Nitroxide radicals as probes for exploring the binding properties of the cucurbit[7]uril host

Article abstract of DOI:10.1002/chem.200601830

EPR spectroscopy was used for the first time to explore the binding properties of cucurbit[7]uril (CB7), a representative member of the cucurbituril family. Evidence for the formation of a complex between nitroxide radicals and the host system in an aqueo

Full text of DOI:10.1002/chem.200601830

FULL PAPER
DOI: 10.1002/chem.200601830
Nitroxide Radicals as Probes for Exploring the Binding Properties of the
Cucurbit[7]uril Host
Elisabetta Mezzina,* Francesca Cruciani, Gian Franco Pedulli, and Marco Lucarini*[a]
Abstract: EPR spectroscopy was used
for the first time to explore the binding
properties of cucurbit[7]uril (CB7), a
representative member of the cucurbi-
turil family. Evidence for the formation
of a complex between nitroxide radi-
cals and the host system in an aqueous
solution was provided by large changes
in the nitrogen hyperfine splitting, at-
tributed to the different polar environ-
ments experienced by the included rad-
ical. In the presence of alkali cations,
the EPR spectra of benzyl tert-butyl ni-
troxide were characterised by new sig-
nals attributed to the radical hosted in
the CB7 cavity in which one metal
cation is in close contact withthe nitro-
xidic oxygen. The formation of the co-
ordination complex results in a sub-
stantial increase in the electron spin
density on the nitrogen in inverse
order with respect to the size of the
cation owing to increased localisation
of negative charge on the oxygen atom
from bonding to the alkali cation. The
EPR spectra showed selective line-
broadening effects as a result of metal
exchange between bulk water and the
coordination complex. Analysis of the
EPR linewidthvariations allowed us to
measure the corresponding kinetic rate
constants for the first time. NMR spec-
troscopy showed that this behaviour is
not peculiar to nitroxides but is also ex-
hibited by the related carbonyl com-
pounds. These data allowed us to quan-
tify the template effect and to reach
the conclusion that, in the presence of
a guest having a coordinating lone pair,
the formation of ternary metal-guest-
CB complexes must be taken into ac-
count when discussing the complexa-
tion behaviour of cucurbituril deriva-
tives in the presence of salts.
Keywords: cucurbiturils
·
EPR
spectroscopy · host–guest chemistry ·
molecular dynamics · nitroxide
Introduction
CB6 homologues CB5, CB7, CB8 and CB10. Very recently,
the isolation and characterisation of inverted CB6 and CB7,
containing a single glycoluril unit directed into the CB
cavity, has also been reported.[4]
Cucurbit[n]urils (CBn, n=5–8, 10) are a new family of
cyclic pumpkin-shaped molecules consisting of n glycoluril
units and characterised by the presence of a hydrophobic
cavity that is accessible through two identical carbonyl-
fringed portals.[1] The isolation and characterisation of the
first member of this family, cucurbit[6]uril, was reported in
1981 by Mock.[2] In the meantime, the groups of Kim,[3a]
Day[3b] and Isaacs[3c] have expanded the family of cucurbitur-
il hosts by reporting the preparation and purification of the
The host–guest chemistry of CBn has been studied exten-
sively.[5–7] Similar to cyclodextrins (CDs), the hydrophobic
interior of CBn provides a potential site for the inclusion of
various small molecules, including gas encapsulation,[8]
dyes[9] and pharmaceuticals.[6f] Unlike CD, the polar carbon-
yl groups at the portals also allow CBn to bind ions through
charge–dipole interactions.[10] Buschmann and co-workers
have published a number of papers on the inclusion com-
plexes of CB5 and its decamethylated derivative (as well as
CB6) and have reported association constants for the inclu-
[11]
sion of alkali, alkaline earthand transition metal ions.
[a] Dr. E. Mezzina, Dr. F. Cruciani, Prof. G. F. Pedulli, Prof. M. Lucarini
Department of Organic Chemistry “A. Mangini”
University of Bologna
The rigid structure and the capability of forming com-
plexes withmolecules and ions make CB attractive not only
as an encapsulating agent, but also as a building block for
supramolecular assemblies. Actually, the recognition proper-
ties of the CBn family are potentially useful in developing
pseudorotaxanes,[12] molecular machines,[13] self-sorting sys-
tems,[14] self-assembling vesicles[15] and dendrimers.[16]
Via San Giacomo 11, 40126 Bologna (Italy)
Fax : (+39)0512-095-688
E-mail: elisabetta.mezzina@unibo.it
marco.lucarini@unibo.it
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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One severe drawback of CBs as a synthetic receptors is
their poor solubility in both aqueous and organic solutions.
Two approaches can be envisaged to overcome this problem.
The first involves the preparation of CBn derivatives with
enhanced solubility in water and organic solvents. This prob-
lem is addressed by the synthesis of new derivatives with im-
proved solubility properties.[17] A simpler approachconsists
of adding alkali cation salts to an aqueous solution of CBs.
In this way, alkali cations being complexed by both ureido
rims provide a significant increase of CB solubility in aque-
ous solutions.[10] Under this condition, however, the amount
of host having at least one portal of CB uncomplexed,
which is essential for guest complexation, decreases result-
ing in a reduction of the value of the apparent equilibrium
constant for the complexation of charged organic guests.[5l,18]
In the last few years, we have shown that the formation of
a host–guest complex can be studied very conveniently with
EPR spectroscopy by the use of an appropriate radical
probe.[19] Benzyl tert-butyl nitroxide and related dialkyl ni-
troxides were found to be very suitable probes to investigate
host–guest interactions in cyclodextrins,[20] calixarenes,[21] mi-
celles[22] and protected nanoparticles.[23] Evidence for the for-
mation of paramagnetic complexes between these radicals
and the host systems was provided by large spectral changes
caused by the different environments experienced by the
radical guest, and to conformational changes occurring upon
complexation. In most cases, the EPR spectra also showed a
strong linewidthdependence on temperature, indicating that
the lifetime of nitroxides in the associated and free form is
comparable to the EPR timescale; this enabled us to mea-
sure the rate constants for the association and dissociation
processes.
