Acid-Regulated Switching of Metal Cation and Anion Guest Binding in Halogen-Bonding Rotaxanes

Article abstract of DOI:10.1002/chem.201803902

The ability of natural enzymes to regulate their guest binding affinities and preferences through the use of co-ligands which alter the features of the binding site is fundamental to biological homeostatic control. Herein, the rarely exploited orthosteric control of guest binding is demonstrated using neutral halogen bonding [2]rotaxanes, in which a chemical stimulus (acid) interacting with the interlocked host binding site switches the host's native guest preference from metal cations to anions. When neutral, the rotaxanes exhibit pronounced transition metal cation affinity and comparatively weak anion binding properties. However, the addition of acid attenuates the rotaxanes’ ability to coordinate cations, while concurrently enabling strong binding of halides through charge assisted halogen bonding and hydrogen bonding interactions in competitive aqueous solvent media. The appendage of a fluorescent anthracene reporter group to the rotaxane framework also enables diagnostic sensory responses to cation/anion binding.

Full text of DOI:10.1002/chem.201803902

A Journal of
Accepted Article
Title: Acid-regulated Switching of Metal Cation and Anion Guest
Binding in Halogen Bonding Rotaxanes
Authors: Xiaoxiong Li, Jason Y.C. Lim, and Paul D. Beer
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Chem. Eur. J. 10.1002/chem.201803902
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Acid-regulated Switching of Metal Cation and Anion Guest
Binding in Halogen Bonding Rotaxanes
[a]
[a]
[a]
Xiaoxiong Li, Jason Y.C. Lim, and Paul D. Beer*
Abstract: The ability of natural enzymes to regulate their guest
binding affinities and preferences through the use of co-ligands
which alter the features of the binding site is fundamental to
biological homeostatic control. Herein, the rarely-exploited
orthosteric control of guest binding is demonstrated using neutral
halogen bonding [2]rotaxanes, where a chemical stimulus (acid)
interacting with the interlocked host binding site switches the host’s
native guest preference from metal cations to anions. When neutral,
the rotaxanes exhibit pronounced transition metal cation affinity and
comparatively weak anion binding properties. However, the addition
of acid attenuates the rotaxanes’ ability to coordinate cations, while
concurrently enabling strong binding of halides through charge
assisted halogen bonding and hydrogen bonding interactions in
competitive aqueous solvent media. The appendage of a fluorescent
anthracene reporter group to the rotaxane framework also enables
diagnostic sensory responses to cation/ anion binding.
separated sodium cation
-
halide anion ion-pair,[15]
a
mechanically bonded interlocked host system with the capability
of switching from binding one class of guest species (e.g.
cations) to another fundamentally-different class (e.g. anions)
triggered simply by the orthosteric action of an external chemical
stimulus (e.g. acid) is to the best of our knowledge
unprecedented.
Herein, we report in this proof-of-concept study the first
neutral halogen bonding (XB) [2]rotaxane hosts capable of
orthosteric-regulated switching between cation and anion guest
binding behaviour triggered by the presence of acid. XB is the
attractive non-covalent interaction between electron-deficient
halogen atoms and Lewis bases such as anions, which has
been shown to outperform analogous hydrogen bonding (HB)
receptors in competitive solvent media.[16,17]
Introduction
In nature, enzymatic host-guest interactions governing
biological processes are subject to natural regulatory feedback
mechanisms which maintain enzymatic activity within stringent
limits. This occurs primarily by changing the affinity of the
enzyme to its target guest species, which can be achieved by
either allosteric or orthosteric regulation,[1,2] and hence are both
attractive targets for drug development.[3,4] Allosteric regulation,
the process by which ligand binding at a site distinct from the
guest binding cavity modulates the latter’s guest affinity by
changing its size and shape, has been demonstrated in
numerous artificial biomimetic systems in recent years,[5–7]
enabling applications such as controlled guest release in
changing chemical media [8,9] and switchable catalysis.[10–12] The
alternative orthosteric regulation mechanism, where direct ligand
coordination within the original binding site itself changes its
native guest affinity and selectivity, by comparison, has received
scant attention in the design of abiotic host systems. Partly due
to the significant challenges in designing receptors containing
binding cavities capable of such chemical stimuli-responsive
behaviour, existing systems capable of orthosteric regulatory
binding are limited to pH-induced modulation of anion selectivity
of acyclic pyridyl thioureas[13] and quaternary ammonium guest
orientation within a cavitand host binding pocket.[14]
Figure 1. Schematic illustration showing dual capability of rotaxane to bind
anions and metal cations via exo-endo dentate conformational inversion of
iodotriazole motifs.
