Relationship between ligand conformations and complexation properties in ditopic biphenyl thioureas

Article abstract of DOI:10.1016/j.tet.2007.05.082

Four new homoditopic biphenyl thiourea derivatives have been prepared to be used in carboxylate sensing. Experiments carried out with these ligands have demonstrated that the conformation of the free ligand has a strong influence on both complex stoichiom

Full text of DOI:10.1016/j.tet.2007.05.082

Tetrahedron 63 (2007) 7899–7905
Relationship between ligand conformations and complexation
properties in ditopic biphenyl thioureas
a,*
b
a
a
Ana M. Costero, Pablo Gavi n˜ a, Gemma M. Rodr ꢀı guez-Mu n˜ iz and Salvador Gil
a
Department of Organic Chemistry, Universidad de Valencia, 46100-Burjassot, Valencia, Spain
b
Instituto de Ciencia Molecular, Universidad de Valencia, Valencia, Spain
Received 14 March 2007; revised 18 May 2007; accepted 22 May 2007
Available online 26 May 2007
Abstract—Four new homoditopic biphenyl thiourea derivatives have been prepared to be used in carboxylate sensing. Experiments carried
out with these ligands have demonstrated that the conformation of the free ligand has a strong influence on both complex stoichiometry and
geometry. High equilibrium constants were obtained in DMSO.
Ó 2007 Elsevier Ltd. All rights reserved.
1
. Introduction
Y-type geometry for these complexes should not be pro-
posed as general and that other factors such as conforma-
tional equilibria, or dimerization processes or even steric
The development of selective and sensitive chemosensors
for anions, especially carboxylates and dicarboxylates, is
a topic that is currently of interest. Many of the carboxylate
7
hindrances should be considered.
1
2
3
binding sites in these systems contain either one or two
Following this topic, we report herein the synthesis of
homo- and heteroditopic neutral carboxylate receptors 1–
4 (Chart 2) based on bis-thioureas and macrolactones
attached to a biphenyl system. Due to the presence of
two anion binding points in these receptors our interest
has been directed towards a,u-dicarboxylates. These target
anions were chosen in order to evaluate the influence that
the length of the aliphatic chain could have in complexa-
tion stoichiometry. Thus, 1:1 complexes could be expected
with the longer dicarboxylates whereas we expected that
a 1:2 stoichiometry should be more favourable with the
dicarboxylates presenting shorter chains. This possible dif-
ferent behaviour could give rise to same selectivity in base
on the length of the aliphatic chain in the studied dicarb-
oxylates. In addition, some control experiments with acetate
were carried out. Finally, influence showed by the crown
moiety could be explored by using different contra-ions
urea or thiourea subunits as hydrogen-bond donor groups.
However, few heteroditopic ligands have been described to
recognize this type of anions. Despite the many efforts
made to understand the complexation mechanism with these
binding motifs, mainly to distinguish real complexation
processes from proton transfer reactions, less interest has
4
5
been directed towards clearly establishing the geometry of
the formed complexes. It is, in general, assumed that thio-
ureas bind to carboxylates through a double hydrogen
bond, which involves both N–H fragments of the thiourea
and both carboxylate oxygens in a Y-type bidentated com-
1
b,2d,3b,6
plex (Chart 1).
ureas and carboxylate complexes are proposed on the sole
In most cases, geometries for thio-
1
a–c
basis of this postulate.
Our group has been interested in
the geometry of the complexes formed between aliphatic
and aromatic mono-carboxylates with mono-thioureas de-
rived from biphenyl and we have recently reported that the
+
4
+
(TMA, NH , Na ).
R2
NHCSNHR
NHCSNHR
O
N
H
H
O
O
R3
S
O
O
N
R1
O
O
O
1
R = 1-Naph
O
3 R = 1-Naph
R = Ph
Chart 1.
2 R = Ph
4
NHCSNHR
NHCSNHR
*
Corresponding author. Tel.: +34 963544410; fax: +34 963543151; e-mail:
ana.costero@uv.es
Chart 2.
0
040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.05.082

7900
A. M. Costero et al. / Tetrahedron 63 (2007) 7899–7905
2
. Results and discussion
solutions. In addition, weak NOE intermolecular correla-
tions also suggest that some degree of aggregation in solu-
tion occurs under the experimental conditions as it has
been observed in related compounds.
