Protonation and Anion Binding Properties of Aromatic Bis-Urea Derivatives—Comprehending the Proton Transfer

Article abstract of DOI:10.1002/chem.201805633

A series of aromatic bis-urea derivatives was prepared and their proton dissociation, as well as anion binding properties in DMSO were investigated. To this end, UV/Vis and ¹H NMR spectroscopies and computational methods were employed. The synt

Full text of DOI:10.1002/chem.201805633

A Journal of
Accepted Article
Title: Protonation and anion binding properties of aromatic bis-urea
derivatives – apprehending the proton transfer
Authors: Dajana Barišić, Nikola Cindro, Marina Juribašić Kulcsár,
Martina Tireli, Krunoslav Užarević, Nikola Bregovic, and
Vladislav Tomišić
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To be cited as: Chem. Eur. J. 10.1002/chem.201805633
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Chemistry - A European Journal
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Protonation and anion binding properties of aromatic bis-urea derivatives – apprehending the
proton transfer
a,b
a
b
b
b
a
D. Barišić, N. Cindro, M. Juribašić Kulcsár, M. Tireli, K. Užarević, N. Bregović* , and V.
Tomišića
a
Division of Physical Chemistry, Department of Chemistry, Faculty of Science, Horvatovac 102a, 10 000 Zagreb,
Croatia
b
Division of Physical Chemistry, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia
Abstract
A series of aromatic bis-urea derivatives was prepared and their proton dissociation, as well as anion
1
binding properties in DMSO were investigated. To this end, UV-Vis and H NMR spectroscopies and
computational methods were employed. The synthesised molecules differed in the relative position of
the urea moieties (ortho- and meta-derivatives) and in the functional groups (–H, –CH
3
, –OCH
3
, –NO )
2
in the para-position of the pendant phenyl groups. Remarkably high acidities of the compounds (log
H
K
1
≈ 14), were ascribed primarily to the stabilising effect of the aromatic subunits. Quantum-chemical
calculations corroborated the conclusions drawn from experimental data and provided information from
the structural point of view. Knowledge regarding protonation properties proved to be essential for
reliable quantitative determination of anion binding affinities. Studied receptors were selective for
acetate and dihydrogen phosphate among several anions. Formation of their complexes of 1:1 and 1:2
(
ligand:anion) stoichiometries was quantitatively characterised. Proton transfer was taken into account
–
in the course of data analysis, which was especially important in the case of AcO . Ortho-receptors
were proven to be more efficient acetate binders, achieving coordination with all four NH-groups. The
meta-analogues preferred dihydrogen phosphate, which acted as both hydrogen bond donor and
–
acceptor. Cooperative binding was detected in the case of 1:2 H
to formation of interanionic hydrogen bonds.
2
PO
4
complexes which was assigned
1.
Introduction
As the field of anion coordination chemistry has evolved, new levels of complexity of the related
systems have been explored, which increased the urge for thorough research of all processes related to
anion coordination.[ In this field, urea derivatives have been among the most studied receptors, and
1–9]
[10–18]
numerous studies of their complexation with diverse anionic species have been reported.
In pursuit
of higher affinity and selectivity, original concepts have been examined with the goal of achieving the
desired receptor properties.[
19–22]
. A prerequisite facilitating the anion receptor development is
comprehensive understanding of the thermodynamics underlying anion binding, leading to
apprehension of structure-reactivity correlation, assessment of the individual contributions to the
complex stability, better insight into the solvent effect on the corresponding equilibria, etc.[
Consequently, the synthetic and other experimental efforts can be steered in the right direction.
In order to gather reliable thermodynamic information about the anion binding processes it is of
great importance to identify and characterise the coupled reactions. In the case of anion receptors
bearing urea, and especially thiourea moieties, one of the most commonly encountered side-reactions
23–26]
is deprotonation of the NH-group, accompanied by protonation of the anion, i.e. receptor to anion proton
transfer.[
27–34]
This process is especially favourable in aprotic organic solvents of lower polarity due to
drastic increase in basicity of the commonly used anions (e.g. fluoride, carboxylates, or dihydrogen
phosphate) with respect to aqueous medium. Although proton transfer has been recognized as an
important process, particularly if fluoride or carboxylate anions are used as guests, it has rarely been
1
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10.1002/chem.201805633
included quantitatively in an adequate manner. This is in great part due to complexity of the established
equilibria in such solutions, which makes the analysis of the related titration data rather complicated.
Namely, for the full characterisation of such systems detailed information on both ligand and anion
protonation properties is essential. Further on, the occurrence of such complex system of chemical
[34]
equilibria can be evasive if standard experimental procedures are applied.
Herein, we present a systematic study on proton dissociation of aromatic bis-urea derivatives (1H
2
-
8
H
2
, Scheme 1) and their anion binding properties, taking into account that these two processes are
1
inherently coupled. To this end, both experimental (UV-Vis, H NMR) and theoretical methods were
applied and recently reported data acid-base properties of phosphoric and acetic acid in DMSO were
implemented.
Scheme 1. Structures of the studied aromatic urea-based anion receptors and the reactions investigated.
2
.
Results and discussion
2.1. Protonation
The proton dissociation of the prepared urea derivatives (1H
2
-8H ) in DMSO was characterised by
2
1
competitive spectrophotometric and H NMR titrations using 1,8-diazabicycloundec-7-ene (DBU) as a
base. DBU was chosen due to low spectral overlap with the urea derivatives, suitable basicity (expected
H
[35]
from the data available in acetonitrile (log K = 24.34) and the fact that its interaction with the studied
ligand (other than deprotonation) is not expected. The protonation of DBU was not previously studied
in DMSO, and for that reason the corresponding equilibrium constant was determined
H
[36]
spectrophotometrically by titrating bromothymol blue (BTBH
2
, log K
1
= 11.3) with DBU (Figure
1
). Significant dependence of UV-Vis spectra of bromothymol blue solution on the concentration of
–
DBU was observed, caused by deprotonation of BTBH (characteristic peak at 638 nm appeared). The
non-linear regression analysis of the obtained titration data allowed the determination of the equilibrium
constant for the protonation of DBU, rendering the value log K = 13.13(7). The lack of spectral changes
H
2
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10.1002/chem.201805633
at n(DBU) / n(BTBH
2
) < 1 (Figure 1) was due to the fact that BTBH is a diprotic acid, with quantitative
2
dissociation of the first proton in DMSO. Thus, changes in the spectrum were observed only after
complete neutralisation of the “free” hydrogen ion, i.e. upon the second dissociation step.
(a)
(b)
2
1
0
A
2
1
0
A
4
00
600
0
1
2
3
4
5

