Anion Recognition in Water, Including Sulfate, by a Bicyclam Bimetallic Receptor: A Process Governed by the Enthalpy/Entropy Compensatory Relationship

Article abstract of DOI:10.1002/chem.201800067

The dimetallic system [Cu^II₂(L)]⁴⁺ contains two facing equivalent metallocyclam subunits and incorporates ambidentate anions, mono- (halides) and poly-atomic (sulfate), which bridge the two Cu^II centres. Isothermal titration calorimetry (ITC) experiments in water showed that the log K values of the inclusion equilibria for halides and sulfate varied over a restricted interval (3.6±0.2), which indicated lack of selectivity and that similarity of ΔG° values resulted from the unbalanced contribution of the ΔH° and TΔS° terms: the more favourable the one, the less favourable the other. In particular, a linear dependence of ΔH° and TΔS° was observed (a typical enthalpy/entropy compensatory diagram), which assigned a major role to hydration terms: 1) a more hydrated anion resulted in a more endothermic dehydration process; and 2) a larger number of water molecules released to the solution resulted in a more positive TΔS°. Limiting cases refer to the complexation 1) of the poorly hydrated iodide (highly exothermic process, entropically disfavoured), and 2) of the highly hydrated sulfate (moderately endothermic process, entropically very favoured). Anion receptors operating in water belong to two main domains: 1) those exhibiting positive ΔH° and positive TΔS° (+/+ signature), and 2) those displaying the opposite behaviour: (?/? signature). The receptor investigated herein connects the two domains, along the ΔH°/TΔS° straight line, thanks to the hidden role of the versatile metal–anion interaction.

Full text of DOI:10.1002/chem.201800067

A Journal of
Accepted Article
Title: Anion Recognition in Water, Including Sulfate, by a bicyclam
Bimetallic Receptor, a Process Governed by the Enthalpy/
Entropy Compensatory Relationship
Authors: Luigi Fabbrizzi
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201800067
Link to VoR: http://dx.doi.org/10.1002/chem.201800067
Supported by

10.1002/chem.201800067
Chemistry - A European Journal
Anion Recognition in Water, Including Sulfate, by a bicyclam
Bimetallic Receptor, a Process Governed by the
Enthalpy/Entropy Compensatory Relationship
Massimo Boiocchi,[c] Marco Bonizzoni,*[a] Carlo Ciarrocchi,[b] Luigi Fabbrizzi,*[b] Michele Invernici,[b]
and Maurizio Licchelli*[b]
Abstract: The dimetallic system [CuII (L)]4+ contains two facing equivalent metallocyclam subunits and
2
incorporates ambidentate anions, mono- (halides) and poly-atomic (sulfate), which bridge the two CuII
centres. ITC experiments in water showed that log K of the inclusion equilibria for halides and sulfate vary
over a restricted interval (3.6  0.2) indicating lack of selectivity and that similarity of ∆G° values resulted
from the unbalanced contribution of the ∆H° and T∆S terms: the more favorable one contribution, the less
favorable the other. In particular, a linear dependence between ∆H° and T∆S° was observed (a typical
enthalpy/entropy compensatory diagram), which assigned a major role to hydration terms: (i) the more
hydrated the anion, the more endothermic the dehydration process; (ii) the larger the number of water
molecules released to the solution, the more positive T∆S°. Limiting cases refer to the complexation (i) of the
poorly hydrated iodide (highly exothermic process, entropically disfavored), and (ii) of the highly hydrated
sulfate (moderately endothermic process, entropically very favored). Anion receptors operating in water
belong to two main domains: 1) those exhibiting positive ∆H° and positive T∆S° (+/+ signature); 2) those
displaying the opposite behaviour: (-/-) signature). The receptor here investigated connects the two domains,
along the ∆H°/T∆S° straight line, thanks to the hidden role of the versatile metal-anion interaction.
[a] Prof. Marco Bonizzoni
Department of Chemistry
The University of Alabama
Tuscaloosa, AL35487, USA
E-mail: marco.bonizzoni@ua.edu4
[b] Dr. Carlo Ciarrocchi, Prof. Luigi Fabbrizzi, Dr. Michele Invernici, Prof. Maurizio Licchelli
Dipartimento di Chimica
Università di Pavia
27100 Pavia, Italy
E-mail: luigi.fabbrizzi@unipv.it
E-mail: maurizio.licchelli@unipv.it
[c] Dr. Massimo Boiocchi
Centro Grandi Strumenti
Università di Pavia
27100 Pavia, Italy
 Supporting Information for this article is given via a link at the end of the document
CCDC 1814887-1814888 contain the supplementary crystallographic data for this paper. These data are
provided free of charge by the Cambridge Crystallographic Data Centre.
This article is protected by copyright. All rights reserved.