2.1. Synthesis and conformational studies of
receptors 1–4
1
0
0
diaminobiphenyl (5) or the macrolactone 6 and the
corresponding isothiocyanates (7 and 8) in refluxing THF.
All compounds were characterized by NMR and MS
Biphenyl thiourea derivatives were prepared from 4,4 -
By contrast, ligand 2 in solution presents the Z,E conforma-
tion shown in Chart 3, which is likely due to the smaller size
of the phenyl group, which gives rise to lower steric hin-
drances. Finally, the main conformation shown by ligands
3 and 4 is the E,Z conformation (Chart 3). Apparently, the
possibility of hydrogen bonding interactions with the thio-
urea NH places the crown moiety in between both aryl
8
(
Scheme 1).
NH2
NH2
(phenyl or naphthyl) groups. Furthermore, there is also an-
O
other conformation present under these conditions (Z,E for
ligand 3 and Z,Z for ligand 4).
O
O
i
O
O
i
1
or 2
O
3 or 4
7 or 8
SCN
O
6
2.2. Complexation studies
7
or
NH2
NH2
The ability of ligands 1–4 for complexing a,u-dicarboxyl-
ates was studied by UV titrations. The complexes’ stoichio-
metries as well as the complexation constant values for
oxalate, succinate and adipate were determined. They are
summarized in Table 1. These a,u-dicarboxylates were pre-
pared as their tetramethylammonium (TMA) salts from the
corresponding carboxylic acids and TMA hydroxide in
DMSO.
5
SCN
8
Scheme 1. Synthesis of receptors 1–4. (i) Et
3
N, THF, reflux.
Thiourea derivatives in solution can adopt three different
conformations (E–Z, Z–E or Z–Z), all of them of a similar en-
ergy, with the size of the substituents in the thiourea group
6
c,9
being responsible for the main conformation in each case.
1
As seen in Table 1 the number of methylene groups in the ali-
phatic chain of the a,u-dicarboxylate has a slight influence
on the complexation constants. These results agree with
complexes’ structures where only one carboxylate is in-
volved in complexation as proposed above.
H NMR studies carried out with ligands 1–4 in DMSO have
demonstrated that the interchange among the different con-
formations is slow in the NMR time scale and that there is
a main conformation for each ligand. Thus, only one set of
resonance is observed in the H NMR spectra in DMSO-d
1
6
for ligand 1, indicating that there is only one predominant
thiourea rotamer in solution (Fig. 1a). The behaviour of li-
gand 2 was similar, even though a very small amount of a sec-
2.2.1. Complexation studies with ligands 1 and 2. The an-
ion binding ability of receptors 1 and 2 was evaluated by the
UV–vis titration of each receptor with the appropriate anion
in DMSO solution. These experiments showed that ligands 1
and 2 display different behaviours upon the addition of di-
carboxylates (Fig. 2). After the addition of TMA succinate
to a solution of ligand 1 (Fig. 2a; for oxalate and adipate,
see the Supplementary data), the band at 315 nm, typical
of the biphenyl chromophore undergoes a red shift. A plot
of molar absorbance at 334 nm indicates only the forma-
tion of a 1:1 complex, even in the presence of a large excess
of anion (10 equiv). As geometric reasons preclude both
1
ond conformation was detected (Fig. 1b). Finally, the H
NMR spectra in DMSO-d of ligands 3 and 4, with the mac-
6
rolactone attached to the biphenyl system, are more compli-
cated (Fig. 1c for ligand 3, and Fig. 1d for ligand 4), showing
at least two sets of signals for each ligand. These results in-
dicate that two different conformations of the thioureas are
present in solution. Additional NMR experiments were car-
ried out to know which conformations were present in solu-
tion in each case. Thus, NOESYexperiments showed that the
Z,Z rotamer of thiourea 1 is mainly present in DMSO
1
Figure 1. H–N H NMR signals of 1 (a), 2 (b), 3 (c) and 4 (d) in DMSO-d
6
.