/ nm
n(DBU) / n(BTBH2)
(c)
(d)
1
00
6
3
0


BTBH
BTBH
7
5
2
5
0
5
0
BTBH2

BTBH2
4
00
600
0
1
2
3
4
5
n(DBU) / n(BTBH2)

/ nm
(c = 3.19 × 10−5 mol dm ) with DBU
= 2.28 mL. Spectra are corrected
for dilution. b) Dependence of absorbance at 638 nm on n(DBU) / n(BTBH ) molar ratio.
experimental, ─ calculated. c) Characteristic UV-Vis spectra of BTBH and its deprotonated form. d)
−3
Figure 1. a) Spectrophotometric titration of BTBH
2
−
3
−3
(
c = 2.37 × 10 mol dm ) in DMSO at (25.0 ± 0.1) °C; l = 1 cm, V
0
2
■
2
Distribution of protonation species of bromothymol blue during the titration of a BTBH
2
solution with
DBU.
Having characterised protonation properties of DBU we were able to use it as a base for the
investigations of the urea-based ligands. By adding DBU to the solution of the ligands, significant
1
changes in the H NMR and UV-Vis spectra were observed. In the case of NMR titrations, all proton
signals exhibited detectable changes in the chemical shift (Figure 2 and Figures S25-S31 in the
Supporting Information). This was most pronounced for singlets ascribed to urea NH-protons, for which
the downfield shift was complemented with a severe broadening and decrease in intensity. Such finding
is in line with the assumption that proton transfer to DBU takes place, indicating that the studied ureas
are indeed prone to proton dissociation. However, the signals of protons involved in dissociation
equilibria were not suitable for quantitative analysis and only the signals of aromatic signals were taken
into account in the fitting procedures. Data analysis was done by means of HypNMR program in a
multivariate fashion, taking into account as many proton signals as possible (Tables S1-S7 in the
Supporting Information).
3
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(b)
8.20
8.15
8.10

