Aroylthioureas: New organic ionophores for heavy-metal ion selective electrodes

Article abstract of DOI:10.1039/b102029n

Thiourea derivatives (46 aroylthioureas) having different substituents close to the sulfur atom were synthesized and their ionophore potential in ion selective electrodes (ISEs) was examined. Structural considerations were taken into account based on the corresponding heavy-metal ISE parameters. As ionophores, some 1-furoyl-3-substitnted thioureas (series 2) gave the best results in Pb(II), Hg(II) and Cd(II) ISEs. The strong intramolecular hydrogen bond in series 2 allows ligand interaction only through the C=S group. Substituents on the furan and phenyl rings give rise to low solubility in the membrane plasticizer. 3-Alkyl substituted furoylthioureas improve solubility but enhance oxidative processes with chain length. New X-ray diffraction (XRD) structures and theoretical DFT calculations were considered in the analysis of the substituent influence on the selectivity of ISEs. These new ionophores have advantages because of their stability, simple synthesis and easy modification of the sulfur binding ability resulting from substitution.

Full text of DOI:10.1039/b102029n

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Aroylthioureas: new organic ionophores for heavy-metal ion
selective electrodes†
Elena Otazo-Sánchez,*‡a,b Leonel Pérez-Marín,b,c Osvaldo Estévez-Hernández,b
Susana Rojas-Limaa and Julián Alonso-Chamarrod
2
a Centro de Investigaciones Químicas (CIQ), Universidad Autónoma del Estado de Hidalgo,
México
b Instituto de Materiales y Reactivos (IMRE), Universidad de la Habana, 10400 La Habana,
Cuba
c Instituto Tecnológico de Toluca, Metepec, 52140 Estado de México, México
d Grup de Sensors y Biosensors, Facultat de Ciènces, Universitat Autònoma de Barcelona,
08193 Bellaterra, Barcelona, España
Received (in Cambridge, UK) 5th March 2001, Accepted 6th August 2001
First published as an Advance Article on the web 10th October 2001
Thiourea derivatives (46 aroylthioureas) having different substituents close to the sulfur atom were synthesized and
their ionophore potential in ion selective electrodes (ISEs) was examined. Structural considerations were taken into
account based on the corresponding heavy-metal ISE parameters. As ionophores, some 1-furoyl-3-substituted
thioureas (series 2) gave the best results in Pb(), Hg() and Cd() ISEs. The strong intramolecular hydrogen bond
in series 2 allows ligand interaction only through the C᎐S group. Substituents on the furan and phenyl rings give
᎐
rise to low solubility in the membrane plasticizer. 3-Alkyl substituted furoylthioureas improve solubility but enhance
oxidative processes with chain length. New X-ray diffraction (XRD) structures and theoretical DFT calculations
were considered in the analysis of the substituent influence on the selectivity of ISEs. These new ionophores have
advantages because of their stability, simple synthesis and easy modification of the sulfur binding ability resulting
from substitution.
focus of study in the early years in order to provide the basis for
Introduction
a good sensitive and selective ISE. So far, the kinetics and
Ionic and molecular recognition materials are subjects of
thermodynamics of the process occurring in the membrane
interest due to their wide application. One such application
have been taken into account. A complicated multivariate
concerns the development of chemical sensors which simplify
mechanism is operative. The stability of the formed complex,
the systematic control and prevention of water pollution and
the protection of the environment.
the partition coefficient and the ion mobility depend on the
media and they are important factors to be taken into account.
The requirements of very low detection limits (LDL) and
The reversible ion–complex formation and the relative stability
lower limits of linear response (LLLR), the reproducibility, the
of the complex between the plasticizer and water, the solubility
Nernstian response of the calibration curve (slope value =
ratio of the ionophore and its complex between both media, the
ion transport through the membrane, and the interface process
59.16/Za mV decadeϪ1), the lifetime and the problem of high
pot
A,B
selectivity properties (K ) limit the suitability of the recent
define the final behaviour and suitability of ISEs. Only a few
liquid and solid state membrane-based ISEs developed
chemical sensors have been developed for monitoring the
for environmental sensing. Liquid-membrane ion selective
heavy-metal ions in water.1d Early reports of Pb2ϩ and Cd2ϩ
electrodes have many advantages.1 The membranes are
ionophores present bis-amide and bis-thioamide functional
currently prepared with PVC, the plasticizer (mediator) and
groups10 in a so-called podand molecule (two arms) which
the immobilized-recognition-compound (so-called ionophore
chelates the ion.
or carrier) directly deposited onto a conductive epoxy resin–
Thioureas are well known as good ligands for metal ions
graphite composite, without internal reference solution.2 The
and this property can be used in cation-selective membranes.
construction of PVC membrane electrodes is easy to imple-
In contrast, they have been reported as neutral ionophores in
ment, inexpensive and reliable.3 These electrodes show good
anion-selective electrodes.11 The sulfur atom in the thioureido
stability and their response is acceptable for analytical
applications.
