Host-guest interactions in nor-seco-cucurbit[10]uril: Novel guest-dependent molecular recognition and stereoisomerism

Article abstract of DOI:10.3762/bjoc.15.166

The unique monomer and excimer fluorescence emissions of pyrene were first exploited as distinctly photophysical signals to identify the possible diastereomers of guests within nor-seco-cucurbit[10]uril (NS-CB[10]) cavities. Further experiments revealed t

Full text of DOI:10.3762/bjoc.15.166

Host–guest interactions in nor-seco-cucurbit[10]uril: novel
guest-dependent molecular recognition and stereoisomerism
Xiaodong Zhang, Wei Wu, Zhu Tao and Xin-Long Ni*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 1705–1711.
Key Laboratory of Macrocyclic and Supramolecular Chemistry of
Guizhou Province, Guizhou University, Guiyang 550025, China
doi:10.3762/bjoc.15.166
Received: 07 May 2019
Accepted: 09 July 2019
Published: 19 July 2019
Email:
Xin-Long Ni* - longni333@163.com
* Corresponding author
This article is part of the thematic issue "Novel macrocycles – and old
ones doing new tricks".
Keywords:
fluorescent; host–guest interaction; macrocycles; molecular
recognition; nor-seco-cucurbit[10]uril; pyrene
Guest Editor: W. Jiang
© 2019 Zhang et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The unique monomer and excimer fluorescence emissions of pyrene were first exploited as distinctly photophysical signals to iden-
tify the possible diastereomers of guests within nor-seco-cucurbit[10]uril (NS-CB[10]) cavities. Further experiments revealed that
balancing the hydrophilic and hydrophobic effects of the guest in aqueous solution can improve the molecular recognition and
binding ability of NS-CB[10].
Introduction
Host–guest interactions that trigger molecular recognition are a homo-aromatic guests in its cavity through host-stabilized
current topic of interest. For example, understanding the pro- charge-transfer or π–π interactions [14,15]. This novel property
tein–ligand molecular recognition is of paramount importance of Q[8] has been utilized as molecular container for biological
in the study of enzymatic catalysis and allosteric regulation of substrates [16,17], as well as in the construction of various
cell signaling, as well as in the design of efficient drugs that supramolecular assemblies with specific structures and proper-
utilize host–guest interactions [1]. Cucurbit[n]urils (Q[n]s or ties [18-22]. However, forming ternary complexes with Q[8] is
CB[n]s) [2,3] having been viewed to have high potential use in challenging because the number of aromatic-derived water-
host–guest chemistry in aqueous solution because of their soluble recognition motifs remains limited.
varying cavity rigidity and larger portal sizes as compared with
those of other macrocyclic hosts [4-13]. For example, In 2006, Isaacs and co-workers reported the synthesis and
cucurbit[8]uril (Q[8] or CB[8]), a large homologue of the Q[n] isolation of nor-seco-cucurbit[10]uril (NS-CB[10], host-1,
family, is unique because of its ability to bind two hetero- and Scheme 1) [23], a new member of the extended Q[n] family that
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contains two identical cavities. Different from the Q[8] host, whereas host-2 tends to include the benzyl group into the
NS-CB[10] can not only accommodate two aromatic guest mol- cavity. This behavior may be attributed to the bridging imida-
ecules such as 4,4-bipyridinium (viologen), but also has the zolidone units of host-2 that rigidify its structure and make it
ability to accommodate two other guest molecules such as selective toward smaller guests. However, we found that the
adamantaneammonium (ADA) or alkylammonium ions into the ADA group can be accommodated into the cavity of host-2
cavity, forming a ternary complex. The novel binding capacity when a larger hydrophobic unit such as pyrene instead of a
of NS-CB[10] has been utilized to form supramolecular poly- benzyl group was appended to the ADA scaffold (G2). Interest-
mers [24-26] and polymer nanoparticles [27]. More important- ingly, the top–center isomer of G2 within both host-1 and host-
ly, Isaacs et al. discovered that when the unsymmetrical guest 2 could be characterized because of the novel monomer and
ADA molecules are bound within NS-CB[10], three diastereo- excimer photophysical property of pyrene as fluorophore. As a
mers such as top–top, center–center, and top–center can be ob- result, we demonstrated here a novel guest-controlled molecu-
served. These diastereomers display homotropic allostery based lar recognition and stereoisomerism for the first time.