0
250
500
n(DBU) / n(8H2)
(c)
1
00
7
5
2
5
0
5
0
2
8

8
H
8H2
0
250
500
n(DBU) / n(8H2)
1
−4
−3
−1
−3
Figure 2. a) H NMR titration of 8H
2
(c = 5.86 × 10 mol dm ) with DBU (c = 4.10 × 10 mol dm )
in DMSO-d
n(8H ) molar ratio. ■ experimental, ─ calculated. c) Distribution of protonation species of 8H
the titration of 8H
6
at (25.0 ± 0.1) °C, V
0
= 0.525 mL. b) Dependence of H
e
proton chemical shift on n(DBU)
/
2
2
during
2
solution with DBU.
1
A satisfactory fit of the H NMR titration curves could be achieved only by assuming two-step
deprotonation of the ligand molecules, yielding protonation equilibrium constants given in Table 1.
UV-Vis titrations of ortho-compounds (Figures S32-S34 in the Supporting Information) afforded first
H
protonation constants, whereas the K
2
was fixed at the value determined by NMR to achieve
H
convergence. The values of K
1
attained by the two methods were in good agreement. In the case of
1
meta-derivatives only H NMR titrations were employed for quantitative characterisation of protonation
equilibrium constants, whereas the UV-Vis data could only be used for calculation of the characteristic
spectra of the protonation species. More details regarding the data processing are provided in the
Experimental part (Section 4.3.5).
4
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Table 1. Protonation constants of the studied compounds in DMSO at 25 °C.
H
H
log K
1
log K
2
1H NMRa
UV-Visb
14.32(6)
14.68(5)
14.48(2)
1H NMRa
13.1(2)
13.5(2)
13.2(2)
14.8(1)
14.5(2)
14.4(2)
13.86(6)
1
2
3
5
6
7
8
H
2
H
2
H
2
H
2
H
2
H
2
H
2
14.36(4)
14.50(5)
14.40(5)
14.98(2)
14.78(5)
14.80(3)
15.27(3)
a
Uncertainties are given in parentheses as standard deviation of the fit
Uncertainties are given in parentheses as standard error of the mean (N = 3)
b
The ability of the compounds to dissociate two protons is not surprising, since the two urea groups are
relatively far apart and somewhat independent of each other. Consequently, differences between log
H
H
K
1
and log K
2
are almost insignificant in the case of meta-derivatives 5H
2
-7H . For the ortho-
2
analogues the difference in log K values is approximately 1, due to a stronger effect of the excess
negative charge formed upon first deprotonation step. The possibility that such behaviour was caused
by intramolecular hydrogen bond between the two urea groups was dismissed by employing
computational methods. We performed detailed conformational searches for compounds 1H
2
and 5H ,
2
as representatives of both ligand classes (ortho- and meta-), starting with several geometries for each
compound (Scheme 2). Modelling was performed in DMSO (zero, one or two explicit solvent molecules
were included), and the calculations were conducted on neutral, mono-, and dianionic forms of the
unsubstituted bis-ureas. None of the reasonably stable conformers of ortho-compound featured
intramolecular –NH···O=C hydrogen bond (denoted as “in-out-2” conformer). Apparently, the
hydrogen bond between the two urea moieties is sterically hindered, and instead, the hydrogen bonding
potential of the urea moieties was saturated by solvent molecules. As a result, in excess DMSO the most
stable conformation of the ortho-compound (regardless of the protonation state) is the one with NH-
groups oriented towards each other (denoted as “out-out” conformer) (Scheme 2). In contrast, the meta-
derivative showed almost no preference between the “out-out” and “in-out” conformers. In this case
carbonyl oxygen atoms can interact with two different aromatic hydrogen atoms (H
b
and H ) which
c
results in two conformers differing in carbonyl oxygen orientation, but exhibiting rather similar
energies. The changes in NMR spectra observed upon deprotonation affirmed the importance of
intramolecular hydrogen bonds involving aromatic hydrogen atoms. In the case of meta-derivatives,
both protons adjacent to urea groups (H
b
and H ) experienced deshielding upon deprotonation (Figure
c
2
and Figures S28-S31 in the Supporting Information), which can be ascribed to enhancement of their
hydrogen bonds with carbonyl atom as it accommodates excess of negative charge. All other hydrogen
nuclei featured an upfield shift, which is in line with the increase in electron density in the phenyl ring
upon proton dissociation. As shown in the following section, preorganisation governed by
intramolecular CH···O= hydrogen bonds had significant impact on the anion complexation properties
of the studied receptors.
5
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Scheme 2. Possible conformers for compounds 1H
2
and 5H which have been used as starting points
2
for calculations.
We also note that computational results for both 1H
2
and 5H in presence of explicit DMSO
2
molecules indicate that a hydrogen atom from the NH-group close to the central phenyl moiety is more
prone to leave the molecule first, followed by deprotonation of the NH-group in the other urea moiety
that is further away from the central benzene ring.
The effect of methyl or methoxy group in the para-position of the pendant benzene rings on the
protonation properties was not considerable. The ligands comprising these substituents exhibited rather
similar dissociation affinity as the unsubstituted derivative, among both ortho- and meta-compounds.
On the other hand, introduction of electron withdrawing NO
2
-functional group greatly affected the
properties of the bis-urea receptors. In the case of 4H
2
(nitro-substituted ortho-derivative) we detected
1
time dependence of the H NMR and UV-Vis spectra upon addition of DBU. As proton signals of
starting compound decayed two new sets appeared indicating a process different from deprotonation.
Reaction was tested on preparative scale and products were isolated using column chromatography and
identified by NMR (Scheme 3). It was confirmed that this was due to decomposition of the ligand
(
Scheme 3).
Scheme 3. Reaction of 4H with DBU in DMSO.
2
Compound 8H
2
(meta-analogue of 4H
2
) proved to be stable upon addition of DBU and the titration
revealed that the first proton dissociation is considerably more favourable compared to other bis-ureas
(
Table 1). In contrast, formation of dianionic species was in this case significantly less favourable,
H
H
reflecting a 26-fold difference between K
1
and K .
2
It should be stressed out that, to the best of our knowledge, compounds 1H
2
-8H exhibit the most
2
pronounced acidity in DMSO, among the urea derivatives studied so far. This affirmed the remarkable
stabilisation of anionic form afforded by charge delocalisation through benzene rings, further assisted
by intramolecular hydrogen bonds. On average, the dissociation constant of the studied ligands is
approximately 12 orders of magnitude greater than the one determined for simple urea and 5 orders
[37]
larger with respect to phenylurea in the same solvent. This aspect of our results is especially important
6
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H
since the K values reported for urea and phenyl urea some 30 years ago are commonly used as a frame
of reference for assessment of urea acidity, even for more elaborate derivatives comprising several
aromatic moieties.[ With this respect, our results strongly suggest that the possibility of proton transfer
in the course of anion binding studies should be treated with much more scrutiny.
38]
2.2. Anion binding
The binding affinity of the prepared receptors towards various weakly basic anions (chloride, nitrate,
perchlorate) in DMSO was examined (Figures S59-S79 in the Supporting Information) by means of
UV-Vis spectroscopy and no significant spectral changes occurred. On the other hand, the addition of
–
acetate (AcO ) and dihydrogen phosphate (DHP) causes significant spectral changes (Figure 3 and 6,
Figures S35-S40, and S47-S58 in the Supporting Information). The processes responsible for this
1
finding have been thoroughly investigated by means of H NMR and UV-Vis titrations. One of the
reactions expected to occur in the course of these titrations is proton transfer. If one takes into account
H
the information given in the previous section regarding protonation properties of the ligands (log K
1
≈
1
4) and previously reported data on acid-base properties of anions, it becomes evident that proton
[39]
transfer is especially prominent in the case of acetate (log K = 12.82).
H
Respectively, we analysed the data using a model including the following reactions: a) formation
of receptor:anion complexes, b) dissociation of the ligands, c) protonation of anion, d) homoassociation
and dimerisation (of neutral species in the case of acetic acid, and anion in the case of DHP) The
equilibrium constants for the “side-reactions” (b-d) were kept fixed in the course of titration data
processing, whereas the anion complex stability constants were varied. Both anions were found to form
1:1 and 1:2 (ligand:anion) complexes. More details regarding the data analysis are provided in the
Experimental part (Section 4.3.6). Since urea derivatives are often prone to form dimers or higher
1
aggregates, we checked the possibility of host aggregation by recording their H NMR spectra in a wide
concentration range (Figures S80-S81 in the Supporting Information) and found no indication of
aggregate formation for any of the investigated ligands. The ion pairing reactions were not considered
in the data analysis since the TBA salts which were used for the addition of anions were not expected
to form ion pairs, and we detected no indication of this reaction.
2.2.1. Acetate
The best fit of the data regarding UV-Vis titrations of the studied compounds with TBAOAc
was attained by assuming formation of complexes comprising one and two anions in addition to partial
deprotonation of the receptors. The latter was accounted for by including the protonation of acetate and
ligand in the fitting model (Figure 3 and Figures S35-S40 in the Supporting Information). The calculated
equilibrium constants are listed in Table 2.
7
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(a)
(b)
1.2
0.6
0.0
A
A
1.2
1.1
1.0
3
00
350
400
450
0
20
40
n(TBAOAc) / n(8H2)

