N-(Acetamido)thiourea based simple neutral hydrogen-bonding receptors for anions

Article abstract of DOI:10.1039/b910255h

N-(Acetamido)-N′-phenylthioureas (4-6) were found to be efficient anion receptors with higher anion affinity than their N-benzamido-N′- phenylthiourea counterparts (1 and 2). The N′-phenylthiourea moiety in 4-6 was shown to be the chromophore with an absorption maximum at ca. 270 nm. It was found that, in the presence of anions, the absorption at ca. 270 nm of 4-6 (except 5f) in acetonitrile (MeCN) was blue shifted and enhanced while a red-shifted shoulder appeared at ca. 295 nm, together with an isosbestic point at ca. 240 nm. The 1:1 anion binding constants of 4-6, for example at 10 ⁶-10⁷ M^-1 order of magnitude for AcO ^- in MeCN, were found to be higher than those of 1 and 2, although the acidity of the thioureido -NH protons in 4-6 is lower than that in 1 and 2. ¹H NMR data indicates that the N-N single bond in 4-6 is twisted but less than that in 1 and 2. A conformation change at the N-N single bond of 4-6 was suggested to occur upon anion binding which leads to a planar hydrogen-bonding network in the anion binding complex in which a charge transfer takes place with the N-acyl moiety being the electron acceptor. Variations in the CD signals of a proline derivative 6 bearing a chiral center in the N-amido moiety provide direct evidence for this conformation change upon its binding with anions in MeCN. The amplified effect of substituent X at the N′-phenyl ring of 5 on the anion binding constant supports the conclusion of anion-binding switched charge transfer in the anion binding complex. ¹H NMR and absorption titrations for 5 indicated that the anion-receptor interaction was of a hydrogen-bonding nature until the N′-phenyl substituent X is as electron-withdrawing as m-CF₃ (5e). With X being the more electron-withdrawing p-NO₂ (5f), deprotonation of the thioureido -NH occurs in the presence of anion. Results reported here confirm that N-amidothioureas derived from both N-aliphatic and N-aromatic amides can in general be a family of efficient hydrogen-bonding receptors, with the aliphatic N-amido derivatives being more efficient. This provides a wider structural diversity for designing thiourea-based functional molecules such as anion receptors and organocatalysts. Preliminary experiments confirm that 6 could catalyse efficiently the reduction of nitrostyrene in CH₂Cl₂ and MeCN.

Full text of DOI:10.1039/b910255h

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
N-(Acetamido)thiourea based simple neutral hydrogen-bonding
receptors for anions†
Wen-Xia Liu,a,b Rui Yang,a,c Ai-Fang Li,a Zhao Li,a Yu-Feng Gao,a Xing-Xing Luo,a Yi-Bin Ruana and
Yun-Bao Jiang*a
Received 26th May 2009, Accepted 29th June 2009
First published as an Advance Article on the web 5th August 2009
DOI: 10.1039/b910255h
N-(Acetamido)-N¢-phenylthioureas (4–6) were found to be efficient anion receptors with higher anion
affinity than their N-benzamido-N¢-phenylthiourea counterparts (1 and 2). The N¢-phenylthiourea
moiety in 4–6 was shown to be the chromophore with an absorption maximum at ca. 270 nm. It was
found that, in the presence of anions, the absorption at ca. 270 nm of 4–6 (except 5f) in acetonitrile
(MeCN) was blue shifted and enhanced while a red-shifted shoulder appeared at ca. 295 nm, together
with an isosbestic point at ca. 240 nm. The 1:1 anion binding constants of 4–6, for example at
106–107 M-1 order of magnitude for AcO- in MeCN, were found to be higher than those of 1 and 2,
although the acidity of the thioureido -NH protons in 4–6 is lower than that in 1 and 2. 1H NMR data
indicates that the N–N single bond in 4–6 is twisted but less than that in 1 and 2. A conformation
change at the N–N single bond of 4–6 was suggested to occur upon anion binding which leads to a
planar hydrogen-bonding network in the anion binding complex in which a charge transfer takes place
with the N-acyl moiety being the electron acceptor. Variations in the CD signals of a proline derivative
6 bearing a chiral center in the N-amido moiety provide direct evidence for this conformation change
upon its binding with anions in MeCN. The amplified effect of substituent X at the N¢-phenyl ring of 5
on the anion binding constant supports the conclusion of anion-binding switched charge transfer in the
anion binding complex. 1H NMR and absorption titrations for 5 indicated that the anion–receptor
interaction was of a hydrogen-bonding nature until the N¢-phenyl substituent X is as
electron-withdrawing as m-CF3 (5e). With X being the more electron-withdrawing p-NO2 (5f),
deprotonation of the thioureido -NH occurs in the presence of anion. Results reported here confirm
that N-amidothioureas derived from both N-aliphatic and N-aromatic amides can in general be a
family of efficient hydrogen-bonding receptors, with the aliphatic N-amido derivatives being more
efficient. This provides a wider structural diversity for designing thiourea-based functional molecules
such as anion receptors and organocatalysts. Preliminary experiments confirm that 6 could catalyse
efficiently the reduction of nitrostyrene in CH2Cl2 and MeCN.
