Development of N-benzamidothioureas as a new generation of thiourea-based receptors for anion recognition and sensing

Article abstract of DOI:10.1021/jo049088f

A series of neutral N-(substituted-benzamido)-N′-phenylthioureas (substituent = p-OC₂H₅, p-CH₃, m-CH ₃, H, p-Cl, p-Br, m-Cl, and p-NO₂) were designed as anion receptors, in which the thiourea binding site was attached to the benzamido moiety via an N-N bond. The absorption spectra of these N-benzamidothioureas in acetonitrile peaked at ca. 270 nm were found to show unprecedented red shifts by 7 373 to 14 325 cm^-1 in the presence of anions such as AcO-, F-, and H₂PO₄^-. Under the same conditions, the classic neutral thiourea receptors, N-(substituted-phenyl)-N′-phenylthioureas, showed absorption spectral shifts in most cases of less than 800 cm^-1 with one exception of 6501 cm^-1. Control experiments, effects of protic solvent, and ¹H NMR titration confirmed the formation of hydrogen-bonding complexes between the new N-benzamidothiourea receptors and anions. The binding constants with AcO-, for example, are at 10 ⁵-10⁷ mol^-1 L order of magnitude, which are 13 to 590 times those of the corresponding classic N-phenylthioureas in the same solvent. It was found that, whereas the absorption of the N-benzamidothiourea receptors showed essentially no dependence on the substituent, the substantially red-shifted new absorption band of the N-benzamidothiourea-anion binding complex was sensitively subject to the substituent. A linear relationship was found between the absorption energies of the N-benzamidothiourea-acetate binding complexes and the Hammett constants of the substituents with a negative slope of -0.34 eV. This led to the assignment that the substantially red-shifted absorption band was the ground-state intramolecular charge-transfer absorption with the substituent locating in the electron acceptor moiety. It was concluded that anion binding to the thiourea moiety of the N-benzamidothiourea receptors switched on their ground-state charge transfer. An anion-binding induced structural change was suggested to occur around the N-N bond in N-benzamidothioureas, which resulted in a substantially increased electron donating ability of the electron donor in the receptor molecules. As a consequence, the ground-state charge transfer takes place in the N-benzamidothiourea-anion binding complexes, leading to unprecedented red shifts in the absorption spectra and substantially enhanced anion binding affinities than those of the corresponding N-phenylthiourea receptors. N-Benzamido- N′-phenylthioureas represent a new generation of neutral thiourea-based anion receptors that show substantially improved anion binding performance important for anion sensing and recognition.

Full text of DOI:10.1021/jo049088f

Develop m en t of N-Ben za m id oth iou r ea s a s a New Gen er a tion of
Th iou r ea -Ba sed Recep tor s for An ion Recogn ition a n d Sen sin g
Li Nie,†,‡ Zhao Li,† J ie Han,† Xuan Zhang,† Rui Yang,†,§ Wen-Xia Liu,† Fang-Ying Wu,†,
J ian-Wei Xie,# Yu-Fen Zhao,† and Yun-Bao J iang*,†
Department of Chemistry, the MOE Key Laboratory of Analytical Sciences, and the Key Laboratory for
Chemical Biology of Fujian Province, Xiamen University, Xiamen 361005, China, Department of
Chemistry, Wanxi College, Lu’an 237012, China, Department of Chemistry, Southwest Normal University,
Chongqing 400715, China, Department of Chemistry, Nanchang University, Nanchang 330047, China,
and Institute of Pharmacology and Toxicology, Beijing 100850, China
ybjiang@xmu.edu.cn
Received J une 1, 2004
A series of neutral N-(substituted-benzamido)-N′-phenylthioureas (substituent ) p-OC2H5, p-CH3,
m-CH3, H, p-Cl, p-Br, m-Cl, and p-NO2) were designed as anion receptors, in which the thiourea
binding site was attached to the benzamido moiety via an N-N bond. The absorption spectra of
these N-benzamidothioureas in acetonitrile peaked at ca. 270 nm were found to show unprecedented
red shifts by 7 373 to 14 325 cm-1 in the presence of anions such as AcO-, F-, and H2PO4-. Under
the same conditions, the classic neutral thiourea receptors, N-(substituted-phenyl)-N′-phenylthio-
ureas, showed absorption spectral shifts in most cases of less than 800 cm-1 with one exception of
6501 cm-1. Control experiments, effects of protic solvent, and 1H NMR titration confirmed the
formation of hydrogen-bonding complexes between the new N-benzamidothiourea receptors and
anions. The binding constants with AcO-, for example, are at 105-107 mol-1 L order of magnitude,
which are 13 to 590 times those of the corresponding classic N-phenylthioureas in the same solvent.
