(Benzylideneamino)thioureas - Chromogenic interactions with anions and N-H deprotonation

Article abstract of DOI:10.1002/ejoc.200600388

A family of neutral N-(R¹-substituted-benzylideneamino)- N′-(R²-substituted-phenyl)thioureas (LH) were designed as anion receptors, and their interactions with anions in MeCN solution were investigated through spectrophotometric and

Full text of DOI:10.1002/ejoc.200600388

FULL PAPER
DOI: 10.1002/ejoc.200600388
(Benzylideneamino)thioureas – Chromogenic Interactions with Anions and
N–H Deprotonation
Marco Bonizzoni,[a] Luigi Fabbrizzi,*[a] Angelo Taglietti,[a] and Federico Tiengo[a]
Keywords: Anion recognition / Hydrogen bonding / Thiourea / Colorimetric sensors
A family of neutral N-(R1-substituted-benzylideneamino)-NЈ-
(R2-substituted-phenyl)thioureas (LH) were designed as
anion receptors, and their interactions with anions in MeCN
solution were investigated through spectrophotometric and
1H NMR titration experiments. While oxo anions (e.g.,
CH3COO–, H2PO4–) form genuine H-bond complexes based
on complementary N–H···O interactions with LH receptors,
the fluoride ion undergoes a two-step interaction, involving
(i) formation of the [LH···F]– complex, and (ii) release of an
HF molecule to give [HF2]– and the deprotonated form of the
receptor (L–). Deprotonation takes place at the N–H fragment
closer to the R2-substituted phenyl ring, as indicated by 1H
NMR spectroscopy. The logK values for the formation of the
[LH···CH3COO]– H-bond complexes vary over the 3.1–3.8
range and are scarcely affected by the natures of the R1 and
R2 substituents. The investigated systems may be of interest
in the design of molecular devices in which the optical prop-
erties of different and distant substituents are modulated
through the interaction of a chosen anion at the thiourea site.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
viding an efficient channel for qualitative and quantitative
evaluation of anion activity in solution.[9,10]
Introduction
Ureas and thioureas participate in bifurcate H-bond in-
teractions and are currently finding use as binding frag-
ments in the design of neutral receptors for anions.[1] Hy-
drogen bonding has been defined as a more advanced or
less advanced (and “frozen”) proton transfer from the do-
nor (the receptor) to the acceptor (the anion).[2] For this
reason, the more acidic thiourea fragment (pKA = 21.1 in
DMSO)[3] typically produces stronger interactions with
anions than urea (pKA = 26.9).[3] In limiting situations,
urea- and thiourea-based receptors, on interaction with
strongly basic anions, may undergo deprotonation of one
N–H fragment. In the presence of an excess of fluoride ion
this is rather common behavior, due to the formation of the
Here we report a new class of thiourea-based receptors
1 that can be easily obtained through Schiff-base condensa-
tion of a benzaldehyde and a phenylthiosemicarbazide, all
cheap and commercially available products. The receptor
consists of a phenylthiourea subunit, suitable to interact
with the anion, covalently linked to a benzylideneamino
moiety, intended to act as a chromogenic signaling unit. We
have investigated the interaction of anions with (benzyl-
ideneamino)thioureas 1a–f in MeCN solution in detail,
through spectroscopic titration experiments. In particular,
we have tried to answer the following questions: (i) Does
an N–H fragment of the receptor deprotonate in the pres-
ence of more basic anions, in particular fluoride? (ii) If yes,
which one of the two N–H fragments deprotonates, that
bound to the imino nitrogen atom or that bound to the
phenyl carbon atom? (iii) To what extent do the R1 and
R2 substituents influence these processes and modulate the
spectral behavior and the color changes?
–
particularly stable HF2 hydrogen-bonding self com-
plex.[4–7] In recent years, moreover, a variety of thiourea-
based receptors have been modified with chromogenic and
fluorogenic substituents to produce chemosensors: molecu-
lar systems capable of communicating the occurrence of the
recognition event to the outside world through an optical
signal (a color change, modulation of the fluorescent emis-
sion).[8] In the case of colorimetric chemosensors, the inter-
action with the anion typically stabilizes the excited state of
the chromophore and induces a greater or lesser degree of
redshift of the charge transfer absorption band, thus pro-
[a] Dipartimento di Chimica Generale, Università di Pavia
Via Taramelli 12, 27100 Pavia, Italy
Fax: +39-0382-528544
E-mail: luigi.fabbrizzi@unipv.it
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M. Bonizzoni, L. Fabbrizzi, A. Taglietti, F. Tiengo
FULL PAPER
It should be noted that structurally related benzami-
dothioureas of type 2 have recently been shown to be versa-
tile colorimetric chemosensors for anions, giving significant
redshifts of the charge-transfer absorption band – distinctly
more pronounced than in the case of simple thioureas – on
– [11]
interaction with F–, CH3COO–, and H2PO4 .
