Urea-, squaramide-, and sulfonamide-based anion receptors: A thermodynamic study

Article abstract of DOI:10.1002/chem.201003411

In this work, we compare the anion-binding capabilities of receptors 1-5, characterized by similar structures, but possessing different hydrogen-bond-donor moieties (urea, squaramide, and sulfonamide). The presence of chromophoric substituents on the receptor's skeleton allowed the determination of association constants by performing UV/Vis titrations with the investigated anions on solutions of the receptors in pure acetonitrile. Additional quantitative studies of the anion-binding properties of receptors 1-5 were performed by isothermal titration calorimetry (ITC). The experimental results indicated that 1 and 2 formed 1:1 hydrogen-bonded complexes with most of the anions investigated. In the case of receptors 3-5, the formation of the 1:1 adduct was observed only with anions of low basicity (i.e., chloride, bromide, iodide, and hydrogen sulfate). With more basic anions (i.e., acetate and dihydrogen phosphate), both spectrophotometric and ITC titrations accounted for the deprotonation of the sulfonamide group, involving the formation of the conjugated base of the receptor. Copyright

Full text of DOI:10.1002/chem.201003411

DOI: 10.1002/chem.201003411
Urea-, Squaramide-, and Sulfonamide-Based Anion Receptors:
A Thermodynamic Study
Valeria Amendola,*[a] Luigi Fabbrizzi,[a] Lorenzo Mosca,[a] and
Franz-Peter Schmidtchen[b]
Abstract: In this work, we compare the
binding properties of receptors 1–5
were performed by isothermal titration
calorimetry (ITC). The experimental
results indicated that 1 and 2 formed
1:1 hydrogen-bonded complexes with
most of the anions investigated. In the
case of receptors 3–5, the formation of
the 1:1 adduct was observed only with
anion-binding capabilities of receptors
1–5, characterized by similar structures,
but possessing different hydrogen-
bond-donor moieties (urea, squara-
mide, and sulfonamide). The presence
of chromophoric substituents on the re-
ceptorꢀs skeleton allowed the determi-
nation of association constants by per-
forming UV/Vis titrations with the in-
vestigated anions on solutions of the
receptors in pure acetonitrile. Addi-
tional quantitative studies of the anion-
anions of low basicity (i.e., chloride,
bromide, iodide, and hydrogen sulfate).
With more basic anions (i.e., acetate
and dihydrogen phosphate), both spec-
trophotometric and ITC titrations ac-
counted for the deprotonation of the
sulfonamide group, involving the for-
mation of the conjugated base of the
receptor.
Keywords: anion
receptors
·
·
·
calorimetry
molecular
·
hydrogen bonds
recognition
supramolecular chemistry
Introduction
cording to the size and shape of the target anion. Higher se-
lectivity can be achieved by placing the donor groups
around the cavity of macrocycles[5] or cage-shaped recep-
Over the past decade, many neutral receptors for anionic
species have been developed. Most of them contain ureas,
thioureas, squaramides, pyrroles, amides, and sulfonamides
as the binding groups, for which the interaction with anions
is mainly based on hydrogen bonding, involving polarized
N H fragments. Except for pyrroles, the hydrogen-bond-
tors.[6] The hydrogen-bond donor ability of N H groups can
ꢀ
be further increased by introducing electron-withdrawing
substituents on the receptor framework. Urea groups ap-
pended to electron-poor aromatic rings are known to display
stronger affinity towards anions with respect to aliphatic
ureas. Besides enhancing the hydrogen-bond donating ten-
dencies, electron-withdrawing groups generally increase the
[1]
ꢀ
ꢀ
donor ability and the polarization of N H depend on the
presence of a proximate electron-withdrawing group (i.e.,
C=O for ureas,[2a] amides, and squaramides;[3] C=S and O=
S=O for thioureas and sulfonamides[4]). In the case of urea-
and thiourea-based receptors, the Y shape of the donor
group has been demonstrated to play an important role in
anion recognition, in particular, by enhancing the receptorꢀs
affinity towards complementary Y-shaped anions, such as
carboxylates.[2b] For plain amide and sulfonamide groups,
the affinity towards anions can be increased and tuned by
providing the receptor with several hydrogen-bond donor
groups, placed at well-defined distances and geometries, ac-
ꢀ
acidity of N H bonds, thus favoring proton-transfer process-
es.[7] In particular, it has been demonstrated that the pres-
ence of 4-nitrophenyl groups appended to urea deeply af-
ꢀ
fects N H acidity, thus favoring proton transfer to strongly
basic anions, such as fluoride, in acetonitrile.[2b] The 4-nitro-
phenyl group also provides urea with a powerful chromo-
phore, thus enabling the operator to distinguish the nature
of the interaction with anions, that is, between proton trans-
fer and hydrogen bonding, by UV/Vis spectroscopy. Recent-
ly, we compared the anion-binding abilities of the receptor
N,N’-di(4-nitrophenyl)urea with those of a squaramide-
based analogue.[8] This comparative study indicated, quite
surprisingly, that, despite the significant geometric differen-
ces between urea and squaramide, the two receptors dis-
played very similar association constants towards oxo-
anions. This result reinforced the hypothesis that, in oxo-
anion recognition, anion basicity plays the major role. On
the other hand, the enhanced affinity of the squaramide re-
ceptor towards halides seemed to depend on a more favora-
ble orientation of the 4-nitrophenyl rings, with respect to
the urea analogue.
[a] Dr. V. Amendola, Prof. L. Fabbrizzi, Dr. L. Mosca
Dipartimento di Chimica Generale, Universitꢁ di Pavia
via Taramelli 12, Pavia (Italy)
Fax : (+39)0382528544
E-mail: valeria.amendola@unipv.it
[b] Prof. F.-P. Schmidtchen
Department of Chemistry
Technical University of Munich
85747 Garching (Germany)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003411.
5972
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 5972 – 5981

FULL PAPER
Table 1. Association constants (as logK values) for the interaction of re-
ceptors 1–5 with anions (as TBA+ salts) in pure acetonitrile at 258C, de-
termined by UV/Vis spectroscopy. Numbers in parentheses are standard
deviations to the last significant figure.