Scheme 1.
Results and Discussion
EPR studies on benzyl tert-butyl nitroxide (1): The EPR
spectrum at 298 K of benzyl tert-butyl nitroxide (1), pro-
duced by the reaction of the magnesium salt of monoperox-
yphthalic acid (0.8 mm) withbenzyl
(0.8 mm) in water, is shown in Figure 1a. The spectrum is
tert-butyl amine
On this basis, we decided to employ EPR spectroscopy to
explore the binding properties of the cucurbit[7]uril host. In
particular, we set out to characterise the picture describing
the interplay between the association of metal ions and the
inclusion of an organic guest taking CB7 as the model host.
The selection of CB7 as the host is dictated by two relevant
factors: firstly, the employed nitroxide fits the CB7 cavity
tightly; secondly, the moderate solubility of CB7 in water
(30 mm)[1c] is sufficient to allow us to compare the complexa-
tion behaviour of CB7 both in the presence and in the ab-
sence of salts. It will be shown that the reported nitroxides
are particularly suitable probes for studying the complexa-
tion behaviour of CB7 by EPR spectroscopy because the
formation of complexes witha different geometry and/or
stoichiometry give rise to additional EPR lines easily distin-
guishable from those of the free radical. In particular, we
were able for the first time, to detect in aqueous solution
the formation of a coordination complex between alkali cat-
ions and a nitroxide–cucurbit[7]uril inclusion complex, thus
demonstrating a template effect for metal cations. We used
NMR spectroscopy to show that this template effect is not
peculiar to nitroxides but is also exhibited by other mole-
cules having an oxygen lone pair (Scheme 1).
Figure 1. EPR spectra of 1 at 298 K recorded in water a) in the absence
and b) in the presence of CB7 (7.0 mm).
straightforwardly interpreted on the basis of the coupling of
the unpaired electron with the nitrogen nucleus and with
the two equivalent benzylic protons. The spectroscopic pa-
rameters are reported in Table 1. In the presence of CB7
(7 mm), the observed EPR spectrum shows additional sig-
nals (Figure 1b) that were assigned to the same radical in-
cluded in the host cavity (CB7@1). Experimental evidence
that these new signals are attributable to the radical hosted
in the cucurbituril cavity in equilibrium with the free nitro-
xide is obtained by changing the amount of CB7 present in
solution. In particular: i) the ratio between the signals of the
complexed and free radical increases withincreasing con-
centration of the dissolved CB7 in solution; ii) strong dilu-
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Cucurbituril Host
FULL PAPER
Table 1. EPR parameters of nitroxides at 298 K in water (1 G=0.1 mT).
The EPR results demonstrate the formation of a stable in-
clusion complex between nitroxide 1 and CB7. However, at-
tempts to obtain the true equilibrium constant (K1,
Scheme 2) were unsuccessful. Actually, the ratio between
free and included radical strongly depends on the initial
concentrations of the amine and the Mg salt of the peracid
employed to generate the nitroxide radical, indicating that
the radical precursors strongly compete with the radical for
the internal cavity of CB7.[27]
Nitroxide
a(N)[G]
a
A
g factor
1
16.80
15.60
17.12
17.08
16.64
16.52
17.30
16.20
10.70
9.57
14.82
15.28
14.65
13.90
–
2.0056
2.0061
2.0058
2.0059
2.0060
2.0061
2.0056
2.0064
CB7@1
CB7@1
CB7@1
ACHTREUNG
ACHTREUNG
CB7@1(K+)
CB7@1
4
CB7@4
(Cs+)
–
tion of the most concentrated solution in CB7 (13 mm) leads
only to the signals produced by the unbound species.
The spectra of radical 1 recorded in the presence of CB7
do not show any evidence of selective line-broadening up to
508C, this being an indication that the exchange between
the nitroxide included in CB7 and the corresponding un-
bound species is slow on the EPR time-scale (residence time
of 1 in the CB cavity >10 ms). We have previously reported
that, in the presence of b-cyclodextrin (b-CD), the EPR
spectra of benzyl tert-butyl nitroxide are characterised by se-
lective line-broadening as a result of exchange between the
nitroxide included in b-CD and the corresponding unbound
species, occurring withrates comparable to the EPR time-
scale.[20b] Although the equatorial width of CB7 is larger
than that of b-CD (the mean diameters of the internal
cavity are 7.3 and 6.5 Š, respectively[1c,24]), the portals guard-
ing the entry to CB are much narrower than the cavity
itself. This results in constrictive binding that produces sig-
nificant steric barriers to guest association and dissocia-
tion.[5l]
Scheme 2.
EPR studies of 2,2,6,6-tetramethyl piperidine-N-oxyl
(TEMPO, 4): When CB7 is added to a solution of TEMPO
in water, the high-field line in the EPR spectrum splits into
two well-separated components that we assign to the free
and complexed radical exchanging slowly on the EPR time-
scale (Figure 2). The complexed guest showed distinctly
Table 1 reports the EPR spectroscopic parameters of the
nitroxide radicals 1 and 4. The values of the nitrogen split-
ting, a(N), and of b-proton splitting, a(2Hb), decrease signifi-
G
cantly upon inclusion into the less polar environment of the
CB7 host cavity, giving rise to the remarkable differences in
the resonance frequencies for the MI
A
included and free species. Nitroxide 1 can be included in the
CB7 cavity in two different ways, either from the tert-butyl
side or from the phenyl side. Nevertheless, only one spe-
cies,[25] identified as the 1:1 inclusion complex, is detected.
