Nanomolar Detection of Palladium (II) through a Novel Seleno-Rhodamine-based fluorescent and colorimetric chemosensor

Article abstract of DOI:10.1016/j.dyepig.2020.108355

A novel reversible fluorescent probe for Pd²⁺ based on a rhodamine-containing selenide (Rh–Se) was designed, synthesized and fully characterized. The probe Rh–Se showed a high selectivity and sensitivity with a detection limit of 32 nM for Pd²⁺ ions. The formation of a complex Rh–Se/Pd²⁺ was confirmed by HRMS. DFT calculations revealed that the proposed square planar geometry is the most stable form of the metallic complex Rh–Se/Pd²⁺. The probe Rh–Se showed to have high potential for the detection of residual Pd²⁺ in synthetic cross-coupling products and simulated pharmaceutical Pd²⁺- contaminated products.

Full text of DOI:10.1016/j.dyepig.2020.108355

Dyes and Pigments 179 (2020) 108355
Contents lists available at ScienceDirect
Dyes and Pigments
journal homepage: http://www.elsevier.com/locate/dyepig
Nanomolar Detection of Palladium (II) through a Novel
Seleno-Rhodamine-based fluorescent and colorimetric chemosensor
a,b,
^
Antonio A. Soares-Paulino
*, Lilian Giroldoa, Noriberto A. Pradiea, Joel S. Reisd,
c
a
d
b,e,**
�
Davi F. Back , Ataualpa A.C. Braga , Helio A. Stefani , Carlos Lodeiro
,
Alcindo A. Dos Santosa
,
***
a
~
~
Departamento de Química Fundamental, Instituto de Química, Universidade de Sao Paulo, Av. Prof. Lineu Prestes, 748, 05508-000, Sao Paulo, SP, Brazil
b BIOSCOPE Group, LAQV-REQUIMTE, Chemistry Department, NOVA Science and Technology School, NOVA University School, 2829-516, Portugal
c
�
^
Departamento de Química, Laboratorio de Materiais Inorganicos, Universidade Federal de Santa Maria, Av. Roraima, n.1000, 97105-900, Santa Maria, RS, Brazil
d
�
^
^
~
~
Departamento de Farmacia, Faculdade de Ciencias Farmaceuticas, Universidade de Sao Paulo, Av. Prof. Lineu Prestes, 580, 05508-000, Sao Paulo, SP, Brazil
e Proteomass Scientific Society, Rua dos Inventores, Madan Park, 2829-516, Caparica, Portugal
A R T I C L E I N F O
A B S T R A C T
A novel reversible fluorescent probe for Pd2þ based on a rhodamine-containing selenide (Rh–Se) was designed,
synthesized and fully characterized. The probe Rh–Se showed a high selectivity and sensitivity with a detection
limit of 32 nM for Pd2þ ions. The formation of a complex Rh–Se/Pd2þ was confirmed by HRMS. DFT calculations
Keywords:
Selenium
Palladium
Rhodamine
Fluorescence
Probe
revealed that the proposed square planar geometry is the most stable form of the metallic complex Rh–Se/Pd2þ
.
The probe Rh–Se showed to have high potential for the detection of residual Pd2þ in synthetic cross-coupling
products and simulated pharmaceutical Pd2þ- contaminated products.
Naked-eye
1. Introduction
properties. These facts are intimately related to their hardness and
softness, as well as their redox properties. In general, the higher the
Rhodamines, compounds that belong to the class of xanthenes, are
known for their excellent photophysical properties, such as high quan-
tum yield, great photostability, high extinction coefficient and emission
with relative long wavelength [1]. Due to these properties, it has being
employed for many different applications like laser dyes [2], yield
quantum standards [3], photosensitizers [4], imaging of live cells [5]
and chemosensors [6]. In the last two decades, several rhodamine-based
probes were developed for diverse applications, including detection of
metals [7–10], endogenous oxidants [11] and thiols [12], pH [13] and
enzymatic activity measurement instruments [14]. The selectivity of
these probes is usually modified through the functionalization of the
spirolactam ring with different tags.
atomic radius the higher the soft character of the chalcogen, as well as its
potential of reduction, which directs the interaction with a specific an-
alyte. Taking advantage of these characteristics, the chalcogens have
been applied in the synthesis of new fluorescent probes to detect mainly
endogenous oxidants [15–19], thiols [20,21] and some metals [22–25].
Palladium is a transition metal belonging to the 10th group of the
Periodic Table. It was discovered by Willian Hyde Wollaston in 1803 and
since its discovery, it has gained applications in several areas as part of
automotive catalytic converters, fuel cells, jewels, dental products,
medical devices, electrical contacts and catalyst in chemical trans-
formations [26]. Concerning this last application, palladium is consid-
ered one of the most effective, versatile, robust and widely explored
metals as catalyst, promoting a myriad of unique transformations
[27–30]. However, the contamination with high levels of this metal can
represent a risk to the human health, once palladium can form stable
Recently, the chalcogen elements (especially sulfur and less
frequently, but also selenium) are being explored like component tags in
the preparation of probes due to their unique chemical bonding
~
~
* Corresponding author. Departamento de Química Fundamental, Instituto de Química, Universidade de Sao Paulo, Av. Prof. Lineu Prestes, 748, 05508-000, Sao
Paulo, SP, Brazil.
** Corresponding author. BIOSCOPE Group, LAQV-REQUIMTE, Chemistry Department, NOVA Science and Technology School, NOVA University School, 2829-516,
Portugal.
*** Corresponding author.
E-mail addresses: antonioasp88@gmail.com (A.A. Soares-Paulino), cle@fct.unl.pt (C. Lodeiro), alcindo@iq.usp.br (A.A. Dos Santos).
https://doi.org/10.1016/j.dyepig.2020.108355
Received 13 February 2020; Received in revised form 10 March 2020; Accepted 11 March 2020
Available online 18 March 2020
0143-7208/© 2020 Elsevier Ltd. All rights reserved.

