SHORT COMMUNICATION

Supramolecular capsules of cucurbit[6]uril and controlled release

Li Liu • Ju Wang • Xiulei Xu • Bingchen Wang

Received: 10 September 2013 / Accepted: 29 January 2014

� Springer Science+Business Media Dordrecht 2014

Abstract Supramolecular capsules of THF and acid

molecules inside cucurbit[6]uril have been prepared via

[C2mim]Br route. The 1:1 ratio of host–guest complexes

have been characterized by 1H NMR, thermal gravimetric

analysis and elemental analysis in solution and in solid

state. Two types of release have been observed in NaCl

aqueous solution, including partial release of THF due to

stronger binding and complete release of acid molecules

(C3–C6) due to weaker binding.

Keywords Supramolecular � Capsule � Cucurbituril �Ionic liquid � Host–guest complex

Introduction

The challenge of precise control over the uptake and

release of the molecules at will prompts the development of

supramolecular capsules based on distinctive complimen-

tary building units and driving forces [1–5]. Macrocyclic

hosts highlight much of the interests due to the inner cavity

capable of encapsulating small guest molecules, leading to

a broad range of applications particularly for drug delivery

and enzyme mimetics [6, 7].

Cucurbit[6]uril (CB[6]) is cyclic hexamer of glycoluril

with interior hydrophobic cavity and polar carbonyl groups

surrounding the two identical portals [8]. It can form

complexes with metal ions and organic ammonium cations

through coordination bonds, ion–dipole interactions,

hydrophobic interactions or hydrogen bonds [9]. Encap-

sulation of neutral guest molecules without ammonium

functionality by CB[6] has been explored to construct

versatile supramolecular capsules. Kim et al. developed a

metal-lidded approach to encapsulate THF inside CB[6] in

the media of salt aqueous solution [10, 11]. Recently a lid-

free approach was presented by Scherman et al. to catch

and release diethyl ether by using [Hmim]MeSO3 [12].

Compared with other macrocyclic host structures, the

research on inclusion complexes of neutral molecules with

CB[6] has been limited mainly due to the poor solubility in

conventional solvents. In this work, the lid-free approach

was applied to capture a variety of neutral guest molecules

using common ionic liquid of [C2mim]Br [13, 14] (Fig. 1),

whereby we investigated how the structural variations of

the neutral molecules affect the encapsulation outcome.

Meanwhile the release phenomena of the guests have been

studied.

Experimental

Instrument

The 1H NMR spectra were recorded on Bruker Avance III

500 MHz spectrometers. Thermal gravimetric analysis

(TGA) was done using a Mettler Toledo model SDTA 815

under nitrogen flows from room temperature to 600 �C

with a heating ramp of 10 �C min-1. Elemental analysis

was determined with the instrument Elementar Vario EL

Electronic supplementary material The online version of thisarticle (doi:10.1007/s10847-014-0388-4) contains supplementarymaterial, which is available to authorized users.

L. Liu (&) � X. Xu � B. Wang

Dalian University of Technology, Dalian 116024, China

e-mail: lliu@dlut.edu.cn

J. Wang

Dalian Institute of Chemical Physics, Chinese Academy of

Sciences, Dalian 116023, China

123

J Incl Phenom Macrocycl Chem

DOI 10.1007/s10847-014-0388-4

III CHN analyzer. Powder X-ray diffractions (XRD) were

recorded on a Rigaku D/max 2400 X-ray diffractometer

equipped with graphite monochromatized Cu Ka radiation

(k = 1.5406 A) from 5� to 50� in 2-theta with a scan rate

of 0.02� s-1.

Synthesis of CB[6]

CB[6] was prepared according to the literature [8]. 1H

NMR (500 MHz, D2O/NaCl): d 4.39 (d, J = 15.6 Hz,

12H), 5.67 (s, 12H), 5.79 (d, J = 15.6 Hz, 12H).

Synthesis of [C2mim]Br [15]

A mixture of N-methylimidazole (51.500 g, 0.63 mol) and

ethyl bromide (75.190 g, 0.69 mol) was refluxed for 8 h.

After TLC showed completeness, the reaction mixture was

washed with THF followed by diethyl ether, then dried

under vacuum yielding white solid (90 %). 1H NMR

(500 MHz, D2O): d 1.50 (t, J = 7.4 Hz, 3H), 3.89 (s, 3H),

4.22 (q, J = 7.4 Hz, 2H), 7.41 (s, 1H), 7.48 (s, 1H), 8.71 (s,

1H).