Information on the preferred geometry of the complex is
obtained from the values of the spectroscopic parameters. It
is well established that the nitrogen hyperfine splitting con-
stant, a(N), of nitroxides is sensitive to the polarity of the
environment where they are dissolved.[26] The significant re-
duction in a(N), with respect to the values in water, that ac-
companies complexation of 1 by CB7 indicates that the NO
group is quite deeply included in the internal apolar envi-
ronment of the host cavity. This complex geometry is ex-
pected to be found if inclusion takes place from the tert-
butyl side, while inclusion from the phenyl side is expected
to leave the NO group exposed to bulk water because of the
larger distance between the radical centre and the aromatic
ring. We could, therefore, hypothesize that in the paramag-
Figure 2. EPR spectrum of 4 (0.1 mm) recorded in the presence of CB7
(0.20 mm) at 298 K.
smaller nitrogen hyperfine splitting and larger g-factor
values than the corresponding free species (Table 1). Al-
though this effect is expected because of the less polar envi-
ronment experienced by the NO group within the CB7
cavity,[26] the spectral resolution of the signals due to the
free and included radical is much higher than that generally
observed in water with other macrocyclic host, such as cy-
clodextrins or calixarenes.[19]
This observation can be justified by assuming that the NO
group of the nitroxide is deeply immersed in the CB7 cavity,
thus experiencing the hydrophobic environment of the inner
part of the cavity. In fact, calculated molecular models for
the CB7@4 complex (AMBER Force Field as provided in
the Macromodel 7.0 package) show that the guest is inserted
in a symmetrical fashion with the NO group lying on the
netic complex nitroxide 1 is located withthe
N-tert-butyl
group well inside the CB7 cavity.
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M. Lucarini, E. Mezzina et al.
Table 2. Stability and kinetic parameters for guest complexation by CB7
at 298 K determined by EPR and NMR.
plane passing through the equatorial carbon–carbon bonds
of the host and with the geminal methyl groups pointing
toward the carbonyl portals (Figure 3).
Guest k+
(X)
1 [mꢁ1 sꢁ1
]
kꢁ
N
]
K1
G
]
K2
N
]
KM1
G
]
KM2 ]
[mꢁ1
E
2
3
slow[a]
slow[a]
1000
27340
4600
25000
4.6”106
470[b]
4
6150[c]
K+
600[c]
53[c]
[a] Relative to the NMR time-scale. [b] From numerical fitting of the ex-
perimental dependence of the CIS on the K+ concentration. [c] From the
decrease in the [CB7@4]/[4] ratio observed by EPR in the presence of
K+ cations.
1.0 mm) to a solution containing 2 (0.8 mm) led to progres-
sive replacement of all guest resonances (Figure 4) by new
signals attributed to the ketone included in the CB cavity.
As proof for the formation of an inclusion complex, the
doublets corresponding to the hostꢁs methylene protons of
the portals in the 1H NMR spectrum of CB7@2 split into
two sets centred at d=5.78, 5.77, 4.16 and 4.18 ppm, reflect-
ing the differences between the two portals created by the
interaction of the unsymmetrical guest with the inner cavity
of the host.[29] The formation of an inclusion complex is also
suggested by the enhanced solubility of benzyl tert-butyl
ketone in aqueous media containing CB7.
The magnitude of the chemical-induced shifts (CIS) of the
guest proton strongly depends on the nature of the group
they belong to. While complexation results in a considerable
upfield shift of the aliphatic protons of 2 (ꢂꢁ0.8 ppm), the
aromatic protons do not significantly change their resonance
frequency apart from a +0.30 CIS experienced by Hortho. Be-
cause it has been generally observed that inclusion inside
the cucurbituril internal cavity leads to upfield shifts of the
included guest protons,[30] the experimental CIS strongly
suggest that the complex CB7@2 is adopting a geometry in
which the tert-butyl residue is deeply immersed in the host
cavity while the guestꢁs phenyl ring is further away and in-
teracts with the carbonyl oxygens on the host portal. This
conclusion is in agreement withthe EPR results reported
for the corresponding nitroxide 1.
Figure 3. Molecular mechanics-minimised structure of the CB7@4 com-
plex. Hydrogen atoms have been omitted for clarity.
Further evidence for the correct assignment of the geome-
try of the CB7@4 complex is obtained by measuring NOE
interactions in the complex formed by CB7 and di-tert-butyl
ketone 5, an alicyclic sterically hindered diamagnetic ana-
logue of TEMPO. ROESY spectra of aqueous solutions of 5
containing a large excess of CB7 show significant NOE in-
teractions (Supporting Information) of the methyl protons
of the tert-butyl groups of the guest molecule with the meth-
ylene hydrogen of the macrocyclic host pointing toward the
carbonyl portals and resonating at d=5.77 ppm. This dem-
onstrates that the guest is lodged in the host cavity with the
methyl groups very close to the carbonyl rims.
