N-Biphenyl thioureas as carboxylate receptors. Effect of the ligand substituents on the geometry of the complexes

Article abstract of DOI:10.1016/j.tet.2006.06.058

Six new biphenyl thiourea derivatives have been prepared to be used in carboxylate sensing. Experiments carried out with these ligands have demonstrated that the type of interaction with TBA carboxylates is strongly dependent on the substituents in the thiourea moiety. These interactions go from the formation of 1:1 hydrogen-bonded complexes to acid-base reactions. In addition, different geometries have been observed for the complexes being dependent on the conformations of the free ligands in solution.

Full text of DOI:10.1016/j.tet.2006.06.058

Tetrahedron 62 (2006) 8571–8577
N-Biphenyl thioureas as carboxylate receptors. Effect of the
ligand substituents on the geometry of the complexes
b
a
a
Ana M. Costero,a, Pablo Gavina, Gemma M. Rodrıguez-Muniz and Salvador Gil
*
´
˜
˜
aDepartment of Organic Chemistry, Universidad de Valencia, 46100 Burjassot, Valencia, Spain
bInstituto de Ciencia Molecular, Universidad de Valencia, Valencia, Spain
Received 12 May 2006; revised 6 June 2006; accepted 15 June 2006
Available online 13 July 2006
Abstract—Six new biphenyl thiourea derivatives have been prepared to be used in carboxylate sensing. Experiments carried out with these
ligands have demonstrated that the type of interaction with TBA carboxylates is strongly dependent on the substituents in the thiourea moiety.
These interactions go from the formation of 1:1 hydrogen-bonded complexes to acid–base reactions. In addition, different geometries have
been observed for the complexes being dependent on the conformations of the free ligands in solution.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
attached to one N atom, as well as receptors 5 and 6 with a bi-
phenyl substituent on the thiourea moiety. These receptors
have been tested with various aromatic carboxylates with dif-
ferent basicities as well as with fluoride and acetate anions.
Our experiments allow us to affirm that the complexes
formed between thiourea receptors and carboxylate anions
do not always show a Y-type geometry. By contrary, with sev-
eral ligands the carboxylate group is only bound to one NH
group of the thiourea as it has been previously described
for amide-based ligands.9 In addition, in some cases the pro-
cess is not a real complexation but an acid–base reaction.10
There is currently a great interest in the development of sen-
sors for carboxylate anions due to their presence in a variety
of biomolecules and particularly in amino acids.1 Many of
the carboxylate binding sites in these systems contain either
one2 or two3 urea or thiourea subunits as hydrogen-bond
donor groups. There has been much discussion about the
thiourea (urea)–carboxylate bonding motif. In general it is
assumed that thioureas bind to carboxylates through a double
hydrogen bond involving both N–H fragments of the thio-
urea and both carboxylate oxygens in a Y-type bidentated
complex (Chart 1).3b,4 However this geometry should not
be proposed in general because other factors such as confor-
mational equilibria4e,5 or dimerization processes6 should
also be considered.
2. Results and discussion
2.1. Synthesis and conformational studies of
receptors 1–6
R2
The structures of the new receptors 1–6 are shown in
Scheme 1. Biphenyl thiourea derivatives were prepared from
4-amino-40-nitrobiphenyl (7)11 or 4-aminobiphenyl (8) and
the corresponding isothiocyanates (9–12) in refluxing THF.
4-Amino-40-nitrobiphenyl (7) was prepared by nitration of
4-nitrobiphenyl with nitric acid, followed by partial reduc-
tion to the p-aminonitro compound by reaction with aqueous
sodium hydrogen sulfide.12 4-Aminobiphenyl (8) was ob-
tained by reduction of 4-nitrobiphenyl with aqueous NaHS.
O
O
N
H
H
R3
S
N
R1
Chart 1.