In the case of squaramide, the two phenyl rings converge
towards the anion, thus stabilizing the adduct through addi-
ꢀ
tional interactions between the polarized C H fragments of
the phenyl groups and the bound anion.[9] Herein, we
extend our study to sulfonamide-based anion receptors. In
particular, we compare the anion-binding capabilities of re-
ceptors 1–5, characterized by similar structures, but possess-
ing different hydrogen-bond donor moieties (urea, squara-
mide, and sulfonamide). The presence of chromophoric sub-
stituents on the receptorꢀs skeleton allowed the determina-
tion of association constants by means of absorption spec-
troscopy; the results were confirmed by isothermal titration
calorimetry (ITC) experiments. ITC also gave the opportu-
nity to study, in depth, anion binding from the thermody-
namic point of view and to better understand which thermo-
dynamic contribution, whether enthalpic or entropic, played
the major role in selectivity.[10]
[a]
[a]
Anion
Clꢀ
Receptor
logK11
Anion
Iꢀ
Receptor
logK11
<2
1
2
3
4
5
1
2
3
4
5
4.14(1)
5.81(1)
3.52(1)
3.81(1)
4.38(2)
3.37(1)
4.57(1)
2.40(3)
2.73(3)
3.15(1)
1
2
3
4
5
1
2
3
4
5
3.34(1)
<2
<2
<2
Brꢀ
HSO4
3.10(1)
3.93(1)
<2
ꢀ
<2
<2
ACTHNUTRGNEUNG
[a] RH2+XꢀQ[RH2···X]ꢀ.
Table 2. Association and deprotonation constants (in logarithmic units)
for the interaction of receptors 1–5 with acetate and dihydrogen phos-
phate (as TBA+ salts) in pure acetonitrile at 258C, determined by UV/
Vis spectroscopy.
[a]
[a]
[a]
Anion
CH3COOꢀ
nH2
logK11
5.88(1)
>6
logb21
logKd
1
2
3–5
1
2
>6
ꢀ
H2PO4
3.37(1)
4.80(1)
9.05(9)
[b]
3–5
[a] RH2+XꢀQ[RH2···X]ꢀ (logK11); 2RH2+XꢀQ[(RH2)2···X]ꢀ (logb21);
ACTHNUTRGENNUG CAHTUNGTRENNUGN
RH2+XꢀQRHꢀ+HX (logKd). [b] Fitting of the experimental data is not
available due to the uncertain stoichiometry of the interaction.
As expected from the formation of hydrogen-bonded ad-
ducts, anion addition causes a redshift of the maximum of
absorbance in the receptorꢀs spectrum. For receptor 1 (3.8ꢃ
10ꢀ4 m in acetonitrile), the band centered at 263 nm, belong-
ing to a charge-transfer transition from the nitrogen atom of
the urea unit to the proximate electron-deficient phenyl
ring, undergoes a bathochromic shift of about 10 nm over
the course of the titration with chloride (6.1ꢃ10ꢀ2 m). The
association constant for Equilibrium (1), logK11 =4.14(1),
was determined by fitting the titration profile. Figure 1d re-
ports the corresponding distribution diagram, with the su-
perimposed plot of molar absorbance versus the number of
equivalents of TBACl.
Results and Discussion
Spectrophotometric studies: The synthesis of receptors 1–5
is reported in the Supporting Information. The affinity of re-
ceptors 1–5 towards anions was first investigated by UV/Vis
spectroscopy. In particular, solutions of receptors 1–5 in ace-
tonitrile were titrated with standard solutions of the tetrabu-
tylammonium (TBA+) salt of the envisaged anion. After
each addition of sub-stoichiometric amounts of the anion,
the UV/Vis spectrum of the solution was recorded.
1H2 þ Clꢀ Ð ½1H2 ꢁ ꢁ ꢁ Clꢂꢀ
ð1Þ
Figures 1 and 2 (see below) show the UV/Vis spectra col-
lected over the course of the titration of receptors 1, 2, and
5 with chloride and acetate. The titration profiles, plotted as
absorbance at a fixed wavelength versus equivalents of
anion (Xꢀ), were fitted by means of a non-linear least-
squares program,[11] thus the association constants shown in
Tables 1 and 2 were obtained. The best titration conditions,
for the safe determination of the binding constants, were de-
termined by means of the p parameter.[12] The spectrophoto-
metric titrations of receptors 1, 2 and 5 with TBACl are re-
ported in Figure 1.
Upon chloride addition to a solution of receptor 2 (2.0ꢃ
10ꢀ5 m) in acetonitrile with TBACl (5.6ꢃ10ꢀ3 m) (see Fig-
ure 1b), the band centered at 330 nm, belonging to a
charge-transfer transition from the nitrogen atom of the
squaramide fragment to the proximate phenyl ring, is red-
shifted to 344 nm (Dlmax =14 nm) and increases in intensity.
Both hyper- and bathochromic effects depend on the in-
creased dipole of the transition due to interactions with the
anion. Two isosbestic points, at 268 and 335 nm, persist over
the course of the titration. A single equilibrium [Equilibri-
Chem. Eur. J. 2011, 17, 5972 – 5981
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5973

V. Amendola et al.
Figure 1. Absorption spectra taken over the course of a) the titration of a solution of 1 (3.8ꢃ10ꢀ4 m) in acetonitrile with a solution of the TBACl (6.1ꢃ
10ꢀ2 m), l=0.1 cm; b) the titration of 2 (2.0ꢃ10ꢀ5 m) with TBACl (5.6ꢃ10ꢀ3 m), l=1 cm; c) the titration of 5 (9.8ꢃ10ꢀ4 m) with TBACl (7.3ꢃ10ꢀ2 m), l=
0.1 cm. The distribution of species present at the equilibrium in titrations a), b), and c), are shown in d), e), and f), respectively. Gray line: free receptor;
black line: bound receptor; black triangles: superimposed plots of molar absorbance (at a fixed wavelength) versus the number of equivalents of TBACl;
T=258C.
um (2)], leading to a 1:1 adduct, is observed (logK11 =
5.81(1)). The corresponding distribution diagram is reported
in Figure 1e.
effect of acetate than chloride reflects the greater affinity of
urea and squaramide towards basic anions (see Table 2).