Simulation of the EPR spectra recorded at different con-
centrations of the macrocyclic host provides a value of
25000ꢀ2000mꢁ1 for the binding constant K1 for TEMPO
complexation (Table 2). This is one order of magnitude
larger than that measured for the same guest with b-cyclo-
dextrin (2950mꢁ1).[28] The huge enhancement of the affinity
constant should be attributed to the larger equatorial width
of CB7 that allows total inclusion of the paramagnetic guest
inside the internal cavity as previously discussed. On the
other hand, the narrower internal cavity of b-CD cannot
When an excess amount of the guest is present, the signals
of the free and bound guests are simultaneously observed,
revealing that the rate of exchange between these species is
slow on the NMR time-scale. Integration of the separate sig-
nals for the free and complexed guest protons as a function
of the CB7 concentration provides the corresponding associ-
ꢁ
easily accommodate the radical guest with the N O bond
perpendicular to the long axis of the macrocylic ring, thus
leaving the N-O group in the complexed radical exposed to
bulk water.
NMR studies on 2 and 3: On
account of the similar geome-
ꢁ
tries adopted around the N O
and C=O bonds, we also decid-
ed to investigate the behaviour
of tert-butyl benzyl ketone (2),
the diamagnetic analogue of 1,
upon complexation withCB7
by recording the corresponding
1H NMR spectra. The addition
of small portions of CB7 (0–
Figure 4. 600 MHz 1H NMR spectrum of benzyl tert-butyl ketone (2, 0.8 mm) in the presence of CB7
&
*
^
(0.48 mm). Assignment:
free guest,
complexed guest,
complexed host. All spectra were recorded at
298 K in D2O solutions withresidual HOD as an internal standard (4.76 ppm).
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Cucurbituril Host
FULL PAPER
ation equilibrium constant (K1) as 27340ꢀ1490mꢁ1. This
value supports the conclusion that benzyl tert-butyl ketone
forms a stable inclusion complex withCB7.
The behaviour of ethyl benzyl ketone (3) in the presence
1
of CB7 was also investigated by H NMR. In this case, in
contrast to what was previously observed with 2, all the
guest signals shift toward a lower frequency upon complexa-
tion by CB7. However, the most pronounced upfield CIS
(see the Supporting Information) are exhibited by the aro-
matic and methylene protons of the guest, suggesting that
ketone 3 is included inside the inner cavity of the host with
the aromatic ring.
As a remarkable manifestation of this difference, complex
1
CB7@3 is characterised by a typical dynamic H NMR spec-
Figure 5. Clustered molecular display. Dynamics of the inclusion complex
CB7@2. Drawings include 20 structures that refer to the 2000 ps simula-
tion. Hydrogen atoms have been omitted for clarity.
trum, indicating that the kinetics of exchange between the
free and complexed guest is comparable on the NMR time-
scale (see the Supporting In-
formation). A complete NMR
line-shape analysis[31] of the
CB7-dependent coalescence of
the resonance of free and com-
plexed 3 as the guest exchange
between these two environ-
ments yield the rate constants
for the complexation process
in water at 298 K as 4.6”
106 mꢁ1 sꢁ1 for the ingression
rate (kþ1 ) and 1000 sꢁ1 for the
egression rate (kꢁ1 ) (K1 =
Table 3. Calculated averaged components of energies [kJmolꢁ1] and distances [Š] at 298 K for the inclusion
complexes CB7@2.
[b]
Total E
Estretch
Ebend
Etor
EVDW
Eelectro
Esolv
hdi
2
CB7
CB7 + 2
CB7@2tBut
CB7@2Ph
110
543
653
599
597
18
47
29
22
5
ꢁ11
–
–
–
133
151
151
151
684
732
742
741
187
216
216
215
ꢁ100
ꢁ78
ꢁ170
ꢁ170
79
84
72
74
ꢁ440
ꢁ451
ꢁ412
ꢁ414
[a]
1.396
3.755
[a]
[a] Labels refer to the two different orientations of the complex (see text). [b] Distances between the carbonyl
carbon of the guest and the plane passing through the equatorial hydrogens of CB7.
4600mꢁ1). The faster rate of exchange of 3 withrespect to 2
can be rationalised in terms of a weaker steric hindrance of
the less bulky phenyl group with the portals during ex-
change.
Effect of alkali cations on the complexation of TEMPO (4):
It is well known that alkali metal cations bind to the carbon-
yl portals of the CBn family. As such, one might expect that
the presence of alkali cations would simply reduce the con-
centration of free CB7 by the formation of CB7@M+ giving
rise to a reduction of the apparent value of K1 for the host–
guest complex.[5l,18] This is indeed what we observed with
TEMPO. Figure 6 reports the plots of the apparent binding
constant KEPR for the CB7@4 complex as a function of K+
ion concentration.
Molecular dynamic simulations: In order to obtain a more
detailed picture of the geometry of CB7@1 and the corre-
sponding diamagnetic CB7@2 complex,[32] stochastic dynam-
ics (SD) simulations were performed withteh AMBER*
force field of the Macromodel 7.0 program. The computa-
tional approach taken in this study is to dock the guest mol-
ecule inside the host cavity, minimise the energy of the com-
plex and then carry out standard equilibrations and produc-
tion runs to derive averaged energies and distances.[33]
Molecular dynamics (Table 3) results indicate that com-
plexation from the phenyl and tert-butyl side are equally en-
ergetically favourable processes. In bothcases, teh main
contribution to complexation arise from van der Waals at-
tractions that are only partially compensated by the non-
bonded repulsion in the stretching and bending energy
values. Nevertheless, only the complex in which the tert-
butyl group is inserted inside the cavity (Figure 5) shows a
calculated distance between the carbonyl carbon of the
guest and the plane passing through the equatorial hydro-
gens of CB7, compatible withteh experimental value of
a(N) found by EPR analysis of CB7@1.
Figure 6. Dependence of the apparent binding constant KEPR for the
CB7@4 complex on the potassium concentration. Numerical fitting of the
experimental data was obtained withEquation (1).
