Acid/base controllable molecular switch based on a neutral phenanthroline guest penetrated pseudorotaxane

Article abstract of DOI:10.1039/b926010b

A ditopic macrocycle with a bisamide and a half dibenzo-crown ether component has been newly synthesized and its complexation behavior toward neutral phenanthroline derivatives is reported. The macrocycle can bind phenanthroline derivatives very strongly by hydrogen bonding and π-electron interaction, yielding pseudorotaxane structures. The inclusion complexes show a pH controllable reversible threading-dethreading molecular switching system.

Full text of DOI:10.1039/b926010b

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Acid/base controllable molecular switch based on a neutral phenanthroline
guest penetrated pseudorotaxane†
Masahiro Muraoka,* Hiromitsu Irie and Yohji Nakatsuji*
Received 10th December 2009, Accepted 8th March 2010
First published as an Advance Article on the web 18th March 2010
DOI: 10.1039/b926010b
A ditopic macrocycle with a bisamide and a half dibenzo-crown ether component has been newly
synthesized and its complexation behavior toward neutral phenanthroline derivatives is reported. The
macrocycle can bind phenanthroline derivatives very strongly by hydrogen bonding and p-electron
interaction, yielding pseudorotaxane structures. The inclusion complexes show a pH controllable
reversible threading–dethreading molecular switching system.
Herein, we describe the formation of the inclusion complexes
of heterocycles such as phenanthroline derivatives 2a and 2b, and
Introduction
Various mechanically interlocked molecules such as rotaxanes
a bipyridine 3, with a ditopic macrocycle 1 bearing a bisamide
and catenanes have been prepared towards future realization of
and a half dibenzo-crown ether component. The formation of
molecular machines.1 Moreover, intense recent research has been
focused on technological applications of exploiting rotaxanes and
1
the complexes was characterized by H NMR spectral changes
1
and H NMR spectroscopic titration experiments. The notable
catenanes as molecular sensors2,3 and catalysts.4 For example,
features of these assembled molecules include high stabilities
Hiratani et al.3 reported that three-dimensional cavities between
axles and wheels in the rotaxanes are capable of binding particular
alkali metal cations and one enantiomer of an aminoalcohol
selectively.
and selectivities towards heterocycles, as well as pH controllable
molecular switching abilities.
Crown ethers and other macrocycles incorporating functional
moieties with hydrogen bonding, ligation, and p–p stacking have
Results and discussion
been widely used in preparing rotaxanes as a ring component in or-
der to accommodate secondary dialkylammonium salts,5 paraquat
derivatives,6 amide esters,7 and aromatic amine derivatives such as
phenanthroline derivatives8 and 2,2¢-bipyridinium salts9 as axle
components. Nonetheless, investigation of new rotaxanes with
respect to both components remains an important challenge. It
is well-established that a strategy for the synthesis of rotaxanes
is mainly interdigitation via p–p stacking,6,9 hydrogen bonding5,7,9
and ion-templated complexation.8,10,11 However, it would seem to
be restrictive that cationic hydrogen-bonded and ion-templated
rotaxanes are applied for a molecular sensor,9,12 presumably due
to the complicated procedures on neutralizing the cationic species
and removing the template ions.13 On the other hand, there have
also been extensive studies on rotaxane synthesis utilizing neutral
axle components.1,2,14 However, it should be desirable to study
different types of threading of neutral axle components through
macrocycles to synthesize interlocked molecules in order to apply
for the molecular sensor and the catalyst.
Synthesis
Inspired by previously reported macrocycles,10,11,15 the ditopic
macrocycle 1 (Fig. 1) was designed to provide two amide
hydrogen bond donating groups towards the aromatic amines
as axle components. In addition, the p-electron-rich aromatic
rings of the macrocycle 1 would also stabilize the p-electron-poor
aromatic rings of neutral phenanthroline derivatives through the
cooperative effects of p–p stacking. The macrocycle 1 was newly
synthesized with the use of a simple three-step approach as shown
in Scheme 1. The Williamson reaction between 4-cyanophenol and
tri(ethylene glycol) ditosylate under basic conditions afforded the
dinitrile 2 in 52% yield, followed by reduction to give the diamine
3 in 72% yield. Intermolecular [1+1] macrocyclization reaction
between the diamine 3 and the isophthaloyl dichloride gave the
Department of Applied Chemistry, Faculty of Engineering, Osaka Insti-
tute of Technology, Ohmiya, Asahi-ku, Osaka, 535-8585, Japan. E-mail:
muraoka@chem.oit.ac.jp, nakatsuji@chem.oit.ac.jp; Fax: +81-6-6957-
2135; Tel: +81-6-6954-4273
† Electronic supplementary information (ESI) available: Fig. S1: Partial
1H NMR spectra of an equimolar mixture (19 mM) of 1 and 2b; Fig. S2:
Partial 1H NMR spectra an equimolar mixture (19 mM) of 1 and 3; Fig. S3–
S7: 1H NMR titration curves for 2a, 2b and 3 with 1; Table S1: Association
constants thermodynamic parameters for complexes of macrocycle 1 with
2a, 2b and 3; Fig. S8: 1H NMR spectra of an equimolar mixture (19 mM)
of 1 and protonated phenanthroline (2a); Fig. S9: Variable temperature 1H
NMR spectral changes for 2a with 1. See DOI: 10.1039/b926010b
Fig. 1 Structure of the wheel and the axles for the [2]pseudorotaxanes.