10.1002/chem.201800067
Chemistry - A European Journal
2
Introduction
Anion recognition chemistry originated from pioneering studies carried out in water involving cage
shaped receptors, in whose cavities positive charges (from ammonium groups) had been
strategically positioned. First receptors included: katapinands by Park and Simmons (containing
two tertiary ammonium groups)[1] and bistren cryptands by Lehn (containing six secondary
ammonium groups)[2]. A polycyclic and possibly rigid structure of the receptor was chosen in order
to minimise the loss of conformational energy experienced by the receptor during anion complex
formation. The nature of the interaction was electrostatic and hydrogen bonding (for receptors
containing highly polarised and properly oriented NH fragments). Apparently, such interactions
were strong enough to overcome the energy spent for dehydrating the anion and the receptor’s
cavity.
Later, neutral receptors were considered (amides,[3-5] ureas,[6,7] thioureas,[8,9] pyrroles)[10]
capable to donate H-bonds through polarised NH fragments to the envisaged anion, from which a
rich and lively anion coordination chemistry developed, however limited to aprotic solvents of
varying polarity (CH2Cl2, MeCN, DMSO). A notable exception is represented by cyclopeptides and
bis-cyclopeptides by Kubik,[11-13] which are able to bind in water highly hydrated anions such as
sulfate, due their extremely preorganised concave arrangement of polarised peptide NH
fragments. More recently, receptors capable to recognize anions in water through the donation of
halogen bonds were introduced.[14,15]
As a further possibility, positive charges inside the receptor’s cavity can be generated through
the inclusion of metal ions.[16] As an example, the bistren complex illustrated by formula 1 contains
two coordinatively unsaturated copper(II) ions and it is prone to include an ambidentate polyatomic


anion (e.g. N3 , HCO3 ), which goes to bridge the two metal centres.[17,18] A sharp peak selectivity
was observed, which was ascribed the more or less favorable matching of the anion bite length
(the distance between two consecutive donor atoms) and the intermetallic distance. Noticeably,
whereas polyammonium receptors operate at pH  3 in order to maintain all the secondary amine
groups protonated, metal containing receptors of type 1 can work at a neutral pH or higher. In any
case, metal-ligand interactions are typically more intense than electrostatic/H-bond interactions
and afford the formation of more stable receptor/anion complexes.
Metallo-receptor 1 contains a substitutionally labile metal centre (CuII) and is therefore subject
to demetallation in the presence of an excess of anion or under acidic conditions (due to the
protonation of the nitrogen atoms). Such an inconvenience can be removed by using
metallocyclam subunits: in particular, transition metal ions, when encircled by the 14-membered
cyclic tetramine cyclam, achieve an extreme inertness towards demetallation even under severe
conditions (due to the kinetic macrocyclic effect).[20] If two metallocyclam subunits are appended to
an appropriate spacer, like in system 2, they provide an opening for the inclusion of an
This article is protected by copyright. All rights reserved.

10.1002/chem.201800067
Chemistry - A European Journal
3
ambidentate anion: matching of the anion bite and of the intermetallic distance may generate
selectivity. In particular, the bicyclam ligand of complex 2 consists of two dimethylcyclam subunits
bridged at the carbon centre with an ortho-xylyl group, thus providing a face-to-face arrangement
of the two macrocycles. Dinickel(II) complexes of bicyclam were investigated in their unique
magnetic properties by Ito and coworkers,[21,22] and later, very thoroughly, by Endicott and
coworkers.[23] More recently, we have studied the behaviour of the [NiII (bicyclam)]4+ complex as an
2
anion receptor in DMSO, with a special reference to the effect of anion inclusion on the NiII-to-NiIII
oxidation processes taking place at the two metal centres.[24]
Here we report a complete thermodynamic investigation on the interaction of the
[CuII (bicyclam)]4+ receptor with anions in pure water. The CuII(cyclam)2+ subunit exhibits a defined
2
tendency to bind further ligands (e.g. anions) in order to achieve five-coordination,[25]
a
circumstance which should favor anion inclusion inside the intermetallic space of
[CuII (bicyclam)]4+. Anion binding equilibria have been investigated through Isothermal Titration
2
Calorimetry (ITC), which allowed the determination of association constants (and ΔG°), as well as
of enthalpy, ΔH°, and entropy contribution, TΔS°. It has been shown that the knowledge of these
thermodynamic quantities may address the interpretation of the solution stability of the anion
complexes in terms of inner effects (receptor-anion bonding, conformational rearrangement of the
receptor’s framework) and outer effects (release of water molecules to the solution due to anion
and receptor dehydration).[26] X-ray diffraction studies on the crystalline complex salts
[CuII (bicyclam)(μ-Br)2]Br2 and [CuII (bicyclam)(μ2-HSO4)(HSO4)2]·HSO4·EtOH·H2O provided a
2
2
direct insight on the geometric nature of the receptor-anion adducts.
Results and Discussion
The structure of bromide and hydrogensulfate complexes: X-ray diffraction studies
Design and details on the synthesis of bicyclam and of the [CuII (bicyclam)](ClO4)4 complex salt are
2
described in the Supporting Information (see Schemes S1 and S2).
The molecular structure of the [CuII (bicyclam)(Br)2]2+ cation present in the
2
[CuII (bicyclam)(μ-Br)2]Br2 crystalline complex salt in shown in Figure 1. A plot showing thermal
2
ellipsoids is drawn in Figure S1 (see Supporting Information).
Figure 1. A simplified sketch of the [CuII (bicyclam)(Br)2]2+ molecular cations, which originate molecular
2
chains held together by weak CuIIBr bond interactions (crystallographic mirror planes normal to the plane of
projection of the figure are drawn with solid lines). The CuIIBr distances are 2.92(1) Å inside the dimer and
2.98(1) Å outside; the CuII···CuII distances are 5.83(1) Å inside the dimer and 5.94(1) Å outside.
The crystals of the bromide salt were obtained by slow evaporation of an aqueous solution of
CuII (bicyclam)(ClO4)4 in the presence of an excess of NaBr. The face-to-face bimacrocycle
2
exhibits a perfect Cs molecular symmetry, because a crystallographic mirror plane passes in the
middle of the ortho-xylyl spacer. The two facing metallocyclam moieties are therefore symmetrically
This article is protected by copyright. All rights reserved.

