A guanidinium ion-based anion- and solvent polarity-controllable molecular switch

Article abstract of DOI:10.1021/ol802638k

(Chemical Equation Presented) The macrocycle bis-p-xylyl[26]crown-6 (BPX26C6) is capable of complexing guanidinium ions in a [2]pseudorotaxane-like manner in solution. A corresponding molecular switch can be operated through changes in solvent polarity or the addition and removal of halogen and acetate anions.

Full text of DOI:10.1021/ol802638k

ORGANIC
LETTERS
2009
Vol. 11, No. 3
613-616
A Guanidinium Ion-Based Anion- and
Solvent Polarity-Controllable Molecular
Switch
Tzu-Chiun Lin,† Chien-Chen Lai,‡ and Sheng-Hsien Chiu*,†
Department of Chemistry, National Taiwan UniVersity, No. 1, Sec. 4, RooseVelt Road,
Taipei, Taiwan, 10617, 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 November 17, 2008
ABSTRACT
The macrocycle bis-p-xylyl[26]crown-6 (BPX26C6) is capable of complexing guanidinium ions in a [2]pseudorotaxane-like manner in solution. A
corresponding molecular switch can be operated through changes in solvent polarity or the addition and removal of halogen and acetate anions.
Arginine plays an important role in the reception pockets of
many enzymes, where its guanidinium residue acts as a
recognition unit for anionic substrates.1 Taking this cue from
Nature, several artificial anion receptors have been prepared
featuring guanidinium derivatives for the recognition of both
spherical halide and Y-shaped carboxylate anions.2 Although
electrons,3 photons,4 cations,5 and heat6 have all been used
as external stimuli to control the operation of molecular
switches, reports of anion-mediated interlocked switches are
rare.7 In theory, an anion-controllable molecular switch could
be constructed by interlocking the components of a [2]pseu-
dorotaxane complex featuring a guanidinium ion-derived
threadlike component because competition between external
† National Taiwan University.
‡ China Medical University Hospital.
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10.1021/ol802638k CCC: $40.75
Published on Web 12/23/2008
2009 American Chemical Society

anions and the macrocyclic component for the guanidinium
ion recognition site would influence the location of the
macrocycle. We are unaware of any such [2]pseudorotaxane
complexes having been reported previously, possibly because
most guanidinium salts are soluble only in polar solvents,
which disfavors their hydrogen bonding with external hosts.
In this paper, we report (i) that the macrocycle bis-p-
xylyl[26]crown-68 (BPX26C6) forms [2]pseudorotaxane-like
complexes with guanidinium ions in solution and (ii) that a
corresponding molecular switch can be operated through
changes in solvent polarity or through the addition and
removal of halogen and acetate anions.
Scheme 2
Previously, we reported that macrocycle 1 forms [2]pseu-
dorotaxane complexes with diphenylurea derivatives in
solution (Scheme 1).7e Because guanidinium ions and
Scheme 1
furnished the corresponding benzoyl thiourea 5, which we
deacylated to provide the thiourea 6. Boc protection of the
NH2 group of 6 followed by an EDCI-activated substitution
reaction with the amine 3 gave the dibromide 8.9 Removal
of the Boc protecting group of 8 under acidic conditions,
followed by anion exchange and column chromatography,
provided 2-H·PF6 as a white solid.
The 1H NMR spectrum of an equimolar mixture of
BPX26C6 and the threadlike guanidinium salt 2-H·PF6 in
CDCl3/CD3CN (10:1) at room temperature displays signifi-
cant shifts in the positions of many of the signals relative to
those for the free species (Figure 1). The upfield shifts for
diphenylurea molecules both feature Y-shaped hydrogen
bond donor units, we suspected that replacing the hydrogen
bond-donating diamidopyridine motif (used to recognize the
CdO group of the urea unit) of macrocycle 1 into another
hydrogen bond-receiving diethylene glycol unit would allow
us to construct a macrocycle capable of forming complexes
with guanidinium ions. Thus, we selected BPX26C6, which
forms complexes with pyridinium and bipyridinium ions
through [C-H···O] hydrogen bonding and complimentary
electrostatic aromatic stacking interactions, to test its ability
to form complexes with planar cationic guanidinium ions.
We synthesized the threadlike guanidinium salt 2-H·PF6
from the 4-bromobenzylamine 3 in five steps (Scheme 2).
The reaction of the amine 3 and benzoyl isothiocyanate 4
(8) (a) Cheng, P.-N.; Lin, C.-F.; Liu, Y.-H.; Lai, C.-C.; Peng, S.-M.;
Chiu, S.-H. Org. Lett. 2006, 8, 435–438. (b) 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, Ito; Chiu, S.-H. J. Org. Chem. 2006, 71, 2373–2383. (c) Chen, N.-
C.; Huang, P.-Y.; Lai, C.-C.; Liu, Y.-H.; Peng, S.-M.; Chiu, S.-H. Chem.
Commun. 2007, 4122–4124. (d) Huang, Y.-L.; Lin, C.-F.; Cheng, P.-N.;
Lai, C.-C.; Liu, Y.-H.; Peng, S.-M.; Chiu, S.-H. Tetrahedron Lett. 2008,
49, 1665–1669. (e) Chen, N.-C.; Lai, C.-C.; Liu, Y.-H.; Peng, S.-M.; Chiu,
S.-H. Chem.-Eur. J. 2008, 14, 2904–2908.
Figure 1. Partial 1H NMR spectra [400 MHz, CDCl3/CD3CN (10:
1), 298 K] of (a) BPX26C6, (b) an equimolar mixture of BPX26C6
and 2-H·PF6 (20 mM), and (c) 2-H·PF6.
(9) For this synthetic approach, please refer to: Linton, B. R.; Carr, A. J.;
Orner, B. P.; Hamilton, A. D. J. Org. Chem. 2000, 65, 1566–1568.
(10) Connors, K. A. Binding Constants; Wiley: New York, 1987.
614
Org. Lett., Vol. 11, No. 3, 2009