It was found that, whereas the absorption of the N-benzamidothiourea receptors showed essentially
no dependence on the substituent, the substantially red-shifted new absorption band of the
N-benzamidothiourea-anion binding complex was sensitively subject to the substituent. A linear
relationship was found between the absorption energies of the N-benzamidothiourea-acetate
binding complexes and the Hammett constants of the substituents with a negative slope of -0.34
eV. This led to the assignment that the substantially red-shifted absorption band was the ground-
state intramolecular charge-transfer absorption with the substituent locating in the electron acceptor
moiety. It was concluded that anion binding to the thiourea moiety of the N-benzamidothiourea
receptors switched on their ground-state charge transfer. An anion-binding induced structural
change was suggested to occur around the N-N bond in N-benzamidothioureas, which resulted in
a substantially increased electron donating ability of the electron donor in the receptor molecules.
As a consequence, the ground-state charge transfer takes place in the N-benzamidothiourea-anion
binding complexes, leading to unprecedented red shifts in the absorption spectra and substantially
enhanced anion binding affinities than those of the corresponding N-phenylthiourea receptors.
N-Benzamido-N′-phenylthioureas represent a new generation of neutral thiourea-based anion
receptors that show substantially improved anion binding performance important for anion sensing
and recognition.
Anion recognition and sensing has recently grown into
a subject of great interest in supramolecular and organic
chemistry.1 As the anion-receptor interactions, mainly
of hydrogen bonding and/or electrostatic nature, are
different from the metal-ligand coordination for the
cation-receptor interactions,2 the design of anion recep-
tors differs substantially from that of cation receptors.
In constructing anion receptors thiourea has been exten-
sively employed as the anion-binding site in a hydrogen-
bonding receptor (Scheme 1).1 It is in general attempted
to modify its N,N′-substituents to enhance the acidity of
the thioureido -NH protons for promoting the hydrogen
(1) (a) Mat´ınez-Ma´n˜ez, R.; Sanceno´n, F. Chem. Rev. 2003, 103, 4419.
(b) Suksai, C.; Tuntulani, T. Chem. Soc. Rev. 2003, 32, 192. (c) For
comprehensive recent reviews, see: Coord. Chem. Rev. 2003, 240,
issues 1 and 2. (d) Wiskur, S. L.; Ait-Haddou, H.; Lavigne, J . J .; Anslyn,
E. V. Acc. Chem. Res. 2001, 34, 963. (e) Sessler, J . L.; Davis, J . M.
Acc. Chem. Res. 2001, 34, 989. (f) Beer, P. D.; Gale, P. A. Angew. Chem.,
Int. Ed. 2001, 40, 486. (g) Gale, P. A. Coord. Chem. Rev. 2001, 213,
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740. (i) Schmidtchen, F. P.; Berger, M. Chem. Rev. 1997, 97, 1609.
(2) (a) de Silva, A. P.; Gunaratne, H. Q. N.; Gunnlaugsson, T.;
Huxley, A. J . M.; McCoy, C. P.; Rademacher, J . T.; Rice, T. E. Chem.
Rev. 1997, 97, 1515. (b) Desvergue, J . P.; Czarnik, A. W., Ed.
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* To whom correspondence should be addressed.
† Xiamen University.
‡ Wanxi College.
§ Southwest Normal University.
Nanchang University.
#
Institute of Pharmacology and Toxicology.
10.1021/jo049088f CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/20/2004
J . Org. Chem. 2004, 69, 6449-6454
6449

Nie et al.
SCHEME 1. Hyd r ogen Bon d in g of
N,N′-Alk yl(a r yl)th iou r ea w ith Aceta te An ion
character of the amide bond to such an extent that the
charge transfer occurs in the binding complex. As a
consequence, the acidity of the thioureido -NH protons
would be enhanced, which in turn reinforces the anion
binding. Herein reported are N-benzamidothiourea-based
anion receptors (2a -h , Chart 1) with substituents rang-
ing from highly electron withdrawing to moderately
electron donating. It will be shown that, in 2a -h , the
hydrazino N-N single bond stops the electronic com-
munication between the thiourea binding site and the
benzamido chromophores and the acidity of the thioure-
ido -NH protons is actually lower than that in 1. Yet,
they show unprecedented red shifts in their absorption
spectra in acetonitrile of as much as 14 325 cm-1 upon
anion binding and substantially enhanced anion binding
affinities, compared to those of the corresponding N-
phenylthiourea counterparts (1, Chart 1).