A single equilibrium [Equilibrium (4)] is involved, leading
to the formation of a 1:1 adduct. Due to the large associa-
tion constants, the titrations were performed in dilute solu-
tions. For receptor 2, the titration profile is too steep to
allow accurate determination of the binding constant, see
Figure 2e.
2H2þClꢀ Ð ½2H2 ꢁ ꢁ ꢁ Clꢂꢀ
ð2Þ
Sulfonamide receptors 3–5 were also titrated with TBACl.
Bathochromic shifts of the UV/Vis bands and formation of
1:1 adducts were observed for all sulfonamide receptors; the
association constants are reported in Table 1. Figure 1c dis-
plays the family of spectra collected over the course of the
titration of receptor 5 (9.8ꢃ10ꢀ4 m) with TBACl (7.3ꢃ
10ꢀ2 m); see Figures S2 and S3 in the Supporting Information
for 3 and 4, respectively. The absorption spectrum of the
RH2þCH3COOꢀ Ð ½RH2 ꢁ ꢁ ꢁ CH3COOꢂꢀ
ð4Þ
Titrations with TBACH3COO were also performed on 3–5.
For sulfonamide-based receptors, the development of new
bands in the absorption spectrum, as well as the change in
the color of the solution, indicate different interactions. The
new bands in the UV/Vis spectra, peculiar to charge-transfer
transitions, reach a plateau for 1:1 stoichiometry and can be
attributed to the deprotonated form of the receptor. The ti-
tration spectra relative to the titration of 5 with the acetate
anion are reported in Figure 2c (see Figures S4 and S5 in
the Supporting Information for receptors 3 and 4, respec-
tively). A single equilibrium [Equilibrium (5)] was observed,
attributable to a proton-transfer process from the receptor
to acetate. The mono-deprotonated form 5Hꢀ is character-
ized by a charge-transfer transition band at 418 nm, reaching
its maximum after the addition of 1 equivalent of anion (see
Figure 2 f). Due to the formation of a charge-transfer band
in the visible region, acetate addition is accompanied by a
change in the color of the solution from pale to bright
yellow. Even when working at micromolar concentrations,
free receptor presents
a benzene-like structured band
around 270 nm, attributable to the phenyl groups, and a
broad band centered at 306 nm, belonging to the nitro sub-
stituents. Also for receptor 5, chloride induces the redshift
of all bands; Equilibrium (3) is characterized by logK11 =
4.38(2). The distribution diagram is reported in Figure 1 f.
5H2þClꢀ Ð ½5H2 ꢁ ꢁ ꢁ Clꢂꢀ
ð3Þ
Figure 2 shows the spectrophotometric titrations of recep-
tors 1, 2, and 5 with TBACH3COO. In particular, Figure 2a
and b show the absorption spectra taken over the course of
the titrations of receptor 1 and 2, respectively, with the ace-
tate anion. With respect to chloride, a larger bathochromic
shift, accompanied by a hyperchromic effect, is observed
(Dlmax =18 nm for 1; Dlmax =20 nm for 2). The stronger
5974
www.chemeurj.org
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 5972 – 5981

Urea-, Squaramide-, and Sulfonamide-Based Anion Receptors
FULL PAPER
Figure 2. Absorption spectra taken over the course of a) the titration of a solution of 1 (2.0ꢃ10ꢀ5 m) in acetonitrile, with a solution of the TBACH3COO
(2.4ꢃ10ꢀ3 m), l=1 cm; b) the titration of 2 (6.7ꢃ10ꢀ6 m) with TBACH3COO (2.4ꢃ10ꢀ3 m), l=1 cm; c) the titration of 5 (8.5ꢃ10ꢀ6 m) with TBACH3COO
(2.4ꢃ10ꢀ3 m), l=1 cm. The distribution of the species present at equilibrium in titration a) are shown in d). Gray line: free receptor; black line: bound re-
ceptor; black triangles: superimposed plots of molar absorbance versus the number of equivalents of TBACH3COO. Plots shown in e) and f) correspond
to the titrations b) and c), respectively.
ꢀ
the experimental data plots of the titrations of 3–5 with ace-
tate are characterized by very steep curves. For this reason,
the corresponding constants could not be safely determined
with non-linear least-squares methods (see Table 2).
tion of C H groups, belonging to electron-deficient aromat-
ic substituents on the receptor, is quite common in the for-
mation of receptor–anion adducts.[14] With the anions report-
ed in Table 1, sulfonamide-based receptors also form 1:1 ad-
ducts; anion affinity varies along the series 5>4>3. These
results indicate that nitro substituents, in particular, those di-
5H2þCH3COOꢀ Ð 5HꢀþCH3COOH
ð5Þ
ꢀ
rectly conjugated to the N H donor groups (as in receptor
ꢀ
The receptors have two N H groups that can interact
with a single acceptor atom (as for halides) or with two ad-
jacent oxygen atoms of an oxo-anion. Selectivity in anion
binding may be interpreted in terms of anion basicity: the
higher the basicity, the stronger the interaction and higher
the stability of the hydrogen-bonded adduct.[13] Table 1 re-
ports the binding constants obtained for the interaction of
1–5 with Clꢀ, Brꢀ, Iꢀ, and HSO4ꢀ; the experimental curves
could be easily interpreted on the basis of a single equilibri-
um [Equilibrium (6)], leading to the formation of 1:1 hydro-
gen-bonded complexes.
5), enhance the hydrogen-bond donor tendencies of the sul-
fonamide residue. Table 2 shows the equilibrium constants
determined for titrations with basic anions: acetate and di-
ꢀ
hydrogen phosphate. On oxo-anion binding, the two N H
groups of the receptors can interact with two adjacent
oxygen atoms of the anion. Receptor 1 forms 1:1 hydrogen-
bonded adducts with both basic anions, whereas, for recep-
tor 2, a single equilibrium was observed only in the titration
with acetate. With dihydrogen phosphate, analysis of the
UV/Vis spectra indicates the formation of two different ad-
ducts characterized by 1:1 and 2:1 receptor/anion stoichiom-
etry, respectively (see Figure S1 in the Supporting Informa-
tion).