Many recognition compounds have been tested as iono-
CS group is expected to be more nucleophilic than the corre-
sponding CS group in thioamides. Some studies have been done
on their complexation properties12 and more recently with
phores in ion selective electrodes. Their structures are cyclic4,5
platinum-group metals.13
or acyclic.6–8 Some ionophores are commercially available9 and
We first reported 2f as a good ionophore for Pb() ISE.14a
others have been reported in recent years.1d
Compounds 2a and 1e were then reported for Pb()15 and
The principal membrane component is the ion recognition
substance whose structural compatibility with ions was the
Cd()16 ISEs, respectively. Our goal was achieved when we
reported Hg() ISEs with ionophores 2b17a and 1,3-diphenyl-
thiourea.17b Both showed good responses/selectivities and
detected Hg() as Hg2ϩ and Hg(OH)ϩ, depending on the pH of
† Electronic supplementary information (ESI) available: detailed NMR
data, including carbon types determined by DEPT experiments. See
http://www.rsc.org/suppdata/p2/b1/b102029n/
the solution. These are important features, as there have been
no reports of good membrane Hg() ISEs. Moreover, the
‡ Present address: Carretera Pachuca Tulancingo Km 4.5, Colonia
response mechanism and the complexation between Hg2ϩ and
Ciudad Universitaria, 42035 Pachuca, Hidalgo, México. E-mail:
Hg(OH)ϩ with the membrane have been demonstrated.17c
elenaotazo@yahoo.com; Fax: (52-771)72000 ext 5075.
DOI: 10.1039/b102029n
J. Chem. Soc., Perkin Trans. 2, 2001, 2211–2218
This journal is © The Royal Society of Chemistry 2001
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Here we report a general structure based analysis of the
behaviour of 46 aroylthioureas (series 1–4) in ISEs. In these
simple structures, the presence of three different heteroatoms
(N, S, O) could result in different types of complex formation
with transition and heavy-metal ions. The presence of various
substituents remote from, or near to the CS group causes differ-
ences in the complex stability and mediator solubility, changing
the behaviour of the constructed heavy-metal ISEs.
Scheme 1
Results and discussion
The ionophores presented have the advantages of quick
and easy synthesis and purification,18 and the potential for
dramatic steric and electronic variation in the region of the
sulfur atom. Therefore, it is relatively simple to modify a
convenient property (see Scheme 1). The stability of these
compounds is such that they can be used for analytical
purposes. We have classified them into four series: 1)
3,3-disubstituted furoylthioureas, 2) 3-monosubstituted furo-
ylthioureas, 3) 1-(5-substituted)-furoyl-3-phenylthioureas and
4) 1-(meta and para substituted)-benzoyl-3-phenylthioureas.
Synthesized 1-furoyl- and 1-benzoylthioureas contain hydro-
phobic substituents and some lipophilic groups, which prevent
the solubility of ionophores in the aqueous solutions tested.
Best yields were obtained with primary and secondary aromatic
amines (60–95%). Very low yields were obtained for aliphatic
amines (30–70%), especially secondary ones, due to their
higher nucleophilic character. In this case, competitive
side-reaction at the C᎐O group was decreased by lowering the
᎐
2212
J. Chem. Soc., Perkin Trans. 2, 2001, 2211–2218

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Fig. 1 ORTEP structures obtained for 2b and 1e.
reaction temperature to Ϫ15 ЊC. A total of 46 aroylthioureas
Therefore, it will be necessary to recalculate the orbital data
(18 of which are new compounds) were synthesized and all were
characterized. Characterization data are given in the supple-
mentary information.†
based on the experimental data reported here for this
compound.
From the published data19 and the XRD structure of 2b, we
can generalize that series 2, 3 and 4 present a strong intra-
molecular hydrogen bond, in a nearly planar rigid E,Z struc-
ture. The theoretical structures calculated for 2f21 and 2a20
agree with this fact, therefore, the reported orbital data are
reliable. Consideration of the frontier orbitals suggests that
coordination with soft heavy-metal ions should only be through
the sulfur atom with no chelate formation taking place. Unlike
series 2, in series 1 chelate formation is more feasible.
XRD Structures
Structures 1e and 2b were obtained by monocrystal XRD.
ORTEP structure diagrams are shown in Fig. 1. The crystallo-
graphic and structural data are given in Tables S1 to S13 of the
Supplementary Information. For the representative compound
2b, the intramolecular hydrogen bond is clearly demonstrated,
as was earlier reported for series 2–4.19 Dihedral angles in the
system CO–NH–CS–NH are close to 0Њ in 2b in a fixed E,Z
conformation with CO and CS groups in an “S”-shaped
arrangement. The furan ring is about 30Њ out of plane in
relation to the CO group, in an anti (OO-trans) conformation.
A quasi-planar structure is observed. Compound 2b shows the
thioureido group in an equatorial position of the cyclohexyl
ring, as expected.
Unlike 2b, 1e shows a nearly planar structure only at the
furoylthioureido group (Fig. 1). The furan ring is only 5Њ out
of plane with respect to the CO group. In addition, they are
in an anti (OO-trans) conformation. The dihedral angles in
the CO–NH–CS–NH system are nearly 0Њ in a Z,Z conform-
ation, resulting in a “U”-shaped arrangement with respect to
the CO and CS groups. The CS group is 22.5Њ out of plane.
Both phenyl and benzyl groups are almost orthogonal with
the thioureido near-plane (see Fig. 1). The R value of 1e is
higher than that of 2b. It is assumed that the reason for this
is the quality (the Rint value is rather high) and weakness of
the crystal.
Sensor behaviour: Nernstian response and selectivity
In ISEs, the criterion for ionophore suitability to a specific ion
sensor is based on its linear (Nernstian) response towards the
analyte ion in a range of concentrations. This range and the
calibration parameters are determined from a graphic potential
(E/mV) vs. activity (α/M) of the analyte ion. Frequently, the
electrode does not give any response, or, it might show an
erratic (non-linear) response. In some cases, even when there is
a linear response, an invalid slope value for an ion is obtained
(slope value ≠ 59.16/Za mV decadeϪ1). In those cases, it is
assumed to be an inadequate ionophore for the detection of the
ion. Fig. 2 shows representative electrochemical behaviour for 2f
in a Pb2ϩ ISE.14 In Fig. 2 the LLLR and LDL are graphically
represented.