A. M. Costero et al. / Tetrahedron 63 (2007) 7899–7905
7901
R=NHCSNH(1-Naph)
a main band at l¼317 nm (corresponding to the biphenyl
moiety) and a shoulder at 298 nm (corresponding to the
phenyl moiety). Upon TMA succinate addition, the band
at 298 nm remained unchanged, but the band at 317 nm
clearly underwent a red shift. In addition, the complex stoi-
R
S Z
Z
α
E
S Z
N
H
N
H
H
α
β
N
H
NOE
N
β
NOE
chiometry was 2:1 (L A) in this case, even though a new spe-
2
1
NOE
cies seems to appear at higher anion concentrations. Control
experiments with TBA acetate also showed the expected red
shift of the band at 317 nm (see Supplementary data). Also
with this anion the complex stoichiometry was 2:1 (L A)
2
and in this case, a new complex was formed under addition
of increasing amounts of anion with a 1:2 stoichiometry.
NOE
O
R
COO
COO
O
S E
N
β
O
Z
H
β
N
H
N
4
R=NHCSNHPh
NOE
H α
α
N
H
NOE
2
S
The different complexation behaviours observed with
ligands 1 and 2 could be related to the different conforma-
tions shown by these ligands and also to the aggregation
shown by ligand 1. Thus, whereas ligand 1 is able to form
the classical Y-type complex with the carboxylate (Chart
6
Chart 3. Main conformations of 1, 2 and 4 in DMSO-d solution.
thiourea groups to be simultaneously involved in a 1:1
complex, one thiourea moiety will remain uncomplexed.
Control experiments were carried out with TBA acetate to
confirm that the effect is due only to the ligand and not to
the studied dicarboxylates. Once more, only the 1:1 complex
was formed even with a large excess of anion (see Supple-
mentary data). This behaviour can only be explained if the
aggregation shown by this ligand in DMSO was so strong
that only one thiourea was free to form complexes with the
anions.
1
2
), at least two ligand molecules are required with ligand
, due to its Z,E conformation, to contribute with the two
NH groups that seem to be essential to form a stable com-
plex. Both thiourea groups in each molecule could be in-
volved in complexation in the presence of higher amounts
of the anion giving rise to L A or LA complexes, respec-
2
3
2
tively, depending on the anion used.
1
H NMR studies were undertaken to obtain additional infor-
mation about the structure of the different complexes in
solution.
Under the same conditions ligand 2 shows a different behav-
iour (Fig. 2b). The UV spectrum of the free ligand showed
1
H NMR studies carried out with ligand 1 showed that
Table 1. Stoichiometries and log b values for receptors 1–4 with dicarb-
ꢀ
changes in the spectrum were observed upon the addition
of 2 equiv of TMA succinate (Fig. 3). Signals arising from
both the biphenyl and the naphthyl protons show strong
shifts. This coincides with a Y-type complex where both
NH are involved in complexation. In addition, intermolecu-
lar NOEs between the biphenyl and naphthyl protons sug-
gest that the aggregation of two ligands is maintained in
the complex. These observations, along with the fact that
stoichiometry and complexation constants are almost insen-
sitive to the chain length of the dicarboxylate, suggest that
only one carboxylate is involved, and leads us to propose
a
oxylates, in DMSO at 25 C
b
Anion
Receptor
1
2
3
4
ꢁ
ꢁ
ꢁ
ꢁ
OOC–COO
L:A
1:1
2:1
2:1
2:1
log b 5.6ꢂ0.2 9.4ꢂ0.2
L:A 1:1 2:1
log b 6.2ꢂ0.3 9.0ꢂ0.2
L:A 1:1 2:1
log b 5.8ꢂ0.4 10.3ꢂ0.3 9.8ꢂ0.2 8.9ꢂ0.2
9.4ꢂ0.3 8.5ꢂ0.2
2:1 2:1
9.5ꢂ0.3 8.1ꢂ0.2
2:1 2:1
OOC–(CH
COO
2
)
2
–
–
ꢁ
OOC–(CH
COO
2
)
4
ꢁ
1
a
the geometry depicted in Figure 4. The control H NMR ex-
periments carried out with TBA acetate showed a completely
The results were calculated by UV–vis titration.
