Synthesis and anion recognition studies of new oligomethylene bis(nitrophenylureylbenzamide) receptors

Article abstract of DOI:10.1039/c9ra05783h

A new series of oligomethylene bis(nitrophenylureylbenzamide) receptors were synthesized varying the relative position of the urea and amide groups (ortho4 and meta8) and the length of the oligomethylene chain (C₂ to C₈). An anion re

Full text of DOI:10.1039/c9ra05783h

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Synthesis and anion recognition studies of new
oligomethylene bis(nitrophenylureylbenzamide)
receptors†
Cite this: RSC Adv., 2019, 9, 39147
a
Jose Garcıa-Elıas,ab Adrian Ochoa-Teran,
Anatoli K. Yatsimirsky,c
*
´
´
´
´
´
d
Hisila Santacruz Ortega,d Karen Ochoa-Lara,
Luis Miguel Lopez-Martınez,a
*
´
´
Christian L. Castro-Riquelme,a A´ngel L. Garcıa,a Domingo Madrigal-Peralta,a
´
Victoria Labastida-Galvane and Mario Ordoneze
´
˜
A new series of oligomethylene bis(nitrophenylureylbenzamide) receptors were synthesized varying the
relative position of the urea and amide groups (ortho and meta 8) and the length of the
4
oligomethylene chain (C2 to C8). An anion recognition study was performed with TBAX salts (X ¼ AcOꢀ,
BzOꢀ, Fꢀ, H2PO4ꢀ, and HP2O73ꢀ) by UV-vis and 1H NMR. The flexibility of these receptors allows
a cooperative effect of both ureylbenzamide units in the receptors. Noteworthy, the ortho position
favored the 1 : 1 stoichiometry in the complexes with the carboxylates. The formation of 2 : 1 receptor–
anion complexes with both types of receptors 4 and 8 and with hydrogen pyrophosphate and high log K
values obtained were very significant in this work. The NMR studies evidenced the formation of
supramolecular complexes, even in a competitive solvent, such as DMSO.
Received 25th July 2019
Accepted 12th November 2019
DOI: 10.1039/c9ra05783h
rsc.li/rsc-advances
a receptor that contains an acid N–H, the affinity is mainly
related to the anion basicity or the pKa of its conjugated acid.7
Introduction
In this context, nitrophenylureas have been prepared due to
the major acidity caused by the resonance effect of the nitro
group.8 Also, this group allows the study of anion recognition
study by spectrophotometric changes; whereby the absorption
bands shi to higher wavelengths in complexes with anions, or
a new band appears when an acid–base reaction occurs.5 The
effect in the analytical response and of the interaction with
anions of nitrophenylurea receptors when varying the position
of the nitro group has been studied, and it was found that the
position of the nitro group inuences the acidity of the urea
hydrogens and the relative affinity toward different anions.6
Gunnlaugsson and coworkers9 prepared receptors with urea
and acetamide groups by changing the relative position of both
groups (ortho, meta, and para). The acetamide position had
a clear effect over the selectivity and stoichiometry in the
complexes with anions. The interaction occurred only in the
urea group with one equivalent of the anion in the meta and
para receptors, while the interaction with the amide hydrogen
occurred forming 1 : 2 receptor : anion complexes. They
proposed this behavior as a “positive allosteric effect” promoted
by conformational changes. Interestingly, the ortho receptor
Articial receptors capable of interacting with anions is a very
important subject in supramolecular chemistry because of their
participation in biological processes, like function, detection,
recognition, catalysis, and transport through the cellular
membrane, among others.1–3 There are many reports related to
anion recognition by urea-based organic receptors. The urea
group is a good hydrogen bond donor due to the presence of
N–H bonds, and due to their functionality and directionality.4,5
These characteristics play a very important role in the selective
recognition of anions with different geometries. The selectivity
is related to the energy of the receptor–anion interaction. The
strongest hydrogen bond interactions are established with the
most basic of anions, such as uoride, carboxylates, and inor-
ganic oxoanions. From a recent point of view, all the hydrogen
bonds behave as proton–transfer reactions.6 Therefore, for
a
´
´
´
´
Centro de Graduados e Investigacion en Quımica, Tecnologico Nacional de Mexico/IT
´
de Tijuana, Tijuana, Mexico. E-mail: ochoa@tectijuana.mx
b
´
´
Unidad Academica de Ciencias de la Tierra, Universidad Autonoma de Zacatecas,
´
Zacatecas, Mexico
c
´
´
´
´
Facultad de Quımica, Universidad Nacional Autonoma de Mexico, Ciudad de Mexico,
1
´
Mexico
formed only 1 : 1 complexes and the H NMR spectra showed
d
´
´
Departamento de Investigacion en Polımeros y Materiales, Universidad de Sonora,
the participation of the three hydrogens, which indicated
a cooperative interaction of the amide hydrogen with the
anions.
´
Hermosillo, Sonora, Mexico. E-mail: karenol@polimeros.unison.mx
e
´
´
Centro de Investigaciones Quımicas-(IICBA), Universidad Autonoma del Estado de
Morelos, Cuernavaca, Mexico
Bis(urea) receptors are excellent hosts for anions with diverse
geometries due to the high number of N–H bonds in their
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9ra05783h
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structure. In addition, these receptors display high pre- bearing the urea and amide groups in the ortho or meta position,
organization and cooperativity, which enhance the complexa- were synthesized and evaluated as anion receptors. We envi-
tion process,10 and exhibit
a limited number of stable sioned that these bifunctional receptors with exible oligo-
congurations for the interaction with the anion.11,12 Each methylene chains may be modulated in their acidity, with the
group forms two hydrogen bonds with the anion, the strength of cooperativity of the binding groups and the size of the receptors
which may differ depending on the ligand nature, the distance cavities allowing interaction with anions of different sizes and
between each urea group, and the size and geometry of the geometries (Fig. 1).
anion.8,13,14
Several bis(urea) receptors for the molecular recognition of
Experimental
Materials and equipment
anions are reported in the literature. Chauhan and coworkers13
prepared four azo bis(urea/tiourea) receptors bearing phenyl or
nitrophenyl substituents in the urea group for the colorimetric
detection of anions. The affinity of these receptors was in the
order Fꢀ > AcOꢀ > H2PO4ꢀ with a change of color from yellow to
red. The 1H NMR studies demonstrated that the hydrogen bond
in the urea group induced different effects in the aromatic
signals, whereby the enhancement of the electronic density in
the phenyl ring generated a shi of the signals to upeld due to
the electronic enrichment, while the polarization of the C–H
bonds through the space caused a deprotecting effect and
shied the signals to downeld.
All chemicals used in the study were obtained from commercial
suppliers and used without further purication. 1H NMR
spectra were recorded using a Bruker 400 MHz NMR spec-
trometer at a probe temperature of 30 ꢁC with TMS as the
internal standard. Electronic impact mass spectra were ob-
tained by direct insertion in an Agilent 5975C mass spectrom-
eter; and the intensities are reported as a relative percentage to
the base peak corresponding to an m/z value. FAB mass spectra
and HRMS were recorded in an MStation JMS-700 JEOL. UV-vis
absorption spectra were obtained using
spectrophotometer.
a
Cary 300
The most studied bis(urea) receptors are the N,N0-1,3-phe-
nylenbis(N0-urea/tiourea) derivatives, initially studied by Nishi-
zawa.14 Complexation studies by 1H NMR in DMSO revealed
association constant values of 110 Mꢀ1 and 43 Mꢀ1 with dihy-
drogen phosphate and acetate, respectively.15 Then, these
receptors showed high affinity toward anions by electro-
chemical methods.16 The complex stoichiometry with acetate
was found to be 1 : 1 by UV-vis measurements and the reported
Procedure for the spectrophotometric titrations
The effect of anions upon the absorbance of receptors 4 and 8
was examined by adding 3 mL of a 5 ꢂ 10ꢀ3 M TBAX solution to
a known volume (3 mL) of a 1 ꢂ 10ꢀ5 M receptor solution. Some
titrations were repeated adding 3 mL of a 1 ꢂ 10ꢀ3 M TBAX (X ¼
ꢀ
H2PO4 and HP2O3ꢀ) solution.
association constant was 210 Mꢀ1 17 A colorimetric anion sensor
.
was developed with a bis(urea) receptor synthetized from 4,5-
dimethyl-1,2-phenylenediamine and nitrophenyl isocyanate.18
Spectroscopic changes were observed only with uoride and
acetate anions, indicating selectivity over the other studied
anions.
Caltagirone and coworkers19 synthesized a series of six
bis(urea) receptors using the diamines 1,3-bis(aminomethyl)
benzene and 2,6-bis(aminomethyl)pyridine, and the isocianates
phenyl : 2-nitrophenyl and 1-naphthyl isocyanates. The binding
properties of these receptors were studied in DMSO with
acetate, benzoate, glutarate, malonate, dihydrogen phosphate
Procedure for the NMR titrations
The effect of anions upon the chemical shi in the signals of the
receptors was examined by adding 5 mL of 0.1 M TBAX stock
solution to a known volume (0.5 mL) of a 5 ꢂ 10ꢀ3 M receptor
solution contained in an NMR tube. The addition was limited to
0.050 mL, so that the dilution remained insignicant.
