Alkyl-Substituted Cucurbit[6]uril Bridged β-Cyclodextrin Dimer Mediated Intramolecular FRET Behavior

Article abstract of DOI:10.1021/acs.joc.9b03513

A novel triazolyl bridged cucurbituril (CB)-cyclodextrin (CD) dimer was synthesized via click reaction of monopropargyl modified octamethylcucurbit[6]uril and mono-6-azido-β-cyclodextrin. Moreover, it could form stable supramolecular inclusion complexes p

Full text of DOI:10.1021/acs.joc.9b03513

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Note
Alkyl-substituted cucurbit[6]uril bridged #-cyclodextrin
dimer mediated intramolecular FRET behavior
Fang-Fang Shen, Ying-Ming Zhang, Xian-Yin Dai, Hao-Yang Zhang, and Yu Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03513 • Publication Date (Web): 08 Apr 2020
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Alkyl-substituted cucurbit[6]uril bridged β-cyclodextrin dimer
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mediated intramolecular FRET behavior
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Fang-Fang Shen, Ying-Ming Zhang, Xian-Yin Dai, Hao-Yang Zhang, Yu Liu*
College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai
University, Tianjin 300071, China
yuliu@nankai.edu.cn
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Graphic Abstract
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Abstract
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A novel triazolyl bridged cucurbituril (CB)-cyclodextrin (CD) dimer was synthesized
via click reaction of mono-propargyl modified octamethylcucurbit[6]uril and
mono-6-azido-β-cyclodextrin. Moreover, it could form stable supramolecular
inclusion complexes possessing efficient fluorescence resonance energy transfer,
which was benefit from that CD and CB can bind amantadine- and
pyridinium-containing fluorophores simultaneously. The supramolecular inclusion
complex behaviors were investigated by NMR spectroscopy, UV–vis absorption and
fluorescence spectroscopy.
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Cucurbit[n]urils (CB[n]s, n = 5–8, 10, 14) are a class of synthetic macrocyclic host
molecules consisting of n glycoluril units with a hydrophobic cavity and two identical
carbonyl-fringed portals.1 Although (CB[n]s) are potentially used as a type of host
receptors2, their practical applications in chemistry, biology and material areas have
been limited, probably due to the insufficient solubility and the difficulty of
introducing functional groups on their surfaces. Since the discovery of the first fully
alkyl-substituted CB[5], decamethylcucurbit[5]uril, in 1992,3 a series of fully and
partially alkyl-substituted cucurbit[n]urils (SCB[n]s) derivatives have been reported
successively.4-6 The physical and chemical properties of alkyl-substituted CB[n]s have
been changed, such as cavity size, shape and electron cloud density of carbonyl
oxygen atoms, which increased the solubility in common solvents and produced other
special functional properties. The introduction of functional groups on skeletons of
CB[n]s has been a huge challenge in CB[n] chemistry due to chemical stability of
CB[n]s. In 2003, Kim and co-workers firstly prepared a series of CB[n] derivatives,
hydroxy-substituted (HO)2nCB[n]s, by simple oxidation of the native CB[n]s with
K2S2O8 in water,7 and this served as a accelerator for the application of functionalized
CB[n]s in vesicles, polymers, nanomaterials, artificial ion channels, and so on.8-13
However, the yields for alkyl-substituted CB[n]s in this method was too low for
practical use. Until 2015, Bardelang and Ouari discovered a photochemical method by
UV and hydrogen peroxide to introduce a limited number of alcohol functional groups
on CB[n]s (n = 5, 6, 7, and 8).14 Although they have made a correction of conversions
from 95-100% to 20-40%,15 this method can be applied to other selected CB[n]s,
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including alkyl-substituted CB[n]s. However, the functionalization of
alkyl-substituted CB[n]s is still rarely reported.16,17
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On the other hand, as one of very important photophysical properties, fluorescence
resonance energy transfer (FRET) is a research hotspot for scientists in miscellaneous
fields. The occurrence of a more effective FRET phenomenon requires some criteria.