A.A. Soares-Paulino et al.
Dyes and Pigments 179 (2020) 108355
complexes with some biomolecules like DNA, RNA, proteins and amino
acids leading to disturbs in a variety of cell processes [26]. One of the
most used analytical techniques to detect and quantify the presence of
palladium in a sample is the inductively coupled plasma mass spec-
trometry (ICP-MS). Although it is a highly sensitive and selective
method, this technique presents a high financial cost, requires well
trained people to operate the equipment and presents complex sample
preparation processes [31]. Alternatively, methods using fluorescent
probes have been extensively explored in recent years [32]. They are
usually based on the catalytic action of palladium cleaving the C–O bond
in allyl and propargyl ethers, where occasionally the addition of addi-
tives like PPh3 and reducing agents is required [33,34]. Other recently
explored methods use coordination compounds where a Pd-complex is
formed through binders containing amines and sulfides [32,35].
In the present study, a selected selenide and the rhodamine moieties
were conjugated to synthesize a new naked-eye fluorescent probe for the
fast detection of palladium with high selectivity and sensitivity. The
molecular probe acts by complexation with palladium by opening of the
spirolactam ring of rhodamine unit, exhibiting an orange fluorescence
answer in good global yield. The Rh–Se probe was fully characterized by
HRMS, 1H NMR, 13C NMR, 77Se NMR, IR, UV–vis, fluorescence and X-
ray diffraction. Additionally, theoretical investigations were conducted
elucidating the mechanism of interaction of the selenide with the metal
ion.
solved by direct methods using SHELXS [38]. Subsequent
Fourier-difference map analyses yielded the positions of the
non-hydrogen atoms. Refinements were carried out with the SHELXL
package [38]. All refinements were made by full-matrix least-squares on
F2 with anisotropic displacement parameters for all non–hydrogen
atoms. Hydrogen atoms were included in the refinement in calculated
positions but the atoms (hydrogen) that are commenting performing
special bond were located in the Fourier map. Drawings were done using
ORTEP-3 for Windows [39]. The pH measurements were recorded on a
Digimed DM-20. The equipment presented the same values of pH, in a
range of 2–12, in an organic/aqueous medium (EtOH/H2O 1:1) when
compared to a purely aquous medium through the addition of HCl e
NaOH.
2.3. Spectrophotometric and spectrofluorimetric measurements
Ultraviolet–visible (UV–vis) spectra were recorded on an Agilent
Technologies Cary 60 spectrophotometer, with a quartz cuvette (path
length, 1 cm). The fluorescence spectra were recorded on a Shimadzu
RF-5301PC spectrofluorimeter (slit widths at excitation and emission of
the spectrofluorimeter are 5-5). A correction for the absorbed light was
performed when necessary. The spectroscopic characterizations and ti-
trations were performed by preparing stock solutions of compound
Rh–Se in EtOH (ca. 10À 3 mol/L) in a 1 mL volumetric flask. The studied
solutions were prepared by appropriate dilution of the stock solutions in
EtOH/H2O (50:50, v/v). All the measurements were performed at 298 K.
The association constant (log K) were obtained from software HypSpec
[40]. Fluorescence quantum yields (Φ) of Rh–Se were measured using a
solution of rhodamine B in absolute ethanol as standard (Φ ¼ 0.70) [41]
and is calculated using the equation:
2. Experimental section
2.1. Chemicals and starting materials
Methyl 2-aminobenzoate, hydrochloric acid (HCl), sodium nitrite
(NaNO2), Sodium tetrafluoroborate (NaBF4), sodium acetate (AcONa),
ethane-1,2-diamine, 1-(4-bromophenyl)ethanone, potassium phenyl-
trifluoroborate, 4-methylbenzene-1-sulfonyl chloride (TsCl), 4-dimethy-
laminopyridine (DMAP), rhodamine-B were purchased from Sigma-
Aldrich. The 1,2-dimethyldiselane (Me2Se2) was prepared as reported
in the literature [36,37]. Metallic salts: Al(NO3)3⋅9H2O, Cr(NO3)3⋅9H2O,
Ga(NO3)3, Co(NO3)2⋅6H2O, Nd(NO3)3⋅6H2O, Pb(ClO4)2⋅3H2O, Ni
(ClO4)2⋅6H2O, Ca(ClO4)2⋅4H2O, Mg(ClO4)⋅6H2O, Zn(ClO4)2⋅6H2O, Cd
(ClO4)2⋅6H2O, Hg(ClO4)2⋅XH2O, Fe(ClO4)3⋅XH2O, Mn(ClO4)2⋅6H2O,
AgClO4, Fe(ClO4)2⋅XH2O, Ba(ClO4)2, LiClO4, Co(ClO4)2⋅6H2O, KCl,
CeCl3, RuCl3⋅3H2O, HAuCl4⋅3H2O, PtCl2, PdCl2, PdBr2, Pd(PhCN)2Cl2,
Pd(AcO)2, Pd(dppe)2, Pd(dba)2, [PdCl(allyl)]2, Pd-PEPPSI-SIPr,
Pd-PEPPSI-IPr, Pd(dppf)Cl2.CH2Cl2, Pd(acac)2 and Pd(PPh3)2Cl2 were
purchased from Alpha Aesar and used as received. All salts were dis-
solved in distilled water except the palladium, platinum and ruthenium
salts, which were dissolved in dimethyl sulfoxide (DMSO). CAUTION!
All compounds (intermediates, reagents and final products) were
manipulated in a fume hood and avoiding contact with skin.
