New family of polyamine macrocycles containing 2,5-diphenyl[1,3,4] oxadiazole as a signaling unit. Synthesis, acid-base and spectrophotometric properties

Article abstract of DOI:10.1039/b921053a

Synthesis and acid-base properties for three fluorescent polyamine macrocycles 9,12,15,24,25-pentaaza-26-oxatetracyclo[21.2.1.0^2,7. 0^17,22]hexaicosa-2,4,6,17,19,21,23,25¹-octaene (L1), 9,12,15,18,27,28-hexaaza-29-oxatetrac

Full text of DOI:10.1039/b921053a

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
New family of polyamine macrocycles containing
2,5-diphenyl[1,3,4]oxadiazole as a signaling unit. Synthesis, acid–base and
spectrophotometric properties†
Gianluca Ambrosi,a Mauro Formica,a Vieri Fusi,*a Luca Giorgi,a Eleonora Macedi,a Mauro Micheloni,*a
Giovanni Piersantib and Roberto Pontellinia
Received 8th October 2009, Accepted 15th December 2009
First published as an Advance Article on the web 28th January 2010
DOI: 10.1039/b921053a
Synthesis and acid–base properties for three fluorescent polyamine macrocycles
9,12,15,24,25-pentaaza-26-oxatetracyclo[21.2.1.02,7.017,22]hexaicosa-2,4,6,17,19,21,23,251-octaene (L1),
9,12,15,18,27,28-hexaaza-29-oxatetracyclo[24.2.1.02,7.020,25]enneicosa-2,4,6,20,22,24,26,281-octaene (L2)
and 9,12,15,18,21,30,31-heptaaza-32-oxatetracyclo[27.2.1.02,7.023,28]diatriconta-2,4,6,23,25,27,29,311-
octaene (L3) are reported. Each ligand contains the 2,5-diphenyl[1,3,4]oxadiazole (PPD) unit
incorporated in the polyamine macrocycle. The protonation constants of L1–L3 were determined by
means of potentiometric measurements in 0.15 mol dm-3 NaCl aqueous solution at 298.1 K. All the
ligands are highly fluorescent in aqueous solution under acidic conditions (pH < 2) and their emission
drastically decreases when the pH is increased. At pH > 8, a total quenching of fluorescence is
observable in all the ligands. The fluorescence is given by the PPD unit, while the behavior as a function
of pH can be rationalized on the basis of photoinduced intramolecular electron transfer (PET) from the
HOMO of the donor macrocycle nitrogen atoms to the excited fluorophore unit. The insertion of PPD
in a polyamine skeleton strongly improves the fluorescence quantum yield of this class of ligands with
respect to those already known.
In this paper, we report the synthesis and a complete
study on the acid–base behavior of a new family of three
fluorescent polyaza-macrocycles suitable for use as photoactive
Introduction
In recent years, efforts have been devoted to the synthesis and char-
acterization of ligands ableto selectivelybind to aspecific metalion
chemosensors:
9,12,15,24,25-pentaaza-26-oxatetracyclo[21.2.
1.02,7.017,22]hexaicosa-2,4,6,17,19,21,23,251-octaene (L1), 9,12,15,
18,27,28-hexaaza-29-oxatetracyclo[24.2.1.02,7.020,25]enneicosa-2,4,
6,20,22,24,26,281-octaene (L2) and 9,12,15,18,21,30,31-heptaaza-
32-oxatetracyclo[27.2.1.02,7.023,28]diatriconta-2,4,6,23,25,27,29,
311-octaene (L3) (Chart 1). Each ligand shows the 2,5-
diphenyl[1,3,4]oxadiazole (PPD) group as a photoactive moiety,
which is inserted in a polyamine macrocyclic skeleton. The
choice of PPD was based on its photochemical properties, as
it is a well known fluorophore belonging to 1,3,4-oxadiazole
derivatives, one of the most widely studied classes of electron-
injection/hole-blocking materials due to their electron deficiency,
high photoluminescence quantum yield, and good thermal
and chemical stabilities.9 Most fluorescent ligands reported in
the literature with an aromatic group inserted in a polyamine
skeleton exhibit medium or low fluorescence quantum yield; the
introduction of PPD improves the photochemical performances
undergoing a concomitant spectroscopic response, such as color
change, variation in fluorescence both in emission wavelength and
intensity, which are important in the host–guest chemistry. An
important class of ligands is the macrocyclic molecules, which are
more selective than open-chain ones and usually form more stable
complexes.1 The presence of a photosensitive group, such as a
chromophore or a fluorophore, makes such compounds suitable
for use as simple optical sensors.2–4
Polyamine macrocycles can be excellent building blocks for
use in molecular recognition studies of several kinds of differ-
ently charged substrates.5 For this reason, one of the synthetic
strategies has been the insertion of one or more photoactive
groups in the polyamine skeleton with the aim to exploit the
photochemical properties of the inserted group preserving those of
the polyamines. In this way, several aza-macrocycles incorporating
phenolic,6 biphenolic,7 and various N- and O-based hetero-
aromatic functions,8 have been synthesized in our group and
studied as potential sensors.
