Predicting self-assembly and structure in diluted aqueous solutions of modified mono- and bis-β-cyclodextrins that contain naphthoxy chromophore groups

Article abstract of DOI:10.1039/c4nj01556h

The water diluted solution behaviour of mono- and bis-β-cyclodextrin (mono- and bis-CD) derivatives, whose appended groups and inter-CD linkers contain a naphthoxy chromophore moiety, has been studied using steady-state and time-resolved fluorescence techniques, circular dichroism and molecular modelling. Mono-CD derivatives form non-covalent dimeric tail-to-tail supramolecular structures via the mutual partial penetration, through their primary sides, of axially oriented naphthoxy appended groups and the self-inclusion of the naphthoxy moiety is rather improbable. Non-covalent dimer formation may compete with any guest complexation. Nevertheless, these assemblies can be broken up by decreasing medium polarity or when the appended group is captured by macrorings such as cucurbit[7]urils or native βCDs. Bis-CD derivatives, however, do not exhibit self-association processes which were observed in the mono-derivatives. This is because the presence of the bulky naphthoxy group in the spacer keeps the βCD cavities, which are capable of accommodating an external guest, away from each other. The dinaphthoxy group, in the bis-NβCD, was located in a quasi-parallel plane conformation between both CDs. This journal is

Full text of DOI:10.1039/c4nj01556h

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Predicting self-assembly and structure in diluted
aqueous solutions of modified mono- and
bis-b-cyclodextrins that contain naphthoxy
chromophore groups†
Cite this:DOI: 10.1039/c4nj01556h
a
b
b
b
b
Thais Carmona, Katia Martina, Laura Rinaldi, Luisa Boffa, Giancarlo Cravotto
a
and Francisco Mendicuti*
The water diluted solution behaviour of mono- and bis-b-cyclodextrin (mono- and bis-CD) derivatives,
whose appended groups and inter-CD linkers contain a naphthoxy chromophore moiety, has been studied
using steady-state and time-resolved fluorescence techniques, circular dichroism and molecular modelling.
Mono-CD derivatives form non-covalent dimeric tail-to-tail supramolecular structures via the mutual partial
penetration, through their primary sides, of axially oriented naphthoxy appended groups and the self-
inclusion of the naphthoxy moiety is rather improbable. Non-covalent dimer formation may compete with
any guest complexation. Nevertheless, these assemblies can be broken up by decreasing medium polarity
or when the appended group is captured by macrorings such as cucurbit[7]urils or native bCDs. Bis-CD
derivatives, however, do not exhibit self-association processes which were observed in the mono-
derivatives. This is because the presence of the bulky naphthoxy group in the spacer keeps the bCD cavities,
which are capable of accommodating an external guest, away from each other. The dinaphthoxy group, in
the bis-NbCD, was located in a quasi-parallel plane conformation between both CDs.
Received (in Montpellier, France)
11th September 2014,
Accepted 10th December 2014
DOI: 10.1039/c4nj01556h
www.rsc.org/njc
or even modifying their capabilities of aggregation into dimers,
according to their shape, size and flexibility of the link to the
Introduction
1
0,12–30
Cyclodextrins (CDs) are cyclic hollow oligosaccharides composed core of the molecule.
Mono-CDs have been extensively
of a-(1 - 4)-linked glucopyranoside units and are used as host investigated for a number of applications, for example, as light
1
3,31–33
molecules in supramolecular chemistry. They are able to include harvesting host molecules,
guest molecules of an appropriate size and thereby act as supramolecular architectures,
building blocks for functional
3
0,34,35
36
catalysts and in sensing
1
,2
37–39
molecular containers.
CDs present two well-differentiated applications.
Attaching another CD to the end of the appended moiety
hydrophilic primary and secondary faces, to which hydroxyl
groups are attached, and a hydrophobic inner cavity. The resulted in bis-CD derivatives. Cooperation between the CDs
complexation of any guest in water means that the polarity and spacer–guest interactions improves bis-CD recognition and
4
0–68
and microviscosity of the surrounding medium substantially sensing capabilities.
varies. These changes influence guest chromophore spectro- The copper-catalyzed azide–alkyne cycloaddition protocol
scopic properties, allowing the thermodynamics and the struc- (CuAAC) is a powerful method for the preparation of CD
3
–11
ture of the complex to be studied.
A chromophore can be derivatives. In a relatively recent work, Cravotto et al. applied
covalently attached to a bCD macroring in order to obtain this technique for the preparation of homo- and heterodimers,
fluorescent mono-CD derivative hosts. Appended groups are as well as CD oligomers whose linkers contained 1,2,3-triazole
6
9–71
capable of hindering or favouring the complexation of guests, groups.
Our group has reported the in solution behaviour
of some mono- and bis-bCD derivatives, which were also
prepared using CuAAC, whose appended groups or linkers
between bCDs contained the 1,3-diphenoxy chromophore
moiety. The use of circular dichroism in conjunction with
MD simulations allowed us to obtain information on the struc-
ture of both derivatives in water solution. The self-inclusion of
the appended moiety for mono- or bis-bCDs was discharged.
Nevertheless, the mono-bCD was capable of forming very stable
a
Departamento de Qu ´ı mica Anal ´ı tica, Qu ´ı mica F ´ı sica e Ingenier ´ı a Qu ´ı mica,
Universidad de Alcal a´ , 28871 Alcal a´ de Henares, Madrid, Spain.
