Synthesis and evaluation of fluorimetric and colorimetric chemosensors for anions based on (oligo)thienyl-thiosemicarbazones

Article abstract of DOI:10.1016/j.tet.2012.06.021

A family of heterocyclic thiosemicarbazone dyes (3a-d) containing thienyl groups has been synthesized, characterized, and their chromo-fluorogenic response in acetonitrile in the presence of selected anions was studied. Acetonitrile solutions of 3a-d show

Full text of DOI:10.1016/j.tet.2012.06.021

Tetrahedron 68 (2012) 7179e7186
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journal homepage: www.elsevier.com/locate/tet
Synthesis and evaluation of fluorimetric and colorimetric chemosensors
for anions based on (oligo)thienyl-thiosemicarbazones
,
,
,
c
Luis E. Santos-Figueroa a b, María E. Moragues a b, M. Manuela M. Raposo c , Rosa M.F. Batista ,
*
c
c
a,
b
a,
b,
a
*
ꢀ
ꢀ
ꢀ
ꢀ~
R. Cristina M. Ferreira , Susana P.G. Costa , Felix Sancenon , Ramon Martínez-Manez
, Juan Soto ,
a,b
ꢀ
Jose Vicente Ros-Lis
a
ꢀ
ꢀ
ꢀ
Centro de Reconocimiento Molecular y Desarrollo Tecnologico (IDM), Unidad Mixta Universidad Politecnica de Valencia-Universidad de Valencia, Universidad Politecnica de
Valencia, Camino de Vera s/n, Valencia 46022, Spain
b CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Spain
c Centro de Química, Universidade do Minho, 4710-057 Braga, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
A family of heterocyclic thiosemicarbazone dyes (3aed) containing thienyl groups has been synthesized,
characterized, and their chromo-fluorogenic response in acetonitrile in the presence of selected anions
was studied. Acetonitrile solutions of 3aed show absorption bands in the 338e425 nm range, which are
modulated by the groups attached to the thiosemicarbazone moiety. The fluoride, chloride, bromide,
iodide, dihydrogen phosphate, hydrogen sulfate, nitrate, acetate, and cyanide anions were used in the
recognition studies. Only sensing features were observed for fluoride, cyanide, acetate, and dihydrogen
phosphate anions. Two different chromogenic responses were found, (i) a small shift of the absorption
band due to coordination of the anions with the thiourea protons and (ii) the appearance of a new
red-shifted band due to deprotonation of the receptor. For the latter process changes in the color
solutions from pale-yellow to orange-red were observed. Fluorescence studies showed a different
Received 29 March 2012
Received in revised form 5 June 2012
Accepted 6 June 2012
Available online 15 June 2012
Keywords:
Chromophoric and fluorogenic sensor
Thienyl thiosemicarbazone receptors
Anion recognition
Hydrogen bond complexation
Deprotonation
emission behavior according to the number of thienyl rings in the
p-conjugated bridges. Stability
Thiophene
constants for the two processes (complex formationþdeprotonation) for receptors 3aed in the presence
of fluoride and acetate anions were determined from spectrophotometric titrations using the HypSpec
program. The interaction of 3d with fluoride was studied through 1H NMR titrations. Semiempirical
calculations to evaluate the hydrogen-donating ability of the receptors were also performed.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
years and today a number of receptors for anion binding have been
described. In most cases they are based on hydrogen bonding,
The development of new molecular-based receptors able to
detect anions, cations, or neutral molecules has recently gained
significance due to the importance of detecting some target species
in biological and environmental samples. In these systems the re-
ceptors are able to transform host-guest interactions into a mea-
surable signal, which allows analyte sensing via electrochemical or
optical modulations.1 In this field, apart from the interest in
developing fluorescent probes, chromogenic sensing has gained
attention due to the possible semi-quantitative detection to the
‘naked-eye’ or using very simple instrumentation.2 Optical
chemosensors for metal cations have been developed for more than
two decades,3 whereas in contrast anionic chromogenic probes
have only recently been investigated.4,5 In particular, the supra-
molecular chemistry of anions has advanced a great deal in the last
electrostatic interactions or coordination with suitable metal
complexes.6 In this area hydrogen bonding ligands are attractive
because show the advantage of being directional allowing dis-
crimination between anions of different hydrogen-bonding re-
quirements or geometries.7 Among neutral anion binding groups
thioureas and thiourea-containing fragments have been widely
used for the formation of complexes with anions.8 In particular
thiourea derivatives have been intensively studied as anion re-
ceptors and a number of ligands containing different number of
thiourea moieties and thioureido NH protons with different acidi-
ties have been described.9 A means of tuning the acidity of thio-
ureido NH protons is to introduce electron-donating or electron-
withdrawing substituents.10 On the other hand, among molecules
containing thiourea fragments the use of thiosemicarbazones has
gained interest recently as potential receptors. For instance Schiff-
base compounds containing thiosemicarbazone groups have also
grown in the areas of biology and chemistry due to their fungicidal,
* Corresponding
authors.
E-mail
address:
rmaez@qim.upv.es
(R.
