Tetrahedron Letters
Hydrophobic interactions in the pillar[5]arene-based host–guest
complexation and their application in the inhibition of acetylcholine
hydrolysis
⇑
Bin Hua, Jiong Zhou, Guocan Yu
Department of Chemistry, Zhejiang University, Hangzhou 310027, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The host–guest complexations between a water-soluble pillar[5]arenes (WP5) and choline derivatives
with different alkyl chain lengths were investigated. The hydrophobic interactions played a significant
role in these pillar[5]arene-based host–guest complexations. By taking advantage of hydrophobic inter-
actions, the cavity of WP5 could be further employed to inhibit the hydrolysis of acetylcholine in the
presence of acetylcholinesterase.
Received 10 October 2014
Revised 29 December 2014
Accepted 9 January 2015
Available online 14 January 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Pillararene
Hydrophobic interaction
Host–guest system
Supramolecular chemistry
The arrival of any novel macrocycles can drive the development
of supramolecular chemistry.1 Host–guest systems based on pil-
lar[n]arenes have attracted remarkable interest from researchers
since its first synthesis in 2008.2a On account of their unique sym-
metrical structures and easy functionalization, pillar[n]arenes,
mainly including pillar[5]arenes2 and pillar[6]arenes,3 have exhib-
ited fantastic prospects for extensive applications in various supra-
molecular systems, such as drug delivery systems,4 cyclic dimers,5
chemosensors,6 cell glue,7 transmembrane channels,8 and supra-
molecular polymers.9 Although the electron-donating cavity and
the rigid architecture afford pillar[n]arenes superior host–guest
properties, one original question is still in debate whether the cav-
ity of pillar[n]arenes is hydrophobic or hydrophilic. Unlike other
macrocyclic hosts, such as cyclodextrins,10 calixarenes11, and
cucurbiturils,12 which have been convincingly demonstrated to
possess hydrophobic cavities. However, Hou and co-workers found
that water molecules were induced into the cavity of pillar[5]arene
to form ordered water wires.8a Therefore, it is of significant impor-
tance to verify the cavity property of pillar[n]arenes for further
studies.
and the guests played a significant role in their host–guest com-
plexations (Scheme 1). By increasing the hydrophobicity of the
guest, the binding affinity was enhanced effectively between
WP5 and the corresponding guest. More importantly, the hydro-
phobic cavity of WP5 could be utilized to inhibit the hydrolysis
of acetylcholine in the presence of acetylcholinesterase (AChE).
The complexations between WP5 and G1–G6 were firstly stud-
ied by 1H NMR (Figs. 1a, S1, S3, S6, S11, and S14). Partial proton
NMR spectra of G4, WP5, and a mixture of G4 and WP5 are dis-
played in Figure 1a. Compared with the spectrum of free G4, signif-
icant upfield shift changes corresponding to the proton signals of
G4 occurred in the presence of 1 equiv of WP5 (
À3.01, À2.64, À0.14, and À0.12 ppm for H4a, H4b, H4c, H4d, and
4e, respectively), which was caused by shielding effect of the elec-
D
d = À2.27,
H
tron-rich cavity upon formation of a threaded structure.13 The peak
related to protons H4f also showed a slight downfield shift due to
the electrostatic interactions between the negative carboxylate
anions and cationic trimethylamine.2j Therefore, we speculated
that the alkyl chain of G4 was deeply penetrated into the cavity
of WP5 and the cationic trimethylamine group appended on the
rim of the host. On the other hand, the resonances of protons H1,
H2, and H3 also exhibited remarkable chemical shift changes,
which were ascribed to the host–guest interactions. The peaks
related to protons H1 on the benzene rings and H3 on the methy-
Herein, we chose choline iodide derivatives with different alkyl
chain lengths in tails (G1–G6) as guests to demonstrate that the
cavity of a water soluble pillar[5]arene (WP5) was more likely
hydrophobic, and the hydrophobic interactions between WP5
lene bridges shifted downfield (Dd = 0.17 and 0.04 ppm for H1
and H3, respectively) due to deshielding effects. Notably, the signal
of methylene protons H2 was observed to split into two overlapped
⇑
Corresponding author.
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.