RH2þXꢀ Ð ½RH2 ꢁ ꢁ ꢁ Xꢂꢀ
ð6Þ
The experimental data could be fitted by taking into ac-
count the Equilibria (7) and (8):
Among halides, the affinity varies along the series chlo-
ride>bromide>iodide, which reflects the decreasing nega-
tive-charge density of the anion. The results in Table 1 high-
light the superiority of receptor 2 in interacting with halides.
The peculiarity of the squaramide-containing aromatic mol-
ecules, as hydrogen-bond donors, has been already described
2H2þH2PO4 Ð ½2H2 ꢁ ꢁ ꢁ H2PO4ꢂꢀ
log K11 ¼ 4:80
ꢀ
ð7Þ
2H2þ½2H2 ꢁ ꢁ ꢁ H2PO4ꢂꢀ Ð ½ð2H2Þ2 ꢁ ꢁ ꢁ H2PO4ꢂꢀ
log K21 ¼ 4:25
by our group[8] and mainly depends on the contribution of
ð8Þ
[9]
ꢀ
the aromatic C Ha bonds, in the interaction. The coopera-
Chem. Eur. J. 2011, 17, 5972 – 5981
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5975

V. Amendola et al.
ꢀ
For receptors 3–5, the acidic properties of the N H frag-
418 nm, very similar to that observed in the spectrophoto-
metric titration with acetate in pure acetonitrile. The doubly
deprotonated species presents two new bands at 370 and
475 nm: the latter is responsible for the red color in solu-
tion. The stronger acidic character of 5, with respect to 3–4,
can be attributed to the stabilizing effect, exerted by the two
nitro groups, on the negative charge(s) originated by depro-
tonation. With respect to 3–4, in which the electron-with-
drawing groups, either CF3 or NO2, are bound to the side
arms of the sulfonamide, the two nitro groups in 5 are posi-
tioned on the central phenyl fragment and are directly con-
ments are thought to be responsible for the behavior of the
sulfonamides towards basic anions (i.e., acetate and dihydro-
gen phosphate). In the titration with acetate, a single equi-
librium [Equilibrium (9)] was observed, leading to the
mono-deprotonated form of the receptor (logKd >6, see
Table 2).
RH2þXꢀ Ð RHꢀþHX
ð9Þ
Proton-transfer processes were also observed with dihy-
drogen phosphate, as indicated by the development of
charge-transfer bands peculiar to the deprotonated species.
With dihydrogen phosphate, the stoichiometry of the inter-
action was more uncertain, probably due to the tendency of
the anion to form aggregates, thus the corresponding associ-
ation constants could not be determined.
ꢀ
jugated to the acidic N H bonds, thus favoring acidic disso-
ciation.
The potentiometric results demonstrate that sulfonamide
groups are more acidic than both urea and squaramide in a
mixture of water/acetonitrile and reinforce the hypothesis
that basic anions can easily induce proton transfer from sul-
fonamide-based receptors in pure acetonitrile. Further con-
firmation comes from the pH-spectrophotometric titrations:
the final spectrum of the titration of receptors 3–5 with ace-
tate in pure acetonitrile corresponds to the absorption bands
of the mono-deprotonated species in a mixture of water/ace-
tonitrile.
The Brønsted acidic behavior of receptors: To clarify the be-
havior of the receptors towards basic anions, we analyzed
the acidic character of 1–5 in aqueous solution, by perform-
ing potentiometric and pH-spectrophotometric titrations in
a mixture of acetonitrile/water (9/1, v/v). The pKa values ob-
tained are shown in Table 3.
Calorimetric studies: Additional quantitative studies of the
anion-binding properties of receptors 1–5 in pure acetoni-
trile were performed by ITC. In a typical experiment, a so-
lution of the receptor in acetonitrile was added to a solution
of the investigated anion, as the TBA+ salt, in the same sol-
vent.
Figure 3 reports the experimental curves corresponding to
the ITC titrations of receptors 1, 2, and 5 with TBACl in
acetonitrile (for receptors 3 and 4, see Figures S12a and
S13a in the Supporting Information, respectively). The ITC
profiles indicate the presence of a single equilibrium in solu-
tion [Equilibrium (10)], corresponding to the formation of
1:1 hydrogen-bonded adducts. Similar results were obtained
for most of the anions investigated, except for acetate and
dihydrogen phosphate; the corresponding thermodynamic
parameters and equilibrium constants are reported in
Table 4.
Table 3. pKa values of receptors 1–5 (5.0ꢀ10ꢀ4 m) measured by potentio-
metric titrations in acetonitrile/water (9/1 v/v; 0.1m in TBAPF6) at 258C.
Numbers in parentheses are standard deviations to the last significant
figure.
[a]
[a]
RH2
pKa1
pKa2
1
2
3
4
5
–
10.9(1)
8.3(1)
8.3(1)
4.3(1)
15.0(2)
13.0(2)
[a] RH2+H2OQnHꢀ+H3O+ (pKa1); RHꢀ+H2OQR2ꢀ+H3O+ (pKa2).
The least acidic compound is 1, for which no deprotona-
tion of the urea group was observed in aqueous solution,
followed by 2 with a pKa value of 10.9(1). The distribution
diagrams are given in the Supporting Information (for the
squaramide-based derivative, see Figure S6). Among the sul-
fonamides, receptor 3 undergoes a single deprotonation
(pKa =8.3(1); see Figure S7 in the Supporting Information);
whereas 4 and 5 can dissociate two protons (4: pKa1 =8.3(1),
pKa2 =15.0(2); 5: pKa1 =4.3(1), pKa2 =13.0(2)), as indicated
by both potentiometric and pH-spectrophotometric titra-
tions (see Figures S8 and S9 in the Supporting Information).
The most acidic receptor is 5, for which the two deprotona-
tion steps are accompanied by a change in the color of the
solution from bright yellow (first step) to dark red (second
step).
RH2þClꢀ Ð ½RH2 ꢁ ꢁ ꢁ Clꢂꢀ
ð10Þ
In Figure 4, the ITC profiles for the titrations of 1, 2, and
5 with TBACH3COO are shown. The experimental curves
for 1 and 2 (see Figure 3a and b) indicate a single equilibri-
um in solution and confirm the formation of hydrogen-
bonded 1:1 adducts. On the contrary, for the sulfonamide-
based receptors 3–5, the ITC titration profiles display multi-
ple equilibria and the stoichiometry of the interaction is un-
certain (see Figure 4c for receptor 5; Figures S12c and S13c
in the Supporting Information for receptors 3 and 4, respec-
tively).