on a guest-size-induced preorganization mechanism [23]. How-
ever, the same ADA guest was not incorporated into the cavity Results and Discussion
after NS-CB[10] was functionalized with imidazolidone (host- We took advantage of the two novel identical cavities and the
2, Scheme 1) [28].
simple formation of ternary diastereomer complexes with
NS-CB[10]-based host-1 and host-2. The size of each cavity of
Herein, we report the supramolecular host–guest interactions of host-1 is similar in size to Q[7], and the cavity size of host-2 is
the two cavities of NS-CB[10]-based host-1 and host-2 with close to that of Q[6]. We first designed and prepared the
two unsymmetrical ADA-based derivatives (G1 and G2, ADA-benzyl-based ammonium guest molecules G1. We syn-
Scheme 1). As expected, hosts-1 and -2 are capable of simulta- thesized this compound because ADA can form a highly stable
neously binding guest G1, thus forming 1:2 ternary complexes complex with Q[7] (the highest reported K value for the
by including different groups of G1 into the cavity. For exam- ADA·Q[7] complex is 1012 M−1) [29]; while benzylammonium
ple, host-1 can accommodate the ADA moiety into the cavity, ions can be included in both cavities of Q[7] and Q[6]. Figure 1
Scheme 1: Chemical structures of host-1, host-2, G1, and G2.
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Figure 1: 1H NMR spectra of G1 (1.0 mmol, D2O, pD = 2.0) in the presence of host-1 at different concentrations at 298K.
shows the 1H NMR spectral changes of the G1 guest in D2O 6.37 ppm), as well as a slight proton downfield shift of the
(pD = 2.0) in the presence of host-1 at different concentrations. ADA moiety in the presence of host-2 (Figure 2). These spec-
Upon gradual addition of host-1 (0–0.4 equiv) to the solution of tral changes suggest that G1 accommodated its benzyl group
G1, the resonances corresponding to the protons on G1 split into the cavities and that the ADA moiety remained in the portal
into two sets of signals. For example, one shifted upfield (ADA of host-2, forming ternary complexes. These findings are also
moiety) or downfield (benzyl moiety), and one remained at the consistent with the behaviors observed by Isaacs and
original position. This result may be attributed to the slow co-workers. That is, the bridging imidazolidone units of host-2
movements of complexed and uncomplexed forms of G1 with rigidify the structure of host-1, which has the ability to expand
host-1 on the NMR time scale; therefore, free G1 and the its cavity to accommodate larger guests. This effect makes it
G1·host-1 complex were individually observed. With increas- selective toward small guests [12].
ing concentrations of host-1 to ca. 0.5 equiv (Figure 1), the
original proton signal disappeared. In particular, the peak As mentioned previously, Isaacs and co-workers reported their
of the protons on the ADA moiety shifted upfield from pioneering work on the host–guest interaction properties of
δ 2.23–1.65 ppm to δ 1.60–1.09 ppm, whereas the signals for host-1 and -2. Several diastereomers of some guests such as
the protons on the benzyl group substantially shifted downfield ADA were observed within ternary complexes of host-1 by
from δ 7.44 ppm to 7.48, 7.65, 7.89, and 8.38 ppm. These 1H NMR spectroscopy [23]. However, when we appended the
results suggest that host-1 cavities encapsulated the ADA benzyl group to the ADA moiety (G1) in the present study, the
moiety of G1 (upfield shift due to the shielding effect of the 1H NMR spectra cannot provide the related proton signals that
hydrophobic cavity) and that the benzyl group was on or near distinguish the possible diastereomers of G1 in host-1 and host-
the host-1 portal (downfield shift due to the deshielding effect 2, despite the clear split of resonances corresponding to the
of the carbonyl-rimmed portal). Isothermal titration calorimetry protons on the hosts.