CHART 1. Str u ctu r e of
N-(Su bstitu ted -p h en yl)-N′-p h en ylth iou r ea s (1) a n d
N-(Su bstitu ted -ben za m id o)-N′-p h en ylth iou r ea s (2)
Resu lts a n d Discu ssion
It appears straightforward to directly attach the thio-
urea moiety to benzoyl to form N-benzoylthioureas, as
that would be expected to deliver more efficiently the
anion-binding message to the benzoyl chromophore. The
intramolecular six-membered-ring hydrogen bond exist-
ing in the N-benzoylthiourea involving carbonyl oxygen
and the other thioureido -NH proton,7 however, might
prevent its double hydrogen bonding with oxoanions.
Indeed, we found that the absorption spectrum of N-
benzoyl-N′-phenylthiourea in acetonitrile showed practi-
cally no change upon introducing AcO- and H2PO4-. To
maintain the dipolar amide bond and the thiourea anion-
binding site, a series of N-(substituted-benzamido)-N′-
phenylthioureas (2a -h , Chart 1) were therefore de-
signed. These N-benzamidothioureas might work as
anion receptors as suggested by our preliminary results
with a derivative of them (X ) p-N(CH3)2).8a The thiourea
moiety in 2a -h is indeed available for anion binding, as
is shown by the anion-induced dramatic changes in the
absorption spectra of 2a -h in acetonitrile that originally
peaked at ca. 235 nm and 270 nm, respectively. An
isosbestic point at ca. 240 nm and a new and substan-
tially red-shifted band at 330-435 nm appeared in the
presence of AcO-; see Figure 1a for the absorption
spectral titration traces of 2d . It was found in Figure 1a
that as little as 10-6 mol L-1 of AcO- could already lead
to appreciable change in the absorption spectrum of 2d .
With the corresponding N,N′-diphenylthiourea (1d ) in
which the anion-binding thiourea moiety is directly
linked to the phenyl chromophore, however, only a slight
change in its absorption spectrum was observed (Figure
2). This shows a higher response sensitivity of 2d toward
this anion. With F- and H2PO4-, similar observations
were made (Figure 1b). Detailed data for the other
members of the N-benzamidothiourea receptors can be
found in Table 1. It deserves to be pointed out that in
bonding.1,3 N-Alkyl and/or N-aryl substitutions have
hitherto been the major options, see for example, N-
(substituted-phenyl)-N′-phenylthioureas (1) in Chart 1.
On the basis of the observations that the charge
transfer (CT) absorption of N-(p-nitrophenyl)thioureas
was shifted to the red upon binding to acetate anion3a-c
and the photoinduced electron transfer (PET) in thiourea-
based fluorescent receptors was enhanced when anions
were bound to the thiourea moiety locating in the electron
donor,3h it was concluded that anion binding to the
thiourea moiety increased its electron-donating ability.
Considering the dipolar character of the amide bond,4 we
decided to attach the thiourea moiety to benzamide to
construct N-benzamidothioureas as a new generation of
thiourea-based anion receptors. In these new receptors
one thioureido nitrogen atom is linked to the rest of the
molecules via an N atom, instead of a C atom in the
classic N-alkyl or N-aryl thiourea-based receptors such
as 1 (Chart 1). It was expected that upon anion binding
to the thiourea moiety in these N-benzamidothiourea
receptors the electron density at the thioureido nitrogen
atom would increase. This, assisted by the substitution
preferably of an electron-withdrawing substituent at the
benzamido phenyl ring, would enhance the dipolar
(3) (a) Nishizawa, S.; Kato, R.; Hayashita, T.; Teramae, N. Anal.
Sci. 1998, 14, 595. (b) Hayashita, T.; Onodera, T.; Kato, R.; Nishizawa,
S.; Teramae, N. Chem. Commun. 2000, 755. (c) Kato, R.; Nishizawa,
S.; Hayashita, T.; Teramae, N. Tetrahedron Lett. 2001, 42, 5053. (d)
Nishizawa, S.; Buhlmann, P.; Iwao, M.; Umezawa, Y. Tetrahedron Lett.
1995, 36, 6483. (e) Xiao, K. P.; Buhlmann, P.; Umezawa, Y. Anal.
