Nitroxide biradicals as thread units in paramagnetic cucurbituril-based rotaxanes

Article abstract of DOI:10.1039/c0ob01160f

The first example of paramagnetic rotaxane containing cucurbit[6]urils has been reported and characterized both by ESR and NMR spectroscopy.

Full text of DOI:10.1039/c0ob01160f

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PAPER
Nitroxide biradicals as thread units in paramagnetic cucurbituril-based
rotaxanes†
Elisabetta Mileo, Costanza Casati, Paola Franchi, Elisabetta Mezzina and Marco Lucarini*
Received 13th December 2010, Accepted 2nd February 2011
DOI: 10.1039/c0ob01160f
The first example of paramagnetic rotaxane containing cucurbit[6]urils has been reported and
characterized both by ESR and NMR spectroscopy.
Introduction
The cucurbit[n]uril (CBn, where n = 5–8 and 10) family of
macrocyclic host molecules, comprised of n glycoluril units
bridged by 2n methylene groups, has been demonstrated to form
particularly stable host–guest complexes with cationic organic
and organometallic guests in aqueous solution, as a result of
a hydrophobic cavity accessed through two restrictive polar
carbonyl fringed portals.1–4 CBn has also been employed in the
preparation of a significant number of mechanically-interlocked
supramolecular complexes, including rotaxanes, pseudorotaxanes,
and catenanes, where CBn is the cyclic component.5 With the
polar carbonyl groups lining the rims of the cucurbiturils, the end
groups on the threads can prevent dissociation of the rotaxanes
into their cyclic bead and linear thread components through steric
and/or electrostatic means. In principle, as already reported with
a-cyclodextrin,6 complexation of a nitroxide biradical can be
exploited for the preparation of mechanically-interlocked para-
Scheme 1
magnetic aggregates, in which the properties of such assemblies
can be merged with the use of nitroxides in materials science and
their applications in the study of biological processes.7 While the
inclusion of mononitroxide radicals by CBn has been already
reported,8–12 preparation of nitroxide biradical-based rotaxane
with CBn has never been reported. In the present study, we
report the behaviour of CB6, CB7 and CB8 in the presence
of nitroxide biradicals containing tetramethylpiperidine-N-oxyl
(TEMPO) units to form host–guest complexes in the forms of
paramagnetic pseudorotaxanes and rotaxane.
reported in Fig. 1 and is characterized by five lines, due to the
exchange interaction between the paramagnetic fragments linked
by the polyether chain, as the exchange coupling constant between
unpaired electrons, J, is greater than the hyperfine splitting, aN.13
This exchange interaction, which leads to the appearance of extra
lines in the ESR spectra, is operating through space and depends
on the frequency of collisions between the paramagnetic moieties.
The complexation of the biradicals with the CB is expected to
significantly reduce the probability of collisions of the nitroxide
termini giving rise to the disappearance of the exchange peaks in
the ESR spectra.14 Thus, besides following aN changes as usually
done with mononitroxide, with biradicals monitoring of the
variation in the intensity of exchange peaks as a function of host
concentration could provide extra information on complexation
behaviour. In Fig. 1 ESR spectral variations of 1a observed by
adding increasing amount of CBn are reported. The exchange
lines in the spectra of 1a decrease continuously with increased
CBn concentration until complete disappearance at around 2 mM
with CB7 and CB8 and ca. 20 mM with CB6. This is consistent
with the complexation with the CBn units which reduces the
exchange interaction. The disappearance of the exchange peaks
Results and discussion
We initially investigated the ESR behaviour of biradical 1a
(Scheme 1) in the presence of CBn having different sizes (n =
6, 7, 8) to verify if the TEMPO unit stopper is bulky enough to act
as an end-cap group of a rotaxane consisting of CBn. The ESR
spectrum of 1a recorded in water (aN = 16.90 G, g = 2.0056) is
Department of Organic Chemistry “A. Mangini”, University of Bologna, Via
San Giacomo 11, I-40126, Bologna, Italy. E-mail: marco.lucarini@unibo.it
† Electronic supplementary information (ESI) available: NMR and EPR
spectra of the products. See DOI: 10.1039/c0ob01160f
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separation between the ESR central and high field lines (DB, see
Fig. 1) as a function of macrocyclic concentration in water at 298 K
(Fig. 2).15
Fig. 2 Field separation between the ESR central and high field lines (DB)
for biradical 1a in the presence of different amount of CB6 ( ), CB7 (
)
᭺
᭹
and CB8 (᭢) in water at 298 K. With CB6 NaCl 0.1 M was added to the
solution.