-NH acidity, N-alkyl and/or N-aryl substitution is a major means
Introduction
hitherto employed.1 This may suffer from deprotonation of the
Thiourea has been a well-known neutral binding site employed in
highly acidic thioureido NH protons in the presence of basic
the design of anion receptors.1 Recently it has received increasing
anions. Incorporating more binding sites in the receptor molecule
attention in organocatalysis.2 In order to enhance its interaction
with anions, structural modifications have been attempted to
increase the acidity of the thioureido -NH protons and/or to
include other interactions such as additional hydrogen-bonding
and electrostatic interactions. In terms of increasing thioureido
has been shown to be successful.3,4 This may need sophisticated
structural design and appreciable synthetic effort. We have been
interested in exploring an alternative possibility of developing
simple thiourea-based anion receptors of enhanced binding ability
but not by increasing the acidity of the thioureido -NH protons.5
We have discovered N-benzamidothioureas (1 and 2, Scheme 1)
whose thioureido -NH protons are not more acidic than those
in the corresponding traditional N-phenylthioureas, yet show
higher anion-binding constants in MeCN by two orders of
magnitude.5 We suggested that the twisted N–N single bond in
N-benzamidothioureas underwent a conformation change upon
anion binding that switched on a charge transfer (CT) in the
anion binding complex, resulting in an amplified substituent
(X) effect on the anion binding of 1.5d A hydrogen-bonding
network involving an N-amido -NH proton was proposed in
the anion binding complex.5d This was nicely supported by the
fact that the absorption and fluorescence spectra of a model
aDepartment of Chemistry, College of Chemistry and Chemical Engineering,
and the MOE Key Laboratory of Analytical Sciences, Xiamen University,
Xiamen 361005, China. E-mail: ybjiang@xmu.edu.cn; Fax: (+86)592-218-
5662; Tel: (+86)592-218-5662
bNational Marine Products Quality Supervision & Inspection Centre,
Zhanjiang 524043, China
cCollege of Chemistry and Chemical Engineering, Southwest University,
Chongqing 400715, China
† Electronic supplementary information (ESI) available: Absorption spec-
tra of 4 and 5 and their AcO- binding complexes in MeCN (Fig. S1);
absorption spectra of 7 in MeCN in the presence of F- (Fig. S2); scans
of 1H NMR and 13C NMR spectra of the new compounds. See DOI:
10.1039/b910255h
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Scheme 1 Structure of N-benzamidothioureas.
Scheme 2 Structure of N-acetamido(thio)urea-based anion receptors. Proton labeling is given for 5.
compound 3 (Scheme 1),5a,6 bearing no amido -NH proton,
showed practically no response toward anions such as AcO-
and F- in MeCN. It was also noted that the anion binding
constant of 2 did not show much dependence on the substituent
Y in the N-benzamido moiety.5f This implies that the aliphatic
N-amido counterparts of N-benzamidothioureas might show
similar anion binding capacity. This, if proved, will certainly
provide more structural diversity for the thiourea-based anion
receptors and organocatalysts as well. We therefore prepared a
series of N-acetamido-N¢-phenylthioureas (4 and 5 in which 4a =
5c, Scheme 2). It was found that 4 and 5 showed stronger hydrogen-
bonding ability towards anions than 1 and 2, despite a lower acidity
of the thioureido -NH protons in 4 and 5. N-Amidothioureas with
both aromatic and aliphatic N-amide moiety are therefore shown
to be hydrogen-bonding receptors with strong affinity towards
hydrogen-bonding acceptors.
Fig. 1 Chemical shifts of -NH and a-CH3 protons in DMSO-d6 against
the Hammett constant of substituent X in 5. Concentration of 5 is
ca. 10 mmol L-1. The chemical shifts were found independent of the
concentration, for example of 5b over 7 to 51 mmol L-1. The linear
relationships found for 1 were d-NH(a) = 0.125sx + 10.14 (n = 6, R =
0.9876), d-NH(b) = 0.467sx + 9.69 (n = 6, R = 0.9754), d-NH(c) = 0.523sx +
9.58 (n = 6, R = 0.9850).5d
Results and discussion
The substituent effect on the 1H NMR signals of -NH and
a-methylene/methyl protons in 4 and 5 was investigated in
DMSO-d6. It was found that, with 4a–d, the chemical shifts of the
a-methylene CH2 protons varied linearly with the electronegativity
(X)7 of the central atom in substituent Y, with a slope of
1.69. NMR signals of three -NH protons, however, were found
insensitive to Y. This means that a change in Y in 4a–d has
practically no influence on the acidity of the amido and thioureido
-NH protons. Fig. 1 shows that, with 5a–f, the NMR signals of
the thioureido -NHs respond linearly with the Hammett constant
of substituent X8 by slopes of 0.505 and 0.397, whereas with those
of amido -NH and a-methyl -CH3 protons the slopes are only
0.123 and 0.040, respectively. The discontinuity in these slopes
indicates that the N–N single bond in 5 disrupts the electronic
communication between the N-amido and thiourea moieties, as
was concluded with 1 and 2 for a twisted N–N single bond.5 On
the basis of the NMR data, we found that the acidity of the -NH
protons in 4 and 5 is lower than that in 15d and 2.5f We also noted
that, while the slopes for thioureido -NHs were lower for 1, the
slope of the N-acetamido -NH proton in 5 was comparable to
that of 1 (Fig. 1). This probably suggests a less twisted N–N single
bond in 4 and 5 than in 1 and 2.
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Table 1 Absorption spectral parameters of 4a–d and 5a–e and their AcO- binding complexes, and anion binding constants in MeCNa
Ka, mol-1
L
lmax
lmRax
, nmb
+
− , nmc
A
Dhn, cm-1d
AcO-
F-
H2PO4
-
R
4a
4b
4c
4d
5a
5b
5d
5e
267
267
266
267
264
266
271
272
262
263
265
265
262
263
265
265
715
570
142
283
289
429
835
971
(1.13 0.07) ¥ 106
(2.47 0.00) ¥ 106
(1.21 0.32) ¥ 107
(4.42 0.50) ¥ 106
(1.07 0.07) ¥ 106
(1.76 0.34) ¥ 106
(6.48 0.62) ¥ 105
(8.62 0.68) ¥ 106
(8.46 0.92) ¥ 105
(3.23 0.29) ¥ 104
(1.03 0.03) ¥ 105
(2.89 0.11) ¥ 104
(3.41 0.25) ¥ 104
(1.74 0.21) ¥ 104
(3.50 0.38) ¥ 104
(4.43 0.75) ¥ 104
(1.39 0.20) ¥ 106
(6.30 0.92) ¥ 106
e
(1.88 0.13) ¥ 106
e
e
a
a
a Data for 5c are not given since 5c = 4a. b Absorption maximum of the receptor. c Absorption maximum of the receptor–AcO- complex. d Anion binding
induced blue shift in the absorption maximum. e The value is over 2 ¥ 107 mol-1 L which is too high to be accurately fitted.