Synthesis
Synthesis of oligomethylene bis(2-aminobenzamides). In
hydrogenpyrophosphate, triphosphate, AMP, and ADP by UV-vis a round-bottom ask was added isatoic anhydride 1 (2.2 equiv.,
spectroscopy and 1H NMR. These receptors showed high affinity 18.30 mmol) in dry THF under an argon atmosphere. Then,
toward acetate, benzoate, and dihydrogen phosphate. The alkyldiamine (1 equiv., 8.3 mmol) was added slowly to the
values of the association constants were in the range of 88 to anhydride mixture under stirring. The mixture was stirred for
299 Mꢀ1 for acetate, 65 to 109 Mꢀ1 for benzoate, and 167 to 698 24 h at reux temperature. Once the reaction was completed,
Mꢀ1 for dihydrogenphosphate. Noteworthy, the hydrogen the solvent was removed by heating under vacuum. The solid
pyrophosphate caused a partial or complete deprotonation to was washed and ltered as many times as needed to give an
most of the receptors, allowing the colorimetric detection of analytically pure compound.
this anion in DMSO. The association constants evaluated for
two of these receptors were 5840 and >104 Mꢀ1, respectively.
N,N'-(Ethane-1,2-diyl)bis(2-aminobenzamide) (2a). Beige solid,
80.6% yield. Mp 235–237 ꢁC. FTIR: 3473, 3367, 3277, 3057, 2944,
All the receptors previously described have a rigid connection 1626, 1580, 1540 cmꢀ1. 1H-NMR (400 MHz, DMSO-d6): d 8.29 (s,
between the two urea units, mainly alkenyl or aromatic back- 2H), 7.48 (d, J ¼ 8.0 Hz, 2H), 7.13 (t, J ¼ 8.0 Hz, 2H), 6.69 (d, J ¼
bones, which confers some structural preorganization in the 8.0 Hz, 2H), 6.50 (t, J ¼ 8.0 Hz, 2H), 6.38 (s, 4H), 3.47–3.22 (m,
anion recognition. Continuing with our interest in the synthesis 4H). 13C-NMR (101 MHz, DMSO-d6): d 169.1, 149.6, 131.6, 128.1,
of new receptors and the study of anion recognition,20 a series of 116.3, 114.8, 114.5, 36.0. HRMS (FAB+) calculated for
new oligomethylene bis(4-nitrophenylureylbenzamide) receptors
C16H19N4O2: 299.1508; found 299.1509.
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N,N'-(Propane-1,3-diyl)bis(3-aminobenzamide) (2b). White
N,N'-(Propane-1,3-diyl)bis(3-(3-(4-nitrophenyl)ureyl)benzamide)
solid, 40.8% yield. Mp 158–160 ꢁC. FTIR: 3470, 3355, 3294, 3055, (4c). Yellow solid, 84.8% yield. Mp 218–220 ꢁC. FTIR: 3278, 3218,
2967, 2931, 1625, 1576, 1531 cmꢀ1. 1H-NMR (400 MHz, DMSO- 3155, 3092, 2924, 2855, 1688, 1616, 1560, 1493 cmꢀ1. H-NMR
1
d6): d 8.21 (s, 2H), 7.47 (d, J ¼ 7.7 Hz, 2H), 7.13 (t, J ¼ 7.2 Hz, 2H), (400 MHz, DMSO-d6): d 10.58 (s, 2H), 10.41 (s, 2H), 8.77 (t, J ¼
6.69 (d, J ¼ 7.7 Hz, 2H), 6.51 (t, J ¼ 7.2 Hz, 2H), 6.37 (s, 4H), 3.27 5.3 Hz, 2H), 8.24 (dd, J ¼ 7.8, 1.2 Hz, 2H), 8.18 (d, J ¼ 9.3 Hz,
(brs, 4H), 1.81–1.61 (m, 2H). 13C-NMR (101 MHz, DMSO-d6): 4H), 7.75 (d, J ¼ 9.3 Hz, 4H), 7.70 (dd, J ¼ 7.8, 1.2 Hz, 2H), 7.48 (t,
d 168.8, 149.4, 131.4, 127.8, 116.2, 114.8, 114.5, 36.5, 29.2. J ¼ 7.3 Hz, 2H), 7.10 (t, J ¼ 7.5 Hz, 2H), 3.40 (q, J ¼ 6.4 Hz, 4H),
HRMS (FAB+) calculated for C17H21N4O2: 313.1665; found 1.88 (qnt, J ¼ 6.9 Hz, 2H). 13C-NMR (101 MHz, DMSO-d6):
313.1699.
d 168.2, 151.8, 146.5, 140.9, 139.0, 131.4, 127.8, 124.9, 121.6,
N,N'-(Butane-1,4-diyl)bis(3-aminobenzamide) (2c). White solid, 121.1, 120.7, 117.6, 28.7, 26.0. HRMS (FAB+) calculated for
72.2% yield. Mp 190–192 ꢁC. FTIR: 3469, 3557, 3284, 3056, 2930,
2860, 1621, 1578, 1534 cmꢀ1 1H-NMR (400 MHz, DMSO-d6):
C
31H29N8O8: 641.2108; found: 641.2122.
.
N,N'-(Butane-1,4-diyl)bis(3-(3-(4-nitrophenyl)ureyl)benzamide)
d 8.19 (t, J ¼ 4.9 Hz, 2H), 7.46 (d, J ¼ 7.85 Hz, 2H), 7.12 (t, J ¼ (4c). Yellow solid, 81.6% yield. Mp 230–232 ꢁC. FTIR: 3268, 3213,
7.4 Hz, 2H), 6.68 (d, J ¼ 7.85 Hz, 2H), 6.49 (t, J ¼ 7.4 Hz, 2H), 6.36 3154, 3087, 2949, 2871, 1693, 1617, 1561, 1496 cmꢀ1. H-NMR
1
(brs, 4H), 3.40–3.18 (m, 4H), 1.59–1.49 (m, 4H). 13C-NMR (101 (400 MHz, DMSO-d6): d 10.62 (s, 2H), 10.42 (s, 2H), 8.76 (t, J ¼
MHz, DMSO-d6): d 168.7, 149.4, 131.3, 127.9, 116.2, 114.9, 114.4, 5.5 Hz, 2H), 8.24 (dd, J ¼ 8.5, 0.9 Hz, 2H), 8.19 (d, J ¼ 9.3 Hz,
38.4, 26.7. HRMS (FAB+) calculated for C18H23N4O2: 327.1821; 4H), 7.76 (d, J ¼ 9.3 Hz, 4H), 7.68 (dd, J ¼ 7.8, 1.5 Hz, 2H), 7.46 (t,
found 327.1820.
J ¼ 8.5 Hz, 1H), 7.08 (t, J ¼ 7.8 Hz, 1H), 3.43–3.23 (m, 4H), 1.69–
N,N'-(Hexane-1,6-diyl)bis(3-aminobenzamide) (2d). White 1.55 (m, 4H). 13C-NMR (101 MHz, DMSO-d6): d 168.2, 151.9,
solid, 54.8% yield. Mp 158–160 ꢁC. FTIR: 3473, 3668, 3292, 3057, 146.7, 141.0, 139.1, 131.5, 127.8, 125.0, 121.6, 121.2, 120.7,
2926, 2858, 1622, 1581, 1538 cmꢀ1. 1H-NMR (400 MHz, DMSO- 117.7, 26.5, 25.1. HRMS (FAB+) calculated for C32H31N8O8:
d6): d 8.16 (t, J ¼ 4.4 Hz, 2H), 7.45 (d, J ¼ 7.9 Hz, 2H), 7.11 (t, J ¼ 655.2265; found: 655.2276.
7.4 Hz, 2H), 6.67 (d, J ¼ 7.9 Hz, 2H), 6.50 (t, J ¼ 7.4 Hz, 2H), 6.34
N,N'-(Hexane-1,6-diyl)bis(3-(3-(4-nitrophenyl)ureyl)benzamide)
(brs, 4H), 3.28–3.10 (m, 4H), 1.59–1.41 (m, 4H), 1.41–1.22 (m, (4d). Yellow solid, 91.9% yield. Mp 236–238 ꢁC. FT-IR: 3276,
4H). 13C-NMR (101 MHz, DMSO-d6): d 169.2, 150.0, 131.9, 128.5, 3216, 3155, 3090, 2964, 2868, 1697, 1621, 1564, 1497 cmꢀ1. 1H-
116.7, 115.6, 115.0, 39.2, 29.7, 26.8.