Different behaviours were observed depending on the size of the
macrocycle. The addition of CB6 to the biradical solution showed
no significant changes in DB value even at high concentration
(>20 mM). At these concentrations, however, the ESR spectra of
the biradicals showed only three lines. This behaviour is consistent
with a weak complexation of 1a in which the nitroxide moiety is
not included inside the hydrophobic cavity of CB6, but is instead
dissolved in the bulk water with the nitroxide function located
among the carbonyl groups of the macrocylcle.
With CB7, the exchange coupling is completely suppressed at
2.0 mM of macrocycle. At this concentration however, the field
separation is still very close to the value measured in water (DDB =
-0.15 G). Both observations strongly support the formation of a
pseudorotaxane (see Scheme 2) in which the macrocycle is located
on the center of the linear chain, thus forcing the biradical to
adopt an elongated conformation having TEMPO units exposed
to the bulk water and suppressed spin exchange (J = 0). The
formation of a strong complex between nitroxide 1a and CB7
is also expected on the basis of the strong interaction between
the ammonium site and the carbonyl oxygens of CB7, as already
found with protonated amines.16 This was confirmed by following
the ESR spectral variations observed by changing the pH from
7 to 13 (see Supporting information). Around pH 7 the ESR
spectrum of a solution containing CB7 (5.5 mM) and biradical 1a
(0.4 mM) showed the three line spectrum due to the paramagnetic
pseudorotaxane. The increase of solution basicity to pH ª 12 with
NaOH reverted the ESR spectrum to the original five lines signals.
This observation strongly suggests that the deprotonated biradical
is released from the pseudorotaxane to the bulk water. The process
is reversible: addition of HCl to give back pH 7 results in the
formation of three lines spectrum and of the pseudorotaxane.
The thermodynamic stability of the pseudorotaxane was
checked by measuring the equilibrium constant K for the asso-
ciation between the diamagnetic analogue (1c) of the biradical
Fig. 1 ESR spectra of 1a (0.26 mM) in the presence of different amount
of CBn in water at 298 K.
is compatible both with the formation of a pseudorotaxane i.e.
with a symmetric complex in which the ethylene glycol units are
surrounded by the macrocycle and also with the inclusion of one
or two nitroxide units (Scheme 2).
Scheme 2
In order to check if the observed changes in the ESR spectra
are caused by formation of a pseudorotaxane or are simply due
to a TEMPO–CBn interaction, we followed the variation of field
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1
and CB7 by H NMR. The signals of the free and bound guests
is detected by significant complexation-induced chemical shifts
(CIS) of the dumbbell with respect to the resonances of the free
thread 2b (Fig. 3, line a). The sign of CIS (Dd = dbound - dfree) gives a
rough indication of the position of the thread within CB, negative
Dd revealing the part of the thread located inside the macrocycle,
and the contrary being for positive values of CISs.5 According
with these assumptions, analysis of the CIS values reported in
Fig. 3 shows that the triazole moieties of the thread are positioned
within the two CB6 macrocycles, as the consistent upfield shift
(-1.64 ppm) displayed by the aromatic proton of the heterocycle
is indicative of the strong involvement of the triazole proton in
complexation.
protons are simultaneously observed, revealing that the rate of
exchange between these species is slow in the NMR time scale
(see ESI†). Integration of the separate signals as a function
of CB7 concentration provides the corresponding association
equilibrium constant (K) as 1879 256 M-1. This value is one
order of magnitude smaller than the K value measured for the
inclusion of TEMPO monoradical by the same host,8 indicating
that the presence of substituents on the piperidine ring results in a
significant decrease in the stability of the complex (vide infra). Only
in the presence of a large excess of CB7 (>3 mM), complexes with
higher CB7/1a stoichiometry, in which TEMPO units are included
inside hydrophobic cavity of CB7, are formed, as indicated by the
significant decrease of DB in the corresponding ESR spectra.