In our group we have been interested in the use of 4,40-disub-
stituted biphenylsas signalling units in cation and anion sens-
ing7 and of thioureas as binding sites for anion recognition.8
We report herein the synthesis of neutral carboxylate recep-
tors 1–4 based on thioureas bearing a 40-nitrobiphenyl group
All compounds were characterized by NMR and MS. For li-
gands 1, 3, 4 and 6, only one resonance is observed for each
proton in the 1H NMR spectra in DMSO-d6, indicating that
there is only one predominant thiourea rotamer in solution,
or a fast equilibrium between different conformations
* Corresponding author. Tel.: +34 963544410; fax: +34 963543152; e-mail:
ana.costero@uv.es
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.058

8572
A. M. Costero et al. / Tetrahedron 62 (2006) 8571–8577
O
N
-
NO2
O
+
S
S
Et
i
1
N
H
N
H
O
EtNCS 9
N
-
O
+
or
R
NH2
SCN
R
N
H
N
H
7
10-12
2 R = H
3 R = NO2
4 R = OCH3
R
i
S
10 or 11
N
H
N
H
5 R = H
NH2
6 R = NO2
8
Scheme 1. Synthesis of receptors 1–6. (i) Et3N, THF, reflux.
(Fig. 1a). By contrast, the 1H NMR spectra in DMSO-d6 of
ligands 2 and 5, with a phenyl group attached to one nitrogen
atom of the thiourea moiety are more complicated (Fig. 1b),
showing at least two sets of signals for each ligand. These
results indicate that two different conformations of the
thioureas are present in solution, with slow E–Z rotameric
interconversion rates on the NMR time-scale. In order to
know which are the conformations present in solution in
each case additional NMR experiments were carried out.
Thus NOE experiments showed that thiourea 2 exists in
DMSO solution as a mixture of E,Z and Z,E rotamers 2a
and 2b (Chart 2).
O
N
g
S
E
Z
O
H
f
N
N
H
NOE
e
S
d
c
E
Z
N
H
NOE
H
2b
N
NOE
NOE
2a
NOE
b
a
NOE
N
O
O
Chart 2. Main conformations of 2 in DMSO-d6 solution.
the way shown in Chart 3 according to the NOE signals ob-
served in the NMR experiments. In addition, when solvent
was changed from DMSO-d6 to the less polar acetone-d6
a much more complex 1H NMR spectrum was obtained re-
flecting the presence of a main conformation in addition to
several rotamers and/or aggregates. This self-association
through hydrogen-bonding is probably inhibited in the two
rotamers of 2.
Similar studies carried out with ligand 3 suggest that some
degree of aggregation in solution occurs under the experi-
mental conditions in contrast with that observed in ureas.13
This self-association seems to situate the aromatic rings in
NO2
O2N
NOE
S
Z
N
H
Z
N
H
O2N
NOE
NO2
S
N
H
N
H
Chart 3. Proposed self-assembled dimer of 3 in DMSO-d6 solution.
2.2. Complexation studies
To study the ability of these ligands to act as sensors for
carboxylates, a series of aromatic carboxylates (benzoate,
p-methylbenzoate, o- and p-nitrobenzoate and o- and p-
methoxybenzoate, all as their tetrabutylammonium (TBA)
Figure 1. N–H and aromatic 1H NMR signals of: (a) 4 and (b) 2 in DMSO-d6.

A. M. Costero et al. / Tetrahedron 62 (2006) 8571–8577
8573
salts) was studied, in order to evaluate the effect of the dif-
ferent substituents on the aromatic ring in the complexation
constants. We also decided to test acetate and fluoride
anions.
because of their lower basicity. Complexation constants
evaluated in these experiments are shown in Table 1. These
experiments in addition to other carried out by using H
NMR in DMSO-d6 demonstrated that all the complexes
have a 1:1 stoichiometry (Fig. 2).
1
Aromatic carboxylates were prepared from the correspond-
ing carboxylic acids and TBA hydroxide in DMSO. Benzo-
ate, acetate and fluoride TBA salts were commercially
available.
If we try to correlate the observed binding constants with the
basicity of the aromatic carboxylates, two different behav-
iours are observed, depending on the thiourea receptor.