Table 1 shows the general primary results obtained from
the studied thioureas in ISEs. Table 2(a), (b) contains the
calibration parameters and selectivity coefficients obtained for
them. As shown in Table 2(a), only 1e, 1f, 2a, 2b, 2f and 2m gave
reversible and Nernstian responses in the respective constructed
sensors.
The structure of 1e has recently been calculated by DFT
methods.20 The calculated structural parameters do not agree
with those reported here by XRD, with the exception of the
observed “U”-shaped arrangement of the CO and CS groups.
The main differences are observed with the dihedral angles. The
theoretical structure locates the phenyl group in a Z position
almost in the plane of the N–CS group. In contrast, XRD
shows this group in an E position, at 84.4Њ to the N–CS plane.
When a Nernstian response is obtained for a sensor, a
second challenge might be solved: selectivity. Fig. 3, 4 and
5 show graphically the selectivity coefficients obtained for
the ISEs. Many methods have been developed22 to deter-
pot
A,B
mine the potentiometric selectivity coefficients K . They
measure changes of potential in the presence of two ions
J. Chem. Soc., Perkin Trans. 2, 2001, 2211–2218
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Table 1 Summary of ionophore behaviour suitability in studied thioureasa
Compound
Solubility in TEHP
Response/ion = slope value
Notes about ionophore
1a, 1g
1b, 1c
1d
Yes
Yes
No
Moderate
Yes
Yes
Yes
Not yet studied
Low yields of 1a
Low yields, difficult to purify
—
No response: poisoned
—
1e
Nernst/Cd = 29.28 mV decadeϪ1
No Nernst/Pb = 45 mV decadeϪ1
Nernst/Pb = 29.17 mV decadeϪ1
Nernst/Hg:
Very low selectivity
1f
2a
Very low selectivity
Very high selectivity
2b
58.72 mV decadeϪ1 at pH = 7
28.32 mV decadeϪ1 at pH = 4
Nernst/Pb = 28 mV decadeϪ1
No Nernst/Ag = 45 mV decadeϪ1
—
2c, 2d, 2eb
2f
2g, 2r, 2s
2h, 2t–z
2i
2j, 2n–q
2k, 2l
2mb
3a, 3c
3b, 3d, 3e
4a
4b
4c, 4e–h
No
Yes
Yes
No
Yes
No
Yes
Yes
Yes
No
Moderate
Yes
No
Turns dark
Good selectivity
—
—
Shows fluorescence
Present interferent functional groups
—
Very high selectivity
—
—
Lower solubility
—
—
Nernst/Pb = 30 mV decadeϪ1
Not yet studied
—
Undergoing study in optical sensors
Not recommended
No response to any ion
Nernst/Pb = 28.7 mV decadeϪ1
Not yet studied
—
No Nernst/Pb = 43 mV decadeϪ1
Not yet studied
—
a Solubility ≥20 mg in 100 g plasticizer TEHP. TEHP was the best solvent for these compounds. b Soluble in DOS and o-NPOE.
simultaneously: the principal and the interfering ions. To facili-
tate the comprehension of the data, it should be mentioned that
pot
A,B
K
(potentiometric selectivity coefficient) is calculated by the
fixed interference method by eqn. (1), where aA and aB are the
pot
A,B
K
= a /(a )zA/zB
(1)
A
B
activities, and ZA and ZB are the charges of the principal (A)
and interfering (B) ions, respectively.
pot
A,B
The quoted values of K
were mostly determined by the
fixed interference method. Other methods approved by IUPAC
pot
have also been tested and no significant differences in K
A,B
pot
values were observed.17b
K
indicates the extent of the selec-
A,B
tivity of a given ion sensor towards the interfering ions. The
reference value is taken for the specific principal ion (log
pot
A,B
K
= 0). Consequently, the values quoted in Table 2(b) reflect
the bigger or smaller selectivity behaviour, between the ion
sensed and the interfering ion, of a given ionophore.
Pb(II) ionophores
Good Pb() ISEs were obtained with ionophores 2f14a
Fig. 2 Calibration curve for Pb2ϩ ISE constructed with 2f. LLLR and
LDL are represented.
and 2m.14b The latter presents the best slope and calibration
pot
pot
A/ZB
Fig. 3 Selectivity in Pb() sensors: potentiometric selectivity coefficient KA,B = aA/(aB)Z . log KA,B ≥ 0, strong interference—the sensor responds
pot
pot
A,B
mainly to the interfering ion; log K between Ϫ2 and Ϫ1, moderate interference; log K ≤ Ϫ3; no interference.
