Synthesis, spectroscopy studies, and theoretical calculations of new fluorescent probes based on pyrazole containing porphyrins for Zn(II), Cd(II), and Hg(II) optical detection

Article abstract of DOI:10.1021/ic500634y

New pyrazole-porphyrin conjugates were successfully prepared from a reaction of β-porphyrin-chalcone derivatives with phenylhydrazine in acetic acid followed by an oxidative step. This fast and efficient synthetic approach provided the expected compounds in yields up to 82%. The sensing ability of the new porphyrin-pyrazole derivatives to detect the metal ions Ag⁺, Na⁺, K⁺, Mg²⁺, Ca²⁺, Ni ²⁺, Cu²⁺, Zn²⁺, Cd²⁺, Hg ²⁺, Pb²⁺, and Cr³⁺ was studied by spectrophotometric and spectrofluorimetric titrations. In the presence of Zn²⁺, the conjugates exhibit changes in the emission spectra that are desired for a ratiometric-type fluoroionophoric detection probe. The studies were extended to gas phase, where the pyrazole-porphyrin conjugates show ability to sense metal ions with high selectivity toward Cu²⁺ and Ag ⁺, and in poly(methyl methacrylate) doped films with promising results for Zn²⁺ detection.

Full text of DOI:10.1021/ic500634y

Article
pubs.acs.org/IC
Synthesis, Spectroscopy Studies, and Theoretical Calculations of New
Fluorescent Probes Based on Pyrazole Containing Porphyrins for
Zn(II), Cd(II), and Hg(II) Optical Detection
Nuno M. M. Moura,†,‡,§ Cristina Nunez,‡,∥,⊥ Sergio M. Santos,# M. Amparo F. Faustino,†
́
́
̃
Jose A. S. Cavaleiro,† M. Graca P. M. S. Neves,*,† Jose Luis Capelo,‡,§ and Carlos Lodeiro*,‡,§
̧
́
́
†Department of Chemistry and QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal
‡BIOSCOPE Group, REQUIMTE-CQFB, Chemistry Department, Faculty of Science and Technology, University NOVA of Lisbon,
2829-516 Caparica, Portugal
§ProteoMass Scientific Society, Madan Park, Rua dos Inventores, 2825-182, Caparica, Portugal
∥Department of Geographical and Life Sciences, Canterbury Christ Church University, CT1 1QU Canterbury, United Kingdom
⊥Inorganic Chemistry Department, Faculty of Chemistry, University of Santiago de Compostela, 15782 Santiago de Compostela,
Spain
#Department of Chemistry and CICECO, University of Aveiro, 3810-193 Aveiro, Portugal
S
* Supporting Information
ABSTRACT: New pyrazole−porphyrin conjugates were successfully prepared from
a reaction of β-porphyrin−chalcone derivatives with phenylhydrazine in acetic acid
followed by an oxidative step. This fast and efficient synthetic approach provided the
expected compounds in yields up to 82%. The sensing ability of the new porphyrin−
pyrazole derivatives to detect the metal ions Ag+, Na+, K+, Mg2+, Ca2+, Ni2+, Cu2+,
Zn2+, Cd2+, Hg2+, Pb2+, and Cr3+ was studied by spectrophotometric and spectrofluorimetric titrations. In the presence of Zn2+,
the conjugates exhibit changes in the emission spectra that are desired for a ratiometric-type fluoroionophoric detection probe.
The studies were extended to gas phase, where the pyrazole−porphyrin conjugates show ability to sense metal ions with high
selectivity toward Cu2+ and Ag+, and in poly(methyl methacrylate) doped films with promising results for Zn2+ detection.
recognition via H-bonding or via deprotonation of the NH in
the receptor.7 Recently, pyrazole based compounds due to their
metal coordination ability have been used as molecular
detection probes of metal ions, such Zn2+, Cd2+, and Hg2+.8
Monitoring soft metal ions such as zinc(II) and copper(II) is
of particular interest due to their well-known significant
biological functions.9,10 Additionally, the high toxicity for living
organisms of heavy metals like mercury(II) and cadmium(II)
makes their detection also a subject of high relevance.11,12
Porphyrins and related macrocycles exhibit interesting
features, such as large Stokes shifts and relatively long excitation
(>400 nm) and emission (>600 nm) wavelengths, to be used as
fluorescent probes.13,14 In fact, several studies show that
porphyrinic derivatives adequately functionalized in meso-
positions are excellent candidates to be used in the detection
of metal ions such as Zn2+, Cd2+, Hg2+, or Pb2+.15 However,
most of the work using porphyrins as molecular probes in the
detection of metal ions is based on macrocyles functionalized
with adequate binding units in meso-positions, and as far as we
know, much less attention is being given to β-funtionalized
porphyrins.16
INTRODUCTION
■
In recent years, the design and synthesis of new optical probes
to be used in the recognition and sensing of a wide range of
analytes have emerged as a research area of considerable
importance.1 In fact, the selection of spectrophotometric and
spectrofluorimetric measurements as analytical tools has
obvious advantages when compared with other alternatives
due to the low cost, versatility, and accessibility of the
techniques associated.2
The molecular devices converting metal ion recognition in
physical recordable signals are continuously growing. Typically,
chemosensors are molecules of abiotic origin that are able to
selectively and reversibly bind the analyte. The main issue in
the design of any effective chemosensor is the association of a
selective molecular recognition event with a concomitant
change in one or more properties of the system, such as
absorption or fluorescence spectra.3,4 Changes in both the
absorption and emission of light can be utilized as signals to
detect and quantify some ions, working as chromophores and
fluorophores (dual probe).4,5 The criteria for these probes are
(i) stability, (ii) metal selectivity, (iii) metal affinity, (iv) signal
transduction, (v) fluorescent signaling, (vi) kinetically rapid
sensitization, and (vii) availability.6
Charged or neutral receptors bearing pyrrole, pyrazole,
amide, or imidazolium moieties have been used in anion
Received: March 19, 2014
© XXXX American Chemical Society
A
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Article
until total consumption of the starting porphyrin. After cooling, the
reaction mixture was washed with water and extracted with
dichloromethane. The organic phase was dried (Na2SO4), and the
solvent was evaporated under reduced pressure. The resulting residues
were crystallized from CH2Cl2/hexane, and the desired compounds
2a−d were obtained in quantitative yields.