Chem. 1999, 71, 1183. (f) Blanco, J . L. J .; Benito, J . M.; Mellet, C. O.;
Ferna´ndez J . M. G. Org. Lett. 1999, 1, 1217. (g) Tozawa, T.; Misawa,
Y.; Tokita, S.; Kubo, Y. Tetrahedron Lett. 2000, 41, 5219. (h) Gunnlaugs-
son, T.; Davis, A. P.; Glynn, M. Chem. Commun. 2001, 2556. (i) Sasaki,
S.; Citterio, D.; Ozawa, S.; Suzuki, K. J . Chem. Soc., Perkin Tran. 2
2001, 2309. (j) Lee, D. H.; Lee, H. Y.; Lee, K. H.; Hong, J . I. Chem.
Commun. 2001, 1188. (k) Hennrich, G.; Sonnenschein, H.; Resch-
Genger, U. Tetrahedron Lett. 2001, 42, 2805. (l) Mei, M. H.; Wu, S. K.
Acta Chim. Sin. 2001, 59, 1112. (m) J ime´nez, D.; Mat´ınez-Ma´n˜ez, R.;
Sanceno´n, F.; Soto, J . Tetrahedron Lett. 2002, 43, 2823. (n) Lee, D.
H.; Lee, H. Y.; Hong, J .-I. Tetrahedron Lett. 2002, 43, 7273. (o) Kondo,
S.; Nagamine, M.; Yano, Y. Tetrahedron Lett. 2003, 44, 8801. (p)
Gunnlaugsson, T.; Kruger, P. E.; Lee. T. C.; Parkesh, R.; Pfeffer, F.
M.; Hussey, G. M. Tetrahedron Lett. 2003, 44, 6575. (q) Sansone, F.;
Chierici, E.; Casnati, A.; Ungaro, R. Org. Biomol. Chem. 2003, 1, 1802.
(4) (a) Galoppini, E.; Fox, M. A. J . Am. Chem. Soc. 1996, 118, 2299.
(b) Zhang, X.; Sun, X.-Y.; Wang, C.-J .; J iang, Y.-B. J . Phys. Chem. A
2002, 106, 5577. (c) Zhang, X.; Wang, C.-J .; Liu, L.-H.; J iang, Y.-B. J .
Phys. Chem. B 2002, 106, 12432.
(5) Otterbacher, T.; Whitmore, F. C. J . Am. Chem. Soc. 1929, 51,
1909.
(6) Karakus, S.; Rollas, S. IL. Farmaco. 2002, 57, 577.
(7) Otazo-Sa´nchez, E.; Pe´rez-Mart´ın, L.; Este´vez-Herna´ndez, O.;
Rojas-Lima, S.; Alonso-Chamarro, J . J . Chem. Soc., Perkin Trans. 2
2001, 2211.
(8) (a) Wu, F.-Y.; Li, Z.; Wen, Z.-C.; Zhou, N.; Zhao Y.-F.; J iang, Y.-
B. Org. Lett. 2002, 4, 3203. (b) Linton, B. R.; Goodman, M. S.; Fan, E.;
van Arman, S. A.; Hamilton, A. D. J . Org. Chem. 2001, 66, 7313.
6450 J . Org. Chem., Vol. 69, No. 19, 2004

N-Benzamidothioureas as Thiourea-Based Receptors
F IGURE 1. (a) Absorption spectra of 2d in acetonitrile in the presence of acetate anion and (b) plots of the absorbance of the
new band at 336 nm against anion concentration. Points in part b are experimental data and the lines through them are fitted
curves. [2d ] ) 1.0 × 10-5 mol L-1. Anions existed in their n-Bu4N+ salts.
F IGURE 2. (a) Variation trace of the absorption spectrum of 1d in acetonitrile with increasing amount of AcO- and (b) plots of
the absorbance at 276 nm versus anion concentration. Points in part b are experimental data and the lines through them are
fitted curves. [1d ] ) 1.9 × 10-5 mol L-1. Anions existed in their n-Bu4N+ salts.
the present work only several anions such as AcO-, F-,
and H2PO4- were tested. This was because these anions
of typical planar, spherical, and tetrahedral shapes,
respectively, could well be taken as model anions to
demonstrate the signal mechanism. Meanwhile, these
anions have also been extensively investigated on their
binding with the classic N,N-diarylthiourea receptors,
thereby making comparison of the N-benzamidothiourea
receptors with these N,N-diarylthiourea receptors pos-
sible.