ꢀ~
Martínez-Manez).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.021

7180
L.E. Santos-Figueroa et al. / Tetrahedron 68 (2012) 7179e7186
bactericidal, antiviral,11 and antitumor properties.12 Recently, we
have demonstrated that (oligo)thiophenes, electronically con-
showed CH]N protons in the 7.97e8.14 ppm range whereas
thiourea-NeH protons were found in the 9.07e9.11 and
9.35e10.49 ppm interval for NeH adjacent to the phenyl ring and
for the NeH adjacent to the CH]N moiety, respectively. When four
nected to recognition sites, are efficient
p-conjugated bridges for
the fluorimetric and/or colorimetric sensing of certain anions (e.g.,
Fꢀ, CNꢀ) and cations (Hþ, Naþ, Pd2þ, Cu2þ, Zn2þ, Hg2þ, Ni2þ).13
Moreover recently thiosemicarbazones have also gained attention
as anion receptors. In fact we and others have recently demon-
compounds are considered the highest variation in d were found for
the NeH protons located in the vicinity of the CH]N moiety ad-
jacent to thiophene (Dd¼0.94 ppm). Moreover, the NeH protons
adjacent to the phenyl ring were the less affected (Dd¼0.04 ppm).
strated that
p-conjugated heterocyclic derivatives, containing thi-
osemicarbazone moieties are suitable systems for the colorimetric
and fluorimetric sensing of anions.14
2.2. Spectroscopic behavior of 3aed
Taking into account our interest in the development of probes
for anions and inspired in this previous work on the use of thio-
semicarbazones as binding sites we report herein the synthesis and
characterization of new (oligo)thienyl-thiosemicarbazones. These
derivatives contain heteroaromatic p-conjugated systems (instead
of the more commonly used aryl groups) and have been tested as
anion chemosensors.
Acetonitrile solutions (C¼1.2ꢁ10ꢀ5 mol dmꢀ3 at 25 ꢂC) of the
thiosemicarbazone-functionalized receptors 3aed showed an
intense absorption band (log εz4.4) in the 338e425 nm region (see
Table 2). Compound 3a containing thiosemicarbazone moiety
surrounded by a phenyl and a thienyl ring, showed an absorption
band at 338 nm. The change of a hydrogen at the thienyl ring by
a better electron acceptor moiety, such as a dicyanovinyl group
(receptor 3b) induced a red shift from 338 to 425 nm. The presence
of one more thienyl group and an electron donor, such as an ethoxy
group (receptor 3c) induced a small red shift when compared
with 3a from 338 to 381 nm. Moreover the presence of two
additional thienyl rings on the framework of 3a (receptor 3d)
induced a bathochromic shift of the band (from 338 to 396 nm),
which is most likely a consequence of the extension of the
conjugation.
2. Results and discussion
2.1. Synthesis and characterization
The new compounds 3aed with thiophene, bithiophene, and
terthiophene
p-conjugated bridges were synthesized in moderate
to good yields (41e77%) through Schiff-base condensation of het-
erocyclic aldehydes 1aed with 4-phenyl-3-thiosemicarbazide 2 in
methanol at room temperature (see Scheme 1).
2.3. UVevis studies involving anions
The UVevis behavior of receptors 3aed in acetonitrile solutions
(C¼1.2ꢁ10ꢀ5 mol dmꢀ3) was studied at 25 ꢂC in the presence of the
fluoride, chloride, bromide, iodide, cyanide, nitrate, acetate,
perchlorate, hydrogen sulfate, and dihydrogen phosphate anions.
For all the receptors the presence (up to 100 equiv) of chloride,
bromide, iodide, hydrogen sulfate, and nitrate induced insignificant
changes in the UVevis spectra strongly suggesting that no
coordination takes place. This behavior contrasts with that
observed in the presence of basic anions, such as fluoride, cyanide,
acetate, and dihydrogen phosphate (see Fig. 1).
Scheme 1. Synthesis of the thienyl-thiosemicarbazone receptors 3aed.
For instance UVevis titrations of receptors 3aed with fluoride
showed an intensity decrease and a small bathochromic shift of the
absorption band together with a simultaneous growth of a new
red-shifted band. Moreover both the position of the new band and
the relative intensity of the absorption band of the receptor with
respect to the band upon addition of fluoride were dependent on
the receptor used. For instance, the behavior observed in the
presence of Fꢀ for receptors 3c and 3d is shown in Figs. 2 and 3.
Receptor 3c in acetonitrile was yellow due to the band at
381 nm. Upon addition of increasing quantities of fluoride this band
progressively decreased while a new absorption at 515 nm
Aldehyde 1a was commercially available whereas aldehydes 1c
and 1d were synthesized as reported elsewhere.15 The 2-((5-
formylthien-2-yl)methylene)malononitrile 1b was synthesized
through reaction of thiophene-2,5-dicarbaldehyde with malono-
nitrile in dry DMF with a catalytic amount of piperidine. Purifica-
tion of the crude product by column chromatography on silica with
increasing amounts of diethyl ether in light petroleum as eluent,
gave the pure compound in 22% yield. All the compounds were
completely characterized by 1H and 13C NMR, IR, MS, EA or HRMS
and the data obtained were in full agreement with the proposed
formulation (see Table 1).
(Dl¼134 nm) increased in intensity (see top of Fig. 2). This induced
The most characteristic signals in the 1H NMR spectrum of this
family of thiosemicarbazones were those corresponding to NeH
and CH]N protons. 1H NMR studies in deuterated chloroform
a color modulation from pale-yellow to orange. This was in
agreement with the expectation that the coordination of an anion
in a donor group in a pushepull system will induce a bathochromic
Table 1
Yields, 1H NMR, and IR data of the oligothienyl-thiosemicarbazone receptors 3aed
Formyl thiophene
Product
Yield (%)
dH (ppm)a
(CH]N)
IRb (cmꢀ1
n )
(C]NeNH)
(S]CeNH)
(]CeH)
(NH)
1a
1b
1c
1d
3a
3b
3c
3d
66
77
50
41
8.14
8.02
8.07
7.97
10.29
9.60
10.49
9.35
9.11
9.07
9.09
9.09
3141
3122
3127
d
3297
3341
3329
3310
a
For the NH proton of the (oligo)thienyl-thiosemicarbazone receptors 3aed (300 MHz, CDCl3).