E-mail: francisco.mendicuti@uah.es
2
9
b
Dipartimento di Scienza e Tecnologia del Farmaco of the University of Torino,
Via Pietro Giuria, 9-10125 Torino, Italy
†
Electronic supplementary information (ESI) available: Synthesis protocols,
characterization and additional figures: Fig. 1S–8S and Tables 1S–3S. See DOI:
0.1039/c4nj01556h
1
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the mono-propargyloxynaphthalenyloxy-triazolyl bCD intermediate
was isolated and the cycloaddition was repeated. Both products
were isolated as a solid material, and chemical structures were
1
13
confirmed by H NMR, C NMR and mass spectroscopy.
Model compound behaviour in solution and in the presence
of a bCD
Emission spectra of MON and dMON aqueous dilute solutions
display single bands centred at B347 nm and B341, respec-
tively; however the latter also presents a little shoulder at
around B330 nm [Fig. 1S, ESI†]. A decrease in medium polarity
(e o 30), by carrying out measurements in different polarity
solvents, means that a shoulder appears at B350 nm in the
emission spectra and that there is a slight shift in the band for
MON by about 3–4 nm to the blue. However, these changes are
more evident in dMON, where a rather significant variation in
the relative intensity of the peak and the shoulder takes place,
Fig. 1 Structures of the modified CDs and model compounds studied.
dimer and oligomer structures in water, where diphenoxy groups, without the occurrence of any band displacements (i.e. the initial
axially oriented in relation to the main CD axis, were partially high energy shoulder becomes a peak whose intensity increases
located outside the cavity. The bis-bCD, however, maintains upon decreasing the polarity of the solvent [Fig. 2S, ESI†]).
a rather open arrangement where both CD macrorings are Lifetimes, t, for both compounds, obtained from the mono-
6
8
relatively distant and parallel. We subsequently discovered that exponential fluorescence intensity decay profiles as a function of
a strong mono-bCD association hindered complexation with a solvent polarity, e, are also depicted in Fig. 1S [ESI†]. Both
7
2
naphthalene dicarboxylate fluorescence probe (DMN) which compounds behave similarly; t varies little at e 4 40, it decreases
is not capable of breaking strong supramolecular structures. when e decreases in the 40 4 e 4 30 range and increases again
However, the DMN gave 1: 1 and 2: 1 stoichiometry complexes at e o 30. The latter is probably due to the viscosity increase in
with the bis-bCD. Cooperativity between CDs improved binding more apolar solvents (water and n-alcohols from methanol to
72
capability, relative to the DMN:bCD complex, by a factor of 7.
heptanol). This behaviour is very similar to what is seen in some
The present work aims to predict the structures of modi- naphthalene carboxylates and dicarboxylates, which are used as
1
1,72
fied bCDs, which contain naphthoxy chromophore groups, in polarity sensitive fluorescence probes.
diluted water solution. These modified bCDs are namely
Absorption spectra of model compounds in water exhibit
-deoxy-6 -(4-((2-naphthyloxy)methyl)-1H-1,2,3-triazol-1-yl)-b-cyclo- bands centred at B225 (232), B272 (275) and B323 (325) nm
I
I
6
I
I
dextrin (mono-NbCD) and 2,7-bis-((1-(6 -deoxy-b-cyclodextrin-6 -yl)- for MON (dMON), both in the absence and presence of the
H-1,2,3-triazol-4-yl)methoxy)naphthalene, (bis-NbCD).
native bCD. Bands displayed a slight intensity increase with
1
A
combination of steady-state and time-resolved fluorescence tech- [bCD]. The addition of the bCD to a dilute MON aqueous
niques, induced circular dichroism (ICD) measurements and solution exerts a shift on the location of the 347 nm peak
molecular mechanics and molecular dynamics (MD) calculations fluorescence emission, due to changes in the polarity surrounding
was used for this purpose. The complexation of 2-methoxy- the guest, but also promotes the appearance of a shoulder at
naphthalene, (MON) and 2,7-dimethoxynaphthalene (dMON), around B350 nm. For dMON, however, the intensity of the peak
chromophoric model compounds, with the native bCD was also at B341 relative to the shoulder at B330 nm moderately
studied [Fig. 1]. Overall results have permitted us to hypothesize increases upon bCD addition.
the structure of these modified CDs in a diluted aqueous
Decay intensity profiles in the presence of the bCD were also
solution. These results will be useful in dealing with the resolved to mono-exponential functions. Lifetime in the
complexation of adducts that contain Gd(III) chelates, which absence of the bCD was 9.8 ns (10.1 ns) for MON (dMON) at
7
1
have applications as contrast agents (CAs) for MRI diagnosis.
25 1C. However, as depicted in Fig. 3S [ESI†], the MON model
This will be one of our main objectives for subsequent studies. shows t increasing with [bCD] while dMON lifetime decreases.
The adjustments of experimental data to the conventional
7
4
equations, assuming a 1 : 1 stoichiometry complex, gave
Results and discussion
ꢁ1
ꢁ1
formation constants of 1050 ꢀ 80 M and 645 ꢀ 84 M at
The naphthoxy chromophore group was bound to the bCD core 25 1C for MON and dMON binding to the bCD, respectively.
by the Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition using There is an effective interaction with the bCD in both model
metallic copper under sonochemical conditions [Schemes S1 compounds that results in the formation of stable complexes.
7
3
I
I
and S2, ESI†].
6 -Azido-6 -deoxy-bCD was reacted with However, whereas emission intensity almost appears to be
2-propargyloxynaphthalene and 2,7-dipropargyloxynaphthalene unaffected by changes in polarity surrounding both guests upon
to obtain mono- and bis-NbCDs, respectively. To maximize the complexation, lifetime is a suitable property to monitor the
yield of the bis-NbCD, the reaction was performed in two steps, inclusion processes of both MON and dMON model compounds.