Then, to the respective copper complex 2a−d (20 mg) dissolved in
acetic acid (2.0 mL), phenylhydrazine (1.5 equiv) was added, and the
resulting mixture was maintained under stirring for 1 to 5 h at 120 °C
(see Table 1). After the required period, the mixture was carefully
neutralized with an ice-cold aqueous saturated solution of Na2CO3
until pH 7, and the reaction mixture was extracted in CH2Cl2. The
organic layer was separated, dried (Na2SO4), and the solvent
evaporated.
The crude obtained was dissolved in dry toluene (1.5 mL), and after
adding o-chloranil (3 equiv), the resulting mixture was stirred for 1 h at
120 °C. After cooling, the reaction mixture was washed with water and
extracted with dichloromethane. The organic phase was dried
(Na2SO4), and the solvent was evaporated under reduced pressure.
The resulting residue was stirred under vigorous agitation in a
minimal amount of a 10% solution of H2SO4 in CHCl3, at room
temperature, for 15 min. The mixture was then carefully neutralized
with an ice-cold aqueous saturated solution of Na2CO3 and then was
extracted with CH2Cl2. The organic layer was separated and dried
(Na2SO4), and the solvent was evaporated under vacuum. The residue
was purified by column chromatography using CH2Cl2/petroleum
ether (3:1) as the eluent. Compounds 4a−d (see Table 1 for the
yields) were obtained pure after crystallization from CH2Cl2/hexane.
The fractions obtained were fully characterized by NMR, mass, and
UV/vis techniques.
Pyrazole derivatives are well known five membered hetero-
cycles with a broad spectrum of promising biological activity,
namely, as anticancer agents.17 Furthermore, pyrazoles are
recognized as important motifs to be used as ligands in
coordination chemistry, as building blocks in heterocyclic
synthesis, as optical brighteners, and UV stabilizers, and also as
units to construct supramolecular and photoinduced electron-
transfer systems.18
Recently, we described an efficient access to porphyrin-
pyrazoline and porphyrin−pyrazole derivatives via 1,3-dipolar
cycloaddition reactions involving N-aryl-C-ethoxycarbonylni-
trile imines, generated in situ by base-induced dehydrobromi-
nation of ethyl hydrazono-α-bromoglyoxylates and 2-vinyl-
5,10,15,20-tetraphenylporphyrin.19 Following our interest in β-
functionalization of meso-tetraarylporphyrins,20 namely, via the
formyl group,21 and considering that the conjugation of these
tetrapyrrolic macrocycles to pyrazoline/pyrazole entities could
potentiate their sensorial ability, we decided to consider here a
more conventional strategy22 to introduce those heterocyclic
moieties in the porphyrin core: the reaction of porphyrins
bearing chalcone units with hydrazine derivatives.
In this Article, we report an efficient synthesis of new
pyrazole−porphyrin conjugates, the photophysical character-
ization of these ligands, and also their coordination interaction
with metal ions via sensorial response to different metals in
solution, solid supports, and gas phase.
EXPERIMENTAL SECTION
2-(1,3-Diphenyl-1H-pyrazol-5-yl)-5,10,15,20-tetraphenylpor-
phyirin, 4a. 1H NMR (300 MHz, CDCl3): δ 8.87 (2H, d, J = 5.0 Hz,
H-β), 8.82−8.77 (2H, m, H-β), 8.77 (1H, AB, J = 5.0 Hz, H-β), 8.70
(1H, s, H-3), 8.67 (1H, AB, J = 5.0 Hz, H-β), 8.23−8.18 (4H, m, H-o-
Ph), 8.06 (2H, d, J = 6.9 Hz, H-o-Ph), 7.88 (2H, d, J = 6.9 Hz, H-o-
Ph), 7.89−7.63 (11H, m, H-m,p-Ph, and H-2‴,6‴), 7.49−7.45 (3H, m,
H-3‴,5‴, and H-4‴), 7.39−7.32 (5H, m, H-Ph, and H-2″,6″), 6.93−
6.89 (3H, m, H-3″,5″, and H-4″), 6.48 (1H, s, H-4′), −2.65 (2H, s,
NH) ppm. 13C NMR (75 MHz, CDCl3): δ 151.4, 142.02, 141.95,
141.7, 140.4, 140.1, 140.0, 134.7, 134.6, 134.5, 133.4, 133.1−129.9 (C-
β), 128.5, 128.3, 128.0, 127.8, 127.6, 126.8, 126.7, 126.6, 126.1, 126.0,
125.9, 123.4, 120.9, 120.5, 120.3, 108.5 ppm. UV−vis (CHCl3): λmax
(log ε) 423,0 (5.46), 519.0 (4.20), 555.0 (3.77), 594.0 (3.76), 651.0
(3.54) nm. MS (MALDI): m/z 833.3 [M + H]+. HRMS-ESI(+): m/z
calculated to C59H41N6 [M + H]+ 833.3387; found, 833.3392.
2-(1-Phenyl-3-(p-tolyl)-1H-pyrazol-5-yl)-5,10,15,20-tetraphenyl-
■
General Remarks. 1H and 13C solution NMR spectra were
recorded on Bruker Avance 300 (300.13 and 75.47 MHz, respectively)
and 500 (500.13 and 125.76 MHz, respectively) spectrometers. CDCl3
was used as solvent and tetramethylsilane (TMS) as internal reference;
the chemical shifts are expressed in δ (ppm) and the coupling
constants (J) in Hertz (Hz).