The appearance of an isosbestic point during the
spectral titrations suggests the formation of well-defined
binding complexes between 2a -h and the tested anions
that should be responsible for the new and red-shifted
absorption band. J ob plots confirmed the 1:1 binding
stoichiometry. Similar spectral changes, however, were
not found in control experiments with thiourea-free
analogues of 2d , benzamide and benzoylhydrazine. This
suggests that the spectral changes observed with 2a -h
are due to anion binding to the thiourea moiety. A urea
counterpart of 2d, N-benzamido-N′-phenylurea, was found
to bind AcO- and H2PO4- to a much less extent than that
of 2d as seen in the absorption spectral variations. This
observation confirmed that the thiourea moiety in 2d was
the anion binding site, since it has been shown that
thiourea has a higher anion binding affinity than the
corresponding urea.8 Evidence for the hydrogen-bonding
nature of the thiourea-anion interaction was further
obtained from the 1H NMR titration of 2d by AcO- in
DMSO-d6. It was noted in Figure 3 that a new and
downfield signal at 10.82 ppm grew at the expense of the
original signals of the -NH protons appearing at 10.54,
9.82, and 9.72 ppm, respectively. Introduction of protic
solvents such as methanol into the acetonitrile solution
J . Org. Chem, Vol. 69, No. 19, 2004 6451

Nie et al.
TABLE 1. Absor p tion Sp ectr a l P a r a m eter s of Recep tor s 1 a n d 2 a n d Recep tor -An ion Bin d in g Com p lexes, a n d
Recep tor -An ion Bin d in g Con sta n ts in Aceton itr ilea
1
2
Ka,
Ka , 106 mol-1
L
max
max
λmR ax
,
λ
,
∆hν,d
λmR ax
,
λ
,
(R+AcO-
)
∆hν, d
104 mol-1
L
c
b
(R+A-
-
X
nmb
nm )
cm-1
AcO-
F-
H2PO4
nm
nmc
cm-1
AcO-
p-OC2H5
p-CH3
m-CH3
H
p-Cl
p-Br
260
268
268
266
268
268
268
268
330
334
335
336
346
346
348
435
8159
7373
7463
7823
8412
8412
8578
14325
1.71
1.84
12.1e
0.297
5.58
1.47
4.05
2.48
0.188
0.157
11.5e
0.0694
0.510
0.158
0.0562
0.685
0.0123
0.0169
32.4e
0.0053
0.0399
0.509
274
274
274
277
279
278
278
278
283
284
525
525
525
765
631
1.27
2.05
1.58
4.90
11.32
m-Cl
p-NO2
0.0900
0.138
333
425
6501
13.50
a
b
Anions existed in their n-Bu4N+ salts. Absorption maximum of the receptor. c Absorption maximum of the receptor-anion binding
complex. Anion binding induced red shift in the absorption maximum. e With high-fitting uncertainties because of the extremely large
d
binding constants.
and in most cases are at 104 mol-1 L orders of magnitude.
With the latter the highest binding constant of 1.35 ×
105 mol-1 L was observed with N-(p-nitrophenyl)-N′-
phenylthiourea (1h ), which has a strong electron-
withdrawing substituent p-NO2 at the N-phenyl ring and
therefore has thioureido -NH protons of much higher
acidity.10 It hence follows that the new N-benzamido-
thiourea receptors reported here show substantially
enhanced anion binding affinity and therefore higher
sensitivity for anion sensing than the corresponding
N-arylthiourea receptors, despite the lower acidity of
their thioureido -NH protons. The latter character would
have, in the normal sense, led to lower anion binding
affinities of the N-benzamidothiourea receptors because
of the hydrogen-bonding nature of the anion-receptor
interaction.1a,c,2 The new receptors also showed good
-
binding selectivity among anions such as AcO-, H2PO4
,
and F- that in most cases followed the order Ka(AcO-) >
Ka(F -) > Ka(H2PO4 -) (see Figure 1b and Table 1). With
2e, for example, the binding constant for AcO- is 11 and
-
140 times that for F and H2PO4-, respectively. Excep-
tions occurred with receptors 2c and 2g bearing meta-
substituent m-CH3 and m-Cl, respectively. In the case
of receptor 2c a possible reason could be its extremely
high binding constants toward anions at 107 mol-1
L
1
F IGURE 3. Portions of the H NMR spectra of 2d in DMSO-
d6 in the presence of increasing equivalents of AcO-. [2d ] )
orders of magnitude. In this case it was already hard to
fit precisely the binding constants by using the employed
nonlinear fitting procedures. However, it is still not
possible to figure out the exact reason for these exceptions
with only two sets of data.
5.0 × 10-3 mol L-1
.
of 2d plus AcO- led to a gradual recovery of the
absorption spectrum of 2d itself, again supporting the
hydrogen-bonding nature of the anion-receptor interac-
tion.
