Phototransformation of benzimidazole and thiabendazole inside cucurbit[8]uril

Article abstract of DOI:10.1039/c3pp50336d

The phototransformation of benzimidazole (BZ) and of the benzimidazole pesticide thiabendazole (TBZ) was investigated in aqueous solution in the absence and presence of the supramolecular host cucurbit[8]uril (CB8). ESI-MS and NMR reveal that both compoun

Full text of DOI:10.1039/c3pp50336d

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Phototransformation of benzimidazole and
thiabendazole inside cucurbit[8]uril†
Cite this: DOI: 10.1039/c3pp50336d
Jaroslav Smitka,a Américo Lemos,b Mintu Porel,c Steffen Jockusch,d
Tomás R. Belderrain,e Eva Tesařováa and José P. Da Silva*b
The phototransformation of benzimidazole (BZ) and of the benzimidazole pesticide thiabendazole (TBZ)
was investigated in aqueous solution in the absence and presence of the supramolecular host cucurbit-
[8]uril (CB8). ESI-MS and NMR reveal that both compounds form stable 1 : 2 host–guest complexes with
CB8 (BZ2@CB8, TBZ2@CB8). The phototransformation of free BZ leads to dehydrodimerization, while for
TBZ the photoreactivity leads to BZ, benzimidazole-2-carboximide and 2-acetylbenzimidazole. Inside
CB8, BZ undergoes photohydrolysis to form 2-aminoformanilide, while for TBZ2@CB8 additional photo-
products were observed which are pH dependent. At pH 1.2 photolysis of TBZ2@CB8 leads to new red-
shifted photoproducts with extended π conjugation.
Received 19th September 2013,
Accepted 1st November 2013
DOI: 10.1039/c3pp50336d
www.rsc.org/pps
Introduction
The control of photoreactions through noncovalent inter-
actions within molecular containers has become a powerful
tool of Supramolecular Chemistry.1–3 The preorganization of
guests by the host in addition to the cavity constraints affect
the photophysical processes as well as the formation of inter-
mediates and final products. Host containers allowing the for-
mation of 1 : 2 host–guest complexes enforce spatial proximity
and orientation of the two reactant molecules, giving rise to
highly selective bimolecular processes.1–4
Cucurbit[8]uril (CB8, Scheme 1), a synthetic macrocycle
composed of eight methylene-bridged glycoluril units, can
accommodate two aromatic guest molecules to form 1 : 2 host–
guest complexes.5–7 The hydrophobic character of the inner
cavity, together with the negative electrostatic potential of the
carbonyl portals, enables CB8 to form stable complexes with
a variety of guest molecules in aqueous solution. These
properties of CB8 have been used to template the [2 + 2] and
Scheme 1 Structures of CB8, BZ and TBZ.
[4 + 4] photodimerization of neutral and positively charged
guests.8–17
Benzimidazoles are a family of heterocyclic compounds
extensively used in medicinal chemistry and agriculture.18–20
Thiabendazole (TBZ, Scheme 1) is a thiazolyl benzimidazole
known to have anthelmintic and fungicidal activity.18,20 While
the photochemistry of benzimidazole (BZ) has received brief
attention,21 the photophysical properties22,23 as well as the
photoproduct distributions24–26 of TBZ have been studied in
organic solvents and aqueous solution. The formation of
inclusion complexes with β-cyclodextrin27,28 and cucurbit[7]-
uril29–31 (CB7) was also reported. Herein we characterize the
complexation and photochemistry of BZ and TBZ, free and
inside CB8 molecular nanocontainers.