All anions were used as their TMA salts.
b
3
.4 A (334 nm)
(a)
3.2
3
(b)
2
.9
.8
1.7
1.6
1.5
2
.8
A (320nm)
1
1
3
2
1
0
2.6
2.4
.2
2
1
0
2
0
0.5
1
1.5
2
equiv anion
2.5
3
3.5
0
0.5
1
1.5 2
eq anion
2.5
3
3.5
255
305
355
nm)
405
250
300
350
(nm)
400
450
(
ꢀ
Figure 2. UV–vis absorption spectrophotometric titration of ligands 1 and 2 with TMA succinate in DMSO at 25 C. Inset: stoichiometry determination for
$TMA succinate at 320 nm, 2$TMA succinate at 334 nm.
1

7902
A. M. Costero et al. / Tetrahedron 63 (2007) 7899–7905
(a)
(b)
8.2
8.0
7.8
7.6
7.4
7.2
8.2
8.0
7.8
7.6
7.4
7.2
1
Figure 3. Aromatic zone of the H NMR spectra (DMSO-d
6
) of ligand 1: (a) free, (b) upon addition of an excess of TMA succinate.
similar pattern to that showed by the studied dicarboxylates
indicating that also with this anion the association of the
ligand is present and Y-type complexes are formed by the
free thiourea moieties.
acetate). However, the largest modifications were observed
for the biphenyl moiety because those signals in the free
ligand appear as two different doublets, yet they lead to
a broad singlet on complexation (see Fig. 5 for succinate
and Supplementary data for the other anions).
Ligand 2 shows small upfield shifts for both the phenyl and
the biphenyl hydrogen atoms upon addition of 0.5 equiv of
all the studied anions (oxalate, succinate, adipate and
This would be in accordance with the structural proposal
shown in Figure 6 where the rotation of the aromatic rings
in the biphenyl systems might be hindered by the proximity
of the second molecule involved in complexation. In addi-
tion, this geometry could also provide an explanation to
the UV spectrum where only the band corresponding to
the biphenyl moiety seems to be shifted.
-
OOC
-
COO
S
O
N
H
H
N
H
O
1
NOE
O
Larger modifications were observed in the H NMR spec-
N
H
O
H
N
H
N
trum when 2 equiv of TMA succinate is present. Then, the
strong upfield shift also involves phenyl protons. When com-
pared to the free ligand, global upfield shifts are Dd¼0.33,
S
S
N
N
H
N
S
H
0
.27, 0.23, 0.28 and 0.46 ppm for H , H , H , H and H , re-
a b c d e
spectively (Fig. 5c). These strong modifications could be due
to deprotonation processes what are in accordance with the
results obtained with this ligand in the presence of TBAOH
(see Supplementary data).
(
1A)2
Figure 4. Structural proposal for the complexes between ligand 1 and excess
of TMA succinate.
1
Figure 5. Aromatic zone of the H NMR spectra (DMSO-d
6
) of ligand 2: (a) free, (b) upon addition of 0.5 equiv TMA succinate and (c) in the presence of
2
equiv of TMA succinate.

A. M. Costero et al. / Tetrahedron 63 (2007) 7899–7905
7903
He
this type of ligands. Figure 8 shows the UV titration exper-
ꢀ
iments with TMA succinate in DMSO at 25 C.
Hd
Hc
Ha
Hb
H
S
The UV spectrum of ligand 3 presents a main band at 315 nm
with a fine structure, which corresponds to the naphthyl
thiourea and a shoulder at 346 nm corresponding to the
biphenyl moiety. After complexation, only the biphenyl
band is modified, which agrees with a complex involving
only this type of NH groups. Two ligand molecules should
be involved to therefore achieve a stable complex given
H
N
N
N
N
H
H
S
O
COO-
O
H
N
S
N
H
N
the observed L A stoichiometry. Ligand 4 displays a similar
2
behaviour. In this case the UV spectrum shows a band at
285 nm corresponding to the thiourea phenyl part and
N
H
S
H
a shoulder at 335 nm due to the biphenyl. Only the biphenyl
moiety was modified after the carboxylate addition as
observed with ligand 3.
Figure 6. Structural proposal for the complexes between ligand 2 and
.5 equiv of TMA succinate.
