The Cyclopentyl Group, As a Small but Bulky Terminal Group, Allows Rapid and Efficient Active Transport

Article abstract of DOI:10.1021/ol5031469

Secondary ammonium salts bearing a cyclopentyl terminal group rapidly formed pseudorotaxane with 1.5 equiv of DB24C8. Acylation of the pseudorotaxane with 50 equiv of benzoyl chloride in the presence of 50 equiv of triethylamine in toluene afforded rotaxane, the product of active transport, in 95% yield. The cyclopentyl group is small enough to allow rapid formation of pseudorotaxane, and bulky enough to facilitate the quantitative active transport by steric repulsion. (Chemical Equation Presented).

Full text of DOI:10.1021/ol5031469

Letter
pubs.acs.org/OrgLett
The Cyclopentyl Group, As a Small but Bulky Terminal Group, Allows
Rapid and Efficient Active Transport
Junya Nishiyama,† Yoshimasa Makita,‡ and Nobuhiro Kihara*,†
†Department of Chemistry, Faculty of Science, Kanagawa University, 2946 Tsuchiya, Hiratsuka 259-1293, Japan
‡Department of Chemistry, Osaka Dental University, 8-1 Kuzuhahanazono-cho, Hirakata 573-1121, Japan
S
* Supporting Information
ABSTRACT: Secondary ammonium salts bearing a cyclopentyl
terminal group rapidly formed pseudorotaxane with 1.5 equiv of
DB24C8. Acylation of the pseudorotaxane with 50 equiv of benzoyl
chloride in the presence of 50 equiv of triethylamine in toluene afforded
rotaxane, the product of active transport, in 95% yield. The cyclopentyl
group is small enough to allow rapid formation of pseudorotaxane, and
bulky enough to facilitate the quantitative active transport by steric repulsion.
Scheme 1
ince the first examples of artificial active transport systems
1
Swere reported,
various researchers have carried out
intensive efforts to achieve rapid and quantitative active
transport.2 In this regard, some rotaxane-based artificial active
transport systems have been developed.3 These systems are
advantageous for studying artificial active transport because the
active transport of the wheel component (mover) on the axle
component (track) can be monitored without dissociating the
components. Most artificial active transport systems are driven
by the photoisomerization of the NN or CC double bond.
In these systems, the efficiency of active transport is often far
less than 100% because of the photoequilibrium in photo-
isomerization. Further, photons with an energy of >100 kJ/mol
are used for the active transport in which only several kJ/mol is
necessary. In contrast, the efficiency of active transport in
biological systems, which is driven by the phosphorylation with
ATP, is very high with high energy efficiency.4 Until now, only
a few chemically driven artificial active transport systems have
been studied.5
thermodynamic product, while 3 is the product of active
transport. Quantitative (>99%) active transport was achieved,
indicating that both k1/k2 and k3/k4 values are fairly larger than
unity. The large k1/k2 value can be attributed to the bulkiness of
R1. Because k3 is large under the rapid acylation conditions, k3/
k4 also becomes large.
When the active transport was started from the dissociation
state (DB24C8 + 1-H+), the bulkiness of R1 suppresses the
progress of the first step. When a tert-butyl group was used as
R1, the approach of DB24C8 to the ammonium salt moiety
over the R1 group became impossible (ka ≈ 0).7c DB24C8
could enter the axle over a cyclohexyl group, even though it
took a very long time (>100 days) to convert 1-H+ into 2-
H+.7a,b We envisioned that with a small R1 group, over which
the cavity of DB24C8 can pass without significant steric
hindrance, 1-H+ may be rapidly converted into 2-H+. However,
a small R1 group would also increase k2 and k4, thus preventing
the active transport. To achieve rapid and efficient active
We have reported a quantitative active transport system
driven by acylation, the chemical equivalent of phosphorylation,
based on the steric hindrance of the terminal group on the axle
component of rotaxane6 (Scheme 1). This system starts from
secondary ammonium salt-type rotaxane 2-H+ containing a
dibenzo-24-crown-8 (DB24C8) unit as the wheel component.
Using a cyclohexyl or tert-butyl group as the terminal group
(R1) is the key to successful active transport. The unstable
rotaxane 2*, which is formed by the neutralization of 2-H+,
dissociates (rate constant k2) into 1 and DB24C8 because of
thermodynamic stability. Because the cavity of DB24C8 is only
slightly larger than the cyclohexyl and tert-butyl groups,7
DB24C8 tentatively moves (rate constant k1) against the
terminal group on the axle component to avoid steric hindrance
before dissociation (rate constant k4) into 1 and DB24C8.