That is, a FRET system includes at least two chromophores, the donor and the
acceptor, which should be located in close proximity and the fluorescence emission
spectrum of donor should sufficiently fall into the absorption spectrum of acceptor.
However, there are still several defects in the constructing FRET materials, such as
the lack of controllability of covalently connected donor and acceptor, the insufficient
solubility in aqueous solution, and the weak interaction between independent
fluorophores. Remarkably, through flexible and controllable regulation of the
interaction between donor and acceptor pairs, the FRET systems constructed in the
form of supramolecular host–guest chemistry could serve as a promising tool to solve
these drawbacks. As a result, many interesting supramolecular FRET systems have
been constructed and applied in various fields.18 For instance, Zhou and Yang
exhibited a acid/base-controllable FRET system by a host−guest complex between a
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rhodamine
B
functionalized pillar[5]arene and cyano-modified boron
dipyrromethene.19 Park and Kim reported a supramolecular nanosystem based on
the fusion assay of two different organelles using a novel host–guest pair,
cucurbit[7]uril-Cy3 and adamantane-Cy5 as a FRET pair.20 Several FRET systems
were also constructed in our research group, using the strategy of supramolecular
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polymers based on host–guest complexation or in a nano-sized noncovalent
supramolecular assembly.21,22 However, in a single supramolecular assembled entity,
the utilization of two different types of macrocyclic receptors to achieve efficient
FRET process still remains challenging.
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In order to study the binding and photophysical behaviors of functionalized SCB[n]s,
we utilized SCB[n]s possessing OH group at designated position to yield a special
oxidation product. Inspired by the complementary molecular binding behaviors of
CB[n]s and cyclodextrins (CDs).23 In this work, we designed and synthesized a novel
macrocyclic dimer H (Figures S4−S6, Supporting Information) consisting of a
symmetrical octamethylcucurbituril (OMeCB[6]) and β-CD, in which two
macrocyclic molecules, (propargyl)1OMeCB[6] (Figures S1−S3, Supporting
Information) and mono-6-azido-β-CD was convalently conjugated via click reaction.
In our case, given that β-CD can incorporate neutral guest molecules possessing an
adamantyl end with high binding affinity, the adamantyl tetraphenylethylene (G1)
(Figures S7−S9, Supporting Information) was accordingly synthesized. Meanwhile,
OMeCB[6] is capable of encapsulating cationic guests in its hydrophobic cavity and
the
binding
constant
between
OMeCB[6]
and
trans-4-[4-(dimethylamino)styryl]-1-methylpyridinium chloride (G2) can reach up to
106 M−1 order of magnitude. Further spectroscopic studies have shown that H has the
larger binding affinity for these two guest molecules (G1 and G2) than individual
macrocycle molecules (CB and CD moieties) (Scheme 1). Due to the superior
solubility of macrocyclic dimers in H, an intramolecular FRET system mediated by
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the conjugation of CB with CD moieties was achieved in an aqueous solution, and the
FRET efficiency was determined to be 70.3%.
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Scheme 1. Schematic illustration of the structural formulas of H, G1 and G2
molecules.
To confirm the formation of the host–guest complexes between the OMeCB[6]
1
moiety of H and G2 as well as free OMeCB[6] and G2, H NMR spectroscopic
titrations were first performed by using G2 as a guest compound and free OMeCB[6]
as a model host compound. As shown in Figure S10 (Supporting Information), upon
the gradual addition of G2, the proton signals of the guest appeared to shift upfield
(Δδ = −0.22, −0.83, −0.09, for H1, H2, H3 respectively), suggesting that these protons
of the guest were included in the cavity of the OMeCB[6] and were shielded by the
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OMeCB[6]. In contrast, the signal of H4, H5 moved downfield by 0.13 and 0.56 ppm,
suggesting that these protons on the guest were excluded at the portals of the
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OMeCB[6]. Additionally, the NMR assignments were made through H-1H COSY
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experiment (Figure S11, Supporting Information). Moreover, when adding 1.0 equiv.
1
of H to G2, similar H NMR complexation induced shifts occurs to protons of G2
compared with OMeCB[6]/G2 complex (Figure S12 Supporting Information),
indicating that H and G2 could form the same host–guest complex as OMeCB[6]/G2
complex.