IR was recorded in Nujol.
b

L.E. Santos-Figueroa et al. / Tetrahedron 68 (2012) 7179e7186
7181
Table 2
Spectroscopic data for compounds 3aed
Receptor
lab LH (nm)
lab Lꢀ (nm)a
Log ε (LH)
lem LH (nm)
Dlem Lꢀ (nm)a
F
Dlabeem LH (nm)
Dnabeem LH (cmꢀ1
)
3a
3b
3c
3d
338
425
381
396
397
626
515
503
4.25
4.35
4.51
4.39
439
560
483
489
447
539
482
517
0.0064
0.0019
0.065
101
135
102
93
6806
5672
5542
4802
0.088
a
Measured upon addition of 100 equiv of fluoride anion.
shift. Receptor 3d showed a similar behavior with fluoride; i.e., the
band at 396 nm suffered a small hypochromic effect and a new
absorption band at 503 nm (Dl¼107 nm) grew in intensity (see top
of Fig. 3). As can be seen, it is apparent from the figure that the ratio
between both bands was different for receptors 3c and 3d. Also it
was clear that for a certain receptor the change observed depends
on the anion used in the titration experiments. It was observed that
fluoride and cyanide anions induced UVevis changes for all the
receptors whereas acetate and hydrogen phosphate displayed
a poorer response and only gave noticeable changes with 3b and 3c
(see for instance the bottom of Figs. 2 and 3). When receptors 3a
and 3d were compared it was found that 3a was able to induce
some changes with acetate, although to a much lesser extent than
3b and 3c.
Fig. 1. Color changes of 3c (top) and 3d (bottom) solution (5ꢁ10ꢀ4 mol dmꢀ3) seen in
the presence of 10 equiv of Fꢀ, Clꢀ, Brꢀ, Iꢀ, CNꢀ, AcOꢀ, ClO4ꢀ, HSO4ꢀ and H2POꢀ4
.
0,40
0,35
0,30
0,25
0,20
0,15
0,10
0,05
0,00
0,30
0,25
0,20
0,15
0,10
0,05
0,00
300
350
400
450
500
550
600
650
300
350
400
450
500
550
600
Wavelength (nm)
Wavelength (nm)
0,45
0,40
0,35
0,30
0,25
0,20
0,15
0,10
0,05
0,00
0,30
0,25
0,20
0,15
0,10
0,05
0,00
300
350
400
450
500
550
600
650
300
350
400
450
500
550
600
Wavelength (nm)
Wavelength (nm)
Fig. 2. UVevis titration of receptors 3c (1.2ꢁ10ꢀ5 mol dmꢀ3) with fluoride (top) and
acetate (bottom) anions (0e30 equiv) in acetonitrile.
Fig. 3. UVevis titration of receptors 3d (1.2ꢁ10ꢀ5 mol dmꢀ3) with fluoride (top) and
acetate (bottom) anions (0e30 equiv) in acetonitrile.

7182
L.E. Santos-Figueroa et al. / Tetrahedron 68 (2012) 7179e7186
The changes observed in the UVevis spectrum upon fluoride
2.5. Fluorogenic studies involving anions
addition were attributed to the formation of hydrogen-bonding
complexes with the thiosemicarbazone groups that eventually
resulted in a deprotonation.16,17 The formation of hydrogen-
bonding complexes was reflected in relatively small variations in
the absorption band of the receptor whereas deprotonation pro-
cesses was related with the appearance of a new absorption band at
longer wavelengths.18 Moreover a close view of the results in-
dicated that the final response of the receptors 3aed towards the
tested anions is dependent on the functional groups attached to the
thiosemicarbazone group that modulated the acidity of the NeH
protons. In our case the UVevis studies suggested that the acidity of
the receptors follows the order 3b>3c>3a>3d. In fact, whereas 3b
and 3c were able to display color changes (deprotonation) with
fluoride, cyanide, acetate and dihydrogen phosphate, receptors 3a
and 3d only showed significant color modulations in the presence
of fluoride and cyanide.
Fluorescence studies in acetonitrile solutions of the receptors
upon addition of increasing amounts of the corresponding anion
were also carried out. Receptors were excited in the pseudo-
isosbestic points observed in the course of UVevis titrations. All
receptors displayed a broad and unstructured emission band.
Quantum yields in acetonitrile (see Table 2) ranged from quite low
(receptor 3a,
F
¼0.0064) to medium (compound 3d, ¼0.088). The
F
addition of chloride, bromide, iodide, hydrogen sulfate, and nitrate
anions to receptors 3aed resulted in negligible changes in the
emission intensity profiles. In contrast, the fluorescence emission in
presence of fluoride, cyanide, acetate, and dihydrogen phosphate
changed significantly.
A different general behavior was found depending on the
anion and the receptor used in the studies. Fig. 4 shows the
changes observed in the emission of 3a in the presence of in-
creasing amounts of fluoride or acetate. In presence of fluoride,
an enhancement of the fluorescence intensity upon the addition
of moderate amounts of fluoride followed by a quenching of the
emission band at higher anion concentrations and the shift of
the final band at longer wavelengths were observed. This be-
havior is in agreement with the changes observed in the ab-
sorption titrations and the coordination plus deprotonation
equilibriums. Thus enhancement of the fluorescence emission is
attributed to the formation of the corresponding hydrogen-
bonding complex (Eq. 1), whereas further quenching and shift
of the band is related with the formation of the deprotonated
species.
Fig. 4 (bottom) also shows the emission behavior found for 3a in
the presence of acetate. In this case only an enhancement of the
fluorescence was found in agreement with the formation of
hydrogen-bonding complex (note that no clear deprotonation
was found for 3a with acetate). A similar emission behavior in
the presence of fluoride and acetate was found when using
receptor 3b.