Synthesis of CB[6] complex

CB[6] (1.110 g, 1.1 mmol) was dissolved in 250 mL of

[C2mim]Br (0.867 g, 4.5 mmol) aqueous solution and

stirred at room temperature for 5 h. After filtration, satu-

rated solution of [C2mim]Br , CB[6] was obtained. Then

the guest molecule (0.5 mL) was added into 20 mL of

[C2mim]Br , CB[6] saturated solution, and the mixture

was stirred at room temperature for 3 h. The white pre-

cipitate was collected, thoroughly washed with water and

dried, whereas the filtrate can be reused by adding CB[6] to

encapsulate the same guest molecule.

Results and discussion

By means of [C2mim]Br route (Fig. 1), THF was firstly

encapsulated inside lid-free CB[6]. As shown from Fig. 2,

upfield shifts from 1.91, 3.78 to 1.11, 2.98 ppm for THF

protons indicate their positioning within the cavity of

CB[6]. Two sets of resonance peaks on the 1H NMR

spectrum of the complex correspond to free guest and

bound guest, exhibiting partial release of THF in NaCl

aqueous solution. The integrations of two sets of signals

add up to be equivalent to CB[6], verifying 1:1 ratio of

THF , CB[6] complex.

From the elemental analysis of THF , CB[6] complex

(C, 38.94; H, 4.99; N, 27.18), the molecular formula of

(C36H36N24O12)�(C4H8O)�9H2O could be derived. In order

to investigate the thermal stability in the solid state, the TG

analysis was performed (Fig. 3). Two stages of mass loss

can be detected. The first stage (from 25 to 150 �C) cor-

responds to the dehydration. The mass loss is ca. 11.0 %,

which is almost in accordance with the water content

deduced from the elemental analysis (13.2 %). The second

stage (above 400 �C) corresponds to the degradation of

CB[6] molecule. The loss of THF molecule was not

Fig. 1 Preparation of CB[6] capsule and controlled release

Fig. 2 1H NMR spectra of THF and THF , CB[6] (4 mM) in D2O/

NaCl (0.5 M). CB[6] protons and HOD are labelled as filled circle

and circle, respectively

Fig. 3 TGA thermogram of THF , CB[6]

J Incl Phenom Macrocycl Chem

123

observed. To exclude the possibility that the loss of THF

molecules take place at the same temperature interval as

for water molecules, the THF , CB[6] complex was fur-

ther heated at 150 �C for 1 h, whereafter the 1:1 integral

ratio from 1H NMR spectrum (Fig. S1) confirmed that the

THF molecule was still encapsulated after the loss of water

molecules. Due to the strong binding, the release of THF in

the solid state is unlikely until the CB[6] skeleton

decomposes, while the non-observation of the loss of

neutral guest molecule by TGA has been also discovered

for other heterocyclic complexes such as pyridine , CB[6]

(Fig. S2).

Furthermore, we attempted to encapsulate functional-

ized neutral guest molecules inside CB[6]. Through

Fig. 4 1H NMR spectra of acid and acid , CB[6] (4 mM) in D2O/NaCl (0.5 M): a HCOOH, b CH3COOH, c CH3CH2COOH,

d CH3(CH2)2COOH, e CH3(CH2)3COOH, f CH3(CH2)4COOH. CB[6] protons and HOD are labelled as filled circle and circle, respectively

J Incl Phenom Macrocycl Chem

123

screening, CB[6] complexes with acid molecules in the

range of C1–C6 have been obtained, whereas 1:1 ratio of

acid to CB[6] have been convinced from the integrations of

the respective peaks on the 1H NMR spectra (Fig. 4). For

acid complexes with shorter chain length, i.e. formic acid

and acetic acid, a slight upfield shift (0.01 ppm for formic

acid and 0.05 ppm for acetic acid) and broadening were

observed, indicating inclusion of the small acid molecules

inside CB[6] cavity. This was also in line with Kim and

Inoue’s report [16] on the experimentally observed lower

affinity in formic acid and acetate buffer versus NaCl

(0.05 M), which was ascribed to neutral HCOOH and

CH3COOH included in Na?-capped CB[6] cavity, hence

acting as competitor to reduce the affinity for desired

guests.