NMR (400 MHz, DMSO-d6): d 10.60 (s, 2H), 10.41 (s, 2H), 8.72 (t,
N,N'-(Octane-1,8-diyl)bis(3-aminobenzamide) (2e). Pearl solid, J ¼ 5.5 Hz, 2H), 8.23 (d, J ¼ 7.8 Hz, 2H), 8.18 (d, J ¼ 9.3 Hz, 4H),
36.1% yield. Mp 164–166 ꢁC. FTIR: 3475, 3670, 3292, 3057, 2926, 7.76 (d, J ¼ 9.3 Hz, 4H), 7.67 (dd, J ¼ 7.8, 1.2 Hz, 2H), 7.46 (t, J ¼
2858, 1622, 1581, 1538 cmꢀ1
.
1H-NMR (400 MHz, DMSO-d6): 8.1 Hz, 2H), 7.09 (t, J ¼ 8.1 Hz, 2H), 3.29 (q, J ¼ 6.6 Hz, 4H), 1.65–
d 8.15 (t, J ¼ 4.9 Hz, 2H), 7.45 (d, J ¼ 7.9 Hz, 2H), 7.11 (t, J ¼ 1.49 (m, 4H), 1.44–1.30 (m, 4H). 13C-NMR (101 MHz, DMSO-d6):
7.4 Hz, 2H), 6.67 (d, J ¼ 7.9 Hz, 2H), 6.49 (t, J ¼ 7.4 Hz, 2H), 6.35 d 168.2, 151.9, 146.7, 141.1, 139.1, 131.4, 127.8, 125.0, 121.7,
(brs, 4H), 3.19 (q, J ¼ 6.6 Hz, 4H), 1.56–1.41 (m, 4H), 1.36–1.19 121.4, 120.8, 117.7, 28.9, 26.3, 25.1.
(m, 8H). 13C-NMR (101 MHz, DMSO-d6): d 169.2, 150.0, 131.9,
N,N'-(Octane-1,8-diyl)bis(3-(3-(4-nitrophenyl)ureyl)benzamide)
128.5, 116.7, 115.6, 115.0, 39.3, 29.6, 29.3, 27.0. EM (FAB+): 383 (4e). Brown solid, 96.0% yield. Mp 236–238 ꢁC. FTIR: 3278 3218,
[M + H]+. HRMS (FAB+) calculated for C22H31N4O2: 383.2447; 3155, 3092, 2924, 2855, 1688, 1616, 1560 cmꢀ1. H-NMR (400
1
found: 383.2469.
MHz, DMSO-d6): d 10.59 (s, 2H), 10.41 (s, 2H), 8.70 (t, J ¼ 5.6 Hz,
Synthesis
of
oligomethylene
bis(2-nitro- 2H), 8.23 (dd, J ¼ 8.4, 1.0 Hz, 2H), 8.19 (d, J ¼ 9.3 Hz, 4H), 7.76
phenylureylbenzamide). In a round-bottom ask was dissolved (d, J ¼ 9.3 Hz, 4H), 7.66 (dd, J ¼ 8.0, 1.3 Hz, 2H), 7.47 (t, J ¼
the intermediate 2 (1 equiv., 1.70 mmol) in dry THF under an Ar 8.4 Hz, 2H), 7.09 (t, J ¼ 8.0 Hz, 2H), 3.27 (q, J ¼ 6.8 Hz, 4H), 1.62–
atmosphere. Then, 1-isocyanate-4-nitrobenzene 3 (2.2 equiv., 1.47 (m, 4H), 1.40–1.22 (m, 8H). 13C-NMR (101 MHz, DMSO-d6):
2.81 mmol) was slowly added to the mixture under stirring. The d 168.1, 151.9, 146.7, 141.0, 139.0, 131.4, 127.8, 125.0, 121.7,
mixture was stirred for 24 h at reux temperature. When the 121.4, 120.7, 117.7, 39.2, 28.8, 26.5. HRMS (FAB+) calculated for
reaction was completed, the solvent was removed by heating
under vacuum to obtain a solid, which was washed with
C
36H39N8O8: 711.2891; found: 711.2901.
Synthesis of oligomethylene bis(3-nitrophenylbenzamides).
different solvents and ltered as many times as needed to give In a 100 mL round-bottom ask with magnetic stirring, 3-
an analytically pure compound.
N,N'-(Ethane-1,2-diyl)bis(2-(3-(4-nitrophenyl)ureyl)benzamide)
nitrobenzoyl chloride (2.2 equiv.) was dissolved in 22 mL of dry
THF and stirred for 15 min under an Ar atmosphere. Then, Et3N
(4a). Yellow solid, 92.9% yield. Mp 214–216 ꢁC. FTIR: 3290, (0.3 mL) and dialkylamine (1.0 equiv.) were added dropwise,
3218, 3157, 3096, 2934, 2872, 1699, 1629, 1562, 1497 cmꢀ1. 1H- and the reaction mixture was stirred for 12 h. The solvent was
NMR (400 MHz, DMSO-d6): d 10.55 (s, 2H), 10.43 (s, 2H), 8.85 removed by heating under vacuum. The solid obtained was
(brs, 2H), 8.20 (d, J ¼ 9.3 Hz, 4H), 8.20 (dd, J ¼ 8.1, 1.0 Hz, 2H), washed with different solvents and ltered as many times as
7.75 (d, J ¼ 9.3 Hz, 4H), 7.71 (dd, J ¼ 8.1, 1.5 Hz, 2H), 7.43 (t, J ¼ needed to give an analytically pure solid.
8.3 Hz, 2H), 7.06 (t, J ¼ 8.3 Hz, 2H), 3.57–3.49 (m, 4H). 13C-NMR
N,N'-(Ethane-1,2-diyl)bis(3-(3-(4-nitrophenyl)benzamide)) (6a).
(101 MHz, DMSO-d6): d 168.4, 151.8, 146.6, 140.9, 139.0, 131.4, White solid, 88.7% yield. Mp 216–218 ꢁC. FTIR: 3300, 3079,
128.0, 124.9, 121.6, 121.2, 120.7, 117.6, 25.0. HRMS (FAB+) 2947, 2869, 1637, 1551, 1453 cmꢀ1. 1H-NMR (400 MHz, DMSO-
calculated for C30H27N8O8: 627.5940; found 627.5919.
d6): d 9.08 (s, 2H), 8.69 (t, J ¼ 2.2 Hz, 2H), 8.38 (ddd, J ¼ 8.2, 2.2,
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1.2 Hz, 2H), 8.32 (td, J ¼ 7.8, 1.2 Hz, 2H), 7.79 (t, J ¼ 8.2 Hz, 2H), DMSO-d6): d 167.0, 148.4, 135.1, 128.3, 116.1, 114.0, 112.6, 37.5.
3.57–3.48 (m, 4H). 13C-NMR (101 MHz, DMSO-d6): d 164.3, MS (FAB+) m/z: 299 [M + H]+. HRMS (FAB+) calculated for
147.6, 135.9, 133.6, 130.0, 125.7, 121.9, 36.5. MS (FAB+) m/z: 359
[M + H]+. HRMS (FAB+) calculated for C16H15N4O6: 359.0992;
found: 359.0981.
C
16H19N4O2: 299.1508; found: 299.1509.
N,N'-(Propane-1,3-diyl)bis(3-aminobenzamide) (7b). Brown
solid, 97.8% yield. Mp 98–100 ꢁC. FTIR: 3324, 3226, 3063, 2931,
N,N'-(Propane-1,3-diyl)bis(3-(3-(4-nitrophenyl)benzamide)) (6b). 1622, 1579, 1528, 1487 cmꢀ1 1H-NMR (200 MHz, DMSO-d6):
.
White solid, 90.5% yield. Mp 210–212 ꢁC. FTIR: 3363, 3098, d 8.29 (t, J ¼ 5.7 Hz, 2H), 7.08 (t, J ¼ 7.7 Hz, 2H), 7.05 (s, 2H), 6.96
1
2945, 2874, 1637, 1548, 1524, 1471 cmꢀ1. H-NMR (400 MHz, (d, J ¼ 7.7 Hz, 2H), 6.69 (ddd, J ¼ 7.7, 2.4, 1.0 Hz, 2H), 5.22 (brs,
DMSO-d6): d 8.93 (t, J ¼ 5.5 Hz, 2H), 8.68 (t, J ¼ 2.0 Hz, 2H), 8.38 4H), 3.35–3.20 (m, 4H). 13C-NMR (50 MHz, DMSO-d6): d 167.5,
(ddd, J ¼ 8.0, 2.0, 1.0 Hz, 2H), 8.31 (td, J ¼ 8.0, 2.0 Hz, 2H), 7.78 149.1, 136.0, 129.1, 116.8, 114.6, 113.2, 37.2, 29.8. MS (FAB+) m/
(t, J ¼ 8.0 Hz, 2H), 3.46–3.36 (m, 4H), 1.87 (qnt, J ¼ 6.9 Hz, 2H). z: 313 [M + H]+. HRMS (FAB+) calculated for C17H21N4O2:
13C-NMR (101 MHz, DMSO-d6): d 164.0, 147.7, 135.9, 133.5, 313.1665; found: 312.1699.