2.4. Stability constants
As stated above, in the interaction of basic anions with the
semithiocarbazone-containing receptors 3aed two different be-
haviors were observed: (i) hydrogen bonding interactions and (ii)
deprotonation (see Eqs. 1 and 2). In order to complete the charac-
terization of 3aed coordination and deprotonation processes were
studied via the evaluation of the corresponding stability constants
that were determined by UVevis spectroscopic titrations between
receptors 3aed and the fluoride and acetate anions, using the
software HypSpec V1.1.18. The obtained data were adjusted to two
consecutive equilibriums corresponding to coordination and
deprotonation (see Eqs.1 and 2) and the results are shown inTable 3.
LH þ Aꢀ$LH$$$Aꢀ
LH$$$Aꢀ þ Aꢀ$Lꢀ þ A2Hꢀ
Table 3
(1)
(2)
Logarithms of the stability constants measured for the interaction of receptors 3aed with fluoride and acetate
Fꢀ
AcOꢀ
LH þ Aꢀ$LH$$$Aꢀ
3.46(4)
5.39(8)
3.62(6)
3.55(6)
LH$$$Aꢀ þ Aꢀ$Lꢀ þ A2Hꢀ
2.75(3)
4.19(4)
2.06(8)
1.06(6)
LH þ Aꢀ$LH$$$Aꢀ
1.29(3)
3.46(2)
LH$$$Aꢀ þ Aꢀ$Lꢀ þ A2Hꢀ
a
3a
3b
3c
3d
1.52(7)
2.36(5)
0.48(2)
a
a
a
No reliable results were obtained.
From Table 3 it can be observed that, as a general trend, the
logarithms of the stability constants measured for both equilibri-
ums with fluoride were higher than those obtained for acetate
when using receptors 3a, 3b and 3c. This was in agreement with
the results detailed above and with the more basic character of
fluoride in acetonitrile when compared with acetate. It can be
observed in Table 3 that the stability constants for the formation of
the corresponding hydrogen-bonding complexes were, for fluo-
ride, at least one order of magnitude larger than the stability
constants for the deprotonation and about two orders of magni-
tude for acetate. Table 3 also shows that deprotonation constants
were more important for fluoride than for acetate. The stability
constants determined in this study are similar than those reported
for other thiosemicarbazones receptors but lower than those
found for other urea/thiourea receptors functionalized with
benzene.19e21
This behavior observed for 3a and 3b contrasts with the emis-
sion behavior found for 3c and 3d. For these latter receptors
a quenching of the fluorescence was observed in the presence of
increasing amounts of both fluoride and acetate. Taking into ac-
count that all four receptors showed a similar UVevis behavior
with anions the strong difference in emission properties should
most likely be attributed to the presence of two and three thienyl
groups in 3c and 3d that would favor deactivations paths that were
not active in compounds 3a and 3b, which contain only one thio-
phene moiety.
2.6. 1H NMR spectroscopic studies in the presence of anions
UVevis and fluorescence studies of thiosemicarbazone re-
ceptors 3aed displayed a varied response in the presence of anions
related with hydrogen bonding interactions and deprotonation of

L.E. Santos-Figueroa et al. / Tetrahedron 68 (2012) 7179e7186
7183
110
100
90
80
70
60
50
40
30
20
10
0
30 equiv
0,04
0,02
Ho
Hg
Hk
Hl
100 equiv
0,00
Ha, b, c, j
Hd, e, f, m
10 equiv
1 equiv
-0,02
-0,04
-0,06
0 equiv
Hp
0
1
2
3
4
5
6
7
8
9
400
450
500
550
600
650
Fluoride equivalents
Wavelength (nm)
Fig. 5. 1H NMR shifts for the protons of receptor 3d in the presence of increasing
quantities of fluoride anion (DMSO-d6).
120
110
100
90
80
70
60
50
40
30
20
10
0
100 equiv
30 equiv
In the presence of fluoride (5 equiv) the most remarkable ob-
servation was the disappearance of the Hk and Hl signals. Moreover
the observed variation in the chemical shifts Dd (ppm) over the
course of the titration with fluoride for other protons in 3d is shown
in Fig. 5.
As could be seen, HaeHg protons showed minor changes,
whereas, in contrast, remarkable shifts were observed for Ho and
Hp suggesting that deprotonation occurs in the NeH group closer to
the phenyl group. Fabbrizzi et al. and ourselves have observed in
closely related thioureas a similar behavior; i.e., the deprotonation
apparently occurs in the protons of the nitrogen attached to the
phenyl ring from NMR studies.22
10 equiv
1 equiv
0 equiv
2.7. Quantum mechanical studies
400
450
500
550
600
650
Wavelength (nm)
The hydrogen bond donating or accepting ability of a mole-
cule at a particular site can be known by studying the depro-
tonation energy in gas-phase using quantum chemical
calculations via the subtraction of the energy of the receptor
alone from that of the deprotonated form. Following this con-
cept, calculations were carried out using a PM3 semiempirical
model that was applied to all the receptors 3aed. As these
thiosemicarbazone receptors contain two NeH groups, the
deprotonation studies were performed assuming that both
protons could be eliminated. The results of this study are shown
in Table 4. Data strongly suggests that the most acidic proton is
Hk (see Scheme 2). As it can be observed there is not an
agreement between the data obtained from the theoretical
calculations and 1H NMR titrations that suggested that depro-
tonation occurs at the Hl proton.
Despite this contradiction, theoretical calculations agree with
the chromogenic behavior observed for the receptors. Quantum
mechanical studies indicated that the dicyanovinyl derivative 3b is
the most acidic followed by the receptor 3c. In fact the theoretical
studies indicated that the acidity of the receptors follow the order
3b>3c>3a>3d (see Table 4). This is in agreement with the chromo-
fluorogenic behavior of the receptors (vide ante) and with the
Fig. 4. Emission changes in 3a (1.2ꢁ10ꢀ5 mol dmꢀ3) in the presence of fluoride (top)
and acetate (bottom) anions. Emission spectra of the receptor in the presence of 0, 1,
10, 30 and 100 equiv of the corresponding anion.
the receptors. In order to study in more detail this dual co-
ordination/deprotonation process the interaction of receptor 3d
with fluoride anion was investigated by means of 1H NMR titration
experiments in DMSO-d6.