10.1002/chem.201800067
Chemistry - A European Journal
4
equivalent and are arranged in a trans-III (RRSS) configuration. The two copper(II) centres are
slightly displaced from the best plane of the tetramine rings, being positioned at 0.06(1) Å from the
equatorial N4 plane and pointing inside the receptor’s cavity. The observed mean CuIIN distance
of 2.03(1) Å corresponds to that expected for a strain-free CuN bond in cyclam and cyclam-like
macrocycles.[27] The CuII coordination of each metal centre is completed by two Br ions placed in
the axial positions of a rather elongated octahedron. Since CuII ions are displaced towards the
inside of the receptors, the two CuIIBr distances are slightly different: CuIINin = 2.92(1) Å,
CuIINout = 2.98(1) Å. The CuII···CuII distance (5.83(1) Å) is comparable to the intermetallic distance
observed in the analogous [NiII (bicyclam)Br3]+ complex, containing a high-spin NiII (bound to inner
2
Br) and a low-spin NiII (not bound).[23]
In the crystal, both the bromide ions in the inner and outer positions are positioned on two
crystallographic mirror planes and bridge the two CuII metal centres, with almost linear two-fold
coordination. The CuIIBr- distance, the CuIIBrCuII angle and the CuII···CuII separation are
2.92(1) Å, 171.7(1)°, 5.83(1) inside the dimer and 2.98(1) Å, 170.9(1)°, 5.94(1) Å outside. These
interactions originate infinite molecular chains of the dimetallic subunits extending along the
direction of the b crystallographic axis (see Figure 1).
The structure of the [CuII (bicyclam)(μ2-HSO4)(HSO4)2]+ molecular cation present in the
2
[CuII (bicyclam)(μ2-HSO4)(HSO4)2]HSO4·EtOH·H2O complex salt is shown in Figure 2. A plot
2
showing thermal ellipsoids is drawn in Figure S2 (see Supporting Information).
Figure 2. A simplified sketch of the
[CuII (bicyclam)(HSO4)(HSO4)2]+ cation
2
(the crystallographic mirror plane normal
to the plane of projection of the figure is
indicated by a solid line). The CuIIO
distances are 2.38(1) Å inside the dimer
and 2.74(1) Å outside; the CuII···CuII
distance is 6.90(1) Å.
Crystals suitable for X-ray diffraction studies were obtained by slow diffusion of EtOH in an
MeCN solution of CuII (bicyclam)(ClO4)4 containing an excess of [Bu4N]HSO4. Also in this case, a
2
crystallographic mirror plane makes equivalent the two facing metallocyclam moieties, arranged in
a trans-III (RRSS) configuration. However, the bimacrocycle assumes a more ordered C2v
molecular symmetry. Each metal centre remains slightly displaced from the best plane of the four
coordinated amine nitrogen atoms (being placed at 0.08(1) Å over the N4 plane and pointing inside
the dimer), while the observed mean CuIIN distance of 2.02(1) Å does not significantly differ from

the value observed in the bromide containing dicopper(II) complex. A HSO4 ion placed inside the
cage bridges the two metal centres with two oxygen atoms, forming two equivalent CuO
coordinate bonds of 2.38(1) Å. Two outer hydrogensulfate ions form longer CuIIO bonds,
completing six-coordination of each CuII centre, according to an elongated octahedral geometry.
In contrast to what observed in the bromide complex, outer hydrogensulfate ions do not
connect directly two metal centres. Connections between adjacent complexes are provided by

hydrogen bonding OH···O interactions established between the OH group of an HSO4 ion

(H-donor) and the oxygen atom of an adjacent HSO4 ion or of an EtOH solvating molecule
(H-acceptors). Further connections are provided by NH···O hydrogen bonding interactions
This article is protected by copyright. All rights reserved.

10.1002/chem.201800067
Chemistry - A European Journal
5
involving the secondary amine groups of cyclam subunits (H-donor) and the oxygen atoms of