/ nm
2

(c)
8
(d)
8
H2

1
00
8H

8
H ·AcO
8
8
8
H2
2


4
8H ·(AcO )
H ·AcO
2
7
5
2
5
0
5
0
2

H ·(AcO )
2
2
2
0

0
20
40
300
350
400
n(TBAOAc) / n(8H2)
 / nm
(c = 3.09 × 10 mol dm ) with TBAOAc (c = 7.94 ×
0 mol dm ) in DMSO at (25.0 ± 0.1) °C; l = 1 cm, V = 2.32 mL. Spectra are corrected for dilution.
b) Dependence of absorbance at 373 nm on n(TBAOAc) / n(8H ) molar ratio. ■ experimental, ─
calculated. c) Distribution of protonation species and acetate complexes of 8H during the titration of
solution with TBAOAc. d) Characteristic UV-Vis spectra of 8H and its acetate complexes.
The same model was applied to describe the NMR titration curves (Figure 4 and Figures S41-S46 in
the Supporting Information), affording K values which were in good agreement with the values
−
5
−3
Figure 3. a) Spectrophotometric titration of 8H
1
2
−
3
−3
0
2
2
8H
2
2
1
calculated from the spectrophotometric data (Table 2). In these cases, the equilibrium constants for
dianionic complexes were fixed at the value determined by the UV-Vis experiment. The signals
ascribed to the NH-nuclei were again excluded from the quantitative data analysis.
Distribution diagrams constructed using the acquired equilibrium constants (Figure 3c and Figures
S35c-S40c in the Supporting Information) clearly demonstrated the relevance of proton transfer
reactions. For example, almost 20 % of the meta-ligands is present in anionic form when one equivalent
of acetate is added. Even the percentage of fully deprotonated form reached considerable values (> 10
%
) at high anion excess (> 50 equivalents).
8
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(c)
8.20
8.17
8.14

0
5
10
n(TBAOAc) / n(8H2)
1
−4
−3
−2
Figure 4. H NMR titration of 8H
2
(c = 5.86 × 10 mol dm ) with TBAOAc (c = 1.04 × 10 mol
−
3
dm ) in DMSO-d
Dependence of H
calculated.
6
at (25.0 ± 0.1) °C, V
0
= 0.525 mL; a) aromatic and b) urea NH-proton signals. c)
) molar ratio. ■ experimental, ─
e
proton chemical shift on n(TBAOAc) / n(8H
2
Ortho-ureas were found to form more stable 1:1 acetate complexes than their meta-analogues (Table
). This could be ascribed to the fact that both urea groups of ortho-receptors easily interacted with the
2
carboxylate anion forming four hydrogen bonds. Computational results and NOESY spectra (Figures
S82-S90, Supporting Information) were in agreement with these assumptions. In the most stable
–
conformations of the 1H
2
AcO complex (Tables S32-S33 in the Supporting Information), the receptor
offered all four NH-protons for interaction with acetate (Figure 5). On the other hand, we propose that
in the case of meta-analogues the urea moieties acted as individual binding sites. Computational
–
analysis of 5H
2
·AcO complex suggested that acetate interacts only with one urea and relative energies
-1
of the corresponding conformers were found within a rather narrow energy window (0.4 kcal mol ). In
the NOESY spectra of 5H2 and 8H solutions and solutions containing predominantly their acetate
2
complexes the interactions NOE interactions were retained, suggesting that the conformational changes
upon complexation were not very significant.
9
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Table 2. Stability constants of acetate complexes with studied urea receptors in DMSO at 25 °C.
log K log K
1
2
UV-Visa
5.33(4)
4.96(4)
4.92(6)
3.92(2)
3.82(4)
3.83(3)
4.61(4)
1H NMRb
UV-Visa
3.35(9)
3.83(9)
3.52(9)
2.60(3)
2.55(3 )
2.63(9)
3.26(9)
1
2
3
5
6
7
8
H
2
H
2
H
2
H
2
H
2
H
2
H
2
5.1(1)
5.2(1)
4.91(9)
3.90(4)
4.0(1)
3.94(5)
4.73(5)
a
Uncertainties are given in parentheses as standard error of the mean (N = 3)
Uncertainties are given in parentheses as standard deviation of the fit
b
Figure 5. The most stable conformers of monoanionic and dianionic acetate complexes of 1H
Energies for the 1H conformers are reported relative to the most stable conformer.
2
and 5H .
2
2
The formation of dianionic complexes was expected, given the fact that both urea moieties can act
as individual binding sites. The relatively high stability of the complexes of 1:2 stoichiometry
(
ligand:anion) in the case of ortho-receptors is somewhat surprising as one might foresee some
–
unfavourable steric effect. However, computational results indicated that the complexation of two AcO
anions by the ortho-receptors attaining the “out-out” or even “in-out-1” conformation is in fact not
sterically hindered.
In general, we detected only minor influence of the pendant benzene ring substituent in the para-
position on the anion binding properties. The unsubstituted ligands exhibited somewhat higher affinity
towards complexation in comparison to receptors containing electron-donating substituent. On the other
2
hand, ligand 8H , comprising electron-withdrawing nitro group formed most stable acetate complex
among meta-derivatives. This finding is in line with previous reports on similar receptor series
10
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examining the impact of NO -functionality on the complex stability, and it is usually explained by better
2
[19,30]
donating affinity of the NH-groups due to electron withdrawing effect of NO
.2.2. Dihydrogen phosphate
2
-group.
2
As mentioned above, dihydrogen phosphate was also studied as a suitable guest for the prepared
= 10.80) than acetate (log K
= 12.82),[
39]
host molecules. This anion is significantly less basic (log K
H
H
and the percentages of the anionic forms of the ligands in the course of the titrations were very low (<
%). Still, we adopted the fitting scheme analogous to the one used for acetate (Figures 6 and 7, Figures
S47-S58 in the Supporting Information), and thus obtained equilibrium constants are given in Table 3.
5
(a)
(b)
A
1.2
0.6
0.0
A
1
.2
.0
1
3
00
350
400
450
0
5
10
15
n(TBAH PO ) / n(8H )

/ nm
2
4
2
(c)
2

(d)
8
8H ·H PO
2 2 4
8H2
8H ·H PO
4
1
00


8H
8H ·(H PO )