Figure 2. Family of spectra recorded over the course of the titration
of an MeCN solution (5.00·10–5  in 1c) with a standard solution
of [Bu4N]OH at 25 °C. Inset: titration profile of the band centered
at 500 nm, corresponding to the deprotonated form of the (benzyl-
ideneamino)thiourea receptor.
Results and Discussion
Structures of (Benzylideneamino)thioureas
The crystal structure of 1g has been reported.[12] Figure 1
shows the molecular structure of the compound, as ob-
tained from the Cambridge Data Base.
It can be observed that, on hydroxide addition, the band
centered at 350 nm, specific to the derivative 1c and attrib-
utable to a charge-transfer transition from the imino nitro-
gen atom to the nitro group within the benzylideneamino
moiety, progressively disappears, while a new band develops
at 500 nm. This band reaches a limiting absorbance
(20000 –1 cm–1) on addition of 1 equiv. of OH–, as indi-
cated by the titration profile shown in the inset of Figure 2.
The presence of sharp isosbestic points indicates that only
two species are present at equilibrium over the course of
the titration experiment, which suggests that an acid-base
neutralization equilibrium takes place, involving the depro-
tonation of one N–H group of the thiourea subunit, as de-
scribed in Equation (1).
Figure 1. Molecular structure of 1g, as obtained from X-ray dif-
fraction studies on a single crystal.[12] The arrangement of the thio-
urea fragment may be stabilized by an H-bond interaction between
one N–H group and the imino nitrogen atom.
LH + OH– p L– + H2O
(1)
Two structural features are noteworthy: (i) the urea frag-
ment lies in the same plane as the benzylideneamino sub-
unit, whereas the phenyl substituent lies on a plane rotated
by ca. 40°, and (ii) the bulky substituents at the C=N
double bonds are (E) to each other. The arrangement of
the thiourea moiety favors the establishment of a hydrogen-
bonding interaction between the N–H fragment linked to
the phenyl substituent and the imino nitrogen atom. It is
tentatively assumed that the analogous derivatives 1a–f have
similar structures, and that these are maintained in MeCN
solution.
The band centered at 500 nm should therefore represent
the deprotonated form of receptor 1c (= LH). In particular,
the negative charge made available on proton release causes
an increase in the intensity of the electrical dipole along
which the optical transition takes place, which accounts for
the substantial redshift of the band (150 nm). Note that the
steepness of the titration profile, as well as the absence of
any curvature at the equivalent point, prevent any reliable
determination of the neutralization equilibrium constant
according to Equation (1), the value of which can only be
estimated (K Ͼ 107).
Semiempirical calculations (PM3 method) on LH and L–
molecular systems confirmed the charge-transfer nature of
the optical transition. Figure 3 shows the HOMOs and
Reaction with OH–
In order to establish the acid-base behavior of derivatives LUMOs of the LH and L– forms of 1c.
1a–f, we preliminarily carried out titration experiments with
It can be observed both for LH and for L– that the elec-
[Bu4N]OH. On addition of hydroxide, the colors of MeCN tron density in the HOMO is essentially centered on the
solutions of the (benzylideneamino)thiourea receptors thiourea sulfur atom, whereas in the LUMO it is mainly
turned from yellow to varying shades of red. Figure 2 shows located on the benzylidene ring. However, delocalization
the family of spectra obtained over the course of the ti- towards the –NO2 group is distinctly more pronounced in
tration of a solution of 1c (5.00·10–5 ) with [Bu4N]OH at the L– form, which accounts for the marked redshift of the
25 °C.
absorption band.
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(Benzylideneamino)thioureas
FULL PAPER
Figure 3. HOMOs and LUMOs of the LH and L– forms of 1c,
calculated by the PM3 method.
Wholly similar behavior – (i) development of an intense
absorption band in the visible region, (ii) achievement of
the limiting absorbance on addition of 1 equiv. of OH–, and
(iii) steep titration profiles that prevented the determination
of the equilibrium constants according to Equation (1) –
was observed on spectrophotometric titration of all the
other derivatives of type 1. The positions of the bands of
LH and L– and the magnitudes of the redshifts varied de-
pending upon the nature of the substituents R1 and R2, as
shown in Table 1.
Figure 4. 1H NMR titration of a 5.00·10–3  solution of 1c in
CD3CN with [Bu4N]OH.
Table 1. Spectral parameters of the neutral (LH) and deprotonated
(L–) forms of receptors 1a–f, determined at 25 °C in MeCN solu-
tion.
