Molecular switch based on very weak association between BPX26C6 and two recognition units

Article abstract of DOI:10.1021/ol4027864

A [2]rotaxane has been constructed through metal ion-templated pseudorotaxane formation from a weakly interacting host (bis-p-xylyl[26]crown-6) /guest (diphenylurea derivative) complex and post-assembly modification to form another weakly interacting tertiary ammonium ion recognition site for the host. The combination of this pair of weakly interacting components allowed bifunctional (pH, Na⁺ ions) switching of the crown ether unit, highlighting the potential applicability of weakly associated components within molecular switches.

Full text of DOI:10.1021/ol4027864

ORGANIC
LETTERS
2013
Vol. 15, No. 22
5742–5745
Molecular Switch Based on Very Weak
Association between BPX26C6 and Two
Recognition Units
Tsan-Wen Lu,† Chia-Fong Chang,† Chien-Chen Lai,‡ and Sheng-Hsien Chiu*,†
Department of Chemistry, National Taiwan University, No. 1, Sec. 4, Roosevelt Road,
Taipei, 10617, Taiwan. R.O.C., and Institute of Molecular Biology, National Chung
Hsing University and Department of Medical Genetics, China Medical University
Hospital, Taichung, Taiwan, R.O.C.
shchiu@ntu.edu.tw
Received September 26, 2013
ABSTRACT
A [2]rotaxane has been constructed through metal ion-templated pseudorotaxane formation from a weakly interacting host (bis-p-xylyl[26]crown-
6)/guest (diphenylurea derivative) complex and post-assembly modification to form another weakly interacting tertiary ammonium ion recognition
site for the host. The combination of this pair of weakly interacting components allowed bifunctional (pH, Naþ ions) switching of the crown ether
unit, highlighting the potential applicability of weakly associated components within molecular switches.
Rotaxane-type molecular switches are prototypical mo-
lecular machines that find applications in such fields as
sensing,1 organogelation,2 materials delivery,3 and mole-
cular memory.4 To ensure clean and clear switching, it is
necessary to balance the stabilization energies of the com-
plexes formed between the interlocked macrocyclic unit
and its various recognition sites in the dumbbell-shaped
unit of the rotaxane, both before and after application
of a stimulus.5 For simplicity, rotaxane-type molecular
switches generally comprise one macrocyclic unit and one
dumbbell-shaped moiety featuring two recognition units,
with a reasonable difference in the two association con-
stants in the ground state.5 The relative difficulty of
deprotonating a simple rotaxane based on recognition of
dibenzo[24]crown-8 (DB24C8) and the dibenzylammo-
nium (DBA) ion, unless another weaker binding station
(e.g., bipyridinium ion) is present in the dumbbell-shaped
component, highlights the importance of selecting an
† National Taiwan University.
‡ National Chung Hsing University and China Medical University
Hospital.
(1) (a) Gassensmith, J. J.; Matthys, S.; Lee, J.-J.; Wojcik, A.; Kamat,
P. V.; Smith, B. D. Chem.;Eur. J. 2010, 16, 2916–2921. (b) Caballero,
A.; Zapata, F.; Beer, P. D. Coord. Chem. Rev. 2013, 257, 2434–2455.
(2) (a) Zhao, Y.-L.; Aprahamian, I.; Trabolsi, A.; Erina, N.; Stoddart,
J. F. J. Am. Chem. Soc. 2008, 130, 6348–6350. (b) Hsueh, S.-Y.; Kuo,
C.-T.; Lu, T.-W.; Lai, C.-C.; Liu, Y.-H.; Hsu, H.-F.; Peng, S.-M.; Chen,
C.-h.; Chiu, S.-H. Angew. Chem., Int. Ed. 2010, 49, 9170–9173. (c)
Kohsaka, Y.; Nakazono, K.; Koyama, Y.; Asai, S.; Takata, T. Angew.