À
�
R
2
Risample
sample
std
R
ФSample
¼
x
x ФStd
(1)
ðRistdÞ2
Φsample and Φstd are the radiative quantum yields of sample and the
standard respectively, Risample and Ristd are the refractive indices of the
sample and standard solutions (pure solvents were assumed respec-
R
R
tively), sample and std the respective areas of emission for sample
and standard. The sample and the standard were excited at the same
wavelength, maintaining equal absorbance. For Detection (LOD) and
quantification (LOQ) limits, ten different analyses for the selected re-
ceptor were performed in order to obtain the LOD and LOQ. The LOD
and LOQ were obtained by applying the formula:
LOD ¼ yblank þ3 std
LOQ ¼ yblank þ 10 std
(2)
(3)
Where yblank ¼ signal detection limit and std ¼ standard deviation.
2.2. Instrumentations
2.4. Computational procedures
Nuclear magnetic resonance (NMR) spectra were recorded on a
Bruker Avance III 200 (200 MHz, 1H; 50 MHz, 13C; 38 MHz, 77Se) and
Bruker DPX 300 (300 MHz, 1H; 75 MHz, 13C) using CDCl3 as solvent and
tetramethylsilane (0 ppm) and diphenyl diselenide (463 ppm) as scale
calibrating standards. High-resolution mass spectra (HRMS) were
recorded at micrOTOF-QII Bruker mass spectra (by electron spray time-
of-flight (ESI-TOF)). Other mass spectra were recorded at a Shimadzu
LCMS-8030 quadrupole mass spectrometer operating in the electrospray
ionization (ESI) mode and GC/MS-QP2010 (70 eV) Shimadzu, chro-
matography column Restek Rtx-5MS. The infra-red (IR) spectra were
recorded on a FTIR-Frontier-PerkinElmer. X-ray diffraction analysis
were collected on a Bruker D8 Venture Photon 100 diffractometer
Geometry optimizations in gas phase were done with density func-
tional M06L. SDD basis set was used for Palladium and selenium atoms
while 6-31G(d) basis set was used for the remaining ones. All the cal-
culations were performed with Gaussian09 rev. D.01 suite of quantum
chemical programs.
The X-ray structure and the geometry optimized with M06L func-
tional and basis set SDD for Pd and Se and 6-31G(d) for the remaining
atoms are compared in Fig. S32. This structure was used in subsequent
calculations after opening the spirolactam ring and adding Pd2þ be-
tween the N of this ring and the Se atom, keeping the two N of amides
deprotonated. Potential energy surface scans were done with PM6 semi
empirical method for looking for new conformations of Rh–Se plus Pd2þ
complex without Cl-anion and with Cl-anion plus H in the N atom of one
of amide groups. The energy minima structures found were used in ge-
ometry optimizations with density functional M06L with SDD basis set
equipped with an Incoatec IμS high brilliance Mo Kα X-ray tube with two
dimensional Montel micro-focusing optics at 100(2) K using an Oxford
Cryosystems Cryostream 800 low temperature unit. The structure was
2

A.A. Soares-Paulino et al.
Dyes and Pigments 179 (2020) 108355
Scheme 1. Synthesis of Rh–Se.
1
for Pd and Se and 6-31G(d) basis set for remaining atoms. The structures
are presented in Fig. S33 and Fig. S34.
the next step without purification. H NMR (200 MHz, CDCl3) δ 7.51
(dd. J ¼ 7.6. 1.2 Hz. 1H). 7.46–7.29 (m. 2H). 7.24–7.14 (m. 1H). 6.70 (sl.
1H). 3.60–3.41 (m. 2H). 3.02–2.89 (m. 2H). 2.27 (s. 2H). 1.85 (sl. 3H).
13C NMR (50 MHz, CDCl3) δ 168.97. 134.64. 133.65. 130.69. 128.27.
127.48. 124.78. 41.90. 40.85. 6.63. 77Se NMR (38 MHz, CDCl3) δ
221.93. HRMS (m/z): [M þ H]þ calcd for C10H15N2OSe, 259.0344;
found: 259.0349.
The optimized structures of lowest energy for Rh–Se, [Rh–Se þ Pd -
H]þand [Rh–Se þ Pd þ Cl]þ were used in single-point energy calcula-
tions with M06L functional and with SDD basis set for Pd and Se and 6-
31G(d) basis set for the remaining atoms and using SMD [42] method to
describe solvation effects of water and ethanol. Geometry optimizations
were done considering solvation effects of water using the same meth-
odology too. From these calculations, highest occupied molecular
orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) and
their respective energies were extracted. The energy band gap between
HOMO and LUMO orbitals are presented in Table S1.
2.8. Synthesis of compound Rh–Se
To a stirred solution of rhodamine-B (300 mg, 0.626 mmol) in dry
CH2Cl2 (3.5 mL) was added p-toluenesulfonyl chloride (221 mg, 1.164
mmol). The mixture was stirred for 15 min. After that, was added 4-
(dimethylamino)pyridine (182 mg, 1.583 mmol). The mixture was
stirred for 15 min. Following, a dry CH2Cl2 (3 mL) solution of compound
4 (145 mg, 0.564 mmol) was added. The reaction mixture was stirred
until consumption of compound 3 (monitored by TLC - hexane:EtOAc,
7:3). The mixture was quenched with saturated aqueous sodium bicar-
bonate solution (10 mL); the mixture was extracted with ethyl acetate (3
x, 20 mL). The resulting organic phase was dried over anhydrous mag-
nesium sulfate, filtered and evaporated. The crude product was purified
by silica-gel flash chromatograph (hexane:EtOAc 7:3). Crystals of good
quality were obtained by slow evaporation from a acetonitrile/MeOH
solution, in an hand-made end-sealed Pasteur pipette tube. The product
was obtained as a light pink solid or as a colorless crystal. Yield ¼ 48%
2.5. Synthesis of compound 2
Methyl 2-aminobenzoate (20 mmol; 3.02 g) was added to a HCl so-
lution (12 mL, 6 M) at 0 �C, followed by a sodium nitrite (23.6 mmol;
1.63 g) aqueous solution (6 mL). After stirring for 30 min, a saturated
NaBF4 aqueous solution was added till no further solid formation. The
solid was removed by filtration, washed with Et2O (4x, 5 mL) and dried
under vacuum. Compound 2 was obtained as a white solid (17.6 mmol;
4.40 g; 88%). MS (ESI) (m/z): [M]þ calcd for C8H7N2Oþ2 , 163.1; found:
163.2. CAS Number: 342-54-1.
2.6. Synthesis of compound 3
overall; mp 181–182 �C; Rf: 0,58 (Hexane:EtOAc 1:1); FTIR (neat, cmÀ 1
)
In a 10 mL-capacity-vial was added compound 2 (1.0 mmol; 250
mg), 1,2-dimethyldiselane (1.0 mmol; 188 mg) and anhydrous sodium
acetate (1.0 mmol; 82 mg), then it was capped with a rubber septum.
The system was purged with dry N2 (10 min). Dry DMSO (5.0 mL) was
added. System was kept under agitation for 5 min after the end of gas
evolution. The resulting mixture was partitioned between Et2O/H2O and
the organic extracts were collected, dried with MgSO4, filtered and
concentrated under vacuum. The reaction mixture was purified by col-
umn chromatography on silica gel with an eluent mixture of hexane/
EtOAc. Compound 3 was obtained as a yellow solid. Rf: 0.41 (Hexano:
EtOAc 7:3); 1H NMR (200 MHz, CDCl3) δ 8.05 (ddd. J ¼ 7.8. 1.5. 0.4 Hz.
1H). 7.50–7.33 (m. 2H). 7.26–7.16 (m. 1H). 3.93 (s. 3H). 2.26 (s. 3H).
13C NMR (50 MHz, CDCl3) δ 167.37. 139.01. 132.79. 131.64. 127.98.
127.22. 124.38. 52.29. 6.38. 77Se NMR (38 MHz, CDCl3) δ 256.19.
HRMS-TOF-ESI (m/z): [M þ Na]þ calcd for C9H10O2Se, 252.9738;
found: 252.9750. CAS Number: 78377-06-7.
3322, 2966, 2925, 2867, 1731, 1663, 1612, 1512, 1263, 1219, 1117,
784, 743, 701. 1H NMR (200 MHz, CDCl3) δ 8.05 (t, J ¼ 3.4 Hz, 1H),
7.97–7.86 (m, 1H), 7.73–7.62 (m, 1H), 7.51–7.39 (m, 1H), 7.39–7.34
(m, 1H), 7.34–7.21 (m, 1H), 7.17–7.03 (m, 1H), 6.45 (d, J ¼ 8.8 Hz, 1H),
6.38 (d, J ¼ 2.5 Hz, 1H), 6.27 (dd, J ¼ 8.9, 2.6 Hz, 1H), 3.48–3.40 (m,
1H), 3.33 (q, J ¼ 7.1 Hz, 3H), 3.24–3.12 (m, 1H), 2.19 (s, 1H), 1.17 (t, J
¼ 7.0 Hz, 4H). 13C NMR (50 MHz, CDCl3) δ 170.35, 168.23, 154.05,
153.35, 149.04, 135.32, 133.93, 132.93, 130.86, 130.43, 128.50,
128.26, 127.75, 125.10, 124.01, 122.97, 108.45, 104.62, 97.80, 65.96,
44.46, 41.84, 40.01, 12.71, 6.73. 77Se NMR (38 MHz, CDCl3) δ 233.89.
UV–Vis (EtOH) λmax (lg ε) 312 (4.13) and cut off at 420 nm; HRMS (ESI-
TOF) (m/z): [M þ H]þ calcd for C38H42N4O3Se, 683.2495; found:
683.2491.
2.9. Synthesis of compound 7
To a 100 mL, two-necked round-bottomed flask, under nitrogen at-
mosphere, were sequentially added 4-bromoacetophenone (8 mmol, 1.6
g), potassium phenyltrifluoroborate (8.8 mmol, 1.62 g), PdCl2 (0.8
mmol, 142 mg), Cs2CO3 (8 mmol, 2.6 g) and methanol (30 mL). The
reaction mixture was stirred during 24 h under reflux. The content was
transferred to a separation funnel and aqueous saturated solution of
2.7. Synthesis of compound 4
A mixture of 1,2-etildiamina (12.2 mmol; 0.736 g; 0.82 mL) and
compound 3 (1.22 mmol; 279 mg) in EtOH (15 mL) was refluxed for 24 h
under N2. The EtOH was evaporated and the crude mixture was used in
3

A.A. Soares-Paulino et al.
Dyes and Pigments 179 (2020) 108355
Fig. 1. The molecular structure with the atom-labeling scheme of the compound Rh–Se with 50% thermal ellipsoids (using ORTEPsoftware).
NH4Cl (100 mL) was added. The extraction was proceeded using EtOAc
(3 � 40 mL) and the combined organic layer was washed with brine
(100 mL) and dried over anhydrous MgSO4. After filtration, the volatiles
were evaporated, and the resulting crude white solid was dried under
vacuum. Half of the solid product was submitted to Pd-content deter-
mination by spectrofluorimetric (Rh–Se) and ICP analysis. The
remaining crude mixture was purified by silica gel flash chromatog-
raphy (hexanes:EtOAc, 9:1). After evaporation of volatiles a white solid
was recovered as the desired coupling product (65% yield). m.p.:
119–121 �C; 1H NMR: (300 MHz, CDCl3) 8.03 (d, J ¼ 8.2 Hz, 2H), 7.68
(d, J ¼ 8.1 Hz, 2H), 7.62 (d, J ¼ 8.1 Hz, 2H), 7.21–7.36 (m, 3H), 2.63 (s,
3H). 13C RMN: (75 MHz, CDCl3) 197.8, 145.9, 140.0, 136.0, 129.0,
129.0, 128.3, 127.4, 127.3, 26.8. IR: λ
(neat, cmÀ 1): 3341, 3077,
max
3002, 1682, 1605, 1488, 1406, 1361, 1287, 1268, 1210, 1182, 984, 838,
767, 724, 694, 681. MS (EI) (m/z)(%): 196(48) [Mþ], 182(15), 181
(100), 153(40), 152(62), 151(18), 127 (6), 77(6), 76(6), 63(4). CAS
Number: 92-91-1.