Unequivocal 1H assignments were made using 2D COSY (1H/1H),
while 13C assignments were made on the basis of 2D HSQC (1H/13C)
and HMBC (delay for long-range J C/H couplings were optimized for
7 Hz) experiments. Mass spectra were recorded using MALDI TOF/
TOF 4800 Analyzer (Applied Biosystems MDS Sciex), with CHCl3 as
solvent and without a matrix. Mass spectra HRMS were recorded on
an APEXQe FT-ICR (Bruker Daltonics, Billerica, MA) mass
spectrometer using CHCl3 as solvent; in m/z (rel. %). The UV−vis
spectra were recorded on an UV-2501 PC Shimatzu spectropho-
tometer using CHCl3 as solvent. Preparative thin-layer chromatog-
raphy was carried out on 20 × 20 cm glass plates coated with silica gel
(0.5 mm thick). Column chromatography was carried out using silica
gel (Merck, 35−70 mesh). Analytical TLC was carried out on
precoated sheets with silica gel (Merck 60, 0.2 mm thick).
1
porphyrin, 4b. H NMR (300 MHz, CDCl3) δ 8.87 (2H, AB, J = 4.9
Hz, H-β), 8.82−8.78 (2H, m, H-β), 8.76 (1H, AB, J = 4.9 Hz, H-β),
8.70 (1H, s, H-3), 8.67 (1H, AB, J = 4.9 Hz, H-β), 8.23−8.18 (4H, m,
H-o-Ph), 8.06 (2H, d, J = 6.9 Hz, H-o-Ph), 7.87 (2H, d, J = 6.9 Hz, H-
o-Ph), 7.80−7.61 (11H, m, H-m,p-Ph, and H-2‴,6‴), 7.37−7.29 (7H,
m, H-Ph, H-2″,6″, and H-3‴,5‴), 6.92−6.86 (3H, m, H-3″,5″, and H-
4″), 6.45 (1H, s, H-4′), 2.44 (3H, s, CH3), −2.66 (2H, s, NH) ppm.
13C NMR (75 MHz, CDCl3) δ 151.4, 142.03, 141.95, 141.7, 140.4,
140.1, 137.4, 134.7, 134.6, 134.5, 134.0−130.8 (C-β), 130.6, 129.2,
129.1, 128.3, 128.0, 127.81, 127.76, 126.8, 126.7, 126.6, 126.1, 125.9,
125.8, 123.4, 120.9, 120.5,120.2, 108.3, 21.4 (CH3) ppm. UV−vis
(CHCl3): λmax (log ε) 423.0 (5.41), 520.0 (4.12), 555.0 (3.67), 594.0
(3.57), 650.0 (3.43) nm. MS (MALDI): m/z 847.3 [M + H]+. HRMS-
ESI(+): m/z calculated to C60H43N6 [M + H]+ 847.3544; found,
847.3553.
All of the chemicals were used as supplied. Solvents were purified or
dried according to the literature procedures.23
Chemicals and Starting Reagents. AgBF4·xH2O, NaBF4, KBF4,
Mg(OTf)2, Ca(BF4)2·xH2O, Ni(BF4)2·xH2O, Cu(BF4)2·6H2O, Zn-
(BF4)2·xH2O, Cd(CF3SO3)2·xH2O, Hg(CF3SO3)2·xH2O, Pb(OTf)2,
and Cr(NO3)3·xH2O were purchased from Strem Chemicals, Sigma-
Aldrich, or Solchemar. All of these chemicals were used without
further purification. The solvents were obtained from Panreac and
Riedel-de-Haen and were used as received or distilled and dried using
̈
standard procedures.
Synthesis of the Porphyrinic Precursors. The porphyrin-
chalcone type derivatives 1a−d were prepared from 2-formyl-
5,10,15,20-tetraphenylporphyrin24 and aryl methyl ketones in the
presence of piperidine and catalytic amounts of La(OTf)3 in dry
toluene, according to a literature procedure.25
General Procedure for the Synthesis of the Organic Ligands.
A solution of the appropriate porphyrin-chalcone 1a−d (25.0 mg) in
CHCl3/MeOH (3:1) was stirred in the presence of Cu(OAc)2·H2O,
(1.5 equiv) for 30 min at 50 °C. The reaction was followed by UV/vis
2-(1-Phenyl-3-(4-nitrophenyl)-1H-pyrazol-5-yl)-5,10,15,20-tetra-
phenylporphyrin, 4c. 1H NMR (300 MHz, CDCl3): δ 8.88 (2H, AB, J
= 5.0 Hz, H-β), 8.82−8.79 (3H, m, H-β), 8.68−8.66 (2H, m, H-β),
8.32 (2H, AB, J = 8.9 Hz, H-3‴,5‴), 8.23−8.18 (4H, m, H-o-Ph), 8.04
(2H, d, J = 7.3 Hz, H-o-Ph), 7.97 (2H, AB, J = 8.9 Hz, H-2‴,6‴), 7.91
(2H, d, J = 7.3 Hz, H-o-Ph), 7.80−7.60 (9H, m, H-m,p-Ph), 7.38−7.28
(5H, m, H-m,p-Ph, and H-2″,6″), 6.99−6.90 (3H, m, H-3″,5″, and H-
4″), 6.53 (1H, s, H-4′), −2.67 (2H, s, NH) ppm. 13C NMR (75 MHz,
CDCl3): δ 148.9, 147.0, 141.9, 141.9,141.6, 140.9, 140.4, 140.0, 139.7,
B
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Scheme 1
134.7, 134.6, 134.5, 134.1−129.8 (C-β), 128.6, 128.5, 127.9, 127.8,
126.8, 126.73, 126.65, 126.57, 126.0, 124.0, 123.6, 120.59, 120.56,
120.4, 108.9 ppm. UV−vis (CHCl3): λmax (log ε) 423.0 (5.40), 519.0
(4.15), 554.0 (3.69), 593.0 (3.62), 652.0 (3.52) nm. MS (MALDI):
m/z 878.3 [M + H]+. HRMS-ESI(+): m/z calculated to C59H40N7O6
[M + H]+ 878.3238; found, 878.3239.