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Fluorescence and circular dichroism for mono- and bis-NbCDs concentrations. Lifetime changes with temperature were in the
in aqueous dilute solution
B9.4 ns (at 5 1C) to B8.2 ns (at 45 1C) and B11.7 ns (at 5 1C) to
B10.7 ns (at 45 1C) ranges for the mono- and bis-NbCDs,
respectively.
Fig. 2 shows absorption spectra of aqueous dilute solutions
of mono- and bis-NbCDs. Bands for the mono-NbCD are
centred at B325 and B272 nm and a particularly intense band
is observed at B225 nm; molar absorptivities are 3400, 9500
All fluorescence experiments, except for the change in emis-
sion intensity with [mono-NbCD], either indicate that there is no
interaction between mono-NbCDs in the range of concentration
used or that, if there is, changes in polarity and microviscosity
surrounding this group during association hardly affect fluores-
cence properties. Our group has reported the self-association of
quite similar cyclodextrin mono-derivatives whose appended
groups were located on the macroring primary face and which
contained diphenoxy groups instead of dinaphthoxy moieties.
In addition, we have also reported the head-to-head association
of modified CDs in aqueous media at the secondary side via a
bidentate ligand which contains diphenoxy and naphthoxy
groups. These non-covalent dimers which are stable in aqueous
ꢁ
1
ꢁ1
and 132 000 M cm , respectively. These bands are accom-
panied by shoulders (s) located at B260, B282 and B310 nm.
However, bands for the bis-NbCD are placed at B325
(
s B 310 nm), B280 nm and B235 nm and molar absorp-
tivities, smaller than for the mono-derivate, are 1600, 3400
ꢁ
1
ꢁ1
and 35 500 M cm , respectively. These bands are slightly
shifted to the red by about 10–12 nm relative to the mono-
3
0
NbCD. As in other naphthalene derivatives, these bands can
1
1
1
be ascribed to the L , L and B transitions, respectively.
b
a
b
Transition moments are contained in the naphthalene ring
plane and oriented along the main axis ( B ), the second
perpendicular to it and along the minor axis ( L
a
third forming a small angle with the previous one ( L ).
Nevertheless, the value of the latter angle is uncertain as it
depends on the substituent bound to the naphthalene group.
For this reason some authors consider both moments as being
1
b
1
0,27,28,30,79,80
1
media dissociate in polar media.
b
) and the
1
On the other hand, circular dichroism (CD) spectra are able
to provide information on the presence or absence of mono-
NbCD association. The simple existence of the Cotton effect
in the zone of chromophore absorption is the unequivocal
evidence of the interaction between the macroring appended
naphthoxy group (ON) and its own cavity or a neighbouring
one, providing information about its location and a mono- or a
3
0,75–78
oriented along the minor axis.
Emission spectra are quite similar to their model compounds
and show single bands with a maximum at B345 nm for the
mono-NbCD, whereas two peaks (B337 and B348 nm) were
found for the bis-NbCD [Fig. 4S, ESI†]. No band shifts were
observed upon increasing the derivative concentration. The
corrected fluorescence intensity [eqn (2) of Instruments and
experimental methods] increased linearly with [bis-NbCD] in
the whole concentration range used. Something similar occurred
for the mono-NbCD. However, the initial linearity observed
disappeared at higher concentrations [Fig. 4S, ESI†].
Fluorescence anisotropy (r) did not exhibit any noticeable
variation with the derivative concentration. Values of r were
close to zero, but slightly larger for the bis-NbCD than the
mono-derivative. Average values of r in the whole concentration
range used were 0.0025 ꢀ 0.0010 and 0.0090 ꢀ 0.0017, respec-
tively. Decay intensity profiles were, as models, always adjusted
to mono-exponential decay functions. t values were rather
similar to those of their respective MON and dMON models
and hardly exhibited any variation with mono- or bis-NbCD
8
1
bis-derivative structure in solution. Fig. 3 shows circular
dichroism spectra of a dilute aqueous solution of the mono-
NbCD and the bis-NbCD at 25 1C. The spectrum of the mono-
1
1
NbCD exhibits weak positive La and Lb transition bands,
1
b
whereas the zone of the B transition shows a double signal
whose maximum and minimum values are located at B248 nm
and B222 nm, respectively. This bi-signal is accompanied by a
little shoulder at B232 nm, whereas the positive band seems to
1
overlap the
a
L band. This combination of signs, positive,
1
1
1
positive and negative for the Lb
y La and Bb transitions,
respectively, would seem to correspond with a substituent
Fig. 3 Circular dichroism (—) and absorption spectra (---) of the mono-
NbCD (a) and the bis-NbCD (b) aqueous dilute solutions at 25 1C.
ꢁ6
Fig. 2 (a) Absorption spectra at 25 1C of aqueous solution of the mono-
Concentrations were 10 ꢂ 10 M. Quartz cells were 10 mm paths for
l o 270 nm in (a) and l o 250 nm in (b), and 100 mm paths for larger l in
both experiments.
ꢁ6
NbCD and the bis-NbCD (dashed) at concentrations of 1.0 ꢂ 10 M and
ꢁ6
1
.7 ꢂ 10 M, respectively. (b) Orientation of the transition moments.
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arrangement by which the ON, located outside a CD cavity interaction with the bCD cavity. Fluorescence decay profiles,
1
(
or partially included), is oriented with the B
b
transition in the carried out both in the absence and in the presence of the bCD,
1
1
direction of the main CD axis and the other two, L and L , were also fitted to mono-exponential functions. As depicted in
b
a
are perpendicular to it.