Another important feature noted in Figures 1a and 2a
and Table 1 was the unprecedented red shifts in the
absorption spectra of 2a -h in the presence of anions,
The binding constants of 2a -h with anions in aceto-
nitrile were obtained by nonlinear fitting9 of the absor-
bance of the new absorption band against anion concen-
tration (Figure 1b) and were reported in Table 1. It is
seen in Table 1 that the binding constants of 2a -h with
AcO-, for instance, are over the range of 2.97 × 105 to
from ca. 270 nm to 330-435 nm by 7 373 to 14 325 cm-1
.
Note that with most of the N-(substituted-phenyl)-N′-
phenylthioureas (1b-f, Chart 1), with which the ground-
state charge transfer (CT) did not occur in the absence
of anion, anion-binding-induced red shifts were within 5
nm around 275 nm by no more than 800 cm-1. In case of
N-(p-nitrophenyl)-N′-phenylthiourea (1h ) with which the
ground-state CT occurs the red shift in the CT absorption
upon AcO- binding was 6500 cm-1 (Figure 2 and Table
1). It should be pointed out that the spectral variations
1.21 × 107 mol-1 L and in most cases are at 106 mol-1
L
orders of magnitude, almost irrespective of the substitu-
ent at the benzamido moiety. It is significant to note that
they are 13-590 times those of the corresponding N-
(substituted-phenyl)-N′-phenylthioureas (1, Chart 1) that
range from 1.27 × 104 to 1.35 × 105 mol-1 L (Table 1)
(10) Chemical shifts of the thioureido -NH protons of N-(p-nitro-
phenyl)-N′-phenylthiourea (1h ) in DMSO-d6 were 10.01 and 9.95 ppm,
respectively, which were located at much lower field than those of
2a -h given in the Supporting Information.
(9) Valeur, B.; Pouget, J .; Bourson, J .; Kaschke, M.; Ersting, N. P.
J . Phys. Chem. 1992, 96, 6545.
6452 J . Org. Chem., Vol. 69, No. 19, 2004

N-Benzamidothioureas as Thiourea-Based Receptors
observed with 2a -h in the presence of anions also
obviously differ from that of a derivative of them bearing
a highly electron-donating substituent (X ) p-N(CH3)2).8a
With the latter its absorption spectrum in acetonitrile
was single-banded with a maximum wavelength of 312
nm, which was shifted to 328 nm by only 1563 cm-1 upon
binding to AcO-, suggesting that 2a -h did not behave
the same as this derivative.
The highly improved anion binding characters of the
new N-benzamidothiourea receptors suggested that they
might be considered a new generation of the thiourea-
based anion receptors. Inspection of the absorption
spectral data helped in understanding the novel anion
binding properties of these new receptors. It was found
that, whereas the absorption maxima of 2a -h in most
cases (2b-h ) remained at essentially the same position
of ca. 270 nm, the substantially red-shifted new absorp-
tion band of the receptor-anion binding complex was
sensitively subject to the substituent at the benzamido
phenyl ring. The absorption of the receptor-anion bind-
ing complex was found to appear at longer wavelength
when the substitutent is more electron withdrawing
(Table 1). A linear correlation was found between the
absorption energy of the binding complex and the Ham-
mett constant of the substituent (σX) with a negative slope
of -0.337 eV (2a -g: hνmax ) 3.67 - 0.337σX, γ )
-0.9800). This pointed to the CT character of the new
absorption band,4b,c,11 which means that anion binding
to the thiourea moiety in the N-benzamidothiourea
receptors 2 indeed switches on the ground-state charge
transfer. The negative slope indicates that the substitu-
ent in receptors 2 exists in the electron acceptor, i.e. the
benzoyl moiety. It was therefore made clear that anion
binding to receptors 2a -h dramatically enhanced the
dipolar character of their amide bonds so that the ground-
state CT was switched on. As a consequence, red shifts
in their absorption spectra upon anion binding by as
much as 14 325 cm-1 and substantially enhanced anion
binding affinities were observed. These should be at-
tributed to the increase in the electron-donating ability
of the electron donor upon anion binding, the N-amino-
thiourea-anion binding unit, compared to that of the
N-aminothiourea moiety. Obviously this increase is
substantially larger than that observed with N-(p-nitro-
phenyl)-N′-phenylthiourea (1h ) in which anion binding
takes place at the same thiourea moiety. The substantial
increase in the electron-donating ability of the N-amino-
thiourea moiety upon anion binding was also reflected
by the fact that even with receptor 2a bearing a moder-
ately electron-donating substituent (X ) p-OC2H5, Chart
1) at the benzamido phenyl ring of the electron acceptor
the ground-state charge transfer still took place upon
anion binding. Also, it might be reasonable to put forward
that the anion affinities of the N-benzamidothiourea
receptors were enhanced so much due to the anion-
binding-induced ground-state charge transfer that other
factors such as substituent at the benzoyl moiety became
less important, explaining thereby the observation that
the binding constants were practically independent of the
substituent (Table 1).