130.0, 125.7, 121.8, 37.4, 28.7. MS (FAB+) m/z: 373 [M + H]+.
N,N'-(Butane-1,4-diyl)bis(3-aminobenzamide) (7c). Orange
HRMS (FAB+) calculated for C17H17N4O6: 373.1148; found: solid, 69.2% yield. Mp 120–122 ꢁC. FTIR: 3433, 3332, 3222, 3057,
1
373.1143.
2943, 2866, 1647, 1583, 1547, 1520 cmꢀ1. H-NMR (200 MHz,
N,N'-(Butane-1,4-diyl)bis(3-(3-(4-nitrophenyl)benzamide)) (6c). DMSO-d6): d 8.23 (t, J ¼ 5.5 Hz, 2H), 7.04 (t, J ¼ 7.5 Hz, 2H), 7.01
White solid, 80.3% yield. Mp 242–244 ꢁC. FTIR: 3361, 3091, (s, 2H), 6.94 (ddd, J ¼ 7.5, 2.7, 1.1 Hz, 2H), 6.67 (ddd, J ¼ 7.5, 2.4,
1
2937, 2861, 1637, 1551, 1523, 1478 cmꢀ1. H-NMR (400 MHz, 1.3 Hz, 2H), 5.21 (brs, 4H), 3.32–3.12 (m, 4H), 1.52 (brs, 4H). MS
DMSO-d6): d 8.87 (t, J ¼ 5.4 Hz, 2H), 8.67 (t, J ¼ 2.0 Hz, 2H), 8.37 (CI+) m/z: 326 [M + H]+. HRMS (FAB+) calculated for C18H23N4O2:
(ddd, J ¼ 0.7, 2.0, 8.1 Hz, 1H), 8.29 (td, J ¼ 1.2, 8.1 Hz, 2H), 7.77 327.1821; found: 327.1820.
(t, J ¼ 8.1 Hz, 2H), 3.39–3.26 (m, 4H), 1.66–1.56 (m, 4H). 13C-
N,N'-(Hexane-1,6-diyl)bis(3-aminobenzamide) (7d). Melon
NMR (101 MHz, DMSO-d6): d 163.8, 147.6, 135.9, 133.5, 130.0, color solid, 80.3% yield. Mp 100–102 ꢁC. FTIR: 3390, 3324, 3218,
125.6, 121.7, 33.6, 26.4. MS (FAB+) m/z: 387 [M + H]+. HRMS 3054, 2928, 2854, 1625, 1582, 1533, 1489 cmꢀ1. H-NMR (200
1
(FAB+) calculated for C18H19N4O6: 387.1305; found: 387.1310.
MHz, DMSO-d6): d 8.18 (t, J ¼ 5.6 Hz, 2H), 7.00 (t, J ¼ 7.6 Hz, 2H),
N,N'-(Hexane-1,6-diyl)bis(3-(3-(4-nitrophenyl)benzamide)) (6d). 7.01 (s, 2H), 6.92 (td, J ¼ 7.6, 0.5 Hz, 2H), 6.66 (ddd, J ¼ 7.6, 2.0,
White solid, 59% yield. Mp 192–194 ꢁC. FTIR: 3309, 3100, 2935, 1.0 Hz, 2H), 5.19 (s, 4H), 3.31–3.08 (m, 4H), 1.63–1.40 (m, 4H),
2873, 1629, 1577, 1530, 1478 cmꢀ1. 1H-NMR (400 MHz, DMSO- 1.31 (brs, 4H). 13C-NMR (50 MHz, DMSO-d6): d 166.9, 148.6,
d6): d 8.83 (t, J ¼ 5.4 Hz, 2H), 8.67 (t, J ¼ 2.0 Hz, 2H), 8.37 (ddd, J 135.8, 128.5, 116.2, 114.2, 112.8, 39.0, 29.2, 26.3.
¼ 8.1, 2.3, 1.0 Hz, 2H), 8.28 (td, J ¼ 8.1, 1.3 Hz, 2H), 7.77 (t, J ¼
N,N'-(Octane-1,8-diyl)bis(3-aminobenzamide) (7e). Beige solid,
ꢁ
8.1 Hz, 2H), 3.38–3.24 (m, 4H), 1.63–1.47 (m, 4H), 1.46–1.30 (m, 337 mg, 0.88 mmol, 90.4% yield. Mp 120–122 C. FTIR: 3393,
4H). 13C-NMR (101 MHz, DMSO-d6): d 163.8, 147.7, 135.9, 133.5, 3349, 3208, 3054, 2926, 2853, 1625, 1583, 1538, 1490 cmꢀ1. 1H-
130.0, 125.6, 121.8, 39.3, 28.8, 26.1. MS (FAB+) m/z: 415 [M + H]+. NMR (200 MHz, DMSO-d6): d 8.17 (t, J ¼ 5.5 Hz, 2H), 7.15–6.85
HRMS (FAB+) calculated for C20H23N4O6: 415.4260; found: (d, J ¼ 7.8 Hz, 2H), 7.01 (s, 2H), 6.92 (dd, J ¼ 7.8, 1.2 Hz, 2H),
415.4268.
6.66 (td, J ¼ 7.8, 1.1 Hz, 1H), 5.19 (brs 4H), 3.19 (q, J ¼ 6.5 Hz,
N,N'-(Octane-1,8-diyl)bis(3-(3-(4-nitrophenyl)benzamide)) (6e). 4H), 1.58–1.39 (m, 4H), 1.28 (s, 8H). 13C-NMR (50 MHz, DMSO-
White solid, 59.0% yield. Mp 178–180 ꢁC. FTIR: 3312, 3100, d6): d 166.9, 148.6, 135.8, 128.5, 116.2, 114.2, 112.9, 29.2, 28.8,
1
2932, 2872, 1629, 1577, 1530, 1477 cmꢀ1. H-NMR (400 MHz, 26.5. MS (FAB+) m/z: 383 [M + H]+. HRMS (FAB+) calculated for
DMSO-d6): d 8.81 (s, 2H), 8.66 (s, 2H), 8.28 (d, J ¼ 7.3 Hz, 2H),
8.37 (d, J ¼ 8.1 Hz, 2H), 7.77 (t, J ¼ 7.3 Hz, 2H), 1.55 (m, 4H),
1.43–1.17 (m, 8H).
C
22H31N4O2: 383.2447; found: 383.2469.
Synthesis de oligomethylene
phenylureabenzamides). In a 100 mL round-bottom ask with
bis(p-nitro-
Synthesis of oligomethylene bis(3-aminobenzamides). In magnetic stirring, the oligomethylene bis(3-aminobenzamide)
a 100 mL round-bottom ask with magnetic stirring, Pd(10%)/C (1.0 equiv.) and the 4-nitrophenyl isocyanate (2.2 equiv.) were
(0.1 equiv.) and the oligomethylene bis(3-nitrobenzamide) were dissolved in dry THF (10 mL ꢂ 1 mmol). The mixture was stir-
added. The air in the ask was purged with Ar and MeOH was red for 24 h at RT under an argon atmosphere. Then, the solvent
added (10 mL ꢂ 1 mmol). The mixture was stirred for 20 min was removed by heating under vacuum. The solid obtained was
and then the Ar was purged with H2 to ensure a pure atmo- washed with different solvents and ltered as many as needed
sphere in the ask. Then, a balloon lled with H2 was connected times to give an analytically pure compound.
to the ask and the reaction mixture was stirred for 24 h.
N,N'-(Propane-1,3-diyl)bis(3-(3-(4-nitrophenyl)ureyl)benzamide)
Finally, the mixture was ltered to separate the catalyst and the (8b). Brown solid, 51.7% yield. Mp 184–186 ꢁC. FTIR: 3288,
solvent was removed by heating under vacuum to obtain the 3088, 1638, 1559 cmꢀ1. 1H-NMR (400 MHz, DMSO-d6): d 9.47 (s,
product.
2H), 9.08 (s, 2H), 8.49 (t, J ¼ 5.6 Hz, 2H), 8.20 (d, J ¼ 9.3 Hz, 4H),
N,N'-(Ethane-1,2-diyl)bis(3-aminobenzamide) (7a). Yellow 7.94 (t, J ¼ 1.7 Hz, 1H), 7.71 (d, J ¼ 9.3 Hz, 4H), 7.64 (ddd, J ¼ 7.9,
solid, 42.0% yield. Mp 280–282 ꢁC. FTIR: 3456, 3330, 3216, 3056, 2.2, 1.2 Hz, 2H), 7.50 (td, J ¼ 7.9, 1.2 Hz, 2H), 7.40 (t, J ¼ 7.9 Hz,
2949, 2912, 1632, 1579, 1537, 1486 cmꢀ1. H-NMR (200 MHz, 2H), 3.59–3.03 (m, 4H), 1.79 (qnt, J ¼ 6.8 Hz, 2H). 13C-NMR (101
1
DMSO-d6): d 8.33 (brs, 2H), 7.07 (t, J ¼ 7.7 Hz, 2H), 7.04 (brs, MHz, DMSO-d6): d 166.1, 151.9, 146.2, 141.0, 139.0, 135.4, 128.7,
2H), 6.95 (dd, J ¼ 7.8, 1.3 Hz, 2H), 6.69 (ddd, J ¼ 7.8, 2.1, 1.0 Hz, 125.0, 121.1, 120.1, 117.7, 117.5, 37.0, 29.2. MS (FAB+) m/z: 641
2H), 5.20 (brs, 4H), 3.64–3.21 (m, 4H). 13C-NMR (50 MHz,
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Fig. 1 Plausible interaction of oligomethylene bis(nitrophenylureylbenzamide) receptors with anions.