aInstitute of Chemical Sciences, University of Urbino, P.zza Rinascimento 6,
I-61029, Urbino, Italy. E-mail: vieri.fusi@uniurb.it; Fax: +39-0722-350032;
Tel: +39-0722-350032
bInstitute of Pharmaceutical Chemistry, University of Urbino, P.zza Rinasci-
mento 6, I-61029, Urbino, Italy
† Electronic supplementary information (ESI) available: 1H and 13C
NMR spectra of compounds 6a, 6b, 6c, L1, L2 and L3. See DOI:
10.1039/b921053a
Chart 1 The ligands
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Table 1 Protonation constants (log K) of ligands L1, L2 and L3
potentiometrically determined in 0.15 mol dm-3 NaCl aqueous solution at
298.1 K
of this class of ligands making them also suitable for use under
high-dilution conditions.
log K
Results and discussion
Reaction
L1
L2
L3
Synthesis
L + H+ = HL+
9.56(2)a
7.10(4)
2.90(4)
—
9.19(1)
8.96(2)
6.11(4)
2.48(4)
—
9.30(1)
9.18(2)
7.23(2)
3.37(3)
2.15(4)
The synthetic pathway used to obtain the ligands L1–
L3 is depicted in Scheme 1. The heteroaromatic scaffold
2,5-bis[2-(chloromethyl)phenyl][1,3,4]oxadiazole (4) was synthe-
sized by chlorination with SO2Cl2 of its precursor 2,5-bis(2-
methylphenyl)[1,3,4]oxadiazole (3), obtained following the proce-
dure reported by Mashraqui and co-workers.10 The reaction used
to obtain the tosylated macrocycles 6a, 6b and 6c, a modification
of the Richman–Atkins method,11 involves cyclization of the
polytosylated polyamines 5a, 5b and 5c, respectively, with 1 equiva-
lent of 2,5-bis[2-(chloromethyl)phenyl][1,3,4]oxadiazole (4), in the
presence of an alkaline carbonate base. The final compounds 6a,
6b and 6c were obtained using a 1 + 1 cyclization scheme and
purified from the crude products by flash chromatography. Finally,
the desired ligands L1–L3 were obtained from the cleavage of
the tosyl groups by using hydrobromic acid in acetic acid. All
the compounds were further purified as hydrobromide salts by
recrystallization from cold water–48% aqueous HBr mixture.
HL+ + H+ = H2L2+
H2L2+ + H+ = H3L3+
H3L3+ + H+ = H4L4+
H4L4+ + H+ = H5L5+
—
a Values in parentheses are the standard deviations on the last significant
figure.
K1 = 9.19, log K2 = 8.96), one of intermediate and one of
much lower value (log K3 = 6.11, log K4 = 2.48), while L3
shows two relatively high basicity constants (log K1 = 9.30,
log K2 = 9.18), one of intermediate (log K3 = 7.23) and two
of lower values for the last two protonation steps (log K4
=
3.37, log K5 = 2.15) (see Table 1). In all the ligands, the trend
of the stepwise basicity constants follows the general criterion
of the minimum electrostatic repulsion between charges of the
same type; this is generally observed in the protonation of
polyamines containing only ethylene chains, and these protonation
constants are in agreement with the corresponding ones for
the polyaza-macrocycles of the polyaza-cyclophane series with
analogous sizes12a also containing heteroaromatic groups, such
as phenantroline,12b bipyridyl12c and terpyridyl,12d suggesting that
the PPD aromatic moiety should not be directly involved in
protonation in the pH range investigated.
UV-Vis and fluorescence studies. UV-Vis absorption and fluo-
rescence electronic spectra were performed at different pH values
to obtain further information about the role of PPD in the acid–
base behavior of the ligands. At pH = 12, all ligands exhibit an
absorption band with lmax at 267 nm (e = 12 300 cm-1mol-1dm3)
for L1, and 275 nm for L2 (e = 14 000 cm-1mol-1dm3) and L3 (e =
13 000 cm-1mol-1dm3); by lowering the pH, a red shift of lmax can
be observed together with an increase in absorptivity. At pH = 2
the lmax is 283, 280 and 278 nm for L1, L2 and L3, respectively
(see Fig. 1a, 2a and 3a), and, as observable, the shift is more
marked for L1 than for L2 and L3. Taking into account that the
absorption and fluorescence spectra of free PPD do not change in
the range of pH (2–12) examined (lmax = 282 nm, lem = 341 nm),
and that the PPD undergoes protonation only under strongly acid
conditions,13 we can suppose that the lmax change observed for the
ligands was not due to the protonation of PPD but most likely
to an interaction via H-bonding between the PPD group and
the protonated secondary amines of the macrocycles, as shown
for other similar ligands containing aza-heteroaromatic moieties
inserted in the polyaza skeleton, reported in the literature;12,14 this
interaction depends on the degree of protonation as well as on the
size of the macrocycle.
Scheme 1 Synthesis of the ligands. Conditions: (a) i. dioxane, 100 ◦C, 2 h,
ii. POCl3, 100 ◦C, 3 h; (b) SO2Cl2, benzoyl peroxide, chlorobenzene, 90 ◦C,
2 h; (c) K2CO3, DMF, 90 ◦C, 2 h; (d) 33% HBr–CH3COOH, 90 ◦C, 24 h.