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M. Lucarini, E. Mezzina et al.
On the basis of the five equilibria (K1, K2, KM1, KM2, KM3
)
reported in Scheme 2 and following the procedure reported
by Nau and co-workers for the complexation of protonated
cyclohexylmethylamine by CB6,[5l] the concentration ratio
between the free and complexed radical in the presence of
potassium cations is given by Equation (1):
½CB7@XŠ
½XŠ
K1 þ KM1K2½MþŠ
ð1Þ
¼ ½CB7Š
1 þ KM1½MþŠ þ KM1KM2½MþŠ
where Xꢃ4 and [CB7]=[CB7]0ꢁ
C
Figure 7. EPR spectra of 1 at 298 K recorded in water in the presence of
^
CB7 (13.0 mm) and a) 1 mm NaCl and c) 400 mm NaCl. + and refer to
To the best of our knowledge, KM1 and KM2 represent the
first determinations of stability constant for the complex for-
mation between CB7 and K+ ions. While the value of the
equilibrium constant for the mono-complexation of K+
(KM1) is rather similar to that reported by Buschmann and
co-workers[11] for CB6 (560mꢁ1), that for the coordination of
two potassium ions by the opposite portals of CB7 (65mꢁ1)
is considerable larger respect to the upper limit of 20mꢁ1 es-
timated for CB6.[11] This binding enhancement can be pre-
sumably attributed to the possibility for the two cations to
be located at a larger distance because of the higher dimen-
sion of CB7, thus reducing the electrostatic repulsion be-
tween the two positive charges.
the signals of the two complexed guests CB7@1 and CB7@1
(Na+), re-
A
*
spectively,
free guest in water. Spectrum b represents the theoretical
simulation of spectrum a obtained withthe spectroscopic parameters re-
ported in Table 1 and k+c1 =2.5”1010 mꢁ1 sꢁ1 and kꢁc1 =3.0”107 sꢁ1 for the
metal-exchange process.
ꢂ6% for Cs+ to ꢂ10% for Li+)[36] at the nitrogen
centre. At the same time, the g factor shows an opposite
trend, decreasing when passing from the binary complex
CB@1 to the ternary complex in the presence of Li+.
Since the hyperfine splittings and g factors of EPR spec-
tra are known to be sensitive to environmental perturba-
tions, the reported behaviour is expected for nitroxide
molecules forming a coordination complex witha metal
cation in close contact withthe nitroxidic oxygen. The
metal cation acting as a Lewis acid site caused a shift of
charge towards the oxygen atom and consequently a
The value obtained for K2 (6150mꢁ1) is somewhat smaller
than that expected exclusively on the basis of the reduction
from two to one of the binding sites available for association
(K1/2=12500mꢁ1). The fact that the simultaneous complexa-
tion of 4 and one potassium ion by CB7 is less favoured
than predictable on a purely statistical basis, indicates the
presence of steric repulsion between the included radical
and the potassium ion associated with the carbonyl portal.
shift of spin density towards the nitrogen atom in inverse
[37]
order withcation size.
Similar variations of the EPR
parameters have been reported for di-tert-butyl nitroxide
included in Y zeolites after ion exchange with a series of
alkali-metal ions.[38]
Effect of alkali cations on complexation of nitroxide 1: Un-
expected results were observed for the EPR spectroscopic
study of the complexation of 1 withCB7 in the presence of
alkali cations. When an alkali chloride, MCl (M=Li, Na, K
or Cs) is added to a solution containing 10 mm CB7 the
EPR signals of CB7@1 complex decrease and eventually dis-
appear, while the signals of the free species together with
those of a new species become visible (Figure 7). This un-
predicted species is identified as the radical hosted in the
CB7 cavity in which one metal cation is in close contact
withthe nitroxidic oxygen, CB7@ 1(M+), on the basis of the
following experimental evidence.
2) The molar ratio between the coordinated and free radi-
cal, obtained from the EPR spectra, strongly depends on
the nature of the metal cation and increases on increas-
ing the concentration of the dissolved MCl salt. At high
concentrations of alkali salt, the spectrum of CB7@
1(M+) becomes dominant (Figure 7c and Supporting In-
formation).
3) The spectra of 1 recorded in the presence of different
alkali cations (0.2m) and in the absence of CB7 are iden-
tical to those obtained in pure water.
4) When the EPR spectrum recorded at 298 K contains
bothsignals of CB7@ 1(M+) and CB7@1 (Figure 7a), the
wing lines of each b-proton triplet are significantly
broader than the central lines. This is attributed to the
exchange of the metal cation between the aqueous phase
and CB7@1(M+), which occurs with a rate comparable
to the EPR time-scale. Under the above conditions, the
species detected by EPR are in equilibrium as reported
in Scheme 3.
1) The nitrogen hyperfine splitting, a(N), increases inverse-
+
ly withcation size, being 16.52 G in the presence of Cs
and rising monotonically to 17.12 G in the presence of
Li+ (relative to 15.60 G for the complex in the absence
of an alkali-metal cation). This trend is a clear indication
that the presence of the metal induces a rather remark-
able gain in the odd-electron (spin) population (from
7228
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Chem. Eur. J. 2007, 13, 7223 – 7233

Cucurbituril Host
FULL PAPER
Scheme 3.
Simulation of the recorded exchange-broadened EPR
spectra (Figure 7b) using well-established procedures based
on the density matrix theory[39] and assuming a three-jump
model as illustrated in Scheme 3, led to the determination of
the rate constants k+ and kꢁ for metal coordination by CB7
containing the radical probe (Table 4).[40]
Table 4. Stability and kinetic parameters for M+ exchange at 298 K.