Fig. 4(b) at several temperatures, t values increase with [bCD]
As far as the region below 250 nm is concerned, the bi-signal up to a [bCD]/[mono-NbCD] molar ratio of B100, where a near
1
1
that overlaps with L
a b
and B bands in the positive and negative plateau is reached. Data can be adjusted to the proper equation
7
4
components, respectively, may correspond, by symmetry and for 1 : 1 stoichiometry complexes, to provide binding constants
ꢁ
1
shape, to an exciton coupling (EC). This would imply that two that vary from 2020 ꢀ 350 M at 5 1C to 850 ꢀ 45 at 45 1C
chromophores, which absorb in this region, are rather close to [Table 1S collects binding constants at other temperatures, ESI†].
each other and that at least one of them exhibits relatively large Constants are very similar to those reported for the complexation
8
2
molar absorptivity. This may either be due to the interaction of some naphthalene dicarboxylates with the bCD.
0
0
between two ON groups or between an ON group and a triazole
one from the same substituent or different ones from two ꢁ18.1 ꢀ 1.0 kJ mol and ꢁ0.8 ꢀ 3.3 J K mol , respectively,
mono-NbCDs. and were obtained from linear van’t Hoff plots [Fig. 5S, ESI†].
Thermodynamics parameters, DH and DS , have values of
ꢁ
1
ꢁ1
ꢁ1
0
However, the circular dichroism spectrum of the bis-NbCD, Negative DH values are related to the presence of favourable
which is given in Fig. 3(b), exhibits positive dichroic signals, attractive, probably van der Waals host–guest interactions.
1
which are fairly intense for the B
b
band and extremely weak for Negative but close to zero entropy changes point to a probably
1
1
b a
L and a low intensity negative signal for the L transition. partial inclusion into the cavity. The entropy gain due to
This combination of signs may correspond, ‘‘a priori’’, to an ordered water loss does not offset the decrease in the degrees
arrangement whereby the 2,7-dinaphthoxy (dON) chromo- of freedom caused by partial ON group inclusion to afford a
phores which interact with a CD cavity are located outside favourable entropic term.
1
any of them and oriented in such a manner that the
B
b
Influence of medium polarity on the association of the mono-
NbCD in solution
transition moment is perpendicular to the main axis of one
or both CDs, and L is parallel to this axis. The sign of the weak
a
1
band would also appear not to be in disagreement with this Emission spectra of dilute mono-NbCD solutions in water
arrangement due to its weakness and the uncertainty concerning showed the typical single band centred at B345 nm. However,
the orientation of its transition moment.
a decrease in medium polarity caused two poorly defined peaks
at B350 and B340 nm to appear [Fig. 6S, ESI†]. A similar effect
was observed during mono-NbCD heteroassociation with
Hetero-association of the mono-NbCD with the bCD
As shown in Fig. 4(a), the single band observed at B345 nm in the bCD and with the change of medium polarity and the
the emission spectrum of the mono-NbCD aqueous solution complexation of model MON with the bCD, i.e., the guest
becomes a double band, whose maxima are placed at B340 and entered into a more apolar cavity. Intensity decay profiles,
B350 nm, upon bCD addition. These results, which are similar monitored at 345 nm upon excitation at 279 nm, were again
to observations of the complexation of MON and the bCD, may adjusted to monoexponential functions. The quantitative values
be related to the fact that the ON group, in the presence of the
bCD, may be located in a more apolar medium, probably via
Fig. 4 (a) Emission spectra of the mono-NbCD in the absence (---) and in
the presence (—) of bCDs at different concentrations ([bCD] = 0, 0.1, 0.5,
Fig. 5 Circular dichroism spectra of the mono-NbCD (a) in water (solid
black), methanol : water (1 : 1) (dashed gray) and ethanol : water (8 : 2)
mixtures (solid gray) and methanol (dashed black); (b) mono-NbCD in
the absence (solid black) and in the presence of the bCD and CB7 at 1 : 10
molar ratios (solid gray) and a large excess of bCD and CB7 (dashed gray) at
ꢁ3
1
.0, 2.0, 4.0, 6.0 8.0 and 10.3 ꢂ 10 M); (b) fluorescence lifetime, t,
variation with the bCD concentration at different temperatures; 5 1C (&),
1
ꢁ5
5 1C (J), 25 1C (n), 35 1C (,) and 45 1C ( ). [Mono-NbCD] was 10 M in
ꢁ5
all experiments.
a fixed mono-NbCD concentration of 10 M.
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of t and their variation with solvent relative permittivity (e) are appended ON group of the mono-NbCD and CB7, together with
depicted in Fig. 6S [ESI†] and are very similar values for the free the fact that, due to the CB7 achirality, the mono-NbCD:CB7
MON model compound.
complex should not show the ICD signal. In fact the association
Fig. 5(a) shows ICD spectra of the dilute solution of the constant for the heteroassociation of mono-NbCDs with CB7
4
ꢁ1
mono-NbCD in solvents of different polarity. The signal was 1.9(ꢀ0.3) ꢂ 10 M at 25 1C [Fig. 7S, ESI†].
1
1
1
b a b
intensity of the B , L and L transitions, including the EC
signal, decreases with decreasing solvent polarity. In fact, the Fluorescence quenching of mono- and bis-NbCD solutions
ICD spectrum of the mono-NbCD disappears in methanol as a
Quenching from fluorescence decay measurements at 25 1C on
consequence of the rupture of possible mono-NbCD inter-
MON, dMON, mono-NbCD and bis-NbCD water dilute solutions
molecular associations in polar solvents.
were performed using the quencher, diacetyl (2,3-butanedione).
Signs of ICD spectra of the mono-NbCD in water would
Fig. 8S [ESI†] depicts linear Stern–Volmer plots. Experiments
appear, which agree with the presence of tail–tail CD dimers
where the ON group of one mono-derivate is axially oriented
and partially included in neighbouring CDs via the primary face
and vice versa. The self-inclusion that would agree with the
signs, in a way similar to CD mono-derivatives containing
phenoxy instead of naphthoxy groups, would be energetically
ꢁ5
ꢁ5
were carried out in 10 M and 8 ꢂ 10 M mono-NbCD water
solutions. Table 1 collects some of the parameters derived from
these representations. Both model compounds show relatively
large and very similar k
q
values.