Acid–base behavior
Potentiometric studies. Table 1 summarizes the basicity con-
stants of L1–L3 potentiometrically determined in 0.15 mol dm-3
NaCl aqueous solution, at 298.1 K, monitoring the 2–12 pH-
range. Under these experimental conditions, all the ligands can
be fully protonated, reaching the cationic species with HkLk+
stoichiometry, where k is the number of secondary amine groups
present in the macrocycle. Examining the stepwise protonation
constants, it appears evident that the number of constants shown
by each ligand coincides with the numbers of secondary amine
functions, thus suggesting that the protonation probably takes
place at these functions. In particular, L1 shows one relatively
high basicity constant (log K1 = 9.56), one of intermediate and
one of much lower value (log K2 = 7.10, log K3 = 2.90), L2
shows two relatively high and similar basicity constants (log
Previous experimental and theoretical studies highlighted that
the dipole moment of the PPD moiety increases almost two-
fold on excitation, suggesting that the excited state is twisted
intramolecular charge transfer (TICT).15 Upon excitation, the
electronic density increases on the oxygen and nitrogen atoms
of the [1,3,4]oxadiazole ring, thus raising its proton affinity with
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Fig. 2 (a) UV-Vis absorption and (b) fluorescence emission (lex = 265 nm)
spectra of L2 registered at various pH values. Experimental conditions:
[L2] = 1 ¥ 10-5 M, I = 0.15 M aqueous NaCl, T = 298.1 K.
Fig. 1 (a) UV-Vis absorption and (b) fluorescence emission (lex = 265 nm)
spectra of L1 registered at various pH values. Experimental conditions:
[L1] = 1 ¥ 10-5 M, I = 0.15 M aqueous NaCl, T = 298.1 K.
emission band due to vibration structure, with the maximum
emission at lem = 350 nm and remarkable emission quantum
yields at pH = 2 (Uf = 0.57, 0.65 and 0.72 for L1, L2 and L3
respectively). The high quantum yield exhibited by this class of
ligands is an upgrade compared to the previously synthesized
polyaza-cyclophanes.12,14 At higher pH the fluorescence emission
decreases and is totally quenched at pH around 8, for all the
ligands. This behavior can be rationalized in terms of quenching
of the excited state due to photoinduced intramolecular electron
transfer (PET) from the lone pairs of the polyamine nitrogen
atoms to the excited fluorophore moiety;3a the closer the amine
function is to PPD the higher the effect is. Total quenching of
the fluorescence takes place when at least one amine function
sufficiently close to PPD is completely deprotonated, i.e. neither
bearing protons nor being involved in any H-bonding. In the most
common case of fluorescent amino macrocycle, the nitrogen atoms
prone to give PET to fluorophore are the benzyl ones, but when
the macrocycle size is small non-benzyl nitrogens can also do it
because the electron transfer is dependent on the distance between
the donor atom and the fluorophore. The trend of the emission
intensity at 350 nm together with the distribution diagram of the
species as a function of pH is reported in Fig. 5.
respect to the fundamental state, as demonstrated by determining
the pKa value for the protonated HPPD+ in water–sulfuric acid
mixtures, which were found to be pKa = -2.29 for the singlet
fundamental state S0 and pKa = 2.63 for the singlet excited state
S1.13 In ligands L1–L3 the PPD electronic levels are perturbed
by the presence of the polyamine base connected to its phenyl
rings. Taking into account that the excited state S1 is more basic
than the fundamental one S0, it can be reasonably supposed that
the presence of protons in the macrocycle better stabilizes the S1
state than S0 via hydrogen bonding, as well as that the N lone-
pairs in the deprotonated species perturb the electronic state of
the PPD, making the S1 state more unstable than the S0 state.
This produces a considerable red shift of the absorption band
going from basic to acid pH values,16 as schematically depicted
in Fig. 4. This effect is particularly marked for L1 probably
because, due to its smaller size and its greater rigidity, the acidic
protons located on the polyamine moiety are held closer to the
oxadiazole ring with respect to the other ligands; in fact, the effect
decreases when the macrocyclic ring size is increased. However,
conformational changes in the aromatic rings (angles between the
planes), occurring in the several protonated species and affected
by both the size and the protonation degree of the macrocycle,
could also explain these data.
NMR studies. In order to monitor the relation between the
trend of the fluorescence with the acidic proton distribution in the
1
Fluorescence emission spectra were recorded for each ligand
upon excitation at the isosbestic point (lex = 265 nm for L1 and
L2; lex = 255 nm for L3). All the ligands were found to be highly
fluorescent in the acid pH range, showing a “four finger”-shaped
species, pH-dependent H NMR spectra were recorded over the
pH range of the potentiometric measurements. 1H–1H and 1H–13C
NMR 2D correlation experiments were performed to assign all the
signals. The pattern of resonances found in the 1H and 13C NMR
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Fig. 4 Proposed model for singlet in fundamental (S0) and excited (S1)
state of the neutral L1 and fully protonated H3L13+ species.
