A Chiral Halogen-Bonding [3]Rotaxane for the Recognition and Sensing of Biologically Relevant Dicarboxylate Anions

Article abstract of DOI:10.1002/anie.201711176

The unprecedented application of a chiral halogen-bonding [3]rotaxane host system for the discrimination of stereo- and E/Z geometric isomers of a dicarboxylate anion guest is described. Synthesised by a chloride anion templation strategy, the [3]rotaxane host recognises dicarboxylates through the formation of 1:1 stoichiometric sandwich complexes. This process was analysed by molecular dynamics simulations, which revealed the critical synergy of halogen and hydrogen bonding interactions in anion discrimination. In addition, the centrally located chiral (S)-BINOL motif of the [3]rotaxane axle component facilitates the complexed dicarboxylate species to be sensed via a fluorescence response.

Full text of DOI:10.1002/anie.201711176

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Accepted Article
Title: A Chiral Halogen Bonding [3]Rotaxane for Recognition and
Sensing of Biologically-relevant Dicarboxylate Anions
Authors: Jason Y. C. Lim, Igor Marques, Vítor Félix, and Paul D. Beer
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201711176
Angew. Chem. 10.1002/ange.201711176
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10.1002/anie.201711176
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COMMUNICATION
A Chiral Halogen Bonding [3]Rotaxane for Recognition and
Sensing of Biologically-relevant Dicarboxylate Anions
Jason Y. C. Lim,[a] Igor Marques,[b] Vítor Félix[b] and Paul D. Beer*[a]
Abstract: The unprecedented application of
a
chiral halogen
we report in a proof-of-concept study, the first example of a
chiral XB [3]rotaxane as a novel dicarboxylate receptor (Fig. 1).
bonding [3]rotaxane host system for discrimination of stereo- and
E/Z geometric dicarboxylate anion guest isomers is described.
Synthesised by a chloride anion templation strategy, the [3]rotaxane
host recognises dicarboxylates via formation of 1:1 stoichiometric
sandwich complexes, which is supported by molecular dynamics
simulations that reveal the critical synergy of halogen and hydrogen
bonding interactions in anion discrimination. In addition, the centrally
located chiral (S)-BINOL motif of the [3]rotaxane’s axle component
facilitates the complexed dicarboxylate species to be sensed via a
fluorescence response.
A
chiral
(S)-1,1’-bi-2-naphthol
(BINOL)
fluorophore[38]
incorporated between two XB-donor 3,5-bis-iodotriazole
pyridinium motifs on the axle component, together with two
mechanically bonded HB macrocycles, enables the XB
[3]rotaxane host to discriminate between DC2- enantiomers (R vs
S-NBoc-Glu2-) and geometric isomers (Mal2- vs Fum2-), via
fluorescence responses. Chiral discrimination by interlocked
host molecules is extremely rare,[39–41] and to the best of our
knowledge, an XB [3]rotaxane capable of both geometric and
stereoisomer discrimination is unprecedented.
Dicarboxylates (DC2-) constitute a large and structurally
diverse class of anions which play crucial roles in biology and
industry,[1] with some (e.g. oxalate) implicated as environmental
pollutants.[2] Their biological importance has primarily driven the
design and development of polytopic abiotic receptors which
utilise hydrogen bonding (HB) interactions[3–12] and Lewis acidic
metal centres[13,14] for binding and sensing.[15] However, DC2- are
highly challenging targets for selective recognition due to their
hydrophilicity[16] and complex overall shapes owing to the
diversity of spacer motifs between their anionic carboxylate
termini. These linker units can contain one or several chiral
centres (e.g. glutamate, tartrate), different functional groups (e.g.
C=O, -OH, -NH2) and exhibit geometric isomerism (e.g. E/Z-
alkenes). To further complicate receptor design, these subtle
structural differences lead to very similar physicochemical
properties amongst isomers. The contrasting bioactivities
exhibited by closely-related analogues such as fumarate (E-
Figure 1. Design of [3]rotaxane host and the structures of the dicarboxylate
anions investigated in this study.