2408 | Org. Biomol. Chem., 2010, 8, 2408–2413
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Scheme 1 Bisamide macrocycle synthesis. Reagents and conditions: (i)
tri(ethylene glycol) ditosylate, K2CO3, CH3CN, reflux, 44 h, 52%; (ii)
LiAlH4, THF, reflux, 4 h, 72%; (iii) isophthaloyl dichloride, Et3N, THF,
14 h, 40%.
desired macrocycle 1 in 40% yield. The heterocycles 2a, 2b, and 3
as axle components are commercially available.
1
Fig. 2 Partial H NMR spectra (300 MHz, CDCl3, 293 K) of (a) 1, (b)
an equimolar mixture (19 mM) of 1 and 2a, and (c) 2a.
1H NMR binding studies
1
The binding behavior of macrocycle 1 with phenanthroline deriva-
bipyridine (3) in d-chloroform and the H NMR shift changes
tives was examined by the addition of 1 molar equivalent of amine
of the macrocyclic isophthalic aromatic proton (c), amide (d), and
benzylic phenyl protons (f, g) were monitored (Fig. S3–S7, ESI†).17
The association constants (Ka) for the complexation are shown in
Table 1. Monitoring the downfield shift in protons (c and d) and
the upfield shift in protons (f and g) upon amine addition allowed
association constants to be determined. Due to very strong binding
of 2,9-dimethylphenanthroline (2b) towards the macrocycle 1 in
d-chloroform, 10% d-methanol in d-chloroform was used for
comparison about the association constants (Fig. S7, ESI†). It
is noteworthy that there is a marked, about 6-fold, increase in
1
to a solution of the macrocycle in d-chloroform. The H NMR
spectra of macrocycle 1, phenanthroline (2a), and an equimolar
mixture of 1 and 2a (1…2a) in d-chloroform are shown in Fig. 2.
Upon addition of phenanthroline (2a), significant downfield shifts
in the macrocyclic amide (d) and the isophthalic aromatic protons
(a, b, and c) were observed, indicating the formation of hydrogen
bonding between the amide hydrogens of the macrocycle 1 and
the nitrogen atoms of the phenanthroline (2a). In the spectrum of
the complex 1…2a, the upfield shifts in the signals of the benzylic
phenyl protons (f and g) of the macrocyle 1 imply the existence of
interactions between the electronically complementary aromatic
rings of the macrocycle 1 and phenanthroline (2a). Therefore,
the 1H NMR spectrum of an equimolar mixture (19 mM) of the
macrocycle 1 and phenanthroline (2a) in d-chloroform suggests
the formation of the pseudorotaxane 1…2a based on various
supramolecular interactions. Other neutral heterocycles, 2,9-
dimethylphenanthroline (2b) and 2,2¢-bipyridine (3), also showed
characteristic chemical shift changes similar to those of 2a upon
addition of an equimolar amount of the macrocycle 1 (see the
ESI†). Thus, it is assumed that the macrocycle 1 binds to these
heterocycles to form a [2]pseudorotaxane.
Table 1 Association constantsa for complexes of macrocycle 1 with
phenanthroline derivatives 2a and 2b, and bipyridine (3) as determined
by 1H NMR titrations in d-chloroform at 293 K
Ka/M-1
b
b
b
Guest
Hc
Hd
Hfb
Hg
2a
2b
3
470 40
430 40
470 30
2480 450
450 45
2580 300
3130 240
2420 370
c
c
c
c
a Determined by four kinds of protons of macrocycle 1 based on the
chemical shift change by the titration experiments followed by non-linear
least square data treatment method reported by Hirose.17 The starting
concentration of the host [1] = 22 mM for 2a and 3, and [1] = 2.0 mM for
2b were used for the titration. b Hc denotes proton (c), Hd denotes proton
(d), Hf denotes proton (f), and Hg denotes proton (g), which were used for
the calculations of Ka, respectively. c Shifts were too small to determine the
binding constant; association constants are estimated at less than 20 M-1.