adjacent HSO4 ions (H-acceptor). A possible H-bond motif, resulting from the assigned positions
of hydrogen atoms belonging to hydrogensulfate ions and MeOH molecules, is shown in Figure S3
(see Supporting Information).
Structural data suggest that the [CuII (bicyclam)]4+ system is a versatile receptor capable to
2
accomodate in its opening ambidentate anions of varying size and shape, either mono- or poly-
atomic. Such a feature seems to be related to the capability of the system to properly orientate, at
a low conformational cost, the two metallocyclam subunits. In the case of the bromide complex, the
two facing metallocyclam moieties are kept close each other and the C···C interatomic distance
between the xylene carbon atoms linked to cyclam ( 5.91(1) Å) results longer than the CuII···CuII
intermetallic distance (5.83(1) Å). On the other hand, in presence of hydrogensulfate, the two
metallocyclam moieties diverge substantially in the portion not linked by the xylene spacer: as a
consequence, the cyclam carbon atoms linked to the ortho-xylene spacer remain at an interatomic
distances of 5.91(1) Å, whereas the intermetallic CuII···CuII distance becomes 6.90(1) Å. Thus, it is
the change of the reciprocal orientation of the two metallocyclam subunits that modulates the
intermetallic distance and allows the inclusion of coordinating anions of varying bite length. Such a
characteristic demonstrates the flexibility of the receptor’s framework and is not expected to favour
selectivity in anion recognition by [CuII (bicyclam)]4+ (bad news).
2
The nature of the [CuII (bicyclam)]4+ receptor in water
2
In order to elucidate the nature of the [CuII (bicyclam)]4+ receptor in water, a solution of
2
Cu2(bicyclam)(ClO4)4 was brought to pH 2 by addition of strong acid, then it was titrated
potentiometrically with standard NaOH. Titration data (emf of the cell vs. mL NaOH curve, see
Figure S4 in Supporting Information) were processed with a non-linear least-squares program.
Best fitting of the titration curve was obtained by assuming the occurrence of the two following
hydrolytic equilibria (L = bicyclam):
[CuII (L)]4+ + H2O  [CuII (L)OH]3+ + H+
(1)
(2)
pKa1 = 9.41(1)
pKa2 = 10.99(1)
2
2
[CuII (L)OH]3+ + H2O  [CuII (L)(OH)2]2+ + H+
2
2
It is suggested that water molecules undergoing hydrolysis lie in the receptor’s cavity and are
coordinated to a CuII centre, as sketched in Figure 3. Outer water molecules complete six-
coordination of each metal ion according to an octahedrally distorted coordination geometry.
Figure 3. Hypothesised structures of the species [CuII (L)]4+, [CuII (L)OH]3+ and [CuII (L)(OH)2]2+ present in
2
2
2
aqueous solution in the absence of any coordinating anion (L = bicyclam). It is suggested that on base
addition protons are released from inner metal coordinated water molecules to give the corresponding
mono- and di-hydroxo complexes.
This article is protected by copyright. All rights reserved.

10.1002/chem.201800067
Chemistry - A European Journal
6
It is assumed that in the di-aquo complex [CuII (L)]4+ CuII ions are displaced from the cyclam
2
plane, pointing towards the cavity, as observed in the bromide and hydrogensulfate inclusion
complexes discussed in the previous Section. In these circumstances, a more intense CuIIO bond
is formed, which makes the inner water molecules more acidic, compared to the outer ones. From
pKa1 and pKa2 values, the distribution diagram shown in Figure 4 was drawn.
3
Figure 4. Distribution diagram of the species at the equilibrium for a solution 5 10 M in [CuII (L)]4+ (L =
2
bicyclam) over the 212 pH range. Species correspond to those illustrated in Figure 3.
It is observed that at neutral pH the complex [CuII (bicyclam)]4+ predominates. In particular, 6.8 is
2
the highest pH at which [CuII (bicyclam)]4+ is present at 100%.
2
ITC studies on the [CuII (bicyclam)]4+/anion association equilibria in water
2
The interaction of anions with [CuII (bicyclam)]4+ was investigated by Isothermal Titration
2
Calorimetry (ITC). In a typical experiment, a solution 5 103 M in [CuII (bicyclam)]4+ and 5 102 M
2
in the HEPES buffer (pH = 6.8, the highest pH at which complex [CuII (bicyclam)]4+ is present at
2
100%) was titrated by a solution of the investigated anion, dissolved as a sodium salt (NaCl, NaBr,
[Bu4N]II, NaN3, NaNCO, NaNCS, Na2SO4). Thermograms and the ITC profiles of titration
experiments are shown in Figures S5 and S6 (see Supporting Information). Best fitting of the
titration data was obtained by assuming the occurrence of one equilibrium, corresponding to the
formation of a 1:1 complex, e.g.
[CuII (bicyclam)]4+ + X  [CuII (bicyclam)X]3+ (3)
2
2
It is suggested that the X anion replaces the two inner water molecules, bridging the two metal
centres, as observed in the solid complex salts. However, in aqueous solution anions cannot
compete with water molecules, present in an overwhelming excess, for the two outer coordination
site. Thus, the 1:1 receptor/anion complex should be correctly described by the formula
[CuII (bicyclam)(Xin)(H2Oout)2]3+, in which each CuII ion experiences an octahedrally distorted
2
coordination geometry.
Table 1 reports the thermodynamic quantities (log K, ∆G°, ∆H°, T∆S°) at 25°C associated to
equilibria of type (3) and obtained by fitting of pertinent titrations curves.
This article is protected by copyright. All rights reserved.

10.1002/chem.201800067
Chemistry - A European Journal
7
Table 1. Thermodynamic quantities for the equilibrium: [CuII (bicyclam)]4+ + Cl  [CuII (bicyclam)Cl]3+ in an
2
2
aqueous solution buffered to pH = 6.8, 25 °C. Standard deviations in parentheses.
1
1
1
∆G°, kcal mol
∆H°, kcal mol
TΔS°, kcal mol
anion
log K
Cl
Br
 4.30(8)
 4.28(4)
 0.79(1)
 3.05(6)
3.15(2)
3.14(1)
3.5(1)
1.8(1)
I
 4.65(4)
 3.93(4)
 3.14(4)
 3.2(4)
 5.66(2)
 2.55(5)
 1.28(3)
 0.62(9)
1.53(9)
1.0 (1)
1.9(1)
1.8 (1)
2.6(1)
5.8(1)
3.41(2)
2.88(1)
2.30(1)
2.33(9)
3.10(1)