R1
R2
LH, λmax [nm] L–, λmax [nm] λ [nm]
1
LH
It was anticipated that the H NMR pattern would indi-
cate that the deprotonation process would take place at the
N–H fragment closer to the phenyl group (labeled with a
star) and that, on deprotonation, the molecule would as-
sume the structural arrangement sketched in the formula
in Figure 4. Before examining the spectroscopic features in
detail, one should consider that two effects would be ex-
pected to result from the deprotonation of one N–H frag-
1a
1b
1c
1d
1e
1f
H
H
NO2
NO2
CF3
CF3
H
OCH3
H
OCH3
H
320
314
360
360
320
324
382
386
500
508
410
410
62
72
140
148
90
OCH3
86
Significant substituent effects on spectral properties are ment: (i) an increase in electron density in the phenyl rings,
observed only for R1 = –NO2, which ensures absorption by through-bond propagation, according to a π-mecha-
bands of relatively low energy for both LH and L– forms nism, which should cause a shielding effect and promote an
and a pronounced redshift (up to 148 nm when R2
=
upfield shift of the C–H signals, and (ii) a polarization of
–OCH3), which may be due to the particular capability of the C–H bonds, induced by a through-space effect, of an
the nitro group to withdraw electrons through π-conjuga- electrostatic nature; in particular, the partial positive charge
tion. Moderate redshifts are observed when R1 = –CF3 shifted onto the proton should cause a deshielding effect
or –H.
and promote a downfield shift. This electrostatic effect
At this stage it seemed important to characterize the should be stronger for protons close to the negatively
structural details of the deprotonation process and, hope- charged thiourea nitrogen atom and should vanish with in-
fully, to define and localize the acidic site. Useful insights in creasing CH···N– distance. It can be observed in Figure 4
this sense were provided by 1H NMR titration experiments: that C–Him and C–Ho proton signals experience downfield
Figure 4 shows a family of 1H NMR spectra taken over the shifts, whereas the signals of all the other aromatic protons
course of a titration of a CD3CN solution of 1c with undergo greater or lesser degrees of upfield shifts.
[Bu4N]OH and illustrates the spectral shifts of the C–H
The variation in the different chemical shifts ∆δ (ppm)
protons induced by base addition.
over the course of the titration is shown in Figure 5.
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M. Bonizzoni, L. Fabbrizzi, A. Taglietti, F. Tiengo
FULL PAPER
form of the receptor, reaches its limiting value on addition
of 2 equiv. of anion [see the titration profile shown in inset
(a) of Figure 6].
Figure 5. Chemical shift values obtained from the 1H NMR ti-
tration in Figure 4.
A negative charge on the N* atom accounts for a domi-
nating electrostatic effect on the nearby Ho atom, responsi-
ble for the downfield shift. Moreover, partial negative
charge is delocalized onto the thiourea sulfur atom through
a π-mechanism, which exerts a rather strong electrostatic
effect on the Him atom and induces an overwhelming down-
field shift. In the cases of all the other C–H protons the
through-space effect vanishes, due to the increased dis-
tances, and the through-bond effect dominates, which in-
duces a general upfield shift. Such an effect is more pro-
nounced for protons on the phenyl ring linked to the N*
atom, in particular the Hp atom, onto which a larger
amount of negative charge is transferred through a π-reso-
Figure 6. Family of spectra taken in the course of the titration of
an MeCN solution (5.00·10–5  in 1c) with a standard solution of
[Bu4N]F at 25 °C. Inset (a): titration profile of the band centered
at 500 nm. Inset (b): titration profile of the band centered at
500 nm for a titration experiment in which [Bu4N]F was added to
an MeCN solution (5.00·10–5  both in 1c and in CF3SO3H).
This indicates the occurrence of the following overall
equilibrium (LH = 1c) [Equation (2)], in which a proton is
abstracted from one of the N–H fragments of the (benzyl-
ideneamino)thiourea receptor and bridges two F– ions, to
give the hydrogen difluoride H-bond self complex.
–
nance mechanism. The through-bond effect and the conse- LH + 2 F– p L– + HF2
(2)
quent downfield shift are less marked for hydrogen atoms
Significant details concerning the fluoride-induced de-
protonation process were obtained through 1H NMR ti-
tration; Figure 7 shows the spectra obtained over the course
of the titration of a CD3CN solution of 1c with [Bu4N]F.
The spectroscopic pattern is very similar to that observed
in the titration with OH–. In particular, Ho and Him signals
are shifted downfield, whereas all the other signals of the
aromatic protons undergo greater or lesser degrees of up-
field shift.
It should be noted, however, that the shift of the C–Him
proton on addition of the first equivalent of fluoride is dis-
tinctly more pronounced than that observed on addition
of OH–. Moreover, the titration profile shown in Figure 8
indicates that a limiting value of ∆δ(Him) is reached on ad-
dition of 1 equiv. of F–.