1H NMR spectrum of 3d showed resonances for the benzene
ring at 7.20 (1H, broad triplet, Hp), 7.39e7.36 (2H, broad multiplet,
Hm), 7.58 (2H, broad doublet, Ho) ppm, whereas protons of the two
2,5-disubstituted thiophene rings (Hd, He and Hf, Hg) appeared as
doublets at 7.31(Hf) and at 7.49 (Hg) ppm for the first ring and as
a broad multiplet in the 7.39e7.36 ppm range (Hd and He) for the
second. Protons of the third 2-monosubstituted thienyl ring
appeared as a double doublet at 7.11 (Hb), a doublet at 7.54 (Hc),
which overlapped with a doublet at 7.35(Ha). Finally, the imine
proton (eCH]N) appeared as a broad singlet at 8.30 (Hj) ppm and
the NeH protons of the thiosemicarbazone group also were broad
singlets at 11.88 (Hk) and 9.84 (Hl) ppm (Scheme 2).
expected
basicity
of
anions
in
acetonitrile
(i.e.,
Fꢀ>CNꢀ>AcOꢀ>H2PO4ꢀ, Clꢀ, HSO4ꢀ, SCNꢀ, NOꢀ3 , Brꢀ, Iꢀ); i.e., the
most acidic receptors 3b and 3c showed color changes in the
presence of fluoride, cyanide, acetate, and dihydrogen phosphate,
whereas the less acidic 3a and 3d ligands were only able to show
a remarkable color modulation in the presence of the most basic
anions fluoride and cyanide anions.
Scheme 2. Proposed mode for the fluoride-induced deprotonation of receptor 3d.

7184
L.E. Santos-Figueroa et al. / Tetrahedron 68 (2012) 7179e7186
Table 4
under reduced pressure to give 2-((5-formylthiophen-2-yl)methy-
lene)malononitrile 1b, which was purified by column chromatog-
raphy on silica with increasing amounts of diethyl ether in light
petroleum as eluent.
Stabilization energies calculated for the deprotonation of the receptors 3aed
Receptors
E(L)eE(LH) (Kcal/mol)
R]NeNHeC(S)eNePha
R]NeNeC(S)eNHePhb
3a
3b
3c
3d
ꢀ4.81
ꢀ10.54
ꢀ6.39
ꢀ12.3
4.2.1. 2-((5-Formylthiophen-2-yl)methylene)malononitrile
ꢀ19.85
ꢀ14.19
ꢀ3.46
1b. Orange solid (22%). Mp 161.1e165.3 ꢂC. IR (CHCl3)
n
2221 (CN),
1663 (C]O), 1571, 1432, 1215, 1069, 795 cmꢀ1
.
1H NMR (CDCl3)
ꢀ0.57
a
d
7.83 (br d, 1H, J¼3.9 Hz, 4-H), 7.80e7.90 (m, 2H, 3-H and]CH),
Deprotonation at the Hl proton (see Scheme 2).
Deprotonation at the Hk proton (see Scheme 2).
10.03 (s, 1H, CHO). MS (EI) m/z (%): 188 (Mþ, 60), 187 (100), 159 (11),
115 (9). HRMS: (EI) m/z (%) for C9H4N2OS; calcd 188.0044; found
188.0049.
b
3. Conclusions
4.3. General procedure for the synthesis of heterocyclic
phenylthiosemicarbazones 3aed
A family of novel heterocyclic thiosemicarbazone containing
thienyl groups, derivatives 3aeb, has been prepared, characterized
and their interactions with anions were studied through UVevis,
fluorescence, 1H NMR and quantum chemical calculations. Two
different chromo-fluorogenic behaviors in the presence of anions in
acetonitrile were observed. The more basic anions fluoride and
cyanide were able to induce dual coordinationedeprotonation for
all 3aed receptors studied, whereas acetate and dihydrogen
phosphate showed poorer coordination ability and deprotonation
was only observed on the more acidic receptors 3b and 3c.
Hydrogen bonding interactions resulted in a small bathochromic
shift, whereas deprotonation was indicated by the appearance of
a new band at longer wavelengths. Color changes from pale-yellow
to yellow-red were observed. In fluorescence studies it was
apparent that hydrogen bonding interactions were visible through
the enhancement or the decay of the emission band according to
Equal amounts (0.4 mmol) of the appropriate aldehyde and
thiosemicarbazide were dissolved in MeOH (30 mL) at room tem-
perature. A solution was obtained, which was stirred overnight.
Compounds precipitated as microcrystalline solids, which were
collected by suction filtration, washed with cold MeOH and diethyl
ether and dried in vacuum. Further recrystallization steps using
CHCl3/petroleum ether mixtures were performed if necessary.
4-Phenyl-1-((thiophen-2-yl)methylene)thiosemicarbazone 3a23
was obtained as a yellow solid (66%). Mp 185.6e186.9 ꢂC. 1H NMR
(CDCl3):
d
¼7.07e7.10 (m, 1H, 40-H), 7.25e7.29 (m, 1H, 4-H), 7.32 (dd,
J¼3.9 and 0.9 Hz, 1H, 30-H), 7.39e7.48 (m, 3H, 3- and 5- and 50-H),
7.66 (br d, J¼9.0 Hz, 2H, 2- and 6-H), 8.11 (s, 1H, eCH]N), 9.11 (s,
1H, S]CeNH), 10.29 (s, 1H, C]NeNH) ppm. IR (Nujol) n 3297(NH),
3141(]CeH), 1588, 1547, 1521, 1505, 1445, 1386, 1311, 1268, 1220,
1204, 1068, 1041, 922, 855, 817, 784, 763, 742, 726, 712, 701, 687,
622, 541 cmꢀ1. MS (FAB): m/z (%)¼262 ([MþH]þ, 100), 228 (3), 168
(17). FAB-HRMS: calcd for C12H11N3S2 262.0475; found 262.0467.