ꢁ5
The mono-NbCD solution, 10 M, gave a k
q
which is half
that of the MON model. However, this value is larger than that
2
9
unfavourable from the conformational point of view. The
presence of EC could be attributed to the monomeric form of
the mono-NbCD, whose appended substituent is rather folded
while the naphthoxy and triazole groups are relatively close
together, but also to the previously stated tail–tail dimer, where
the ON and triazole groups of neighbouring CDs are quite
close. A non-polar medium would dissociate the dimer and
probably extend the appended substituent chain in the mono-
meric form, decreasing both the EC signals.
found for a mono-derivate solution whose concentration was
ꢁ5
8
ꢂ 10 M (ꢂ8). A decrease in quencher accessibility to the ON
group occurs upon dimer formation as the ON group is partially
included in the bCD cavity. The dimer fraction should increase
with [mono-NbCD]. The bis-NbCD solution, however, presents
q
k that is very similar to the one found for the mono-derivative
at the highest concentration, probably due to the significant
shielding of the chromophore group located between both CDs.
A means to prove this statement can be found in capturing
the substituent which contains the ON group of mono-NbCD
monomers, to impede the approach of the ON-to-triazole group
by adding other macrocycles, like the native natural bCD or
CB7, to the water dilute solution of the mono-NbCD. These
macrocycles should be able to favourably complex with mono-
derivates and thus compete with dimerization. In fact, the
feasibility of mono-NbCD hetero-association with the bCD has
been quantitatively studied earlier in this paper.
Molecular dynamics simulations for isolated mono- and
bis-NbCDs
3
ns MD simulations were performed on isolated mono- and
bis-derivative structures depicted in Fig. 1 (see Computational
protocols section). Averages of some of the more significant
geometrical parameters obtained from the analysis of MD
trajectories are collected in Table 3S [ESI†]. For example,
average distances throughout the trajectory between the bCD
macroring and ON group centres of mass and between the
ON and triazole groups centres of mass were 9.6 ꢀ 2.2 Å and
Fig. 5(b) shows ICD spectra in the EC zone from a dilute
mono-NbCD solution in the presence of the bCD, with which it
forms a complex, or CB7, at 1 : 10 molar mono-NbCD : host
ratios and at a large host excess. Hardly any shape or intensity
changes take place in the circular dichroism spectrum upon the
addition of the bCD, up to a 1 : 10 ratio; however, an increase in
the amount of bCD progressively translates into the disappear-
ance of the induced signals. Although the equilibrium constant
for the heteroassociation of the mono-NbCD and the bCD,
studied in the previous section, is not too large, the complexa-
tion process can favourably compete with dimer formation,
causing dissociation. This dissociation hardly occurred for CD
mono-derivatives which contained diphenoxy groups instead of
6
.0 ꢀ 0.9 Å, respectively, for the mono-NbCD. The average
1 1
a b
angles between the main bCD axis and the L and B transi-
tion moments for the ON group were 84 ꢀ 31 and 92 ꢀ 221,
respectively. Only conformations whose bCD–ON distances
were smaller than 8 Å, i.e. those for which ON would in fact
interact with the CD cavity, and were considered for these
calculations. 25% of the conformations fulfilled this condition,
which explains the low intensity ICD spectra. Angle averages
would appear to indicate that the ON plane is located almost
perpendicularly to the main CD axis (parallel to the plane of CD
2
9
dinaphthoxy ones, whose dimers seemed to be rather more
stable. Adding the bCD in that case barely displaced the dimer
equilibrium toward the monomer form. In fact, it was necessary
to add a strong competitor, an adamantane derivative, to
Table 1 Stern–Volmer constants (KS–V), fluorescence lifetimes in the
0 q
absence of diacetyl (t ) and bimolecular quenching constants (k )
ꢁ1
9
ꢁ1 ꢁ1
System
K
S–V (M
)
t
0
(ns)
k
q
ꢂ 10 (M
s )
5
2,83
dissociate it.
The effect is more evident upon the addition MON
28.9 ꢀ 0.7
17.6 ꢀ 0.2 11.0
9.7
3.0 ꢀ 0.7
1.6 ꢀ 0.2
1.0 ꢀ 0.5
2.7 ꢀ 0.6
0.9 ꢀ 0.1
ꢁ5
Mono-NbCD (10 M)
of CB7 to the mono-NbCD solution and the intensity decreases
faster than when using the bCD. This would seem to agree with
the occurrence of more efficient complexation between the Bis-NbCD
ꢁ5
Mono-NbCD (8 ꢂ 10 M) 11.6 ꢀ 0.5 11.6
dMON
27.0 ꢀ 0.6 10.1
7.2 ꢀ 0.1 8.4
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bridging oxygen atoms), which would only explain the sign of L
NJC
1
a
,
in the macroring centre to naphthoxy chromophore group
1
but not the negative sign of the B
b
transition and the presence of distances, whose average values are around 9–10 Å, were found
in either system. However, the probability distributions,
EC in the ICD spectra, in mono-NbCD aqueous solutions.