Ha and Hb on the other, more distant aromatic ring. It
should be noted that extended π-delocalization implies that
on N*–H deprotonation the phenyl ring becomes coplanar
with the rest of the molecular framework. We suggest that
it is solely the favorable energy term associated with the
coplanarization of the phenyl ring that determines the de-
protonation of the N*–H group. Such a contribution could
not be observed on deprotonation of the No–H fragment,
as the adjoining benzylideneamino system is already copla-
nar with the thiourea moiety.
On a purely spectroscopic basis, the deprotonation of the
No–H fragment must be excluded because this circumstance
(i) would not be compatible with the prominent downfield
shift of the Ho signal, and (ii) would not account for the
more pronounced upfield shift experienced by Hp and Hm
signals relative to Ha and Hb signals.
This suggests that, in the first step, the fluoride ion estab-
lishes a hydrogen-bonding interaction with a thiourea sub-
unit of the receptor, which, on complexation, should be ar-
ranged as illustrated in the formula in Scheme 1. In this
situation, the H-bound anion may exert an effective electro-
Interaction with Fluoride
Similar spectrophotometric behavior was observed on ti- static effect on the nearby Him proton, inducing significant
tration with fluoride; Figure 5 shows the family of spectra deshielding and a downfield shift. Then, on addition of the
obtained over the course of the titration of a solution of 1c second F– ion, an HF molecule is released from the H-bond
with [Bu4]NF. The spectral pattern is the same as observed complex, with formation of the [HF2]– self complex and of
in Figure 2, the only difference being that the absorption the deprotonated receptor. The two stepwise equilibria are
band centered at 500 nm, representing the deprotonated described by Equations (3) and (4).
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(Benzylideneamino)thioureas
FULL PAPER
pears to be much more sensitive than the spectrophotomet-
ric investigation for the characterization of the receptor-
fluoride H-bond complex. Moreover, it should be noted
that the interaction of 1c with hydroxide and fluoride in-
volves conformational changes of the receptor, as inferred
from spectroscopic studies and illustrated in Scheme 1.
Scheme 1. The interaction of receptor 1c with OH– (single step)
Figure 7. 1H NMR titration of
a CD3CN solution of 1c
and F– (two steps).
(5.00·10–3 ) with fluoride.
In conclusion, it appears that the strong base OH– di-
rectly takes up a proton from LH, whilst the F– ion is not
basic enough to abstract a proton and preliminarily forms
an H-bond complex. On addition of a second F–, however,
the very stable [HF2]– species can form and the receptor
may undergo deprotonatation. Thus, although one F– is not
an especially strong base, two F– ions are. Similar spectro-
scopic behavior was observed for all the other investigated
(benzylideneamino)thiourea receptors.
We also carried out an additional experiment that con-
firmed the higher affinity of fluoride towards HF than
towards urea-based receptors of type 1. In particular, an
MeCN solution (5.00·10–5  both in 1c and in triflic acid)
was titrated with fluoride and UV/Vis spectra were re-
corded. No spectral changes were observed on addition of
the first 2 equiv. of F–, whilst after 2 equiv., the band at
500 nm formed and developed to reach its limiting ab-
sorbance value on addition of 4 equiv. of fluoride. The ti-
tration profile, based on the absorbance at 500 nm, is shown
in Figure 5, inset (b). The profile clearly indicates that the
first equiv. of F– reacts with H+ to give HF, and that the
second equiv. of F–, in the presence of the two neutral re-
ceptors HF and LH (= 1c), then reacts with this to give the
[HF2]– complex. On further addition, fluoride goes on to
interact with LH according to Equations (3) and (4), as de-
scribed previously.
Figure 8. Chemical shift values obtained from the 1H NMR ti-
tration in Figure 7.
LH + F– p [LH···F]–
(3)
(4)
[LH···F]– + F–– p L– + [HF2]–
The formation of the H-bond complex could not be de-
tected by spectrophotometric titration experiments, as
[LH···F]– and L– exhibit the same or very similar absorp-
tion spectra. In fact, the hydrogen-bonding interaction can
be regarded as an either more pronounced or less pro-
nounced proton transfer from the donor (the receptor) to
the acceptor (the anion).[2] In the case of the basic fluoride
ion, the proton transfer should be at a rather advanced
state, which would account for a substantial increase in the
negative charge on the thiourea nitrogen atom and a conse-
Interaction with Oxo Anions
Figure 9 shows the family of spectra obtained over the
quent modification of the dipole through which the optical course of the titration of a 5.00·10–5  solution of 1c in
1
transition takes place. The H NMR experiment thus ap- MeCN with [Bu4N]CH3COO.