Compounds 4a–d in MeCN show absorption maxima at ca.
270 nm that hardly changes with substituent Y. The absorption
maximum of 5a–e shows a red shift from 264 nm (5a) through
267 nm (5c) to 272 nm (5e), with increasing electron-withdrawing
ability of the substituent X (Table 1). These observations in-
dicate that the absorption of 4 and 5 originates from their
N¢-phenylthiourea moiety. Fig. 2a shows the absorption spectra
of 4a in MeCN in the presence of AcO-. It is observed that, with
increasing AcO- concentration, the absorption maximum of 4a
is blue shifted from 267 nm to 262 nm and a shoulder appears
over 280 to 340 nm, together with an isosbestic point at 238 nm.
This means that a clear 4a–AcO- binding interaction occurs in the
solution. Addition of competitive hydrogen-bonding solvents such
as water or methanol to the 4a–AcO- solution in MeCN led to a
reversal change in the absorption spectrum back towards that of
free 4a, an observation indicative of the hydrogen-bonding nature
of the AcO-–4a interaction in MeCN. Similar variation profiles
5e (Table 1). Meanwhile, the shoulder of the 5–AcO- complex at
ca. 295 nm shows a tendency to red-shift with increasing electron-
withdrawing ability of the substituent X (Fig. S1†). Note that the
corresponding new bands in the absorption spectra of the anion
binding complexes of 2 in MeCN were at 335 nm,5f which are
energetically much lower than those (ca. 295 nm) of the anion
binding complexes of 4 and 5. Referring to the CT nature of
the 335 nm absorption of the anion binding complexes of 2 with
an N-benzoyl moiety being the electron acceptor,5f and the less
electron-accepting capacity of the aliphatic N-acyl moiety in 4
and 5 than that of the aromatic N-benzoyl in 2, the fact that the
shoulder in the absorption spectra of anion binding complexes of
4 and 5 appears at shorter wavelengths probes their CT character.
The anion binding ability of the urea counterpart of 4a (5c),
N-acetamido-N¢-phenylurea (7, Scheme 2), was found to be
weaker than that of 4a. For example (Fig. S2†), absorption spectral
titration in MeCN gives a binding constant of F- with 7 of (1.27
0.44)¥105 mol-1 L, which is lower by one order of magnitude than
that of 4a (Table 1). This again supports the hydrogen-bonding
nature of the anion interaction with the (thio)urea binding site.5g
were observed in the presence of F- and H2PO4 . HSO4 has a
-
-
weaker impact whereas other anions such as Cl-, Br-, I-, NO3 ,
-
and ClO4- exert practically no influence (Fig. 2b). Other members
in series 4 and 5a–e indicated similar spectral responses toward
the tested anions in MeCN (Fig. S1 in the ESI†). Upon addition
of AcO-, the blue shift of the absorption maximum of 5–AcO-
from that of free 5 increases from 289 cm-1 for 5a to 971 cm-1 for
Absorption spectrum of 5f bearing
a highly electron-
withdrawing substituent p-NO2 at the N¢-phenyl ring, however,
differs quite a lot from those of the other members of 5 (Fig. 3).
Upon addition of anions (F-, AcO-, H2PO4 ), a new band at
-
Fig. 2 (a) Absorption spectra of 4a in MeCN in the presence of increasing
concentrations of AcO- and (b) plots of absorbance of 4a at 290 nm versus
anion concentration. Lines through data points in (b) are nonlinear fitted
curves, for fitting details see text. [4a] = 1.74 ¥ 10-5 mol L-1.
Fig. 3 Absorption spectra of 5f in MeCN in the presence of increasing
concentrations of AcO- over 0 to 2.5 ¥ 10-4 mol L-1. [5f] = 1.57 ¥
10-5 mol L-1.
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396 nm is developed at the expense of the 331 nm band, accounting
for the observed solution colour change from colourless to
yellow. Meanwhile, the absorbance at 240 nm increases together
with the appearance of two isosbestic points at 290 nm and
345 nm, respectively. We will show later that this is because of
the deprotonation of thioureido -NH proton of 5f in the presence
of anions.
To probe if a conformation change occurs at the N–N bond
upon anion binding,5d we synthesized a chiral N-amidothiourea (6,
Scheme 2) bearing an L-proline moiety, an important component
in current organocatalysts.9 With increasing anion concentration,
the absorption spectrum of 6 in MeCN varies in a manner similar
to that of 4 (Fig. 4a) and its binding constants with anions AcO-,
F-, and H2PO4 are at 105–106 mol-1 L orders of magnitude.
-
Fig. 5 Traces of the 1H NMR titration of 4a by F- in CD3CN at portions
of (a) -NH and (b) aromatic CH protons of the N¢-phenyl ring. [4a] is 1.5 ¥
10-2 mol L-1 and concentration ratios of 4a to F- are indicated in the figure.
In the CD spectrum of 6 (Fig. 4b), two positive Cotton effects
centered at 216 nm and 277 nm, respectively, and a negative Cotton
effect at 236 nm were observed. The CD signals at 216 nm and
236 nm are due to the proline amide group,10 while that at 277 nm
is due to the N¢-phenylthiourea with two thioureido -NHs in
trans-conformation.11 Upon AcO- addition, the CD signals of the
proline amide moiety decreased and finally disappeared, while that
at 277 nm due to the thiourea moiety was reversed in sign and blue-
shifted to 264 nm, a wavelength that is the same as that observed in
the absorption spectrum of the 6–AcO- binding complex (Fig. 4a).