results reveal a 2:1 G1/host-1 stoichiometry with a binding con-
stant (Ka) of 1.32 × 105 M−1 (Table 1). These observations A number of studies suggest that pyrene is one of the most use-
clearly indicate that host-1 recognizes and prefers to include the ful fluorogenic units, being sensitive to conformational change
ADA moieties in both of the identical cavities with homotropic because of its relatively efficient monomer and excimer emis-
allostery effect.
sions [30]. For example, when pyrene instead of the benzyl
group was appended to the ADA moiety (G2) in the present
In the case of the 1H NMR titration experiments for host–guest work, the top–center diastereomers of ADA-based derivatives
interactions of G1·host-2, the chemical shift changes in G1 with within the host cavities could be distinguished by the novel
increasing host-2 concentration are similar to those observed in photophysical property of pyrene (Scheme 2).
the host-1 systems. However, the largest difference in the
host–guest interaction properties between G1·host-2 and Figure 3a shows changes in the fluorescence emission spectra
G1·host-1 is that the proton peaks on the benzyl group of G1 of G2 in the presence of host-1. As can be seen, free G2 pro-
undergoes a large upfield shift (from δ 7.44 ppm to 6.75 and duced typical monomer emissions at around 378 and 396 nm in
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Figure 2: 1H NMR spectra of G1 (1.0 mmol, D2O, pD = 2.0) in the presence of host-2 at different concentrations at 298 K.
Scheme 2: Plausible diastereomers showing the fluorescence response of G2 with host-1.
Figure 3: Fluorescence spectral changes of G2 (10.0 μM) in the presence of host-1 (a) and host-2 (b) at different concentrations in aqueous solution
(pH 2.0) at 298 K.
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aqueous solution (pH 2) upon excitation of the pyrene fluoro- ns-CB[10] [23], it is thus believed that the upfield shift of the
phore at 340 nm. When we added host-1 at increasing concen- pyrene protons is attributed the intermolecular π–π stacking be-
trations to the G2 solution, the fluorescence intensity of the G2 tween the two pyrenyl moieties as proposed in the plausible
monomer emissions gradually decreased, while the maximum inclusion modes in Scheme 2. Importantly, the 1H NMR spec-
emission intensity at around 485 nm (typical excimer emissions tral changes indicate that the rigid cavities of host-2 can accom-
of pyrene) increased. The excimer emission band of G2 can be modate the ADA moiety of G2 (Supporting Information File 1,
attributed to the interaction of two pyrene units resulting in Figure S5). The upfield shift of protons on the ADA moiety can
intermolecular π–π stacking, which was due to the two iden- be observed despite the fast formation of a precipitate upon the
tical cavities of host-1. Consequently, the top–center isomerism addition of host-2 to a G2 solution. This result is very different
of the G2·host-1 ternary complexes was conveniently con- from our previous observations on the host–guest interactions
firmed from the optical signal after the changes in monomer/ of G1 with host-2 and those of a study on ADA with host-2 by
excimer fluorescence emissions of the pyrene groups on G2. Isaacs and co-workers. In both cases, the ADA moiety was
Surprisingly, the fluorescence spectral changes of G2 always rejected by the cavity of host-2.
(Figure 3b) suggest that a similar host–guest interaction trig-
gered monomer-to-excimer binding response between G2 and Generally, the recognition binding ability for Q[n]s in aqueous
host 2, similar to host 1 with G2, when we attempted to add solution is mainly due to the attraction between Q[n] hosts and
host-2 to the G2 solution under the same conditions. Both of the guest based on the size or shape complementarily. This ability
complexes of G2 with the host-1 ad host-2 were further studied is aided by ion–dipole and dipole–dipole interactions arising
by UV–vis spectra (Supporting Information File 1, Figure S3) from the electron-rich carbonyl rims of Q[n]s, the nonclassical
and Job plot (Supporting Information File 1, Figure S4).