the signals of the xylyl and guanidinium protons of BPX26C6
and thread 2-H·PF6, respectively, are consistent with the
proposed geometry of the [2]pseudorotaxane [(BPX26C6⊃2-
H)·PF6], in which the cationic guanidinium ion is located
between the two xylyl groups of BPX26C6. Using 1H NMR
spectroscopic dilution experiments, we determined the as-
sociation constant (Ka) for the interaction between the two
species in CDCl3/CD3CN (10:1) to be 200 ( 20 M-1.10 We
Scheme 3. Synthesis of the Molecular Switch 17-H·2PF6
1
observed negligible shifts for the signals in the H NMR
spectra of the same mixture in CD3CN, CD3NO2, and CDCl3/
CD3CN (1:1), relative to those of the free species, indicating
that the interactions between the host and guest are very weak
in moderately polar solvents.
To prove the existence of the [2]pseudorotaxane [(BPX-
26C6⊃2-H)·PF6] in solution, we prepared a corresponding
interlocked [2]rotaxane from a related complex formed
between the threadlike guanidinium salt 9-H·PF6 and
BPX26C6. We synthesized 9-H·PF6 from the amine 10
(Scheme 2) following a reaction pathway similar to that used
to synthesize 2-H·PF6. The reaction of 3,5-di-tert-butylbenzyl
bromide (16), BPX26C6, and the threadlike guanidinium salt
9-H·PF6 (each 150 mM) in CHCl3/CH3CN (10:1) at room
temperature gave the [2]rotaxane 17-H·2PF6 (Scheme 3) and
the dumbbell-shaped salt 18-H·2PF6 in 18 and 52% yield,
respectively, after ion exchange and column chromatogra-
phy.11 This result confirmed that BPX26C6 encircles thread-
like guanidinium ions in the form of [2]pseudorotaxanes in
CDCl3/CD3CN (10:1) solution.
We suspected that [N-H···O] hydrogen bonding between
the BPX26C6 unit and the guanidinium station of the
[2]rotaxane 17-H·2PF6 would be more energetically favorable
in CDCl3 than would be [N+C-H···O] hydrogen bonding and
any π-π interactions between the BPX26C6 unit and the
pyridinium station; i.e., BPX26C6 should encircle the
guanidinium station in nonpolar solvents. The observation
that only small shifts in the positions of the signals of the
pyridinium unit (HR and Hꢀ) and its adjacent CH2 group of
the [2]rotaxane 17-H·2PF6 in CDCl3 relative to those in the
1H NMR spectrum of the free dumbbell-shaped salt 18-
H·2PF6 under the same conditions and the lack of cross
signals between these protons and the aromatic protons of
the BPX26C6 unit in 2D NOSEY spectra supported that the
macrocyclic component is not residue on the pyridinium
station of the [2]rotaxane 17-H·2PF6 in CDCl3 (see the
Supporting Information). The addition of CD3CN to the
CDCl3 solution of the [2]rotaxane 17-H·2PF6 led to gradual,
yet significant, upfield shifts in the positions of the signals
of the pyridinium (and adjacent CH2) and xylyl protons in
1
the H NMR spectra (Figure 2). From a comparison with
1
(11) Data for [2]rotaxane 17-H·2PF6: mp 105-106 °C; H NMR (400
the spectra of the dumbbell-shaped salt 18-H·2PF6 in these