Spectrophotometric and Spectrofluorimetric Measure-
ments. Absorption spectra were recorded on a JASCO V-650
spectrophotometer, and fluorescence emission spectra were recorded
on a Horiba Jobin-Yvon Fluoromax 4 spectrofluorimeter. The linearity
of the fluorescence emission versus the concentration was checked in
the concentration range used (10−4−10−6 M). The correction of the
absorbed light was performed when it was considered necessary. The
spectrophotometric characterizations and titrations were performed by
preparing stock solutions of the compounds in chloroform (ca. 10−3
M) in a 10 mL volumetric flask. The studied solutions were prepared
by appropriate dilution of the stock solutions up to 10−5−10−6 M.
Titrations of the probes (4a−d) were carried out by the addition of
microliter amounts of standard solutions of the metal ions in
acetonitrile in a 1 cm quartz cell. All of the measurements were
performed at 298 K.
Luminescence quantum yields of compounds 4a−d were measured
using a solution of crystal violet in methanol as standard ([Φ] =
0.54),26 and all values were corrected taking into account the solvent
refractions index. Fluorescence spectra of solid samples were recorded
using a fiber optic system connected to a Horiba Jobin-Yvon
Fluoromax 4 spectrofluorimetric excited at appropriated λ (nm) of
the solid compounds.
Preparation of PMMA Polymer Films Doped with Com-
pound 4a. The preparation of the poly(methyl methacrylate)
(PMMA) film was performed by dissolving the PMMA powder
(100 mg) in chloroform, followed by the addition of ligand 4a (1−5
mg) dissolved in the same solvent. The polymer film was obtained
after evaporation of solvent at 40 °C under vacuum for 24 h.27,28
Because of the spectroscopic characteristics, the film doped with 5 mg
of the ligand was selected for the studies with the metal ions.
Theoretical Studies. Theoretical calculations were performed
using density functional theory with the B3LYP functional and the
LanL2DZ basis set using Gaussian 09.29 Default parameters were used
in all geometry optimizations.
2-(1-Phenyl-3-(2-pyridil)-1H-pirazol-5-yl)-5,10,15,20-tetraphenyl-
1
porphyrin, 4d. H NMR (300 MHz, CDCl3): δ 8.89 and 8.87 (2H,
AB, J = 5.0 Hz, H-β), 8.82−8.78 (3H, m, H-β), 8.74 (1H, AB, J = 4.9
Hz, H-β), 8.71 (1H, ddd, J = 1.7 and 4.9 Hz, H-6‴), 8.62 (1H, AB, J =
4.9 Hz, H-β), 8.23−8.17 (4H, m, H-o-Ph), 8.11 (2H, d, J = 7.0 Hz, H-
o-Ph), 7.87 (1H, d, J = 7.9 Hz, H-3‴), 7.82−7.67 (12H, m, H-o,m,p-
Ph, and H-4‴), 7.36−7.26 (6H, m, H-Ph, H-2″,6″, and H-5‴), 6.96
(1H, s, H-4′), 6.88−6.82 (3H, m, H-3″,5″, and H-4″), −2.65 (2H, s,
NH) ppm. 13C NMR (75 MHz, CDCl3): δ 152.2, 151.4, 149.3, 142.0,
141.9, 141.7, 140.5, 140.3, 139.7, 136.5, 134.7, 134.6, 134.5, 132.6−
139.7 (C-β), 128.2, 127.8, 127.8, 127.7, 126.8, 126.7, 126.2, 126.0,
123.2, 122.4, 121.0, 120.5, 120.4, 120.3, 120.2, 109.8 ppm. UV−vis
(CHCl3): λmax (log ε) 423.0 (5.53), 520.0 (4.25), 554.0 (3.81), 594.0
(3.72), 650.0 (3.60) nm. MS (MALDI): m/z 834.3 [M + H]+. HRMS-
ESI(+): m/z calculated to C58H40N7 [M + H]+ 834.3340; found,
843.3336.
Physical Measurements. The MALDI-MS analyses were
performed in a MALDI-TOF-TOF-MS model Ultraflex II (Bruker,
Germany) equipped with nitrogen, from the BIOSCOPE group. Each
spectrum represents accumulations of 5 × 50 laser shots. The
reflection mode was used. The ion source and flight tube pressure
were less than 1.80 × 10−7 and 5.60 × 10−8 Torr, respectively. The
MALDI mass spectra of the soluble samples (1 or 2 μg/μL) were
recorded using the “dried droplet” and the “layer-by-layer” sample
preparation methods. In both methods, the ligands were dissolved in
chloroform and the metal salts in acetonitrile, but the introduction in
the sample holder was different. In the dried-droplet method, the two
solutions containing the ligand (1 μL) and the metal salt (1 μL) were
mixed and then applied to the MALDI-TOF-MS sample holder. In the
layer-by-layer method, a solution of each ligand was spotted in the
MALDI-TOF plate and then dried; subsequently, 1 μL of the solution
containing the metal salt was placed on the sample holder, which was
then inserted into the ion source. In this case, the chemical reaction
between the ligand and the metal salts occurred in the holder, and the
complex species were produced in gas phase.
RESULTS AND DISCUSSION
■
Synthesis. The new pyrazole−porphyrin conjugates 4a−d
were synthesized as outlined in Scheme 1. The starting
porphyrin-chalcone derivatives 1a−d were prepared from the
condensation of 2-formyl-5,10,15,20-tetraphenylporphyrin24
with the adequate aryl methyl ketone using piperidine as base
C
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Inorganic Chemistry
Article
in the presence of catalytic amounts of La(OTf)3 according to
the literature.25
Table 1. Reaction Times and Overall Yields Obtained in the
Synthesis of Compounds 4a−d
In the first attempts to obtain 4a−d, we tried to perform the
reaction using the free-base chalcones 1a−d and phenyl-
hydrazine. The condensation was done in refluxing toluene, and
after 48 h of reaction, we were able to isolate the respective
porphyrin-pyrazoline derivative but in very low yields (∼20%)
and accompanied by an appreciable amount of the starting
porphyrin (∼75%). However, these pyrazoline derivatives were
highly unstable when subjected to chromatography and even
when kept under storage (Scheme 1, via 1). This fact prompts
us to modify the approach having in mind that the
condensation conditions must be improved and that we must
proceed directly to pyrazole−porphyrin conjugates without
purification of the pyrazoline intermediates (Scheme 1, via 2).