In our rotaxane design (Figure 1), we integrate a novel XB
bis-iodotriazole-secondary amine functional motif into the axle
and macrocycle components of the mechanically interlocked
molecule (MIM) structural framework. The conformational
flexibility of the combined antagonistic Lewis basic (triazole and
secondary amine N-donors) and Lewis acidic XB (iodotriazole)
groups facilitates the rotaxane in the neutral state to bind
transition metal cations via bis-tridentate N-donor coordination
and to bind anions relatively weakly through XB and HB
interactions. Protonation of the secondary amine functionalities,
concomitant with the conformational inversion of the XB
iodotriazole motifs, activates the binding cavity for strong charge
assisted XB and HB anion coordination in competitive aqueous
While we recently reported a rotaxane containing separate
Lewis basic and acidic sites for simultaneously binding an axle
[
a]
X. Li, Dr 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
Supporting information (SI) for this article is given via a link at the
end of the document.
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solvent media whilst concurrently attenuating metal cation Results and Discussion
binding. Notably, the mechanically-interlocked nature of the
rotaxanes is integral to this orthosteric acid-regulation of binding
preferences, which maintains the highly-preorganised nature of
the cavity to facilitate guest binding, whilst also allowing
sufficient endo/exo flexibility of the iodotriazole motifs for
anion/cation coordination within the rotaxane cavity. We also
demonstrate that the appendage of an anthracene reporter
group to the rotaxane host expedites the diagnostic fluorescence
sensing of both metal cation and anion binding in neutral and
protonated states.
Synthesis of Rotaxanes
The target neutral [2]rotaxanes were constructed using the
active metal template (AMT) strategy,[18,19] where coordination of
a metal catalyst within the cavity of a macrocycle facilitates the
formation of
a
covalent bond between appropriately-
functionalised axle precursors. Despite the presence of the
electron-withdrawing iodine atoms of iodotriazole motifs, we
have previously shown that the triazole nitrogen atoms are
sufficiently basic for coordination to Cu(I),[20] allowing
Scheme 1. Synthesis of (A) secondary amine-containing XB macrocycle 4 and (B) Neutral XB rotaxanes 1 and 2 (C) Neutral acyclic receptors 3.XB and 3.HB.
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the AMT approach to be used for the synthesis of a series of
quantities of anions, as their tetrabutylammonium (TBA) salts,
[
2]rotaxanes containing XB interlocked cavities for halide
were added to separate solutions of rotaxanes 1 and 2 in d
acetone. As shown in Figure 2A, the addition of Cl to rotaxane 1
6
-
binding[
20–22]
and chiral oxoanion discrimination
[23]
with the
-
copper(I)-catalysed azide-(iodo)alkyne cycloaddition (CuAAC)
reaction. In the novel rotaxane design described herein (Figure
resulted in downfield shifts of H
2 d
and H as well as significant
upfield shifts of H , H , and H . Notably, the perturbations of
c
1
4
1
), the presence of the central Lewis basic amine motif of the
these signals, arising from protons flanking the interlocked
binding cavity containing the iodotriazole units, suggest that Cl-
was binding in its vicinity. At the same time, anion binding
resulted in conformational changes to the rotaxane framework,
evident from the shifts of the macrocycle component’s
macrocycle component is expected to facilitate Cu(I)
coordination for CuAAC-AMT rotaxane assembly.[24,25]
The synthesis of the key XB macrocycle component 4 is
summarised in Scheme 1A. N-Boc-protected bis-alkyne 5 was
prepared in two steps from reaction of Boc-anhydride with
propargyl amine[26] followed by addition of sodium hydride and
propargyl bromide. The reaction of iodine with 5 under basic
conditions afforded the bis-iodinated-alkyne intermediate 6 in
quantitative yield. CuAAC macrocycle ring-closing of equimolar
amounts of 6 with bis-azide 7[27] under high-dilution conditions
afforded N-Boc-protected macrocycle 8 in 60 % yield. The high
yield of the XB macrocycle synthesis reaction is especially
noteworthy, given the lack of a template used to facilitate
macrocyclisation over non-productive formation of acyclic
oligomers. Subsequent N-Boc-deprotection with trifluoroacetic
acid (TFA) afforded the target XB macrocycle 4 quantitatively.