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M. Bonizzoni, L. Fabbrizzi, A. Taglietti, F. Tiengo
FULL PAPER
displays the spectra obtained over the course of the titration
of a CD3CN solution of 1c with [Bu4N]CH3COO.
Spectra observed on titration with OH– and with F–
show similar features, such as downfield shifts of Ho and
H
im signals and upfield shift of the signals of the other aro-
matic protons. However, two main differences are observed:
(i) chemical shifts are less pronounced, and (ii) most signals
undergo pronounced broadening. Such features may be in-
dicative of the formation of a discrete H-bond complex,
[LH···CH3COO]–, the formula of which is indicated as 3.
Figure 9. Family of spectra taken over the course of the titration
of an MeCN solution of 1c (5·10–5 ) with a standard solution of
[Bu4N]CH3COO at 25 °C. Inset: titration profile of the band cen-
tered at 500 nm.
The spectral features are the same as observed on ti-
tration with hydroxide and fluoride anions: a decrease in
the band at 350 nm and the development of a band at
500 nm with a limiting absorbance of 20000 –1 cm–1. Best
fitting of spectrophotometric data was achieved on as-
suming the occurrence of a 1:1 equilibrium, with a corre-
sponding logK = 3.62 0.01. Spectrophotometric investiga-
tion by itself, however, cannot tell us whether the equilib-
rium involves the formation of a genuine [LH···CH3COO]–
complex or the deprotonation of LH, but such information
In particular, complex formation slows down the rotation
of the two aromatic rings, which causes line broadening.
This effect is more pronounced for protons on the phenyl
ring directly bound to the thioureido nitrogen atom, which
is closer to the H-bound acetate. In any case, after the hy-
drogen-bonding interaction with CH3COO–, negative
charge is transferred onto the receptor framework, which
accounts for the distinct shifts of the C–H protons. More-
over, transfer of negative charge onto the receptor frame-
work modifies the dipole along which the optical transition
takes place to the same extent as observed in the case of
LH deprotonation, which results in a completely similar
change of spectral features. If the hydrogen-bonding inter-
action is considered an incipient proton transfer from the
1
has been provided by the H NMR experiment. Figure 10
–
donor (e.g., –N–H) to the acceptor (e.g. O–), these results
would suggest that the proton transfer is in a rather ad-
vanced state in the case of the strongly basic CH3COO–
anion, and that the electronic properties of the receptor in
the acetate complex are very similar to those of its depro-
tonated form.
Similar behavior was observed for all the other investi-
gated receptors of type 1. Table 2 reports the equilibrium
constants for the formation of H-bond complexes of
CH3COO– with systems 1a–f, determined through spectro-
photometric titration experiments.
The values given in Table 2 indicate that R1 and R2 sub-
stituents play only a minor role in determining the H-bond
donor tendencies of the receptor. In fact, it can be seen that,
taking 1a (R1 = R2 = H) as a reference, the presence of an
electron-withdrawing group (–NO2, –CF3) in the R1 posi-
tion induces an increase of Յ0.3 in logK, while the presence
of the electron-donating group –OCH3 in R2 causes a de-
crease of Ϸ0.3 in logK.
On addition of the tetrabutylammonium salts of other
common inorganic anions to MeCN solutions of 1c, dis-
tinctive spectral changes were observed only in the case of
Figure 10. 1H NMR titration of a solution of 1c in CD3CN
(5.00·10–3 ) with [Bu4N]CH3COO.
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(Benzylideneamino)thioureas
FULL PAPER
Table 2. Constants of the complexation equilibrium LH
+
successful competition from the medium (e.g., water), does
not favor analytical applications. However, we believe that
systems of type 1 may be of interest for the design of molec-
ular devices possessing optical properties that can be con-
trolled and modulated through a chemical input. In particu-
lar, systems such as 1 provide the potential for independent
and inequivalent functionalization at the two distant sites
R1 and R2 (e.g. with chromogenic and/or fluorogenic sub-
stituents), while the thiourea fragment may act as a control
unit (to be activated through the interaction with a chosen
anion). Preliminary investigations in this prospect are cur-
rently in progress in this laboratory.
CH3COO– p [LH···CH3COO]– in an MeCN solution at 25 °C. In
parentheses, standard deviations in the last figure.