Guest M+ 10ꢁ8k+
(X)
A
]
10ꢁ6kꢁ
A
]
Kc1
A
]
Kc2
U
]
Kc1/
KM1
1
Li+ 2.3
Na+ 250
K+ 130
Cs+ 30
K+
6.0
30
11
45
38
833
1180
66
1300
85
1.97
[a]
2
3
4
2.17
0.14
0
K+
5.2
ꢂ0
K+
ꢂ0
[a] Undetermined (see text).
Analysis of the EPR spectra shows that the life-time of
the ternary complex is independent of the concentration of
solvated cations. Thus, the dominant exchange process
occurs through a monomolecular decomplexation mecha-
nism, as shown in Scheme 3. The variation in the selectivity
patterns exhibited by CB7@1 withrespect to the different
metal cations is determined by the changing balance be-
tween the solvating power of the solvent, namely, the solva-
tion energy of M+, and the binding energy of CB7@1. In
the present case, the most favoured energy balance is shown
by cations of intermediate size (Na+ and K+), which is simi-
lar to the results reported for the complexation of metal cat-
ions by free CB6.[11]
Figure 8. Plausible structure of the ternary CB7@1
(Na+) complex. a) side
view, b) top view.
A
The very fast rates of exchange between CB7@1 and
CB7@1(M+) rules out the possibility that the radical guest
undergoes a substantial modification in the spatial position
adopted inside the CB7 cavity during the coordination pro-
cess and suggests that the geometry of the ternary CB7@
1(M+) complex should be similar to that predicted for the
CB7@1 complex in the absence of the metal cation. Accord-
ingly, a plausible structure for CB7@1(M+) is that reported
in Figure 8, in which the tert-butyl group of the guest is in-
cluded in the host molecule and the metal ion is coordinated
by the nitroxidic oxygen and two neighbouring portal
oxygen atoms.
The increase in the molar ratio between the coordinated
and free radical, observed when the concentration of dis-
solved MCl is increased, lead to the conclusion that the
binding of the metal ions is favoured in the presence of the
encapsulated nitroxide. A measure of the effectiveness of
this templation is given by the ratio between the affinity of
and in the presence (KC1) of the radical guest. In the case of
K+, this value is equal to 1.97, confirming the existence of
an additional stabilisation through the coordination of the
metal cation by the nitroxidic oxygen of the encapsulated
paramagnetic guest.
Effect of potassium cations on the complexation of ketones
2 and 3: In order to check whether the template effect is pe-
culiar to the radical probe 1 or is also present in diamagnetic
molecules having an oxygen lone pair, we recorded NMR
spectra of 2 and 3 in the presence of CB7 and potassium cat-
ions. Addition of KCl to solutions containing exclusively the
CB7@2 complex, that is, in the presence of a large excess of
CB7 respect to the ketone, give rise to remarkable changes
in the corresponding 1H NMR spectra (Figure 9). For in-
stance, by keeping the CB concentration constant (8.4 mm)
and increasing the amount of KCl up to 0.2m, all signals
gradually underwent downfield shifts. No signals attributable
the metal cation for CB7 measured in the absence (KM1
)
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M. Lucarini, E. Mezzina et al.
Figure 9. Phenyl region of 1H NMR spectra of benzyl tert-butyl ketone
(2; 0.8 mm). a) In water, b) CB7 (8.4 mm), c) CB7 (8.4 mm), KCl (0.24m).
to the free guest species are observed under the above con-
ditions. Similarly to the results obtained by EPR of the re-
lated radical 1, the new signals were attributed to a new in-
clusion complex in which one metal cation is in close con-
tact with the guest carbonylic oxygen thus providing an ad-
ditional stabilisation through ion–dipole interactions. As ex-
pected, only the concentration-weighted averaged sig-
nals are observed for the two complexes CB7@2 and
CB7@2(K+), this being an indication that the coordinated
K+ cations are exchanging too rapidly with those in solution
on the NMR time-scale.
Figure 10. Plot of the complexation-induced chemical shift (CIS) of the
hydrogens for a) 2 and b) 3 versus the concentration of K+ in the pres-
ence of CB7 at concentrations of 8.4 and 12.0 mm, respectively. The lines
represent the theoretical dependence of the CIS on the potassium ion
concentration calculated by numerically fitting the experimental data to
The expression for the concentration ratio of the two dif-
ferent complexes in the presence of a metal cation is given
by Equation (2).
K1KC1 þ KM1K2KC2½MþŠ
Equations (1) and (2) with
d
N
d(CB7@
N
½CB7@XðMފ
½CB7@XŠ
¼ ½CB7Š½MþŠ
ð2Þ
2)ortho-H=7.39 ppm,
d
A
d
ACHTREUNG
1 þ KM1½MþŠ þ KM1KM2½MþŠ
0.29 ppm.
ꢃ
where X 2 or 3, [CB7]=[CB7]0ꢁ
N
[CB7@X(M)]
are exchanging rapidly on the NMR time-scale to produce
concentration-weighted averaged signals for the three differ-
Non-linear least-squares fitting of the experimental de-
pendence of the CIS on the K+ concentration (Figure 10a)
by employing the known values for K1, KM1 and KM2 in
Equation (2) is possible; however, the resulting errors in the
values of Kc1, Kc2 and K2 are too large. However, variation
of the product Kc2K2 from the statistical upper limit (K1Kc1)/
2 to zero, give rise to the same value for the equilibrium
constant Kc1 (1300mꢁ1). This value, which represents a mea-
sure of the template effect, is very close to that found for
radical 1, thus confirming the similarity in the behaviour of
the two probes.