With macrocycle 4 (1.0 equiv.), CuAAC-AMT rotaxane
formation was performed using a stoichiometric quantity of
hydroquinone proton signals and those from the axle’s proximal
1
stopper protons H
b
. Similarly, the H NMR spectrum of rotaxane
-
2 displayed considerable changes upon Cl addition (Figure 2B),
[
Cu(CH
3 4 6
CN) ]PF in dichloromethane with either bis-iodoalkyne
6
(4.0 equiv.) and stoppered azide 9 (8.0 equiv.); or azide 9 (5.0
equiv.) and stoppered-iodoalkyne 10 (5.0 equiv.) (Scheme 1B).
This method afforded neutral rotaxanes 11 and 12 in 34 % and
30 % isolated yields respectively after Cu(I) decomplexation and
chromatographic purification. The interlocked nature of both
rotaxanes 11 and 12 was evident from the diagnostic upfield
shifts of their macrocycle components’ hydroquinone protons
resulting from aromatic donor-acceptor π-π stacking interactions
with the axle units’ iodotriazole motifs (Figures S2-10 and S2-16,
1
1
SI), and conclusively demonstrated with H- H ROESY
spectroscopy (Figures S2-45 and S2-46, SI). Target neutral XB
rotaxane 1 was then produced by N-Boc-deprotection of the axle
component of rotaxane 11 using trifluoroacetic acid (TFA). The
fluorescent anthracene-appended rotaxane 2 was prepared via
the reaction of rotaxane 12 with 9-(chloromethyl)anthracene
under basic conditions. Anthracene-appended acyclic receptors
3.XB and 3.HB were also synthesised through similar protocol
(
see Section S1, SI, for full synthetic details).
Guest Binding Properties of Neutral Rotaxanes
Rotaxanes 1 and 2 contain multiple iodotriazole motifs
flanking their three-dimensional interlocked cavities, which are
capable of multi-dentate anion binding interactions via their
Lewis acidic XB-donor iodine atoms.[20] The presence of
methylene spacers immediately adjacent to the iodotriazole units
provides sufficient flexibility for endo/exo-dentate flipping of the
iodotriazoles such that their Lewis basic nitrogen atoms[28] can
also coordinate to metal cations within the rotaxanes’ cavities,
aided by the proximal secondary amine donor units.
Figure 2. Partial 1H NMR spectra of neutral rotaxanes (A) 1 and (B) 2 in the
-
The anion binding properties of both rotaxanes were first
probed by 1H NMR titration experiments, where increasing
presence of 0.0, 1.0 and 10.0 equivalents of Cl in d
6
-acetone ([rotaxane] = 1.0
mM, T = 298 K).
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most notably the downfield shift of H
anthracene unit and a large upfield shift of axle proton H ,
d
suggesting that the halide was binding just above the interlocked
cavity. WinEQNMR2[29] analysis of the 1H NMR titration data,
2
on the macrocycle’s
enhancement of fluorescence intensity was observed for acyclic
receptors 3.XB and 3.HB upon Cl- addition in acetonitrile
(Figures S4-1 and S4-2, SI).
monitoring the shifts of protons H
b 2
and H of rotaxanes 1 and 2
respectively as a function of anion concentration, afforded host-
-
1
guest 1:1 stoichiometric association constants (K
a
/M )
summarised in Table 1.
-
1
Table 1. Association constants (Ka [M ]) of halides with neutral rotaxanes 1
and 2, as well as acyclic receptors 3.XB and 3.HB in d
6
-acetone. [
a]
Rotaxane 1
Rotaxane 2
Receptor
.XB
Receptor
3.HB
3
Cl-
(8.0 ± 0.1) x 102
(8.2 ± 0.1) x 102
(7.2 ± 0.3) x
(1.5 ± 0.1) x
1
1
10
10
Br-
-c
(3.4 ± 0.1)x 102
-b
-b
[
a] Values of K
a
are calculated by the WinEQNMR2[29] software using a 1:1
Figure 3. Fluorescence spectra of rotaxane
2 in the presence of 200
host-guest stoichiometric binding model. Errors (±) are in parentheses
-
-
equivalents of Cl ([rotaxane 2] = 5 μM, T = 293 K, solvent = CH
3
CN, λex = 368
(
<10%). No binding observed for NO
3
to rotaxane 1. No binding observed for
-
-
-
nm).