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704–710. (b) Baumes, J. M.; Gassensmith, J. J.; Giblin, J.; Lee, J.-J.;
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2002, 67, 9175–9181. For a recent review, see: (b) Berba, J.; Goldup,
S. M.; Lee, A.-L.; Leigh, D. A.; Symes, M. D.; Teobaldi, G.; Zerbeto, F.
Angew. Chem., Int. Ed. 2008, 47, 4392–4396. (c) Coskun, A.; Banaszak,
M.; Astumian, R. D.; Stoddart, J. F.; Grzybowski, B. A. Chem. Soc. Rev.
2012, 41, 19–30.
Stoddart, J. F.; Kuekes, P. J.; Williams, R. S.; Heath, J. R. Science 1999,
285, 391–394. (b) Green, J. E.; Choi, J. W.; Boukai, A.; Bunimovich, Y.;
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r
10.1021/ol4027864
Published on Web 10/30/2013
2013 American Chemical Society

appropriate second station when designing a molecular
switch.6 The search for new threading guests for macro-
cycles with reasonable affinity in solution is never straight-
forward, thereby limiting the development of new molec-
ular switches. Theoretically, weakly binding guest units
would serve as perfectly acceptable primary recognition
sites in molecular switches if an even weaker recognition
unit for the macrocycle were present in the dumbbell-
shaped component. Using this concept, many guest units
that do not, when isolated, exhibit particularly high binding
affinities for macrocycles have the potential to act as
primary or secondary recognition sites in interlocked mo-
lecular switches, potentially increasing the number of re-
cognition units available for the construction of new
molecular switches. Two questions arise: (i) How do we
assemble rotaxanes efficiently from weakly associated host/
guest components? (ii) How do we choose which combina-
tions of recognition units are appropriate for constructing
molecular switches? Herein, we report a new molecular
switch constructed using the concept of weak recognition.
We constructed this [2]rotaxane first by using a metal ion
to template the formation of a pseudorotaxane from bis-p-
xylyl[26]crown-6 (BPX26C6)7 and a diphenylurea deriva-
tive and then modifying the pseudorotaxane post-assembly
to form another weakly interacting tertiary ammonium ion
recognition site for the crown ether component, the migra-
tion of which between the tertiary ammonium center and
the diphenylurea station we could control using in situ base/
acid treatment or metal ion addition/removal.
Scheme 1. Synthesis of the Molecular Switch 4-H PF6
3
To facilitate the synthesis of the [2]rotaxane, we sought a
host/guest system that associates with the requirement of a
template because the binding strength would be weakened
significantly simply by removing the template after inter-
locking the components. Previously, we reported that a
diphenylurea unit can thread through the macrocycle
BPX26C6 in the presence of a templating Naþ ion;8 we
suspected that the ethylene glycol units of BPX26C6 would
interact weakly with the NH units of the diphenylurea
station in the resulting rotaxane after removal of the
template. For the stoppering reaction, we chose reductive
amination9 because of the potential to covalently modify
the resulting secondary amine to form a tertiary ammo-
nium center that would interact significantly weaker with
the crown ether component.10 Thus, after removal of the
Naþ ion that facilitated the synthesis, we expected the
tertiary ammonium center and the diphenylurea unit to
serve as suitable stations for the translocation of the
BPX26C6 component.
We isolated the [2]rotaxane 1-H PF6 in 25% yield after
3
(i) mixing BPX26C6, the aldehyde 2, the amine 3, and
NaClO4 in CH2Cl2, (ii) reducing the resulting imine, and
(iii) acidification (Scheme 1). Two triplets (at δ 2.75ꢀ2.90)
for the methylene protons adjacent to the NH2þ center ap-
peared in the 1H NMR spectrum of 1-H PF6 (Figure 1a);
3
strong cross-signals for these protons to the aromatic and
ethylene glycol protons of BPX26C6 appeared in the 2D
NOESY spectrum, suggesting that the macrocyclic unit
resided about the NH2þ center in the ground state of this
[2]rotaxane. The very weak interaction between BPX26C6
and the diphenylurea station, relative to that between the
macrocyclic unit and the DBAþ station, was confirmed by
our inability to transfer the macrocyclic component to the
diphenylurea station upon the addition of Et3N in CDCl3,
even when we added more than 50 equiv of the base.