The single- and double-deprotonated forms of 5 are char-
acterized by different absorption bands: the mono-deproton-
ated species presents an intense charge-transfer band at
To clarify the behavior of sulfonamide receptors with ace-
tate, “reversed” titrations have been performed, by filling
the cell of the calorimeter with the solution of receptor in
5976
www.chemeurj.org
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 5972 – 5981

Urea-, Squaramide-, and Sulfonamide-Based Anion Receptors
FULL PAPER
Figure 3. ITC profiles taken over the course of a) the titration of a solution of TBACl (1.59ꢃ10ꢀ3 m) in acetonitrile (Vcell =1.345 mL) with a solution of 1
(1.91ꢃ10ꢀ2 m); b) the titration of TBACl (1.0ꢃ10ꢀ4 m) with 2 (1.8ꢃ10ꢀ3 m); c) the titration of TBACl (1.59ꢃ10ꢀ3 m) with 5 (1.71ꢃ10ꢀ2 m). Circles: experi-
mental data; line: fitting profile (one site model; ligand in the cell); T=308C.
acetonitrile and by adding the solution of TBACH3COO
with a syringe. The ITC plots for 3–5 are reported in
Figure 5 and the corresponding thermodynamic parameters
are given in Table 5. The “reversed” ITC titration profiles
clearly indicate two steps; the first step can be attributed to
the proton-transfer process involving the sulfonamide recep-
tor and the acetate anion, according to Equilibrium (11):
uted to the formation of the acetic acid/acetate self-com-
plex, according to Equilibrium (12):
CH3COOHþCH3COOꢀ Ð ½CH3COO ꢁ ꢁ ꢁ H ꢁ ꢁ ꢁ CH3COOꢂꢀ
ð12Þ
This hypothesis was confirmed by comparing the thermo-
dynamic parameters of the second step reported in Table 5,
with those obtained by performing the ITC titration of a so-
lution of CH3COOH in acetonitrile with TBACH3COO (see
Figure 6).
Tables 4 and 5 collect the thermodynamic parameters ob-
tained under both the direct (Table 4) and reversed titration
conditions (Table 5). ITC ex-
RH2þCH3COOꢀ Ð RHꢀþCH3COOH
ð11Þ
Equilibrium (11), which is consistent with the spectropho-
tometric results, leads to the formation of acetic acid and
the conjugated base of the receptor (RHꢀ). The second step,
which is not detected by the UV/Vis titration, can be attrib-
periments on receptor 2 were
limited by the low solubility of
Table 4. Thermodynamic parameters at 308C (logK11, ꢀDH11, TDS11) obtained from fitting of ITC titration
curves (“direct” titrations) of receptors 1–5. Numbers in parentheses are standard deviations to the last signifi-
cant figure.
squaramide in acetonitrile, thus
titrations were performed only
with chloride, bromide, and
acetate (see Table 4). The inter-
action with halides (chloride,
bromide, and iodide) is exother-
mic and characterized by posi-
tive TDS11 values. This result is
compatible with the formation
of hydrogen-bonding receptor–
anion interactions. The affinity
reflects the decreasing negative-
charge density of the anion, as
Anion Receptor logK11 ꢀDH11
[kcalmolꢀ1
TDS11
Anion
Receptor logK11 ꢀDH11
[kcalmolꢀ1
TDS11
[kcalmolꢀ1
[a]
]
[kcalmolꢀ1
]
]
]
Clꢀ
1
3.95(1) 3.24(1)
2.3
3.5
1.1
1.9
2.2
1.8
2.4
§
Iꢀ
1
1
1
2
3–5
1
ffi2
[a]
ꢀ
2
3
4
5
1
2
5.76(5) 4.49(5)
3.49(1) 3.74(1)
3.70(2) 3.23(5)
4.38(1) 3.91(1)
3.21(2) 2.63(2)
4.62(3) 4.04(5)
HSO4
2.87(3) 3.69(5)
5.80(2) 8.01(2)
6.08(6) 5.70(7)
0.3
0.1
CH3COOꢀ
2.7
[a]
[a]
[a]
Brꢀ
H2PO4
3.86(2) 6.14(5)
ꢀ0.8
ꢀ
[a]
[a]
[a]
2–5
3–4
5
ffi2
§
2.97(3) 2.82(2)
1.3
[a] No reliable fit could be made.
Chem. Eur. J. 2011, 17, 5972 – 5981
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5977

V. Amendola et al.
Figure 4. ITC profiles taken over the course of a) the titration of a solution of TBACH3COO (5.6ꢃ10ꢀ4 m) in acetonitrile (Vcell =1.345 mL) with a solu-
tion of receptor 1 (1.91ꢃ10ꢀ2 m); b) the titration of TBACH3COO (1.0ꢃ10ꢀ4 m) with 2 (1.8ꢃ10ꢀ3 m); c) the titration of TBACH3COO (5.1ꢃ10ꢀ4 m) with 5
(6.97ꢃ10ꢀ3 m). Circles: experimental data; line: fitting profile (one site model; ligand in the cell); T=308C.
hypothesized when discussing the results of spectrophoto-
metric titrations. For the urea-based receptor, the interac-
tion with oxo-anions is exothermic, but characterized by
zero or negative entropic contributions. A remarkable dif-
Figure 5. ITC plots corresponding to a) the titration of a solution of receptor 3 (8.2ꢃ10ꢀ4 m) in acetonitrile (Vcell =1.345 mL) with a solution of
TBACH3COO (1.64ꢃ10ꢀ2 m); b) the titration of 4 (8.2ꢃ10ꢀ4 m) with TBACH3COO (1.64ꢃ10ꢀ2 m); c) the titration of 5 (8.4ꢃ10ꢀ4 m) with TBACH3COO
(1.64ꢃ10ꢀ2 m). All experimental curves have been fitted for ligand in the cell; T=308C.