I , NO
3
and ReO to rotaxane 2.
4
[
b] no binding. [c] not conducted.
Having probed the anion binding, and with rotaxane 2, the
fluorescence anion sensing properties of the MIMs, we
investigated the possibility of using the rotaxanes as
multidentate ligands for the coordination of metal cations. The
complexation reaction of 1 with Zn2+ was performed under
ambient conditions by stirring a solution of the neutral rotaxane
From Table 1, both rotaxanes 1 and 2 show comparable
affinities for Cl- in d
-acetone despite the former’s greater
number of XB-donor iodotriazole units. This may be
consequence of rotaxane 2’s more preorganised cavity due to a
lower number of conformationally-flexible methylene units, and
the bulky anthracene unit favouring endo-orientation of the XB
donor iodine atoms on the macrocycle component for
convergent anion coordination. Compared with Cl , rotaxane 2
binds Br more weakly, which is likely to be a consequence of its
lower charge density. Interestingly, no significant interactions of
rotaxane 2 with I , NO
6
a
4 2 2 2 2 3
with equimolar Zn(ClO ) ·6H O in CH Cl / CH OH 1:1 v/v to
2
+
afford the Zn -bound rotaxane in quantitative yield.
A
1
comparison of the H NMR spectra of free rotaxane 1 and its
Zn2+ complex revealed clear evidence of metal cation
-
-
coordination (Figure 4A), with signals from protons H
and H
polyether portion of the macrocycle component (H
2
, H
4
, H
c
d
displaying large downfield shifts, while those of the
-
-and ReO -
3
4
were observed, presumably
3
5
, H , H
6
)
due primarily to their poor shape/size-complementarity with the
exhibited very small perturbations. These observations indicated
that Zn2 was coordinating in the rotaxane cavity flanked by the
two tridentate triazole-secondary amine N-donors of the MIM’s
axle and macrocycle components, and not interacting with the
polyether group of the macrocycle. At the same time, increased
splitting of the macrocycle component’s hydroquinone signals
was seen, showing that Zn2+ coordination further amplified the
differences between both hydroquinone proton environments as
a result of its interlocked cavity binding location. To confirm the
+
rotaxane’s binding cavity. Similarly, rotaxane 1 did not show any
binding to NO
3
-. Nonetheless, both rotaxanes were found to bind
-
Cl with K
a
values more than an order-of-magnitude larger than
acyclic model receptor 3.XB (Table 1), which emphasizes the
importance of the preorganised rotaxane interlocked cavity and
convergent XB interactions for anion coordination. Furthermore,
-
the greatly-enhanced Cl affinity of 3.XB compared to its acyclic
HB receptor analogue 3.HB highlights the superiority of XB over
1
2+
HB for anion binding. When the H NMR titration experiments of
participation of the iodotriazole N-donors in Zn coordination, a
qualitative UV-Vis titration was performed where 1.0 equivalent
rotaxanes
1
and
2
with Cl- were repeated in the more
competitive solvent mixture of CDCl
evidence of anion binding was found.
The appendage of the anthracene reporter group to
rotaxane 2’s macrocycle component also enabled the host to
sense anions via fluorescence responses. In acetonitrile,
rotaxane 2 exhibits fluorescence emission between 370 and 530
3
/CD
3
OD (1:1 v/v), no
4 2 2
of Zn(ClO ) ·6H O was added to an acetonitrile solution of
rotaxane 1, resulting in an intensity decrease of the 290 nm
absorbance peak (Figure S2-25, SI). These changes are
consistent with those observed during triazole N-coordination to
transition metal cations such as Cu+[20,34] and Zn2+[35] due to
perturbations of the energy levels of the heterocycle’s frontier
molecular orbitals. It is noteworthy that the presence of methanol
[
30]
nm which is typical of an anthracene emission spectrum
-
(
Figure 3). In the presence of Cl , significant fluorescence
2 2 3
in the CH Cl /CH OH 1:1 v/v solvent mixture used to prepare the
enhancement was observed, likely due to rigidification of the
rotaxane framework upon anion binding which reduces the
likelihood of non-radiative decay pathways.[31–33] Similar
zinc (II) complex with 1, was found to negate the rotaxane’s
ability to bind anions (vide supra). This observation clearly
demonstrates that the neutral interlocked host 1 favours metal
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cation binding over anions.[36] Unequivocal evidence of Zn2+
coordination within the rotaxane structure was obtained from
high-resolution electrospray ionisation mass spectrometry
(
Figures S2-24, SI).