F IGURE 4. Chemical shifts of the -NH protons in 2a -h
versus Hammett substituent constant.
It is known that, due to the repulsion of nonpaired
electrons at the neighboring nitrogen atoms, the N-N
bond in neutral hydrazines is highly twisted12a and
therefore acts as a conjugation stopper.12b In our previous
report on a derivative of 2a -h with X ) p-N(CH3)2,8a we
proposed the existence of two five-membered intramo-
lecular ring hydrogen bonds between its amido -NH
proton and the S atom of the thiourea moiety and
between its thioureido -NH proton and the amido
carbonyl O atom, respectively. The nature of the N-N
single bond, twisted or not, in that derivative was not
discussed.8a It should be pointed out that with 2a -h
reported here such hydrogen bonds could not be excluded,
since the chemical shifts of the -NH protons in 2a -h
were similar to those of the X ) p-N(CH3)2 derivative.8a
With an extended series of derivatives in hand, however,
we found that the 1H NMR data of 2a -h did suggest that
the electronic communication of the substituent effect in
2a -h to their thiourea moiety was stopped by the N-N
bond. The chemical shifts of the -NH protons in 2a -h
were found to vary linearly with the Hammett constant
of the substituent with slopes of 0.46 for the benzamido
-NH protons whereas only of 0.10 and 0.13 for the
thioureido -NH protons, respectively (Figure 4). It was
obvious that, whereas the NMR signal of the benzamido
-NH proton was, as expected, sensitive to the substitu-
ent, those of the thioureido -NH protons showed much
weaker dependence on the substituent. Note that the
chemical shifts of the -NH protons in the X ) p-N(CH3)2
derivative of 2a -h (10.14, 9.71, and 9.57 ppm, respec-
tively)8a followed these linear correlations too, which
means that the N-N bond conformation in this molecule
is similar to that in 2a -h . With the NMR signals of the
aromatic protons (Figure 5), it was noted that, while
those of the aromatic protons (Ha and Hb) at the benzoyl
phenyl ring bearing substituent were sensitive to the
substituent, those of the other phenyl ring protons (Hc,
Hd, and He) showed essentially no response to the
presence of the substituent. It was therefore made clear
that the thiourea moiety, the anion binding site, in these
N-benzamidothiourea receptors was electronically de-
coupled from the benzoyl moiety, the signal reporter. This
should have led to a consequence that anion binding to
(11) (a) Kosower, E. M. Acc. Chem. Res. 1982, 15, 259. (b) Reichardt,
C. Solvents and Solvent Effects in Organic Solvents, 2nd ed.; VCH:
Weinheim, Germany, 1990; p 343. (c) Huang, W.; Zhang, X.; Ma, L.-
H.; Wang, C.-J .; J iang, Y.-B. Chem. Phys. Lett. 2002, 352, 401.
(12) (a) Nelsen S. F.; Pladziewicz, J . R. Acc. Chem. Res. 2002, 35,
247. (b) Lewis, M.; Glaser, R. J . Org. Chem. 2002, 67, 1441.
J . Org. Chem, Vol. 69, No. 19, 2004 6453

Nie et al.
novel anion sensors capable of naked-eye detection of
current interest1 that require not only large absorbance
change but also large color change as well during binding
to anion, and probably will also be of use in designing
electrochemical sensors of improved performance.
Although the designing principle reported here was
shown in an organic solvent, work is underway to extend
this principle to anion receptors operative in aqueous
solutions of practical use. Our preliminary understanding
on the anion binding mechanism has actually helped to
find possible structural modification to reach new N-
benzamidothiourea receptors that show anion binding
capacity at least in water-containing organic solvents. For
example, we found that N-(p-ethoxybenzamido)-N′-(p-
nitrophenyl)thiourea in acetonitrile containing 10% water
by volume showed a sensitive and selective binding to
AcO- with a binding constant of 1.74 × 105 mol-1 L that
is even higher than that of N-phenyl-N′-(p-nitrophenyl)-
thiourea (1h ) for binding AcO- in pure acetonitrile (Table
1). Investigations are continuing to figure out the meth-
ods of structural modifications to achieve better N-
benzamidothiourea-based receptors for aqueous solution
use and to design related receptors with electrochemical
signaling capacity.