Fig. 3 (a) UV-Vis absorption and (b) fluorescence emission (lex = 255 nm)
spectra of L3 registered at various pH values. Experimental conditions:
[L3] = 1 ¥ 10-5 M, I = 0.15 M aqueous NaCl, T = 298.1 K.
aliphatic resonances. This situation affects the fluorescence, and in
fact the ligand becomes weakly fluorescent (Fig. 5b). The third and
fourth protonation steps take place on the two non-benzyl amine
functions, as highlighted by the downfield shift observed for the
signals of H8 and H7 from pH = 7.8 to pH = 4.6 (corresponding to
the H2L22+→H3L23+ step), as well as from pH = 4.6 to pH = 2.0,
where the fully protonated H4L24+ species is prevalent in solution
(Fig. 5b). Taking into account that the first two protonation steps
take place, above all, on the benzylic positions, we can suppose that
in L2, PET starts mainly from the benzyl nitrogen atoms. However,
the sharing of the acidic protons on all the amine functions, as well
as the presence of close lone pairs, do not allow full emission of the
PPD in the H2L22+ species. The main fluorescent species is the fully
protonated one, in which the benzyl N atoms are fully protonated,
while the H3L23+ species, in which one of the two amine function
are not fully protonated (see Fig. 6), is less fluorescent. Analogous
remarks can be made for L3 (data not reported, see Fig. 6).
The behavior of L1 is slightly different. Fig. 8 reports the
chemical shifts in the most significant resonances of L1, reported
as a function of pH. From pH = 12 to pH = 8, when the HL1+
species is prevalent in solution, all the aliphatic resonances shift
downfield due to the increase of positive charge density on the
macrocycle, showing that the first H+ is fully shared between all
the three amine functions. By lowering the pH to 5, when the
di-protonated H2L12+ species is prevalent (see Fig. 5a), a marked
downfield shift of H6 and H5 resonances was observed, while
the signal of H7 did not shift. This suggests that the second
protonation fixes the two acidic protons on the benzylic functions
spectra (see experimental part) indicates a C2v symmetry on the
NMR time scale for all the ligands, which is preserved throughout
the pH range investigated. A proposed proton disposition in all
the species of the ligands is depicted in Fig. 6.
Fig. 7 reports the chemical shifts in the most significant
1
resonances of L2, reported as a function of pH. The H NMR
spectrum recorded at pH = 12, where the neutral L2 species is
prevalent in solution, shows three aliphatic and four aromatic
resonances: a singlet at d = 2.73 ppm integrating four protons
(4H) attributed to the resonance of H8 (H8, 4H), a multiplet at
d = 2.80 ppm (H7 and H6, 8H), a singlet at d = 3.67 ppm (H5,
4H), a multiplet at d = 7.39 ppm (H2, 2H), a doublet of doublets
at d = 7.48 ppm (H4, 2H), a multiplet at d = 7.60 ppm (H3, 2H)
and a doublet of doublets at d = 7.69 ppm (H1, 2H).
Examining Fig. 7, starting from pH = 12 and going towards
pH = 9.3, where the HL2+ species is prevalent in solution, all
the aliphatic resonances shift downfield. In particular, the signals
of H5 and H6 exhibit a marked shift, thus suggesting that the
first protonation step mainly involves the benzyl nitrogen atoms,
which are, however, shared and stabilized via H-bond with the
closer amine function. By lowering the pH to 7.8, at which H2L22+
is prevalent in solution, the resonances of H6 and H5 further
shift downfield, highlighting that the second acidic proton is
again mainly located on the other benzyl amine function (see
Fig. 6). However, the protons, although mainly located in those
positions, are shared and/or stabilized via H-bonding with all the
other amine functions, as highlighted by the downfield shift in all
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for two protons (H1). In the neutral species, all the resonances
shift upfield in agreement with the reduced positive charge density
on the ligands. L2 and L3 show a similar pattern of signals, while
L1 slightly differs, exhibiting a pattern of signals similar to the
protonated species. Once again, this could be ascribed to the small
size of L1; this makes L1 stiff also in the neutral species, affecting
the PPD conformation in a similar way in all the species.
Concluding remarks
The new polyamine macrocyclic ligands L1, L2 and L3 synthesized
and characterized contain the photoactive heterocycle PPD (2,5-
diphenyl[1,3,4]oxadiazole) inserted in polyaza-macrocycle frag-
ments of different size and with different numbers of secondary
amine functions. In aqueous solution, all the ligands show the
typical acid–base behavior of a polyaza-cyclophane of comparable
size, where the aromatic part is not involved in the acid–base
processes. This suggests that the PPD group is not directly involved
in the protonation steps. The fluorescence emission depends on
the protonation state of the ligands and it can be rationalized on
the basis of quenching of the excited state due to photoinduced
intramolecular electron transfer (PET) from the lone-pair of the
macrocycle nitrogen atoms to the excited state of the fluorophore
moiety; in fact, going from acidic pH, at which the fully protonated
species are prevalent in solutions, to alkaline solutions, a gradual
quenching of fluorescence was observed for all the ligands. It is to
highlight the high emission quantum yield of the fully protonated
ligands, ranging from 0.57 to 0.75, making this class of ligands
more sensitive with respect to the other polyaza-cyclophanes
previously reported. The study of the fluorescence emission trend
highlighted the on–off fluorescence behavior modulated by pH
exhibited by the entire family, thus making these systems appealing
for multiple applications.
Fig. 5 Distribution curves of the species (—) and emission intensity at
lem = 350 nm (᭜) of L1 (a), L2 (b) and L3 (c) in aqueous solution as a
Experimental section
function of pH; [L] = 1 ¥ 10-5 M, I = 0.15 M NaCl, T = 298.1 K, lex
265 nm (L1), 265 nm (L2), 255 nm (L3).
=
General methods
UV absorption spectra were recorded at 298 K on a Varian Cary-
100 spectrophotometer equipped with a temperature control unit.