With rotaxane 2, the binding of different transition metal
cations, added as their perchlorate salts, in acetonitrile elicited
contrasting fluorescence responses. The binding of closed-shell
Zn2+ resulted in
a dramatic increase in the rotaxane’s
fluorescence intensity (Figure 4B), which was likely primarily due
to metal coordination of the Lewis basic lone pair on the
macrocycle component’s tertiary amine functionality responsible
for photoinduced electron transfer (PET) quenching of the
anthracene’s fluorescence.[32,37] In stark contrast, the binding of
redox-active Cu2+ and Ni2+ to rotaxane 2 elicited significant
fluorescence quenching (Figure 4C and Figure S4-3, SI,
respectively) which probably results from an electron transfer
quenching mechanism from the photoexcited anthracene moiety
to the respective transition metal centre.[38,39]
(B)
Acid-triggered Changes in Rotaxane Guest Binding
Behaviour
After demonstrating the predisposition of the neutral binding
cavities of both rotaxanes 1 and 2 for metal cation coordination
over chloride anion recognition in methanol containing solvent
media, the orthosteric modulation of their binding properties
upon protonation was investigated. The effects of protonation on
the structure of the neutral [2]rotaxanes was initially investigated
1
using H NMR spectroscopy. As shown in Figure 5A, upon the
addition of 2.0 equivalents of HBF
CDCl / CD OD/ D O (45:45:10 v/v/v), the largest downfield shift
was observed for proton signal H immediately adjacent to the
4
to a solution of rotaxane 1 in
3
3
2
4
secondary amine moiety on the macrocycle (Δδ = +0.4 ppm),
consistent with increased electron-deficiency arising from
protonation of the adjacent amine unit. At the same time,
perturbations of the signals arising from the macrocycle
(C)
3 5 6
component’s polyether unit (H , H , H ) may be attributed to HB
interactions between the protonated ammonium moiety on the
axle and the oxygen atoms. This is also likely to restrict the
rotational freedom of the macrocycle unit around the axle,
resulting in greater desymmetrisation of the macrocycle
hydroquinone protons. Notable conformational changes of the
rotaxane framework occur upon protonation as well, as evident
d
from the dramatic upfield signal shift of axle proton H (Δδ = -0.2
ppm), possibly as a result of increased shielding from the
macrocycle hydroquinone motifs. These structural changes, as
well as being in close proximity to a dicationic bis-protonated
rotaxane cavity, result in notable deshielding and downfield
b c e
shifts of axle proton signals H , H and H . Compared to
rotaxane 1, the changes upon addition of one equivalent of HBF
to rotaxane 2’s H NMR spectrum are more modest, owing to its
single tertiary amine moiety available for protonation (Figure S3-
4
1
Figure 4. (A) 1H NMR spectra of free rotaxane 1 and its Zn2+ complex in d
-
6
9
, SI). Notably however, the largest downfield shift was also
acetone showing the effects of cation association ([rotaxane 1] = 2 mM, T =
298 K); Fluorescence spectra of rotaxane 2 before and after addition of (B)
6
observed for the anthracene methylene protons H adjacent to
the ammonium unit (Δδ = +0.4 ppm), with the
Zn2+ and (C) Cu2+. (λex = 368 nm, solvent = CH
3
CN)
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axle protons next to the iodotriazole moiety showing much
smaller shifts. This clearly indicates that despite the presence of
Lewis basic nitrogen atoms on the iodotriazoles, the amine unit
showed no evidence of interaction with anions in protic
methanolic solvent media, further demonstrating the greatly
augmented anion affinities of the protonated rotaxanes’ cavities.
While the direct involvement of HB from the cationic ammonium
motifs in anion binding could not be unambiguously determined
4
is preferentially protonated. In further support, HBF addition to
rotaxane 2 led to a large turn-on fluorescence response from the
anthracene fluorophore (Figure S4-4, SI), which results from the
loss of PET fluorescence quenching pathways upon amine
1
from H NMR titrations, fluorescence titrations proved insightful.