alkene) and maleate (Z-alkene)[17–19] provides
a powerful
impetus to develop abiotic receptors able to recognise and
sense dicarboxylates regio-[20–22] and stereoselectively.[23–26]
Mechanically-interlocked molecules such as rotaxanes and
catenanes have been exploited for the binding and sensing of
charged species.[27–29] Although rare, higher order interlocked
host architectures can also provide unique opportunities for
host-guest recognition.[30–32] In recent years, halogen bonding
(XB), the attractive supramolecular interaction between an
electron-deficient halogen atom and a Lewis base, was shown to
be highly effective for the recognition of anions, often
outperforming HB receptor analogues attributable to XB’s more
stringent linearity and greater covalent character.[33–37] Herein,
The target [3]rotaxane was prepared by a chloride anion-
template clipping methodology, exploiting the potent halide
affinity of the two 3,5-bis-iodotriazole pyridinium axle motifs, in
37% yield (Scheme 1).[35,42] Electrospray ionisation mass
spectrometry (m/z = 1921 [M2+]) and 1H NMR spectroscopy
confirmed the identity and interlocked nature of the [3]rotaxane,
which showed dramatic upfield shifts and desymmetrisation of
the macrocycle hydroquinone signals (Fig. S2-6). This is
consistent with strong donor-acceptor aromatic π-π stacking
interactions between the macrocycles and the axle’s XB
pyridinium units, supported by 2D ROESY spectroscopy (Fig.
S2-4), forming the DC2- binding pocket shown in Figure 1.
[a]
[b]
J.Y.C. Lim, Prof. P.D.Beer
Chemistry Research Laboratory, Department of Chemistry
University of Oxford
12 Mansfield Road, Oxford, OX1 3TA (UK)
E-mail: paul.beer@chem.ox.ac.uk
I. Marques, Prof. V. Félix
Department of Chemistry, CICECO - Aveiro Institute of Materials,
and Department of Medical Sciences, iBiMED - Institute of
Biomedicine
University of Aveiro
3810-193 Aveiro, Portugal
Supporting information (SI) for this article is given via a link at the
end of the document.
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COMMUNICATION
Scheme 1. Chloride anion templated synthesis of [3]rotaxane 4.(PF6)2.
The anion binding properties of [3]rotaxane 4.(PF6)2 were
initially probed using 1H NMR titrations with tetrabutylammonium
(TBA) salts of DC2- in CDCl3/CD3OD/D2O 60:39:1 (v/v),[43]
revealing important differences between DC2- and Cl-
complexation. For example, S-Glu2- binding (Fig. 2) is
accompanied by modest shifts of signals Hb and H1, which are
much smaller in magnitude in comparison to Cl- (Fig. S3-1). This
suggested that, unlike Cl-, the dianion was too large to fit into
each interlocked binding site. S-Glu2- binding also elicited greater
downfield shifts of axle external pyridinium Ha‘ proton signals
than the other (Ha‘‘), implying a closer proximity to the bound
guest. In contrast, Cl- resulted in similar Ha‘ and Ha‘‘ signal
downfield perturbations without the diagnostic signal 'crossover'
seen for S-Glu2-. Furthermore, the modest upfield shifts of the
centrally-located Hd methylene protons during the S-Glu2-
titration were absent with Cl-. Together, this 1H NMR titration
evidence implied that S-Glu2- was binding in the space between
4.(PF6)2 also revealed much larger spectral changes during
Fum2- binding than Cl- (Fig. S5-1), which suggests larger
rotaxane conformational changes occur upon DC2- sandwich
complex formation. Although the magnitudes of the respective
DC2- anion-induced 1H NMR signal shifts were too small for
accurate association constant (K) determination using the
WinEQNMR2 software,[44] analysis of the Hb shifts with Cl- using
a host-guest 1:2 stoichiometric binding model confirmed the
halide’s ability to bind strongly within each individual interlocked
cavity site (K1:1 = 2609 ± 201 M-1 and K1:2 = 123 ± 10 M-1).
DC2- binding by 4.(PF6)2 was also probed by fluorescence
anion titration experiments in CHCl3/CH3OH/H2O 60:39:1 v/v,
resulting in notable (S)-BINOL fluorescence quenching (Fig. 3
and Section S4). In contrast, Cl- and Ox2- addition elicited much
smaller changes, presumably due to their inability to form
sandwich complexes. BindFit[45] analysis of the DC2-
fluorescence titration data with [3]rotaxane 4.(PF6)2 and free axle
both macrocycles to form a 1:1 stoichiometric sandwich complex, 1.(PF6)2 determined the association constants shown in Table 1.
whilst Cl- was likely binding near each individual interlocked
For 4.(PF6)2, the values of K1:1 >> K1:2 for all DC2- confirmed the
1:1 stoichiometric sandwich complex as the predominant host-
guest species. Importantly, 4.(PF6)2 showed impressive chiral
discrimination towards S-Glu2- with a selectivity of KS/KR = 5.7 ±
0.3. 4.(PF6)2 also exhibited a high degree of geometric isomer
1
cavity. Similar patterns of H NMR signal shifts as S-Glu2- were
seen for R-Glu2-, Fum2- and Mal2-, albeit of different magnitudes,
clearly indicating that these DC2- guests were binding in the
same manner (Fig. S3-2). Circular dichroism spectroscopy of
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Table 1. Association constants K/ M-1 of axle 1.(PF6)2 and rotaxane 4.(PF6)2
discrimination with a selectivity for Fum2- over Mal2- of 4.4 ± 0.3.