For acid complexes between C3 and C6, only one set of

guest peaks was observed without upfield moving of the

chemical shifts, suggesting the acid guest molecules have

been completely released in NaCl aqueous solution. Take

hexanoic acid , CB[6] for example, the molecular formula

of (C36H36N24O12)�(C6H12O2)�7H2O could be derived from

the elemental analysis (C, 40.37; H, 4.95; N, 27.08). The

TG analysis was performed (Fig. 5) to compare the thermal

stability of hexanoic acid , CB[6] in the solid state. In this

case, three stages of mass loss can be detected. The first

stage (from 25 to 150 �C) corresponds to the loss of water

molecules (10.2 %). The second stage (from 150 to

350 �C) corresponds to the loss of 1 hexanoic acid mole-

cule (9.4 %). The third stage (above 350 �C) corresponds

to the degradation of CB[6] molecule. Due to the weak

binding, the release of hexanoic acid takes place before the

CB[6] skeleton degrades. What is more, as shown on the

TGA thermograms from propanoic acid , CB[6] to hex-

anoic acid , CB[6] (Fig. S3), the initial temperature of the

loss of acid molecule rises gradually with elongating the

aliphatic chain length, which indicates stronger host–guest

binding interactions enhance the thermal stability.

Hydrophobic effect turns out to be the major driving

force for CB[6] encapsulation in lid-free fashion. 12

acids have been screened, and totally six acid , CB[6]

complexes have been prepared varying from C1 to C6.

For those acid molecules longer than C6, which exceed

the cavity depth of 9.1 A for CB[6] [9], the lower

binding strength originating from incompatible structural

size causes incomplete encapsulation or even inability to

encapsulate. For heptanoic acid, three-component mixture

of CB[6], heptanoic acid and residual [C2mim]Br has

been obtained, with integral ratio of 1:0.85:0.36 from the1H NMR spectrum (Fig. S4), as a result of incomplete

displacement. For octanoic acid, it failed to be encap-

sulated completely. Besides, some bi-functionalized acid

molecules could not be encapsulated either, including

butanedioic acid, cis/trans-butenedioic acid and L-glu-

tamic acid, implying the hydrophobic interactions are not

strong enough as driving forces for acid guest molecules

with more than two hydrophilic head groups to form

CB[6] capsules. The complex formation is favored by

entropic contributions over enthalpies, in accordance

with the theory based on hydrophobic interactions [17].

With respect to the release phenomena, partial release

for THF and complete release for acid (C3–C6) have

been observed in NaCl aqueous solution (Fig. 1),

ascribing to different binding strength between the

complimentary pairs of guest and host molecules. The

binding constants of THF and hexanoic acid with CB[6]

were reported to be 1,700 [18] and 589 M-1 [17], which

is also in good agreement with the thermal stability in

the solid state as demonstrated by TGA. Apart from

host–guest binding strength, TGA also relies on solid-

state packing. According to the powder XRD studies

(Fig. S5), the crystalline patterns of THF , CB[6] and

hexanoic acid , CB[6] complexes are similar albeit

some differences in line intensities [19], suggesting their

basic frameworks are probably the same and shedding

light on the TGA results in line with the release phe-

nomena. Once the release of guest molecules could be

tailored in different modes and rates, many practical

applications would be foreseen, such as controlled and

delayed release of target molecules upon choice of

environment.

Conclusion

In summary, supramolecular capsules of THF and acid

molecules inside CB[6] have been prepared via

[C2mim]Br route. The 1:1 ratio of host–guest complexes

thereby formed have been characterized by 1H NMR, TGA

Fig. 5 TGA thermogram of hexanoic acid , CB[6]

J Incl Phenom Macrocycl Chem

123

and elemental analysis in solution and in solid state. Two

types of release have been observed in NaCl aqueous

solution, including partial release of THF due to stronger

binding and complete release of acid molecules (C3–C6)

due to weaker binding. These results provide useful prin-

ciples for tailor-made supramolecular capsules at molec-

ular level.

Acknowledgments This project was supported by the National

Natural Science Foundation of China (No. 21003123), the Funda-

mental Research Funds for the Central Universities, and a grant from

Advanced Programs for the Returned Overseas Chinese Scholars,

Ministry of Human Resources and Social Security.

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