In an attempt to find better conditions for the reaction and
based on literature,30 we decided to use acetic acid as solvent.
We found that in this medium, the condensation of
phenylhydrazine with the free base porphyrins 1a−d did not
occur and that the starting porphyrin was fully recovered.
Therefore, in order to avoid the protonation of the inner core
of the macrocyle by the acidic medium, probably responsible
for the unsuccessful condensation with the free bases, we
decided to prepare the copper(II) complexes 2a−d following
the typical procedure described in the literature to introduce
this metal in porphyrins.31 After this key step, the reactions of
chalcones 2a−d with phenylhydrazine were performed at 60
°C, and after 1 to 5 h, depending on the porphyrin derivative
used, the reaction’s TLC revealed the absence of starting
metalloporphyrin 2a−d and the formation in all cases of only
one new product, the porphyrin-pyrazoline derivative 3a−d.
Then, the resulting crude obtained after workup was dissolved
in toluene, and refluxed for 1 h in the presence of o-chloranil (3
equiv). After this period, TLC monitoring revealed the total
consumption of the starting substrate and the formation of a
new more polar compound, which was then treated with 10%
H2SO4 conc/CHCl3 in order to remove the paramagnetic
metal. After workup and column chromatography (silica gel),
the pyrazole−porphyrin conjugates 4a−d were isolated in
yields between 82% and 87% (see in Table 1 the yields of the
compounds 4a−d obtained after optimization of the reaction
conditions).
a
i., complexation; ii., condensation with phenylhydrazine; iii.,
oxidation; and iv., descomplexation.
Table 2. Photophysical Data of Compounds 4a−d in CHCl3
and in Solid State at 298 K
λem
(nm)
Stokes shift
(nm)
compd λmax (nm)/log ε
ΦFlu λem (nm)solid
4a
4b
4c
4d
423:5.46
519:4.20
555:3.77
594:3.76
651:3.54
423:5.41
520:4.12
555:3.67
594:3.57
650:3.43
423:5.40
519:4.15
554:3.69
593:3.62
652:3.52
423:5.53
520:4.25
554:3.81
594:3.72
650:3.60
658, 719
660, 719
659, 720
660, 719
7
0.02 668, 737,
822
10
7
0.02 667, 732,
819
0.02 669, 738,
821
10
0.02 673, 731,
821
The structures of all conjugates were unambiguously
confirmed by spectroscopic data, namely, NMR, UV−vis, and
mass spectroscopy techniques.
1
The H NMR spectra of the pyrazole−porphyrin conjugates
4a−d are consistent with β-substituted porphyrins showing the
resonance of the corresponding H-3 as a singlet at ca. 8.7 ppm.
The hydrogens of the meso-phenyl groups appear as multiplets
between ca. 7.6 and 8.2 ppm, while the proton resonances of
the aryl group at position 3 in the pyrazole unit appear with the
expected AB pattern for compounds 4a and 4c. In the
particular case of compound 4d, the attribution of the signals
generated by the resonance of the hydrogens in the pyridine
ring were done using 2D COSY experiments. The resonances
of the N-phenyl group hydrogens appear as two multiplets in
ranges of 6.8−7.0 and 7.2−7.4 ppm.
Considering the resonances of the pyrazole moiety hydro-
gens, the most important features are the presence of a
characteristic signal at ca. 6.5 ppm due to the resonance of
hydrogen H-4′. As expected, the singlets generated by the inner
pyrrolic hydrogens appear around −2.65 ppm.
Figure 1. Absorption and normalized emission and excitation of
chemosensor 4b in CHCl3 ([4b] = 2.50 × 10−6 M, λexc4b = 601 nm,
and λemiss4b = 728 nm) and emission of spectra in solid state at room
temperature.
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Figure 2. Spectrophotometric (A) and spectrofluorimetric (B) titrations of compound 4a in chloroform as a function of added Zn2+ in acetonitrile.
The inset shows the partial absorption spectra between 500 and 750 nm (A). (C) Absorption at 521 and 563 nm and (D) the normalized
fluorescence intensity at 608 and 719 (B) ([4a] = 2.50 × 10−6 M, and λexc4a = 539 nm).
and 4d). In the same figure is also shown the emission spectra
obtained from the solid state of the same derivative.
Table 3. Stability Constants and Stoichiometry for
Chemosensors 4a−d in CHCl3 in the Presence of Zn2+, Hg2+,
Cd2+, and Cu2+
The absorption spectra of porphyrin−pyrazole type deriva-
tives 4a−d show the typical features of free base porphyrins due
to π−π* transitions: the highly intense Soret band at 423 nm
and the four well-defined Q bands with decreased intensity
between 519 and 652 nm. The perfect match between the
absorption and the excitation spectra rules out the presence of
any emissive impurity.