2
2
4
2
2
2
4
2
0
8H2

8
H ·(H PO )
2
2
4
2
7
5
2
5
0
5
0

0
5
10
15
300
350
400
450
n(TBAH PO ) / n(8H )
2
4
2
 / nm
−
5
−3
Figure 6. a) Spectrophotometric titration of 8H
2
(c = 3.04 × 10 mol dm ) with TBAH
10 mol dm ) in DMSO at (25.0 ± 0.1) °C; l = 1 cm, V = 2.32 mL. Spectra are corrected for dilution.
b) Dependence of absorbance at 373 nm on n(TBAH PO ) / n(8H ) molar ratio. ■ experimental,
calculated. c) Distribution of protonation species and dihydrogen phosphate complexes of 8H during
the titration of 8H solution with TBAH PO . d) Characteristic UV-Vis spectra of 8H and its
dihydrogen phosphate complexes.
2
PO
4
(c = 1.07
−
3
−3
×
0
2
4
2
─
2
2
2
4
2
11
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10.1002/chem.201805633
(c)
8
.19
.16

8
0
5
10
n(TBAH PO ) / n(8H )
2
4
2
1
−4
−3
−3
Figure 7. H NMR titration of 8H
2
(c = 5.86 × 10 mol dm ) with TBAH
2
PO
4
(c = 9.49 × 10 mol
−
3
dm ) in DMSO-d
Dependence of H
calculated.
6
at (25.0 ± 0.1) °C, V
0
= 0.525 mL; a) aromatic and b) urea NH-proton signals. c)
PO ) / n(8H ) molar ratio. ■ experimental, ─
e
proton chemical shift on n(TBAH
2
4
2
Table 3. Stability constants of dihydrogen phosphate complexes with studied urea receptors in DMSO
at 25 °C.
log K
1
log K
2
UV-Visa
5.21(8)
4.90(6)
4.80(4)
4.65(8)
4.38(9)
4.47(5)
4.17(5)
1H NMRb
5.13(3)
5.01(6)
4.79(4)
4.63(7)
4.60(9)
4.49(9)
4.36(8)
UV-Visa
1
2
3
5
6
7
8
H
2
H
2
H
2
H
2
H
2
H
2
H
2
3.7(1)
3.56(8)
2.84(4)
3.4(1)
3.42(5)
3.35(9)
4.37(5)
a
Uncertainties are given in parentheses as standard error of the mean (N = 3)
Uncertainties are given in parentheses as standard deviation of the fit
b
Again, two types of complexes, comprising one or two anions have been detected. In the case of
ortho-receptors, similar stabilities of DHP complexes were found as in the case of acetate analogues.
On the other hand, meta-receptors proved to be more efficient binders for DHP with respect to acetate,
12
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Chemistry - A European Journal
10.1002/chem.201805633
featuring almost ten times greater stability constants for DHP complexes. This finding pointed out that
cooperative interactions existed in the case of DHP complexes of meta-receptors, which was clarified
by in silico results. As already elaborated, coordination of anion by all four NH-moieties is not
geometrically favourable in the case of meta-ligands. However, dihydrogen phosphate can act both as
an hydrogen bond donor and acceptor. As a donor, it can engage in a PO–H∙∙∙O=C interaction with the
carbonyl oxygen atom of one urea group. Acting as an acceptor, it can form two NH∙∙∙O=C hydrogen
bonds with the ligand. Such array of interactions is sterically and energetically favourable for the in-out
conformer of 5H , leading to its highest stability among all examined conformers (Figure 8).
2
Figure 8. The most stable conformers of 1:1 and 1:2 dihydrogen phosphate anions (DHP) complexes
of 1H and 5H . Energies for the 1H conformers are reported relative to the most stable conformer.
2
2
2
Binding of the second dihydrogen phosphate was also much more favourable in the case of meta-
derivatives, especially in the case of compound 8H . For this receptor the successive stability constant
2
of dianionic DHP complex was greater than the one characterising the monoanionic complex. This can
be ascribed to strong stabilising influence of the PO–H∙∙∙O=P hydrogen bonds formed between two
anions within the complex, apart from the common NH∙∙∙O=P interactions. In the conformational space
of dianionic DHP complexes of 5H
2
the structure in which such pairing between two anions is achieved
proved to be > 10 kcal mol more stable in comparison to other obtained minima.
Further on, the dramatic changes in the chemical shifts related to H and H
during the titrations with TBAH PO (Figure 7 and Figures S53-S58 in the Supporting Information)
were in agreement with the assumptions given above and the structural insights provided by quantum-
chemical calculations. The significant downfield shift of the H proton is caused by destabilisation of
the associated intramolecular CH ···O=C hydrogen bond, while the opposite was observed for H . This
is even more pronounced in the case of dianionic complex formation, since 5H ·(H PO complex
–)
preferred the “out-out” conformation. This results in disruption of the intermolecular hydrogen bond
involving H proton, encouraging the CH ···O=C interaction. Such behaviour was not detected in the
-1
b
c
protons observed
2
4
c
c
b
2
2
4
2
c
b
–
case of AcO which indicated that the conformational changes induced by complexation were much
less significant.
13
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It should be noted that the compounds 1H
2
and 4H have been included in a previous study reported
2
by Gale et al.,[11,13,19,22,30] and their anion binding (1:1 complex stoichiometry) was characterised by H
1
NMR titrations in DMSO containing 0.5 % water. Most recently, Gunnlaugsson et al. investigated anion
–
binding of meta derivative 7H
2
, characterising both mono- and dianionic complexes with AcO and
DHP.[ In these studies stability constants determined by NMR spectroscopy were somewhat lower
than those determined by us. This is most likely caused by the fact that significantly higher ligand
concentrations were used and proton transfer was not accounted for. Consequently, the refinement
yielded conditional constants which are concentration dependent. It is not surprising that the proton
transfer was not detected in previous studies of compounds belonging to the ligand class studied in this
work since: a) acidity of urea-group has generally been considered very low and the effect of the
aromatic subunits on its properties was underestimated, b) titration data could be easily fitted to simple
binding models in spite of proton transfer occurring in the system, which was clearly shown by
Yatsimirsky et al,[34] c) the relevance of this reaction is less pronounced at higher ligand concentrations