Finally, with CB8, a strong decrease of both field separation and
intensity of exchange lines was observed when increasing macro-
cyle concentration in water solution. This behaviour indicated that
complexation by CB8 occurs preferentially in the immediacy of
TEMPO radical units rather than on the ethylene glycol units. We
have previously shown8–9 that with CB8 the larger size of the cavity
and the presence of a strong interaction between the ammonium
cation and the carbonyl groups should favour a geometry in which
the longer axis of the nitroxide is parallel to the short principal
axis of the macrocyle. This is not possible in the presence of the
smaller macrocycle, CB7, where TEMPO radical is forced to be
inserted with the NO group lying on the plane passing through the
equatorial carbon–carbon bonds of the host and with the geminal
methyl groups pointing toward the carbonyl portals.
All these observation led to the conclusion that TEMPO
unit cannot pass through the CB6 cavity, while with the larger
member of the cucurbituril family the reversible formation of a
pseudorotaxane or a complex between the tetramethylpiperidine
ring and the cucurbituril is possible. Thus we decided to construct
a CB6-based rotaxane having the 2,2,6,6-tetramethylpiperidine-
N-oxyl ring as the end-cap group. The synthesis of the rotaxane
was achieved using CB6 as catalyst in the 1,3-dipolar cycloaddition
between suitably functionalized alkyne and azide groups to give
1,4-disubstituted triazole.17 By this approach the N-propargyl
derivative of 4-amino-TEMPO 4 (0.18 mmol) and diazide 5 (0.09
mmol) were added to CB6 (0.18 mmol) dissolved in aqueous HCl
6 M and the resulting solution was stirred at 60 ◦C for 24 h
(Scheme 3). After reduced pressure solvent removal, the bis-N-
hydroxy derivative of paramagnetic [3]rotaxane (3b) was obtained
as a light yellow solid in 75% yield. The rotaxane diradical 3a was
recovered by treating 3b in water solution with an excess of Ag2O.18
Fig. 3 1H NMR spectrum in D2O of a) thread 2b (1 mM); b) [3]rotaxane
3b (1 mM) with complexation induced chemical shifts (Dd in ppm).
Considerable negative CISs are detected also for the adja-
cent protons labeled with c and d letters, while phenyl and
piperidine ring protons exhibit positive shift, confirming their
position outside the cavity near the carbonyl portals of the
macrocycle. Unexpectedly, spectrum of 3b shows an additional
peak at 7.6 ppm, which, on the basis of ROESY experiments,
was assigned to the ammonium protons linked to the 4-position
of N-hydroxy TEMPO (see ESI†). The presence of such slow-
exchangeable protons in deuterated water strongly supports that
the ammonium protons linked to the 4-position of N-hydroxy
TEMPO are hydrogen-bonded to the CB carbonyl-lined portal in
the [3]rotaxane.20
The room-temperature ESR spectrum of rotaxane 3a in water
(aN = 16.75 G, g = 2.0057, see Fig. 4b) consists of three lines as
expected for a nitroxide biradical in the extended conformation
in which the TEMPO fragments behave as two single nitroxide
radicals. This spectrum is clearly different form that obtained
under the same experimental condition with the free thread 2a
(aN = 16.80 G, g = 2.0057), which is characterized by broaden
exchange peaks, due to the exchange interaction between the
Scheme 3 Structures of the alkyne 4 and of the azide 5 used in the
synthesis of the [3]rotaxane 3a.