Fig. 2. Absorption, corrected normalized emission and excitation spectra of
compound Rh–Se in EtOH/H2O (1:1 v/v). (T ¼ 298 K; [Rh–Se] ¼ 1.0 � 10À 5
mol/L; λem ¼ 500 nm; λexc ¼ 315 nm; slit ¼ 10).
3. Results and discussion
3.1. Design, synthesis and structure characterization of the Rh–Se
NMR (Figs. S10–S13), HRMS (Fig. S14), FTIR (Fig. S15), X-ray diffrac-
tion (Fig. 1), UV–visible absorption and fluorescence emission spec-
troscopy (Fig. 2). The crystal structures of Rh–Se was unequivocally
unveiled using single-crystal X-ray diffraction studies (Fig. 1). For this, a
monocrystal was obtained from a acetonitrile solution of compound
Rh–Se. For more information, see Table S2 and Table S3 in the sup-
porting information.
With the objective of developing a fluorescent probe to detect
metallic cations in a selective, sensitive and fast way, we sum the great
abilities of complexation of ethylenediamine subunit [43], the soft se-
lenium ability [22,44,45] with the excellent photophysical properties of
rhodamine. The idealized probe Rh–Se was synthetized in 4 steps in
good yield as shown in Scheme 1. The first step consisted in the prep-
aration of the diazonium tetrafluoroborate salt 2 (from the commercially
available methyl 2-aminobenzoate 1). Then, the intermediate 3 was
prepared in virtually quantitative yield (99%) through the methodology
developed by Wangelin and coworkers [46], where a radical aromatic
substitution using dichalcogenides and aryl diazonium salt takes place.
The selenium ligand 4 was obtained through the condensation of the
methyl ester 3 with ethylenediamine. The compound 4 was used in the
following synthetic step without purification. In the last step, a new
rhodamine-selenium Rh–Se derivative was obtained from the conden-
sation reaction between rhodamine B and compound 4 [47]. The com-
pound Rh–Se was isolated in 48% global yield.
Table 1
Photophysical data of Rh–Se in EtOH/H2O (1:1 v/v) at 298 K.
Absorption Data
Emission Data
λmax (nm)
Log
ε
Stokes Shift (nm)
λmax (nm)
Φ
315
272
4.10
4.51
137
179
451
<0.01
1
The compound Rh–Se was fully characterized by H, 13C and 77Se
4

A.A. Soares-Paulino et al.
Dyes and Pigments 179 (2020) 108355
Fig. 3. Fluorescence responses of Rh–Se to several metals (1 equiv) and mixtures of PdCl2 with other metals in EtOH/H2O (1:1 v/v) after 60 min. T ¼ 298 K;
[Rh–Se] ¼ 1 � 10À 5 mol/L; [Metal] ¼ 1.0 � 10À 2 mol/L); λexc ¼ 515 nm. Bottom: Visual changes of Rh–Se under UV light (λexc ¼ 256 nm) after addition of
metal ions.
3.2. Photophysical characterization
alkaline metals (Liþ and Kþ), alkaline earth metals (Ca2þ, Ba2þ and
Mg2þ), transition metals (Pd2þ, Pt2þ, Au3þ, Co2þ, Ni2þ, Cu2þ, Fe3þ
Fe2þ, Cr3þ, Agþ, Mn2þ, and Ru3þ), post-transition metals (Zn2þ, Cd2þ
,
,
The Rh–Se compound has some of its optical properties investigated
in EtOH/H2O (1:1, v/v) at 298 K, and the main photophysical data are
reported in Table 1. The absorption, emission and excitation spectra can
be seen in Fig. 2. The absorption spectrum shows two transition bands at
Hg2þ, Pb2þ, Al3þ and Ga3þ) and lanthanides (Ce3þ and Nd3þ) were
mixed. The response for the detection of the metals was monitored by
fluorescence emission spectroscopy. As can be seen in Fig. 3 (black bars),
the compound Rh–Se showed a high selectivity for Pd2þ ions, being not
observed significant response for the other metals. In order to study the
selectivity, it was also explored the detection of Pd2þ in the presence of
the other metal ions (Fig. 3, gray bars). The fluorescence intensities
obtained suggest that even in an environment containing other metals,
the compound Rh–Se presents a great selectivity for the ions Pd2þ once
in none of the cases it was observed a meaningful change in the fluo-
rescence intensity. The detection of Pd2þ occurs with a very fast raise in
the fluorescence intensity, taking only 2 min to the fluorescence emis-
sion stabilization (Fig. S19). Therewith, all the subsequent experiments
were monitored after reaching balance, i. e., 2 min after the addition of
the Pd2þ solution. Once rhodamine derivatives are sensible to pH vari-
ation, the fluorescence responses of Rh–Se and Rh–Se/Pd2þ were
investigated in a pH ranging from 3 to 10 (Figs. S20–A). The free com-
pound Rh–Se shows only fluorescence at pH < 6. However, the complex
Rh–Se/Pd2þ shows fluorescence until pH > 10, demonstrating to be
useful as fluorescent probe for Pd2þ in solution systems in a vary of pH
condition ranging from 6 to 10. Moreover, despite the species Rh–Se/Hþ
272 nm and 315 nm, attributed to the high π-π* energy transitions in the
organic chromophore. The solution of Rh–Se in EtOH/H2O (1:1, v/v)
was colorless – condition in which the spirolactam ring is in its closed
form. This can be confirmed by the absence of an absorption band in the
500–600 nm region (typical for open rhodamine ring), and by the weak
fluorescence emission band centered at 451 nm following by a low
quantum yield of Φ < 0.01. The relative quantum yield was calculated
using the rhodamine B compound as standard (Φ ¼ 0.70, in abs. ethanol)
[41]. In these conditions, the compound Rh–Se shows a high Stokes shift
of 137 nm. Moreover, the similarity between the absorption and exci-
tation spectrums shows that the system is free from any emissive im-
purities or precursors.