As far as bis-NbCD is concerned, the centres of mass of both depicted in the bottom panels of Fig. 6, are a little different.
bCD macrorings are separated by an average distance of 13.2 ꢀ The distribution is relatively symmetric and centred at B9 Å for
2.6 Å, whereas the centre of mass of each CD and the dON the mono-NbCD, whereas two rather different distributions
group are placed at distances of 9.2 ꢀ 2.2 Å and 9.4 ꢀ 1.8 Å. The were obtained for the two CD–dON distances in the bis-NbCD.
dON group never penetrates any of the CD cavities in any of the The CD –dON distance distribution is rather symmetric and
conformations and prefers to locate itself between the macro- centred at B9–10 Å. However, the CD –dON distribution
1
2
rings. The distances between the dON centre of mass and each has two maxima located at B7 and B11 Å. These latter
triazole group were 5.8 ꢀ 0.9 and 6.0 ꢀ 1.0 Å, which are quite distributions describe two different arrangements: (i) the most
similar to those obtained for the mono-NbCD. This probably probable, where both CD cavities are relatively close to the dON
indicates that the EC signal, which appears in the mono-NbCD group making this group adopt a plane-parallel conformation
but not in the bis-NbCD, cannot be attributed to ON-triazole relative to the CD plane of bridging oxygen atoms; (ii) where
intramolecular interactions.
Angles for the main CD axis and L
dON group were close to 901 for all of the four angles (Table 1S, between the
both CDs are more distant, the linker is relatively extended and
1
1
a
and B
b
transition for the the dON group tends to adopt orientations where the angles
1
a
L transition and any of the CD main axis are
ESI†), which is in accordance with a geometrical arrangement in smaller than 54.71. These conformations are responsible for the
1
which the dON and bridging oxygen atom planes are parallel. negative low intensity La band observed in the bis-NbCD
However, these results partially disagree with the combination of circular dichroism spectra. Concluding that the most plausible
signs from the ICD spectra since they explain the positive sign arrangements for the bis-NbCD, which agree the experimental
1
1
for the B
b
transition but not the low negative intensity L
a
band. finding, are those in which the dinaphthoxy group laid in a
1
Nevertheless, the probability distribution for the L
angles are much wider than for the B
a
-CDmainaxis quasi-parallel plane conformation between both CD macro-
b
-CDmainaxis, which would rings [Fig. 9S, ESI†].
1
seem to indicate that there is a certain probability of finding
1
conformations where the L
a
-CDmainaxis angles are smaller than
2
Simulation of non-covalent (mono-NbCD) dimers
5
4.71. 21% and 15% of the conformations fulfil this condition.
1
MD simulations were also performed for two different non-
covalent mono-NbCD dimer arrangements, TH and TT depicted
in Fig. 7, in the presence of water. More details are provided in
the last section of this manuscript. The top of Fig. 8 depicts the
optimized TH and TT starting structures for the MD simula-
tions. Table 2S [ESI†] brings together some of the geometrical
and energetic parameters for both dimers. Fig. 8 shows
histories for both CD macroring centres of mass, as well as
for the total binding energies and contributions. The results
show that TH dimers are not stable. Interaction energies
throughout the trajectory are less favourable for the TH dimer
than for the TT analogue, in fact they become zero at the end of
the trajectory, indicating TH complex dissociation. However,
The La transition band in the circular dichroism spectra of
this small number of conformations would be negative and the
intensity, obviously, low.
The top panels in Fig. 6 show the histories of the CD–ON
distance for the mono-derivative and the CD
1
–dON and
CD –dON ones for the bis-derivative. No significant differences
2
the (mono-NbCD) TT arrangement remains stable during and
2
Fig. 6 (top panels): History of the CD–ON (—) distance for the mono-NbCD
left) and the same for CD –dON (—) and CD –dON ( ) distances for the
bis-NbCD (right). (bottom panels): Probability distributions for the CD–ON
-&-) (left), and CD –dON (-J-) and CD –dON ( ) distances (right).
(
1
2
2
Fig. 7 TH and TT dimer (mono-NbCD) arrangements used as starting
conformations for MD simulations.
(
1
2
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NJC
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groups is close but slightly outside the CD cavity. Angles
1
1
b a
between the CD axis and B and L transition moments for
each CD show the presence of conformations where axially
oriented ON groups are located outside the neighbouring CD
cavity. These conformations would appear to agree with the
negative and positive signs observed in the circular dichroism
1
1
b a
spectra for the B and L bands of the mono-NbCD and also
with the presence of the excitonic coupling signal observed in
the mono-NbCD, but not for the bis-NbCD. Table 2S [ESI†]
shows the average TT dimer distances between each ON group
and the triazole from the neighbouring CD, which in some
cases is smaller than B5 Å. This distance is short enough to
provide an interaction that is favourable for EC. The circular
dichroism spectra could never be explained without the
presence of these TT dimers. Unfortunately, the low solubility
of these compounds makes it impossible to use NMR techni-
ques to further prove the presence of these dimeric structures.
Conclusions
The aqueous solution structures of mono- and bis-b-cyclodextrin
Fig. 8 (top panel): Optimized non-covalent TH (left) and TT (right)
(
mono- and bis-NbCD) derivatives that contain dinaphthoxy
groups, either as appended moieties or inter-CD linkers, have
ON2–CD1 (gray); and (bottom panels) for the total binding energies been predicted using fluorescence and circular dichroism
(
mono-NbCD)
2
dimers used as starting structures for MD. (middle panels):
Histories of the distances between CDs (black), ON1–CD2 (light gray) and
(black), electrostatics (gray) and van der Waals forces (light gray) for both
spectroscopy and molecular dynamics simulations. Absorption
the TH (left) and TT (right) arrangements.
spectra of model compounds, mono- and bis-bCD derivatives,
1
exhibit typical naphthoxy bands which originate from the B ,
b
1
1
L and L transitions. Emission spectra of mono- and bis-bCD
a
b
derivatives show characteristics that are similar to their corre-
sponding model compounds. Fluorescence anisotropy and
lifetime measurements are hardly sensitivity to changes in the
microenvironment surrounding the naphthoxy chromophore.