A,B
2214
J. Chem. Soc., Perkin Trans. 2, 2001, 2211–2218

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Table 2 Summary of experimental data obtained for thiourea-based heavy metal ISEs
(a) Calibration parameters
Ionophore
1,3-Diphenylthiourea
2f
1e
2a
2b
2m
1f
4a
Ion sensor
Slopea
Hg2ϩ and Hg(OH)ϩ
30.8 and 58.6
Pb2ϩ
30
Cd2ϩ
Pb2ϩ
29.17
Hg2ϩ and Hg(OH)ϩ
28.32 and 58.72
7 × 10Ϫ6 and 4.15 × 10Ϫ6
5.0 × 10Ϫ6 and 3.4 × 10Ϫ6
8 weeks
Pb2ϩ
28.7
Pb2ϩ
45
Pb2ϩ
43
29.28
LLLRb
LDLc
2.0 × 10Ϫ6 and 6 × 10Ϫ6
2 × 10Ϫ6 and 4 × 10Ϫ6
6 weeks
3.7 × 10Ϫ6
1.7 × 10Ϫ6
8 months
TEHP
2 × 10Ϫ4
8 × 10Ϫ5
6 weeks
TEHP
3.7 × 10Ϫ3
3.7 × 10Ϫ5
6 weeks
TEHP
4.8 × 10Ϫ7
3.6 × 10Ϫ8
4 months
o-NPOE
1.99 × 10Ϫ4
6.3 × 10Ϫ5
20 days
TEHP
N.S.e
N.S.e
15 days
TEHP
Lifetime
Plasticizer
TEHP
TEHP
(b) Selectivity parameters
Selectivity: log K for reliable sensorsd
pot
A,B
Ionophore
1,3-Diphenylthiourea
2b
2a
2f
2m
0.00
0.00
Ϫ4.00
Ϫ4.00
0
Ϫ4.00
Ϫ4.00
Ϫ1.29
N.S.e
Ϫ2.56
Ϫ4.00
1e
0.00
Hgϩ
Agϩ
0
0
0.00
0.00
Ϫ3.45
0.00
0
0.00
Ϫ1.75
Ϫ2.14
Ϫ2.77
Ϫ1.05
N.S.e
0.00
0.00
Ϫ0.20
Ϫ4.57
Ϫ4.10
Ϫ4.27
Ϫ3.15
Ϫ4.87
Ϫ4.58
Ϫ4.70
N.S.e
Ϫ1.44
Ϫ4.54
Ϫ4.51
Ϫ4.32
Ϫ4.55
Ϫ4.50
Ϫ4.55
Ϫ4.51
Ϫ4.57
N.S.e
Ϫ0.03
Ϫ1.84
Ϫ1.75
0.20
Co2ϩ
Cu2ϩ
Pb2ϩ
Mn2ϩ
Cd2ϩ
Zn2ϩ
Sr2ϩ
N.S.e
Ϫ1.00
0
Ϫ3.10
Ϫ2.17
Ϫ2.76
Ϫ2.89
Ϫ3.20
Ϫ3.26
N.S.e
0
N.S.e
Ϫ1.97
N.S.e
N.S.e
Ca2ϩ
Ni2ϩ
N.S.e
a Slope = Sensitivity in linear response range of calibration curve. (Ideal value for M2ϩ ion = 29.6 mV decadeϪ1 and for Mϩ = 59.1 mV decadeϪ1).
pot
pot
A/ZB
b Lower limit of linear response. c Lower detection limit. d Potentiometric selectivity coefficient KA,B = aA/(aB)Z . log KA,B ≅ 0, strong interference:
pot
pot
A,B
the sensor responds mainly to the interfering ion; log K between Ϫ2 and Ϫ1, moderate interference; log K < Ϫ3, no interference. e N.S. = not
A,B
studied: no data reported.
sensor was also constructed with a different plasticizer,
o-nitrophenyl octyl ether (o-NPOE).
A mediocre Pb() ISE was made with 2a. It exhibited a
Nernstian response towards Pb2ϩ with a very low selectivity. A
chelate interaction with most ions was proposed20 to explain
this poor selectivity. Due to the high stability of the chelates, the
reversibility of the processes is very low and the lifetime, LDL,
LLLR and selectivity of the ISEs are consequently very poor.
Substituents with ion-complexing groups in the side chains are
strongly not recommended. Compound 1f gave a very poor
Pb() sensor, with a very low lifetime. The selectivity was not
studied.
Cd(II) ionophores
We obtained a linear response for the ISE constructed with 1e16
towards Cd2ϩ. Pb2ϩ causes significant interference, as do Hg2ϩ
and Agϩ. The log KApo,Bt values are represented graphically in Fig.
4. The introduction of another group (benzyl) at N(3) prevents
the fixed intramolecular H-bonded configuration and causes
a dramatic change in the behaviour of 1e and 2f in the ISEs.
This fact suggests that the site of interaction with ions differs
between both types of ionophore. It seems that the oxygen
atom of CO has an important role in the coordination of Cd2ϩ
by chelate formation in 1e as has been proposed.20 This Cd()
ISE showed many important interferences. Hence, this is not a
recommended ionophore due to its low selectivity. Note that a
similar situation was observed for the 1f-constructed Pb() ISE.
Fig. 4 Selectivity in the Cd() sensor: potentiometric selectivity
pot
pot
A/ZB
coefficient K
= aA/(aB)Z . log KA,B ≥ 0, strong interference—the
A,B
pot
A,B
sensor responds mainly to the interfering ion; log K between Ϫ2 and
pot
Ϫ1, moderate interference; log K ≥ Ϫ3; no interference.