Figure 1. Emission spectra (a) and intensity changes of G2 at 580 nm (b) upon the
gradual addition of H in an aqueous solution ([G2] = 2×10-5 M, [H] = 0-3.67 × 10-5 M,
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25 °C).
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It is known that CB[6] and G2 guest could form an 1:1 inclusion complex with the
absorbance at 450 nm and 270 times fluorescence enhancement at 580 nm.24 To
investigate the binding behavior between OMeCB[6] moiety of H and G2, UV–vis
absorption and fluorescence experiments were further conducted. As discerned from
the UV–vis absorption spectra, Job plot of OMeCB[6]/G2 complex showed a 1:1
stoichiometry by plotting the absorbance at 450 nm against the molar fraction of
OMeCB[6] and G2 (Figure S13b, Supporting Information).
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For the complexation of H and G2, the stoichiometry was also determined to be 1:1
based on the fluorescence intensity of G2 in the presence of H (Figure S13a,
Supporting Information). These results also confirmed that the guest molecule G2
could be exclusively included into the hydrophobic cavity of OMeCB[6] in aqueous
solution. Meanwhile, according to the fluorescence spectra, G2 (20 μM) displayed
very poor fluorescence with a maximum emission at 607 nm in aqueous solution,
while upon addition of OMeCB[6] or H from 0.1 equiv. to 1.0 equiv., the emission
intensity increased significantly. Additionally, a blue shift from 607 nm to 582 nm
indicated the host–guest interactions between OMeCB[6] moiety and G2 (Figure 1a,
S14a). The association constant (Ka) of H/G2 was calculated to be 3.57 × 106 M−1 by
curve fitting method (Figure 1b). As shown in Figure S14b (Supporting Information),
the Ka value for OMeCB[6]/G2 was 3.22 × 106 M−1, which was in good consistence
with the one in H/G2 complexation.
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Figure 2. UV-vis spectra (a) and absorbance changes of G1 at 345 nm (b) upon
addition of H in an aqueous solution containing 3% DMSO ([G1] = 3.0 × 10−5 M, [H]
= 0-2.6 × 10−4 M, 25 °C).
It is well-known that β-CD could associate with adamantyl guests in aqueous solution.
Then, the 1H NMR spectra was utilized by using β-CD and 1-adamanty bromomethyl
1
ketone (ABK) as model compound. The H NMR titration spectra for a fixed
concentration of ABK upon incremental addition of β-CD showed the gradual
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downfield shifts of adamantyl protons signals (Figure S15, Supporting Information),
indicating the inclusion of the adamantyl moiety of ABK guest in the β-CD cavity.25
Compared with the free β-CD, the 1H NMR spectra also showed that upon addition of
1.0 equiv. of H, the peaks of protons Ha-c on ABK shifted downfield significantly (Δδ
= 0.09, 0.08 and 0.22 ppm for Ha-c, respectively, Figure S16, Supporting
Information). Meanwhile, 2D NOESY NMR spectrum of equimolar ABK to H was
conducted to prove the formation of host–guest complex. The NOE (nuclear
Overhauser enhancement) correlations were observed between adamantyl protons of
ABK and β-CD moiety of H, corroborating that adamantyl moiety was included in
β-CD’s cavity to form host–guest complex (Figure S17, Supporting Information).
The host–guest complexes of H/G1 and β-CD/G1 were also studied by UV–vis
spectroscopy. From the absorption titration spectra, upon addition of β-CD to an
aqueous solution of G1 with a fixed concentration, the absorbance peak at 345 nm of
G1 experienced slightly red shift and the absorbance intensity was decreasing
gradually (Figure 2a). The binding constant for β-CD/G1 complex was determined to
be (5.38 ± 0.04) × 103 M-1 (Figure 2b). Compared to the β-CD/G1 system, the
absorption spectra of H/G1 showed the quite similar changes. These results revealed
that the adamantyl moiety of G1 was included in the cavity of β-CD moiety of H. In
addition, the Ka value of H/G1 was calculated to be (5.44 ± 0.16) × 103 M-1, which
was similar to the one of β-CD/G2 complex (Figure S18, Supporting Information).