A cis-conformation of the two thioureido -NHs of 6 was therefore
probed in its anion binding complex11,12 and a conformation
change in the proline amide moiety was indicated, which was
previously assigned to occur around the N–N single bond that
leads to a planar hydrogen-bonding network.5a,d It is important
to point out that a new CD signal is developed at 264 nm, the
absorption maximum of the anion binding complex (Fig. 4). This
means that the anion binding complex of 6 remains chiral, which
might be of relevance to the design of N-amidothiourea based
organocatalysts since the chirality of the anion binding complex
originates from the chiral center in the proline moiety.
downfield from 8.62 ppm, 8.22 ppm and 7.83 ppm to 9.72 ppm
and 9.36 ppm. This reflects a hydrogen-bonding interaction of
4a with F-. The aromatic protons Hd and Hh that are close to
the anion binding site show pronounced downfield shifts in their
NMR signals, whereas protons Hg, He and Hf that are a bit far away
from the binding site, undergo significant upfield shifts in their
NMR signals. This shifting pattern has previously been assigned
by Fabbrizzi et al.13 to the hydrogen-bonding interaction of anions
with the receptor. Similar shifting profiles were observed with 5e
titrated by F- (Fig. 6) and AcO- (spectra not shown). With 5f
bearing a highly electron-withdrawing substituent p-NO2 at the
N¢-phenyl ring, the NMR titration profile differs a lot (Fig. 7).
Upon titration by F- and AcO-, part of the signals of the -NH
protons shifted downfield while the others shifted slightly upfield
and finally disappeared. Meanwhile, the signals of all the aromatic
protons now underwent upfield shifts. This is indicative of the
Fig. 4 Absorption (a) and CD (b) spectra of 6 in MeCN in the presence
of increasing concentrations of AcO- over 0 to 2.5 ¥ 10-4 mol L-1. [6] =
1.92 ¥ 10-5 (a) and 1.46 ¥ 10-4 (b) mol L-1.
The interaction of N-acetamido-N¢-phenylthioureas with an-
1
ions was further investigated by H NMR titrations in CD3CN.
Fig. 5 shows as an example the NMR traces of 4a titrated by F-
in the ranges of the -NH and aromatic protons. It is observed
that the signals of the -NH protons are broadened and shifted
Fig. 6 Partial NMR spectra of 5e in CD3CN in the presence of increasing
equivalents of F-. [5e] = 1.3 ¥ 10-2 mol L-1 and equivalents of F- are
indicated in the figure.
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Fig. 7 NMR titration traces of 5f in CD3CN by F-. [5f] = 1.6 ¥
Fig. 9 Semilogarithm plots of the AcO- binding constants of 4 and 5 in
MeCN against electronegativity of the central atom in Y in 4a–d (a) and
Hammett constant of substituent X in 5a–e (b).
10-2 mol L-1 and F- equivalents are shown in the figure.
deprotonation of the thioureido -NHs in 5f. This is likely due to the
highly electron-withdrawing substituent p-NO2 at the N¢-phenyl
ring which substantially increases the acidity of the thioureido
-NHs in 5f. This conclusion agrees well with that of Gale el al.14 on
the deprotonation of highly acidic -NH protons. It was therefore
concluded that with 4a–d and 5a–e, in particular with 5e bearing
a substantially electron-withdrawing substituent X = m-CF3, it
is hydrogen-bonding, and not deprotonation, that occurs with
anions. The discussion below on anion binding will therefore be
limited to 4a–d and 5a–e.
Hammett constant of substituent X by a slope of 7.64. It is
hence made clear that, with N-(acetamido)-N¢-phenylthioureas,
it is also more effective to enhance their anion binding by varying
the substituent on the N¢-phenyl ring. The aforementioned linear
slope of 7.64 for 5 was found to be lower than the corresponding
slope of 1 (10.57).5d This is probably because of the more planar
conformation of the N-amidothiourea moiety (less twisting of
the N–N bond) in 4 and 5 that requires less conformational
change upon anion binding in order to reach the final planar
hydrogen-bonding network. A lower positive feedback of the
substituent effect on the anion binding would hence be expected.5d
The extended investigation reported here therefore confirms that
N-amidothioureas with both aromatic and aliphatic N-amide
structures are efficient anion receptors under a hydrogen-bonding
motif and provide a wider diversity for N-amidothiouea-based
organocatalysts. Indeed, our preliminary experiments confirmed
that 6 can catalyse the reduction of nitrostyrene by Hantzsch
ester in CH2Cl2 and MeCN,16 with isolated yields of 80% and
60%, respectively, which are comparable to the yield of 88% in
CH2Cl2 and higher than the yield of 39% in MeCN obtained
by using the traditional diphenylthiourea organocatalyst N,N¢-
bis(3,5-ditrifluoromethylphenyl)thiourea that bears highly acidic
thioureido -NHs.16
Job plots show that in MeCN 4 and 5 form anion binding
complexes in 1:1 stoichiometry (Fig. 8). Anion binding constants
of 4 and 5 in MeCN were obtained from absorption spectral
titration data by nonlinear fitting15 and are presented in Table 1.