A,B
Hg(II) ionophores
The Hg() ion is not easily tested by means of ISEs. There are
very few acceptable ionophores reported, and those have many
disadvantages1d and a limited pH range for their use. In the
literature, almost all ISEs studied respond non-linearly towards
Hg() or have a very short lifetime.5 This ion has poisoned the
membrane in many of our studied ISEs due to the strong
attraction to the sulfur atom. However, the new compound 2b is
able to meet this challenge.
parameters23 (see Table 2(a)). Both sensors also have excellent
lifetimes and good selectivity. Fig. 3 compares the selectivity of
the three reported Pb() sensors. However, there is significant
interference due to Hg2ϩ and Agϩ. As shown in Fig. 3, 2m
displays better selectivity than 2f. It might be assumed that
the most satisfactory parameters and selectivity are due to the
presence of a lipophilic group C14H29 in the molecule. A 2m
J. Chem. Soc., Perkin Trans. 2, 2001, 2211–2218
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Table 3 Summary of relevant orbital features calculated on structures 2f and 1,3-diphenylthiourea
Parameter
1,3-Diphenylthiourea
2f
ELUMO/eV
EHOMO/eV
EHOMOϪ1/eV
EHOMOϪ2/eV
ηa
Ϫ2.326
Ϫ4.943
Ϫ5.310
Ϫ5.933
1.302
0.768
3.634
Ϫ3.095
Ϫ5.437
Ϫ5.654
Ϫ6.374
1.171
Ϫ0.854
4.266
σb
χc
Charge on S atom
Ϫ0.210
1.67
Ϫ0.189
1.689
Bond order S᎐C
᎐
%S coefficient on HOMOs
%O coefficient on HOMOs
68.19 and 48.26
—
70.87 and 30.18
0.33 and 0.17
a Hardness η = ∆E/2. b Softness σ = 1/η. c Absolute electronegativity χ = (EHOMO ϩ ELUMO)/2. Energy units, eV.
pot
pot
A/ZB
Fig. 5 Selectivity in Hg() sensors; potentiometric selectivity coefficient KA,B = aA/(aB)Z . log KA,B ≥ 0, strong interference—the sensor responds
pot
pot
A,B
mainly to the interfering ion; log K between Ϫ2 and Ϫ1, moderate interference; log K ≥ Ϫ3, no interference.
A,B
The change of the phenyl group in 2f for a cyclohexyl in 2b,
resulted in an excellent sensor for Hg().17a It experiences no
interferences from other ions and the lifetime is acceptable. This
fact suggests that the nearby planar phenyl group participates
in the coordination of 2f with Hg() ions. The interaction
centre is not only the S atom. The saturated cyclohexyl group
raises the selectivity and lowers the reactivity towards the two
detected Hg() species: Hg2ϩ and Hg(OH)ϩ. The wider range of
pH for the medium is also another advantage of this sensor.
In order to observe the influence of the furoyl group and the
intramolecular hydrogen bond present in the most suitable
series 2, ISEs were constructed with 4a and the commercially
available 1,3-diphenylthiourea. The benzoylthiourea 4a was
not soluble enough in any plasticizer used for the membrane
preparation and the ISE showed poor results with very short
lifetimes (see Tables 1 and 2). The furoyl group confers
better membrane solubility on the structure than the benzoyl
group does.
HOMO and HOMO-1, very similar to 1,3-diphenylthiourea.
The carbonyl oxygen atom participates hardly at all in the
HOMOs of 2f. The calculated χ is slightly greater in 2f. The
introduction of a furoyl group in the thioureido system
increases the softness of the sulfur atom. Both facts might
explain the greater reactivity of 2f towards Hg() species than
1,3-diphenylthiourea.
It has also been stated20 that hydrogen-bonded carbonyl-
thioureido systems (in 2a and 2f) exhibit independent behaviour
of the OC–NH and SC–NH groups, regarding their bond order
sequences.
Structure of the plasticizer
Solubility in the plasticizer is an important feature which influ-
ences the response of the sensor. Fig. 6 shows the structures of
some frequently used plasticizers in membrane preparations.
The most suitable for the solubility of the thioureas studied
were TEHP, dibutyl phthalate (DBP) and o-NPOE. They con-
tain big lipophilic chains and basic groups which interact with
the more acidic NH-1 in aroylthioureas. Both facts make the
compounds advantageous as plasticizers with these thioureas
and support the ionophore behaviour. In general, the best
results were obtained with TEHP, the most basic and lipo-
philic solvent. The interaction with the acidic NH promotes
the solubility and enhances the nucleophilic character of the
neighbouring sulfur atom.
In contrast with 2f, the reactivity of 1,3-diphenylthiourea
towards heavy metal ions was reduced, resulting in another
Hg() sensor with very high selectivity, except for the Agϩ
ion.17b As seen in Fig. 5 for the two reported Hg() sensors, 2b
shows better selectivity than 1,3-diphenylthiourea. This is
probably due to the higher solubility of 2b in TEHP [tris-
(2-ethylhexyl) phosphate].
Frontier orbital analysis
An example is given in the comparison of the results between
2f and 2m. Lipophilic groups in 2m raise the LLLR and LDL in
comparison with 2f. There is better solubility in other medi-
ators, such as o-NPOE. This solvent also has inferior basic
properties compared with TEHP. This might explain the lower
Table 3 shows the principal orbital parameters calculated for 2f
and 1,3-diphenylthiourea. In this paper, we reject the orbital
data reported for 1e due to the differences between calculated
and XRD structures. Also, we have calculated the absolute
electronegativity χ of both structures. 1,3-Diphenylthiourea
and 2f present a very similar picture as regards HOMO–
HOMO-1 separation. They are so close that it may be assumed
that both have almost the same weight in the nucleophilic
response. The sulfur atom makes a large contribution to the
reactivity and better selectivity of 2m towards Cu2ϩ and Cd2ϩ
.