The importance of the [3]rotaxane structure in DC2- isomer
discrimination can be further discerned by comparing its binding
behaviour with free axle 1.(PF6)2. Although the axle alone still
displayed appreciable DC2- binding affinities (Table 1), 1.(PF6)2
showed much poorer enantioselectivity (KS/KR = 0.96 ± 0.02) for
S/R-Glu2- and complex binding equilibria for Mal2-.[46]
with different anions from fluorescence binding studies.[a]
Anion
S-Glu2-
Rotaxane 4.(PF6)2
Free axle 1.(PF6)2
K1:1 = 1598 ± 18
K1:1 = 35227 ± 2114
K1:2 = 13 ± 1
R-Glu2-
Fum2-
Mal2-
K1:1 = 6226 ± 68
K1:2 = 111 ± 1
K1:1 = 1660 ± 25
K1:1 = 18365 ± 1164
K1:2 = 139 ± 1
K1:1 = 106 ± 2
K12 = 589 ± 9
[c]
K1:1 = 4179 ± 81
K1:2 = 12.6 ± 0.4
-
[b]
Ox2-
-
K1:1 = 1427 ± 26
K1:2 = 357 ± 6
[a] K values determined using BindFit[45] to a host-guest 1:2 binding model; T
= 293 K, [host] = 50 μM, λex.= 280 nm, CHCl3/CH3OH/H2O 60:39:1 v/v; [b]
Fluorescence changes too small for K value determination; [c] Complex
binding equilibria.
Figure 2. Partial 1H NMR spectra of 4.(PF6)2 in the presence of incremental
quantities of S-Glu2- ([4.(PF6)2] = 1.0 mM, T = 298 K, CDCl3/CD3OD/D2O =
60:39:1 v/v). Proton labels follow those in Scheme 1.
[3]Rotaxane discrimination of Mal2- and Fum2- resulted
from host-guest size complementarity and differing DC2-
solvation within the binding pocket. MP2/6-31+G(d) geometry
optimisations revealed the planarity of Fum2-, with an
intramolecular carboxylate (CC=O···CC=O) distance of 3.987 Å and
a dipole moment of 0.00 D, while both carboxylate groups of
Mal2- have a relative twist of 47.7° and a 3.440 Å CC=O···CC=O
separation, resulting in a 5.20 D dipole moment (Fig S6-2). To
accommodate these differing stereoelectronic requirements, the
rotaxane underwent a greater structural deformation to bind the
latter anion (Fig. 4A), resulting in a decrease of the average
distance between the centres of mass of both iodine atoms in
each pyridinium bis-iodotriazole motif from 10.48 ± 0.20 Å in free
uncomplexed 4.(PF6)2, to 8.60 ± 0.12 Å and 9.67 ± 0.13 Å for the
Mal2- and Fum2- adducts respectively. More importantly, the
bound anions are solvated to different extents by H2O and
CH3OH (Table S6-3). Although CH3OH is present in a 17-fold
molar excess, Mal2-’s carboxylate groups are preferentially
solvated by H2O, while those of the more lipophilic Fum2- are
surrounded by more CH3OH molecules (Table S6-5), following
the MD-simulated solvation trends of the free anions as their
TBA salts (Table S6-4). Thus, the H2O molecules strongly
compete with the isophthalamide binding unit for the carboxylate
groups, leading to 2.9 ± 0.7 NHhost···Oanion HB interactions for
Figure 3. Fluorescence titrations of 4.(PF6)2 with (A) (TBA)2(Fum2-) and (B)
TBACl ([4.(PF6)2] = 50 μM, λex = 280 nm, T = 293 K, CHCl3/CH3OH/H2O =
60:39:1 v/v).
The origins of the rotaxane’s geometric and
stereoselective DC2- binding properties were probed with
molecular dynamics (MD) simulations using Amber16,[47–49] with
the anion complexes immersed in cubic boxes of randomly-
distributed solvent molecules in the same ratio used for binding
studies. The host and guest molecules were described with
GAFF,[50,51] and the XB interactions were simulated with resort to
an extra-point of charge (full computational details in Section S6).