The binding constants of F- and AcO- are higher than those
-
of H2PO4 . In particular, anion binding constants of 4 and 5
are higher than those of their N-benzamido- counterparts 1 and
2, despite a lower acidity of the NH protons in 4 and 5. It is
seen in Fig. 9 that the logarithm of the AcO- binding constants
of 4 correlates with the electronegativity of the central atom
in Y by a slope of 1.36 and those of 5 correlates with the
The herein reported N-acetamido-N¢-phenylthioureas are struc-
turally extremely simple yet show a surprisingly high sensing
efficiency for anions in MeCN containing water up to 10% by
volume (Table 2 and Fig. 10). In H2O–MeCN solutions the anion
binding constants were found to be lower than those in pure
MeCN, yet the binding is still strong enough, in particular in the
case of 5e which has a binding constant for AcO- of 105 mol-1
L
order of magnitude in 10% H2O–MeCN. Note that the AcO-
binding constant of N,N¢-diphenylthioureadecreases dramatically
from 3.27 ¥ 104 mol-1 L in pure MeCN to 9.12 ¥ 101 mol-1 L in
1% H2O–MeCN. The N-acetamido-N¢-phenylthioureas reported
here also showed a higher tolerance against the highly competitive
water molecules than the corresponding N-benzamidothiourea
counterparts.5d,f This observation may ease their applications in,
for example, organocatalysis because dehydration of solvents will
not have to be carried out.
Fig. 8 Job plots for binding of AcO- and F- to 4c in MeCN by monitoring
the difference of absorbance at 300 nm of anion–4c mixture from that of
4c. Total concentration of AcO- and 4c is 4.74 ¥ 10-5 mol L-1 and that of
F- and 4c is 2.58 ¥ 10-5 mol L-1.
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lmRax lmax
Table 2 AcO- binding constants in mol-1 L of 4a–d and 5a–e and
in nm in H2O–MeCNa
−
+
R
A
[H2O], v/v
0
1%
3%
5%
8%
10%
b
b
4a
4b
4c
4d
5a
5b
5d
5e
(1.13 0.07) ¥ 106
267/262
(1.09 0.14) ¥ 105
266/262
(6.87 0.79) ¥ 104
266/263
(2.50 1.21) ¥ 104
265/262
b
b
b
b
b
b
b
b
b
(2.47 0.00) ¥ 106
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(1.16 0.11) ¥ 105
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(7.24 0.39) ¥ 104
266/262
(1.21 0.32) ¥ 107
266/265
(5.68 0.19) ¥ 105
265/264
(1.91 0.16) ¥ 105
266/263
(5.46 1.21) ¥ 105
265/263
(4.42 0.50) ¥ 106
267/265
(5.88 0.83) ¥ 105
267/264
(1.80 0.05) ¥ 105
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(1.37 0.04) ¥ 105
(3.53 0.76) ¥ 105
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266/262
b
b
(1.07 0.07) ¥ 106
264/262
(8.64 0.85) ¥ 104
264/263
(3.43 2.35) ¥ 103
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b
b
(1.88 0.13) ¥ 106
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(1.53 0.15) ¥ 105
265/263
(3.05 5.9) ¥ 103
264/263
c
–
(5.46 0.87) ¥ 106
271/265
(9.41 0.50) ¥ 105
272/265
(1.06 0.05) ¥ 105
270/265
(1.06 0.20) ¥ 105
268/266
271/265
c
–
(1.73 0.18) ¥ 106
271/265
(3.33 0.21) ¥ 105
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(5.24 0.43) ¥ 105
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(4.44 0.60) ¥ 105
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272/265
a Data for 5c are not shown since 5c = 4a. b Spectral change was too minor to allow for an accurate evaluation. c The binding constant is too high to be
fitted accurately.
Solvents used for the syntheses of receptors were commercially
available and of AR grade. Solvents for spectral investigations were
purified by re-distillations until no fluorescent impurity could be
detected. Tetrabutylammonium salts of anions were prepared by
neutralization of the corresponding acids by (n-Bu)4N+ OH-. All
reagents for syntheses were used as received from Aldrich or Fluka.
Synthesis and characterizations
(4b). A mixture of dodecanoic acid (0.3 g, 1.50 mmol) and
SOCl2 (5.0 mL) was refluxed for 6 hours and excess SOCl2
were evaporated under reduced pressure to afford dodecanoyl
chloride. Dodecanoyl chloride in CH2Cl2 (3.0 mL) was added to
a solution of triethylamine (0.28 mL, 2.00 mmol) and N-amino-
Fig. 10 Plots of absorbance at 262 nm of 5e versus AcO- concentration
N¢-phenylthiourea (0.25 g, 1.50 mmol) in CH2Cl2 (5.0 mL). The
in H2O–MeCN (v/v). [5e] = 2.5 ¥ 10-5 mol L-1. Lines through the data
solution was stirred at room temperature for 3 hours and the
solvent was removed. The product was purified by recrystallization
from absolute ethanol to afford 4b as a white solid. H NMR
points are fitted curves for 1:1 complex following a reported procedure.15
logK is the logarithm of anion binding constant.
1
(500 MHz, DMSO-d6, TMS), d (ppm): 9.79 (s, 1H, NH), 9.52 (s,
1H, NH), 9.49 (s, 1H, NH), 7.43 (d, J = 6.5 Hz, 2H, Ar-H), 7.33
(t, J = 7.5 Hz, 2H, Ar-H), 7.16(t, J = 7.0 Hz, 1H, Ar-H), 2.16
(t, J = 7.5 Hz, 2H, COCH2), 1.53 (m, 2H, CH2), 1.20–1.30 (m,
16H, C8H16), 0.86 (t, J = 7.0 Hz, 3H, CH3). 13C NMR (125 MHz,
DMSO-d6), d (ppm): 181.0, 172.0, 139.1, 128.0, 125.6, 124.8, 33.3,
31.2, 29.0, 28.9, 28.7, 28.6, 24.5, 22.0, 13.8. IR (KBr, cm-1): 3389,
3276, 3136, 3029, 2919, 2850, 2360, 1697, 1684, 1535, 1508, 1171,
696. HRMS exact mass calcd for [C19H31N3OS + H]+ 350.2266,
found 350.2261.