5978
www.chemeurj.org
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 5972 – 5981

Urea-, Squaramide-, and Sulfonamide-Based Anion Receptors
FULL PAPER
Table 5. Thermodynamic parameters at 308C obtained in the “reverse” ITC titration experiments of receptors
3–5 and acetic acid. Numbers in parentheses are standard deviations to the last significant figure.
with the anion). The corre-
sponding thermodynamic pa-
rameters are reported in
Table 5.
The ITC plots of the reversed
titrations indicated two consec-
utive equilibria, Equilibria (13)
and (14):
Anion
Receptor
logK1
ꢀDH1
TDS1
logK2
ꢀDH2
TDS2
[kcalmolꢀ1
]
[kcalmolꢀ1
]
[kcalmolꢀ1
]
[kcalmolꢀ1
]
CH3COOꢀ
3
4
5
7.52(1)
6.97(1)
6.82(6)
2.15(2)
2.08(2)
7.23(3)
8.3
7.6
2.2
4.00(2)
4.03(2)
4.19(2)
4.09(1)
5.65(5)
5.26(6)
4.17(6)
5.17(4)
ꢀ0.1
0.3
1.6
CH3COOH
0.5
RH2þCH3COOꢀ Ð RHꢀþCH3COOH
log K1
ð13Þ
CH3COOꢀþCH3COOH Ð ½CH3COO ꢁ ꢁ ꢁ H ꢁ ꢁ ꢁ CH3COOꢂꢀ
log K2
ð14Þ
For the first step, Equilibrium (13), the DH1 parameter
contains i) the endothermic contribution of the deprotona-
tion of the receptor and ii) the enthalpic contribution of op-
posite sign (i.e., exothermic) relative to acetic acid forma-
tion. Table 5 indicates that for sulfonamide 5, the deprotona-
tion contribution of the receptor is less unfavorable than for
3 and 4: the two nitro groups on the central phenyl ring
probably favor deprotonation of 5, thus stabilizing the corre-
sponding conjugated base. Such an enthalpic advantage of
receptor 5, with respect to 3 and 4, is mitigated by the en-
tropic term, which is distinctly more positive for 3 and 4.
The second step of the ITC plots was attributed to the for-
mation of the acetic acid/acetate self-complex [Equilibri-
um (14)]. The nature of this second step was confirmed by
the titration of acetic acid with TBA+ acetate in acetonitrile
(see Figure 6): the obtained thermodynamic parameters
(logK=4.09(1);
ꢀDH=5.17(4) kcalmolꢀ1
;
TDS=
Figure 6. ITC plot of the interaction of CH3COOH (4.5ꢃ10ꢀ4 m) with
TBACH3COO (1.7ꢃ10ꢀ2 m) in acetonitrile; T=308C.
0.5 kcalmolꢀ1) are consistent with those obtained in the
second step of the titration of sulfonamide-based receptors
with acetate, in particular for 3 and 4 (the differences ob-
served in the comparison with receptor 5 are attributable to
the bad quality of this receptorꢀs experimental data). Of the
two steps observed by ITC, only the first directly involves
the receptor and can be detected in the UV/Vis titration.
The discrepancy between ITC and spectrophotometric re-
sults (which gave 1:1 equilibria for all receptors with ace-
tate) marks the difference and, in this particular case, estab-
lishes the superiority of ITC with respect to the spectropho-
tometric technique. Actually, spectrophotometric titrations
directly follow the effect of anion binding on the absorption
properties of the receptor, whereas calorimetry determines
the integral heat response of all processes happening simul-
taneously in solution upon anion binding.
ference between 1 and 2 was observed with acetate. For re-
ceptors 1 and 2, results obtained by ITC and absorption
spectroscopy are in good agreement with each other and
confirm the formation of 1:1 hydrogen-bonded adducts with
all anions. The corresponding thermodynamic parameters
(logK11, ꢀDH11, TDS11) are shown in Table 4. For 1, the in-
teraction is mainly driven by the enthalpic contribution
(ꢀDH11 =8.01(2) kcalmolꢀ1; TDS11 =0.1 kcalmolꢀ1). Where-
as for 2, the entropic effect seems to play a not negligible
role (logK11 =6.08(6); ꢀDH11 =5.70(7) kcalmolꢀ1; TDS11 =
2.7 kcalmolꢀ1). ITC experiments on sulfonamide-based re-
ceptors 3–5 do not always confirm the spectrophotometric
results. In particular, the formation of genuine 1:1 hydrogen-
bonded adducts is verified only for the investigated halides
(see Table 4), whereas with more basic oxo-anions, such as
acetate and dihydrogen phosphate, ITC binding curves dis-
play multiple equilibria. In the case of acetate, best-fitting
results were obtained by performing reversed titrations (i.e.,
by filling the cell with the receptor solution and the syringe
Calorimetric titrations on sulfonamides 3–5 were also per-
formed with dihydrogen phosphate (ITC curves are avail-
able in the Supporting Information). With respect to acetate,
the prevalence of multiple equilibria and the lack of calori-
metric events at distinct integral equivalents precluded accu-
rate curve fitting.
Chem. Eur. J. 2011, 17, 5972 – 5981
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5979

V. Amendola et al.
1
1H NMR spectroscopic titration experiments: To assess the
the receptor, could not be detected by both H NMR and
equilibria in solution and to confirm the results obtained
spectrophotometrically and by ITC, we performed H NMR
UV/Vis spectroscopy. Notably, the basic structures of the re-
ceptors are vastly different (urea, squaramide, and sulfona-
mide), therefore, their basic solvation patterns will also
differ. Solvation plays a fundamental role in the stabilization
of both the initial and final state of complexation. For this
reason, a discussion on binding selectivity should take into
account the solvation effects and should not be done only in
terms of weaker/better interactions of hydrogen bonding in
the complexed state. Moreover, the calorimetric results
show that the entropy component for most systems consti-
tutes a major part (30–50% of the enthalpy; in some cases
the entropic contribution is even the dominant component).
Thus, it is not possible to focus the explanation on enthalpy
only (in terms of geometric complementarity, distance, con-
verging hydrogen bonds, etc.). In conclusion, even for the
simple systems presented herein, there are still too many de-
grees of freedom to single out the individual contributions
and to assign a defined cause for better binding.