Job plots16 (Fig. 3) based on 1H NMR spectroscopic data
measured in d-chloroform demonstrated that the complexes
of 1…2a and 1…2b were of 1 : 1 stoichiometry in solution.
The binding properties of the macrocycle 1 were estimated by
1
quantitative H NMR titration experiments of the macrocycle 1
with phenanthroline (2a), 2,9-dimethylphenanthroline (2b) and
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adding acid and base to the pseudorotaxanes in d-chloroform.
When 3 drops of trifluoroacetic acid as an acid stimulus were
added into an equimolar mixture (19 mM) of the macrocycle
1 and phenanthroline (2a) in d-chloroform, the chemical shifts
corresponding to benzylic phenyl protons (f and g) and to
tri(ethylene glycol) ether protons (h, i, j) of the macrocycle 1
returned to almost their uncomplexed chemical shifts as shown
in Fig. 4 (a) and (c), indicating that the protonated salt of 2a
was completely dethreaded from the macrocycle 1.18 These signal
changes imply that the protonated salt of 2a is located outside the
macrocycle 1 and not associated with the ether oxygen atoms in
the tri(ethylene glycol) moiety by hydrogen bonds.9,19 After 4 drops
of triethylamine as a base stimulus were added to this solution,
neutral phenanthroline (2a) was bound back to the macrocycle 1,
since large upfield changes of the chemical shifts corresponding to
benzylic phenylprotons (f andg) of the macrocycle 1 were observed
again, as shown in Fig. 4 (b), (c) and (d) (see the ESI† about
the same result for 1…2b). Therefore, the threading–dethreading
switching phenomena of the pseudorotaxanes between bisamide
macrocycle 1 and neutral aromatic amines 2a and 2b can be
controlled reversibly by changing the solution pH, due to the
reversible protonation of the phenanthroline derivatives 2a and 2b.
Fig. 3 Job plot showing the 1 : 1 stoichiometry of the complex between
(a) 1 and 2a in CDCl3 and (b) 1 and 2b in CDCl3: [1] + [2a] = 4.0 mM;
[1] + [2b] = 3.0 mM; Dd = chemical shift change for proton (c) of 1.
the macrocycle’s binding affinity for 2,9-dimethylphenanthroline
(2b) over unsubstituted phenanthroline (2a). Because the phenan-
throlyl nitrogen atom of 2,9-dimethylphenanthroline (2b) is more
basic than that of phenanthroline (2a) due to its high electron
density resulting from the electron-donating methyl groups at-
tached to the phenanthroline ring, it is likely that the binding
affinity for 2,9-dimethylphenanthroline (2b) is higher than that
for unsubstituted phenanthroline (2a). Interestingly, with the
macrocycle 1, bipyridine (3) is bound the most weakly of three
aromatic amines. This highlights the cooperative recognition of
phenanthroline derivatives by favorable hydrogen bond acceptor
ability. In addition, the macrocycle 1 provides an optimal size and
shape complementarity to these phenanthroline derivatives.
1
Fig. 4 Partial H NMR spectra (300 MHz, CDCl3, 293 K) of (a) 1, (b)
an equimolar mixture (19 mM) of 1 and 2a, (c) the mixture obtained
after adding trifluoroacetic acid (3 drops) to the solution in (b), and (d)
the mixture obtained after adding triethylamine (4 drops) to the solution
in (c).
NOE experiments are effective for useful information on further
evidence of the threading–dethreading switching process. In the
NOESY spectra of the pseudorotaxane 1…2a in d-chloroform
as shown in Fig. 5(a), clear correlations were observed between
Acid–base controlled switching studies
The molecular switching properties of the pseudorotaxanes
1…2a and 1…2b by pH-controlled stimuli were investigated by
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the macrocycle 1 and protons (4, 5) of phenanthroline (2a),
confirming that phenanthroline (2a) was incorporated within the
macrocycle 1 in d-chloroform. When 3 drops of trifluoroacetic
acid as an acid stimulus were added into the pseudorotaxane
1…2a in d-chloroform, no distinct cross peaks were observed
between the protons (f, g, h, i, j) of the macrocycle 1 and the
protons (2, 4, 5) of phenanthroline (2a) in the NOESY spectra
as shown in Fig. 5(b). These results clearly show the protonated
phenanthroline is located outside the macrocycle 1. In fact, when
protonated phenanthroline (2a) was added into the macrocycle 1
in d-chloroform, 1H NMR signals of oxyethylene protons (h, i, j)
of the macrocycle 1 remained in the same positions as those of
uncomplexed macrocycle 1 (Fig. S8, ESI†).