N3
NCO
NCS
2

SO4
 4.23(4)
For a visual understanding, ∆G°, ∆H° and T∆S° values of Table 1 are plotted in Figure 6a as a
bar diagram.
Figure 6. Bar diagram of the thermodynamic quantities referring to anion complex formation with: (a)
receptor [CuII (bicyclam)]4+ (data from Table 1); (b) bis(cyclopeptide) receptor 8 (data from ref. 42).
2
Inspection of thermodynamic quantities indicates that similarity of ΔG° values (= RTln K)
results from the combination of very different and sometimes contrasting ΔH° and TΔS°
contributions. For instance, complexation of iodide is highly exothermic (ΔH° = 5.7 kcal mol1) and
entropically disfavored (TΔS° = 1.5 kcal mol1), whereas complexation of sulfate is moderately
endothermic (ΔH° = 1.5 kcal mol1) and characterised by an extremely favorable entropy term
(TΔS° = 5.8 kcal mol1). In the middle, progressive decrease of exothermicity and concomitant
increase of TΔS° are observed. Moreover, on plotting TΔS° vs. ΔH° a straight line is obtained, with
a positive slope (see Figure 7), an example of enthalpy/entropy compensation relationship.
This article is protected by copyright. All rights reserved.

10.1002/chem.201800067
Chemistry - A European Journal
8
Figure 7. (a) Enthalpy /entropy compensation diagram for anion complexation by [CuII (bicyclam)]4+ (colour
2
symbols) and corresponding regression line (dashed); (b) the same diagram as in (a), with added symbols
(grey triangles), which refer to halide and sulfate complexation by the bis(cyclopeptide) 3.[28]
The compensatory enthalpy/entropy relationship has often been observed empirically for
thermodynamic quantities determined for a large variety of equilibria, including recognition.29,30 The
slope β of the TΔS vs. ΔH° plot indicates to what extent the enthalpic gain induced by
complexation is canceled by the accompanying entropic loss. In other words, only a fraction (1 − β)
of the enthalpic gain can contribute to the enhancement of complex stability.29 According to the
regression straight line for anion complexation by [CuII (bicyclam)]4+ in Figure 7, such a fraction
2
corresponds to (1.0 – 0.9) = 0.1 (10%). It should be noted at this stage that ΔH° is comprehensive
of several hidden contributions, either endo- or exo-thermic. Endothermic contributions derive from
the following processes: dehydration of the anion, dehydration of the receptor (associated to the
removal of the two inner metal-bound water molecules), conformational rearrangement of the
receptor’s framework to adjust the intermetallic distance to the anion’s bite length (achieved
through a modification of the orientation of the two metallocyclam subunits). Exothermic
contributions are related to the hydration of the complex (probably not relevant) and to the
establishing of the coordinative interactions CuIIXCuII. Major and contrasting contributions are
the anion dehydration enthalpy and the coordinative bond enthalpy.
For halides the intensity of the metal ligand interactions, expressed for instance by Dq values
of Crystal Field Theory, decreases along the series: Cl > Br > I. Noticeably, complexation
exothermicity ∆H° follows the reverse direction: I > Br > Cl, which may suggest that the
dehydration term prevails over coordinate bonding enthalpy. In particular, ∆H° values of anion
complexation shown an inverse linear relationship with anion hydration enthalpies (∆H°hydr-X-),31 i.e.
the enthalpy changes associated to the process: X(gas) + H2O  X(aq) (see Figure 8, red symbols
and red regression line).
This article is protected by copyright. All rights reserved.

10.1002/chem.201800067
Chemistry - A European Journal
9
Figure 8. Plot of the complexation
enthalpies (∆H°) in Table 1 vs. the anion
hydration enthalpies (∆H°hydr-X-),41 i.e
the enthalpy changes associated to the
process: X(gas) + H2O  X
.
(aq)
The less endothermic the anion dehydration, the less endothermic the anion complexation. In
particular, iodide is enthalpically favored in complex formation because it is less hydrated than
other halides and suffers to a lesser extent from dehydration. Thus, the enthalpy of formation of the
CuIIICuII bonds prevails over the dehydration term and complexation is exothermic.
Pseudohalides display a completely different behaviour: first, the complexation exothermicity

follows the spectrochemical series (N3 > NCO > NCS); second, ∆H° shows a direct linear
dependence upon hydration enthalpy ∆H°hydr-X- (blue triangles and blue dashed line in Figure 8):
the more endothermic the anion dehydration, the more exothermic the anion complexation. These
two features suggest that the enthalpy change associated to the metal-anion interaction (∆H°MX
)
plays a prominent role with respect to the hydration term ∆H°hydr-X-. This may be due to the fact that
each pseudohalide anion offers two distinct donor atoms for coordination, thus allowing the
formation of more intense coordinative interactions and reinforcing ∆H°MX
.
The compensatory effect illustrated in Figure 7 seems therefore essentially related to the anion
solvational effects: the enthalpically disfavored anion dehydration is compensated by the increase
in translational entropy associated to the release of water molecules to the solution. Indeed,
receptor arrangement requires that the anion release all hydration molecules before to take refuge
into the bicyclam’s cavity and to bridge the two CuII centres. In any case, the more endothermic the
anion dehydration, the more favorable the entropy contribution. Notice that the intercept α of the
TΔS° vs ΔH° regression line in Figure 7 corresponds to a complex process which is only
entropically driven (ΔH° = 0, ΔG° = TΔS° = 4 kcal mol1). Of the anions investigated here, only
sulfate exhibits a ΔH° > 0, which is more than compensated by an extremely favorable entropy
contribution TΔS° (5.8 kcal mol1). Sulfate, due to the double negative charge and to the
symmetrical positions of its four oxygen atoms (each formally detaining ½ negative charge) is
highly hydrated, from which an extremely large hydration enthalpy derives (∆H°hydr-X- = 253 kcal
mol1), which can be hardly compensated by the ∆H°MX term. The X-ray structure previously
described refers to the [CuII (bicyclam)(HSO4)]3+ complex, which contains a bridging
2
2