[M + H]+. HRMS (FAB+) calculated for C31H29N8O8: 641.2108;
Molecular modeling
found: 641.2143.
The molecular optimization of the geometries for the proposed
complexes was carried out by DFT method, using B3LYP and the
6-31G(d) base in the Gaussian 09 computational program.24
N,N'-(Buthane-1,4-diyl)bis(3-(3-(4-nitrophenyl)ureyl)benzamide)
(8c). Pink solid, 77.0% yield. Mp 262–264 ꢁC. FTIR: 3256, 3058,
1633, 1535 cmꢀ1. 1H-NMR (400 MHz, DMSO-d6): d 9.45 (s, 2H),
9.06 (s, 2H), 8.46 (t, J ¼ 5.5 Hz, 2H), 8.20 (d, J ¼ 9.4 Hz, 4H), 7.91
(t, J ¼ 1.8 Hz, 2H), 7.71 (d, J ¼ 9.4 Hz, 4H), 7.63 (ddd, J ¼ 8.0, 2.2,
1.2 Hz, 2H), 7.49 (td, J ¼ 8.0, 1.1 Hz, 2H), 7.39 (t, J ¼ 8.0 Hz, 2H),
3.32–3.21 (m, 4H), 1.64–1.51 (m, 4H). 13C-NMR (101 MHz,
DMSO-d6): d 166.0, 151.9, 146.2, 141.0, 139.0, 135.5, 128.6,
125.0, 121.0, 120.9, 117.8, 117.5, 38.9, 26.7. MS (FAB+) m/z: 655
[M + H]+. HRMS (FAB+) calculated for C32H31N8O8: 655.2265;
found: 656.2221.
N,N'-(Hexane-1,6-diyl)bis(3-(3-(4-nitrophenyl)ureyl)benzamide)
(8d). Yellow solid, 70.8% yield. Mp 241–243 ꢁC. FTIR: 3328,
3093, 1624, 1550 cmꢀ1. 1H-NMR (400 MHz, DMSO-d6): d 9.45 (s,
2H), 9.05 (s, 2H), 8.42 (t, J ¼ 5.1 Hz, 2H), 8.19 (d, J ¼ 9.0 Hz, 4H),
7.90 (s, 2H), 7.70 (d, J ¼ 9.0 Hz, 4H), 7.62 (d, J ¼ 8.1 Hz, 2H), 7.47
(d, J ¼ 7.6 Hz, 2H), 7.38 (t, J ¼ 7.8 Hz, 2H), 3.29–3.15 (m, 4H),
1.61–1.45 (m, 4H), 1.42–1.27 (m, 4H). MS (FAB+) m/z: 683 [M +
H]+. HRMS (FAB+) calculated for C34H35N8O8: 683.2578; found:
683.2586.
Results and discussion
Synthesis and characterization
The synthesis of bis(ureas) 4 (ortho receptors) started with the
reaction of isatoic anhydride (1) and an alkyldiamine (a: ethane-
1,2-diamine, b: propane-1,3-diamine, c: buthane-1,4-diamine,
d: hexane-1,6-diamine, e: octane-1,8-diamine) in THF at reux
temperature to obtain the corresponding oligomethylene bis(2-
aminobenzamides) 2 with 81%, 41%, 72%, 55%, and 36%
yields, respectively. The intermediates 2 were directly reacted
with 4-nitrophenyl isocyanate in THF to obtain receptors 4 in
93%, 85%, 82%, 92%, and 96% yields, respectively (Scheme 1).
An ortho mono-ureylbenzamide was synthetized under the same
experimental conditions using propylamine in a 36% global
yield.
N,N'-(Octane-1,8-diyl)bis(3-(3-(4-nitrophenyl)ureyl)benzamide)
(8e). Yellow solid, 97% yield. Mp 266–268 ꢁC. FTIR: 3278, 3082,
In the FTIR spectra, stretching N–H vibrations for amide and
urea groups were observed in the range of 3154 to 3290 cmꢀ1
.
2930, 2855, 1706, 1628, 1585, 1543 cmꢀ1. H-NMR (400 MHz,
1
The vibrations for urea carbonyls were found at 1705 to
1720 cmꢀ1 and the amide carbonyls at 1688 to 1705 cmꢀ1. The
1H NMR spectra display the typical ABCD pattern for the ortho-
disubstituted benzamide and the A2B2 pattern for the nitro-
phenyl group. Both urea hydrogens are shied downeld in the
range of 10.40 to 10.62 ppm and the amide hydrogen at 8.70 to
8.85 ppm. The signals for the aliphatic hydrogens appear
upeld (Fig. S1–S6†).
DMSO-d6): d 9.46 (s, 2H), 9.06 (s, 2H), 8.41 (t, J ¼ 5.5 Hz, 2H),
8.20 (d, J ¼ 9.3 Hz, 4H), 7.90 (t, J ¼ 1.8 Hz, 2H), 7.71 (d, J ¼
9.3 Hz, 4H), 7.63 (ddd, J ¼ 8.0, 2.2, 1.0 Hz, 2H), 7.47 (td, J ¼ 8.0,
1.5 Hz, 2H), 7.38 (t, J ¼ 8.0 Hz, 2H), 3.29–3.19 (m, 4H), 1.61–1.45
(m, 4H), 1.32 (s, 8H). 13C-NMR (101 MHz, DMSO-d6): d 165.8,
151.8, 146.1, 140.8, 138.8, 135.4, 128.5, 124.9, 120.7, 117.6,
117.3, 39.0, 28.9, 28.6, 26.3.
Scheme 1
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Scheme 2
For the synthesis of bis(ureas) 8 (meta receptors), 3-nitro- 80%, 59%, and 25% yields, respectively. Then, the nitro groups
benzoyl chloride (5) was reacted with a dialkylamine in the were reduced to amino using an H2 atmosphere and Pd (10%)/C
presence of TEA at RT in anhydrous THF. The bis-(3-nitro- at RT in dry MeOH. The bis-(3-aminobenzamide) intermediates
benzamide) intermediates 6 were obtained with 88%, 90%, 7 were obtained with 42%, 98%, 69%, 80%, and 90% yields.
Fig. 2 UV-vis spectra and absorbance profiles obtained in the titration of 4d (a and b) and 8d (c and d) with TBAA in acetonitrile [4d] and [8d] ¼ 1
ꢂ 10ꢀ5 M.
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Compounds 7 were reacted with 4-nitrophenyl isocyanate in the ortho position. The acidity and the spatial availability of
THF to obtain the bis-urea receptors 8 in 52%, 77%, 71%, and these hydrogens depends on the position and may result in
97% yields (Scheme 2). A meta mono-ureylbenzamide was syn- different interaction strength with anions.
thetized under the same experimental conditions using pro-
pylamine in a 20% global yield.
Study of anion recognition by UV-vis
In the FTIR spectra, stretching N–H vibrations for amide and
urea groups were observed in the range of 3221 to 3331 cmꢀ1
.
The ortho and meta N-propyl ureabenzamides and receptors 4
and 8 presented an absorption band at 330–340 nm due to the
nitrophenyl chromophore. The changes in this band were
monitored by titration with different TBAX salts (X ¼ AcOꢀ (A),
The vibrations for urea carbonyls were found in the range 1706–
1714 cmꢀ1 and the amide carbonyls in the range 1625–
1640 cmꢀ1. In the 1H NMR spectra, the typical ABCX pattern for
the meta-disubstituted benzamide and the A2B2 pattern for the
nitrophenyl group were observed. Both urea hydrogens were
shied downeld in the range of 9.05 to 9.47 ppm and the
amide hydrogen at 8.41 to 8.49 ppm. The signals for the
aliphatic hydrogens appeared upeld (Fig. S7–S11†).