Conclusions
The design and synthesis of a ditopic macrocycle having a
bisamide and a half dibenzo-crown ether component has been
achieved. This ditopic macrocyclic structure has been shown to
exhibit complexation behavior towards neutral aromatic amines
by hydrogen bonding and p-electron interaction. As a result, we
have developed a simple synthetic strategy for a pseudorotaxane
by using phenanthroline derivatives without ion-templates and
have proved the pseudorotaxane to be a pH-controllable reversible
threading–dethreading molecular switch. We are currently con-
tinuing the construction of rotaxanes providing shuttling1 and
rotating20 movements for molecular sensing applications utilizing
the oxyethylene moieties as a binding site toward neutral or ionic
sensing targets.
Experimental
All chemicals were of commercially-available reagent grade, and
were used without further purification. THF was dried over
1
sodium benzophenone ketyl and distilled prior to use. H and
13C NMR spectra were recorded with a Varian Mercury 300
spectrometer for solution in CDCl3 and DMSO-d6 with SiMe4
as an internal standard. Mass spectra were measured on a JEOL
JMS-DX-303 mass spectrometer. Elemental analyses were carried
out with a Yanaco CHN-Corder MT-5 analyzer.
1,10-Bis(p-cyanophenyl)-1,4,7,10-tetraoxadecane (4)21
4-Cyanophenol (20.0 g, 0.168 mol), tri(ethylene glycol) ditosylate
(30.8 g, 0.0672 mol) and potassium carbonate (69.7 g, 0.504 mol)
were refluxed in acetonitrile (300 ml) for 44 h. After cooling to
room temperature, the mixture was filtered and concentrated in
vacuo to give a white solid, which was dissolved in CH2Cl2 (300 ml)
and the solution was filtered three times with Celite. The organic
layer was dried over anhydrous magnesium sulfate, filtered, and
the solvent was evaporated to yield the crude product 4 as a white
solid, which was subjected to column chromatography over silica
gel (eluent: 50 : 50 hexane–ethyl acetate) to give◦the pure product
Fig. 5 Partial NOESY spectra (300 MHz, CDCl3, 293 K) of an equimolar
mixture (19 mM) of 1 and 2a (a) before, and (b) after the addition of
trifluoroacetic acid (3 drops).
◦
1
the benzylic phenyl protons (f) of the macrocycle 1 and proton
(2) of phenanthroline (2a), benzylic phenyl protons (g) of the
macrocycle 1 and protons (4, 5) of phenanthroline (2a), benzylic
phenyl protons (f) of the macrocycle 1 and protons (2) of
phenanthroline (2a), and the oxyethylene protons (h, i, j) of
4 as a white solid (11.6 g, 52%). M.p. 107-108 C (119 C19); H
NMR (CDCl3, 300 MHz): d (ppm) 3.75 (s, 4H), 3.88 (t, J = 4.8 Hz,
4H), 4.17 (t, J = 4.8 Hz, 4H), 6.96 (d, J = 9.0 Hz, 4H), 7.58 (d,
J = 9.0 Hz, 4H); elemental analysis calcd (%) for C20H20N2O4: C
68.17, H 5.72; found: C 67.85, H 5.68.
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1,10-Bis[p-(aminomethyl)phenyl]-1,4,7,10-tetraoxadecane (5)
based on the chemical shift change by the titration experiment fol-
lowed by non-linear least-square data treatment method with 95%
confidence interval applied by Student’s t-distribution reported by
Hirose.17 The volume change for the titrated solutions was properly
accounted for in the Hirose’s method. The limiting chemical shifts,
D0, which mean the difference in d values for the protons of the
host 1 in the uncomplexed and fully complexed species, and the
standard deviations as the curve fitting errors for the association
constants were determined by SOLVSTAT.22
To a suspension of LiAlH4 (4.56 g, 0.120 mol) in THF (100 ml),
a solution of 4 (5.48 g, 0.0156 mol) in THF (170 ml) was added
dropwise over a period of 40 min at 0 ◦C. The resulting mixture was
stirred for 30 min at room temperature and then refluxed for 4 h.