When the position of DB24C8 in the resulting transient
conformer 2 is fixed by the rapid acylation of the amino group
(rate constant k3), rotaxane 3 is obtained. Thus, 4 is a
Received: November 20, 2014
Published: December 16, 2014
© 2014 American Chemical Society
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Letter
transport from the dissociation state (DB24C8 + 1-H+) to 3, an
appropriate R1 group and reaction conditions should be found
by which ka is enhanced, but both k2 and k4 are suppressed. In
this study, we demonstrate that the cyclopentyl group is not
only a small enough group to allow the rapid formation of 2-
H+, but also a bulky enough group to enable quantitative active
transport.
ammonium salts were scarcely soluble in chloroform, while
pseudorotaxane 2-H+ was soluble in chloroform. Therefore, the
acylation reaction was carried out after the system became
homogeneous. The results are summarized in Table 2.
Table 2. Acylative Active Transport Using a Cyclopentyl
a
Group As the Terminal Group
The effects of R1 on the rate of association (ka) and
dissociation (kd) were evaluated. Because the direct measure-
ments of k2 and k4 are impossible, kd was used as the relative
index of k2 and k4. Secondary ammonium salts 1b-H+ and 1c-
H+ were prepared, and their complexation with DB24C8 was
carried out. Association constant Ka and rate constant ka were
measured using the 1H NMR spectra of [1-H+]0 = [DB24C8]0
= 0.01 M in CD3CN/CDCl3 (1:3, v/v) at 23 °C,7a and the
dissociation rate constant kd was calculated as ka/Ka.8 The
results are summarized in Table 1.
yield
RCOX
Et3N
DMAP
DB24C8
(equiv)
of 3
entry
1
1
b
(equiv) (equiv) (equiv)
solvent
CHCl3
(%)
Boc2O
(50)
50
50
50
50
30
50
50
50
50
50
50
50
1
1
1
1
1
5
0
0
0
0
0
0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.5
1.5
0
78
74
38
57
61
63
60
38
72
77
95
2
b
c
c
c
c
b
c
b
c
c
c
BzCl
(50)
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
toluene
toluene
CHCl3
toluene
Table 1. Stability Constant Ka and Rate Constants of
a
Association (ka) and Dissociation (kd) of 2-H+
3
BzCl
(50)
4
BzCl
(50)
5
BzCl
(50)
6
BzCl
(50)
7
BzCl
(50)
8
BzCl
(50)
9
BzCl
(50)
10
11
12
BzCl
(50)
BzCl
(50)
BzCl
(50)
a
Reactions were carried out at 0 °C for 40 min. A mixture of DB24C8
and 1-H+ was stirred until the system became homogeneous before the
addition of RCOX followed by Et3N.
2-H+
ka (M−1 s−1
)
kd (s−1
)
Ka (M−1
)
We have previously reported that an active transport with
74% efficiency occurred when 2d-H+ bearing the cyclohexyl
terminal group was treated with 50 equiv of di-tert-butyl
dicarbonate (Boc2O) in the presence of 50 equiv of Et3N and 1
equiv of DMAP.6 Therefore, 2b-H+ prepared from 1b-H+ with
2 equiv of DB24C8 was subjected to the same reaction
conditions (entry 1). However, no rotaxane 3b, the product of
active transport, was obtained; however, 4b, the thermody-
namic product, was obtained quantitatively. To enhance k3, a
more electrophilic acylation agent, benzoyl chloride, was used
(entry 2). As expected, the product of active transport 3b was
obtained in 78% yield. This result shows that k2 and k4 are small
enough even with the cyclopentyl group as the terminal group,
and the efficiency of active transport can be controlled by k3.
1c-H+ also afforded the product of active transport 3c in 74%
yield under the same reaction conditions (entry 3). The
efficiency of active transport decreased with the decrease in the
amount of acylation agent or Et3N (entries 4 and 5). Although
k3 may increase with the amount of DMAP, the efficiency of
active transport decreased (entry 6). Excess DMAP would
inhibit the pseudorotaxane formation. Surprisingly, the decrease
in the efficiency of active transport was not significant even
b
a
4.8 × 10−7
4.2 × 10−2
5.0 × 10−2
4.4 × 10−9
1.1 × 10−4
1.2 × 10−4
110
400
420
b
c
a
At 23 °C and [1-H+]0 = [DB24C8]0 = 0.01 M in CD3CN/CDCl3
(1:3, v/v). Reference 7a. Temperature is 20 °C.
b
Stoddart et al. reported that the cyclopentyl group is too
small to act as the terminal group of rotaxane.7a Credi et al.
used the cyclopentyl group in a unidirectional transport system
as the terminal group that is slightly bulkier than the phenyl
group.3c Thus, the formation of 2-H+ from 1b-H+ or 1c-H+
with DB24C8 approached equilibrium within 1.5 h because the
cyclopentyl group is smaller than the cyclohexyl group. Due to
the same reason, the kd values for 2b-H+ and 2c-H+ are 104
times larger than that for 2a-H+. In general, a bulkier terminal
group is necessary for the quantitative active transport because
active transport occurs because of the steric repulsion of the
terminal group.