1-((5-(2,2-Dicyanovinyl)thiophen-2-yl)methylene)-4-phenyl-
the number of thienyl rings at the p-conjugated bridges. Quantum
mechanical studies suggested that the acidity of the receptors
follows the order 3b>3c>3a>3d, which was in agreement with the
experimentally observed behavior.
thiosemicarbazone 3b was obtained as a red solid (77%). Mp
4. Experimental section
185.0e186.0 ꢂC. 1H NMR (CDCl3):
d
¼7.22e7.28 (br t, J¼7.2 Hz, 1H, 4-
H), 7.37 (br d, J¼7.8 Hz, 2H, 3- and 5-H), 7.52 (br d, J¼7.2 Hz, 2H, 2-
and 6-H), 7.82 (br s,1H, 40-H), 7.87 (br s,1H, 30-H), 7.96 (s,1H, eCH]
N), 8.02 (s,1H, eCH]C(CN)2), 9.08 (s,1H, S]CeNH), 9.60 (s,1H, C]
4.1. Materials and methods
Thin layer chromatography was carried out on 0.25 mm thick
precoated silica plates (Merck Fertigplatten Kieselgel 60F254). All
melting points were measured on a Gallenkamp melting point ap-
paratus and are uncorrected. NMR spectrawereobtained on a Varian
Unity PlusSpectrometerat an operating frequencyof300 MHzfor1H
and 75.4 MHz for 13C or a Bruker Avance III 400 at an operating
frequencyof400 MHzfor 1H and 100.6 MHzfor 13C, using the solvent
peak as internal reference. The solvents are indicated in parenthesis
NeNH) ppm. IR (Nujol) n 3341 (NH), 3122 (]CeH), 2223 (CN),1596,
1579, 1568, 1540, 1517, 1498, 1261, 1198, 1097, 1061, 915, 811, 748,
705, 690, 610 cmꢀ1. MS (FAB): m/z (%)¼338 ([MþH]þ, 100), 306 (9).
FAB-HRMS: calcd for C16H11N5S2 338.0529; found 338.0526.
1-((5-(5-Ethoxythiophen-2-yl)thiophen-2-yl)methylene)-4-phe-
nylthiosemicarbazone 3c was obtained as a brown solid (50%). Mp
171.3e171.6 ꢂC. 1H NMR (CDCl3):
d
¼1.44 (t, J¼7.2 Hz, 3H, OCH2CH3),
4.14 (q, J¼7.2 Hz, 2H, OCH2CH3), 6.15 (d, J¼3.9 Hz, 1H, 400-H), 6.91 (d,
J¼3.9 Hz,1H, 300-H), 6.93 (d, J¼3.9 Hz,1H, 30-H), 7.15 (d, J¼3.9 Hz,1H,
40-H), 7.25e7.32 (m, 1H, 4-H), 7.43 (br t, J¼7.5 Hz, 2H, 3- and 5-H),
7.67 (br d, J¼7.5 Hz, 2H, 2- and 6-H), 8.07 (s, 1H, eCH]N), 9.09 (s,
1H, S]CeNH), 10.50 (s, 1H, C]NeNH) ppm. 13C NMR (CDCl3):
before the chemical shift values (d relative to TMS and given in parts
per million). IR spectra were run on a FTIR PerkineElmer 1600
spectrophotometer. Elemental analyses were carried out on a Leco
CHNS 932 instrument. Mass spectrometry analyses were performed
at the C.A.C.T.I. e Unidad de Espectrometria de Masas of the Uni-
versity of Vigo, Spain, on a Hewlett Packard 5989 A spectrometer for
low resolution spectra and a VG Autospec M spectrometer for high
resolution mass spectra. All the solvents were of spectrophotomet-
rical grade. The aldehyde 1a and 4-phenyl-3-thiosemicarbazide 2
were purchased from SigmaeAldrich reagents and used without
further purification. The synthesis of the aldehydes 1c and 1d was
reported elsewhere.15
d
¼14.6 (OCH2CH3), 69.6 (OCH2CH3), 105.7 (C400), 122.2 (C300), 122.9
(C30), 123.0 (C20), 124.7 (C2 and C6), 126.3 (C4), 128.8 (C3 and C5),
132.4 (C40), 134.8 (C50), 137.6 (CH]N), 137.8 (C1), 141.7 (C200), 165.7
(C500), 175.0 (C]S) ppm. IR (Nujol)
n 3329 (NH), 3127 (]CeH), 1588,
1550, 1509, 1483, 1465, 1384, 1322, 1274, 1245, 1206, 1079, 1039,
912, 873, 779, 764, 743, 729, 703, 692, 614 cmꢀ1. C18H17N3OS3
(387.54): calcd. C 55.79, H 4.42, N 10.84, S 24.82; found C 56.21, H
4.51, N 10.51, S 25.09.
4.2. Synthesis of 2-((5-formylthiophen-2-yl)methylene)
malononitrile 1b
4-Phenyl-1-((5-(5-(thiophen-2-yl)thiophen-2-yl)thiophen-2-yl)
methylene)thiosemicarbazone 3d was obtained as an orange solid
(41%). Mp >216 ꢂC. 1H NMR (CDCl3):
d
¼7.05e7.18 (m, 8H, 4-H and
To a solution of malononitrile (0.094 g, 1.4 mmol) and thio-
phene-2,5-dicarbaldehyde (0.2 g, 1.4 mmol) in dry DMF (15 mL),
was added piperidine (1 drop). The solution was heated at 120 ꢂC
during 2 h. After cooling the mixture the solvent was removed
thienyl-H), 7.21 (t, 2H, 3- and 5-H), 7.70 (d, 2H, 2- and 6-H), 7.97 (s,
1H, eCH]N), 9.09 (s, 1H, S]CeNH), 9.35 (s, 1H, C]NeNH) ppm.