solvents and from the cross signals observed between the
aromatic protons of the BPX26C6 unit and the pyridinium/
CH2 protons in the 2D NOSEY spectrum of 17-H·2PF6 in
CD3CN, we infer that the BPX26C6 unit prefers to encircle
the pyridinium station of this [2]rotaxane in relatively polar
solvents. Thus, the [2]rotaxane 17-H·2PF6 behaves as a
reversible molecular switch in which the BPX26C6 unit
resides selectively on the guanidinium station in nonpolar
solvents and on the pyridinium station in polar solvents.12
In addition to modifying the polarity of the solvent system,
we expected that we could also operate the molecular switch
by introducing, into a solution of the [2]rotaxane 17-H·2PF6
in a nonpolar solvent, an anion that binds tightly to
guanidinium ions, thereby forcing the BPX26C6 unit to
migrate to the pyridinium station (Scheme 4). Indeed, after
adding 3 equiv of tetra-n-butylammonium chloride (Bu4NCl)
to a CD3NO2 solution of the [2]rotaxane 17-H·2PF6, we
observed significant upfield shifts of the signals of the
MHz, CDCl3): δ ) 1.34 (s, 18H), 1.37 (s, 18H), 3.65-3.69 (m, 16H),
3.80-3.98 (br, 4H), 4.22-4.32 (m, 4H), 5.47 (br, 2H), 5.86 (br, 2H),
6.22-6.38 (br, 2H), 6.92 (s, 8H), 7.05 (s, 2H), 7.26(s, 2H), 7.35-7.39 (br,
2H), 7.40 (s, 1H), 7.53 (s, 1H), 7.80 (d, J ) 8 Hz, 2H), 8.11-8.19 (br,
2H), 8.57-8.61 (br, 2H). 13C NMR (100 MHz, CDCl3): δ ) 31.3, 31.5,
35.0, 35.0, 44.1, 45.8, 65.0, 69.8, 70.5, 73.4, 121.9, 122.3, 123.6, 124.2,
125.0, 127.9, 128.7, 128.8, 131.0, 132.5, 134.5, 136.7, 140.1, 143.6, 151.2,
152.5, 153.8, 155.4. HR-MS(ESI): m/z calcd for [17-H·PF6]+ C67H92N4O6PF6
1193.6659, found 1193.6659; [17-H]2+ C67H92N4O6 524.3509, found
524.3508. Data for Dumbbell 18-H·2PF6: mp 112-115 °C. 1H NMR (400
MHz, CD3CN): δ ) 1.28 (s, 18H), 1.32 (s, 18H), 4.36 (d, 6 Hz, 2H), 4.51
(d, 6 Hz, 2H), 5.65 (s, 2H), 6.25 (br, 2H), 6.75-6.78 (m, 2H), 7.13 (s,
2H), 7.37 (s, 2H), 7.40-7.44 (m, 3H), 7.56 (s, 1H), 7.86 (d, J ) 8 Hz,
2H), 8.22 (d, J ) 7 Hz, 2H), 8.76 (d, J ) 7 Hz, 2H). 13C NMR (100 MHz,
CD3CN): 31.4, 31.5, 35.4, 35.6, 44.9, 46.0, 64.9, 121.7, 122.2, 123.7, 124.2,
125.4, 128.3, 128.6, 132.6, 133.3, 135.1, 140.8, 144.2, 151.4, 152.4, 155.8
(one signal is missing, possibly because of signal overlapping). HR-
MS(ESI): m/z calcd for [18-H·PF6]+ C43H60N4PF6 777.4460, found 777.4459;
[18-H]2+ C43H60N4 316.2409, found 316.2408.
(12) For other molecular switches that can be operated through changes
in solvent polarity, see: (a) Lane, A. S.; Leigh, D. A.; Murphy, A. J. Am.
Chem. Soc. 1997, 119, 11092–11093. (b) Ambrosi, G.; Dapporto, P.;
Formica, M.; Fusi, V.; Giorgi, L.; Guerri, A.; Micheloni, M.; Paoli, P.;
Pontellini, R.; Rossi, P. Chem.-Eur. J. 2003, 9, 800–810. (c) Chiang, P.-
T.; Cheng, P.-N.; Lin, C.-F.; Liu, Y.-H.; Lai, C.-C.; Peng, S.-M.; Chiu,
S.-H. Chem.-Eur. J. 2006, 12, 865–876.
Org. Lett., Vol. 11, No. 3, 2009
615