3.3. Metallic ion sensing studies
The Rh–Se was used as a selective and sensitive fluorescent sensor
for palladium (II). In order to investigate the selectivity of the metal
cation complexation, stoichiometric quantities of Rh–Se and salts of
Fig. 4. Spectrophotometric (A) and spectrofluo-
rometric (B) titrations of Rh–Se (10
μmol/L)
with increasing amounts of Pd2þ (10 mmol/L).
Inset: Absorption (A) and fluorescence (B) in-
tensity as a function of Pd2þ concentration (0–14
μ
mol/L) at 565 nm and 588 nm, respectively;
photos show changes in the visible color (A) and
fluorescence color under UV light (λexc ¼ 256
nm) (B) upon addition of Pd2þ
. Conditions:
ethanol–H2O (1 : 1, v/v, 25 �C) solution, λex
¼
515 nm. (For interpretation of the references to
color in this figure legend, the reader is referred
to the Web version of this article.)
5

A.A. Soares-Paulino et al.
Dyes and Pigments 179 (2020) 108355
the selenium atom and a chlorine atom (Scheme 2). With the data ob-
tained from the spectrometric titration and using the stoichiometric
relation 1 : 1, the association constants of the compound formed by
Rh–Se and Pd2þ were determined using the software HypSpec [40]
(Table 2). Similar association constants were obtained with an order of
log K � 6. This high value of log K indicates that there is a strong
Table 2
UV–vis, fluorescence and stability constants data for complex Rh–Se–Pd ob-
tained from absorbance and fluorescence titration data in EtOH/H2O 1:1 (v/v).
For stability constants, the HypSpec program was applied considering 1 : 1
interaction.
UV–vis
Fluorescence
interaction between Rh–Se and Pd2þ
.
λabs
(nm)
log
log
K
λem
(nm)
Stokes’
Bathochromic
Shift (nm)
Φ
log
K
The reversibility of the complexation reaction was investigated by
the addition of aliquots of EDTA-4Na solution into a solution of the
Rh–Se:Pd2þ complex (Fig. S25). The addition of EDTA-4Na resulted in
the almost total suppression of the fluorescence, indicating that the
EDTA-4Na sequesters Pd2þ from the Rh–Se:Pd2þ complex. A new
addition of Pd2þ caused a raise in the emission fluorescence intensity,
however, lower than the initially observed. This result indicates that the
probe Rh–Se can be used in cycles of detection of Pd2þ. The emission not
being totally suppressed in the first addition of EDTA-4Na can be asso-
ε
Shift
(nm)
565
4.09
6.1
�
588
23
137
0.17
�
6.2
�
0.4
0.01
0.5
and Rh–Se/Pd2þ present similar fluorescence emission spectra, the in-
tensity maximums occur in different regions, being 581 nm and 588 nm
for Rh–Se/Hþ and Rh–Se/Pd2þ, respectively (Figs. S20–B). Thus, using
only the fluorescence emission spectra it is possible to distinguish if the
ciated to the strong bond that exists between the Se residue and Pd2þ
,
being the EDTA-4Na unable of complexing all the Pd2þ ions available in
the solution. Consequently, the residual EDTA-4Na present in the
environment can chelate part of the Pd2þ added in the following cycles
causing the intensity of fluorescence emission to be decreasing each
cycle. The kinetics of this reaction was investigated (Fig. S26) and a
slowly diminish in the fluorescence intensity in 588 nm was observed,
being stable after 10 min.
response of the sensor Rh–Se is due to the pH or Pd2þ
.
With these results in hands, the spectrophotometric and spectroflu-
orometric titrations of the probe Rh–Se and Pd2þ solutions were carried
out (Fig. 4). The photophysical data are summarized in Table 2. After
increasing additions of Pd2þ, it was observed a naked-eye change in the
color of the solution, from colorless to intense pink. This indicates that
the spirolactam ring has been opened induced by the presence of Pd2þ
ions. The absorption spectrum analyses (Fig. 4A) shows the appearance
The European Agency for the Evaluation of Medical Products
(EMEA) regulates the presence of palladium in pharmaceutical products
destined to oral administration cannot exceed the limit of 5 ppm, and
0.5 ppm for parenteral administration [49]. Moreover, a restriction was
imposed on the maximum dietetic ingestion of palladium being <15 mg
per person per day. Based on this information, the sensibility of the
Rh–Se sensor for Pd2þ ions detection was investigated. According to the
methodology described in the experimental section, the limits of
detection (LOD) and quantification (LOQ) were determined. As can be
seen in Table 3, the compound Rh–Se showed to be able to detect Pd2þ
in highly diluted solutions (32 nM; 4 ppb) and to quantify the ion from
72 nM solutions.
of a new band with a maximum absorption of 565 nm (log
ε ¼ 4.09 –
Table 2). It was also observed a maximum emission at 588 nm (Fig. 4B).