aDepartment of Physical and Macromolecular Chemistry, Faculty of Science, Charles
University in Prague, Albertov 2030, 128 43 Prague 2, Czech Republic
bCIQA, Faculdade de Ciências e Tecnologia, Universidade do Algarve, Campus de
Gambelas, 8005-139 Faro, Portugal. E-mail: jpsilva@ualg.pt;
Fax: +00 351 289 800066; Tel: +00 351 289 800900
cDepartment of Chemical Engineering, Columbia University, New York,
New York 10027, USA
Experimental
Materials
dDepartment of Chemistry, Columbia University, New York, New York 10027, USA
eLaboratorio de Catálisis Homogénea, Departamento de Química y Ciencias de los
Materiales, Unidad Asociada al CSIC, Centro de Investigacioń en Química Sostenible
(CIQSO), Campus de El Carmen s/n, Universidad de Huelva, 21007-Huelva, Spain
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c3pp50336d
BZ, TBZ, CB8, deuterated methanol (Aldrich), methanol, HCl,
ammonia (VWR), D2O and DCl (Cambridge Isotope Labora-
tories) were used as received. Water was of Milli-Q purity.
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Sample preparation, irradiation and isolation of the
photoproduct
ESI-MS
The ESI-MS spectra were obtained with a Bruker Daltonics
The aqueous solutions of the free guest and complexes used HCT ultra (ion trap) mass spectrometer equipped with an ESI
for ESI-MS and product studies (100 μM or 30 μM) were pre- source (Agilent). The ions were generated by infusing the
pared using a 1 mM aqueous solution of BZ or a saturated aqueous sample solution (4 μL min−1) into the source with the
aqueous solution of TBZ (pH ∼ 6.5, ∼150 μM). Aqueous solu- help of a syringe pump (KdScientific, model 781100, USA).
tions with lower pH (pH 1.2) were obtained by adding 5 μL of Typical experimental conditions were as follows: capillary
concentrated HCl per mL. The irradiations were performed voltage, 3.5 kV; capillary exit voltage (CE), 75 V; skimmer
using a home-made high-pressure xenon lamp setup in con- voltage, 15 V; drying gas, 300 °C at 6 L min−1; nebulizer gas
junction with a water filter to prevent heating of the sample pressure, 20 psi.
solution. An additional glass filter was inserted to remove UV
light below 320 nm. The formation of products was followed
LC-DAD-MS
by UV-Vis absorption spectroscopy, NMR, GC-MS (Gas The LC-DAD-MS system was an Agilent Technologies 1200
Chromatography-Mass
Spectrometry),
LC-DAD
(Liquid Series LC coupled to the above described mass spectrometer.
Chromatography-Diode Array Detection) and LC-MS (Liquid A Hamilton PRP-1 reversed phase LC column (15.0 cm length,
Chromatography-Mass Spectrometry). For GC-MS analysis, the 2.1 mm internal diameter, 5 μm particle diameter), stabilised
photoproducts were extracted with ethyl acetate. The extracts at 25 °C, was used. The eluent system used to separate the
were dried using CaCl2 before injection.
compounds in the irradiated solutions was methanol (A) and
The photoproduct observed in the presence of CB8 at water (B), both with 0.1% of ammonia. The gradient started
pH 1.2 was isolated by HPLC.
with 25% of A during one minute, followed by a linear increase
up to 100% A in 10 min. After 5 minutes at 100% of A, the
eluent was allowed to recover the initial conditions (25% of A
and 75% of B) in 0.5 min and then stabilise for an additional
4 minutes before the next run.
UV-Vis absorption spectroscopy and steady-state and time
resolved fluorescence
Absorbance spectra were recorded on a Lambda 40 spectro-
photometer (Perkin Elmer, Norwalk, CT, USA) at room tempe-
rature using quartz cuvettes with a path length of 1 cm.
Fluorescence emission spectra were recorded at room tempera-
ture on a SPEX Fluorolog-3 spectrometer FL3-22 (J. Y. Horiba,
Edison, NJ, USA).