Fluorescence emission spectra were recorded at 298 K on a Varian
Cary-Eclypse spectrofluorimeter and the spectra are uncorrected.
The fluorescence quantum yields of fully protonated ligands (Uf)
were determined by comparing the integrated fluorescence spectra
of the sample in aqueous HCl at pH = 2 with 2,2¢-biphenol
in acetonitrile (Uf = 0.29).17 ESI-MS spectra were recorded on
due to the minimization of electrostatic repulsion. This species is
very poorly emitting, showing that PET takes place mainly from
the central non-benzylic nitrogen, which, due to the small size
of the macrocycle, is close to the PPD moiety. Moving to pH =
2, where the fully protonated species is prevalent in solution, the
signal of H7 undergoes the greater downfield shift while those
of H5 did not substantially shift, reaching the highest emitting
H3L13+ species.
Fig. 9 reports the spectra of the aromatic part of all ligands
recorded at pH = 12 and 2; all the resonances shift downfield
moving from the free to the fully protonated species. The shift, as
previously reported, cannot be attributed to a direct protonation
of the PPD unit, but to an increase of the positive charge density
on the ligand and its participation in the stabilization of the fully
protonated species via H-bonding, as previously suggested by the
UV-Vis absorption experiments. It is possible to observe that all
the three ligands show a similar pattern of resonances when present
in the fully protonated species. Under these conditions, the overall
molecules are stiffened and, for this reason, the PPD units are
probably arranged in the same way in all the ligands; the resulting
spectra show a multiplet integrating six protons (H2, H3 and H4,
see Fig. 7 and 8) and a signal (dd) at lower field, which accounts
1
a Thermo Quest LCQ Duo LC/MS/MS spectrometer. H and
13C NMR spectra were recorded at 298.1 K on a Bruker Avance
instrument, operating at 200.13 and 50.33 MHz, respectively. For
the spectra recorded in D2O, the peak positions are reported
with respect to HOD (4.75 ppm) for 1H NMR spectra, while
dioxane was used as reference standard in 13C NMR spectra (d =
67.4 ppm). For the spectra recorded in CDCl3 the peak positions
are reported with respect to TMS. All reagents and solvents used
were of analytical grade.
EMF measurements
Equilibrium constants for protonation and complexation reac-
tions of the ligands were determined by pH-metric measurements
in 0.15 mol dm-3 NaCl at 298.1 0.1 K, using the fully automatic
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Fig. 6 Proposed disposition of the H+ in the protonated forms of the ligands.
1
Fig. 7 Trend of the H NMR signals for the L2 aliphatic protons as a
function of pH. (ꢀ = H8, ᭢ = H7, ꢀ = H6, ᭹ = H5).
1
Fig. 8 Trend of the H NMR signals for the L1 aliphatic protons as a
function of pH. (ꢀ = H7, ᭹ = H6, ꢀ = H5).
equipment that has already been described;18a EMF data were
acquired with the PASAT computer program.18b The combined
glass electrode was calibrated as a hydrogen concentration probe
bytitratingknown amounts ofHClwith CO2-free NaOH solutions
and determining the equivalent point by Gran’s method,18c,d
which gives the standard potential E◦ and the ionic product
of water (pKw = 13.83(1) at 298.1 K in 0.15 mol dm-3 NaCl,
Kw = [H+][OH-]). At least three potentiometric titrations were
performed for each system in the pH range 2–12, and all titrations
were treated either as single sets or as separate entities, for each
system; no significant variations were found in the values of the
determined constants. The HYPERQUAD computer program
was used to process the potentiometric data.18e
Bis(2-methylphenyl)[1,3,4]oxadiazole (3) was prepared from
2-methylbenzoyl chloride (1) (Aldrich) and 2-methylbenz-
hydrazide (2) as reported.10 2,5-Bis[2-(chloromethyl)phenyl]-
[1,3,4]oxadiazole (4) was prepared as reported.19 1,4,7-Tris(4-
methylbenzensulfonyl)-1,4,7-triazaheptane
(5a),
1,4,7,10-
tetrakis(4-methylbenzensulfonyl)-1,4,7,10-tetraazadecane20a (5b)
and 1,4,7,10,13-pentakis(4-methylbenzensulfonyl)-1,4,7,10,13-
pentaazatridecane20b (5c) were prepared as reported.
9,12,15-Tris(4-methylbenzensulfonyl)-9,12,15,24,25-pentaaza-26-
oxatetracyclo[21.2.1.02,7.017,22]hexaicosa-2,4,6,17,19,21,23,251-
octaene (6a)
Over a period of 4 h, a solution of 5a (1.8 g, 3.1 mmol) in 100 cm3 of
anhydrous DMF was added to a suspension of 4 (1.0 g, 3.1 mmol)
and K2CO3 (4.3 g, 31.0 mmol) in 200 cm3 of anhydrous DMF,
at 90 ◦C under nitrogen. The reaction mixture was maintained at
Synthesis
All chemicals were purchased from Aldrich, Fluka and
Lancaster in the highest quality commercially available. 2,5-
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9,12,15,18,21-Pentakis(4-methylbenzensulfonyl)-
9,12,15,18,21,30,31-heptaaza-32-oxatetracyclo[27.2.1.02,7.023,28]-
diatriconta-2,4,6,23,25,27,29,311-octaene (6c)
This compound was synthesized from 5c (7.0 g, 7.1 mmol), 4
(2.3 g, 7.1 mmol) and K2CO3 (9.7 g, 70.0 mmol) following the
same procedure reported for 6a obtaining 6c as a white solid (4.6 g,
54%).