hydrogensulfate. However, it seems reasonable to assume that SO4 occupies, like HSO4 , the
receptor’cavity and bridges with two oxygen atoms the two CuII centres. Inclusion between the two
facing metallocyclam subunits completely undresses the anion from water molecules, to which a
large increase of translational entropy corresponds. On the other hand, sulfate, like oxoanions in
general, exerts relatively weak metal-ligand interactions, which cannot contrast the pronounced
endothermicity of the H-bond breaking process of anion dehydration.
This article is protected by copyright. All rights reserved.

10.1002/chem.201800067
Chemistry - A European Journal
10
The enthalpy/entropy compensation relationship extended to varying anion receptors in
water
Recognition of sulfate is attracting the attention of researchers in view of the dianion importance in
biology,32 and in the environment,33 including treatment of nuclear waste.34 One of the most stable
aqueous sulfate complexes, whose formation has been thoroughly investigated from a
thermodynamic point of view, involves the Kubik’s bis(cyclopeptide) neutral receptor 3.[28]
Thermodynamic quantities for the inclusion of sulfate and halides by 3 in water are illustrated by
the bar diagram in Figure 6b.
The sulfate complex of the bis(cyclopeptide) receptor is a bit more stable than the
corresponding complex of [CuII (bicyclam)]4+ (log K = 3.30 and 3.15, respectively). For both
2
systems, the relatively high solution stability results from a remarkably positive TΔS° term, that
overcomes a moderately unfavorable enthalpy term (endothermic processes). Moreover, bar
diagram in Figure 6b shows that halide complexation by the bis(cyclopeptide) receptor 3 is in any
case entropically very favored, whereas the enthalpy term is unfavorable (chloride and bromide) or
moderately favorable (iodide). Noticeably, bis(cyclopeptide) complexes roughly obey the
enthalpy/entropy compensatory relationship (see Figure 7b), even if they span a narrower range
than [CuII (bicyclam)]4+ complexes. In any case, dehydration processes play a significant role. In
2
particular, each cyclopeptide ring of the uncomplexed receptor 3 may contain an (H2O)3 trimer
tightly bound to three NH peptide fragments, for a total of six H-bonds (such an arrangement has
been observed in the monocyclic derivative).[13] On anion inclusion, these six bonds are broken and
replaced by the six bonds established on anion complexation, whose energy is expected to
decrease with the H-bond acceptor properties of the anion decreasing along the series: Cl > Br >
I. In any case, bonding exothermicity is overcome by the highly endothermic anion dehydration.
Only the poorly hydrated iodide gives an exothermic complexation. The entropy term is in all cases
favorable due to the large release of water molecules (from the anion and from the cyclopeptide
rings).
This article is protected by copyright. All rights reserved.

10.1002/chem.201800067
Chemistry - A European Journal
11
At this stage, we wanted to briefly consider the behaviour of other families of aqueous anion
receptors with respect to the enthalpy/entropy compensatory plot (see Figure 9). In particular,
diagram includes ∆H° and T∆S° values for complexes of bambus[6]uril (4)[35] and biotin[6]uril
(5)[36,37] with halides (comparison was limited to these anions for reasons of homogeneity). Halide
complexation by the two macrocyclic receptors is characterised by a largely negative ∆H° (high
exothermicity) and by a negative T∆S°.
Figure 9. Enthalpy/entropy compensation
diagram for halide complex formation in
water with receptors: bambus[6]uril (4),[35]
biotin[6]uril (5),[36] [CuII (bicyclam)]4+ (2),
2
bis(cyclopeptide (3).[28]
The two macrocycles bambus[6]uril and biotin[6]uril offer a shelter in which the anion receive
twelve CH···X hydrogen bonds from the polarised CH2 groups linking the nitrogen atoms of
two adjacent heterocycles, which accounts for complexation exothermicity. It may be surprising
that dehydration of the included anion does not result in a strongly positive entropy term. However,
it has been pointed out that, since the solution contains a 0.1 M phosphate buffer, it is possible that