The chemical shi of urea and amide hydrogens in receptors
4 and 8 was directly related with the relative position of both
functional groups, which was the result of a combination of
resonance and inductive effects. The effect of the two electron-
withdrawing groups, i.e., the nitrophenyl and benzamide, over
these hydrogens was dramatically enhanced when they were in
BzOꢀ (B), Fꢀ (F), H2PO4 (HP), and HP2O7 (HPP)) in aceto-
nitrile. All the receptors showed spectral changes in the titration
depending on the receptor structure and the anion. Fig. 2 shows
the spectra obtained in the titration of receptors 4d and 8d with
TBAA in acetonitrile. There were bathochromic and hypo-
chromic shis in the absorption of receptor 4d at 338 nm
during the titration, indicating the interaction with the anion,
while there were bathochromic and hyperchromic shis in the
absorption band at 336 nm in receptor 8d. A new maximum
absorbance band was observed at 362 nm. As can be seen, the
changes in 8d were more evident than in 4d. In general, there
ꢀ
3ꢀ
Table 1 Association constants (log K)a for receptors 4 with TBAX salts Table 2 Association constants (log K)a for receptors 8 with TBAX salts
determined by UV-vis in CH3CN determined by UV-vis in CH3CN
Receptor
X
log K11
log K12
log K21
Receptor
X
log K11
log K12
log K21
13.7(4)
13.5(2)
AcOꢀ
BzOꢀ
Fꢀ
10.11(2)
10.92(2)
AcOꢀ
BzOꢀ
Fꢀ
H2PO4
HP2O7
7.5(2)
5.931(4)
8.1(2)
6.31(1)
6.31(1)
5.62(1)
5.09(2)
ꢀ
ꢀ
3ꢀ
H2PO4
12.1(1)
4a
4b
4c
4d
4e
AcOꢀ
BzOꢀ
Fꢀ
H2PO4
HP2O7
AcOꢀ
BzOꢀ
Fꢀ
H2PO4
HP2O7
AcOꢀ
BzOꢀ
Fꢀ
H2PO4
HP2O7
AcOꢀ
BzOꢀ
Fꢀ
6.51(2)
5.322(4)
6.64(6)
6.3(1)
5.55(4)
5.689(4)
4.661(4)
6.08(5)
5.2(1)
4.86(6)
6.012(8)
4.941(2)
6.34(7)
7.54(6)
5.73(5)
5.321(2)
4.806(3)
6.07(4)
6.55(2)
7.4(4)
8a
8b
8c
8d
8e
AcOꢀ
BzOꢀ
Fꢀ
H2PO4
HP2O7
AcOꢀ
BzOꢀ
Fꢀ
H2PO4
HP2O7
AcOꢀ
BzOꢀ
Fꢀ
H2PO4
HP2O7
AcOꢀ
BzOꢀ
Fꢀ
6.84(2)
6.007(6)
5.050(4)
5.76(5)
12.87(5)
11.9(1)
ꢀ
3ꢀ
ꢀ
3ꢀ
11.17(4)
10.75(7)
10.38(5)
11.27(9)
13.9(9)
10.93(2)
10.94(1)
14.3(1)
5.90(5)
5.83(4)
8.4(3)
10.0(2)
9.83(9)
13.9(3)
11.29(1)
11.41(4)
10.64(6)
ꢀ
3ꢀ
ꢀ
3ꢀ
5.932(8)
5.502(6)
5.160(5)
8.6(3)
11.98(7)
12.50(8)
14.7(3)
10.51(3)
ꢀ
3ꢀ
ꢀ
3ꢀ
5.12(3)
7.02(7)
6.01(5)
5.80(3)
5.20(2)
7.74(7)
6.80(9)
5.89(6)
5.55(5)
10.0(2)
10.25(5)
11.50(3)
ꢀ
3ꢀ
ꢀ
3ꢀ
H2PO4
HP2O7
AcOꢀ
BzOꢀ
Fꢀ
H2PO4
HP2O7
AcOꢀ
BzOꢀ
Fꢀ
13.43(7)
14.5(1)
4.997(3)
4.716(3)
9.8(5)
9.2(4)
9.14(2)
12.24(7)
ꢀ
3ꢀ
ꢀ
3ꢀ
H2PO4
HP2O7
6.85(2)
6.9(1)
H2PO4
HP2O7
6.07(3)
11.88(4)
13.3(3)
11.90(3)
a
a
Standard deviation of the t is given in parenthesis.
Standard deviation of the t is given in parenthesis.
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Fig. 3 Partial 1H-NMR spectra of free 4b and with two molar equivalents of TBAA, TBAB, TBAHP, and TBAF in DMSO-d6.
were more evident spectroscopic changes in receptors 8 than in were added. This was probably due to the higher number
receptors 4, which was directly related to the relative position of negative charges and the geometry of this anion. The TBAHPP
the urea and benzamide groups in these receptors (Fig. S12– salt induced a partial deprotonation at the ortho N-propyl ure-
S23†). All the receptors showed a spectroscopic response toward abenzamide, which was evidenced by the presence of a band at
the studied anions. However, the TBHPP induced the greatest 450 nm (Fig. S12i†). However, this new band was not observed
changes in the absorption bands when lower molar equivalents
Fig. 4 Partial 1H-NMR spectra obtained in the titration of 4b (6 mM) with TBAA in DMSO-d6.
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Table 3 Association constants (log K)a for the complexes of receptors
4 with different TBAX salts determined by H-NMR
and TBAHPP, which agreed with the possible cooperativity of
both ureylbenzamide units in receptors 4 with the shorter oli-
gomethylene spacer chains, and 1 : 1 complexes with TBAF and
TBAHP. This behavior was not observed with the previously
reported N-benzyl ortho mono-ureylbenzamide,20 where all the
complexes had a 1 : 1 stoichiometry and the log K values ranged
from 3.85 to 4.35. Thus, the stoichiometry and affinity toward
the anions were improved with the N-propyl substituent. All
receptors 4 formed exclusively a 1 : 1 complex with TBAA and
TBAB and there was a tendency for the log K11 to decrease as the
oligomethylene chain length increased. This behavior suggests
the cooperativity of both ureylbenzamide units interacting with
the carboxylate unit in these complexes. Two complexes with
1 : 1 and 1 : 2 (receptor : anion) stoichiometry were observed
with TBAF and TBAHP; in particular, receptor 4e formed only
the 1 : 2 complex. Noteworthy, two complexes with 2 : 1 and
1 : 1 stoichiometry were detected with TBAHPP and the values
of log K11 and log K21 increased as the spacer length increased.
This unusual behavior with pyrophosphate was due to its
differences in size, shape, and charge. Also, the log K11 values
for uoride and phosphate complexes with receptors 4 were one
or two units higher compared to the mono ureylbenzamide,
which may indicate a cooperative effect of both interaction
sites.
1
Receptor
X
log K11
log K12
AcOꢀ
BzOꢀ
H2PO4
1.902(9)
1.701(7)
2.23(1)
ꢀ
4b
4c
4d
AcOꢀ
BzOꢀ
H2PO4
AcOꢀ
BzOꢀ
H2PO4
AcOꢀ
BzOꢀ
H2PO4
2.09(2)
1.99(4)
3.1
2.02(2)
2.11(1)
2.5
1.92(4)
1.85(2)
2.3
5.6
5.1
4.1
ꢀb
ꢀb
ꢀb
a
b
Standard deviation of the t is given in parenthesis. Excessive
standard deviation.
in the titrations of meta N-propyl ureabenzamide and receptors
4 and 8.
Table 1 lists the association constants (log K) for the
complexes of receptors 4 calculated from the absorbance data
using the HypSpec program,21–23 and are compared with those
obtained with the ortho mono-ureylbenzamide receptor. Inter-
estingly, the N-propyl mono-ureylbenzamide formed complexes
with a 2 : 1 (receptor : anion) stoichiometry with TBAA, TBAB,
Table 2 lists the association constants (log K) for the
complexes of receptors 8 calculated from the absorbance data
using the HypSpec program21–23 and these are compared with
those obtained with the corresponding meta mono-
ureylbenzamide. The mono-ureylbenzamide mainly formed
Fig. 5 Partial 1H-NMR spectra of free 8b and with two molar equivalents of TBAA, TBAB, TBAHP, and TBAF in DMSO-d6.
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Fig. 6 1H NMR spectra obtained in the titration of 8b with TBAA in DMSO.
complexes of a 1 : 1 receptor–anion stoichiometry with all the receptors 8 formed complexes with both 1 : 1 and 1 : 2 stoichi-
TBAX salts, and formed 2 : 1 complexes with acetate and uo- ometries with the TBAX salts, and a 2 : 1 complex with TBAHPP.
ride, indicating a different behavior with its ortho analogue. The This anion may serve as a template for the self-assembly of two
log K values were one to three units higher than those obtained receptor molecules at low concentration, and there was
with the N-benzyl ortho mono-ureylbenzamide previously re- a tendency for log K21 to increase as the oligomethylene chain
ported,20 evidencing the positive effect of the N-propyl substit- length increased, indicating a higher affinity. The receptor 8a
uent in the affinity toward anions. Also, there were difference in (with the shorter spacer chain) formed a 1 : 1 complex with
the complex stoichiometries with TBAA and TBAF. In general,
Fig. 7 1H NMR spectra obtained in the titration of 8b with TBAHP in DMSO-d6.