1
MS m/z (ESI): 1206.3 (M + H+); H NMR (CDCl3) d = 7.93
(2H, d), 7.83 (2H, d), 7.78 (4H, d), 7.63 (4H, d) 7.57 (2H, t), 7.44
(2H, t), 7.34 (2H, d), 7.32 (4H, d), 7.29 (4H, d), 7.23 (2H, d), 5.07
(4H, s), 3.53 (4H, m), 3.07 (12H, m), 2.47 (6H, s), 2.44 (6H, s), 2.41
(3H, s); 13C NMR (CDCl3): d = 164.0, 143.8, 143.6, 143.3, 137.2,
136.8, 134.6, 133.8, 131.8, 131.7, 129.8, 129.6, 128.2, 127.6, 127.5,
127.4, 122.8, 51.1, 50.5, 49.9, 48.8, 47.1, 21.6, 21.6, 21.5 ppm;
Anal. for C59H63N7O11S5 (1206.5): Calcd (%) C 58.74, H 5.26, N
8.13; Found (%) C 58.8, H 5.2, N 8.1.
9,12,15,24,25-Pentaaza-26-oxatetracyclo[21.2.1.02,7.017,22]-
hexaicosa-2,4,6,17,19,21,23,251-octaene (L1)
Macrocycle 6a (1.8 g, 2.2 mmol) and phenol (5.0 g, 53.2 mmol)
were dissolved in HBr–CH3COOH (33%, 40 ml). The solution
was stirred at 90 ◦C for 24 h. The resulting suspension was filtered
and washed with CH2Cl2 several times. The solid obtained was
recrystallized from cold water–48% aqueous HBr mixture to give
L1·3HBr as a white solid (0.9 g, 70%).
Fig. 9 1H NMR spectra of the aromatic resonances recorded in D2O
solution at pH = 2 and 12.
90 ◦C for further 2 h. Subsequently, the mixture was cooled to
room temperature then concentrated under reduced pressure to
one third of the initial volume, then poured under stirring into
cold water (1 dm3). The resulting white precipitate was filtered off,
washed with cold water, dried under vacuum and purified by flash
chromatography (silica gel, chloroform) obtaining 6a as a white
solid (1.8 g, 72%).
1
MS m/z (ESI): 350.2 (M + H+); H NMR (DMSO-d6) d =
9.09 (6H, br), 8.34 (2H, m), 7.79 (6H, m), 4.93 (4H, br), 3.82 (4H,
br), 3.58 (4H, br) ppm; 13C NMR (DMSO-d6): d = 164.3, 134.7,
133.3, 131.4, 131.1, 130.0, 122.8, 49.7, 44.1, 43.6 ppm; Anal. for
C20H26Br3N5O (592.2): Calcd (%) C 40.57, H 4.43, N 11.83; Found
(%) C 40.7, H 4.6, N 11.7; UV-Vis (NaOHaq, pH = 12) lmax
=
267 nm, e = 12300 mol-1 cm-1 dm3.
1
MS m/z (ESI): 812.2 (M + H+); H NMR (CDCl3) d = 7.92
(2H, dd), 7.85 (6H, d) 7.72 (2H, d), 7.53 (4H, m), 7.36 (4H,
d), 7.26 (2H, d), 5.08 (4H, s), 3.04 (8H, m), 2.46 (6H, s), 2.39
(3H, s); 13C NMR (CDCl3): d = 164.5, 143.7, 143.6, 137.6,
136.0, 135.6, 133.5, 132.4, 129.9, 129.8, 128.9, 128.8, 127.7, 127.6,
122.3, 49.1, 47.8, 47.5, 21.6 ppm; Anal. for C41H41N5O7S3 (812.0):
Calcd (%) C 60.65, H 5.09, N 8.62; Found (%) C 60.5, H 5.2,
N 8.5.
9,12,15,18,27,28-Hexaaza-29-oxatetracyclo[24.2.1.02,7.020,25]-
enneaicosa-2,4,6,20,22,24,26,281-octaene (L2)
This compound was synthesized from 6b (2.2 g, 2.2 mmol), phenol
(6.6 g, 70.2 mmol) and HBr–CH3COOH (33%, 55 ml) following
the same procedure reported for L1, obtaining L2·4HBr as a white
solid (0.8 g, 54%).
MS m/z (ESI): 393.2 (M + H+); 1H NMR (D2O, pH = 3) d =
8.12 (2H, m), 7.63 (6H, m), 4.54 (4H, s), 3.56 (4H, m), 3.51 (4H,
m), 3.36 (4H, s); 13C NMR (D2O, pH = 3): d = 163.9, 133.2,
133.1, 131.1, 129.9, 129.2, 122.7, 50.4, 42.5, 42.4, 41.7 ppm; Anal.
for C22H32Br4N6O (716.2): Calcd (%) C 36.90, H 4.50, N 11.73;
Found (%) C 37.0, H 4.6, N 11.7; UV-Vis (NaOHaq, pH = 12)
lmax = 275 nm, e = 14000 mol-1 cm-1 dm3.