2
H2PO4 /HPO4 occupies the receptor’cavity prior to X complexation:[35] thus, the release of water
molecules by incoming X is compensated by the uptake of water molecules from the solution by
the extruded phosphate. Quite surprisingly, if one considers the very different nature of the four
receptors, all halide complexes satisfactorily obey the ∆H°/T∆S° relationship. While more data are
needed before to draw sound conclusions and to formulate convincing interpretations, it seems
quite reasonable to hypothesise that the common behaviour must be in some way related to
solvational terms, a contribute especially relevant in water. In any case, the diagram in Figure 9
clearly defines the domains of the thermodynamic signatures of anion complex formation in water:
(negative ∆H° and negative∆S°: /) for bambus[6]uril and biotin[6]uril; (+/+) for bis(cyclopeptide),
excepting iodide; a mixed combination, (/+) and (+/) for [CuII (bicyclam)]4+.
2
Conclusions
Confident in the strength of the metal-ligand interactions, we looked to a metal containing receptor
capable to recognise anions in water and we chose the water soluble dicopper(II) bicyclam
complex 2. We expected that selectivity could arise from a geometrical factor, i.e. from the
matching of the distance between the interaction sites (the two metal centres) with the bite length
of the included ambidentate anion, either mono- or poly-atomic. Discouraging news came from
X-ray diffraction studies on single crystals of the two complex salts [CuII (bicyclam)(μ2-Br)2]Br2 and
2
[CuII (bicyclam)(μ2-HSO4)(HSO4)2]·HSO4·EtOH·H2O. In particular, it was observed that the cavity
2
constituted by the two facing metallocyclam subunits was able to include both the monoatomic
bromide and the polyatomic hydrogensulfate, and that the intermetallic distance could be
This article is protected by copyright. All rights reserved.

10.1002/chem.201800067
Chemistry - A European Journal
12
modulated by adjusting the reciprocal orientations of the two metallocyclam subunits, probably with
a moderate conformational energy cost.
Indeed, equilibrium studies in water showed lack of selectivity, as log K values for
complexation of halides and sulfate in water varied over the 3.2  0.2 range. Pseudohalides formed
less stable complexes, again in the absence of a marked selectivity (2.3  log K  2.9). However,
examination of enthalpy and entropy terms showed that similarity of ∆G° values resulted from the
rather unbalanced and sometimes contrasting contributions of the ∆H° term and the T∆S° term. In
particular, a linear dependence between ∆H° and T∆S° was observed (a typical compensation
diagram), which assigned a major role to hydration terms: the more hydrated the anion, the more
endothermic the dehydration process (the more positive ∆H°); the larger the number of water
molecules released to the solution, the more positive T∆S°. Limiting cases refer to the
complexation (i) of the poorly hydrated iodide (very exothermic process, entropically disfavored),
and (ii) of the highly hydrated sulfate (endothermic process, entropically very favored).
Anion receptors operating in water are currently divided in two main domains, each showing its
personal signature: 1) those whose complexation is endothermic, but characterised by a favorable
entropy change (positive ∆H° and positive T∆S°, signature +/+); those displaying the opposite
thermodynamic behaviour: (negative ∆H° and negative T∆S°, signature /). The dimetallic
bicyclam receptor here investigated presents multiple signatures (/; /+; +/) and connects the
two domains. Such a versatility may depend upon the particular nature of the coordinative bond,
whose energy (∆H°MX) varies over a range of several tens of kcal mol1.
Experimental Section
Synthesis of bicyclam and of its dicopper(II) complex.
[CuII (bicyclam)](ClO4)4 was prepared through 3 steps: (i) synthesis of the [NiII (bicyclam)](ClO4)4
2
2
complex salt; (ii) demetalation with cyanide of [NiII (bicyclam)](ClO4)4 to obtain the free ligand
2
.
bicyclam; (iii) metalation of bicyclam with Cu(ClO4)2 6H2O to give [CuII (bicyclam)](ClO4)4. Details
2
on the syntheses and characterization are reported in the Supporting Information.
Isothermal titration calorimetry (ITC) experiments.
ITC titrations were performed by using a Nano ITC Low Volume isothermal titration calorimeter
(from TA Instruments). All titrations were performed at 25 °C, using solutions buffered to pH = 6.8
with HEPES 0.05 M. In particular, a solution of the sodium salt of the envisaged anion was added
stepwise to a solution of [CuII (bicyclam)](ClO4)4, placed in the sample cell. The thermodynamic
2
quantities (K, ∆H°, and ∆S°), as well as the interaction stoichiometry, were determined by a fitting
procedure using the software AFFINImeter.[38] Blank titrations were performed and subtracted from
the corresponding titrations to remove the effect of dilution.
Potentiometric titrations
Potentiometric titrations were performed at 25° C by using a carbonate-free NaOH solution as a
titrant, under a nitrogen atmosphere. In a typical experiment, a 5 × 10-4 M solution of
[CuII (bicyclam)](ClO4)4 (15mL), made acidic (pH = 2) with standard HNO3, was titrated with
2
standard NaOH. Titration was run by addition of 10 μL portions of a standard 0.1 M solution of
NaOH and 165 points were collected. Prior to the potentiometric titration, the standard
electrochemical potential (E*) of the glass electrode was determined in pure water, by a titration
experiment according to the Gran method.[39] On curve fitting of titration data (emf vs. mL of NaOH
curve, see Figure S4 in Supporting Information) by using a non-linear least-squares procedure,[40]
pKa1 and pKa2 values were determined.
This article is protected by copyright. All rights reserved.