With ligands 1 and 4 a linear correlation is observed between
the acid strengths of the para substituted benzoic acids and
the binding constants of the corresponding complexes, fol-
lowing a Hammet-type behaviour (see Fig. 3). Thus, for
ligand 1 the highest binding constant is observed with the
more basic p-methoxybenzoate anion (log K 4.5) whereas
the lowest binding constant is observed for p-nitrobenzoate
(log K 3.1). In anion complexation generally for higher anion
basicity, stronger complexation constants are observed.14
This relationship indicates that the complexation of the
anions to the receptor 1 is free from steric effects due to
the substituent on the phenyl ring, and only electronic factors
should be taken into account.
2.2.1. UV–vis studies. The anion binding ability of receptors
1–6 was evaluated by UV–vis titration of each receptor with
the appropriate anion in DMSO solution. Changes in the UV
spectra agree with the expected results. Thus, in the presence
of the same anion, larger changes were observed with thio-
ureas containing two aromatic substituents (2–6) than with
thiourea derivative 1 (Fig. 2).
The presence of an electron withdrawing nitro group at the
para position of the phenyl ring makes ligand 3 acid enough
to experiment deprotonation reactions under some experi-
mental conditions.10 The deprotonation was characterized
by the presence of a new band in the UV spectrum at
464 nm. As it was expected this band does not appear in
the presence of both p-nitrobenzoate and o-nitrobenzoate
In contrast, with ligands 2 and 5, there is no apparent rela-
tionship between basicities and binding constants. As we ob-
serve in Table 1 for receptor 2, similar association constants
are observed for p-nitro and p-methoxybenzoate (log K 3.4
and 3.6), whereas the highest log K is observed for benzoate
anion (5.0), with no substituent on the phenyl ring. One ex-
planation to this behaviour can be found in the previously de-
scribed conformational equilibrium shown by these ligands.
Thus, the determined values correspond not only to the com-
plexation process but to the overall equilibrium between
both conformations of the free ligand and their correspond-
ing complexes.
1.87
1+benzoate TBA
1.86
1.85
2
1.84
1.83
1.8
1.82
0
0.5
1
1.5
2
2.5
1.6
1.4
1.2
1
equivalents of benzoate
0.8
0.6
0.4
0.2
0
Finally, ligands 3 and 6 experiment deprotonation reactions
(except in the presence of p- and o-nitrobenzoate) and the
values obtained with the more basic carboxylates are related
to this acid–base process and for this reason has a very
similar value for each ligand.
310
360
410
460
(nm)
2+benzoate
1,60
1,50
1,40
1,30
1,20
1.6
1.4
1.2
1
These receptors were also tested against acetate and fluoride
anions, which are more basic than the previous aromatic
carboxylate anions (Table 2). A ‘naked-eye’ colour change
was observed during most of these titrations.15 The strongest
colour changes were observed for Fꢀ anion, which is the
strongest base under these conditions (see Fig. 4).
0
1
2
3
4
equivalents of benzoate
0.8
0.6
0.4
0.2
0
330
380
430
(nm)
480
The results indicate that an acid–base reaction is taking
place, resulting in deprotonation of the receptor. In fact,
when 3 equiv of fluoride was added to ligand 3 in DMSO-
d6 both a broad signal in the 1H NMR spectrum at
15.7 ppm and a peak at ꢀ145.5 ppm in the 19F NMR appear,
which can be assigned to the HFꢀ2 species.7a In addition, the
band at 464 nm observed in the UV spectrum also confirms
the deprotonation reaction with these more basic anions
(Fig. 5). This deprotonation process was confirmed by addi-
tional experiments with ligand 3 and TBA hydroxide. An
instantaneous orange colour was observed upon addition of
base, and the UV–vis spectra were very similar to those ob-
tained in the presence of fluorides or acetate anions (see Sup-
plementary data). As it was expected the effect was stronger
3+benzoate TBA
3.5
3
2.5
2
1.5
1
0.5
0
300
400
500
600
(nm)
Figure 2. UV–vis absorption spectrophotometric titration of ligands 1, 2
and 3 with TBA benzoate in DMSO at 25 ꢁC. Inset: stoichiometry determi-
nation for 1+TBA benzoate at 360.5 nm and 2+TBA benzoate at 360 nm.