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TBAA, TBAB, and TBAF and a 1 : 2 complex with TBAHP, while TBAA and TBAB. Both log K11 and log K12 values depended on
8c did this with TBAA and TBAB.
the oligomethylene chain length decreasing as the oligo-
methylene chain increased. The values of log K with TBAF and
TBAHPP could not be calculated due to the deprotonation
reaction. The stoichiometry of the supramolecular complexes
1
Study of anion recognition by H NMR
The interaction of the ortho monorureylbenzamide, 4b, 4c, and was in agreement with those found by UV-vis for these
4d with TBAA, TBAB, TBAF, TBAHP, and TBAHPP was analyzed receptors.
by 1H NMR in DMSO-d6 due to the solubility of these receptors
The interaction of the receptors meta mono-ureylbenzamide,
(Fig. S24–S43†). As depicted in Fig. 3, all the anions promoted 8b, 8c, and 8d with TBAA, TBAB, TBAF, TBAHP, and TBAHPP
different changes in the NMR signals of receptor 4b once the was analyzed by 1H NMR in DMSO-d6 (Fig. S44–S63†). As seen in
complex was formed in solution because of their differences in Fig. 5, all the TBAX salts promoted different changes in the
size, shape, and basicity. There was a non-equivalent downeld signals of receptor 8b once the complex was formed in solution.
shi of the urea signals with TBAA and TBAB, indicating that Here, an equivalent downeld shi of the urea signals with
both hydrogens H1 and H2 interacted with the anion, but not TBAA and TBAB was observed, indicating that both hydrogens
with the same strength. The spectra obtained during the titra- interacted with the anion with the same strength. The spectra
tion (Fig. 4) indicated that H2 was more affected than H1. Also, it obtained during the titration with TBAA (Fig. 6) indicated that
is interesting that the amide hydrogen (H3) signal was broad- both H2 and H1 were gradually shied downeld when up to
ened, which means this hydrogen was also involved in the two equivalents of TBAA were added. The amide hydrogen (H3)
complex, and the H4 hydrogen at the ortho position to the amide slightly shied to upeld and interestingly, the hydrogen at the
carbonyl shied to upeld when the interaction with the anion amide carbonyl and urea ortho position (H4) shied to down-
occurred. The same spectral changes were observed in the other eld, suggesting a bond polarization due to a C–H/O interac-
the receptors with these anions.
tion in the complex. This effect over the H4 signal was stronger
There was a downeld shi and broadening of the H1, H2, with TBAB than with TBAA, and it was partially lost by
and H3 signals, indicating a strong participation of the three increasing the oligomethylene chain length in receptors 8c and
hydrogens in the supramolecular complex with TBAHP. Again, 8d.
H2 was more affected than H1 and H4, being considerably
The successive formation of three different complexes was
shied upeld, probably due to a conformational change in the detected in the titration of 8b with TBAHP (Fig. 7). The two urea
amide group, where the “ortho effect” over H4 was avoided. In signals were shied downeld with the same magnitude when
the titration with TBAF, all the NH hydrogens disappeared, one equivalent of TBAHP was added. Then, the chemical shi of
indicating an acid–base reaction; a change of color also H1 was higher than H2 when from one to three equivalents of
occurred in the solution. The titration with TBAHPP showed the anion was added, but beyond this concentration it remained
deprotonation of urea hydrogens since the rst anion aliquot constant. The signal of H2 was gradually shied downeld when
due to an acid–base reaction. Also, the signal of the amide up to two equivalents of anion were added. The amide signal
hydrogens H3 underwent a downeld shi and widening, became wide when one equivalent of anion was added, and was
indicating a strong interaction with this hydrogen. The signal then shied downeld with the addition from one to three
for H4 was considerably shied to upeld and became broad.
Noteworthy, there were exceptional changes in the NMR spectra
Table 4 Association constants (log K)a for the complexes of receptor
8 with different TBAX salts determined by H-NMR in DMSO-d6
when more than two equivalents of TBAHPP were added to the
solution. The signals of the A2B2 system for the nitrophenyl
group were collapsed in one signal, and the rest of the signals
showed signicant changes in their chemical shis and become
broad. The same patterns were observed with the rest of the
studied receptors (Fig. S28, S33, S38 and S43†).
The association constants for the complexes of ortho mono-
ureylbenzamide, 4b, 4c, and 4d receptors were calculated from
the chemical shis data using the HypNMR program21–23 and
are reported in Table 3. As expected, the ortho mono-
ureylbenzamide receptor formed complexes with a 1 : 1 stoi-
chiometry with all the studied anions. The chemical shi
proles obtained with TBAA and TBAB tted the 1 : 1 stoichi-
ometry model, and the values of log K11 decreased as the oli-
gomethylene chain length increased in receptors 4. These
association constants are comparable to those reported in the
literature for other receptors,19 even though receptors 4 had
a exible interconnection chain. The chemical shi proles in
the titration with TBAHP tted 1 : 1 and 1 : 2 stoichiometries
and the values of log K11 were higher than those obtained with
1
Receptor
X
log K11
log K12
log K13
AcOꢀ
BzOꢀ
H2PO4
3.61(6)
3.25(3)
5.0
ꢀb
8.2
11.0
8b
8c
8d
AcOꢀ
BzOꢀ
H2PO4
AcOꢀ
BzOꢀ
H2PO4
AcOꢀ
BzOꢀ
H2PO4
4.1(1)
5.3(4)
5.1
7.6(2)
8.9(7)
9.4
5.46(8)
5.33(1)
9.0
5.29(1)
5.91(9)
4.47
12.6
11.3
ꢀb
ꢀb
ꢀb
4.9
3.0(6)
2.50
a
b
Standard deviation of the t is given in parenthesis. Excessive
standard deviation.
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Fig. 8 Optimized structures of monoureabenzamide-TBAA complexes I (a) and II (b) by DFT.
equivalents and then remained constant. Interestingly, the Then, all the signals recovered their multiplicity when 1.2
signal of H4 was shied to upeld and the signal of H7 was equivalents were added, and the H3 signal was shied
shied to downeld, indicating a signicant change in the 1.8 ppm downeld, indicating the interaction with the anion.
chemical environment of these hydrogens. Considering the These changes showed the formation of a 1 : 1 complex.
changes of the signals, the urea hydrogens as well as the amide Interestingly, an additional signal shied about 0.5 ppm
hydrogen equally participated in the 1 : 1 complex (see appeared for H3, and the two signal of the nitrophenyl group
Fig. S66†), while the hydrogens H1 and H3 were more affected in collapsed into one at 2.4 equivalents of TBAHPP added,
the 1 : 2 complex. The chemical shis of H4 and H7 indicated showing changes in the complex. All these changes in the
a conformational change in the receptor, allowing the interac- NMR spectra indicated an acid–base reaction, but also the
tion with a third anion unit, where the H1 and H3 hydrogens interaction with the anion in different forms depending on
were the most affected. Receptors 8c and 8d showed a similar the anion concentration.
signal pattern with TBAHP, although the H3 signal was less
affected as the oligomethylene chain increased (Fig. S57 and receptors meta mono-ureylbenzamide, 8b, 8c, and 8d were
S62†). calculated from the chemical shis and are reported in Table 4.
The association constants (log K) for the complexes of
The titrations of 8b, 8c, and 8d with TBAHPP showed The meta mono-ureylbenzamide formed 1 : 1 complexes with
deprotonation of the urea groups since the rst aliquot was TBAA and TBAB salts, and the data tting showed the presence
added. Interestingly, all the signals become broad and shif- of additional complexes with TBAHP. The chemical shi
ted in different ways, indicating three clear stages during the proles obtained with TBAA and TBAB tted with a 1 : 1 and
course of the titration. All the signals showed the maximum 1 : 2 stoichiometry model, where the values of log K decreased
broadening between 0.4 and 0.6 molar equivalents of as the oligomethylene chain length increased in receptors 8.
TBAHPP added, suggesting a 2 : 1 (receptor : anion) complex. The values of log K were considerably superior compared to
The same behavior was also found with the UV titrations. those obtained with receptors 4.
Fig. 9 Optimized structures III (a) and IV (b) for complex 4b-AcOꢀ by DFT.
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Fig. 10 Optimized structures V (a) and VI (b) for the complexes 4b-H2PO4ꢀ and 4b-HP2O73ꢀ by DFT.