The 1:1 stoichiometric DC2--[3]rotaxane complexes (Fig S6-1),
were maintained throughout the simulation time via convergent
C-I···Oanion XB interactions from the axle unit and N-H···Oanion
Fum2- and 1.9
±
0.8 for Mal2- (Table S6-2). Given the
comparable XB interactions with both anions (Table S6-1),
differing anion solvation mainly accounts for the geometric
selectivity of the rotaxane for Fum2-.
hydrogen
bonds
from
the
macrocycle
components’
isophthalamide units (Fig. 4, Tables S6-1 and S6-2).
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Figure 4. MD illustrative binding scenarios of the 1:1 sandwich complexes of 42+ and (A) Fum2-/Mal2- and (B) S/R-Glu2-. The XB and HB interactions are depicted
as purple and blue dashed lines, respectively.
Contrastingly, the enantioselectivity of 42+ arises primarily
from host-guest structural complementarity with less solvent
influence. The encapsulated S/R-Glu2- stereoisomers interact
almost exclusively with CH3OH (Table S6-5), averaging 3.1 ± 0.9
and 1.8 ± 0.7 HB interactions for the S- and R-enantiomers
respectively, which do not significantly interfere with anion
binding due to their weakness. However, both anion
enantiomers form structurally distinct diastereomeric host-guest
complexes (Fig. 4B) with important variations in the extents of
their XB and HB interactions. For instance, both carboxylate
groups of R-Glu2- are held by XB interactions of comparable
strengths, while one is more tightly halogen bonded than the
other in the S-Glu2- complex (Table S6-1). Furthermore, R-Glu2-
is held by fewer HB interactions (2.8 ± 0.8) than the S-
enantiomer (3.3 ± 0.9) (Table S6-2). The difference in interaction
energy of both diastereomeric complexes (∆Eint) was estimated
from the computed molecular mechanics energies of the host-
guest complex (Ecomplex), free 42+ (Ehost) and anion (Eguest),
considering only the electrostatic and van der Waals (vdW)
The MD simulations of axle 12+ with the S/R-Glu2- show
that the absence of the macrocycle units renders XB the only
DC2--binding interaction. At the same time, this increases the
exposure of the bound dianion to solvent molecules (Table S6-7),
allowing as many as 7 HB interactions to be established
between the carboxylate groups and CH3OH (Table S6-8).
Compared to the [3]rotaxane, whose structure is rigidified and
preorganised by the presence of both macrocycles, the free axle
adopts a more conformationally-flexible DC2- binding cavity. As a
result, the binding geometries of the diasteromeric complexes
between axle 12+ and S/R-Glu2- are very similar, such that the
anion enantiomers are held together by equivalent numbers of
XB interactions (R-Glu2-: 3.3 ± 0.7; S-Glu2-: 3.0 ± 0.8) (Table S6-
9 and Fig S6-3) to give comparable binding affinities. This
further highlights the importance of XB/HB synergy and the role
of the macrocycle units in governing the augmented selectivity of
[3]rotaxane 4.(PF6)2.
In conclusion, we have reported the first example of a
chiral XB [3]rotaxane able to distinguish DC2- enantiomers and
geometric isomers via formation of distinct 1:1 stoichiometric
sandwich binding complexes. Crucially, smaller anions (e.g. Cl-)
unable to span the length between both macrocycle motifs are
bound more weakly and exhibit significantly diminished
fluorescence responses compared to DC2- complexation. MD
energetic contributions (Table S6-6). Using the equation ∆Eint
=
Ecomplex – Ehost – Eguest, the binding of S-Glu2- was favoured over
the R-enantiomer by c.a. 27 kcal mol-1, corroborating the
experimental enantioselectivity trend (Table 1).
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Keywords: dicarboxylates • halogen bonding • molecular
recognition • rotaxane • molecular dynamics
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10.1002/anie.201711176
Angewandte Chemie International Edition
COMMUNICATION
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COMMUNICATION
The first chiral halogen bonding
[3]rotaxane capable of discriminating
between dicarboxylate stereo- and
geometric isomers via fluorescence
spectroscopy is reported.
Computational modelling studies
reveal the critical synergy between
the rotaxane host’s axle and
Jason Y. C. Lim, Igor Marques, Vítor
Félix and Paul D. Beer*
Page No. – Page No.
A Chiral Halogen Bonding
[3]Rotaxane for Recognition and
Sensing of Biologically-relevant
Dicarboxylate Anions
macrocycle components in achieving
dicarboxylate guest selectivity.
This article is protected by copyright. All rights reserved.