interaction
(M/L)
compd
Σ log β (Abs)
Σ log β (emiss)
4a
Zn2+ (1:2)
Hg2+ (1:2)
Cd2+ (1:2)
Cu2+ (1:2)
Zn2+ (1:2)
Hg2+ (1:2)
Cd2+ (1:2)
Cu2+ (1:2)
Zn2+ (1:2)
Hg2+ (1:2)
Cd2+ (1:2)
Cu2+ (1:2)
Zn2+ (2:1)
Hg2+ (2:1)
Cd2+ (2:1)
Cu2+ (2:1)
13.10 2.38 × 10−3
13.34 3.53 × 10−3
12.40 1.04 × 10−3
11.91 2.59 × 10−3
11.28 4.67 × 10−3
11.71 2.10 × 10−3
11.35 1.37 × 10−3
13.26 1.52 × 10−3
12.30 2.99 × 10−3
13.29 2.01 × 10−3
12.42 1.34 × 10−3
12.40 1.81 × 10−3
11.94 2.03 × 10−3
12.04 2.61 × 10−3
11.25 2.93 × 10−3
12.77 2.27 × 10−3
12.76 7.38 × 10−3
13.71 2.22 × 10−2
12.36 8.45 × 10−3
12.49 3.05 × 10−3
10.39 4.96 × 10−2
11.71 2.10 × 10−3
11.35 1.37 × 10−3
13.26 1.52 × 10−3
12.30 2.99 × 10−3
13.29 2.01 × 10−3
11.15 1.66 × 10−2
13.11 2.36 × 10−2
11.94 2.03 × 10−3
12.14 1.13 × 10−2
10.55 1.57 × 10−2
13.15 8.56 × 10−3
The fluorescence emission spectra of compounds 4a−d
obtained after excitation at ca. 595 nm present two bands
centered at ca. 660 and 720 nm that are characteristic of
porphyrin derivatives (see Figure 1) and where the first
vibrational mode of the fluorescence is more pronounced. The
porphyrin−pyrazole type derivatives 4a−e showed Stokes shifts
between 7 and 10 nm. The fluorescence quantum yields (ΦFlu),
determined by the internal reference method with respect to a
solution of crystal violet in methanol as a standard ([ΦFlu] =
0.54),26 are shown in Table 2. The values of fluorescence
quantum yields for compounds 4a−d were 0.02. Compounds
4a−d presented lower relative fluorescence quantum yields
(0.02) than the related free base porphyrins (ΦFlu of TPP =
0.11). The low fluorescence efficiency of this type of molecules
can probably be attributed to an alteration of the planarity of
the porphyrin core, due to the presence of the extra chain that
can be responsible by a more reduced π-electron mobility.32
The emission spectra of the solid powder of ligands 4a−d
were also measured, using a fiber optic system connected to the
Horiba Jobin-Yvon Fluoromax 4 (Table 2 and Figure 1). These
4b
4c
4d
Photophysical Characterization. The photophysical
characterization of compounds 4a−d was performed in
chloroform solution at 298 K, and the main photophysical
data are summarized in Table 2. In Figure 1 is shown the
absorption, excitation, and emission spectra of compound 4b as
an example of the pyrazole−porphyrin conjugates (see also
Figure S12 in Supporting Information for compounds 4a, 4c,
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Figure 3. Spectrophometric (A and C) and spectrofluorimetric (B and D) titrations of conjugates 4b and 4d in chloroform as a function of added
Hg2+ and Cu2+, respectively, in acetonitrile. The insets show the absorption at 423 and 446 nm (A) and at 519 and 543 nm (C); and the normalized
fluorescence intensity at 660 and 704 (B) and at 660 nm (D) ([4b] = [4d] = 2.50 × 10−6 M, λexc4b = λexc4d = 538 nm).
solid state spectra show fluorescence bands between 667 and
822 nm with maximum intensities different from the ones
observed in solution.
conjugate at 659 nm decreases significantly, while a new
fluorescent emission peak appears at 608 nm, leading to a
significant change in the ratio of F608/F659. This new emission
band, which increases with the addition of Zn2+, can be
assigned to a metal-to-ligand charge transfer and indicates the
generation of a new fluorophore arising from the metal-
loporphyrin association. Compounds 4b−d show spectral
behavior similar to the one described for compound 4a after
titration with Zn2+.
Metal Binding Studies. The sensorial ability of conjugates
4a−d toward the different charged metal ions Ag+, Na+, K+,
Mg2+, Ca2+, Ni2+, Cu2+, Zn2+, Cd2+, Hg2+, Pb2+, and Cr3+ was
investigated by the titration of the ligands, dissolved in
chloroform, with small amounts of the adequate metal salt
dissolved in acetonitrile. These experiments were followed by
UV/vis and fluorescence emission spectroscopy and were
performed at 25 °C. No changes were detected for compounds
4a−d when titrated with the metal ions Na+, K+, Ca2+, Mg2+,
Pb2+, Ni2+, Ag+, and Cr3+. The most significant changes in the
ground and excited states were observed in the presence of
Cu2+, Zn2+, Cd2+, and Hg2+.
The association constants for the interaction of Zn2+ with the
different ligands were determined using the HypSpec34
program and are summarized in Table 3. The results from
the titrations of conjugates 4a−d with Zn2+ suggest complex
formation in a stoichiometry of one metal ion per two ligands
(M/L = 1:2), with ligands 4a−c, and two metals per ligand
(M/L = 2:1), for ligand 4d. The binding modes between
ligands 4a−d and Zn2+ are shown in Figures 6 and 7 (see the
Theoretical Calculations section).
The titration of compounds 4a−d with Zn2+ induces
significant changes in the absorption spectra with a small
bathochromic shift (∼5 nm) of the initial Soret band. These
changes in the Soret band region are accompanied by a
decrease of the Q-band at ca. 520 nm, a small increase of the
band centered at ca. 555 nm, and by the formation of a new
band at 660 nm (Figure 2A). These changes in the absorption
spectra suggest the binding of the metal ion to the nitrogen
atoms in the inner core of the porphyrinic macrocycle without
deprotonation.33
Therefore, compounds 4a−d exhibit changes in the emission
spectra upon the binding of the Zn2+ ion typical for a
ratiometric-type fluoroionophoric probe.
The titration of ligands 4a−d with Hg2+ shows alterations
similar to the ones observed in the presence of Zn2+ but with a
more prominent red shift of the Soret band from 423 to 448
nm. This shift is accompanied by the formation of a new band
at ca. 670 nm and a drastic decrease of the four initial Q bands
centered between 520 and 652 nm; two well-defined isosbestic
points were observed at ca. 438 and 510 nm (see Figure 3A).
