful halogen bonding donor motif capable of
halide anion recognition in aqueous media. For the first time, a
near quantitative isolated yield of a discrete anion template
directed assembly of a MIM host structure is achieved via
exceptionally strong XB donor—chloride interactions. Moreover,
the chloride anion association strength of the axle component’s
XB donor motif correlates with rotaxane formation yield.
Importantly, anion binding studies in competitive 50% water
containing aqueous media reveal the monocationic XB rotaxane
1·PF6 to exhibit remarkable halide binding affinities at least three
orders of magnitude greater than a HB rotaxane analogue.
These observations provide further evidence for highlighting XB
as a novel tool for achieving anion recognition in aqueous media.
macrocycle component were monitored as
a function of
equivalents of anion added (Figure 5c). WinEQNMR2 analysis of
the titration data for both 1·PF6 and 14·PF6 revealed 1:1
stoichiometric association constants for halide anions (Table 3).
In the highly competitive 50% aqueous mixture, the
halogen bonding rotaxane 1·PF6 displays remarkably strong
binding for Cl-, Br-, and I- anions. Indeed, the association
constant for iodide binding is >105 M-1, whilst those of bromide
and chloride are 1727 M-1 and 930 M-1 (Table 3, Entry 1),
respectively. This preferential binding to the larger and less
highly hydrated halide anions is presumably governed by the
Hofmeister series bias.[27–29] In contrast, the halide anion
recognition strength of the hydrogen bonding rotaxane analogue
14·PF6, where iodotriazole groups are substituted with C—H
prototriazole motifs is dramatically diminished, demonstrating
only very weak affinity to I- and no binding for Cl- and Br- (Table
3, Entry 2). The remarkable enhancement of halide
complexation by XB 1·PF6 rotaxane by at the very least three
orders of magnitude in comparison to HB rotaxane 14·PF6
illustrates again the superiority of halogen bonding over
hydrogen bonding in aqueous anion recognition. [7,9,12–15]
Finally, in an effort to elucidate the effect of incorporating
the perfluoroaryl motif into the axle component of 1·PF6, the
halide anion binding properties of monocationic XB rotaxane
15·PF6 were determined (Table 3 Entry 3). As expected, 1·PF6
demonstrates notable enhancement of halide binding, with the
strength of iodide complexation at least two orders of magnitude
greater than 15·PF6 rotaxane (Table 3, Entry 1 and 3), which
can be attributed to the rigid, electron deficient and hydrophobic
nature of the perfluoroaryl substituents of the pyridinium bis-
Acknowledgements
T.B. would like to thank the Development and Promotion of
Science and Technology Talents (DPST) Project, Thailand, for a
full student scholarship. A.D. thanks the EPSRC for
a
studentship. The authors thank Dr. Nader Amin and Dr. Jason
Lim, University of Oxford, for helpful discussions.
Keywords: Anion Recognition • Halogen Bonding • Rotaxanes •
Supramolecular
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COMMUNICATION
Thanthapatra Bunchuay, Andrew
Docker, Antonio J. Martinez−Martinez,
and Paul D. Beer*
The covalent appendage of electron
deficient perfluoroaryl substituents to a
bis-iodotriazole
pyridinium
group
Page No. – Page No.
produces powerful halogen bond
a
A Remarkably Potent Halogen-
Bonding Donor Motif for Anion
Recognition and Anion Template
Mechanical Bond Synthesis
donor. Using this motif, halogen bonding
anion templation is demonstrated as a
highly efficient method for constructing a
rotaxane in near quantitative yield,
capable of strong halide binding in 50%
water aqueous media.
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