1
The results obtained by UV-vis and H NMR demonstrated anions in receptors 4, where the two ureylbenzamide units
that receptors 4 and 8 established interactions with all the participated in the interaction with one unit of the anion. Also
anions (TBAX salts) used in the study. However, there were the increase of the association constants in the receptors with
signicant differences regarding the urea and amide position, the shorter oligomethylene chains (4a and 4b) conrmed
the oligomethylene chain length, and the geometry and charge a major cooperativity between the two units due to their prox-
of the anion. Receptors 8 showed more evident spectroscopic imity. Instead, there was an opposite tendency with TBAHPP in
changes due to the interaction with the anion compared with both 1 : 1 and 2 : 1 (receptor : anion) complexes, probably due
the observed response of receptors 4, which was attributed to to the different geometry and higher number of negative
the different position of the urea and amide groups in the charges. The successive formation of 1 : 1 and 1 : 2 complexes
receptors. The values of the association constants obtained by with TBAF and TBAHP indicated a low stability of the 1 : 1
UV-vis were in the same orders for both types of receptors complexes, probably due to size and geometry of these anions
(log K11 ¼ 4–8, log K12 ¼ 10–15, log K21 ¼ 10–15). This similarity compared with the carboxylates and pyrophosphate.
in the affinity was related to the strength of the interaction with
The successive formation of 1 : 1 and 1 : 2 with TBAA, TBAB,
the anions, considering that in receptors 4, three hydrogen TBAF, and TBAHP, and only 2 : 1 complexes with TBAHPP at low
bonding per each ureabenzamide unit may participate in the concentration occurred in receptors 8, where this latter case is
supramolecular complex, as was observed in the NMR analysis. an interesting peculiarity. A signicant difference in receptors 8
The tting of the absorbance data revealed the formation of was the strong equivalent interaction of the urea hydrogens and
2 : 1 (receptor : anion) complexes with TBAA, TBAB, and the apparent C–H/O interaction with carboxylates. Interest-
TBAHPP with the ortho mono-ureylbenzamide. This behavior ingly, the tetrahedral geometry of dihydrogen phosphate
was consistent with the formation of 1 : 1 complexes with these induces an interaction with the receptor with different
Fig. 11 Optimized structures for the complexes 4c-AcOꢀ and 4d-AcOꢀ by DFT.
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stoichiometries, where even the amide hydrogen is involved in
the 1 : 2 and 1 : 3 complexes (receptor : anion). The formation
of higher ratio complexes with TBAHP even with the meta N-
propyl ureabenzamide up to 1 : 3 was rather unexpected. The
tting quality with this anion was also poor, but all attempts to
exclude the higher ratio complexes failed; tting to a simpler
model always was divergent and did not allow any estimate of
the binding constants. We believe that these complications
resulted from the recently established strong auto-association
of dihydrogen phosphate anion, particularly complicated by
a possible contribution of free phosphoric acid, which may be
generated by water traces in the solvent employed.25 Moreover,
the UV-vis and NMR studies with TBAHPP demonstrated the
formation of supramolecular complexes of different stoichi-
ometries with all receptors at high concentration, which was
consistent with the tendency observed in the UV-vis studies at
low concentration.
Theoretical calculations of the supramolecular complexes
In order to support these experimental ndings, the geometries
of the supramolecular complexes were optimized by theoretical
calculations using DFT with a B3LYP 6-31G(d) basis set.24 First,
the mono-ureylbenzamide complexes with AcOꢀ were calcu-
lated and interesting differences were observed (Fig. 8). The
distance between the urea hydrogens H1 and H2 and the
carboxylate was not equivalent, indicating a different strength
in the ortho complex (structure I), and a strong interaction with
amide hydrogen. The inequivalent chemical shi of the urea
hydrogen signals and broadening of the amide hydrogen in the
NMR spectra is now evident (Fig. S24†). Also, the amide
carbonyl lay out of the plane with the aromatic ring, which is
consistent with the upeld shi of H4 signal in the NMR
spectra, indicating the loss of the “ortho effect” over this
hydrogen by the carbonyl. In the meta complex (structure II), the
H1, H2, H3, and H4 hydrogens were oriented toward the
Fig. 12 Optimized structures for the complexes 8b-AcOꢀ (a and b) and 8d-AcOꢀ (c and d) by DFT.
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carboxylate; the interaction of both urea hydrogens was equiv- interacting groups were minimal and the hydrogen bonding
alent and an interaction with amide hydrogen was present, but was established in the cavity of the receptor in this arrange-
the distance between the carboxylate and the hydrogen was ment. The ureylbenzamide units adopted a perpendicular
longer than that observed for the ortho complex. In this complex position to form a compact cavity, where H1, H2, H3, and H4
˚
the distance of the C–H4 with the carboxylate was about 2.2 A, were oriented to the anion in the complex of 8d with acetate
indicating a C–H/O interaction which was consistent with the (Fig. 12c and d). The exibility of the oligomethylene spacer
downeld of the H4 signal during the titration. The interactions chain allowed the necessary conformational changes to form
in this model are in agreement with the results obtained in the a 1 : 1 complex despite the distance between both ure-
NMR experiment (Fig. S44†).
ylbenzamide in these receptors (Fig. S65†).
Then, the interaction of 4b with AcOꢀ was analyzed, opti-
The optimization of the complexes with phosphate and
mizing a complex in which the AcOꢀ interacts only with one pyrophosphate showed congurational changes in the oligo-
ureylbenzamide unit (structure III) and another structure where methylene chain induced by the size and geometry of the anion
both units participate in the complexation (structure IV). This in order to minimize the distance between the interaction sites
calculation was done in order to elucidate which complex would and the anions (Fig. S66 and S67†). Interestingly, the complexes
be favored based on their total energy. The results indicated with 8b showed both anions located in a supercial position on
that structure IV was 9.76 kcal molꢀ1 more stable than structure the cavity formed by the two ureylbenzamide units. The
III (Fig. 9). As can be seen in Fig. 9a, complex IV showed more distances allowed the interaction of the anions with the H1, H2,
hydrogen bond interactions between the receptor and the AcOꢀ H3, and H4 hydrogens. The receptors 8d and 8e with a longer
compared with complex III and the nitrophenyl groups appear oligomethylene spacer formed a big cavity and the anions
face to face, indicating a possible additional interaction. This occupied an internal or equatorial position. These observations
structure agrees with the chemical shis and the signals partially explain or justify the high values of log K for 1 : 1
affected during the titration with TBAA by NMR, which are very complexes in receptors with long spacer chain.
similar to those observed with the mono-ureylbenzamide
(Fig. 4).
ꢀ
3ꢀ
The complexes with H2PO4 and HP2O7 were also opti- Conclusions
ꢀ
mized (Fig. 10). In the 1 : 1 4b-H2PO4 complex (structure V),
The results obtained by UV-vis and 1H NMR as well as the values
both urea units interacted with the anion through the N–H2,
leaving the N–H1 free, while only one of the N–H3 interacted
with the anion. This means that three sites were available to
interact with a second anion. In fact, the NMR experiment
showed a wide signal for H1 with the TBAHP addition but no
shi to downeld was observed (see Fig. S32†). This result was
consistent with the experimental observed tendency of these
receptors to form multi-equivalent complexes with H2PO4ꢀ. The
of log K and the theoretical analysis revealed a strong interac-
tion of receptors 4 and 8 with the anions due to their bifunc-
tionality. The exible oligomethylene chain in these receptors
enhance the possibility to adopt different conformational
arrangement to form 1 : 1 complexes regardless of differences
in the size and shape of the anion. Receptors 4 formed 1 : 1
complexes with carboxylates due to the singular helical
conformation of the receptors, which is an obvious conse-
quence of the relative ortho position of the urea and amide
groups. The anions with different sizes and geometries also
formed 1 : 1 complexes, but the helical conformation was dis-
torted to maximize the interactions. These results also revealed
the formation of complexes with variable stoichiometry with
dihydrogen phosphate and pyrophosphate due to their geom-
etry, charge number, and autoassociation process.
3ꢀ
complex with HP2O7 showed deprotonation of the N–H2 in
one urea unit. This acid–base reaction was evident in the NMR
titrations, and a change of color in the solution was also
observed. Almost all the hydrogen bonding sites interacted with
the anion in the complex.
It was noteworthy that the complexes of 4c and 4d with AcOꢀ
showed a helical conformation, where both ureylbenzamide
units had a coplanar and antiparallel position allowing the
interaction with the anion through ve hydrogen bonds
(Fig. 11). The enhancement of the spacer chain from four to six
methylenes favored the coplanarity between the two units. The
complex with BnOꢀ showed a similar helical conformation
(Fig. S64†). This singular conformation with the carboxylate
anions may induce the exclusive formation of 1 : 1 complexes,
as identied by the UV-vis and NMR techniques. The helical
conformation of receptor 4d was distorted in the complexes
Conflicts of interest
There are no conicts to declare.
Acknowledgements
ꢀ
3ꢀ
´
with H2PO4 and HP2O7 due to the differences in the sizes Authors thank Consejo Nacional de Ciencia y Tecnologıa
and geometry of these anions (Fig. S64†).
(CONACyT Mexico) (Grant No. CB-2014-239581) for nancial
´
´
´
The 1 : 1 complex of receptor 8b with acetate was optimized support for this project. Jose Garcıa-Elıas thanks to CONACyT
at the same level of theory. The “saddle” shape of the receptor in for the graduate fellowship. The authors acknowledge grateful
the complex allowed the H1, H2, H3, and H4 hydrogens of both support from the Supramolecular Chemistry Thematic Network
ureylbenzamide units to be oriented in the direction of the (CONACyT Grant No. 294810). Also, thank CONACyT for the ITT
anion (Fig. 12a and b). The distance between the anion and the NMR facilities (Grant INFR-201103-173395).
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¨
15 P. Buhlmann, S. Nishizawa, K. P. Xiao and Y. Umezawa,
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