hydrophobic effect of Q[n]s, and the classical hydrophobic
effect of the guest [31-33]. The desolvation of the Q[n] host
In order to obtain detailed information on the mechanism of the cavity delivers high-energy water trapped in the cavity; as it has
complexation of G2 with host-1 and -2, 1H NMR titration ex- a favorable enthalpic signature, this is a nonclassical hydro-
periments in acidic aqueous solution were carried out. The phobic effect. Contrary to that, the desolvation of the guest mol-
spectral changes are shown in Figure 4. Upon addition of 0.5 ecules is a classical hydrophobic effect; it has a favorable entro-
equiv of host-1 to the solution of G2, the chemical shift of some pic component due to the delivery of surface-bound solvent
protons on the ADA moiety and pyrene group shifted upfield. molecules on the guest. Therefore, isothermal titration calorim-
Expectably, the upfield shift of ADA protons can be ascribed to etry could be employed to quantify the enthalpic and entropic
the cavity’s encapsulation of this moiety. Pyrene group, that are contributions to the binding interactions between the hosts and
too large for the individual CB[6]–CB[7] sized cavities of guests (results are shown in Table 1 and Figures S6 and S7 in
Figure 4: 1H NMR spectra of G2 (1.0 mmol, D2O, pD = 2.0) in the presence of different concentrations of host-1.
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Table 1: Thermodynamic binding data for G1·host-1, G2·host-1, G1·host-2, and G2·host-2 (error = 10%).
Guest–host
n
Ka (L·mol−1)
ΔG (kJ·mol−1)
ΔH (kJ·mol−1)
TΔS (kJ·mol−1)
G1·host-1
G2·host-1
G1·host-2
G2·host-2
1.92
1.98
2.03
1.99
1.32 × 105
7.64 × 106
4.51 × 106
1.08 × 107
−29.24
−39.3
−37.99
−40.42
−50.90
−65.77
−39.01
−30.96
−21.66
−26.46
−1.02
9.46
Supporting Information File 1). The obtained thermodynamic
parameters suggest that the ternary host–guest interactions
of host-1 with G1 and G2, host-2 with G1 are almost
exclusively enthalpy-driven (ΔH = −50.90 kJ·mol−1 and
TΔS = −21.66 kJ·mol−1 for inclusion complex G1·host-1;
ΔH = −65.77 kJ·mol−1 and TΔS = −26.46 kJ·mol−1 for the
inclusion complex G2·host-1; ΔH = −39.01 kJ·mol−1 and
TΔS = −1.02 kJ·mol−1 for the inclusion complex G1·host-2);
while only the formation of the inclusion complexes of host-2
with G2 is driven by both enthalpy and entropy
(ΔH = −30.96 kJ·mol−1 and TΔS = 9.46 kJ·mol−1). Evidently,
the high enthalpy gain for host-1 with G1 and G2, host-2 with
G1 may be attributed to the strong ion–dipole interactions be-
tween the guest and host. However, the host–guest interactions
in the case of complexes of G2·host-2 are derived not only from
the ion–dipole interactions between the host and guest, but also
in the assistant of the hydrophobic effect. Notably, the entropic
gain achieved with the G2·host-2 system was higher than that
obtained with other host–guest systems, indicating that the large
hydrophobic side group pyrene is enabling the classical hydro-
phobic effect in aqueous solution as the guest indeed. On the
other hand, the thermodynamic parameters obtained in the
present study also suggest that the rigidify cavity structure such
as host-2 is benefit for the classical hydrophobic effect of guest
in aqueous solution.
Supporting Information
Supporting Information File 1
Experimental data, additional 1H NMR spectra and others.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-15-166-S1.pdf]
Acknowledgements
This work was supported by the National Natural Science Foun-
dation of China (21871063), the Science and Technology Foun-
dation of Guizhou Province (20165656) and Guizhou Univer-
sity (20175788, 20185781).
ORCID® iDs
Xin-Long Ni - https://orcid.org/0000-0002-5557-1631
Preprint
A non-peer-reviewed version of this article has been previously published
as a preprint doi:10.3762/bxiv.2019.19.v1
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In summary, we evaluated the molecular recognition triggered
by a novel host–guest interaction of NS-CB[10]-based host-1
and host-2. The unique monomer and excimer fluorescence
emissions of pyrene due to the two-cavities of the host–guest
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hosts was eventually identified from the distinct photophysical
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