9,12,15,18-Tetrakis(4-methylbenzensulfonyl)-9,12,15,18,27,28-
hexaaza-29-oxatetracyclo[24.2.1.02,7.020,25]enneaicosa-
2,4,6,20,22,24,26,281-octaene (6b)
This compound was synthesized from 5b (1.6 g, 2.2 mmol), 4
(0.7 g, 2.2 mmol) and K2CO3 (3.0 g, 22.0 mmol) following the
same procedure reported for 6a obtaining 6b as a white solid
(1.2 g, 54%).
9,12,15,18,21,30,31-Heptaaza-32-oxatetracyclo[27.2.1.02,7.023,28]-
diatriconta-2,4,6,23,25,27,29,311-octaene (L3)
1
MS m/z (ESI): 1009.3 (M + H+); H NMR (CDCl3) d = 7.91
(2H, d), 7.80 (6H, d) 7.67 (4H, d), 7.51 (4H, m), 7.30 (8H, m), 4.99
(4H, s), 3.38 (4H, m), 3.20 (4H, m), 3.13 (4H, s), 2.44 (6H, s), 2.42
(6H, s); 13C NMR (CDCl3): d = 164.0, 143.6, 143.5, 137.2, 136.8,
134.8, 132.6, 132.2, 129.9, 129.8, 129.1, 128.6, 127.7, 127.5, 122.3,
50.2, 49.2, 48.9, 47.4, 21.6 ppm; Anal. for C50H52N6O9S4 (1009.2):
Calcd (%) C 59.51, H 5.19, N 8.33; Found (%) C 59.4, H 5.2, N
8.2.
This compound was synthesized from 6c (2.0 g, 1.7 mmol), phenol
(6.4 g, 68.0 mmol) and HBr–CH3COOH (33%, 50 ml) following
the same procedure reported for L1, obtaining L3·5HBr as a white
solid (1.0 g, 71%).
1
MS m/z (ESI): 436.3 (M + H+); H NMR (D2O, pH=3) d =
8.17 (2H, m), 7.62 (6H, m), 4.59 (4H, s), 3.72 (4H, t), 3.51 (4H, t),
3.29 (4H, t,br), 3.11 (4H, t,br); 13C NMR (D2O, pH = 3): 13C NMR
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(D2O, pH=3): d = 163.8, 133.2, 132.7, 131.3, 129.8, 129.3, 122.7,
51.3, 44.6, 44.2, 43.9, 41.8 ppm; Anal. for C24H38Br5N7O (840.1):
Calcd (%) C 34.31, H 4.56, N 11.67; Found (%) C 34.3, H
4.6, N 11.6; UV-Vis (NaOHaq, pH=12) lmax = 275 nm, e =
13000 mol-1 cm-1 dm3.
Inorg. Chem., 2000, 39, 2156; (c) J. A. Aguilar, A. B. Descalzo, P. Diaz,
V. Fusi, E. Garcia-Espan˜a, S. V. Luis, M. Micheloni, J. A. Ram`ırez, P.
Romani and C. Soriano, J. Chem. Soc., Perkin Trans. 2, 2000, 1187.
7 (a) M. Formica, V. Fusi, L. Giorgi, M. Micheloni, P. Palma and R.
Pontellini, Eur. J. Org. Chem., 2002, 402; (b) G. Ambrosi, P. Dapporto,
M. Formica, V. Fusi, L. Giorgi, A. Guerri, M. Micheloni, P. Paoli, R.
Pontellini and P. Rossi, Chem.–Eur. J., 2003, 9, 800.
8 (a) M. Formica, V. Fusi, L. Giorgi, A. Guerri, S. Lucarini, M.
Micheloni, P. Paoli, R. Pontellini, P. Rossi, G. Tarzia and G. Zappia,
New J. Chem., 2003, 27, 1575; (b) A. Baggioni, M. Formica, V. Fusi,
L. Giorgi, S. Lucarini, M. Micheloni, F. Secco, M. Venturini and G.
Zappia, Dalton Trans., 2005, 485; (c) G. Ambrosi, M. Formica, V. Fusi,
L. Giorgi, A. Guerri, M. Micheloni, P. Paoli, Pontellini and P. Rossi,
Chem.–Eur. J., 2007, 13, 702.
Acknowledgements
The authors thank the Italian Ministero dell’Istruzione
dell’Universita` e della Ricerca (MIUR), PRIN2007 for financial
support.
9 (a) Z. Xu, Y. Li, X. Ma, X. Gao and H. Tian, Tetrahedron, 2008, 64,
1860; (b) Y. Kaminorz, B. Schulz and L. Brehmer, Synth. Met., 2000,
111–112, 75.
10 S. H. Mashraqui, S. Sundaram, T. Khan and A. Bhasikuttan, Tetrahe-
dron, 2007, 63, 11093.
11 J. E. Richman and T. J. Atkins, J. Am. Chem. Soc., 1974, 96, 2268.
12 (a) A. Bencini, A. Bianchi, E. Garcia-Espan˜a, M. Micheloni and J. A.
Ramirez, Coord. Chem. Rev., 1999, 188, 97; (b) A. Bencini, M. A.
Bernardo, A. Bianchi, V. Fusi, C. Giorgi, F. Pina and B. Valtancoli,
Eur. J. Inorg. Chem., 1999, 1911; (c) C. Lodeiro, A. J. Parola, F. Pina,
C. Bazzicalupi, A. Bencini, A. Bianchi, C. Giorgi, A. Masotti and B.
Valtancoli, Inorg. Chem., 2001, 40(13), 2968; (d) C. Bazzicalupi, A.