In addition, the spectroscopic titration experiments were also performed in D2O
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containing 3% DMSO, showing quite similar molecular binding behaviors (Figures
S19-S21, Supporting Information).
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It is well known that the fluorescence emission spectrum of donor should sufficiently
fall into the UV–vis absorption spectra of acceptor in an effective FRET process.
Theoretical calculation showed that the optimized structure of the inclusion
complexes between H and two guest molecules (G1 and G2) is appropriate for FRET
by the molecular mechanics modeling (Figure S22, Supporting Information). As can
be seen in Figure 3a, upon excitation at 338 nm that corresponded to absorption band
of the host−guest complex of H/G1, the 1:1 supramolecular complex of H/G1
exhibited a strong fluorescence intensity centered around 475 nm in water, which was
well overlapped with the absorption band of H/G2 complex in the range of 450–550
nm. To further investigate the FRET process of host–guest complexes based on the
macrocyclic dimer, fluorescence titration experiments were conducted in
aqueoussolution. As shown in Figure 3b, with the stepwise addition of G2 to the
H/G1 (1:1 molar ratio), the fluorescence intensity of H/G1 was gradually decreased
along with the enhancement of emission of H/G2 when excited at 338 nm. Meanwhile,
the color that corresponded to fluorescence emission was accordingly changed from
blue to yellow. In the control experiments, either H/G2 or free G2 barely gave
fluorescence emission in the same experimental conditions (λex = 338 nm; Figure S23,
Supporting Information). Furthermore, the energy-transfer efficiency was calculated
as high as 70.3%.
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Figure 3. (a) Normalized absorption spectra of H/G2 and emission spectrum of H/G1.
(b) Fluorescence spectra of H/G1 ([H] = [G1] = 1.0 × 10-4 M) in the solution of
H2O/DMSO (97:3) with different concentrations of G2. The concentrations of G2
were 0, 4.0 × 10−6, 1.6 × 10−5, 2.0 × 10−5 M, respectively. Inset: left, photographic
images of H/G1, and right, H/G1/G2 under UV light (365 nm) ([H] = [G1] = 1.0 ×
10-4 M, [G2] = 2.0 × 10−5 M).
In conclusion, a newly macrocyclic dimer H bearing CD and CB moiety was
synthesized via click chemistry. OMeCB[6] was chosen to construct this dimer
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instead of CB[6], because the solubility of parent CB[6] was rather limited in water.
Tetraphenylethylene modified with adamantyl moiety was synthesized to be
selectively trapped in the β-CD’s cavity. After interaction with the host molecule H,
there is a strong blue emission centered at 478 nm. Then the G2 molecule as a
receptor could be well encapsulated in the cavity of OMeCB[6] moiety in an aqueous
solution and the absorption spectrum had a good overlap with the donor emission
spectrum. Benefiting the good solubility of this conjugated dimeric host, a newly
intramolecular FRET system was constructed conveniently based on the
supramolecular host–guest strategy. Therefore, all the research results indicated that
novel macrocyclic dimer CB-CD-based host–guest complexation may be significant
for designing novel molecular sensors and devices and have potential application in
other fields such as materials and biology systems, including drug delivery, cell
imaging, and biosensors.