We methylated the DBAþ center of the [2]rotaxane
(6) (a) Chiu, S.-H.; Rowan, S. J.; Cantrill, S. J.; Stoddart, J. F.; White,
A. J. P.; Williams, D. J. Chem.;Eur. J. 2002, 8, 5170–5183. (b)
Nakazono, K.; Takata, T. Chem.;Eur. J. 2010, 16, 13783–13794.
(7) (a) Cheng, P.-N.; Huang, P.-Y.; Li, W.-S.; Ueng, S.-H.; Hung,
W.-C.; Liu, Y.-H.; Lai, C.-C.; Peng, S.-M.; Chao, I.; Chiu, S.-H. J. Org.
Chem. 2006, 71, 2373–2383. (b) Chen, N.-C.; Huang, P.-Y.; Lai, C.-C.;
Liu, Y.-H.; Peng, S.-M.; Chiu, S.-H. Chem. Commun. 2007, 4122–4124.
(c) You, Y.-C.; Tzeng, M.-C.; Lai, C.-C.; Chiu, S.-H. Org. Lett. 2012, 14,
1046–1049.
1-H PF6 through treatment with formaldehyde and for-
3
mic acid,10b providing the [2]rotaxane 4 after washing the
resulting solution with aqueous NaOH and purifying the
residue through column chromatography; acidification
(8) Lin, Y.-H.; Lai, C.-C.; Liu, Y.-H.; Peng, S.-M.; Chiu, S.-H.
Angew. Chem., Int. Ed. 2013, 52, 10231–10236.
(9) For more examples of using this method to synthesize rotaxanes,
see: (a) Cantrill, S. J.; Rowan, S. J.; Stoddart, J. F. Org. Lett. 1999, 1,
1363–1366. (b) Eelkema, R.; Maeda, K.; Odell, B.; Anderson, H. L.
J. Am. Chem. Soc. 2007, 129, 12384–12385.
(10) (a) Nakazono, K.; Kuwata, S.; Takata, T. Tetrahedron Lett.
2008, 49, 2397–2401. (b) Suzuki, S.; Nakazono, K.; Takata, T. Org. Lett.
2010, 12, 712–715.
and anion exchange gave the [2]rotaxane 4-H PF6. We
3
recorded 2D COSY and NOESY spectra to identify the
signals of the protons of the two methylated [2]rotaxanes
(see the Supporting Information) and the positions of their
interlocked BPX26C6 components. The observation of
Org. Lett., Vol. 15, No. 22, 2013
5743

an upfield shift of the aromatic protons near the urea
0
0
station (Hf , Hg ). These signals suggest the successful
deprotonation of the tertiary ammonium ion and subse-
quent migration of the BPX26C6 unit from the tertiary
amine center to the urea station. Introducing 12 equiv of
HPF6 to this solution resulted in a spectrum similar to that of
the [2]rotaxane 4-H PF6 in the absence of any additive,
3
indicating that, under these conditions, the macrocyclic
component had returned to encircle the protonated tertiary
amine center. Because N,N-bis(4-tert-butylbenzyl)-N-methy-
lammonium hexafluorophosphate12 and bis(4-(hexyloxy)-
phenyl)urea13 both exhibited very weak binding affinities
toward BPX26C6 in their equimolar mixtures in CDCl3
(10 mM), the [2]rotaxane 4-H PF6 acts as an unique acid/
3
base-controllable molecular switch in solution, which fea-
tures two very weakly associating recognition units.
If we assume that the selectivities for the interlocked
Figure 1. 1H NMR spectra (400 MHz, CDCl3, 298 K) of the
[2]rotaxanes (a) 1-H PF6, (b) 4, and (c) 4-H PF6.