The solubility of these compounds was tested in all the
plasticizers. It was seen that the plasticizer with the best
capacity was TEHP, the one with the strongest interaction with
the acidic NH and bigger lipophilic groups. Only the general
2216
J. Chem. Soc., Perkin Trans. 2, 2001, 2211–2218

View Online
good membrane solubility, might be tested. In the case of 2e
the plasticizer cannot be TEHP, but it was soluble enough in
o-NPOE and bis(2-ethylhexyl) sebacate (DOS), which could
have the advantage of a lower NH interaction. (g) 3-Aryl-
substituted furoylthioureas of series 2 with quasi-planar fixed
intramolecularly bonded structures gave long-lifetime sensors
for Pb2ϩ. It is presumed that the phenyl group participates in
the complex formation with Pb(), but also with the inter-
fering ions. Compounds of series 2 with bulky and electron-
withdrawing substituents near the C᎐S group, which prevent
᎐
interactions with the sulfur atom, should be synthesized and
tested as sensors for softer ions. Compounds 2f, 2m, 2b and 1,3-
diphenylthiourea are the most recommended new ionophores
for Pb2ϩ and Hg2ϩ sensors.
Experimental
Ionophores
Some thioureas of series 2–4 have been synthesized and
reported in previous papers.18 Identification data for such
known thioureas and eighteen new ones are included in the
electronic supplementary information.† Reagents for their
synthesis were commercially available from Merck and Fluka
(amines, furoic acid, and substituted benzoic acids) and were
dried and used without further purification. NH4SCN (Merck)
was recrystallized from ethanol and kept under dry conditions.
Furoyl chloride was obtained by reaction of dried furoic acid
with freshly distilled SOCl2 which was refluxed for 5–6 h. Excess
of SOCl2 was removed and furoyl chloride was distilled at
normal pressure (fraction of bp 160–165 ЊC). Substituted furoyl
chlorides and benzoyl chlorides were obtained similarly, and
the excess of SOCl2 removed without further distillation. Sol-
vents (acetone, ethanol) were dried with Na2SO4, distilled and
stored over molecular sieves. Melting points are uncorrected
and were determined on a micro stage block. Elemental anal-
yses were performed at the Instrumental Service of the Faculty
of Sciences at the Autonomous University of Barcelona. FTIR
spectra were recorded on a Philips Analytical PU9600 Fourier
Fig.
6
Structures of plasticizers commonly used in membrane
preparations.
solubility tests in TEHP are shown in Table 1. Many com-
pounds of series 2, 3 and 4 were not soluble enough in many
plasticizers. It was assumed that a solubility of ≥20 mg in 100
mg of plasticizer is more than suitable for the preparation of
the membrane.
1
transform spectrometer. H and 13C NMR spectra were meas-
ured at 250 MHz an a Bruker AC-250F with an ASPECT 3000
computer at frequencies of 250 MHz (1H) and 62.89 MHz (13C)
at 25 ЊC. Samples were dissolved in DMSO-d6 at 5% (w/v) and
TMS was used as internal reference. DEPT experiments were
done with protonic pulses at 135Њ and 90Њ. Some assignments
were made by HETCOR 13C–1H. Detailed NMR data (includ-
ing carbon types determined by DEPT experiments) are
included in the supplementary information.†
Conclusions
To gauge the usefulness for potentiometric sensors, forty six
aroylthioureas were tested as ionophores. Regarding the struc-
tures of thioureas as heavy-metal ionophores for ISEs, the best
choices for high selectivity and sensibility are the following:
(a) 3-monosubstituted furoylthioureas (series 2) are strongly
recommended. Their coordination strength and liposolubility
can be easily modulated. (b) Series 3 and 4 are not suitable
due to their low solubility in the plasticizers. Non-substituted
1-benzoyl-3-phenylthiourea shows poor reproducibility with no
Nernstian responses, however, furoylthioureas do (series 2 and
4). (c) In all cases, long carbon chains are recommended as
substituents in phenyl or furan rings, in order to raise liposolu-
bility and to prevent the loss of the ionophore from the mem-
brane. It is seen that the LDL and LLLD improve with this
modification. (d ) Series 1 showed poor selectivity due to chelate
formation with metal ions. These compounds are not recom-
mended as ionophores. For the same reason, functionalised side
groups should be avoided to prevent chelate formation, which
diminishes the lifetime of the sensor or poisons the membrane
due to very stable complex formation. (e) Weakly reactive furo-
ylthioureas, 3-cycloalkyl-substituted, or simply 1,3-diaryl-
thioureas make the best sensors for Hg2ϩ. In both cases the
substituent group lowers the nucleophilic character of the
sulfur atom and raises the liposolubility. ( f ) Compounds 2e
and 2k, the latter with strong electron-withdrawing groups and
General procedure for syntheses18
CAUTION:: many aroyl chlorides are lachrymators, especially,
furoyl chloride. The crude products have a strong, foul smell.
All procedures must be carried out in a well-ventilated hood.
Under dry conditions, the aroyl chloride (30 mmol) was added
to a solution of (30 mmol, 2.28 g) NH4SCN in dried acetone
(15 ml) with magnetic stirring, at room temperature over
10 min, after which a white precipitate of NH4Cl appeared.