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Experimental Section
Preparation of compound G1: Compound 126 (1.7 g, 4.86 mmol) and1-adamantyl
bromomethyl ketone (1.25 g, 4.86 mmol) were dissolved in acetone (50 mL), and
potassium carbonate (2.02 g, 14.58 mmol) was added. The mixture was refluxed using
an oil bath over night. After cooling to room temperature, the solution was filtered,
and the filtrate was dried under reduced pressure to remove the solvent. The residue
was purified by column chromatography (silica gel, petroleum ether : CH2Cl2 = 1:2,
1
v/v) to give compound 1 as white powder (2.42 g, 95% yield). H NMR (400 MHz,
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DMSO-d6, TMS): δ1.66 (m, 6H, H of adamantane), 1.82 (m, 6H, H of adamantane),
1.98 (s, 3H, H of adamantane), 4.98 (s, 2H, H of CH2), 6.60-6.62 (d, J = 8Hz, 2H, H
of benzene), 6.82-6.84 (d, J = 8 Hz, 2H, H of benzene) 6.93-7.18 (m, 14H, H of
benzene); 13C {1H} NMR (100 MHz, DMSO-d6, TMS): δ27.1, 35.8, 36.9, 44.5, 68.1,
113.7, 126.3, 127.6, 127.8, 130.5, 130.5, 130.6, 131.6, 143.3, 156.3, 208.8 ppm; MS
(MALDI) m/z : [M + H]+ Calcd for C38H37O2 525.30; Found 525.34; [M + Na]+ Calcd
for C38H36O2Na 547.26; Found m/z 547.31. Anal. Calcd for C38H36O2: C, 86.99; H,
6.92; O, 6.10. Found: C, 86.96; H, 6.90; O, 6.09.
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Preparation of compound 3: To a solution of 216 (30 mg, 0.027 mmol) and N,
N′-dihexylviologen bromide salt (13.10 mg, 0.027 mmol) in anhydrous DMSO (2
mL), NaH (10 mg, 0.4 mmol) was added and stirred at room temperature for 15
minutes. propargyl bromide (0.5 mL, 5.8 mmol) was added subsequently at 0ºC and
the reaction mixture was stirred at room temperature for 12 hours. The reaction was
then diluted with 50 mL diethyl ether and filtered. The remaining solid was triturated
with acetone (3 × 50mL) and dried under vacuum to give a yellow solid (15 mg,
72%).1H NMR (400 MHz, D2O): δ 1.78 (m, 24H), 3.01 (s, H), 4.38 (m, 12H),
4.50-4.54 (d, J = 16 Hz, 2H), 5.55 (m, 5H), 5.70 (m, 10H); 13C {1H} NMR (100 MHz,
D2O): δ 15.9, 16.5, 42.9, 44.0, 47.9, 48.1, 52.3, 70.8, 72.5, 77.2, 77.7, 78.0, 97.0,
155.7, 156.8 ppm; HRMS (MALDI) m/z : [M + Na]+ Calcd for C47H54N24O13Na
1185.4200; Found 1185.4198. Anal. Calcd for C47H54N24O13: C, 48.54; H, 4.68; N,
28.90. Found: C, 48.52; H, 4.64; N, 28.87.
Preparation of compound H: CuI (64.48 mg, 0.34 mmol) was added to a solution of
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3 (79.02 mg, 0.068 mmol) and 427 (78.88 mg, 0.068 mmol) in dry DMF (10 mL), and
the reaction mixture was stirred at 80°C using an oil bath for 24 h under argon. After
cooling to room temperature, the mixture was filtered to remove any insoluble copper
salt, and the filtrate was evaporated under a reduced pressure to remove excess DMF.
The residue was purified by column chromatography (silica gel) with water/acetic
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acid as eluent to give H as a white solid (101mg, yield 64%). H NMR (400 MHz,
D2O): δ 1.68-1.90 (m, 24 H), 3.48-3.96 (m,42 H ), 4.25-4.52 (m, 14 H), 4.99-5.10 (m,
7 H), 5.52-5.77 (m, 15 H), 8.16 (s, H); 13C {1H} NMR (100 MHz, D2O): δ 15.9, 16.5,
42.9, 44.1, 48.2, 51.4, 60.3, 70.4, 70.8, 71.8, 72.0, 72.8, 73.1, 77.8, 78.1, 81.3, 102.0,
156.3 ppm; MS (MALDI) m/z : [M + Na]+ Calcd for C89H123N27O47Na 2344.796;
Found 2344.777. Anal. Calcd for C89H123N27O47: C, 46.02; H, 5.34; N, 16.28. Found:
C, 46.05; H, 5.35; N, 16.30.
Supporting Information: Detailed synthesis, characterization data, Job’s plots,
1
association constant, absorption and emission spectra, H NMR spectra and
theoretical calculation. This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgements. We thank NNSFC (21432004, 21871154, 21772099, and
21861132001) for financial support.
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