Meanwhile, a significant change also occurs in the fluorescent
emission spectrum of pyrazole−porphyrin conjugates 4a−d
after the addition of Zn2+, as is exemplified in Figure 2B for
compound 4a. The fluorescent emission intensity of this
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intensity in the presence of this metal for all conjugates was
detected.
The addition of Cu2+ to conjugates 4a−d induces in the first
part of the titration, a decrease in the Soret band and in the Q-
band centered at ca. 520 nm with the concomitant appearance
of a new band at ∼660 nm. However, in the last part of the
titration a decrease of this red-shifted band that was followed by
the appearance of a more prominent band at 544 nm and a
small hypsochromic shift of the initial Soret band (ca. 4 nm)
were observed. These final spectral changes can be attributed to
the formation of the copper(II) complex. The formation of a
well-defined isosbestic point at 530 nm is in accordance with
the presence of two species in solution, corresponding to the
free ligand and to the metal complex. These changes in the
ground state are exemplified in Figure 3C for compound 4d.
Considering the emission spectra, the addition of Cu2+ is
responsible for the quenching of ca. 99% in the two bands
centered at ca. 660 and 719 nm as is exemplified in Figure 3D
for compound 4d. This behavior can be justified by
nonradiative deactivation processes due to the Cu2+ heavy
metal effect. This phenomenon is particularly favored in the
presence of paramagnetic metals.36 Therefore, compounds 4a−
d exhibit fluorescence quenching upon the binding of the Cu2+
ion typical of on−off type fluoroionophoric probes. The
stability constants for the interaction of compounds 4a−d with
Cu2+ were also determined and are summarized in Table 3,
maintaining the stoichiometry observed for the other metals.
MALDI-TOF-MS and Solid Support Studies. Since the
pyrazole−porphyrin conjugates 4a−d revealed promising
ability for the detection of metal ions in solution, we decided
also to study their ability as metal ion chemosensors in gas
phase and in solid state supports. The interaction of conjugates
4a, as representatives of ligands 4a−c, and 4d, as molecular
probes in gas phase, was studied by MALDI-TOF-MS in the
presence of Cu2+, Zn2+, Cd2+, Ag+, and Hg2+ ions using molar
ratios of metal/ligand of 2:1, 1:1, and 1:2. The ligands were
dissolved in chloroform and the metal salts in acetonitrile as
previously described. The metal ion titrations were performed
using the dried-droplet approach and layer-by-layer deposition
(see Experimental Section). In both methods, the pyrazole−
porphyrin conjugates act as an internal matrix.
In the titrations with Cu2+as exemplified in Figure 4 for
compound 4d, the peak at m/z = 833.1 was unambiguously
identified as corresponding to the free base molecular ion [L]+•.
After the addition of 0.5 equiv of Cu2+, the peak at 893.8 m/z
with 100% of intensity was identified as being due to the
mononuclear species [(4d-2H)+Cu(II)]+•. A second peak at
m/z 956.7 whose intensity increases with the ratio metal/ligand
was attributed to the dinuclear species [(4d-2H)+2Cu(II)]+•.
The peak assigned to the free-base ligand disappears after the
addition of 1 equiv of Cu2+ when the layer-by-layer deposition
method was used and after the addition of 2 equiv when the
dried-droplet approach was used (see Figure 4). The titrations
with Ag+ shows behavior similar to the one described for Cu2+,
but the peaks detected at 940 and 1048 m/z were assigned to
the mono- and dinuclear species [4d+Ag(I)]+ and [4d
+2Ag(I)]+•, respectively; in these cases, the ligands maintained
the nitrogen inner protons.
Figure 4. MALDI-TOF mass spectra of compound 4d before (A) and
after titration with 0.5 (B), 1.0 (C), and 2.0 (D) equiv of Cu(BF4)2·
6H2O using the layer-by-layer deposition method.
In the excited state, upon the addition of Hg2+ aliquots to
pyrazole−porphyrin conjugates 4a and 4b a decrease in the
emission intensity of the two initial bands centered at ca. 660
and 719 nm followed by the formation of a new band at 704
nm (Figure 3B) was observed. It is worth noting that usually
the Hg2+ ion acts as a fluorescence quencher via a spin−orbital
coupling effect.35 In fact, this was the behavior of ligands 4c and
4d upon binding with Hg2+ where a quenching of the two initial
bands was detected. The stability constants for the interaction
of compounds 4a−d with Hg2+ and the stoichiometry of the
complexes are summarized in Table 3.
In the others metal titrations, peaks corresponding to the
mononuclear species [L+M]+• but with low intensity were
detected. In some cases, as in the titration of compound 4d
with Hg2+ by dried-droplet deposition only the peak assignable
to the protonated ligand was detected (see Table S1,
When compounds 4a−d were titrated with Cd2+, the spectral
changes in the ground state were analogous to the ones
described in the titrations with the previous metal ions. In the
excited state, a pronounced quenching (∼55%) in the emission
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Figure 5. (a) Physical appearance of a PMMA film doped with compound 4a at visible light (top row) and under an UV lamp (λ = 365 nm) (bottom
row). (b) Emission spectra of the PMMA doped film with compound 4a and after immersion in aqueous Zn2+. (Dried films after 1, 4, 9, 14, 19, 24,
29, and 24 min, [Zn2+] = 1.0 × 10−3 M, and λexc4a = 539 nm.)
Figure 6. Two views of the 1:2 (M/L) complex involving Zn2+ and 4a, in which one of the ligands has been replaced by a 4a-like replacement (see
main text for additional details), as calculated at the B3LYP/LanL2DZ level. The inset highlights the N···Zn2+ distances in the same orientation as
the complex. Color code: teal/beige, carbon; green, zinc; blue, nitrogen; white, hydrogen (noninteracting hydrogens have been omitted for the sake
of clarity).
Figure 7. Two views of the 2:1 (M/L) complex involving Zn2+ and 4d, as calculated at the B3LYP/LanL2DZ level. The remaining details are as
described in Figure 6.