Furthermore, the system showed a fluorescent quantum yield of Φ ¼
0.17, and a Stokes shift of 23 nm accompanied by a high bathochromic
shift of 137 nm (Table 2). The intensities of the absorption and fluo-
rescence vary linearly with the Pd2þ concentrations in a range from 0 to
1 ppm. This linearity can be observed both to the naked eye by the
simple observation of the gradual increase in the color intensity of
Rh–Se (Fig. S21), as well by the absorption and emission spectra (Fig. 4
and Fig. S28).
The stoichiometric relation between Rh–Se and Pd2þ was deter-
mined by the traditional continuous variation method (Job’s plot,
Fig. S22) presenting a 1 : 1 relation (Rh–Se: Pd2þ). Other experimental
data that suggest this stoichiometric relation are the absorption and
emission spectra obtained during the titration of Rh–Se with Pd2þ
(Fig. 4). It is possible to observe in them that its intensities are stabilized
after the addition of 1 equiv. of Pd2þ, suggesting a stoichiometric rela-
tion of 1 : 1 between Rh–Se and Pd2þ. In order to confirm the stoichi-
ometry, the complex was investigated by high-resolution mass
spectrometry (ESI-micrOTOF-MS - Fig. S23). The presence of a 1 : 1
complex, attributed to Rh–Se/Pd2þ was confirmed by the identification
of mass peaks relative to [Rh–Se þ Pd þ Cl]þ ¼ 823.1145 m/z (m/
zcalculated ¼ 823.1140) and [Rh–Se þ Pd - H]þ ¼ 787.1378 m/z (m/
zcalculated ¼ 787.1373). Also, the isotope pattern of the clusters is in
accordance to the theoretical analysis (Fig. S24). From these data and
knowing that d8 metal ions with strong field ligands form square planar
complexes [48], we propose a mechanism of complexation where the
ion Pd2þ forms a complex with square planar geometry with both ni-
trogen atoms (from the ethylenediamine group, a strong field ligand),
In order to explore the potential for practical application of this
Rh–Se probe, a qualitative experiment was conducted to evaluate the
ability of Rh–Se to detect other species of palladium commonly used
(Fig. 5) in organic synthesis. Rh–Se compound showed a emission
fluorescence for several palladium salts, being more pronounced for the
Pd2þ salts, especially for PdCl2 and Pd(PhCN)2Cl2. A small emission
fluorescence was observed for Pd0 [Pd(dppe)2]. It is understandable that
Pd0 is less Lewis acidic than Pd2þ for the effect of ring-opening reaction
of the spirolactam moiety of Rh–Se.
Table 3
Minimal detectable (LOD) and quantified (LOQ) of Rh–Se for Pd2þ in EtOH/H2O
1:1 (v/v). Relative standard deviation (RSD) of the values measured was below
10%, n ¼ 6. Data collected at 565 nm (absorbance) and 588 nm (fluorescence).
Limit
Absorbance nmol/L (ppb)
Fluorescence nmol/L (ppb)
Detectable
Quantified
365 (42)
728 (84)
32 (4)
72 (8)
Scheme 2. Proposed Mechanism for the fluorescent changes of Rh–Se upon the addition of Pd2þ
.
6

A.A. Soares-Paulino et al.
Dyes and Pigments 179 (2020) 108355
Fig. 5. Fluorescence responses of Rh–Se to diverse palladium salts (1 equiv) in EtOH/H2O 1:1 (v/v) solution after 10 min. Conditions: T ¼ 298 K; [Rh–Se] ¼ 1.0 �
10À 5 mol/L; [Pd2þ] ¼ [Pd0] ¼ 10 � 10À 3 mol/L; λexc ¼ 515 nm.
Fig. 6. Orbitals and energy diagram for HOMO and LUMO calculated using density functional M06L and SDD basis set for Pd and Se atoms, and 6-31G(d) for the
remaining ones. Geometry optimized in gas phase and solvation effects of water calculated with the continuum solvation model SMD. A: compound without Pd2þ,B:
compound with Pd2þ,C: compound with Pd2þ and ClÀ .
As the products of the reactions catalyzed by palladium can have
different solubility in organic/aqueous environment, it was studied the
sensorial ability of Rh–Se in different proportions of EtOH/H2O
(Fig. S27). It was verified that Rh–Se is able to detect Pd2þ in a range of
30–80% of H2O, having a maximum fluorescence emission in a system
containing 60% of H2O. Moreover, the raise in polarity in the environ-
ment causes a bathochromic shift up to 6 nm (587 nm → 593 nm).
excitation energy [50]. Despite the difference between experimental and
calculated band gap, it has been observed a good correlation between
these values, making de HOMO and LUMO orbitals obtained in DFT
calculation suitable for a qualitative study of the band gap for the energy
excitation of the electron [51].
DFT calculations have been used in order to rationalize the effects of
formation of the Rh–Se/Pd2þcomplex to the HOMO-LUMO band gap
compared to the Rh–Se isolated molecule. All the optimizations and
conformation study were performed without any symmetry restriction
with the Gaussian09 suite of programs [52]. The density functional
M06L [53,54] was used in this study since it has produced good results
for palladium complexes [55]. The SDD [56] basis set, with its associ-
ated relativistic pseudopotential, was used for Pd and Se, while the
3.4. Theoretical calculations
Kohn–Sham (KS) molecular orbital model of density functional the-
ory (DFT) may be used to determine HOMO-LUMO energy difference,
which in turn is a good approximation to the band gap for the first
7

A.A. Soares-Paulino et al.
Dyes and Pigments 179 (2020) 108355
Scheme 3. Synthesis using Suzuki-Miyaura cross-coupling.
6-31G(d) [57–62] basis set was employed for the rest of atoms. The
solvent effect has been considered through the SMD method [42]. See
the Supporting Information for more details on the computational
methodology and conformation search.