BPX26C6 components in the [2]rotaxanes 1-H PF6 and 4
3
for encircling their corresponding diphenylurea stations
are 0 and 100%, respectively, we then can estimate the
preference for the macrocyclic unit residing about the
tertiary ammonium ion center over the diphenylurea sta-
3
3
cross-peaks between the signals of the ethylene glycol
protons of the BPX26C6 unit and only the protons ad-
jacent to the diphenylurea station (Hf, Hg) in 4 (Figure 1b)
and only the protons associated with the tertiary ammo-
tion in the [2]rotaxane 4-H PF6 simply by considering the
3
chemical shifts of its urea-adjacent aromatic protons as
molar fraction averages of those same signals in the
[2]rotaxanes 1-H PF6 and 4. Using the aromatic protons
0
nium ion center (Hb , Hc , Hd , He ) in 4-H PF6 (Figure 1c)
0
0
0
3
3
suggested that the macrocyclic component encircled the
urea station in the former [2]rotaxane and the tertiary
ammonium ion station in the latter. Thus, the binding
affinity of the BPX26C6 unit toward the tertiary amine
station in the [2]rotaxane 4 is significantly weaker than it is
toward the diphenylurea station, implying that the
0
0
Hf and Hg as references, we calculated that in CDCl3 the
interlocked BPX26C6 unit residues predominately about
the tertiary ammonium ion center, rather than the diphe-
nylurea station, in the [2]rotaxane 4-H PF6 with a 97:3
3
distribution ratio, providing a difference in free energy of
2.1 kcal molꢀ1 between the two translational isomers.14
Next, after proving that the [2]rotaxane 4-H PF6 behaves
[2]rotaxane 4-H PF6 is a molecular switch that can be
operated through in situ base/acid control (Scheme 2).11
3
3
as a base/acid-controllable molecular switch, we were inter-
ested in finding other stimuli to reverse the stabilization
energy preference of the BPX26C6 unit toward the two
Scheme 2
stations so that the operation of the switch 4-H PF6 could
3
also be achieved without significantly weakening the binding
affinity of the macrocyclic component to the tertiary ammo-
nium ion center. Previously, we had demonstrated that
a [2]rotaxane comprising a BPX26C6 unit and a dumbbell-
shaped component featuring a diphenylurea unit could be
synthesized by taking advantage of the templating effects
of metal ions.8 We suspected that the same collaboration
among recognition components would provide sufficiently
strong interactions to attract the macrocycle away from the
þN(CH3)H center and toward the urea station. If so, the
addition and removal of metal ions would drive the transfer
of the BPX26C6 unit between the diphenylurea and tertiary
Addition of 12 equiv of Et3N to a CDCl3 solution of the
[2]rotaxane 4-H PF6 resulted in a spectrum (Figure 2b)
similar to that of the [2]rotaxane 4; i.e., disappearance of
the complicated splitting pattern of the methylene protons
3
ammonium stations, allowing the [2]rotaxane 4-H PF6 to
function as a molecular switch that is controlled through
3
host/guestꢀcollaborated metal ion complexation (Scheme 3).
0
0
adjacent to the ammonium center (Hc , Hd ) and of the
benzylic protons of the BPX26C6 unit (caused by the local
asymmetry of the tertiary ammonium ion center), together
with a downfield shift of the signals of the aromatic
(12) The association constant (Ka) of this tertiary ammonium salt to
BPX26C6 in CDCl3 was determined by 1H NMR titration experiments
to be 11 ( 2 Mꢀ1. See the Supporting Information for the titration curve.
(13) Huang, Y.-L.; Hung, W.-C.; Lai, C.-C.; Liu, Y.-H.; Peng, S.-M.;
Chiu, S.-H. Angew. Chem., Int. Ed. 2007, 46, 6629–6633.
0
protons closest to the ammonium center (Hb , He ) and
0
(11) An acid/base-controllable molecular switch based on a tertiary
ammonium ion and DB24C8 has been reported; see ref 10b.
(14) The association constant (Ka) of the diphenylurea station to
.