LH
R1
R2
logK
1a
1b
1c
1d
1e
1f
H
H
NO2
NO2
CF3
CF3
H
OCH3
H
OCH3
H
3.38(4)
3.12(1)
3.62(1)
3.75(1)
3.77(1)
3.09(1)
OCH3
–
H2PO4 , which produced a family of spectra very similar to
1
that obtained on titration with acetate. In addition, the H
NMR spectra were also very similar to those obtained in
the titration with acetate, which suggested the formation of
a genuine H-bond complex, the association constant of
which, determined from a spectrophotometric titration, was
Experimental Section
Materials: 4-[4-(Methoxy)phenyl]-3-thiosemicarbazide was pur-
chased from Trans World Chemicals. MeCN, MeOH, 4-phenyl-3-
thiosemicarbazide, all aldehydes, and tetraalkylammonium salts of
anions (the counterion was Bu4N+ for all anions except for chlo-
ride, for which BzEt3N+ was used) were purchased from Sigma–
Aldrich Chemical Co. Commercial reagents were used without fur-
ther purification. 1H and 13C NMR spectra were recorded with
a Bruker AMX 400 (400 MHz) spectrometer; chemical shifts are
reported in ppm downfield from TMS. Mass spectra were obtained
with a Thermo Finnigan LCQ Advantage Max spectrometer fitted
with an ESI source and an ion trap. UV/Vis spectra were taken
with either a diode-array Hewlett–Packard 8452A or a scanning
Varian Cary 100 Scan spectrophotometer.
–
–
3.34 0.05 log units. No other anion (HSO4 , NO3 , Cl–,
Br–) induced any detectable spectral change in a 5.00·10–5

solution of 1c, even if added in large excess. Such lack of
interaction has to be attributed to the poor basicity of the
anions and confirms that the selectivity of thiourea-based
receptors (in the absence of designed steric constraints) is
strictly related to the pKA value of HA, the conjugated acid
of the anion A–.
Conclusions
General Procedures for Preparing 1-(4-Substituted-benzylidene)-4-
(4-substituted-phenyl)thiosemicarbazides
1:
Equal
amounts
We report a new family of (benzylideneamino)thiourea
receptors, suitable for interaction with anions in aprotic me-
dia. The benzylidene derivative acts as an efficient chromo-
phore, characterized by a charge-transfer transition, the en-
ergy of which is strongly influenced by the interaction with
(0.30 mmol) of the appropriate aldehyde and thiosemicarbazide
were dissolved in MeOH (20 mL). A solution was obtained, which
was stirred overnight. Compounds 1a, 1b, 1c, and 1d precipitated as
microcrystalline solids, which were collected by suction filtration,
washed with MeOH, and dried in vacuo. When precipitation did
not spontaneously occur (1e, 1f), the solution was concentrated by
rotary evaporation until a substantial quantity of precipitate had
formed, and this was collected by filtration, washed with cold
MeOH, and dried under vacuum. In general, yields were not very
high (mostly around 40%), presumably because of poor product
recovery inherent in the workup methods presented; nonetheless,
they were considered acceptable, in view of the high purity (verified
through MS and NMR analyses) and ease of synthesis of the re-
sulting compounds.
the anion: in the most favorable case (R1 = NO2; R2
=
OCH3) a ∆λ value of 148 nm was observed. The natures of
the receptor–anion interactions were unambiguously de-
fined, whether (a) an acid-base neutralization process (with
OH–), (b) formation of an H-bond complex followed by
receptor’s deprotonation (with F–), or (c) H-bond complex
–
formation (with CH3COO– and H2PO4 ) occurred. The sys-
tems investigated here are structurally similar to the pre-
viously studied systems 2,[11] in which the benzamido moi-
ety is expected to increase the receptor’s acidity, relative to
the benzylideneamino subunit of 1. Indeed, to point to a
comparative example, the unsubstituted receptor 2 (R = H)
forms an H-bond complex with acetate (logK = 5.47 in
MeCN) distinctly more stable than its unsubstituted coun-
terpart 1 (1a: logK = 3.38). However, in spite of the in-
creased Brønsted acidity of the receptor 2, the possibility
of fluoride-induced N–H deprotonation was not considered
by the authors.[11]
1
1-Benzylidene-4-phenylthiosemicarbazide (1a): H NMR: δ = 11.84
(br. s, 1 H, NH), 10.13 (br. s, 1 H, NH), 8.16 (s, 1 H, CH=N),
7.919–7.985 (m, 2 H), 7.565 (d, J = 7.6 Hz, 2 H), 7.435–7.420 (m,
3 H), 7.373 (t, J = 7.6 Hz, 2 H), 7.210 (t, J = 8.5 Hz, 1 H) ppm.
ESI-MS: m/z = 256.4 [M+H]+.
1-Benzylidene-4-(4-methoxyphenyl)thiosemicarbazide
(1b):
1H
NMR: δ = 11.76 (br. s, 1 H, NH), 10.22 (br. s, 1 H, NH), 8.14 (s,
1 H, CH=N), 7.90 (dd, J1 = 6.6, J2 = 2.6 Hz, 2 H), 7.43–7.38 (m,
5 H), 6.93 (d, J = 8.8 Hz, 2 H), 3.77 (s, 3 H, OCH3) ppm. ESI-MS:
m/z (%) = 320.4 (100), 322.4 (33) [M+Cl]–, 286.4 (70) [M+H]+.