Results and discussion
Complexation of BZ and TBZ with CB8
The formation of host–guest complexes between guest BZ and
TBZ and CB8 was evaluated by ESI-MS and NMR. ESI-MS full
scan spectra obtained at pH 6.5 for aqueous solutions contain-
ing BZ and CB8 at a 1 : 1 stoichiometry (25 μM) showed a
single signal peaking at m/z 783.2 (Fig. S1, ESI†). Based on the
m/z value, charge state and fragmentation behaviour (Fig. S2,
ESI†), this signal was assigned to the 1 : 2 host–guest complex
(BZ2@CB8). ESI-MS full scan spectra for TBZ and CB8 at 1 : 1
stoichiometry (30 μM, pH 6.5) showed two major signals at m/z
765.8 and 866.8 (Fig. S3a, ESI†). The fragmentation of the
signal at m/z 765.8 originates from the free guest (m/z 202.0)
and the empty single protonated host (m/z 1329.6) (Fig. S2,
ESI†). The fragmentation of the signal at m/z 866.8 gave rise to
m/z 202.0 and 1530.6, the free guest and the single protonated
1 : 1 complex, respectively (Fig. S4, ESI†). Based on the m/z
values, charge states and fragmentation behaviour, the signals
at m/z 765.8 and 866.8 were assigned to the 1 : 1 and 1 : 2 host–
guest complexes, respectively. At pH 1.2 only the signal of the
1 : 2 complex was observed (Fig. S3b, ESI†).
NMR
All 1H NMR spectra of TBZ, CB8 and their complexes were
obtained in solutions of D2O with a Bruker 500 MHz spectro-
meter at 25 °C. DCl was used for studies at lower pH. A 1H
NMR spectrum of 600 μL of 1 mM of the guest was recorded
first. The host was then added step by step. After each addition
the mixture was shaken well for about 5 min before the spec-
trum was recorded. The formation of the complexes was moni-
1
tored by the gradual shift of guest H signal positions and by
line broadening. The solutions containing 1 : 2 host–guest
complexes were used for irradiation studies. Spectra were
taken immediately after irradiation and after 4 hours of
storage in the dark.
GC-MS
The GC-MS analyses were performed using a Hewlett Packard
NMR gave further evidence for the formation of 1 : 2 host–
6890N GC and a 5973 series mass selective detector (E.I. guest complexes. Fig. S5, ESI,† shows the aromatic hydrogen
70 eV). The system was used with a DB-5MS capillary column region of the NMR spectra of aqueous solutions of TBZ and
(J&W Scientific) of 30 m length, 0.25 mm I.D. and 0.25 μm film CB8 with different stoichiometries at pH 1.2 (see Fig. S6, ESI,†
thickness with the following oven temperature program: 2 min for full spectra). The stepwise addition of CB8 induces an
at 70 °C, 10 °C increase per min up to 270 °C and 10 min at upfield shift of all guest hydrogen signals. The shielding effect
270 °C. The injector was set to 270 °C and the injection on the aromatic hydrogen signals (4–7) is largest, leading to
volume was 1 μL.
the broadening and overlapping of these aromatic signals.
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This was previously observed for benzimidazoles included in
CB7 and was assigned to the formation of inclusion com-
plexes.29,30 The signal of the aromatic hydrogens shows
the largest shift at a 1 : 1 stoichiometry (bottom spectrum, f).
At 1 : 2 host–guest composition (spectrum c), hydrogen signals
4–7 are still upfield shifted and merged, suggesting the for-
mation of 1 : 2 complexes (TBZ2@CB8) as detected by ESI-MS
(see above). Further increase in the guest/host ratio leads to
the recovery of the free guest signals.
An increase in the fluorescence intensity of TBZ upon
inclusion in CB7 has been reported.31 However, we observed a
decrease in fluorescence intensity of TBZ in the presence of
CB8 (see Fig. S7, ESI†). This reduction in fluorescence can be
explained by the self-quenching induced by the formation of
1 : 2 complexes, which was observed previously for 1 : 2 host–
guest complexes of coumarins with CB8.16 The fluorescence
lifetime of the free guest (pH 1.2) was found to be 0.86 ns,
which is of the same order as the reported values (0.53 ns) in
Scheme 2 Photoreaction products of BZ.