Without filtration, 30 mmol of the appropriate aromatic amine
in acetone (20 ml) were slowly added at room temperature
(30 ЊC) with stirring. The recommended temperature for the
addition of aliphatic primary amines is 0–5 ЊC and for second-
ary aliphatic amines Ϫ15 ЊC. When the mixture reached room
temperature, it was refluxed for 10 min. After cooling, the reac-
tion mixture was poured slowly into 400 ml ice–water with
strong stirring. The aroylthiourea precipitated as a solid or an
oily product. In the latter case, the mixture was left to stir over-
night. The crude product was filtered off, dried and recrystal-
lized (ethanol or DMF–ethanol 20 : 80), then washed with cool
diethyl ether. The purity was tested by TLC (glass plates of 2.6
× 7.5 cm, 0.25 mm thick, Silica Gel G Nach Stahl Ϫ60). The
J. Chem. Soc., Perkin Trans. 2, 2001, 2211–2218
2217

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(b) J. Janata, Anal Chem., 1992, 64, 196R and references cited
therein; (c) E. Bakker, P. Bühlmann and E. Pretsch, Chem. Rev.,
1997, 97, 3083 and references cited therein; (d ) P. Bühlmann,
E. Pretsch and E. Bakker, Chem. Rev., 1998, 98, 1593 and references
cited therein.
2 (a) S. Alegret and E. Martínez-Fábregas, Biosensors, 1989, 4, 287;
(b) S. Alegret and A. Florido, Analyst, 1991, 116, 473; (c) S. Alegret,
J. Alonso, J. Bartroli and E. Martínez-Fabregas, Analyst, 1989, 114,
1443.
solvents used were benzene–chloroform (90 : 10) and chloro-
form–water (saturated). This method was used to prepare 46
aroylthioureas, which were recrystallized twice for analytical
purposes. The ionophore 1,3-diphenylthiourea (Merck) was
purified by double recrystallization from ethanol and dried over
CaCl2 for several days.
XRD measurements
3 (a) A. Craggs, G. Moody and J. Thomas, Analyst, 1970, 95, 910;
(b) A. Machado, Analyst, 1994, 119, 2263.
4 S. Sheen and J. Shih, Analyst, 1992, 117, 1691.
The X-ray crystallographic studies for compounds 1e and 2b§
were done on a Bruker Smart 6000 diffractometer, λ(Mo
=
Kα)
0.71069 Å, graphite monochromator, T = 293 K, ω/2θ, range
2 < θ < 25Њ. After optical alignment the cell parameters were
determined by using the reflections collected on four sets of 20
frames each (program SMART23). Data were collected in the
hemisphere mode. Data on a total of 1321 frames were used for
data reduction (program SAINT-NT24). Corrections were
made for Lorentz and polarization effects. Data were obtained
by rotating φ successively by 0.3Њ using two different χ settings.
The structure solution and refinement was performed with the
program package SHELXTL-NT.25 Non-hydrogen atoms were
refined anisotropically by full-matrix least squares. Hydrogen
atoms were positioned geometrically and refined using a “riding
model”.
5 D. M. Rudkevich, W. Verboom and D. N. Reinhoud, J. Org. Chem.,
1994, 59, 3683.
6 I. Ibrahim, Y. Cemal and B. Humeyra, Analyst, 1996, 121, 1873.
7 E. Malinowska, Analyst, 1990, 115, 1085.
8 A. Borracino, L. Campanella, M. Sammartino and M. Tomassetti,
Sens. Actuators, B, 1992, 535.
9 Fluka Catalogue of Ionophores, Fluka Chemie AG, Buchs,
Switzerland, 1998.
10 (a) U. Oesch and W. Simon, Anal. Chem., 1980, 52, 602; (b) E.
Lindner, K. Toth, E. Pungor, F. Behm, P. Oggenfuss, D. H. Welti,
D. Ammann, W. E. Morf, E. Pretsch and W. Simon, Anal. Chem.,
1984, 56, 1127; (c) M. Lerchi, E. Bakker, B. Rusteholz and
W. Simon, Anal. Chem., 1992, 64, 1534.
11 (a) K. P. Xiao, P. Bühlmann, S. Nishizawa, S. Amemiya and
Y. Umezawa, Anal. Chem., 1997, 69, 1038; (b) S. Nishizawa,
P. Bühlmann, K. P. Xiao and Y. Umezawa, Anal. Chim. Acta, 1998,
358, 35; (c) S. Amemiya, P. Bühlmann, Y. Umezawa, R. C. Jagessar
and D. H. Burns, Anal. Chem., 1999, 71, 1049.
12 (a) L. Beyer, E. Hoyer, H. Hennig and R. Kirmse, J. Prakt. Chem.,
1975, 317, 829; (b) O. Seidelmann, L. Beyer, G. Zdovinsky,
R. Kirmse, F. Dietze and R. Richter, Z. Anorg. Allg. Chem., 1996,
622, 692.
13 K. R. Koch, C. Sacht, T. Grimmbacher and S. Bourne, S. Afr.
J. Chem., 1995, 48 (1/2), 71.
Potentiometric measurements
These were made with a Cole Parmer digital potentiometer
Model 59003–00, 0.1 mV sensitivity. The reference electrode
was an Orion Model 90–00–01, double-junction Ag/AgCl elec-
trode. pH values were determined with a Cole Parmer Model
05772–20 simple junction glass electrode. LABNET Model
V–20, 2–20 µl and BRAND 20–100 µl micropipettes were used.
14 (a) L. Pérez, Y. Martínez, O. Arias, O. Fonseca, E. Otazo, O. Estévez,
Y. Fajardo, J. Alonso and J. Casabó, Afinidad, 1998, LV,
No. 474, 130; (b) O. Fonseca, J. Alonso-Chamarro, E. Otazo and
L. Pérez-Marín, presentation at IBERSENSOR 98, La Habana,
1998.