8574
A. M. Costero et al. / Tetrahedron 62 (2006) 8571–8577
Table 1. Log K values for receptors 1–6 with aromatic carboxylates, in DMSO at 25 ꢁCa
Anionb
Receptor
1
2
3
4
5
6
C6H5COOꢀ
3.8ꢂ0.1
3.1ꢂ0.2
4.1ꢂ0.3
4.5ꢂ0.3
3.6ꢂ0.2
5.2ꢂ0.4
5.0ꢂ0.2
3.4ꢂ0.2
4.4ꢂ0.2
3.6ꢂ0.3
3.2ꢂ0.2
4.5ꢂ0.3
5.2ꢂ0.4
3.2ꢂ0.2
5.3ꢂ0.4
5.2ꢂ0.4
4.1ꢂ0.4
5.3ꢂ0.4
4.4ꢂ0.4
3.1ꢂ0.3
4.8ꢂ0.3
5.8ꢂ0.4
3.4ꢂ0.2
5.0ꢂ0.4
4.0ꢂ0.3
4.4ꢂ0.2
4.1ꢂ0.4
3.7ꢂ0.1
3.5ꢂ0.1
2.7ꢂ0.4
5.8ꢂ0.5
3.5ꢂ0.1
5.9ꢂ0.6
5.8ꢂ0.3
3.5ꢂ0.1
5.6ꢂ0.4
p-NO2C6H4COOꢀ
p-MeC6H4COOꢀ
p-MeOC6H4COOꢀ
o-NO2C6H4COOꢀ
o-MeOC6H4COOꢀ
a
The results were calculated by UV–vis titration.
All anions were used as their TBA salts.
b
1.5
1
2+TBA fluoride
2
1.5
1
0.5
0
Ligand 1
Ligand 4
-0.5
-1
0.5
0
300
350
400
450
500
-1.5
-2
(nm)
-0.4
-0.2
pKa-pKa (benzoic acid)
0
0.2
3+TBA fluoride
3.5
3
Figure 3. Correlation of the acid dissociation constants of benzoic acids
with the binding constants between benzoate anions and receptors 1 and 4.
2.5
2
Table 2. Log K values for the interaction of receptors 1–6 with fluoride and
1.5
1
acetate anion, in DMSO at 25 ꢁCa
Anionb
Receptor
0.5
0
1
2
3
4
5
6
300
350
400
450
500
550
CH3COOꢀ 4.3ꢂ0.4
—
4.1ꢂ0.1 10.4ꢂ0.2
6.0ꢂ0.5 4.6ꢂ0.6 5.3ꢂ0.5 6.5ꢂ0.5
5.5ꢂ0.4 4.6ꢂ0.1 6.7ꢂ0.4
Fꢀ
—
(nm)
a
Figure 5. UV–vis absorption spectrophotometric titration of ligands 2 and 3
with TBA fluoride in DMSO at 25 ꢁC.
The results were calculated by UV–vis titration.
All anions were used as their TBA salts.
b
1
2.2.2. H NMR studies. In order to get some information
about the structure of the complex in solution, 1H NMR stud-
ies were undertaken. Figures. 6 and 7 show the H NMR
with ligand 3 than with ligand 6 due to the second nitro
group present in ligand 3, which makes the receptor more
acidic.
1
spectra in DMSO-d6 of ligands 1 and 2 in the presence of
1 equiv of TBA benzoate. As it can be seen, the NH signals
corresponding to ligand 1 are shifted downfield after the an-
ion addition. The Dd showed by both signals are very similar
(2.43 ppm for Ha and 2.35 ppm for Hb) what agrees with a
Y-type complex involving both thiourea hydrogens. Similar
complexes can be proposed for ligand 4. With ligands 3 and
1
6 the NH signals do not appear in the H NMR spectrum,
which is also coherent with the deprotonation previously
proposed.10
Finally, ligands 2 and 5 showed a clearly different behaviour
similar to what was observed with the free ligands. Addition
of TBA p-methoxybenzoate to DMSO solutions of 2 or 5
gave rise in each case to two different 1:1 complexes, corre-
sponding very likely to the two different thiourea rotamers
originally present in solution. Thus, as it can be seen in
Figure 7 in the case of ligand 2, four signals are observed
for the N–H hydrogen, these signals, as it was expected are
Figure 4. Colour changes observed on addition of TBA salts (10 equiv) to
a DMSO solution of receptor 3. Left to right: no addition, fluoride, acetate,
o-methoxybenzoate and o-nitrobenzoate.