0
By contrast, the results obtained after the addition of 2 equiv
of TBA acetate demonstrated that this anion is not basic
enough to cause the deprotonation reaction. Thus, in this
case, downfield shifts were observed (Dd¼0.10 and
Complexes with a higher stoichiometry or deprotonated
species were never observed with these ligands even in the
presence of a high concentration of anion (10 equiv). This
b
behaviour could be due to a hydrogen bond between NH
0
.16 ppm for H , and H , respectively). These changes
and the crown moiety. This can stabilize a conformation
similar to that described for the free ligand (Chart 3) that pre-
cludes the conformational change observed with ligand 2
and excess of some of the carboxylates.
a
c
clearly support that, in the newly formed complex LA2,
both NH groups are involved in the complexation to the ace-
tate, which implies a conformational change in the ligand
(
Fig. 7b).
In addition, UVexperiments carried out with ligands 3 and 4
upon addition of ammonium and sodium acetates demon-
strated that the presence of the lactone cavity has a slight
influence on the complexation constants.
Finally, fluorescence studies were carried out with these li-
gands and the studied anions. Nonetheless no modification
in the emission spectra was induced in any case.
1
2.2.2. Complexation studies with ligands 3 and 4. Similar
studies were carried out with ligands 3 and 4 to know the in-
fluence that the crown moiety has on the complexation with
H NMR studies carried out with these ligands in the pres-
ence of the studied anions were not conclusive given the
broadness of the signals in the spectra.
(a)
(b)
CH3
O
S
N
O
H
N
O
N
H
H
N
H
O
S
H C
3
1
Figure 7. (a) Structural proposal for the complexes between ligand 2 and 2 equiv of TBA acetate. (b) Aromatic zone of the H NMR spectra (DMSO-d
ligand 2 upon addition of 2 equiv of TBA acetate.
6
) of
0
.8 A=370 nm
(
a) 1.8
(b)
0.7
0
.6
3
.5
2
0.9
0.6
0.3
0
1
1
1
.6
.4
.2
1
0.5
(A=370 nm)
0
0
.4
.3
0.2
2
0.1
0
0
0.5
1
1.5
eq anion
2
2.5
3
3.5
0
0.5
1
1.5
eq anion
2
2.5
3
3.5
0
0
0
0
.8
.6
.4
.2
0
1.5
1
0
.5
0
250
300
350
nm)
400
450
260
310
360
(nm)
410
(
ꢀ
Figure 8. UV–vis absorption spectrophotometric titration of ligands (a) 3 and (b) 4 with TMA succinate in DMSO at 25 C. Inset: stoichiometry determination
for 3$TMA succinate at 370 nm and 4$TMA succinate at 370 nm.

7904
A. M. Costero et al. / Tetrahedron 63 (2007) 7899–7905
(a)
(b) 150
1
1
50
00
100
50
50
400
500
Wavelength (nm)
600
400
500
Wavelength (nm)
600
Figure 9. Fluorescence titration of ligand 3 in DMSO (a) with TMA oxalate and (b) with TMA adipate.
1
13
Finally, fluorescence studies carried out with ligands 3 and 4
showed that a quenching of the fluorescence was induced
by the anions. However, this quenching was insensitive to
the length of the chain in the a,u-dicarboxylate (Fig. 9 for
ligand 3; for ligand 4 see Supplementary data).
(Merck) plates were used for TLC. H and C NMR spectra
were recorded with the deuterated solvent as the lock and
residual solvent as the internal reference. High-resolution
mass spectra (FAB) were recorded in the positive ion
mode. UV–vis spectra were recorded using a 1 cm path
length quartz cuvette. All measurements were carried out
at 293 K (thermostatted). Fluorescence spectra were carried
out in a Varian Cary Eclipse Fluorimeter.