13C NMR (DMSO-d6):
128.1,128.6, 132.3, 134.8, 135.8, 136.3, 137.4, 137.6,138.3, 139.0, 175.5
d
¼124.6,124.7,125.2,125.3,125.6,125.9,126.1,

L.E. Santos-Figueroa et al. / Tetrahedron 68 (2012) 7179e7186
7185
Prodi, L.; Bolletta, F.; Montalti, M.; Zaccheroni, N. Coord. Chem. Rev. 2000, 205,
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(C]S) ppm. IR (Nujol)
n 3310 (NH), 1742, 1586, 1546, 1463, 1456,
1377, 1307, 1270, 1202, 1169, 1156, 1076, 1059, 967, 922, 892, 783,
722, 703, 514 cmꢀ1. MS (FAB): m/z (%)¼426 ([MþH]þ,100), 424 (98),
394 (47), 338 (47), 288 (11). FAB-HRMS: calcd for C20H15N3S4
426.0221; found 426.0218.
K. Spectrochim. Acta, Part
A 2001, 57, 2161e2195; (e) De Silva, A. P.;
McCaughan, B.; McKinney, B. O. F.; Querol, M. Dalton Trans. 2003, 1902e1913;
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ꢀ~
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4. (a) Martínez-Manez, R.; Sancenon, F. Chem. Rev. 2003, 103, 4419e4476; (b)
ꢀ~
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Moragues, M. E.; Martínez-Manez, R.; Sancenon, F. Chem. Soc. Rev. 2011, 40,
4.4. Physical measurements
ꢀ~
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2593e2643; (c) Martínez-Manez, R.; Sancenon, F. J. Fluoresc. 2005, 15,
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Suksai, C.; Tuntulani, T. Chem. Soc. Rev. 2003, 32, 192e202; (f) Xu, Z.; Chen, X.;
Kim, H. N.; Yoon, J. Chem. Soc. Rev. 2010, 39, 127e137.
Stock solutions of the anions (Fꢀ, Clꢀ, Brꢀ, Iꢀ, NOꢀ3 , H2POꢀ4 , HSOꢀ4 ,
AcOꢀ, BzOꢀ, CNꢀ as tetrabutylammonium salts) were prepared at
10ꢀ2 and 10ꢀ3 mol dmꢀ3 in acetonitrile. The concentrations of li-
gands used in these measurements were ca. 1.2ꢁ10ꢀ4 and
5. (a) Schmidtchen, F. P.; Berger, M. Chem. Rev. 1997, 97, 1609e1646; (b) Gale, P. A.
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1.2ꢁ10ꢀ5 mol dmꢀ3
.
1H NMR experiments were carried out in
~ꢀ
ꢀ
240, 77e99; (d) Martínez-Manez, R.; Sancenon, F. Coord. Chem. Rev. 2006, 250,
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DMSO-d6. At high concentrations the receptors showed low solu-
bility in acetonitrile.
6. (a) Gale, P. A. Acc. Chem. Res. 2006, 39, 465e475; (b) Yoon, J.; Kim, S. K.; Singh,
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ꢀ
ꢀ
In fluorimetric titrations, all receptors were excited in wave-
length of the pseudo-isosbestic points observed in the course of
UVevis titrations with fluoride anion. The electronic absorption
spectra were obtained on a Perkin Elmer Instruments Lambda 35
UV/visible spectrometer and fluorescence spectra were recorded on
a Quanta Master 40 steady state fluorescence spectrofluorometer
from Photon Technology Internation (PTI); all in quartz cuvettes
(1 cm). 1H NMR titrations spectra were acquired with Varian 300
spectrometer.
Perez-Fernandez, R.; De Mendoza, J. Chem. Soc. Rev. 2007, 36, 198e210; (d)
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7. (a) Li, F.; Carvalho, S.; Delgado, R.; Drew, M. G. B.; Felix, V. Dalton Trans. 2010, 39,
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Gale, P. A.; Plavec, J. Beilstein J. Org. Chem. 2011, 7, 1205e1214; (b) Lin, Y.-S.;
Zheng, J.-X.; Tsui, Y.-K.; Yien, Y.-P. Spectrochim. Acta, Part A 2011, 79, 1552e1558;
(c) Odago, M. O.; Colabello, D. M.; Lees, A. J. Tetrahedron 2010, 66, 7465e7471;
ꢀ~
ꢀ
(d) Coll, C.; Aznar, E.; Martínez-Manez, R.; Marcos, M. D.; Sancenon, F.; Soto, J.;
ꢀ
Amoros, P.; Cano, J.; Ruiz, E. Chem.dEur. J. 2010, 16, 10048e10061; (e) Devaraj,
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Li, Z.; Wu, F.-Y.; Guo, L.; Li, A.-F.; Jiang, Y. B. J. Phys. Chem. B 2008, 112,
7071e7079; (g) Ros-Lis, J. V.; Martínez-Manez, R.; Sancenon, F.; Soto, J.; Rurack,
K.; Weißhoff, H. Eur. J. Org. Chem. 2007, 17, 2449e2458; (h) Nie, L.; Li, Z.; Han, J.;
Zhang, X.; Yang, R.; Liu, W.-X.; Wu, F.-Y.; Xie, J.-W.; Zhao, Y.-F.; Jiang, Y.-B. J. Org.
Chem. 2004, 69, 6449e6454; (i) Jose, D. A.; Kumar, D. K.; Ganguly, B.; Das, A.