0.1
N a biexponential
HCl.22 In the presence of CB8,
fluorescence decay was observed. The long-lived component
(0.82 ns) was assigned to free TBZ in solution and 1 : 1 host–
guest complexes, whereas the short component (0.14 ns) was
assigned to 1 : 2 host–guest complexes. The significantly
shorter fluorescence lifetime is consistent with self-quenching
of TBZ in the complex.
Photoreaction of BZ
The role of CB8 in the phototransformation of BZ was first
studied by comparing the UV-Vis absorption spectra after
irradiation of free BZ and of BZ2@CB8. The photoreaction
leads to products absorbing above 300 nm under both con-
ditions (Fig. S8, ESI†). However, the spectral signature is dis-
tinct and the absorption below 280 nm decreases for
BZ2@CB8 while no significant changes were observed for free
BZ.
The LC-DAD traces of the irradiated BZ in the absence of
CB8 showed the formation of two major products absorbing
above 280 nm (Fig. S9, ESI†). LC-MS traces indicated a mole-
cular weight of 234 Da, as both compounds gave rise to signals
at m/z 235 under positive polarity, and the fragmentation
pattern was also similar (Fig. S9, ESI†). Compounds 1 and 2
were assigned to BZ dehydrodimerization products
(Scheme 2), which were reported earlier as major phototrans-
formation products of BZ.21
The LC-DAD analysis of the irradiated BZ2@CB8 aqueous
solutions showed a reduction in the formation of BZ dehydro-
dimerization products (1, 2) by a factor of five, together with
the formation of a new major product observed at a retention
time of 6.63 min (Fig. 1). The LC-MS traces indicated a mole-
cular weight of 136 Da, as the compound gives rise to a signal
Fig. 1 LC-DAD traces and LC-MS traces at m/z 137 and 235 of an irra-
diated aqueous solution with BZ2@CB8 (100–50 μM) at pH 6.5. The
insets show the absorbance spectra and structure of photoproduct 3.
optical properties and MS fragmentation pattern and by com-
parison with the GC-MS mass spectra library (NIST05), we
assign compound
Scheme 2).
3 to 2-aminoformanilide (Fig. 1 and
Photoreaction of free TBZ in aqueous solution
at m/z 137 under positive polarity. The fragmentation pattern Free TBZ undergoes phototransformation in aqueous solution
of m/z 137 shows the losses of 28 Da first, followed by an after irradiation (λ > 320 nm) at pH 6.5 and 1.2 (Fig. S12a,
additional loss of 17 Da (Fig. S10, ESI†), which is compatible ESI†). The analysis of the LC-MS traces indicated that, as
with an aldehyde structure. The GC-MS trace of photoproducts reported previously,23–25 benzimidazole (4), benzimidazole-2-
revealed a compound with a molecular ion at m/z 136 showing carboximide (5) and 2-acetylbenzimidazole (6) are among the
the equivalent mass losses (Fig. S11, ESI†). Based on the major photoproducts (Scheme 3 and Fig. S13a, ESI†). Other
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Scheme 3 Photoreaction products of free TBZ.
Scheme 4 Photoreaction products of TBZ2@CB8 at pH 1.2.
formation of a benzimidazole ion (m/z 119) together with the
loss of 118 Da, both indicating the presence of the benzimid-
1
azole moiety in the new product (Fig. S15, ESI†). The H NMR
spectrum of the isolated product confirmed the presence of
two benzimidazole units (see Fig. S16, ESI,† for a detail of the
aromatic region).
The 1H NMR spectrum of the photoproduct also shows that
hydrogen signals of the thiazole residue are not present
(Fig. S9, ESI†). Therefore, we conclude that the photoproduct
is probably formed through a reaction of two thiazole rings
(Scheme 4, product 9).