After the mixture was cooled to room temperature, water (3 ml),
15% aqueous NaOH (3 ml) and water (8 ml) were added by turns.
The mixture was stirred for 30 min and filtered. Water (250 ml) was
added to the mixture and then it was extracted with CH2Cl2 (3 ¥
250 ml). The organic layer was dried over anhydrous magnesium
sulfate, filtered, and the solvent was evaporated to yi◦eld the crude
product 5 as a white solid (4.07 g, 72%). M.p. 131-135 C; 1H NMR
(CDCl3, 300 MHz): d (ppm) 3.76 (s, 4H), 3.79 (s, 4H), 3.86 (t, J =
4.9 Hz, 4H), 4.12 (t, J = 4.9 Hz, 4H) 6.88 (d, J = 8.7 Hz, 4H),
7.21 (d, J = 8.7 Hz, 4H); 13C NMR (CDCl3, 75 MHz): d (ppm)
45.9, 67.5, 69.8, 70.8, 114.7, 128.2, 135.8, 157.7; elemental analysis
calcd (%) for C20H28N2O4: C 66.64, H 7.83; found: C 66.62, H 7.80.
Acknowledgements
We thank Profs. Y. Tobe and K. Hirose of Osaka University for
valuable advice about quantitative 1H NMR titration experiments.
Notes and references
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1,7-Diaza-13,16,19,22-tetraoxa-2,6-dioxo-3,5,9,12,23,26-
tribenzocycloheptacosane (1)
5 (1.02 g, 2.83 ¥ 10-3 mol) was dissolved in THF (140 ml).
Separately, isophthaloyl dichloride (0.580 g, 2.86 ¥ 10-3 mol) was
dissolved in dry THF (40 ml). A three necked round-bottomed
flask (500 ml) was charged with THF (150 ml) and NEt3 (2 ml).
Via two pressure-equalizing dropping funnels, both solutions were
added simultaneously dropwise to the flask with stirring over a
period of 2 h at room temperature. The reaction mixture was
stirred under argon atmosphere overnight at room temperature.
The solvent was evaporated under reduced pressure to leave a pale
yellow solid. The residue was purified by silica gel chromatography
(eluent: CHCl3) to give the pure product 1 as a white solid
(0.550 g, 40%). An analytical sample of 1 was obtained after
recrystallization from dioxane–toluene. M.p.: 228-233 ◦C; 1H
NMR (CDCl3, 300 MHz): d (ppm) 3.72 (s, 4H), 3.85 (t, J =
4.3 Hz, 4H), 4.10 (t, J = 4.3 Hz, 4H), 4.46 (d, J = 5.1 Hz, 4H)
6.51 (brs, 2H), 6.80 (d, J = 8.6 Hz, 4H), 7.18 (d, J = 8.6 Hz,
4H), 7.45 (t, J = 7.8 Hz, 1H), 7.69 (s, 1H), 7.99 (d, J = 7.8 Hz,
2H); 1H-NMR (DMSO-d6, 300 MHz): d (ppm) 3.55 (s, 4H), 3.67-
3.71 (m, 4H), 4.06-4.09 (m, 4H), 4.37 (d, J = 5.2 Hz, 4H), 6.88
(d, J = 8.4 Hz, 4H), 7.25 (d, J = 8.4 Hz, 4H), 7.56 (t, J =
7.8 Hz, 1H), 7.88 (d, J = 7.8 Hz, 2H), 8.01 (s, 1H), 8.61 (t, J =
5.2 Hz, 2H); 13C NMR (75 MHz, DMSO-d6): d (ppm) 42.7, 67.4,
68.9, 70.2, 114.6, 125.8, 128.9, 129.6, 130.2, 131.1, 135.2, 157.8,
166.4; HRMS(FAB): m/z: for C28H30N2O6: calcd: 490.2104; found:
490.2107; elemental analysis calcd (%) for C28H30N2O6: C 68.56,
H 6.16; found: C 68.31, H 6.17.
Determination of the association constants (Ka)
All titration results were acquired by a Varian 300 MHz NMR
spectrometer and performed with the starting concentration of
host 1 at 22 mM for 2a and 3, and 2.0 mM for 2b. Appropriate
aliquots of guests 2a and 3 at 890 mM, and 2b at 20 mM solutions
with a microsyringe. The protons (c, d, f, and g) for the host 1
were followed during the course of the titration. The complexation
equilibrium was fast on the NMR time scale and gave signals at
weight averaged chemical shifts of the free and complexed host.
The association constants (Ka) for the complexation were obtained
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2412 | Org. Biomol. Chem., 2010, 8, 2408–2413
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