Systems of type 1 add to the broad family of neutral
colorimetric sensors for anions, although, like all such re-
ceptors containing a single urea or thiourea subunit, they
display a selectivity related solely to the anion basicity.
Moreover, the fact that recognition studies unavoidably
1
1-(4-Nitrobenzylidene)-4-phenylthiosemicarbazide (1c): H NMR: δ
= 12.11 (br. s, 1 H, NH), 10.34 (br. s, 1 H, NH), 8.25 (d, J = 9.0 Hz,
2 H), 8.23 (s, 1 H, CH=N), 8.20 (d, J = 9.0 Hz, 2 H), 7.54 (d, J =
7.3 Hz, 2 H), 7.40 (t, J = 7.9 Hz, 2 H), 7.24 (t, J = 7.3 Hz, 1 H)
ppm. ESI-MS: m/z (%) = 335.1 (100), 337.1 (33) [M+Cl]–, 301.1
have to be carried out in aprotic solvents, in order to avoid (50) [M+H]+.
Eur. J. Org. Chem. 2006, 3567–3574
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3573

M. Bonizzoni, L. Fabbrizzi, A. Taglietti, F. Tiengo
FULL PAPER
[2]
[3]
[4]
T. Steiner, Angew. Chem. Int. Ed. 2002, 41, 48–76.
F. G. Bordwell, Acc. Chem. Res. 1988, 21, 456–463.
1-(4-Nitrobenzylidene)-4-(4-methoxyphenyl)thiosemicarbazide (1d):
1H NMR: δ = 12.03 (s, 1 H, NH), 10.24 (s, 1 H, NH), 8.24 (d, J =
8.8 Hz, 2 H), 8.22 (s, 1 H, CH=N), 8.19 (d, J = 9.1 Hz, 2 H), 7.38
(s, J = 8.8 Hz, 2 H), 6.95 (d, J = 9.1 Hz, 2 H), 3.77 (s, 3 H, OCH3)
ppm. ESI-MS: m/z = 331.0 [M+H]+.
M. Boiocchi, L. Del Boca, D. Esteban-Gómez, L. Fabbrizzi,
M. Licchelli, E. Monzani, J. Am. Chem. Soc. 2004, 126, 16507.
M. Boiocchi, L. Del Boca, D. Esteban-Gómez, L. Fabbrizzi,
M. Licchelli, E. Monzani, Chem. Eur. J. 2005, 11, 3097.
D. Esteban-Gómez, L. Fabbrizzi, M. Licchelli, J. Org. Chem.
2005, 70, 5717–5720.
[5]
[6]
[7]
[8]
1-[4-(Trifluoromethyl)benzylidene]-4-phenylthiosemicarbazide (1e):
1H NMR: δ = 12.07 (br. s, 1 H, NH), 10.33 (br. s, 1 H, NH), 8.21
(s, 1 H, CH=N), 8.14 (d, J = 8.0 Hz, 2 H), 7.77 (d, J = 8.4 Hz, 2
H), 7.54 (d, J = 8.0 Hz, 2 H), 7.39 (t, 2 H, 7.8 Hz), 7.23 (t, J =
7.4 Hz, 1 H) ppm. ESI-MS: m/z = 324.1 [M+H]+.
V. Amendola, D. Esteban-Gómez, L. Fabbrizzi, M. Licchelli,
Acc. Chem. Res. 2006, 39, 343–353.
a) S. Nishizawa, P. Buhlmann, M. Iwao, Y. Umezawa, Tetrahe-
dron Lett. 1995, 36, 6483; b) S. Nishizawa, R. Kato, T. Hayash-
ita, N. Teramae, Anal. Sci. 1998, 14, 595; c) K. P. Xiao, P.
Buhlmann, Y. Umezawa, Anal. Chem. 1999, 71, 1183; d) J. L. J.
Blanco, J. M. Benito, C. O. Mellet, J. M. G. Fernández, Org.
Lett. 1999, 1, 1217; e) T. Hayashita, T. Onodera, R. Kato, S.
Nishizawa, N. Teramae, Chem. Commun. 2000, 755; f) T. Toz-
awa, Y. Misawa, S. Tokita, Y. Kubo, Tetrahedron Lett. 2000,
41, 5219; g) R. Kato, S. Nishizawa, T. Hayashita, N. Teramae,
Tetrahedron Lett. 2001, 42, 5053; h) T. Gunnlaugsson, A. P.