4. Conclusions
Summarizing, it was successfully synthesized and investigated the
properties of a new fluorescent probe for Pd2þ based on a rhodamine-
selenide compound (Rh–Se). The probe Rh–Se showed a high selec-
tivity for Pd2þ versus 24 other metallic cations, leading to a pink naked-
eye and orange emissive water-soluble complex. With a linear relation
between fluorescence emission and the concentration of Pd2þ, Rh–Se
shows a high sensibility with a limit of detection of 32 nM. The high
affinity for Pd2þ (log K � 6.1) was associated to the strong bond formed
by Se–Pd. Additionally, fast detection for Pd2þ ions was observed with
only 2 min being required. The theoretical studies show Pd2þ atom co-
ordinated with Rh–Se in a square planar geometry and a decrease in the
band-gap energy between the HOMO and LUMO orbitals when the
Rh–Se/Pd2þcomplex is formed in accordance with the bathochromic
deviation observed in the experimental spectra. The great sensorial
characteristics of Rh–Se to detect Pd2þ, allowed its usage as potential
sensor for detection Pd2þ ions in real situations involving a cross-
coupling organic synthetic compound and pharmaceutical products.
The structures of lowest energy for the complexes present square
planar geometry as the most stable form. HOMO and LUMO band-gap
values and orbital representation for the structures corresponding to
the free Rh–Se molecule and for the lowest energy structures of Rh–Se
coordinated to the Pd2þ, with and without ClÀ anion, are depicted in
Fig. 6. The free Rh–Se molecule and the Rh–Se/Pd2þcomplex, presented
its corresponding HOMO orbitals localized on the electron-rich xan-
thene moiety, whereas the LUMO orbital is mainly localized in the N-(2-
aminoethyl)-2-(methylselanyl) benzamide moiety and in the orbitals
associated with the metal center (see Fig. 6). A decrease in the band gap
between HOMO and LUMO orbitals was observed for the Rh–Se/
Pd2þcomplex when compared to the free Rh–Se molecule. The calcu-
lated band gap presents a clear bathochromic shift from 2.81 eV to 1.83
eV and 1.61 eV, in absence and presence of chloride, respectively.
3.5. Investigation of the application of the probe Rh–Se
Declaration of competing interest
In organic synthesis, various methodologies for the formation of C–C
bond were developed in the last decades involving palladium catalysts.
Some methodologies were developed mainly by Suzuki [63], Heck [64],
Stille [65], Sonogashira [66] and Negishi [66]. These methodologies are
widely used by the pharmaceutical industry in the synthesis of several
drugs like Singulair®, Relpax®, Hyzaar®, Lamsil®, Edurant® and Ne-
virapine® [67]. Having this in mind, it was investigated the capacity of
Rh–Se to detect residual Pd2þ in products of cross-coupling reactions
and commercially available pharmaceutical products.
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgments
A. A. Dos Santos and A. A. Soares-Paulino (CNPq scholarship holder –
Brazil) are tankful to CNPq (141454/2013-0, 207311/2015-3 and
153759/2016-0), FAPESP (2016/09579-0) and also to the financial and
A well-known Suzuki-Miyaura cross-coupling reaction was per-
formed between aryl bromide 5 and an organic trifluoroborate (6)
employing PdCl2 (Pd2þ ¼ 2833 ppm) as catalyst, Cs2CO3 as non-
nucleophilic base and MeOH as solvent (Scheme 3) [68]. After the
extraction of the crude product, it was obtained a solid (7) with which
was prepared a solution (5 mg/mL in EtOH/H2O 1:1 v/v). The con-
centration of residual Pd2þ, after the extraction was determined using a
calibration curve (Fig. S28), obtained from the spectrofluorometric ti-
trations. The quantity of residual Pd2þ was measured in 3.7 ppm
(Fig. S29). This same sample was analyzed by ICP-OES, reveling 229
ppm as the total amount of palladium. This difference can be attributed
to the presence of other palladium species in the sample as a result of the
redox expected cycle involved in this kind of chemical processes. As we
demonstrated, our fluorescent sensor presents a high speciation, differ-
entiating Pd2þ from other palladium species.
~
structural support offered by the University of Sao Paulo through the
NAP-CatSinQ (Research Core in Catalysis and Chemical Synthesis). A. A.
Dos Santos and C. Lodeiro are also thanks to the CNPq program, Science
without borders 2014–2016 for the “Special Guest Researcher” grant
(Brazil). C. Lodeiro thanks The Associate Laboratory Research Unit for
Green Chemistry - Clean Processes and Technologies - LAQV which is
financed by national funds from FCT/MEC (UID/QUI/50006/2013) and
co-financed by the ERDF under the PT2020 Partnership Agreement
(POCI-01-0145-FEDER - 007265) and the Scientific Society PROTEO-
MASS (Portugal) for funding support (General Funding Grant). A. A. C.
Braga appreciates the support from FAPESP (14/25770-6 and 15/
01491-3). H. A. Stefani appreciates the support from CNPq (306119/
2014-5). J. S. Reis appreciates the support from FAPESP (2016/02392-
1).
Pharmaceutical industries represent one the most productive and
profit industries in the world. Thinking in these applications, the com-
pound Rh–Se was used to detect Pd2þ in pharmaceutical products,
simulating real samples with ibuprofen and paracetamol (isolated from
commercial medicaments by extraction with MeOH). Solutions of the
active principles (10 mg/mL) were prepared and doped with Pd2þ (1
ppm - Figs. S30–S31). It was not detected traces of Pd2þ in the analysis of
solutions containing only the active principles. However, after these
solutions being contaminated with 1 ppm of Pd2þ (PdCl2) and subse-
quent addition of Rh–Se sensor, it was observed an intense fluorescence
emission, indicating traces of Pd2þ ions. The probe Rh–Se showed a
good sensibility in the detection of Pd2þ ions in solutions of these
pharmaceuticals.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.dyepig.2020.108355.
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