Role of CB8 in the photoreactivity of BZ and TBZ
The inclusion of BZ and TBZ in CB8 changes the photoreacti-
vity of both compounds but in different ways. While for BZ,
photohydrolysis of the CvN bond to form 2-aminoformanilide
(3) is the new major reaction process, for TBZ, although the
reactivity remains centred at the thiazole moiety, new products
are formed through coupling at the thiazole rings.
The photohydrolysis of CvN bonds in conjugation with
aromatic systems is known.32 The efficiency of the process was
associated with a high degree of polarization of the 1(ππ*)
Fig. 2 LC-DAD traces of an irradiated sample of TBZ2@CB8 (20 μM),
300 (red) and 400 (blue) nm. The inset shows the UV-Vis spectra
obtained at 8.80 and 11.16 min.
non-identified products (7, 8) were also detected (m/z 179 and excited state. Cucurbiturils are known to bind and stabilize cat-
239, Fig. S13b, ESI†).
ionic guests and reaction intermediates5–7 and shift the
In the presence of CB8 at pH 6.5 the same products were effective pKa values of included guests.33,34 As an example, the
observed (Fig. S12b, ESI†). However, at pH 1.2 and in the pres- stabilization of reaction intermediates by cucurbit[7]uril has
ence of CB8 new photoproducts absorbing above 350 nm are been invoked to explain its catalytic effect over the solvolysis of
formed (Fig. S12b, ESI†). The LC-DAD traces at 400 nm con- benzoyl chlorides undergoing a dissociative mechanism.35 The
firmed the presence of a major product at 8.80 min (Fig. 2). inclusion of BZ in CB8 is expected to stabilize the cationic
The new photoproduct has an absorption maximum at intermediates promoting the photohydrolysis process.
390 nm, which indicates that a compound is formed with a
more extended π conjugation than TBZ (inset of Fig. 2).
The formation of photodimers after irradiation of
1 : 2 host–guest complexes with CB8 is known.8–17 However,
The LC-MS traces in the positive polarity revealed a peak at dimerizations resulting from cycloaddition reactions involving
m/z 373, indicating a molecular weight of 372 Da. This is in double bonds would reduce the π conjugation and lead to pro-
agreement with the UV-Vis spectra, as the compound shows ducts with a blue-shifted absorption compared to TBZ. Com-
higher mass than TBZ. Consecutive fragmentation studies pound 9 shows a red-shifted absorption with higher π
(MSn) gave further insights into the structure. The first two conjugation than TBZ, suggesting that photocyclodimerization
consecutive fragmentations (MS2 and MS3) gave rise to con- is not the major reaction process. These photoproduct studies
secutive losses of 45 and 28 Da (Fig. S14, ESI†). MS4 shows the suggest that CB8 brings together the reactive sites of TBZ
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formation of 9. The observation of product 9 at pH 1.2 but not
at pH 6.5 indicates that the pH has a fundamental role in the
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CB8 forms 1 : 2 host–guest complexes with BZ and TBZ in
aqueous solutions. The inclusion of BZ within CB8 promotes
the photohydrolysis of the CvN bond to form 2-aminoform-
anilide (3). The photoreactivity of TBZ is centred in the thiazole
ring. However, at pH 1.2 TBZ2@CB8 shifts to an orientation
that brings together two thiazole rings, subsequently forming
a photoproduct with extended π conjugation. The formation of
stable BZ2@CB8 and TBZ2@CB8 host–guest complexes asserts
the potential of cucurbiturils for drug delivery of benzimid-
azole compounds.33,34 Furthermore, cucurbiturils might
also be used to prepare controlled-release formulations for
pesticide applications.36
Acknowledgements
JS and ET wish to acknowledge the KONTAKT AMVIS project
LH11018 for financial support. JS is grateful for the stay at the
laboratory of Dr J. P. Da Silva in the framework of the
ERASMUS project. SJ thanks NSF for financial support
through grant CHE-1111392. TRB thank the MINECO
(CTQ2011–24502) for financial support.
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S. Yamadab, Regiospecific [2 + 2] photocyclodimerization
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