-
As shown in Figure 5B, addition of 80 equivalents of Cl to
protonation.[32,37,40,41]
+
-
4
rotaxane [2•H ]BF in acetonitrile resulted in an approximately
+
-)
The cationic binding cavities of rotaxanes [1•2H ](BF
4
2
60 % reduction in fluorescence intensity, attributable to strong
+
-
-
and [2•H ]BF
competitive solvent media. Indeed, in the organic-aqueous
solvent mixture CDCl CD OD/
(45:45:10 v/v/v), Cl-
-)
once again elicited numerous
4
were now expected to bind anions strongly in
ammonium - Cl HB interactions which partially restore the PET
quenching properties of the macrocycle’s amine moiety. In the
more competitive solvent mixture of CHCl / CH OH 1:1 v/v, a
3 3
3
/
3
D
2
O
+
addition to rotaxane [1•2H ](BF
changes to its H NMR spectrum (Figure 5A), the most
4
2
considerably smaller fluorescence ‘turn-off’ quenching response
1
-
was recorded after adding the same amount of Cl anion (Figure
noteworthy of which are the downfield shifts of H
d
and H
4
, which
5B), consistent with greater competition from the protic solvent
-
likely arise from anion binding in close proximity to the
interlocked cavity which results in further structural changes to
mixture for HB interactions with the highly charge-dense Cl .
1
Nonetheless, by monitoring the H NMR shifts of protons H10 of
+
-
the rotaxane. For rotaxane [2•H ]BF
4
in CDCl
3
/ CD
3
OD (1:1 v/v),
the protonated rotaxanes as a function of anion concentration,
host-guest 1:1 stoichiometric association constants were
an upfield shift was observed for the corresponding macrocycle
-
determined using the WinEQNMR2[29] software, and compared
methylene protons H10 after addition of Cl , showing clear
hydrogen bonding between Cl- to the protonated tertiary
ammonium unit (Figure S3-10, SI). These changes are
especially notable given that the neutral rotaxanes 1 and 2
+
with those of acyclic protonated receptors [3XB•H ]BF
4
and
+
[3HB•H ]BF
4
(Table 2).
Figure 5. (A) Partial 1H NMR spectra of neutral rotaxane 1 and doubly-protonated [1•2H ](BF
+
-)
in the presence of 0 and 10 equivalents of TBACl ([host] = 1.0
4
2
mM, CDCl
3
/ CD
3
OD/ D
2
O 45:45:10 v/v/v, T = 298 K); (B) Fluorescence spectra showing the changes in anthracene fluorescence intensity of singly-protonated
+
-
-
rotaxane [2•H ]BF
4
upon Cl addition in acetonitrile (top) and CHCl
3
/ CH
3
OH 1:1 v/v (bottom) ([host] = 5 μM , T = 298K, λex = 368 nm)
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rotaxane
2
upon protonation was also supported by
2
+
2+
2+
-
1
fluorescence spectroscopy. For the Zn , Cu and Ni -bound
Table 2. Association constants (K
a
[M ]) of anions with cationic rotaxanes
+
-
+
-
+
-
complexes of rotaxane 2, the addition of 1.0 equivalent of HBF4
resulted in significant fluorescence ‘turn-on’ responses
suggesting the respective metal cation’s displacement from the
rotaxane cavity by protonation of the macrocycle component’s
tertiary amine unit (Figures S4-5 – S4-7, SI).
[
1•2H ](BF
4
)
2
and [2•H ]BF
4
, as well as acyclic receptors [3XB•H ]BF
4
and
+
-. [a]
[
3HB •H ]BF
4
+
-)
+
-
+
-
+
-
[
1•2H ](BF
4
2
[2•H ]BF
4
[3XB•H ]BF
4
[3HB•H ]BF
4
[
b]
[c]
[c]
[c]
Cl-
(8.1 ± 0.1) x
(6.6 ± 0.1) x
(4.9 ± 0.4) x 102
(1.0 ± 0.1) x
2
2
2
10
10
10
Br-
-[d]
-[e]
-[e]
Conclusions
(4.8 ± 0.4) x
2
10
In conclusion, we have constructed the first examples of MIM
hosts which, by virtue of their novel antagonistic Lewis basic
triazole-secondary amine and Lewis acidic XB bis-iodotriazole
functional motifs, are capable of acid-triggered switching of
metal cation and anion guest binding behaviour. When neutral,
the rotaxanes are capable of strong metal cation binding
whereas anions are bound relatively weakly. Importantly, upon
protonation the greatly augmented anion affinities observed for
the cationic protonated rotaxanes also results in the
unprecedented observation of anti-Hofmeister anion binding bias
for Cl- in aqueous solvent media by XB [2]rotaxanes.