3. Conclusion
A series of biphenyl dithioureas have been prepared. Their
conformation in DMSO solutions has been studied by proton
NMR and their ability to bind a,u-dicarboxylates and ace-
tate has been evaluated by UV–vis titration, fluorescence
and NMR experiments. These studies allow us to establish
that not only the geometry but also the stoichiometry of
the complexes formed between these carboxylates and the
thiourea receptors is strongly dependent on their conforma-
tional behaviour. Thus, when the ligand is mainly in a Z,Z
conformation, a Y-type complex can be postulated. By con-
trast, the stoichiometry of the complex is 2:1 when other
rotamers are present in the solution. In addition, deprotona-
tion reaction has been observed in ligand 2 in the presence
of an excess of a,u-dicarboxylates whereas the less basic
anion acetate did not give rise to this process and the corre-
sponding 1:2 complex was observed. When strong aggrega-
tion is present in the ligand (ligand 1) neither deprotonation
reaction nor complexes with higher stoichiometries were
observed. Our experiments allow us to affirm that both the
substituent in the thiourea moiety and the presence of the
macrolactone have a strong influence on complexation and
on the properties of the prepared ligands. Finally, the three
a,u-dicarboxylates studied presented a similar spectro-
scopic behaviour which precludes ligands 1–4 to be used as
selective sensors.
4.1.1. Syntheses.
0
4.1.1.1. 4,4 -Bis-(naphthylthiourea)biphenyl, 1. Benz-
idine (1.0 g, 5.4 mmol) in dry THF (30 mL) was heated till
the reflux was achieved. Then, 1-naphthylisocyanate
(2 equiv, 2.0 g, 10.8 mmol) was added. A white precipitate
was appearing as the dithiourea was formed. After refluxing
for 2 h the reaction was left to room temperature. The result-
ing white solid was filtered and 50 mL of hexane was added
to the solution of THF, where the rest of the dithiourea
precipitated. After filtration both solids were joined and
1
dried in vacuum to yield 1 (2.64 g, 88%). H NMR
(CDCl 300 MHz) d (ppm): 9.92 (br s, 2H, 2NH), 9.85 (br
3
,
s, 2H, 2NH), 8.01–7.96 (m, 8H), 7.90–7.80 (m, 4H), 7.63–
C NMR (DMSO-d , 100.5 MHz)
6
1
3
7.50 (m, 10H).
d (ppm): 181.2, 138.9, 135.7, 135.1, 134.0, 130.0, 128.2,
126.8, 126.3, 126.1, 126.0, 125.7, 125.4, 124.3, 123.2.
HRMS (FAB ): found 555.1675; C H N S (MH )
required 555.1677.
+
+
3
4 27 4 2
0
4.1.1.2. 4,4 -Bis-(phenylthiourea)biphenyl, 2. Benz-
idine (1.0 g, 5.4 mmol) in dry THF (30 mL) was heated to
reflux. Then, phenylisothiocyanate (1.3 mL, 12.5 mmol)
was dropped during 1 h. A white solid appeared immedi-
ately. The reaction was heated for 3 h. When room temper-
ature was achieved, the solution was poured over 40 mL of
hexane, and kept in the fridge for 24 h. The white solid
was filtered and dried in a vacuum pump to give 2 (1.28 g,
52%). H NMR (DMSO-d , 400 MHz) d (ppm): 9.87 (s,
1
4. Experimental
6
2
H, 2NH), 9.84 (s, 2H, 2NH), 7.64 (d, J¼8.8 Hz, 4H),
4
.1. General procedures and materials
7.57 (d, J¼8.8 Hz, 4H), 7.50 (d, J¼8.7 Hz, 4H), 7.34 (t,
1
3
J¼7.9 Hz, 4H), 7.14 (t, J¼7.2 Hz, 2H). C NMR (DMSO-
8
Compound 6 was prepared as previously reported. All other
reagents were commercially available, and were used with-
out purification. Triethylamine was freshly distilled from
d , 100.5 MHz) d (ppm): 179.8, 139.5, 138.7, 135.5, 128.4,
6
+
+
126.3, 124.4, 123.8, 123.6. HRMS (FAB ): MH found:
455.1357. C H N S required 455.1364.
2
6 23 4 2
CaH . THF was distilled from Na/benzophenone under Ar
2
prior to use. Column chromatography was performed with
silica gel 60 (230–400 mesh, Merck). Silica gel 60 F254
0
biphenyl, 3. In a round bottom flask under argon were
0
4.1.1.3. 4,4 -Bis-(naphthylthiourea)-2,2 -macrolactone-

A. M. Costero et al. / Tetrahedron 63 (2007) 7899–7905
7905
added, in this order, diamine 6 (280 mg, 0.65 mmol), dry
THF (30 mL), dry triethylamine (180 mL, 1.3 mmol) and
-naphthylisocyanate (121 mg, 0.65 mmol). The mixture
Supplementary data
1
13
1
H NMR of ligands 1–4 in DMSO-d6; C NMR of ligands 1
and 2 in DMSO-d ; UV titrations of ligands 1–4 with TMA
was heated until reflux and was kept for two days. After
the solution was cold, it was poured over hexane (100 mL)
and kept in the fridge. The precipitate was filtered and dried
6
oxalate and adipate (from 0 to 3 equiv). Supplementary data
associated with this article can be found in the online ver-
sion, at doi:10.1016/j.tet.2007.05.082.
1
to get 3 as a pale pink solid (338 mg, 65%). H NMR
(
DMSO-d , 400 MHz) (mixture of conformers) d (ppm):
6
1
8
7
1
1
1
7
0.17 and 9.80 (br s, NH), 10.01 and 9.94 (br s, NH),
.07–7.90 (m, 6H), 7.88–7.83 (m, 4H), 7.69–7.55 (m, 8H),
.16–7.11 (m, 2H), 4.12–4.02 (m, 4H), 3.55–3.32 (m,
References and notes
1
3
2H). C NMR (DMSO-d , 100 MHz) d (ppm): 182.1,
6
1. (a) Zeng, Z.-Y.; He, Y.-B.; Wu, J.-L.; Wei, L.-H.; Liu, X.;
Meng, L.-Z.; Yang, X. Eur. J. Org. Chem. 2004, 2888; (b)
Nie, L.; Li, Z.; Han, J.; Zhang, X.; Yang, R.; Liu, W.-X.; Wu,
F.-Y.; Xie, J.-W.; Zhao, Y.-Z.; Jiang, Y.-B. J. Org. Chem.
2004, 69, 6449; (c) Wu, J.-L.; He, Y.-B.; Zeng, Z.-Y.; Wei,
L.-H.; Meng, L.-Z.; Yang, T.-X. Tetrahedron 2004, 60, 4309;
(d) Evans, L. S.; Gale, P. A.; Lighat, M. E.; Quesada, R.
Chem. Commun. 2006, 965.
2. (a) Smith, P. J.; Reddington, M. V.; Wilcox, C. S. Tetrahedron
Lett. 1992, 33, 6085; (b) Fan, E.; van Arman, S. A.; Kincaid, S.;
Hamilton, A. D. J. Am. Chem. Soc. 1993, 115, 369; (c) Kelly,
T. R.; Kim, M. H. J. Am. Chem. Soc. 1994, 116, 7072; (d)
Kato, R.; Nishizawa, S.; Hayashita, T.; Teramae, N.
Tetrahedron Lett. 2001, 42, 5053; (e) Linton, B.; Hamilton,
A. D. Tetrahedron 1999, 55, 6027; (f) Gunnlaugsson, T.;
Kruger, P. E.; Lee, T. C.; Parkesh, R.; Pfeffer, F. M.; Hussey,
G. M. Tetrahedron Lett. 2003, 44, 6575.
3. (a) Hamann, B. C.; Branda, N. R.; Rebek, J., Jr. Tetrahedron
Lett. 1993, 34, 6837; (b) Lee, D. H.; Lee, H. Y.; Lee, K. H.;
Hong, J. I. Chem. Commun. 2001, 1188.
. Tumcharem, G.; Tuntulani, T.; Coles, S. J.; Hursthouse, M. B.;
Kilburn, J. D. Org. Lett. 2003, 5, 4971 and references therein.
5. (a) Amendola, V.; Esteban-G ꢀo mez, D.; Fabbrizzi, L.; Licchelli,
M. Acc. Chem. Res. 2006, 39, 343; (b) Evans, L. S.; Gale, P. A.;
Light, M. E.; Quesada, R. New J. Chem. 2006, 30, 1019.