Finally, we devote some more attention to the cooperativity manifested as the enhanced stability
of 1:2 DHP complexes. This characteristic, owing its existence to interanionic hydrogen bonds, has
15]
[
18,40–43]
been recognised in several examples during the last decade,
including complex of an analogue
[12]
of 1 comprising a cyclohexane linker. However, the thermodynamics of the effect was thoroughly
[39]
explored only recently,
which led to exploitation of attractive interaction between dihydrogen
phosphates to afford interesting self-assembled systems with advantageous properties.[44–46] In this
context, our results present a valuable contribution, providing an insight in the spatial arrangement of
the donor moieties required for optimal interaction between the two DHP units. It is our strong belief
that hydrogen bonds between phosphate moieties could be exploited as a valuable interaction affording
exciting new supramolecular systems in the future.
3.
Conclusion
The presented research provided a systematic study of anion binding by urea-based receptors,
acknowledging the importance of ligand to anion proton transfer. Quantitative examination of the
protonation properties revealed that in DMSO these two processes are inherently coupled. Striking
effect of the aromatic rings attached to urea subunits was detected, i.e. their presence remarkably
increased the acidity of the NH-protons.
In the context of anion coordination, the studied receptors were found to be selective for
dihydrogen phosphate and acetate, forming complexes with either one or two anions, whereas the
binding of other, less basic, anions was not detected under the experimental conditions used. By careful
consideration of the experimental data in synergy with computational results, we were able to identify
the interactions responsible for the stabilisation of the anion complexes. In addition to “conventional”
hydrogen bonds between anion and receptor with urea NH-groups acting as donors, hydrogen bond
accepting potential of carbonyl oxygen atom was found to be of pivotal importance in the case of 1:1
DHP complexes enhancing their stabilities. Further on, formation of hydrogen bonds between two
bound dihydrogen phosphate anions gave rise to cooperative binding, resulting in unusually high
stability of dianionic complexes of DHP.
We hope that our results will encourage researchers focused on anion binding to take the possibility
of proton transfer into account in their future research. Arguably, this work provides guidelines for the
implementation of such approach, as the methodology developed can be applied to a variety of receptor
classes. We also envision that information regarding structure-reactivity relationship and an array of
involved interactions (especially in the case of DHP) will inspire new advances in anion receptor
chemistry.
14
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4.
Experimental section
4.1. General
All solvents and reagents are commercially available from Aldrich and were used as received without
further purification, unless stated otherwise. Water content in DMSO used for spectrophotometry was
[
39]
<
0.06 %, determined by Karl-Fischer titration.
.2. Synthesis
Bis-urea derivatives 1H
equivalents of para-substituted phenyl isocyanates in DCM (Scheme 4). Compounds 1H
4
2
-8H were prepared by reaction of ortho- or meta-phenylenediamine with two
2
2
, 4H
2
, 5H and
2
8
H
2
were prepared by slight modification of previously published procedures (see Supporting
[11]
Information). Procedures for the synthesis of novel bis-urea derivatives 2H
as 7H
2
, 3H
2
, and 6H
2
, as well
2
for which a new synthetic path was devised can be found in the Supporting Information, together
with the characterisation data (see Figures S1-S24 in the Supporting Information). These single-step
synthetic paths involving simple purification procedures afforded excellent yields. It should be
mentioned that in the case of 7H
2
the overall yield was significantly improved (52 % to 90 %).
1
13
H and C NMR spectra of all products were recorded on Bruker Ascend 400 MHz at rt using
TMS as a reference in proton spectra and middle signal of DMSO (39.52) in carbon spectra (chemical
shifts are reported in ppm). Fourier-transform infrared attenuated total reflectance (FT-IR-ATR)
measurements were performed with a PerkinElmer Spectrum Two instrument equipped with a diamond
crystal Quest ATR Accessory. HRMS spectra of novel compounds (2H
2
, 3H
2
, and 6H ) were obtained
2
on a Bruker Microflex MALDI/TOF instrument.
Scheme 4. Synthesis of bis-urea derivatives 1H -8H2.
2
4
4
.3. Physicochemical measurements
.3.1. Materials
The solvents (dimethyl sulfoxide (DMSO, Sigma-Aldrich, spectrophotometric grade) and deuterated
dimethyl sulfoxide (DMSO-d , Sigma-Aldrich, >99.8 %)) were used as received. The salts used were
tetrabutylammonium dihydrogen phosphate (TBAH PO Sigma–Aldrich, >97 %),
tetrabutylammonium acetate (TBAOAc, Sigma–Aldrich, >97 %), tetraethylammonium chloride
TEACl, Sigma–Aldrich, >98 %), tetrabutylammonium perchlorate (TBAClO , Sigma–Aldrich, >98
) and tetrabutylammonium nitrate (TBANO , Sigma–Aldrich, >99 %). Bromothymol blue (BTBH
Kemika, >95 %), and 1,8-diazabicycloundec-7-ene (DBU, Sigma–Aldrich > 99.0 %).
6
2
4
,
(
4
%
3
2
,
Bromothymol blue and DBU solutions were standardised prior to use by means of
potentiometric titrations performed in the following way: a known amount of titrant was dissolved in
water and titrated with the standardised solution of hydrochloric acid (in the case of DBU) or sodium
hydroxide (in the case of BTBH
obtained titration curves.
2
). The concentration was calculated using the inflection point of the
15
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Chemistry - A European Journal
10.1002/chem.201805633
4.3.2. Spectrophotometry
Spectrophotometric titrations were carried out at (25.0 ± 0.1) °C by means of a Varian Cary 5
spectrophotometer equipped with a thermostatting device. The titrant solution was added in stepwise