Furthermore, the presence of the anthracene fluorophore in
rotaxane 2 allowed distinctive and diagnostic fluorescence
responses towards the identity of guest species bound within its
cavity. Overall, this present work demonstrates a rare example
of orthosteric regulation of guest binding in abiotic receptors,
which is unprecedented with MIM hosts, where the proton acts
as the orthosteric ligand protonating the rotaxane interlocked
binding cavity to significantly modulate guest binding
preferences. This simple, yet effective method of switching
between metal cation and anion binding in interlocked host
structures heralds new possibilities in their applications as
-
-[d]
-[e]
-[e]
NO
3
(5.8 ± 0.4) x
2
10
[
a] Values of K
host-guest stoichiometric binding model, monitoring proton H
S3-12 and Figure S3-13, SI) respectively. Errors (±) are in parentheses
a
are calculated by the WinEQNMR2[29] software using a 1:1
and H (Figure
8
9
-
-
+
-
(
[
[
<10%). No binding observed for I and ReO
4
with both [1•2H ](BF
O 45:45:10 v/v monitoring H .
4 2
) and
+
-
2•H ]BF
4
. [b] Performed in CDCl
/ CD
3
/ CD
3
OD/ D
2
4
c] Performed in CDCl
3
3
OD 1:1 v/v. [d] no binding. [e] not conducted
As shown in Table 2, both protonated XB rotaxane hosts
-
display notable affinities for Cl in the competitive protic solvent
medium. Importantly, for [1•2H ](BF
binding trend was observed for the anions tested, with the less
strongly-hydrated anions Br and NO
+
-)
4
2
, an anti-Hofmeister
-
-
3
more weakly bound than
-
-
-
Cl . No appreciable binding was observed for I and ReO
4
, which
may be due to their inability to fit into the preorganised rotaxane
cavity. Given the inherent preference of XB donor host
molecules to bind to the heavier and ‘softer’ halides in aqueous
solvents due to their greater ease of dehydration,[16,20,42,43] this
result is especially notable since it is the first example of an XB
rotaxane preferentially binding the most strongly-hydrated Cl in
the presence of water, and only the second XB receptor known
to display an anti-Hofmeister binding bias.
1•2H ](BF
-
molecular sensors, organocatalysts and molecular machines.[
45–
[
44]
47]
While rotaxane
+
-)
displays stronger Cl- binding compared to
[
[
4
2
+
-
4
2•H ]BF , which is likely to be a consequence of its dicationic
character, [2•H ]BF
+
-
displayed rare exclusive Cl- selectivity. Acknowledgements
4
Once again, the importance of XB interactions for anion binding,
even with the contribution of HB interactions from the
ammonium group(s), can be seen from the significantly stronger
Cl- binding affinities of protonated XB acyclic receptor
X.L. thanks the CSC (China Scholarship Council) for
a
postgraduate scholarship. J.Y.C.L. thanks the Agency for
Science, Technology and Research (A*STAR), Singapore, for
postdoctoral funding support.
+
+
[
3XB•H ]BF
4
compared with [3HB•H ]BF
4
. Hence the observed
-
Cl selectivity for both rotaxanes is likely to result from a
combination of favourable ammonium HB- and XB-chloride
interactions together with a preorganised interlocked binding
cavity which is of complementary shape and size to the halide
guest species.
Keywords: halogen bonding • rotaxane • orthosteric regulation •
anion recognition • transition metal recognition
In contrast to anion binding, as expected the addition of
acid proved highly detrimental to the rotaxanes’ inherent metal
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4
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By virtue of their novel antagonistic
X. Li, J.Y.C Lim, P.D. Beer*
Lewis
basic
triazole-secondary
amine and Lewis acidic halogen
bonding bis-iodotriazole functional
Page No. – Page No.
Acid-regulated Switching of Metal
Cation and Anion Guest Binding in
Halogen Bonding Rotaxanes
motifs,
mechanically
bonded
interlocked rotaxane hosts are
capable of acid-triggered switching
of metal cation and anion guest
binding behaviour.
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