However, an analysis of the circular dichroism spectra of the
mono-NbCD, in media of different polarity and in the presence
of other macrorings, supported molecular dynamics simulations
and confirmed that the mono-NbCD forms stable tail-to-tail
dimers via the partial axial interpenetration of naphthoxy groups
from the appended moiety into the primary faces of their
neighbouring CDs. Dimers also explain the presence of an
exciton coupling ICD signal, which is caused by intermolecular
interactions between naphthoxy and triazole groups from neigh-
bouring CDs. There was no EC signal in the ICD spectra of
the bis-NbCD. The dinaphthoxy unit in the aqueous solution
bis-NbCD linker is located between the CDs in a quasi parallel-
plane arrangement with respect to the bridging bCD oxygen
atoms and the dinaphthoxy group long (minor) axis is perpendi-
cular (forming an angle smaller than 54.71) to the main bCD axis
Fig. 9 Structures for the TH (top) and TT (bottom) arrangements for
(
2
mono-NbCD) dimers at the end of 2 ns MD trajectories.
at the end of the MD trajectory. van der Waals contributions direction.
are responsible for this stability. Fig. 9 depicts the TH and TT
structures at the end of the MD trajectories.
It has been demonstrated that the hydrophobic nature of
the appended mono-NbCD naphthalene moiety promotes the
Average angles between the main axis of each CD and the formation of relatively stable dimeric supramolecular struc-
1
1
B
b
and L
01 (311) and 971 (721) for the ON
In addition, CD –ON and CD –ON
and 2.6 Å, respectively, indicate that at least one of the ON other hand, the aqueous solution bis-derivatives present an
a
transition moments for the TT dimer were close to tures in aqueous solution. These structures partially block the
–CD (ON –CD ) interactions. primary or secondary faces of the cyclodextrin cavities and thus
distance averages of B1.0 compete with the complexation of any guest molecule. On the
1
1
2
2
1
1
2
2
1
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NJC
arrangement where the cavities of both macrorings remain free (15 ml) and K
2
CO
3
(6.89 g, 49.9 mmol, 8 equiv.) was added
and are therefore capable of accommodating molecule guests to the solution. The mixture was kept at 70 1C for 30 min under
between or inside their cavities. The complexation of bis-NbCD magnetic stirring. Then, propargyl bromide (1.62 ml, 14.98 mmol,
adducts containing Gd(III) chelates will be part of future work. 2.4 equiv.) was added and the reaction was left at 70 1C
for 4 h. The crude product was extracted using CH Cl2 and
2
then purified on a silica gel obtaining 865 mg of the pure
Experimental and theoretical protocols
Materials and methods
product (3.66 mmol, 59% yield). 2,7-Dipropargyloxynaphtha-
I
lene (244 mg, 1.033 mmol, 3 equiv.) was reacted with 6 -azido-
I
6
-deoxy-b-CD (400 mg, 0.345 mmol, 1 equiv.) in DMF (10 ml) in
Synthesis, reagents and solutions. Commercially available
reagents and solvents for the syntheses were used without
further purification. Native CDs were kindly provided by
Wacker Chemie. Reactions under combined MW/US irradiation
were performed in a professional multimode oven, (Microsynth,
Milestone), operating at 2.45 GHz, equipped with a high-power
the presence of metallic copper powder (200 mg). The reaction
was carried out under combined MW/US irradiation at 100 1C
for 1.5 h. The copper was filtered off and the crude product was
precipitated in a water–acetone mixture then purified on RP18.
I
I
4
58.4 mg of 6 deoxy-6 -(4-((7-propargyloxynaphthalen-2-yloxy)-
s
methyl)-1H-1,2,3-triazol-1-yl)-b-CD (0.328 mmol, 76% yield) and
pyrex US probe (20.5 kHz working frequency), while tempera-
I
I
pure 2,7-bis-((1-(6 -deoxy-b-cyclodextrin-6 -yl)-1H-1,2,3-triazol-4-
yl)methoxy)naphthalene (bis-NbCD) (70 mg, 0.0274 mmol,
yield 13%) were isolated. In order to increase the dimer yield,
the same synthetic procedure was repeated on 0.150 mg of
ture was strictly monitored by a fibre optic thermometer inside
the reaction vessel.
Commercial 2-methoxynaphthalene, MON and 2,7-dimethoxy-
naphthalene, dMON (Aldrich, Z98%) were used as model
compounds for mono- and bis-NbCDs, respectively. They were
checked using fluorescence and then used without any further
purification. The native bCD was purchased from Aldrich and a
Karl–Fischer analysis revealed that it contained a water content
of 12.94%. Cucurbituril of seven glycoluril units, CB7 (Aldrich,
water content 22.1%) was used without further purification.
I
I
6
6
1
-azido-6 -deoxy-b-CD (0.129 mmol, 1 equiv.) and 180 mg of
I
I
-deoxy-6 -(4-((7-propargyloxynaphthalen-2-yloxy)methyl)-1H-
,2,3-triazol-1-yl)-b-CD (0.129 mmol, 1 equiv.). In this case, after
purification the bis-NbCD was recovered with a 28% yield
(92 mg, 0.036 mmol).
Instruments and experimental methods. Absorption spectra
were obtained by using a Perkin-Elmer Lambda-35 Spectrometer.
Steady-state fluorescence and time-resolved measurements were
performed on SLM 8100 AMINCO and TCSPC FL900 Edinburgh
Instruments spectrofluorometers. Characteristics and measure-
4 6 2
2,3-Butanedione (C H O , diacetyl, Aldrich) was used as a
fluorescence quencher for the naphthoxy group. Solvents were:
deionised Milli-Q water, linear n-alcohols from methanol to
n-heptanol (Aldrich spectrophotometric grade or purity 498%).