fashion directly into the measuring quartz cell (Hellma, Suprasil QX, l = 1 cm) using calibrated syringes
(
Hamilton). The spectral changes were recorded after each addition. Absorbances were sampled at 1
nm intervals with an integration time of 0.2 s. All titrations were done in triplicate. Spectrophotometric
[
47]
data were processed by nonlinear regression analysis using the HypSpec program.
.3.3. NMR titrations
4
NMR spectra were recorded using a Bruker Avance III HD 400 MHz/54 mm Ascend spectrometer. The
temperature was kept constant at 25 °C. Chemical shifts are reported in ppm and referenced to residual
solvent signal. Calibrated syringes (Hamilton) were used for the addition of titrant and titrand solutions.
All NMR titration data were processed by nonlinear regression analysis using the HypNMR program.[
In all cases the fitting procedure was performed in a multivariate fashion, and all proton signals which
exhibited significant changes and could be monitored throughout the titration were included in the data
processing. Tables S1-S21 (Supporting Information) contain the calculated characteristic chemical
48]
shifts for the species in equilibria, indicating which proton signals were used in the data analyses.
1
Concentration dependence of H NMR spectra of all investigated receptors other than 4H
2
in DMSO-
d at 25 °C was acquired to dismiss the possibility of ligand aggregation. The concentration was varied
6
−
2
−3
by stepwise addition of receptors stock solutions (c ≈ 1.2 × 10 mol dm ) to DMSO-d in covering the
6
−
4
−3
−2
range 1.2 × 10 < c(receptors) / mol dm < 1.2 × 10 .
.3.4. Protonation constant of DBU
Protonation constant of DBU in DMSO was determined by means of spectrophotometric titrations
4
−
3
−3
which were carried out by adding solution of DBU (c ≈ 2.4 × 10 mol dm ) to solution of bromothymol
−
5
−3
blue (c ≈ 3.2 × 10 mol dm , V
protonation constant of bromothymol blue was kept fixed at the literature value (log K = 11.3).
Characteristic spectrum of the protonated form of bromothymol blue was fixed using the spectrum of
BTBH solution acquired prior to the addition of DBU.
0
= 2.28 mL) in DMSO at 25 °C. In the course of analysis of the data,
H
[36]
2
4.3.5. Protonation constants of bis-urea receptors
1
Protonation constants of 1H
2
-3H
2
and 5H
2
-8H were determined by means of H NMR titrations.
2
−
2
−3
−1
−3
Solution of DBU (c ≈ 6.5 × 10 mol dm in the case of ortho-derivatives and c ≈ 4.0 × 10 mol dm
in the case of meta-derivatives) was added to solutions of investigated receptors (c ≈ 6.0 × 10 mol
at 25 °C. When meta-derivatives were, time between addition of
DBU solutions to receptor solutions and acquisition of H NMR spectra was approximately 10 minutes
which was the time needed for reaching chemical equilibrium. In the data fitting procedure, protonation
−
4
−
3
dm , V
0
= 0.525 mL) in DMSO-d
6
1
1
constant of DBU was kept fixed at the value determined spectrophotometrically and H NMR chemical
shifts of protons characteristic for protonated forms of receptors were kept fixed at the values acquired
prior to the addition of DBU.
Spectrophotometric titrations of ortho-receptors with DBU were performed by adding solutions of
−
2
−3
−5
−3
DBU (c ≈ 1.0 × 10 mol dm ) to solutions of 1H
2
−4H
2
(c ≈ 3.0 × 10 mol dm , V = 2.32 mL) in
0
DMSO at 25 °C. Spectra were recorded approximately 5 minutes after the addition of DBU solution,
which was the time needed for chemical equilibrium to occur observed in no time dependence of UV-
Vis spectral signals. Acquired UV-Vis titration curves were processed by fixing the protonation
constant of DBU in DMSO at the value determined spectrophotometrically as well as the first
1
protonation constant of receptors determined by H NMR titrations. The second protonation constant
was fitted. Characteristic spectra of protonated forms of receptors were kept fixed at the values
16
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Chemistry - A European Journal
10.1002/chem.201805633
determined by recording spectra without the addition of DBU. Characteristic spectra of protonated and
deprotonated forms of DBU were fixed as well. Characteristic spectra of protonated form of DBU was
obtained by adding solution of HCl in DMSO to the solution of DBU until no visible spectral changes
resulting from protonation of DBU were observed. Characteristic spectra of deprotonated form of DBU
was obtained by recording spectra of pure DBU in DMSO. Spectrophotometric titrations were used for
quantitative analysis in the case of all ortho-receptors other than 4H due to observed chemical reaction
2
with DBU.
In the case of meta-receptors, spectrophotometric titrations were used for determining
characteristic spectra of deprotonated forms of receptors. Due to slow kinetics of deprotonation (proton
transfer) reaction, batch titrations were performed. Solutions of meta-receptors and DBU of different
n(meta-receptors) / n(DBU) molar ratios were prepared in plastic Eppendorf tubes and the spectra were
recorded approximately 18 hours after the preparation of solutions. Concentrations of receptors during
−
5
−3
the titrations were kept fixed (c ≈ 3.0 × 10 mol dm ) and the n(meta-receptors) / n(DBU) molar ratios
at the end of titration were ≈ 55. Characteristic spectra of deprotonated forms were calculated by fixing
1
protonation constants of meta-receptors at the values determined using H NMR titrations as well as
fixing the characteristic spectra of protonated form of receptors and characteristic spectra of protonated
and deprotonated forms of DBU.
4
.3.6. Anion complexation
Anion complexation properties of studied compounds (except 4H
performing spectrophotometric titrations of receptors with solutions of TBAOAc, TBAH
TBANO and TBAClO in DMSO at 25 °C.
Solutions of TBAOAc (c ≈ 1.2 × 10 mol dm in the case of ortho-receptors and c ≈ 3.8 × 10
2
) were investigated by
2
4
PO , TEACl,
3
4
−
3
−3
−3
−
3
−3
−3
−3
mol dm to c ≈ 7.9 × 10 mol dm in the case of meta-receptors) and TBAH