15 L. Pérez-Marín, G. Macedo-Miranda, P. Avila-Pérez, E. Otazo-
Sánchez, H. Carrasco-Ábrego, H. López-Valdivia, J. Alonso-
Chamarro and O. Estévez-Hernández, Afinidad, 1999, LVI, No. 483,
295.
Membrane and electrode preparations
The conventional method was employed26,2c for electrode prep-
aration and calibration.
K
pot determinations
The fixed interference method was utilized. The detailed
experimental methodology is fully described.21
16 L. Pérez-Marín, G. Ortiz-Macedo, P. Ávila-Pérez, E. Otazo-
Sánchez, H. López-Valdivia, J. Alonso-Chamarro and O. Estévez-
Hernández, Afinidad, 1999, LVI, No. 484, 397.
Reagents and solutions for electrode preparation and
potentiometric measurements
17 (a) L. Pérez-Marín, O. Gutiérrez-Lozano, P. Avila-Pérez, E. Otazo-
Sánchez, H. López-Valdivia and J. Alonso-Chamarro, Afinidad,
2001, in the press; (b) L. Pérez-Marín, E. Otazo-Sánchez, G. Macedo-
Miranda, P. Avila-Pérez, J. Alonso Chamarro and H. López-
Valdivia, Analyst, 2000, 125, 1787; (c) L. Pérez-Marín, H. López-
Valdivia, P. Avila-Pérez, E. Otazo-Sánchez, G. Macedo-Miranda,
O. Gutiérrez-Lozano, J. Alonso Chamarro, J. De la Torres-Orozco
and L. Carapia-Morales, Analyst, 2001, 126, 501.
18 (a) I. B. Douglas and F. B. Dains, J. Am. Chem. Soc., 1934, 56, 719;
(b) I. G. Gakh and Z. N. Nazarova, Zh. Obshch. Khim., 1960, 30,
2183; (c) I. G. Gakh and Z. N. Nazarova, Zh. Obshch. Khim., 1962,
32, 2548; (d ) A. Macías, E. Otazo and I. P. Beletskaia, Zh. Org.
Khim., 1982, 18, 681.
Standard solutions with pure water (0.1 µS cmϪ1) and the
appropriate analytical-reagent grade salts were prepared
according to the literature.9–16 Tris(2-ethylhexyl) phosphate
(TEHP) was used as the solvent mediator in most cases. High
molecular weight poly(vinyl chloride) (PVC) and tetrahydro-
furan (THF) were purchased from Aldrich. The graphite–epoxy
transductor was prepared with powdered graphite (1–2 µm)
purchased from Aldrich, Araldite M4 and hardener (HR)
HY5162 from Ciba-Geigy (Basel, Switzerland).
19 (a) A. Macías, E. Otazo, G. Pita, R. Gra and I. P. Beletskaia,
Zh. Org. Khim., 1982, 8, 905; (b) E. Otazo, R. Gra and A. Macias,
Rev. CENIC, Cienc. Quim., 1979, 10, 321; (c) E. Otazo, R. Gra and
A. Macias, Rev. CENIC, Cienc. Quim., 1979, 10, 331.
20 L. Pérez-Marín, M. Castro, E. Otazo-Sánchez and G. A. Cisneros,
Int. J. Quantum Chem., 2000, 80, 609.
21 J. A. Asencio, L. Pérez-Marín, E. Otazo-Sánchez, M. Castro,
D. Contreras-Pulido and G. A. Cisneros, Afinidad, 2000, LVII, No.
487, 180.
22 (a) Y. Umezawa, K. Umezawa and H. Sato, Pure Appl. Chem., 1995,
67, 507; (b) R. P. Buck and E. Lindner, Pure Appl. Chem., 1994, 66,
2547; (c) E. Bakker, Anal. Chem., 1997, 69, 1061; (d ) E. Bakker,
J. Electrochem. Soc., 1996, 143; (e) E. Bakker, E. Pretsch and
P. Bühlmann, Anal. Chem., 2000, 72, 1127.
23 Bruker Analytical X-ray Systems, Madison, USA. SMART: Bruker
Molecular Analysis Research Tool V. 5.057 c, 1997–1998.
24 Bruker Analytical X-ray Systems, Madison, USA. SAINT ϩ NT
Version 6.01, 1999.
Acknowledgements
We are grateful to the CONACYT project 32718-E and for the
support given by the Hidalgo State Autonomous University
of Mexico. OEH acknowledges
No. 99–227 RG/CHE/LA. EOS and JACh appreciate the grant
from the Ibero-American Cooperation Agency (Spain). EOS
acknowledges grant 980090 from CONACYT (Mexico). EOS,
OEH and LPM thank the Higher Education Ministry of the
Republic of Cuba for the sensor project.
a TWAS grant (RGA)
§ CCDC reference numbers 160086 and 160087. See http://www.rsc.org/
suppdata/p2/b1/b102029n for crystallographic files in .cif or other
electronic format.
References
25 Bruker Analytical X-ray Systems, Madison, USA. SHELXTL-NT
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26 J. L. F. C. Lima and A. A. S. C. Machado, Analyst, 1986, 111, 799.
1 (a) Y. Umezawa, Handbook of Ion Selective Electrodes: Selectivity
Coefficients, CRC Press, Boca Raton, Ann Arbor, Boston, 1990;
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J. Chem. Soc., Perkin Trans. 2, 2001, 2211–2218