1
spectroscopic titrations on receptors 1, 2, and 3 in CD3CN
with two different anions: bromide and acetate. The NMR
spectroscopy experiments with TBABr confirmed the results
obtained by UV/Vis spectroscopy and calorimetry: the en-
visaged receptors formed stable 1:1 adducts with bromide
and the affinity decreased along the series 2>1>3 (1:
logK11 =3.27(2); 2: logK11 =4.61(6); 3: logK11 =2.37(1)).
ꢀ
Bromide induced the downfield shift of the N H protons,
involved in the receptor–anion interaction. Experimental
conditions, titrations profiles, distribution diagrams, and the
1
family of H NMR spectra are available in the Supporting
Information (see Figures S15, S17, and S19 for titrations of
1, 2, and 3, respectively, with TBABr).
In
the
1H NMR
spectroscopic
titration
with
ꢀ
TBACH3COO, the downfield shift of the N H proton of 1
indicated the formation of the 1:1 adduct involving the urea
1
moiety. Unfortunately, the H NMR spectroscopic titration
profile was too steep to allow the determination of the bind-
ing constant (Figure S16 in the Supporting Information).
Also for the sulfonamide-based receptor (3), a 1:1 equilibri-
um was observed. In this case, the disappearance of the NH
signal and the remarkable upfield shift of Ha on the central
phenyl ring may be interpreted as anion-induced deprotona-
tion of the sulfonamide group (Figure S20 in the Supporting
Information). Deprotonation was confirmed by recording
the UV/Vis spectrum of the final sample. Note that deproto-
nation was already observed for all sulfonamide receptors
by UV/Vis spectroscopy and ITC titrations with acetate.
The 1H NMR titration of 2 with TBACH3COO indicated
two equilibria, corresponding to the formation of 1:1 and
2:1 receptor/anion adducts (Figure S18 in the Supporting In-
formation). Note that both ITC and spectrophotometric ti-
trations evidenced only a single equilibrium in solution, cor-
responding to the formation of the 1:1 adduct. The forma-
tion of the 2:1 (receptor/anion) adduct could be followed
only by 1H NMR spectroscopy, probably because of the
higher concentration used for both receptor and anion.
Experimental Section
General: All reagents were purchased by Aldrich and Fluka. TBA+ salts
were all greater than 98% pure and dried in vacuo overnight before use.
The solutions used for UV/Vis spectroscopy and ITC titrations were
made from freshly opened, dry acetonitrile (ꢃ0.001% H2O) packaged in
crown-cap bottles over molecular sieves (Aldrich). Mass spectra were ac-
quired on a Thermo-Finnigan ion-trap LCQ Advantage Max instrument
equipped with an ESI source, NMR spectra were acquired on a Bruker
AVANCE 400 spectrometer (operating at 9.37 T, 400 MHz). UV/Vis
spectra were run on a Varian Cary 100 SCAN spectrophotometer. The
potentiometric titrations were made with a Radiometer TitraLab 90 titra-
tion system.
Spectrophotometric titrations: All titrations were performed at 258C. For
the determination of binding constants in acetonitrile, the solution of re-
ceptor (1–5) was titrated with a 100-fold more concentrated solution of
the anion as the TBA+ salt. After each addition of a sub-stoichiometric
amount of anion, the UV/Vis spectrum was recorded. The concentration
of the receptor solution was chosen on the basis of the p parameter (p=
[concentration of complex]/[maximum possible concentration of com-
plex]), which ranged from 0.2 to 0.8.[12] Titration data were processed
with the Hyperquad package[11] to determine the equilibrium constants.
Potentiometric titrations: All potentiometric titrations were performed at
258C by using carbonate-free NaOH. Acidic dissociation constants of re-
ceptors 1–5 were determined in a mixture of acetonitrile/H2O (9:1), with
0.05m TBAPF6 (see Table 3).Titrations were performed under a nitrogen
atmosphere. In a typical experiment, a 5.0ꢃ10ꢀ4 m solution of the recep-
tor (15mL) was treated with an excess of a 1.0m standard solution of
HNO3. Titrations were run by the addition of 10 mL portions of a stan-
dard 0.1m solution of NaOH and collecting 80–100 points for each titra-
tion. Prior to each potentiometric titration, the standard electrochemical
potential (E8) of the glass electrode was determined in a mixture of ace-
tonitrile/H2O (9:1, v/v), by a titration experiment according to the Gran
method. Protonation and complexation titration data (emf vs. mL of
NaOH) were processed with the Hyperquad package to determine the
equilibrium constants.[11]
Conclusion
The affinities of receptors 1–5 towards anions were com-
pared by performing spectrophotometric, ITC, and H NMR
1
spectroscopic titrations in acetonitrile. The results indicated
that 1 and 2 formed 1:1 hydrogen-bonded complexes with
most of the anions investigated. In the case of receptors 3–5,
hydrogen-bonding interactions were observed only towards
anions of low basicity, for which single equilibria leading to
1:1 adducts were observed, whereas with the more basic
anions, acetate and dihydrogen phosphate, the experimental
data indicated proton-transfer processes from the receptor
to the anion. Further equilibria, leading to the formation of
self-complexes of the anions, could only be detected in calo-
rimetric experiments. These processes, not directly involving
Isothermal titration calorimetry (ITC): ITC titrations were performed by
using a MCS-ITC instrument (from MicroCal). All binding experiments
were performed at 308C. Stock solutions were prepared by directly
weighing the substances into volumetric flasks. The results reported in
Table 4 correspond to ITC experiments performed by adding the recep-
tor solution to the TBA+ salt solution, placed in the instrument cell,
5980
www.chemeurj.org
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 5972 – 5981

Urea-, Squaramide-, and Sulfonamide-Based Anion Receptors
FULL PAPER
whereas for the results in Table 5, the TBA+ salt solution was added with
a syringe to the receptor solution in the instrument cell. The association
parameters (K, DH, and DS reported in Tables 4 and 5), as well as the in-
teraction stoichiometry, were experimentally determined by the fitting
procedure. Blank titrations in acetonitrile were performed and subtracted
from the corresponding titrations to remove the effect of dilution.