A more complicated behaviour is found with ketone 3.
The initial increase in the amount of KCl up to ꢂ0.01–
0.05m produced a high-field shift of the signals of the ali-
phatic protons, while those of the aromatic hydrogens re-
mained at the same resonating frequency. A subsequent ad-
dition of metal salt produces, instead, a down-field shift of
all signals. As an example, Figure 10b shows the complexa-
tion-induced chemical shift (CIS) of the ethyl hydrogens ob-
served when the concentration of K+ is increased to 0.22m
([CB7]=12.0 mm). This finding can be only be explained by
assuming the simultaneous presence of the guest in the free
and in the CB7@2 and CB7@2(K+) complexed forms that
ent species. Inserting the known values for K1, KM1 and KM2,
a non-linear least-squares fitting of the experimental de-
pendence of the CIS on the K+ concentration by means of
Equations (1) and (2) affords the values of Kc1, Kc2 and K2
(Table 2 and Table 4).
The ratio between the affinity of the metal cation for CB7
in the absence (KM1) and in the presence (KC1) of the organ-
ic guest found by the numerical analysis, 0.14, indicates that
the effectiveness of templation is lower withthe carbonylic
guest 3, than with 2. A possible explanation of this result is
that in the pre-organised CB@3 complex the carbonyl group
of the guest is not located in the optimum position to permit
the coordination of the metal cation. The consequent
change in the geometry of the complex, required to ensure
contact between the guest and the cation, leads to a reduc-
tion of the favourable complexation energy, which is only
partially compensated by the additional ion–dipole interac-
tion. As expected, the complexation of a second potassium
ion by the CB7@3 complex, Kc2, is even less favoured by
about one order of magnitude because of the electrostatic
repulsion between the two positive charges.
Finally, the value obtained for K2 (470) is about five times
smaller than that estimated exclusively on the basis of the
7230
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Chem. Eur. J. 2007, 13, 7223 – 7233

Cucurbituril Host
FULL PAPER
reduction of the number of binding sites available for associ-
ation (K1/2=2300mꢁ1), this being an indication that the po-
tassium ion associated with the carbonyl portal makes the
complexation of the guest more difficult because of partial
steric repulsion.
In conclusion, we have shown that EPR spectroscopy can
add to the palette of analytical methods that afford useful
information on cucurbituril-based supramolecular com-
plexes.
Experimental Section
Conclusion
Materials: Benzyl tert-butyl ketone[41] and cucurbit[7]uril[3a] were pre-
pared following literature procedures. All the other products are com-
mercially available and were used as received.
The use of EPR and NMR spectroscopies together with mo-
lecular dynamics provides a detailed description of supra-
molecular complexes formed by CB7 in solution. In particu-
lar, we were able for the first time to detect in aqueous solu-
tion the formation of a coordination complex between alkali
cations and a nitroxide–CB7 inclusion complex.[41] The char-
acteristic time-scale of EPR spectroscopy allowed us to de-
termine the exchange rates of the metal cation between the
aqueous phase and the nitroxide–CB7 inclusion complex.
We employed NMR to demonstrate that this behaviour is
not peculiar to nitroxides but is also exhibited by other mol-
ecules having an oxygen lone pair.
These results lead to the conclusion that, in the presence
of guests having a coordinating lone pair, the formation of
ternary metal-guest–CB complexes must be taken into ac-
count when discussing the complexation behaviour of cucur-
bituril derivatives in the presence of salts. In particular,
based on the efficacy of the template effect, we can consider
three different situations:
EPR spectroscopy: EPR spectra were recorded on a Bruker ESP300
spectrometer equipped withan NMR gaussmeter for field calibration
and a Hewlett Packard 5350B microwave frequency counter for the de-
termination of the g factors, which were referred to that of the perylene
radical cation in concentrated H2SO4 (g=2.00258). The sample tempera-
ture was controlled witha standard variable-temperature accessory and
was monitored before and after eachrun by means of a copper-constan-
tan thermocouple. The instrument settings were as follows: microwave
power 5.0 mW, modulation amplitude 0.05 mT, modulation frequency
100 kHz, scan time 180 s. Digitised EPR spectra were transferred to a
personal computer and were analysed by means of digital simulations
carried out witha program developed in our laboratory and based on a
Monte Carlo procedure.[20b] Nitroxide 1 is generated by mixing a solution
of the corresponding amine (ꢂ0.8 mm) witha solution of the magnesium
salt of monoperoxyphthalic acid (Aldrich, technical grade; ꢂ0.8 mm). In
order to achieve a sufficiently large steady-state radical concentration
(ꢂ0.05 mm), the mixed solution was heated at 408C for 1 min. Aliquots
from a concentrated CB7 solution were added to the solution of nitroxide
to yield the required concentrations. Samples were then transferred in ca-
pillary tubes (1 mm i.d.) and the EPR spectra was recorded immediately.
NMR spectroscopy: All spectra were recorded at 298 K on Varian Inova
spectrometers operating at 400 and 600 MHz, respectively. NMR experi-
ments were performed in D2O solutions withresidual HOD as an inter-
nal standard (d=4.76 ppm). Titrations of ketones withCB7 were carried
out on a Varian Inova 600 at 298 K. Equilibrium constants were calculat-
ed withan iterative procedure based on a least-squares minimisation by
means of the Gauss-Newton-Marquardt algorithm.
1) KC1 >KM1 (1 and 2): The coordination process does not
require for the guest molecule a significant modification
of the spatial position inside the CB7 cavity with respect
to that assumed in the complex in the absence of the
metal cation. The additional ion–dipole interaction leads
to an increase in the affinity of the metal cation for the
CB cavity. The complex ternary metal-guest–CB complex
is the most stable and abundant species in solution.