Experimental
General procedures and materials
UV–vis spectra were recorded on a Varian CARY-300 spectropho-
tometer using a 1 cm quartz cell. 1H NMR (400 MHz or 500 MHz)
and 13C NMR (100 MHz or 125 MHz) spectra were obtained
on a Bruker AV400 or Varian Unity 500+ NMR spectrometer in
DMSO-d6 or CD3CN using TMS as an internal standard or the
residual solvent peak as a standard. IR spectra were recorded
on Nicolet AVATAR FT-IR360 infrared spectrophotometer using
KBr pellet sample. HRMS were obtained with Micromass-LCT
high resolution mass spectrometer by injection of methanol
solution of the sample. CD spectra were acquired on Jasco
J-810 spectropolarimeter using a 0.5 cm quartz cell. Absorption
spectral titrations for anion binding were carried out by adding
an aliquot of anion solution into bulk receptor solution at
a given concentration. Organocatalysis by 6 of the reduction
of nitrostyrene by Hantzsch ester was performed following the
same procedures described in reference 16 in which N,N¢-bis(3,5-
ditrifluoromethylphenyl)thiourea was the catalyst.
(4c). Triethylamine (0.30 mL, 2.10 mmol) and phenyl isothio-
cyanate (0.13 mL, 1.05 mmol) were added to a solution of N,N-
dimethylglycine hydrazide dihydrochloride (0.20 g, 1.05 mmol) in
ethanol (10.0 mL). The mixture was stirred at room temperature
for 3 hours and concentrated to remove the solvent. The product
was purified by recrystallization from absolute ethanol to afford
1
4c as a white crystalline solid. H NMR (400 MHz, DMSO-d6,
TMS), d (ppm): 9.80 (s, 1H, NH), 9.50 (s, 2H, NH), 7.45 (d, J =
6.0 Hz, 2H, Ar-H), 7.32 (t, J = 7.5 Hz, 2H, Ar-H), 7.16 (t, J =
6.5 Hz, 1H, Ar-H), 3.05 (s, 2H, COCH2), 2.27 (s, 6H, N(CH3)2).
4026 | Org. Biomol. Chem., 2009, 7, 4021–4028
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1
13C NMR (100 MHz, DMSO-d6), d (ppm): 180.3, 169.1, 139.3,
128.1, 125.6, 124.8, 61.1, 45.4. IR (KBr, cm-1): 3303, 3272, 3023,
3009, 2680, 2614, 2552, 1604, 1587, 1528, 1395, 1273, 1140, 1069,
955, 716, 692. HRMS exact mass calcd for [C11H16N4OS + H]+
253.1123, found 253.1134.
found 210.0703. 5d: H NMR (400 MHz, DMSO-d6, TMS), d
(ppm): 9.89 (s, 1H, NH), 9.68 (s, 2H, NH), 7.72 (s, 1H, Ar-H),
7.49 (d, J = 7.6 Hz, 1H, Ar-H), 7.35 (d, J = 8.0 Hz, 1H, Ar-H),
7.29 (t, J = 8.0 Hz, 1H, Ar-H), 1.89 (s, 3H, COCH3). 13C NMR
(100 MHz, DMSO-d6,), d (ppm): 180.8, 169.3, 140.8, 129.9, 128.0,
127.6, 124.6, 120.4, 21.0. IR (KBr, cm-1): 3266, 3241, 3124, 3023,
2871, 1696, 1685, 1589, 1575, 1533, 1516, 1470, 1243, 1221, 1121,
670. HRMS exact mass calcd for [C9H10BrN3OS + H]+ 287.9806,
(4d). Methyl 2-chloroacetate (0.18 mL, 1.67 mmol) was added
to a solution of sodium methanolate (1.67 mmol) in methanol
(5.0 mL). The mixture was stirred at room temperature for
3 hours and then excess hydrazine monohydrate (80%, 0.31 mL,
5.01 mmol) was added, and the mixture was further heated at
80 ◦C under stirring for 8 hours. After removing the solvent, it
was washed with iced ethanol and dried, 2-methoxyacetohydrazide
was produced. 2-methoxyacetohydrazide was reacted with phenyl
isothiocyanate (0.20 mL, 1.67 mmol) in ethanol (10.0 mL) for
3 hours at room temperature, which after removing solvent led to
product that after purification by recrystallization from absolute
ethanol produced 4d as a white crystalline solid. 1H NMR
(400 MHz, DMSO-d6, TMS), d (ppm): 9.92 (s, 1H, NH), 9.54
(s, 2H, NH), 7.42 (d, J = 5.5 Hz, 2H, Ar-H), 7.33 (t, J = 8.0 Hz,
2H, Ar-H), 7.16 (t, J = 7.0 Hz, 1H, Ar-H), 3.95 (s, 2H, COCH2),
3.34 (s, 3H, OCH3). 13C NMR (100 MHz, DMSO-d6), d (ppm):
180.9, 168.8, 139.0, 128.0, 125.7, 125.0, 70.6, 58.7. IR (KBr, cm-1):
3320, 3268, 3223, 3153, 3125, 2939, 1671, 1626, 1567, 1497, 1367,
1327, 1115, 999, 730. HRMS exact mass calcd for [C10H13N3O2S +
H]+ 240.0807, found 240.0811.