F IGURE 5. Chemical shifts of the aromatic protons as a
function of the para substituent (X).
the thiourea moiety of these N-benzamidothiourea recep-
tors would result in no or minor change in the absorption
of the benzamide chromophore. Actually it was found that
anion binding to 2a -h switched on the ground-state
charge transfer, suggesting that a structural change
around the N-N bond took place that established the
electronic communication through the N-N bond and
hence allowed for the occurrence of the ground-state
charge transfer.13 The electron donor therefore actually
varied from the benzamido -NH group before anion
binding to -NH plus the thiourea-anion binding unit
after anion binding. This accounts for the enlarged
increment in the electron-donor strength compared to
that observed with N-(p-nitrophenyl)-N′-phenylthiourea
(1h ) whose electron donor varied from thiourea to the
thiourea-anion binding unit.
Exp er im en ta l Section
Chemicals used for synthesis were market available of AR
grade. Solvents such as acetonitrile and methanol used for
spectral investigations were further purified by distillation and
checked to have no impurity. Tetrabutylammonium salts of
anions were prepared from neutralization reactions of tet-
rabutylammonium hydroxide and the corresponding acids and
were purified by recrystallization from ethyl acetate. N-
(Substituted-phenyl)-N′-pheylthioureas (1) were either market
available or known molecules prepared in one step according
to a reported method5 by reaction of substituted anilines with
phenylisothiocyanate in ethanol.
Con clu sion s
N-Alkyl and N-aryl thioureas have long been employed
as binding moiety in anion receptors since the early stage
of anion recognition and sensing research. N-Aminothio-
ureas, however, receive much less attention.8a Reported
in this article are a family of simple N-aminothiourea
based anion receptors, N-(substituted-benzamido)-N′-
phenylthioureas with substituents ranging from electron
withdrawing to moderately electron donating. These
receptors showed unprecedented red shifts in their
absorption spectra by as much as 14 325 cm-1 upon anion
binding and substantially enhanced anion affinities. This
is significant since (i) the thioureido -NH acidity in these
N-benzamidothiourea receptors is not higher than that
in the corresponding N-phenylthiourea counterparts,
which should have led to lower binding affinities of the
new receptors because of the hydrogen-bonding nature
of the receptor-anion interaction, and (ii) the thiourea
anion-binding site in these N-benzamidothiourea recep-
tors is electronically decoupled from the chromophore by
the N-N single bond that would have been expected to
produce no or minor response of the receptors toward
anion binding to their thiourea moiety. A structural
change around the N-N bond upon anion binding was
suggested, which led to an unprecedented increase in the
electron-donating ability of the N-amidothiourea moiety.
As a consequence, the ground-state charge transfer
occurs that accounts for the unprecedented red shifts in
the absorption spectra and the substantially enhanced
anion binding affinities. The N-benzamidothiourea struc-
tural framework could therefore be useful in constructing
Gen er a l P r oced u r es for P r ep a r in g N-(Su bstitu ted -
ben za m id o)-N′-p h en ylth iou r ea s (2). 2 was synthesized in
three steps6 starting from substituted-benzoic acid. Ethyl
benzoate was first prepared by esterification of substituted-
benzoic acid in refluxing ethanol in the presence of concen-
trated H2SO4. This benzoate was then reacted with aqueous
hydrazine (50%) in ethanol under refluxing for 3 h to afford
substituted-benzoylhydrazine, which was finally reacted in
ethanol at room temperature with phenyl isothiocyanate until
TLC showed the completion of the reaction. The as-obtained
products were purified by repeated recrystallizations from
ethanol. Compounds 2a -h were fully characterized and the
detailed spectral data were supplied in the Supporting Infor-
mation.
Ack n ow led gm en t. The support received from the
National Natural Science Foundation of China
(20175020), the Natural Science Foundation of Fujian
Province (D0220001), the Ministry of Education (MOE)
of China (TRAPOYT program), and VolkswagenStiftung
(I/77 072) are gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: General description
for acquiring spectra and detailed spectral data for charac-
terization of compounds 2a -h (1H and 13C NMR, HRMS, and
elemental analysis data). This material is available free of
charge via the Internet at http://pubs.acs.org.
(13) Rurack, K.; Resch-Genger, U. Chem. Soc. Rev. 2002, 31, 116.
6454 J . Org. Chem., Vol. 69, No. 19, 2004
J O049088F