2) KC1 <KM1 (3): The coordinating group of the guest in the
pre-organised CB@3 complex is not located in the opti-
mum position to permit coordination of the metal cation.
The consequent change in the geometry of the complex,
required to ensure contact between the guest and the
cation, gives rise to a reduction in the favourable com-
plexation energy that is only partially compensated by
the additional ion–dipole interaction. Nevertheless, a
sizeable amount of the ternary complex is present in so-
lution.
3) KC1 =0 (4): In this case, metal coordination requires a
dramatic reorganization of the complex geometry with a
large loss of guest–host complexation energy. This is the
case for TEMPO, in which the presence of the methyl
groups prevents the tilting of the radical guest inside the
cavity, which is necessary to allow coordination of the
alkali metal ion by the nitroxidic oxygen. Similar behav-
iour is also expected to be shown by organic guests that
do not posses a good coordinating atom suchas proton-
ated amines,[5l] or methyl viologen.[18]
Dynamic simulations: SD simulations were carried out withthe Macro-
ꢁ
Model 7.0 program. The N O bond was modelled by the C=O bond
owing to their similar geometries and the lack of corresponding parame-
ters in the AMBER* force field.[43] Extended non-bonded cutoff distan-
ces were set to 8 and 20 Š for the van der Waals and electrostatic inter-
ꢁ
ꢁ
actions, respectively. All C H and O H bond lengths were held fixed by
means of the SHAKE algorithm. Translational and rotational momentum
were removed every 0.1 ps. The calculation began with a seven-fold sym-
metric CB7 with the guest molecule docked in its interior. The origin of
a Cartesian reference frame was placed at the centre of mass of the CB7
withthe z axis aligned with the C7 symmetry axis of CB7. The guest was
translated along the z axis in order to have the quaternary carbon (tert-
butyl complex) or the centre of mass of the phenyl ring located in the
plane passing through the equatorial hydrogens of CB7. At the end of
this procedure, minimisation of the ensemble led to the starting geometry
for SD simulations. The simulations were run at 298 K with time steps of
1 fs and an equilibrium time of 500 ps before eachdynamic run. The
total simulation time was set to 5000 ps in order to achieve full conver-
gence.
Acknowledgements
Financial support from MIUR (Rome; researchproject “Free Radical
Processes in Chemistry and Biology: Fundamental Aspects and Applica-
tions in Environment and Material Sciences”) and from the University of
Bologna are gratefully acknowledged. We like also to thank Mrs. Fiam-
metta Ferroni for technical assistance.
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M. Lucarini, E. Mezzina et al.
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Chem. Eur. J. 2007, 13, 7223 – 7233

Cucurbituril Host
FULL PAPER
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on the plane passing through the equatorial carbon–carbon bonds of
the host.
[30] CIS of ꢂꢁ1.0, ꢁ0.8 and ꢁ0.7 ppm have been found in the presence
of CB6 for 1,5-diaminopentane,[1a] THF,[5d] and cyclohexylmethylam-
monium ion,[5l] respectively.
[31] a) J. Sandstrçm in Dynamic NMR-Spectroscopy; Academic Press,
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[34] Because the concentration of the added host and salt is comparable
to that of the probe in most cases, the free concentrations of the
components were calculated by solving the mass balance equations
by means of the Newton–Raphson method.[35]
[35] a) H. J. Schneider, A. Yatsimirsky in Principles and Methods in
Supramolecular Chemistry, Wiley, Chicester, 2000, p. 137; b) W. H.
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[25] In the first series of experiments, the spectrum of 1 recorded in the
presence of commercially available CB7 (Aldrich), showed addition-
al signals in addition to those attributable to the free and included
species that were erroneously assigned to the nitroxide included in
CB7 from the benzyl side on the basis of the a(N) values. However,
repetition of the EPR experiments with new batches of commercial
CB7 resulted in the formation of only one included species that was
attributed to the nitroxide included from a single side (see text).
Analogous results were obtained withCB7 synthesised in our labo-
ratory. We suppose that traces of some impurities present in the first
batchof commercial CB7 employed were responsible for the forma-
tion of a different type of complex.
[26] For examples, see: a) R. Briere, H. Lemaire, A. Rassat, Bull. Soc.
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vent in determining the hyperfine coupling constants of free radi-
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[27] It is well known that amines are strongly bound by CB7 in acidic
conditions.[1]
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[39] A. Hudson, G. R. Luckhurst, Chem. Rev. 1969, 69, 191–225.
[40] Radical 1 shows an unexpected low persistence in the presence of
CB7 at temperatures higher than 408C. For this reason, an accurate
determination of the activation parameters for the coordination pro-
cess was not possible.
[41] Similar solution-phase ternary complexes having calixarenes as mac-
rocyclic hosts have been recently reported: H. Bakirci, A. L. Koner,
M. H. Dickman, U. Kortz, W. M. Nau, Angew. Chem. 2006, 118,
7560–7564; Angew. Chem. Int. Ed. 2006, 45, 7400–7404.
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[28] a) J. Martinie, J. Michon, A. Rassat, J. Am. Chem. Soc. 1975, 97,
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[29] On the contrary, the 1H NMR spectrum of CB7@4 does not shown
any differentiation of the hostꢁs methylene protons of the portals, re-
flecting the different nature of the complex in which the TEMPO
radical is inserted in a symmetrical fashion with the NO group lying
Received: December 19, 2006
Revised: April 3, 2007
Published online: June 14, 2007
Chem. Eur. J. 2007, 13, 7223 – 7233
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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