A. M. Costero et al. / Tetrahedron 62 (2006) 8571–8577
8575
conclusive is that the two conformations observed in the
ligand are also present in the complex. This fact excludes
a Y-type complex in this case.
(a)
3. Conclusion
β
α
A series of biphenyl substituted thioureas have been pre-
pared and their ability to bind aromatic carboxylates has
been evaluated by UV–vis titration and NMR experiments.
These studies allow us to establish that the geometry of the
complexes formed between carboxylate and thiourea recep-
tors is strongly dependent on the substituent in the thiourea
group and on their conformational behaviour.17 Thus, when
the ligand is mainly in a Z,Z conformation, a Y-type complex
can be postulated. By contrast, when other rotamers are pres-
ent in the solution the geometry of the 1:1 complex can be
different with the carboxylate group only bound by one
oxygen atom to the more acidic NH atom. Finally, when
the thiourea NH groups are acidic enough to give rise to
acid–base reactions, strong colour changes are observed
with the most basic anions.
(b)
Figure 6. 1H NMR aromatic and amide zone in DMSO-d6 of: (a) ligand 1
and (b) ligand 1+1 equiv of TBA benzoate.
4. Experimental
4.1. General procedures and materials
4-Amino-40-nitrobiphenyl, 7, was prepared as previously
reported, by nitration of 4-nitrobiphenyl with nitric acid
followed by partial reduction of the isolated product with
sodium hydrogen sulfide.12 All other reagents were commer-
cially available, and were used without purification. Triethyl-
amine was freshly distilled from CaH2. THF was distilled
from Na/benzophenone under Ar prior to use. Column chro-
matography was performed with silica gel 60 (230–400
mesh, Merck). Silica gel 60 F254 (Merck) plates were used
Figure 7. 1H NMR aromatic and amide zone in DMSO-d6 of ligand
2+1 equiv of TBA p-methoxybenzoate. Inset: NH zone of the free ligand.
1
for TLC. H and 13C NMR spectra were recorded with the
deuterated solvent as the lock and residual solvent as the in-
ternal reference. High-resolution mass spectra (FAB) were
recorded in the positive ion mode. UV–vis spectra were re-
corded using a 1 cm path length quartz cuvette. All measure-
ments were carried out at 293 K (thermostatted).
downfield shifted as a consequence of the complexation. In
addition, NOE0s experiments suggest for one of the com-
plexes the structure shown in Figure 8, which is also in accor-
dance with the structure obtained by PCModel.16 Of course
the system is present in the solution in a dynamic equilibrium
containing the four possible complexes. This is in good
agreement with the strong shifting observed for the four
NH signals in the NMR spectrum. Anyway, what is
4.2. Syntheses
4.2.1. N-Ethyl-N0-(40-nitro[1,10-biphenyl]-4-yl)thiourea,
1. Ethylisothiocyanate, 9 (0.24 mL, 2.8 mmol) and dry
Et3N (0.2 mL, 1.4 mmol) were slowly added to a 60 ꢁC solu-
tion of 4-amino-40-nitrobiphenyl, 7 (0.30 g, 1.4 mmol) in
THF (3 mL). The mixture was refluxed overnight and then
was allowed to reach room temperature. The resulting yellow
precipitate was filtered off and dried in vacuum, to give 1
(0.173 g, 42%) as a yellow powder. Mp: 214–216 ꢁC. IR
(KBr): 3370 (NHEt), 3145 (NHAr), 2986 (Ar), 1594
(C]C), 1510 (N]O), 1524 (N]O), 1344 (C]S), 850
(C–N) cmꢀ1. 1H NMR (DMSO-d6, 300 MHz): d 9.67 (br s,
1H, NH), 8.29 (d, J¼8.9 Hz, 2H), 7.95 (br s, 1H, NH), 7.94
(d, J¼8.9 Hz, 2H), 7.76 (d, J¼8.6 Hz, 2H), 7.64 (d,
J¼8.6 Hz, 2H), 3.52 (q, J¼7.0 Hz, 2H), 1.15 (t, J¼7.0 Hz,
3H). 13C NMR (DMSO-d6, 100.6 MHz): d 180.0, 146.2,
146.1, 140.6, 132.6, 127.4, 127.2, 124.1, 122.7, 38.7, 14.1.