Bencini, E. Berni, A. Bianchi, A. Danesi, C. Giorgi, B. Valtancoli, C.
Lodeiro, J. C. Lima and F. Pina, Inorg. Chem., 2004, 43(16), 5134.
13 R. E. Trifonov, N. I. Rtishchev and V. A. Ostrovskii, Spectrochim. Acta,
Part A, 1996, 52, 1875.
14 C. Lodeiro and F. Pina, Coord. Chem. Rev., 2009, 253, 1353.
15 D. S. Biradar, B. Siddlingeshwar and S. M. Hanagodimath, J. Mol.
Struct., 2008, 875, 108.
16 A. Sharma and S. G. Shulman, in Introduction to fluorescence spec-
troscopy, John Wiley & Sons Inc., New York, 1999.
17 M. Jyotirmayee, H. Pal and A. V. Sapre, Bull. Chem. Soc. Jpn., 1999,
72, 2193.
18 (a) P. Dapporto, V. Fusi, M. Micheloni, P. Palma, P. Paoli and R.
Pontellini, Inorg. Chim. Acta, 1998, 168, 275; (b) M. Fontanelli and
M. Micheloni M. in 1st Spanish-Italian Congress: Thermodynamics
of Metal Complexes, Pen˜iscola, Spain, June 3-6, 1990, University of
Valencia, Valencia, Spain, 1990, 41; (c) G. Gran, Analyst, 1952, 77,
661; (d) F. J. Rossotti and H. Rossotti, J. Chem. Educ., 1965, 42, 375;
(e) P. Gans, A. Sabatini and A. Vacca, Talanta, 1996, 43, 1739.
19 S. Wang, S.-P. Zheng, H. Meng and W.-T. Hua, Synth. Met., 1998, 93,
181.
20 (a) A. Bencini, A. Bianchi, E. Garcia-Espan˜a, M. Giusti, S. Mangani,
M. Micheloni, P. Orioli and P. Paoletti, Inorg. Chem., 1987, 23, 3903;
(b) A. Bencini, A. Bianchi, E. Garcia-Espan˜a, M. Giusti, M. Micheloni
and P. Paoletti, Inorg. Chem., 1987, 26, 681.
References
1 (a) L. F. Lyndoy, in The Chemistry of Macrocyclic Ligands Complexes,
Cambridge University Press, Cambridge, 1989; (b) E. Weber, in In
Crown Ethers and Analogs, ed. S. Patai and A. Rapport, Wiley, New
York, 1988; (c) J. S. Bradshaw, in Aza-crown Macrocycles, Wiley, New
York, 1993.
2 D. J. Cram, R. A. Carmak and R. C. Helgeson, J. Am. Chem. Soc.,
1988, 110, 571.
3 (a) A. W. Czarnik, in Fluorescent Chemosensor for Ion and Molecule
Recognition, American Chemical Society, Washington, DC, 1993;
(b) R. A. Bissel, A. P. De Silva, H. Q. N. Gunaratne, P. L. M. Lynch,
G. E. M. Maguire, C. P. McCoy and K. R. A. S. Sandanayake, Top
Curr. Chem., 1993, 168, 223; (c) R. Bergonzi, L. Fabbrizzi, M. Licchelli
and C. Mangano, Coord. Chem. Rev., 1998, 170, 31; (d) A. P. De Silva
and R. A. D. D. Rupasinghe, J. Chem. Soc., Chem. Commun., 1985,
1669; (e) U. E. Spichiger-Keller, in Chemical Sensors and Biosensors
for Medical and Biological Applications, Wiley-VCH, Weinheim, 1998;
(f) A. B. Ellis and D. R. Walt, Chem. Rev., 2000, 100, 2477, special
issue on chemical sensors, guest ed. A. B. Ellis and D. R. Walt; (g) E. V.
Aslin, Tetrahedron, 2004, 60, 11055, special issue on synthetic receptors
as sensors, guest ed. E.V. Aslin; (h) A. P. De Silva and P. Tecilla, J. Mater.
Chem., 2005, 15, 2617, special issue on luminescent sensors, guest ed.
A. P. De Silva and P. Tecilla.
4 (a) C. Bazzicalupi, A. Bencini, M. Ciampolini, V. Fusi, M. Micheloni,
N. Nardi, I. Razzolini and B. Valtancoli, Supramol. Chem., 1996, 7, 61;
(b) E. Bardazzi, M. Ciampolini, V. Fusi, M. Micheloni, N. Nardi, R.
Pontellini and P. Romani, J. Org. Chem., 1999, 64, 1335.
5 (a) W. Zazulak, E. Chapoteau, B. P. Czech and A. Kumar, J. Org.
Chem., 1992, 57, 6720; (b) A. Mason, A. Sheridan, I. O. Sutherland
and A. Vincent, J. Chem. Soc., Chem. Commun., 1992, 1716.
6 (a) V. Fusi, A. Llobet, J. Mahia, M. Micheloni, P. Paoli, X. Ribas and
P. Rossi, Eur. J. Inorg. Chem., 2002, 987; (b) P. Dapporto, M. Formica,
V. Fusi, M. Micheloni, P. Paoli, R. Pontellini, P. Romani and P. Rossi,
1478 | Org. Biomol. Chem., 2010, 8, 1471–1478
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