chloride anions from solution through precipitation of
AgClsgave a spectrum (Figure 3e) similar to that of the
Figure 3.
Partial 1H NMR spectra (400 MHz, CD3NO2, 298 K) of
Figure 2.
Partial 1H NMR spectra (400 MHz, 298 K) of the
(a) the molecular switch 17-H·2PF6, (b) the mixture obtained after
adding Bu4NCl (1 equiv) to the solution in (a), (c) the mixture
obtained after adding Bu4NCl (2 equiv) to the solution in (b), (d)
the mixture obtained after adding AgPF6 (1 equiv) to the solution
in (c), and (e) the mixture obtained after adding AgPF6 (2 equiv)
to the solution in (d).
[2]rotaxane 17-H·2PF6 in (a) CDCl3, (b) CDCl3/CD3CN (2:1), (c)
CDCl3/CD3CN (1:1), (d) CDCl3/CD3CN (1:4), and (e) CD3CN.
Scheme 4. Using Anions to Operate the Molecular Switch
17-H·2PF6
original [2]rotaxane 17-H·2PF6, suggesting that the BPX26C6
unit had migrated back to the guanidinium station. Thus,
reversible switching of the BPX26C6 unit between the
guanidinium and pyridinium stations of the [2]rotaxane 17-
H·2PF6 was possible in situ through the addition and removal
of chloride anions. Indeed, we also operated this unique
anion-controllable molecular switch through the addition and
removal of bromide and acetate anions (see the Supporting
Information).
We have demonstrated that guanidinium ions can thread
through the cavity of BPX26C6 to form [2]pseudorotaxane-
like complexes in low-polarity solvents. A [2]rotaxane
derived from this new recognition system functions as a
molecular switch, in which translational movement of the
macrocyclic component can be controlled two ways: through
changes in solvent polarity and through exchange of the
counteranions.
pyridinium protons (HR and Hꢀ) and of the aromatic protons
(HAr) of the BPX26C6 unit, suggesting that the macrocyclic
component now resided on the pyridinium station. The
migration of the BPX26C6 unit from the guanidinium to the
pyridinium station upon the addition of the chloride anions
was supported by 2D NOSEY spectra, which revealed cross
peaks between the signals of the aromatic/ethylene glycol
protons of the BPX26C6 moiety and the pyridinium protons
after we had added Bu4NCl into the solution, but not before.
Subsequent addition of 3 equiv of AgPF6sto remove the
Acknowledgment. We thank the National Science Council
(Taiwan) for financial support (NSC-95-2113-M-002-016-
MY3).
Supporting Information Available: Synthetic procedures
and characterization data for the [2]rotaxane 17-H·2PF6. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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