Anal. calcd for C15H15N3SO2: C, 59.78%; H, 5.02%;
Figure 8. Structural proposal based on PC model 8.016 for the complexes
between ligands 1 with benzoate (Y-type complex) and 2 with p-methoxy-
benzoate (open complex).

8576
A. M. Costero et al. / Tetrahedron 62 (2006) 8571–8577
1
N, 13.94%; S, 10.62%. Found: C, 59.15%; H, 4.94%;
N, 13.66%; S, 10.23%. HRMS (FAB): calcd for
C15H15N3SO2: 301.116; found: 301.094.
86%). Mp 158–160 ꢁC. H NMR (DMSO-d6, 300 MHz):
d 9.91 and 9.87, 9.80 (3ꢃs, 2H, 2NH), 7.70–7.10 (m,
14H). 13C NMR (DMSO-d6, 100.6 MHz): d 179.6, 139.7,
139.5, 139.4, 136.0, 129.3, 129.0, 128.4, 127.2, 126.6,
126.4, 124.4, 123.6. HRMS (FAB) calcd for C19H16N2S:
304.103; found: 304.104.
4.2.2. N-(40-Nitro[1,10-biphenyl]-4-yl)-N0-phenylthio-
urea, 2. In a similar way, 2 was prepared from 7 (1.4 g,
6.09 mmol), phenylisothiocyanate, 10 (0.75 mL, 6.3 mmol)
and Et3N (0.9 mL, 6.3 mmol) in refluxing THF (12 mL) for
4 h. The yellow precipitate was filtered off and purified by
column chromatography on silica gel (CH2Cl2) to yield 2
as a pale yellow solid (1.47 g, 70%). Mp 175–177 ꢁC. IR:
3203 (NH), 1348 (C]S), 1594 (NO2), 1513 (C]C), 830,
730. 1H NMR (DMSO-d6, 400 MHz): (mixture of con-
formers) d 10.16, 10.00, 9.94, 9.78 (2NH), 8.30 (d,
J¼8 Hz, 2H), 7.98 (m, 2H), 7.80 (m, 2H), 7.70 (m, 2H),
7.49 (m, 2H), 7.34 (m, 2H), 7.14 (m, 1H). 13C NMR
(DMSO-d6, 100.6 MHz): d 179.4, 146.3, 146.1, 140.6,
140.5, 139.4, 139.3, 133.3, 133.1, 128.5, 128.4, 127.4,
127.3, 124.5, 124.4, 124.1, 123.6, 123.5. HRMS (FAB) calcd
for C19H15N3O2S: 349.406; found: 349.401.
4.2.6. N-(1,10-Biphenyl-4-yl)-N0-(4-nitrophenyl)thiourea,
6. Reaction of 8 (0.30 g, 1.5 mmol), 11 (0.27 g, 1.5 mmol)
and Et3N (0.26 mL) in refluxing THF (6 mL) for 24 h, gave
1
6 (0.48 g, 91%) as a white powder. Mp 184–187 ꢁC. H
NMR (DMSO-d6, 300 MHz): d 10.43 (br s, 2H, 2NH), 8.22
(d, J¼9.0 Hz, 2H), 7.86 (d, J¼9.0 Hz, 2H), 7.70–7.58 (m,
6H), 7.47 (t, J¼7.9 Hz, 2H) and 7.35 (t, J¼7.2 Hz, 1H).