6. (a) Kyne, G. M.; Light, M. E.; Hursthouse, M. B.; de Mendoza,
J.; Kilburn, J. D. J. Chem. Soc., Perkin Trans. 1 2001, 1258; (b)
Amendola, V.; Estaban-G ꢀo mez, D.; Fabbrizzi, L.; Licchelli,
M.; Monzani, E.; Sancen ꢀo n, F. Inorg. Chem. 2005, 44, 8690;
(c) Jim ꢀe nez-Blanco, J. L.; Benito, J. M.; Ortiz-Mellet, C.;
Garc ꢀı a-Fern ꢀa ndez, J. M. Org. Lett. 1999, 1, 1217.
66.4, 138.7, 138.3, 134.8, 133.9, 129.9, 129.0, 128.1,
26.9, 126.2, 126.1, 125.9, 125.6, 125.3, 124.8, 123.0,
0.1, 69.8, 67.8, 63.5. HRMS (FAB ): found 801.2475.
+
+
C H N O S (MH ) required 801.2417.
4 41 4 7 2
4
0
0
4
.1.1.4. 4,4 -Bis-(phenylthiourea)-2,2 -macrolactone-
biphenyl, 4. In a similar way, from diamine 9 (260 mg,
.6 mmol), dry triethylamine (173 ml, 1.2 mmol) in THF
45 mL) and phenylisocyanate (144 ml, 1.2 mmol), 4 was
0
(
1
prepared as a yellow solid (240 mg, 57%). H NMR
DMSO-d , 300 MHz) (mixture of conformers) d (ppm):
(
6
1
0.22 and 9.80 (br s, NH), 10.04 and 9.97 (br s, NH), 8.09
(
7
4
s, 2H), 7.81 (d, J¼8.3 Hz, 2H), 7.52 (d, J¼7.8 Hz, 4H),
.36 (t, J¼7.8 Hz, 4H), 7.17–7.13 (m, 4H), 4.10–3.98 (m,
3
1
3
H), 3.54–3.35 (m, 12H). C NMR (CD CN, 100 MHz)
d (ppm): 179.7, 165.9, 139.3, 138.6, 138.3, 130.3, 129.2,
28.6, 126.4, 124.4, 123.6, 70.1, 69.8, 67.8, 63.5. HRMS
1
+
+
(
FAB ): found 700.2020. C H N O S (MH ) required
36 36 4 7 2
7
00.2025.
.1.2. Binding studies. Binding constants of ligands 1–4 to-
wards tetramethylammonium dicarboxylates were evaluated
4
4
ꢁ
4
by UV–vis titrations in DMSO. Typically, 10 M solutions
of the receptors in DMSO (3 mL) were titrated by adding
2
TMA salts) in DMSO and registering the UV–vis spectrum
after each addition. The value of log K was calculated by
c
fitting all spectrophotometric titration curves with the
SPECFIT program [SPECFIT/32 Global Analysis System v.
mL aliquots of the envisaged dicarboxylates (as their
3.0, Spectrum Associates (Marlborough, MA, USA),
www.bio-logic.info/rapid-kinetics/specfit.html].
7. Costero, A. M.; Gavi n˜ a, P.; Rodr ꢀı guez-Mu n˜ iz, G. M.; Gil, S.
Tetrahedron 2006, 62, 8571.
8
. Costero, A. M.; Andreu, C.; Pitarch, M.; Andreu, R.
Tetrahedron 1996, 52, 3683.
Acknowledgements
9
. (a) Rang, K.; Sandstrom, J.; Svensson, C. Can. J. Chem. 1998,
76, 811; (b) Sullivan, R. H.; Nix, P.; Summers, E. L., Jr.; Parker,
S. L. Org. Magn. Reson. 1983, 21, 293.
We thank the Spanish Ministerio de Ciencia y Tecnologia
for financial support (Project CTQ2006-15456-02).
G.M.R.-M. also acknowledges the Spanish Government
for a Ph.D. grant. We also thank de SCSIE of the University
of Valencia.
10. (a) Alajar ꢀı n, M.; Pastor, A.; Orenes, R.-A.; Steed, J. W. J. Org.
Chem. 2002, 67, 7091; (b) Masunov, A.; Dannenberg, J. J.
J. Phys. Chem. A 1999, 103, 178.