dm ) were added in stepwise manner to the solutions of investigated receptors (c ≈ 3.0 × 10 mol dm ,
2
PO
4
(c ≈ 1.1 × 10 mol
−
3
−3
−3
V
0
= 2.32 mL). In the fitting procedures, protonation constants and characteristic spectra of deprotonated
1
forms of receptors were kept fixed at the values determined by H NMR titrations and
spectrophotometric titrations with DBU respectively. Acid-base processes of acetic and phosphoric acid
in DMSO (protonation, homoassociation and dimerisation) were accounted for and their equilibrium
H
constants were kept fixed at the values recently reported by us: (log K (AcOH) = 12.82, log
−
d
H
d
−
K(AcOH·AcO ) = 2.45, log K ((AcOH)
K(H PO ·H PO PO ·(H
−) = 4.23, log K(H
other studied anions were performed by adding solutions of TEACl, TBANO
2
) = 1.45, log K (H
PO
−) ) = 2.92).[39] Spectrophotometric titrations regarding
and TBAClO (c ≈ 7 ×
= 2.32 mL) in DMSO at 25 °C until
3
PO
4
) = 10.80, log K ((H
2
PO
4
)
2
) = 2.26, log
3
4
2
4
3
4
2
4
2
3
4
−
3
−3
−3
−3
10 mol dm ) to receptor solutions (c ≈ 3.0 × 10 mol dm , V
0
the n(salt) / n(receptor) molar ratio was around 100.
1
H NMR titrations of investigated receptors with TBAOAc and TBAH
2
PO
4
were conducted by
−
4
−3
recording spectral changes of a solution of receptors (c ≈ 6.0 × 10 mol dm , V
0
= 0.525 mL) upon
−
2
−3
−2
stepwise addition of a solution of TBAOAc (c ≈ 1.0 × 10 mol dm ) or TBAH
2
PO (c ≈ 1.0 × 10
4
−
3
1
mol dm ). H NMR titration curves were processed by fixing the protonation constants of receptors as
1
well as the characteristic spectra of deprotonated forms of receptors obtained by H NMR titrations with
DBU. Characteristic spectra of fully protonated form of receptors was kept fixed at the value determined
by recording spectra prior to the salt addition. As in the case of spectrophotometric titrations with
TBAOAc and TBAH
2
PO , acid-base properties of acetic and phosphoric acid in DMSO were taken into
4
account. Equilibrium constants for the formation of dianionic complexes with bis-urea receptors were
kept fixed at the values determined spectrophotometrically, and the ones for monoanionic complexes
were varied.
17
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Chemistry - A European Journal
10.1002/chem.201805633
4.4. Computational details.
Calculations were carried out using Gaussian09.[49] A density functional theory (DFT) approach with
the wB97X-D exchange-correlation functional was applied to better account for the intramolecular
dispersion interactions.[50] A relatively large basis set, 6-311++G(d,p), was used to minimize the
[51]
intramolecular basis set superposition error. For implicit solvation, a polarizable continuum model
[52]
using the integral equation formalism (IEF-PCM) was used to model dimethyl sulfoxide (DMSO,
46.83). Frequency calculations identified all stationary points as minima (zero imaginary frequencies).
Computational methods were employed in order to get a better insight in proton dissociation
processes and anion binding, mainly from the structural viewpoint. Parent bis-urea compounds 1H
2
and
5
H
2
as well as their mono- and dianions have been modelled using (trans,trans) conformation of the
[53][54]
urea parts which is the accepted conformation for the N,N'-diarylureas with NH–C(=O)–NH core.
We note that trans/cis nomenclature is used for the conformations of N,N'-diarylurea bonds, based on
the spatial relationship between N-aryl group and carbonyl oxygen atom. Taking advantage of this
conformational preference, a detailed conformational searches of relative orientation of two
(
trans,trans) urea substituents on the central phenyl group have been performed for neutral diurea
compounds as well as for their mono- and dianions (for details see the Supporting Information).
Modelled anions have one deprotonated nitrogen per urea group. Since DMSO can serve both as a
donor and acceptor of the hydrogen bond, it is expected that the solvent molecules interact with the urea
functional groups. Thus, we performed calculations including either one or two discrete DMSO
molecules, initially positioned in such a way to facilitate ligand-solvent interactions. This was achieved
by directing the DMSO oxygen atom towards urea NH-groups, and/or pointing methyl groups of the
solvent molecule towards carbonyl oxygen or deprotonated urea nitrogen. In general, higher
stabilization was obtained if S=O groups were involved in interaction with NH-groups, than if methyl
groups were pointing toward the keto C=O group of the urea moiety in neutral compounds.
ACKNOWLEDGMENT
This work was fully supported by Croatian Science Foundation, Projects IP-2014-09-7309 (SupraCAR)
and UIP-2014-09-4744 (MECHANOCONTROL). We also acknowledge the support of European
Regional Development Fund and Ministry of Science Education and Sports (RC.2.2.08-0024) regarding
NMR facility. Computations were done on the Isabella cluster at SRCE, Zagreb.
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FULL PAPER
Aromatic ureas and basic anions -
competition leading to partnership
D. Barišić, N. Cindro, M. Juribašić
Kulcsár, M. Tireli, K. Užarević, N.
Bregović , and V. Tomišić
*
Study of aromatic bis-urea
derivatives in DMSO revealed their
unexpectedly high acidity (pKa ≈ 14).
Consequently, partial proton transfer
occurs in their reaction with basic
anions (AcO and H PO ). This
2 4
process was quantitatively
accounted for in the course of anion
binding studies. Reliable stability
constants of anion complexes (1:1
and 1:2, receptor:anion) were
determined. Factors defining the
anion binding properties of the
studied ligand series were
Protonation and anion binding
properties of aromatic bis-urea
derivatives – apprehending the
proton transfer
(
(Insert TOC Graphic here: max. width:
.5 cm; max. height: 5.0 cm))
5
–
–
a,b
a
D. Barišić, N. Cindro, M. Juribašić
b
b
b
Kulcsár, M. Tireli, K. Užarević, N.
Bregović* , and V. Tomišića
a
thoroughly discussed.
21
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