Davis, M. Glynn, Chem. Commun. 2001, 2556; i) S. Sasaki, D.
Citterio, S. Ozawa, K. Suzuki, J. Chem. Soc. Perkin Trans. 2
2001, 2309; j) D. H. Lee, H. Y. Lee, K. H. Lee, J. L. Hong,
Chem. Commun. 2001, 1188; k) G. Hennrich, H. Sonnenschein,
U. Resch-Genger, Tetrahedron Lett. 2001, 42, 2805; l) M. H.
Mei, S. K. Wu, Acta Chim. Sin. 2001, 59, 1112; m) D. Jiménez,
R. Martínez-Máñez, F. Sancenón, J. Soto, Tetrahedron Lett.
2002, 43, 2823; n) D. H. Lee, H. Y. Lee, J.-I. Hong, Tetrahedron
Lett. 2002, 43, 7273; o) S. Kondo, M. Nagamine, Y. Yano, Tet-
rahedron Lett. 2003, 44, 8801; p) T. Gunnlaugsson, P. E. Kru-
ger, T. C. Lee, R. Parkesh, F. M. Pfeffer, G. M. Hussey, Tetrahe-
dron Lett. 2003, 44, 6575; q) F. Sansone, E. Chierici, A. Cas-
nati, R. Ungaro, Org. Biomol. Chem. 2003, 1, 1802; r) T.
Gunnlaugsson, A. P. Davis, G. M. Hussey, J. Tierney, M.
Glynn, Org. Biomol. Chem. 2004, 2, 1856–1863.
1-[4-(Trifluoromethyl)benzylidene]-4-(4-methoxyphenyl)thiosemicar-
bazide (1f): 1H NMR: δ = 11.93 (br. s, 1 H, NH), 10.18 (br. s, 1 H,
NH), 8.20 (s, 1 H, CH=N), 8.14 (d, J = 8.0 Hz, 2 H), 7.77 (d, J =
8.0 Hz, 2 H), 7.38 (d, J = 8.0 Hz, 2 H), 6.95 (d, J = 8.0 Hz, 2 H),
3.78 (s, 3 H, OCH3) ppm. ESI-MS: m/z = 354.2 [M+H]+.
Methodologies: All titration experiments were performed in MeCN
(polarographic grade) at 5.00·10–5  receptor concentration (1a–f).
The quartz cuvette (1 cm path length) was kept in a cell holder
thermostatted at 25 °C with circulating water. Typically, aliquots of
a fresh alkylammonium salt standard solution of the anion of inter-
est were added and the UV/Vis spectra of the samples were re-
corded. All spectrophotometric titration curves were fitted with the
HYPERQUAD program.[13] The p parameter (p = [concentration
of complex]/[maximum possible concentration of complex]), which
should be Ͻ 0.8 for the safe determination of a reliable equilibrium
constant,[14] was calculated for each titration. Such a requirement
was fulfilled only in titration experiments with CH3COO– and
–
H2PO4 . 1H NMR titrations were carried out on CD3CN solutions,
at a higher concentration of 1 (5.00·10–3 ).
Acknowledgments
[9] R. Martínez-Máñez, F. Sancenón, Chem. Rev. 2003, 103, 4419.
[10] C. Suksai, T. Tuntulani, Chem. Soc. Rev. 2003, 32, 192.
[11] L. Nie, Z. Zhao Li, J. Han, X. Zhang, R. Yang, W.-X. Liu, F.-
Y. Wu, J.-W. Xie, Y.-F. Zhao, Y.-B. Jiang, J. Org. Chem. 2004,
69, 6450–6454.
[12] M. B. Ferrari, S. Capacchi, G. Reffo, G. Pelosi, P. Tarasconi,
R. Albertini, S. Pinelli, P. Lunghi, J. Inorg. Biochem. 2000, 81,
89–97.
[13] P. Gans, A. Sabatini, A. Vacca, Talanta 1996, 43, 1739–1753.
[14] C. S. Wilcox, in: Frontiers in Supramolecular Chemistry and
Photochemistry, VCH, Weinheim, 1991, pp. 123–143.
Received: May 2, 2006
The financial support of the Italian Ministry of Universities and
Research (PRIN – Dispositivi Supramolecolari; FIRB – Project
RBNE019H9K) is gratefully acknowledged. We thank the Centro
1
Grandi Strumenti (Università di Pavia) for H NMR facilities. We
are indebted to Dr. Enrico Monzani for discussion on 1H NMR
titration experiments.
[1] P. A. Gale, “Amide- and urea-based anion receptors”, in: Ency-
clopedia of Supramolecular Chemistry, Marcel Dekker, New
York, 2004, pp. 31–41.
Published Online: July 13, 2006
3574
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3567–3574