1
0,28,30,80
I
I
ment conditions have been previously described.
Excita-
Mono- and bis-derivatives of b-cyclodextrin, 6 -deoxy-6 -(4-
(2-naphthyloxy)methyl)-1H-1,2,3-triazol-1-yl)-b-cyclodextrin and
tion for the time-resolved measurements was carried out using
sub-nanosecond pulsed NanoLED (IBH), emitting at 279 nm.
Data acquisition was performed on 1024 channels at a time
window width of 200 ns with a total of 10000 counts measured
at the maximum of the intensity profile. Samples were held at
a constant temperature by two Huber Ministat baths in both
instruments. Right angle geometry and magic angle (for steady-
state) conditions were used. Decay intensity profiles were fitted
to a sum of exponential decay functions by the iterative recon-
(
I
I
2
,7-bis-((1-(6 -deoxy-b-cyclodextrin-6 -yl)-1H-1,2,3-triazol-4-yl)-
methoxy)naphthalene, named as mono- and bis-NbCDs respec-
tively, are depicted in Fig. 1. The syntheses were carried out via
7
4
CuAAC using metallic copper under sonochemical conditions.
I
I
Synthesis of 6 -deoxy-6 -(4-((2-naphthyloxy)methyl)-1H-1,2,3-
triazol-1-yl)-b-cyclodextrin (mono-NbCD). b-Naphthol (400 mg,
2.78 mmol, 1 eq.) was dissolved in 10 ml of acetone and
8
4
volution method. The intensity weighted average lifetime of a
K CO (1.53 g, 11.12 mmol, 4 eq.) was added to the solution.
2
3
8
5
multiple-exponential decay function was then defined as
The mixture was kept at 70 1C for 30 min under magnetic
stirring. Then, propargyl bromide (360 ml, 3.34 mmol, 1.2 eq.)
was added and the reaction was left at 70 1C for 4 h. The crude
n
P
2
Aiti
i¼1
product was extracted using CH
2
Cl
2
and then purified on a
hti ¼
n
(1)
P
silica gel. 126 mg of the pure product (0.690 mmol, 4 eq.) were
Aiti
i¼1
I
I
reacted with 6 -azido-6 -deoxy-b-CD (200 mg, 0.172 mmol, 1 eq.)
in 10 ml of DMF in the presence of 100 mg of Cu. The reaction
was carried out under combined MW/US irradiation at 100 1C
for 1.5 h. The copper was filtered off and the crude product was
precipitated in a water–acetone mixture and then purified on
RP18. 173 mg of the pure product were obtained (0.129 mmol,
where A is the pre-exponential factor of the component and t is
i
i
the lifetime of the multi-exponential function intensity decay.
Corrections due to the inner effect, which is only significant
86
at the highest concentrations, were made:
ꢀ
ꢁ
75%). Scheme and more details are provided in the ESI.†
Aex þ Aem
Icorr ¼ Iobsantilog
(2)
2
I
I
Synthesis of 2,7-bis-((1-(6 -deoxy-b-cyclodextrin-6 -yl)-1H-1,2,3-
triazol-4-yl)methoxy) naphthalene (bis-NbCD). 2,7-Dihydroxy- where Aex and Aem are the absorption at the wavelength of
naphthalene (1 g, 6.24 mmol, 1 equiv.) was dissolved in acetone excitation and emission, respectively.
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Paper
Induced circular dichroism (ICD) spectra were obtained using References
a JASCO J-715 spectropolarimeter. Recorded spectra were the
ꢁ
1
1 H. Dodziuk, Cyclodextrins and their Complexes, Wiley-VCH
Verlag GmbH & Co., Darmstadt, 2008.
average of three scans taken at a speed of 20 nm min with a
time response of 0.125 s. In order to maintain the absorbance
around 1 at the maximum of the selected absorption band,
several quartz cell paths (from 1 to 100 mm) were used. The
sensitivity and resolution were set at 20 mdeg and 0.5 nm,
respectively. Measurements were performed at 25 1C.
2
F. Davis and S. Higson, Macrocycles: Construction, Chemistry and
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A. Douhal, Cyclodextrins Materials, Photochemistry, Photo-
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lated mono- and bis-NbCDs were performed on the analysis of
the 3 ns molecular dynamics simulations (MD) under vacuum
8
7
88
5 P. R. Sainz-Rozas, J. R. Isasi and G. Gonzalez-Gaitano,
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using Sybyl-X2.0 and the Tripos force field. The potential
energy of each system was evaluated as the sum of bond
stretching, bond angle bending, torsional, van der Waals,
electrostatic and out of plane energy contributions. A relative
permittivity of e = 1 was used. Partial atomic charges were
calculated using MOPAC and an AM1 Hamiltonian by separately
obtaining charges for the CDs and for the appended group or
6
7
8
9
A. Di Marino and F. Mendicuti, Appl. Spectrosc., 2004, 58,
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8
8
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a spacer (in the all trans conformation). Charges for the
MON and dMON model compounds were obtained using the
same method. Optimization was carried out using the simplex
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0 M. J. Gonz ´a lez-Alvarez, A. Di Marino and F. Mendicuti,
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´
1
ꢁ
1 90
tion method with gradients of 0.05 kcal mol
.
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1
1
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performed on the optimized all trans (for the appended group
or spacer) and non-distorted (for the macro-ring) mono- and
bis-derivative structures at 500 K following procedures described
1
2
9
elsewhere. Conformations were saved every 200 fs, yielding
5000 images per trajectory for subsequent analysis. The average
of any property was calculated by equally weighing each image.
The structures of (mono-NbCD) dimers, however, were
1
1
1
1
1
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ꢁ1
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9
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