The formation of the interlocked molecule is evidenced when
comparing 1H NMR spectral data of the thread recorded in D2O,
with those of rotaxane.19
In the proton spectrum of the [3]rotaxane 3b (see Fig. 3, line
b) the presence of the macrocycle wrapping the diradical thread
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All reagents were commercially available and were used without
further purification. Compound 4 was synthesized according to
literature procedure.21
Synthesis of N,N¢-(1,4-phenylenebis(methylene))bis(2-
azidoethanamine) 5
A solution of 1,4-bis(bromomethyl)benzene (0.38 g, 1.45 mmol)
in CH2Cl2 (10 ml) was added dropwise to freshly prepared
azidoethylamine22 (1.25 g, 14.5 mmol) at room temperature. The
resulting solution was stirred at room temperature for 24 h. A
white precipitate was obtained which was filtered and dissolved in
HCl 2N. The solvent was removed under reduced pressure and the
solid residue was recrystallised from ethanol/diethyl ether 2 : 1,
obtaining the product (0.238 g, 60%) as white crystals.
Fig. 4 ESR spectra of free thread 2a (a) and rotaxane 3a (b) in water at
340 K.
paramagnetic fragments (see Fig. 4a). The high field ESR line of 3a
is characterized by a lower height respect to that obtained with 2a,
this being due to the slower motion in solution of the rotaxane
biradical, resulting in incomplete averaging of the anisotropic
components of the hyperfine and g-tensors.
M. p.: > 300◦ C (decomp).
Elemental analysis for C12H20N8 Calc.: C, 52.16; H, 7.29; N,
1
40.55; Found: C, 52.21; H, 7.39; N, 40.40. H NMR (600 MHz,
D2O): d 3.26 (t, 4H, J = 6.0 Hz, CH2), 3.75 (t, 4H, J = 6.0 Hz,
CH2), 4.30 (s, 4H, CH2), 7.55 (s, 4H, Ph). 13C NMR (100 MHz,
D2O, DSS): d 48.48, 49.43, 53.15, 133.32, 134.58. Positive ESI-MS:
m/z 274.9 (M - H)+.
Conclusions
Synthesis of diradical 2a
In conclusion, we reported the first example of a paramagnetic
rotaxane containing CB6 as wheel. We also showed that it is
possible to reversibly trigger spin exchange by simply changing the
pH of the solution in the presence of nitroxide biradical 1a and
the larger CB7 derivative. In our view, the presence of persistent
radical centers in pseudorotaxanes and rotaxanes is potentially
an attractive functionality that can be exploited to modulate the
behavior of molecular devices.
CuSO4 (0.01 g, 0.04 mmol) and ascorbic acid (0.014 g, 0.08 mmol)
were added to a solution of azide 5 (0.027 g, 0.1 mmol) and alkyne 4
(0.045 g, 0.21 mmol) in water (4 ml). The resulting suspension was
stirred at room temperature overnight. The product was purified
by gel filtration over a Sephadex G-15 column to yield a light
orange solid (0.075 g, 50%). Positive ESI-MS: m/z 715.3 (M +
Na)+.
Elemental analysis for C36H60N12O2 Calc.: C, 62.31; H, 8.86; N,
24.22; Found: C, 62.50; H, 8.65; N, 23.94. UV-Vis (H2O): l 376
nm. EPR: (aN = 16.85 G, g = 2.0057). 1H NMR (600 MHz, D2O):
d 3.30–3.80 (m, 4H, b), 3.80–4.50 (m, 4-H, c, d), 7.44 (bs, 4H, Ph),
8.00–8.60 (m, 2H, t).
Experimentals
General
ESR spectra has been recorded by using the following instrument
settings: microwave power 0.79 mW, modulation amplitude 0.04
mT, modulation frequency 100 kHz, scan time 180 s, 2 K data
points.
The proton spectrum of 2b was obtained by Na2S2O4 reduction
of the NMR sample containing 2a to afford the corresponding
bis-N-hydroxy amine.
1H NMR (600 MHz, D2O): d 1.47 (s, 12H, CH3), 1.50 (s, 12H,
CH3), 2.07 (t, 4H, J = 13.2 Hz, Ha), 2.56 (d, 4H, J = 13.2 Hz, He),
3.71 (bs, 4H, b), 3.89 (m, 2H, 4-H), 4.35 (s, 4H, d), 4.50 (bs, 4H,
c), 4.87 (s, 4H, a), 7.57 (s, 4H, Ph), 8.27 (s, 2H, t).