Supporting Information). These results suggest the instability
Considering the possibility of constructing a real solid sensor
based on the reported compounds, we prepared thin films using
the low cost polymer poly(methyl methacrylate) (PMMA) and
ligand 4a, in the absence of water. The fluorescence emission
properties of the polymer doped with the selected conjugate
were explored using an optical fiber device connected to the
spectrofluorimeter. The strategy is very simple and is
commonly applied to emissive lanthanide complexes that
of the complexes formed when the titrations were performed
using the same stoichiometric metal/ligand amounts.
The MALDI-TOF-MS studies suggest that ligands based on
pyrazole−porphyrin conjugates 4a−d can be used to sense
metal ions in gas phase with high selectivity toward Cu2+ and
Ag+.
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increase the luminescence and brightness in the absence of
water.37
CONCLUSIONS
■
In this work, an efficient access to prepare the new pyrazole−
porphyrin conjugates 4a−d that use the tetrapyrrolic core and
the pyrazole moiety as the signaling fluorophore and as metal
ion receptor was developed. The binding of these new
conjugates with Zn2+ induces significant changes in the ground
state and in the ratio of the fluorescence peaks typical from a
ratiometric-type fluoroionophoric probe. Upon their binding
with Cu2+, pyrazole−porphyrin ligands present a quenching of
the emission intensity characteristic of an on−off type
fluoroionophoric probe. When the ability of these conjugates
in the detection of metal ions in gas phase is combined to their
immobilization in PMMA films, pyrazole−porphyrin conjugates
emerge as versatile porphyrin-based molecular sensors.
The PMMA doped films were immersed in an 1.0 × 10−3
M
aqueous solution of Zn2+, Cu2+, Cd2+, Ag+, or Hg2+ at room
temperature and dried with air. The emission intensity was
measured after each spraying. In Figure 5 is represented the
variation in the fluorescence intensity of PMMA film doped
with conjugate 4a in the presence of aqueous Zn2+. It clearly
shows an interaction with the ligand, and as a consequence, the
fluorescence emission with a maximum at 719 nm was
enhanced over time.
When the PMMA doped films were sprayed with aqueous
solutions of others metal ions under study (Cu2+, Cd2+, Hg2+,
or Ag+), no variation in the fluorescence intensity were
observed. These preliminary results show clearly a promising
application of pyrazole−porphyrin conjugates in the PMMA
polymer as a new solid supported metal chemosensor to detect
Zn2+ in water.
Theoretical Calculations. The conformational aspects
pertaining to the complexation of 4a and 4d to the metal
cations in their experimentally determined 2:1 and 1:2 (metal-
to-ligand) stoichiometries, respectively, were studied through
density functional theory (DFT) calculations. The Zn2+
complexes were chosen as being representative of the
remaining binding arrangements. In the case of 4d, where
two ligand molecules bind to a single metal cation, one of the
ligand molecules was replaced by a model ligand to reduce
conformational degrees of freedom while still being representa-
tive of the entire complex, particularly the interaction of the
pyrazole fragment with the cation and the porphyrinic core of
the other ligand.
ASSOCIATED CONTENT
* Supporting Information
Full nuclear magnetic ressonance data for all new compounds
and additional photophysical characterization of compounds
4a, 4c, and 4d, and major peaks observed in the metal titration
of chemosensor 4d. This material is available free of charge via
the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Authors
*(M.G.P.M.S.N.) Tel: +351 234370710. Fax: +351 234370084.
E-mail: gneves@ua.pt.
*(C.L.) Tel: +351 212948300. Fax: +351 212948550. E-mail:
cle@fct.unl.pt.
■
Notes
The authors declare no competing financial interest.
In Figure 6 is shown the lowest energy conformation of the
complex formed by one 4a ligand, one 4a-like ligand, and a
single Zn2+ cation, modeling the 1:2 (M/L) complex. The
cation sits inside the porphyrinic core, slightly above the plane
defined by the four core nitrogens, coordinating to the
porphyrin nitrogens with Nporphyrin···Zn2+ distances ranging
from 2.14 to 2.31 Å. The pyrazole fragment from the other
ligand hovers over the porphyrinic core of the first ligand,
allowing the establishment of a shorter Npyrazol···Zn2+
interaction with length 2.02 Å. The two phenyl fragments
attached to the pyrazole ring are almost coplanar with the
porphyrin core of the other ligand, suggesting the possibility of
π···π interactions between both aromatic systems. The entire
binding arrangement leads to a coordination sphere resembling
a square-based pyramid.
In the 2:1 (M/L) complexation involving ligand 4d (Figure
7), one of the metals sits, similarly to that in the complex with
4a, inside the porphyrinic core, just slightly above the plane
defined by the four nitrogens. In this case, the Nporphyrin···Zn2+
distances are slightly shorter, ranging from 2.03 to 2.25 Å; the
two inner-core protons point outside the ring, opposite the
cation, thus minimizing the electrostatic repulsion between
themselves and the cation. The two Nporphyrin···Zn2+ distances
involving the protonated nitrogens are ca. 0.1 to 0.2 Å longer
than the remaining two (a similar result is encountered in the
complex involving 4a). The second Zn2+ cation coordinates to
the pyrazole fragment through the chelate pyrazole and
pyridine nitrogens, leading to the N···Zn2+ distances of 1.98
and 2.03 Å.
ACKNOWLEDGMENTS
We are grateful to the Universidade de Aveiro, Fundaca
■
̧
o para a
̃
Cien
̂
cia e a Tecnologia (FCT), European Union, QREN,
FEDER, and COMPETE for funding the QOPNA research
unit (project PEst-C/QUI/UI0062/2013). We acknowledge
the Portuguese National NMR Network (RNRMN), supported
by funds from FCT, Scientific PROTEOMASS Association
(Portugal), and REQUIMTE (PESt-C/EQB/La0006/2013)
for general funding. N.M.M.M. and S.M.S. thank FCT/MEC
for their Post-Doctoral Grants SFRH/BPD/84216/2012 and
SFRH/BPD/64752/2009. C.N. thanks the Xunta de Galicia
(Spain) for her postdoctoral contract (I2C program).
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