13C NMR (DMSO-d6, 100.6 MHz): d 179.1, 142.3, 139.6,
138.4, 136.6, 129.0, 127.3, 126.8, 126.5, 126.4, 124.4,
123.9, 121.6. HRMS (FAB): calcd for C19H15N3O2S,
350.0963; found: 350.0970.
4.3. Binding studies
4.2.3. N-(40-Nitro[1,10-biphenyl]-4-yl)-N0-(4-nitrophenyl)-
thiourea, 3. This compound was prepared from 7
(1.5 g, 7.0 mmol), p-nitrophenylisothiocyanate, 11 (1.26 g,
7.0 mmol) and Et3N (1.0 mL, 7.0 mmol) in THF (20 mL) as
described above. The solvent was partially evaporated,
giving rise to an orange precipitate, which was filtered off
Binding constants of ligands 1–6 toward tetrabutylammo-
nium carboxylates were evaluated by UV–visible titrations
in DMSO. Typically, 10ꢀ4 M solutions of the receptors in
DMSO (3 mL) were titrated by adding 2 mL aliquots of the
envisaged carboxylates (as their TBA salts) in DMSO and
registering the UV–visible spectrum after each addition.
Log Kc was calculated by fitting all spectrophotometric titra-
tion curves with the SPECFIT program.18
1
and dried in vacuum (1.49 g, 54%). Mp 217–219 ꢁC. H
NMR (DMSO-d6, 300 MHz): d 10.50 (br d, 2H, 2NH),
8.30 (d, J¼9.0 Hz, 2H), 8.22 (d, J¼9.2 Hz, 2H), 7.97 (d,
J¼9.0 Hz, 2H), 7.87–7.80 (m, 4H), 7.69 (d, J¼8.7 Hz, 2H).
13C NMR (DMSO-d6, 100.6 MHz): d 179.1, 146.4, 146.2,
146.0, 142.4, 140.0, 133.8, 127.5, 127.4, 124.4, 124.2,
123.7, 121.7. HRMS (FAB) calcd for C19H15N3O2:
394.400; found: 394.403.
Acknowledgements
We thank the Spanish Ministerio de Ciencia y Tecnologia for
financial support (Project CTQ2005-07562-01) and PG ac-
knowledges the Spanish Ministerio de Ciencia y Tecnologia
for a Ramoꢀn y Cajal contract. GMRM also acknowledges the
Spanish Government for a PhD grant. We also thank de
SCSIE of the University of Valencia.
4.2.4. N-(40-Nitro[1,10-biphenyl]-4-yl)-N0-(4-methoxy-
phenyl)thiourea, 4. p-Methoxy phenylisothiocyanate 12
(0.25 mL, 1.8 mmol), Et3N (0.2 mL, 0.14 mmol) and
TBAF (1 M in THF, 20 mL) were added to a refluxing solu-
tion of 7 (0.39 g, 1.8 mmol) in THF (15 mL). After 20 h of
refluxing, another equivalent of 12 was added to the reaction
mixture, and the reflux was maintained for another 20 h. The
solvent was evaporated and the crude product was purified
by column chromatography on silica gel (hexane–EtAcO)
to give 4 as a yellow solid (0.27 g, 40%). Mp 178–182 ꢁC.
1H NMR (DMSO-d6, 300 MHz): d 9.83 (s, 1H, NH), 9.76
(s, 1H, NH), 8.29 (d, J¼9.0 Hz, 2H), 7.96 (d, J¼9.0 Hz,
2H), 7.78 (d, J¼9.0 Hz, 2H), 7.68 (d, J¼9.0 Hz, 2H), 7.35
(d, J¼9.0 Hz, 2H), 6.92 (d, J¼9.0 Hz, 2H), 3.75 (s, 3H).
13C NMR (DMSO-d6, 100.5 MHz): d 179.7, 156.6, 146.3,
146.1, 140.7, 133.3, 133.0, 132.0, 127.3, 126.0, 124.1,
123.5, 113.7, 55.2. HRMS (FAB) calcd for C20H17N3O3S:
379.543; found: 379.547.
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