1H and 2D NMR spectra were recorded at 298 K on a Varian
Inova spectrometer operating at 600 MHz in D2O solutions using
the solvent peak as an internal standard (4.76 ppm). 13C NMR
spectra were recorded on a Varian Mercury operating at 100 MHz
in D2O solutions using DSS (3-(trimethylsilyl)-1-propanesulfonic
acid, sodium salt) as an external standard. Chemical shifts are
reported in parts per million (d scale). ROESY data were collected
using a 90◦ pulse width of 6.7 ms and a spectral width of 6000 Hz in
each dimension, respectively. The data were recorded in the phase
sensitive mode using a CW spin-lock field of 2 KHz, without
spinning the sample. Acquisitions were recorded at mixing times
300 ms. Other instrumental settings were: 64 increments of 2 K
data points, 8 scans per t, 1, 1.5 s delay time for each scan.
ESI-MS spectra were recorded with Micromass ZMD spec-
trometer by using the following instrumental settings: positive
ions; desolvation gas (N2) 230 L h-1; cone gas (skimmer): 50 L h-1;
desolvation temp. 120◦ C; capillary voltage: 3.2 kV; cone voltage:
40 and 100 V; hexapole extractor: 3 V.
Synthesis of [3]Rotaxane 3b
CB6 (0.183 g, 0.18 mmol) was dissolved in HCl 6 M (3 ml) and
the resulting solution was stirred for 30 min. Alkyne 4 (0.038 g,
0.18 mmol) and subsequently azide 5 (0.025 g, 0.09 mmol) were
added under vigorous stirr◦ing at room temperature. The resulting
solution was stirred at 60 C for 24 h. The solvent was removed
under reduced pressure to obtain a light yellow solid (0.181 g,
75%). M. p.: > 300◦ C (decomp). Uv-Vis (H2O): l 312 nm.
1H NMR (600 MHz, D2O): d 1.62 (s, 12H, CH3), 1.65 (s, 12H,
CH3), 2.37 (t, 4H, J = 13.2 Hz, Ha), 2.95 (d, 4H, J = 13.2 Hz,
He), 3.85 (t, 4H, J = 6.7 Hz, b), 4.15 (m, 2H, 4-H), 4.26 (t, 4H,
J = 6.7 Hz, c), 4.30 (s, 4H, d overlapped with CB6), 4.29 (d, 12H,
J = 15.6 Hz, CB6), 4.30 (d, 12H, J = 15.6 Hz, CB6), 4.66 (s, 4H,
a), 5.54 (s, 24H, CB6), 5.73 (d, 12H, J = 15.6 Hz, CB6), 5.76
UV-Vis spectra were taken on a Jasco V-550 spectrometer.
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+
(d, 12H, J = 15.6 Hz, CB6), 6.57 (s, 1H, t), 7.61 (bs, 4H, NH2 ),
10 D. Bardelang, K. Banaszak, H. Karoui, A. Rockenbauer, M. Waite, K.
Udachin, J. A. Ripmeester, C. I. Ratcliffe, O. Ouari and P. Tordo, J.
Am. Chem. Soc., 2009, 131, 5402.
7.85 (s, 4H, Ph). 13C NMR (100 MHz, D2O, DSS): d 21.94, 29.94,
41.50, 42.96, 48.12, 48.45, 52.16, 53.67, 53.96, 54.17, 70.62, 72.97,
122.88, 133.06, 135.62, 141.21, 158.97, 159.43. Positive ESI-MS:
m/z 672.6 (M)4+, 897.2 (M)3+.
The rotaxane diradical 3a was recovered by treating 3b in water
solution with an excess of Ag2O.
11 I. Kirilyuk, D. Polovyanenko, S. Semenov, I. Grigor’ev, O. Gerasko,
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15 We choose to follow DB and not aN because the spectrum is the
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19 1H NMR spectrum of the thread 2b was recorded at pH 4.
20 The spectrum of the same sample recorded after 2 h shows
+
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2924 | Org. Biomol. Chem., 2011, 9, 2920–2924
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