BPX26C6 in CDCl3 was, thus, estimated to be ca. 0.3 Mꢀ1
5744
Org. Lett., Vol. 15, No. 22, 2013

Figure 2. Partial 1H NMR spectra (400 MHz, CDCl3, 298 K) of (a)
the [2]rotaxane 4-H PF6 (3 mM); (b) the mixture obtained after
3
adding Et3N (12 equiv) to the solution in (a); and (c) the mixture
obtained after adding HPF6 (12 equiv) to the solution in (b).
Figure 3. Partial 1H NMR spectra (400 MHz, CDCl3, 298 K) of
(a) the [2]rotaxane 4-H PF6 (3 mM); (bꢀe) the mixtures ob-
3
tained after adding (b) 0.5, (c) 1.0, (d) 1.5, and (e) 2.0 equiv of
NaClO4 to the solution in (a); (f) the mixture obtained after
adding NBu4H2PO4 (2 equiv) to the solution in (e); and (g) a
Scheme 3
mixture of 4-H PF6 (3 mM) and NBu4ClO4 (6 mM).
3
ureastation and the ethylene glycol chains of the BPX26C6
unit, forming the less soluble NaH2PO415 and resulting in a
1H NMR spectrum similar to that of the original [2]rotaxane
4-H PF6.16 In other words, removing the Naþ ion from the
3
[2]rotaxane shifted the macrocyclic component back to en-
circle the tertiary ammonium center. Thus, the [2]rotaxane
4-H PF6 behaves as a molecular switch that can be operated
3
also by the addition and removal of Naþ ions.
Gradual addition of NaClO4 to a CDCl3 solution of the
[2]rotaxane 4-H PF6 at room temperature resulted in a
Our demonstration of the use of two very weakly inter-
acting stations to construct a bifunctional (pH and Naþ ion)
molecular switch highlights the potential importance of
weakly associated components within molecular switches.
This approach offers the possibility of incorporating some of
the many weakly associated species, which we might have
overlooked previously, as useful components for the con-
struction of molecular switches exhibiting versatile functions
when suitably integrated into interlocked molecules.
3
1
decrease in the intensity of its signals in the H NMR
spectrum (Figure 3) together with a new set of signals of
increasing intensity, suggesting that the rate of exchange
between the two species was slow under these conditions.
1
The growing signal at δ 2.76 in the H NMR spectra,
associated with the methyl protons of the tertiary ammo-
nium ion center, is positioned very close to that of the same
protons of the corresponding isolated dumbbell-shaped
salt component of the [2]rotaxane 4-H PF6; together with
the upfield and downfield shifts of the aromatic protons
3
Acknowledgment. This study was supported by the Na-
tional Science Council of Taiwan (NSC-102-2119-M-002-007)
and National Taiwan University (NTU-101-R890913).
þ
00
close to the diphenylurea (Hf , Hg ) and N(CH3)H (Hb ,
00
00
1
He ) centers, respectively, in the H NMR spectra, these
00
signals suggest that the BPX26C6 component resided
about the diphenylurea station under these conditions.
The addition of 2 equiv of tetrabutylammonium phos-
Supporting Information Available. Synthetic procedures
and characterization data for the [2]rotaxanes. This material is
available free of charge via the Internet at http://pubs.acs.org
phate (NBu4H2PO4) to a solution of 4-H PF6 and
3
NaClO4 removed the Naþ ions, which had presumably
coordinated in the pocket formed by the CdO group of the
1
(16) The H NMR spectrum of a solution of NBu4ClO4 (6 mM) and
4-H PF6 (3 mM) in CDCl3 (Figure 3g) indicated that the presence of this salt
3
may be responsible for the slight differences in the signal found in Figure 3a,f.
(15) The precipitation of NaH2PO4 from CDCl3 had been reported;
see: Oh, J. M.; Cho, E. J.; Ryu, B. J.; Lee, Y. J.; Nam, K. C. Bull. Korean
Chem. Soc. 2003, 24, 1538–1540.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 22, 2013
5745