1H NMR spectroscopy titrations: All measurements were performed at
258C in CD3CN. For the determination of binding constants, the receptor
(1–3) was titrated with a 100-fold more concentrated solution of the
anion as the TBA+ salt. After each addition of sub-stoichiometric
amount of anion, the 1H NMR spectrum was recorded. Titration data
were processed with the Hyperquad package[11] to determine the equilib-
rium constants.
Morey, P. Ballester, A. Costa, Tetrahedron Lett. 2001, 42, 4933–
4936; M. Neus PiÇa, C. Rotger, B. Soberats, P. Ballester, P. M. Deyꢁ,
A. Costa, Chem. Commun. 2007, 963.
[4] T. Gunnlaugsson, A. P. Davis, J. E. OꢀBrien, M. Glynn, Org. Lett.
2002, 4, 2449–2452; C. Pꢆrez-Casas, Anatoly K. Yatsimirsky, J. Org.
Chem. 2008, 73, 2275–2284; F. M. Pfeffer, T. Gunnlaugsson, P,
Jensen, P. E. Kruger, Org. Lett. 2005, 7, 5357–5360; M. M. Raposo,
B. Garcia-Acosta, T. Abalos, P. Calero, R. Martinez-Manez, J. V.
Ros-Lis, J. Soto, J. Org. Chem. 2010, 75, 2922–2933.
[5] A. P. Davis, S. M. Draper, G. Dunne, P. Ashton, Chem. Commun.
1999, 2265–2266; E. A. Katayev, G. D. Pantos, M. D. Reshetova,
V. N. Khrustalev, V. M. Lynch, Y. A. Ustynyuk, J. L. Sessler, Angew.
Chem. 2005, 117, 7552; Angew. Chem. Int. Ed. 2005, 44, 7386; S. J.
Brooks, S. E. Garcꢇa-Garrido, M. E. Light, P. A. Cole, P. A. Gale,
Chem. Eur. J. 2007, 13, 3320–3329; G. Ambrosi, M. Formica, V.
Fusi, L. Giorgi, A. Guerri, M. Micheloni, P. Paoli, R. Pontellini, P.
Rossi, Chem. Eur. J. 2007, 13, 702–712.
Acknowledgements
[6] K. Bowman-James, Acc. Chem. Res. 2005, 38, 671; S. O. Kang, V. W.
Day, K. Bowman-James, Inorg. Chem. 2010, 49, 8629–8636; P. Bal-
lester, Chem. Soc. Rev. 2010, 39, 3810–3830.
This work was financially supported by the Italian Ministry of Research
(MIUR), project Supramolecular Devices.
[7] C. Pꢆrez-Casas, A. K. Yatsimirsky, J. Org. Chem. 2008, 73, 2275–
2284.
[8] V. Amendola, G. Bergamaschi, M. Boiocchi, L. Fabbrizzi, M.
Milani, Chem. Eur. J. 2010, 16, 4368–4380.
[9] V. Amendola, L. Fabbrizzi, L. Mosca, Chem. Soc. Rev. 2010, 39,
3889–3915; B. P. Hay, V. S. Bryantsev, Chem. Commun. 2008, 2417–
2428.
[10] F. P. Schmidtchen, Encyclopedia of Supramolecular Chemistry 2004,
1225–1230; F. P. Schmidtchen, Chem. Soc. Rev. 2010, 39, 3916–3935.
[11] P. Gans, A. Sabatini, A. Vacca, Talanta 1996, 43, 1739–1753; http://
www.hyperquad.co.uk/index.htm.
[12] C. S. Wilcox in Frontiers in Supramolecular Chemistry and Photo-
chemistry (Eds.: H.-J. Schneider, H. Dꢈrr), VCH, Weinheim, 1991.
[13] P. Gilli, L. Pretto, V. Bertolasi, G. Gilli, Acc. Chem. Res. 2009, 42,
33–44.
[1] a) P. A. Gale in Encyclopedia of Supramolecular Chemistry (Eds.:
J. L. Atwood, J. W. Steed), Marcel Dekker, New York, 2004,
pp. 3141; b) J. L. Sessler, P. A. Gale, W.-S. Cho, Anion Receptor
Chemistry, Royal Society of Chemistry, Cambridge, UK, 2006;
c) P. A. Gale, S. E. Garcꢄa-Garrido, J. Garric, Chem. Soc. Rev. 2008,
37, 151–190; C. Caltagirone, P. A. Gale, Chem. Soc. Rev. 2009, 38,
520–563; A.-F. Li, J.-H. Wang, F. Wang, Y.-B. Jiang, Chem. Soc.
Rev. 2010, 39, 3729–3745.
[2] a) A. Dorazco-Gonzalez, H. Hopfl, F. Medrano, A. K. Yatsimirsky,
J. Org. Chem. 2010, 75, 2259–2273; I. A. Carasel, C. R. Yamnitz,
R. K. Winter, G. W. Gokel, J. Org. Chem. 2010, 75, 8112–8116;
b) M. Boiocchi, L. Del Boca, D. Esteban-Gꢅmez, L. Fabbrizzi, M.
Licchelli, E. Monzani, J. Am. Chem. Soc. 2004, 126, 16507–16514;
V. Amendola, D. Esteban-Gꢅmez, L. Fabbrizzi, M. Licchelli, Acc.
Chem. Res. 2006, 39, 343–353.
[14] M. R. Sambrook, P. D. Beer, J. A. Wisner, R. L. Paul, A. R. Cowley,
F. Szemes, M. G. B. Drew, J. Am. Chem. Soc. 2005, 127, 2292.
[3] S. Tomꢁs, R. Prohens, M. Vega, M. C. Rotger, P. M. Deyꢁ, P. Balles-
ter, A. Costa, J. Org. Chem. 1996, 61, 9394; R. Prohens, S. Tomꢁs, J.
Morey, P. M. Deyꢁ, P. Ballester, A. Costa, Tetrahedron Lett. 1998,
39, 1063; R. Prohens, M. G. Rotger, M. Neus PiÇa, P. M. Deyꢁ, J.
Received: November 25, 2010
Published online: April 6, 2011
Chem. Eur. J. 2011, 17, 5972 – 5981
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5981