4.5. Theoretical studies
ꢀ~
ꢀ
Quantum chemical calculations at semiempirical level (PM3,
within restricted HartreeeFock level) were carried out in vacuum
with the aid of Hyperchem V6.03. The PolareRibiere algorithm was
used for the optimization. The convergence limit and the rms
gradient were set to 0.01 kcal molꢀ1. The stability constants were
estimated with the HypSpec Software V1.1.18 with data of titration
of receptors with selected anions.
ꢀ
ꢀ~
ꢀ
ꢀ
Org. Lett. 2004, 6, 3445e3448; (j) Jimenez, D.; Martínez-Manez, R.; Sancenon,
F.; Soto, J. Tetrahedron Lett. 2002, 43, 2823e2825; (k) Agostini, A.; Mondragon,
L.; Coll, C.; Aznar, E.; Marcos, M. D.; Martínez-Manez, R.; Sancenon, F.; Soto, J.;
Perez-Paya, E.; Amoros, P. ChemistryOpen 2012, 1, 17e20.
ꢀ~
ꢀ
ꢀ
ꢀ
ꢀ
9. For recent examples see: (a) Krishnamurthi, J.; Ono, T.; Amemori, S.;
Komatsu, H.; Shinkai, S.; Sada, K. Chem. Commun. 2011, 1571e1573; (b)
Pia˛tek, P. Chem. Commun. 2011, 4745e4747; (c) He, X.; Herranz, F.; Cheng, E.
C.-C.; Vilar, R.; Yam, V. W.-W. Chem.dEur. J. 2010, 16, 9123e9131; (d) Jun, E.
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3103e3106.
Acknowledgements
10. (a) Camiolo, S.; Gale, P. A.; Hursthouse, M. B.; Light, M. E. Org. Biomol. Chem.
2003, 1, 741e744; (b) Gunnlaugsson, T.; Kruger, P. E.; Jensen, P.; Pfeffer, F.
M.; Hussey, G. M. Tetrahedron Lett. 2003, 44, 8909e8913; (c) Esteban-
We thank the Spanish Government (project MAT2009-14564-
C04-01) and the Generalitat Valencia (project PROMETEO/2009/
ˇ
ꢀ
Gomez, D.; Fabbrizzi, L.; Licchelli, M. J. Org. Chem. 2005, 70, 5717e5720; (d)
Evans, L. S.; Gale, P. A.; Light, M. E.; Quesada, R. New J. Chem. 2006, 30,
1019e1025.
~
016) for support. Thanks are due to the Fundac¸ ao para a Ciencia e
Tecnologia (Portugal) and FEDER-COMPETE for financial support
through the Centro de Química - Universidade do Minho, Project
PEst-C/QUI/UI0686/2011 (F-COMP-01-0124-FEDER-022716) and
a Post-doctoral grant to R.M.F.B. (SFRH/BPD/79333/2011). The NMR
spectrometer Bruker Avance III 400 is part of the National NMR
Network and was purchased within the framework of the National
Program for Scientific Re-equipment, with funds from FCT. The
11. (a) Withnall, J.; Howard, J.; Ponka, P.; Richardson, D. R. Proc. Natl. Acad. Sci. U.S.A.
2006, 103, 14901e14906; (b) Zhang, H.-J.; Qin, X.; Liu, K.; Zhu, D.-D.; Wang,
X.-M.; Zhu, H. L. Bioorg. Med. Chem. 2011, 19, 5708e5715.
12. See for example: Tian, Y.-P.; Duan, C.-Y.; Zhao, C.-Y.; You, X.-Z. Inorg. Chem. 1997,
36, 1247e1252.
13. (a) Batista, R. M. F.; Oliveira, E.; Costa, S. P. G.; Lodeiro, C.; Raposo, M. M. M. Org.
Lett. 2007, 9, 3201e3204; (b) Costa, S. P. G.; Oliveira, E.; Lodeiro, C.; Raposo, M.
M. M. Tetrahedron Lett. 2008, 49, 5258e5261; (c) Batista, R. M. F.; Oliveira, E.;
Costa, S. P. G.; Lodeiro, C.; Raposo, M. M. M. Tetrahedron Lett. 2008, 49,
~
authors are also indebted to program ‘Acc¸ oes Integradas Luso-
~
6575e6578; (d) Batista, R. M. F.; Oliveira, E.; Nunez, C.; Costa, S. P. G.; Lodeiro,
Espanholas/CRUP’, for the bilateral agreement number E-144/10.
C.; Raposo, M. M. M. J. Phys. Org. Chem. 2009, 22, 362e366; (e) Batista, R. M. F.;
Oliveira, E.; Costa, S. P. G.; Lodeiro, C.; Raposo, M. M. M. Tetrahedron 2011, 67,
7106e7113; (f) Batista, R. M. F.; Oliveira, E.; Costa, S. P. G.; Lodeiro, C.; Raposo,
M. M. M. Talanta 2011, 85, 2470e2478.
ꢀ
Thanks also to Fundacion Carolina and UPNFM-Honduras for
a doctoral grant to L.E.S.-F. and the Spanish Ministerio de Ciencia e
ꢀ
Innovacion for an FPU grant to M.E.M..
ꢀ
ꢀ~
14. (a) Raposo, M. M. M.; García-Acosta, B.; Abalos, T.; Calero, P.; Martínez-Manez,
R.; Ros-Lis, J. V.; Soto, J. J. Org. Chem. 2010, 75, 2922e2933; (b) Amendola, V.;
Boiocchi, M.; Fabbrizzi, L.; Mosca, L. Chem.dEur. J. 2008, 14, 9683e9696.
15. (a) Raposo, M. M. M.; Kirsch, G. Tetrahedron 2003, 59, 4891e4899; (b) Batista,
R. M. F.; Costa, S. P. G.; Belsley, M.; Lodeiro, C.; Raposo, M. M. M. Tetrahedron
2008, 64, 9230e9238.
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