1
found 287.9819. 5e: H NMR (400 MHz, DMSO-d6, TMS), d
(ppm): 9.92 (s, 1H, NH), 9.76 (s, 2H, NH), 7.82 (d, J = 7.6 Hz,
2H, Ar-H), 7.57 (t, J = 8.0 Hz, 1H, Ar-H), 7.50 (d, J = 7.6 Hz,
1H, Ar-H), 1.91 (s, 3H, COCH3). 13C NMR (100 MHz, DMSO-
d6), d (ppm): 180.9, 169.3, 140.0, 132.6, 130.7, 129.1, 125.4, 121.8,
121.4, 21.0. IR (KBr, cm-1): 3273, 3218, 3142, 3031, 2992, 1704,
1692, 1683, 1538, 1516, 1456, 1333, 1309, 1244, 1166, 1121, 1137.
HRMS exact mass calcd for [C10H10F3N3OS + H]+ 278.0575, found
278.0582. 5f: 1H NMR (400 MHz, DMSO-d6, TMS), d (ppm): 9.96
(s, 3H, NH), 8.21 (d, J = 8.8 Hz, 2H, Ar-H), 8.00 (d, J = 8.8 Hz,
2H, Ar-H), 1.92 (s, 3H, COCH3). 13C NMR (100 MHz, DMSO-d6,
23 ◦C), d (ppm): 180.5, 169.4, 145.6, 143.3, 124.7, 123.6, 21.0. IR
(KBr, cm-1): 3293, 3241, 3187, 3163, 3136, 3015, 1679, 1636, 1591,
1508, 1494, 1338, 1303, 1234, 1114, 1002, 848, 750. HRMS exact
mass calcd for [C9H10N4O3S + H]+ 255.0552, found 255.0556.
(6). Triethylamine (0.48 mL, 3.4 mmol) was added to a solu-
tion of L-proline (0.3 g, 2.6 mmol) in methanol (10.0 mL) and the
mixture was stirred at room temperature, to which a diethyl ether
(5.0 mL) solution of di-tert-butyldicarbonate (0.57 g, 2.6 mmol)
was added dropwise, followed by stirring at room temperature
for 18 hours. A viscous liquid was obtained after removing the
solvent under reduced pressure. Adjusting the solution’s pH to
4 by 0.1 mol L-1 HCl led to N-Boc-L-proline. N-Boc-L-proline
and triethylamine (0.36 mL, 2.6 mmol) were dissolved in THF
(30 mL), to which ethyl chloroformate (0.30 mL, 2.6 mmol) was
added dropwise at 0 ◦C within 15 min. After stirring for 30 min,
N-amino-N¢-phenylthiourea (0.43 g, 2.6 mmo◦l) was added in
15 min. The resulting solution was stirred at 0 C for 1 hour, at
room temperature for 16 hours, and then refluxed for 3 hours. After
cooled to room temperature, the solution was washed with ethyl
acetate and all solids were filtered off. The residue was purified by
chromatography on a silica gel column eluted with petroleum ether
and ethyl acetate (1:2, v/v) to give 6. 1H NMR (400 MHz, DMSO-
d6, TMS), d (ppm): 10.49 (s, 1H, NH), 9.78 (s, 1H, NH), 9.13 (s,
1H, NH), 7.59 (d, J = 7.0 Hz, 2H, Ar-H), 7.31 (t, J = 7.5 Hz, 2H,
Ar-H), 7.14 (t, J = 7.0 Hz, 1H, Ar-H), 4.08 (s, 1H, CH), 3.37 (m,
2H, CH2), 2.14 (m, 2H, CH2), 1.93 (m, 2H, CH2), 1.83 (m, 2H,
CH2), 1.35 (s, 2H), 1.30 (s, 7H). 13C NMR (100 MHz, DMSO-d6),
d (ppm): 180.2, 171.5, 154.4, 138.8, 128.4, 128.0, 124.3, 79.7, 58.5,
46.8, 29.4, 28.0, 24.2. HRMS exact mass calcd for [C17H24N4O3S +
Na]+ 387.1467, found 387.1460.
(5a–f). Substituted phenylisothiocyanate (2.0 mmol) was
added to a solution of hydrazine monohydrate (80%, 0.38 mL,
6.0 mmol) in ethanol (10.0 mL), which was stirred at room
temperature for 2 hours. The formed precipitate was filtered,
washed with iced ethanol (3 ¥ 5.0 mL) and iced water
(3 ¥ 10.0 mL), respectively, and dried, leading to N-amino-
N¢-(substituted-phenyl)thiourea as white solid. N-Amino-N¢-
(substituted-phenyl)thiourea (1.5 mmol) was added to a solution
of acetic anhydride (1.5 mmol) in acetic acid (3.0 mL) followed
by stirring at room temperature for 1 hour. The precipitate was
isolated and the solid product was recrystallized from absolute
ethanol, giving 5a–f. 5a: 1H NMR (400 MHz, DMSO-d6, TMS),
d (ppm): 9.82 (s, 1H, NH), 9.48 (s, 1H, NH), 9.40 (s, 1H, NH),
7.25 (d, J = 8.4 Hz, 2H, Ar-H), 6.89 (d, J = 8.8 Hz, 2H, Ar-H),
3.74 (s, 3H, OCH3), 1.88 (s, 3H, COCH3). 13C NMR (100 MHz,
DMSO-d6), d (ppm): 181.3, 169.1, 156.7, 132.0, 127.4, 113.2, 55.2,
21.0. IR (KBr, cm-1): 3362, 3253, 3191, 2996, 1686, 1649, 1531,
1509, 1246, 1217. HRMS exact mass calcd for [C10H13N3O2S +
H]+ 240.0807, found 240.0811. 5b: 1H NMR (400 MHz, DMSO-
d6, TMS), d (ppm): 9.83 (s, 1H, NH), 9.53 (s, 1H, NH), 9.44 (s,
1H, NH), 7.28 (d, J = 7.6 Hz, 2H, Ar-H), 7.13 (d, J = 8.0 Hz,
2H, Ar-H), 2.28 (s, 3H, CH3), 1.88 (s, 3H, COCH3). 13C NMR
(100 MHz, DMSO-d6), d (ppm): 181.0, 169.1, 136.6, 134.2, 128.5,
125.7, 21.0, 20.5. IR (KBr, cm-1): 3254, 3096, 3061, 2927, 2761,
2727, 1697, 1686, 1579, 1517, 1496, 1407, 1327, 1244. HRMS exact
mass calcd for [C10H13N3OS + H]+ 224.0858, found 224.0868. 5c:
1H NMR (400 MHz, DMSO-d6, TMS), d (ppm): 9.86 (s, 1H, NH),
9.60 (s, 1H, NH), 9.50 (s, 1H, NH), 7.42 (d, J = 7.6 Hz, 2H, Ar-H),
7.33 (t, J = 7.2 Hz, 2H, Ar-H), 7.16 (t, J = 7.2 Hz, 1H, Ar-H), 1.89
(s, 3H, COCH3). 13C NMR (100 MHz, DMSO-d6), d (ppm): 181.0,
169.2, 139.2, 128.0, 125.8, 125.1, 21.0. IR (KBr, cm-1): 3261, 3140,
3029, 2871, 1694, 1686, 1590, 1531, 1516, 1498, 1451, 1366, 1248,
1217. HRMS exact mass calcd for [C9H11N3OS + H]+ 210.0701,
(7). Phenylisocyanate (0.22 mL, 2.0 mmol) was added to
a solution of excessive hydrazine monohydrate (80%, 0.38 mL,
6.0 mmol) in ethanol (10.0 mL) and stirred at room temperature
for 2 hours. A precipitate was formed, which after filtration, was
washed with iced ethanol (3 ¥ 5.0 mL) and iced water (3 ¥ 10.0 mL),
and dried to produce N-amino-N¢-phenylurea as a white solid.