The active transport was studied in chloroform. Either 1b-H+
or 1c-H+ was mixed with DB24C8 in chloroform. The
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without DMAP (entries 7 and 8). Therefore, further study was
carried out in the absence of DMAP to simplify the reaction
system. When toluene was used as the solvent, the efficiency of
active transport decreased in the case of 1b-H+ (entry 9), but
increased in the case of 1c-H+ (entry 10). The solubility of 1-
H+ and 2-H+ in toluene affected the efficiency of active
transport. Further, [DB24C8]/[1-H+] strongly affected the
efficiency of active transport. When the amount of DB24C8
was reduced to 1.5 equiv, the efficiency of active transport
increased to 77% in chloroform and reached 95% in toluene.
Thus, rapid and almost quantitative active transport was
achieved using the cyclopentyl group as the terminal group
under facile acylation conditions. The efficiency of active
transport decreased to 43% when isocyanate was used as the
acylation agent. No active transport was observed when acetic
anhydride was used as the acylation agent because of its low
electrophilicity. When highly electrophilic trifluoroacetic
anhydride was used as the acylation agent, the efficiency of
active transport significantly increased to 88%.
Scheme 2
Figure 1 shows the change in the 1H NMR spectra during the
active transport from 1c-H+ to 3c. When DB24C8 was added
group is too bulky to allow threading.7c Benzoylation of the
resulting pseudorotaxane 2e-H+ furnished the product of active
transport 3e in 68% yield. During this process, the DB24C8
mover was transferred to the right side again. On heating the
DMSO-d6 solution of 3e at 60 °C, the DB24C8 in 3e
dethreaded from the track to afford 4e in 75% yield. Because
the benzoyl group is too bulky for DB24C8 to overcome,
DB24C8 passed over the tert-butyl group at the right end. Thus,
the DB24C8 was moved over the 1e-H+ track unidirectionally
from the left end to the right end.
We demonstrated that the cyclopentyl group can be used as a
terminal group that allows the rapid and quantitative active
transport of the DB24C8 mover on a secondary ammonium
salt track. The cyclopentyl group is small enough to make
DB24C8 pass over it rapidly. The cyclopentyl group is also
sufficiently bulky enough to cause the DB24C8 in the
neutralized rotaxane to move away from the cyclopentyl
group; facile acylation of the secondary amino group facilitates
the quantitative active transport by fixation of the transient
rotaxane structure. The development of a multistep active
transport system using the cyclopentyl group as the terminal
group of the rotaxane is in progress.
Figure 1. 1H-NMR spectra (500 MHz, CDCl3/CD3CN (1:3, v/v)) of
(a) 1c-H+, (b) a mixture of 1c-H+ and DB24C8, and (c) 3c.
to the 1c-H+ solution, a new set of signals corresponding to 2c-
H+ appeared. The peaks of protons dp and fp appeared at lower
field as compared to the peaks for protons d and f because of
9
1
the anisotropic effect of the crown ether. In the H NMR
spectrum of 3c, the peaks of the protons dr and fr appeared at
higher field than did the peaks of protons dp and fp because of
the absence of the crown ether. Instead, the peak of lr appeared
at higher field than that of Ip owing to the shielding effect of the
aromatic rings of DB24C8.
As an application of the cyclopentyl-terminal-group-based
rapid active transport system, a simple two-step unidirectional
transport system was developed (Scheme 2). Secondary
ammonium salt 1e-H+ with a cyclopentyl group at the left
end and a tert-butyl group at the right end of the track was
synthesized. When 1e-H+ was mixed with DB24C8, the mover
was set on the track from the left side because the tert-butyl
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Letter
ASSOCIATED CONTENT
* Supporting Information
■
S
The experimental procedures, 1H NMR spectra, and high
resolution MS. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: kihara@kanagawa-u.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the financial support of a Grant-in-Aid for Joint
Researches in the Research Institute for Integrated Science,
Kanagawa University.
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