N-amino-N¢-phenylurea (0.23 g, 1.5 mmol) was added to a
solution of acetic anhydride (1.5 mmol) in acetic acid (3.0 mL) and
stirred at room temperature for 1 hour. The formed precipitate was
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recrystallized from absolute ethanol, affording 7 as a white crys-
talline solid. 1H NMR (400 MHz, DMSO-d6, TMS), d (ppm): 9.63
(s, 1H, NH), 8.69 (s, 1H, NH), 7.96 (s, 1H, NH), 7.44 (d, J = 7.6 Hz,
2H, Ar-H), 7.25 (d, J = 7.2 Hz, 2H, Ar-H), 6.95 (s, 1H, Ar-H), 1.86
(s, 3H, COCH3). 13C NMR (100 MHz, DMSO-d6), d (ppm): 169.2,
155.4, 139.6, 128.6, 121.8, 118.4, 20.6. IR (KBr, cm-1): 3433, 3332,
3288, 3264.43, 3202, 3144, 3101, 3035, 1697, 1670, 1623, 1610,
1561, 1500, 1443, 1315, 1237, 749, 688. HRMS exact mass calcd
for [C9H11N3O2 + H]+ 194.0930, found 194.0937.
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Conclusions
A systematic investigation on the anion binding behavior of
N-(substituted-acetamido)-N¢-(substituted-phenyl)thioureas has
clearly shown that they are efficient anion receptors via hydrogen-
bonding interactions with N¢-phenyl substituents X as electron-
withdrawing as m-CF3. Together with the previously reported
high anion affinity of the N-(substituted-benzamido)thiourea
counterparts,5 it has now been made clear that N-amidothioureas
can in general be a family of hydrogen-bonding receptors. The
N-acetamidothioureas reported here showed a slightly lower
acidity of their thioureido -NH protons than those in the
N-benzamidothioureas, yet demonstrated a higher anion binding
constant up to 107 mol-1 L for AcO- in MeCN. The N–N
single bond in N-acetamidothioureas was identified to be twisted
but less than that in N-benzamidothioureas. The substan-
tially red-shifted absorption of the anion binding complexes of
N-acetamidothioureas suggested the occurrence of charge transfer
in the complexes with the N-acyl moiety being the electron accep-
tor. A conformation change was shown to occur around the N–N
bond upon anion binding that switches on the charge transfer. This
charge transfer in turn reinforces anion binding, thereby leading
to an enhanced promotion of the substituent X at the N¢-phenyl
ring on the anion binding constant. The present report provides
further clues for designing functional N-amidothioureas with
much more choice in structural variations. Together with reports
recently released from the laboratory of Gunnlaugsson3a,g,17 on
the anion binding of N-acetamidoureas, we may now make
a conclusion that N-amido(thio)ureas are important hydrogen-
bonding receptors with application potentials beyond the classic
anion sensing and recognition, towards other fields such as
organocatalysis.2 Preliminary experiments confirmed that our
N-acetamidothioureas could indeed be efficient hydrogen-
bonding based organocatalysts.
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Principles and Applications, (2nd Ed) 2000, Wiley-VCH, New York.
11 K. Rang, J. Sandstro¨m and C. Svensson, Can. J. Chem., 1998, 76,
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Acknowledgements
This project has been supported by the National Natural Science
Foundation of China through grants Nos. 20835005, 20675069
and J0630429. We thank Prof. Peter R. Schreiner of Giessen
University, Germany, and Prof. Liu-Zhu Gong of USTC, China,
for the suggestions of thiourea-catalyzed model reactions.
14 (a) L. S. Evans, P. A. Gale, M. E. Light and R. Quesada, Chem.
Commun., 2006, 965–967; (b) L. S. Evans, P. A. Gale, M. E. Light
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15 K. A. Connors, Binding Constants. The Measurement of Molecular
Complex Stability, 1987, John-Wiley & Sons, New York.
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17 E. Quinlan, S. E. Matthews and T. Gunnlaugsson, Tetrahedron Lett.,
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4028 | Org. Biomol. Chem., 2009, 7, 4021–4028
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©