10.1002/chem.201800067
Chemistry - A European Journal
13
X-ray Crystallographic Studies
Diffraction data for [CuII (bicyclam)(μ-Br)2]Br2 (violet, prismatic, 0.07 x 0.07 x 0.15 mm3) and for
2
[CuII (bicyclam)(μ-HSO4)(HSO4)2]HSO4 · EtOH · H2O (pale red, lamellar, 0.02 x 0.32 x 0.50 mm3)
2
crystals have been collected by means of a Bruker-Axs CCD-based three circle diffractometer,
working at ambient temperature with graphite-monochromatised Mo Kα X-radiation (λ = 0.7107 Å).
Crystal data are reported in Table S1 in Supporting Information. Data reductions were performed
with the SAINT software,[41] and intensities were corrected for Lorentz and polarization effects.
Absorption effects were empirically evaluated by the SADABS software,[42] and absorption
corrections were applied to the data. Crystal structures were solved by direct methods (SIR 97)[43]
and refined by full-matrix least-square procedures on F2 using all reflections (SHELXL 2014/7).[44]
Further details are reported in the Supporting Information.
Acknowledgements
Authors are indebted to the Università di Pavia and to the University of Alabama for financial
support.
Conflict of interest
The authors declare no conflict of interest.
Keywords: anion recognition • receptors • macrocycles • enthalpy/entropy compensation •
supramolecular chemistry
[1] C. H. Park, H. E. Simmons, J. Am. Chem. Soc. 1968, 90, 24312432.
[2] J.-M. Lehn, E. Sonveaux, A. K. Willard, J. Am. Chem. Soc. 1978, 100, 49144916.
[3] S. Valiyaveettil, J. F. J. Engbersen, W. Verboom, D. N. Reinhoudt, Angew. Chem. 1993, 105,
942944; Angew. Chem., Int. Ed. Engl. 1993, 32, 900901.
[4] S.-O. Kang, J. M. Llinares, D. Powell, D. VanderVelde, K. Bowman-James, J. Am. Chem.
Soc. 2003, 125, 1015210153.
[5] C. R. Bondy, S. J. Loeb, Coord. Chem. Rev. 2003, 240, 7799.
[6] A.-F. Li, J.-H. Wang, F. Wang, Y.-B. Jiang, Chem. Soc. Rev. 2010, 39, 37293745.
[7] V. Amendola, L. Fabbrizzi , L. Mosca, Chem. Soc. Rev. 2010, 39, 38893915.
[8] T. Gunnlaugsson, A. P. Davis, G. M. Hussey, J. Tierney, M. Glynn, Org. Biomol. Chem.
2004, 2, 18561863.
[9] D. Esteban Gómez, L. Fabbrizzi, M. Licchelli, E. Monzani, Org. Biomol. Chem. 2005, 3,
1495–1500
[10] J. L. Sessler, J. M. Davis, Acc. Chem. Res. 2001, 34, 989997.
[11] S. Kubik, R. Goddard, R. Kirchner, D. Nolting, J. Seidel, Angew. Chem. 2001, 113,
27222725; Angew. Chem., Int. Ed. 2001, 40, 2648– 2651.
[12] S. Kubik, R. Kirchner, D. Nolting, J. Seidel, J. Am. Chem. Soc. 2002, 124, 12752– 12760.
[13] S. Kubik, Acc. Chem. Res., 2017, 50, 2870–2878.
[14] M. J. Langton, S. W. Robinson, I. Marques, V. Félix, P. D. Beer, Nat. Chem. 2014, 6,
10391043.
[15] S. P. Cornes, M. R. Sambrook, P. D. Beer, Chem. Commun. 2017, 53, 38663869.
This article is protected by copyright. All rights reserved.

10.1002/chem.201800067
Chemistry - A European Journal
14
[16] J.-M. Lehn, S. H. Pine, E. Watanabe, A. K. Willard, J. Am. Chem. Soc. 1977, 99, 67666768
[17] L. Fabbrizzi, P. Pallavicini, A. Perotti, L. Parodi, A. Taglietti, Inorg. Chim. Acta 1995, 238,
58.
[18] L. Fabbrizzi, A. Leone, A. Taglietti, Angew. Chem. 2001, 113, 31563159; Angew. Chem.,
Int. Ed., 2001, 40, 30663069.
[19] L. Fabbrizzi, Cryptands and Cryptates, World Scientific, London, 2018.
[20] L. Fabbrizzi, A Lifetime Walk in the Realm of Cyclam, in Macrocyclic and Supramolecular
Chemistry: How Izatt-Christensen Award Winners Shaped the Field (Ed. R. M. Izatt,), John
Wiley & Sons, New York, 2016, pp 165199,
[21] T. Kajiwara, T. Yamaguchi, H. Kido, S. Kawabuta, R. Kuroda, T. Ito, T. Inorg. Chem. 1993,
32, 49904991.
[22] T. Kajiwara, T. Yamaguchi, H. Oshio, T. Ito, Bull. Chem. Soc. Jpn. 1994, 67, 21302135.
[23] K. T. Szacilowski, P. Xie, A. Y. S. Malkhasian, M. J. Heeg, M. Y. Udugala-Ganehenege, L. E.
Wenger, J. F. Endicott, Inorg. Chem. 2005, 44, 6019−6033.
[24] M. Boiocchi, L. Fabbrizzi, N. Fusco, M. Invernici, M. Licchelli, A. Poggi, Inorg. Chem. 2016,
55, 2946–2959.
[25] L. Fabbrizzi, A. Poggi, Chem. Soc. Rev., 2013, 42, 16811699.
[26] F. P. Schmidtchen, Chem. Soc. Rev. 2010, 39, 3916–3935.
[27] V. J. Th m, J. C. A. Boeyens, G. J. McDougall, R. D. J. Hancock, J. Am. Chem. Soc. 1984,
106, 31983207.
[28] F. Sommer, Y. Marcus, S. Kubik, ACS Omega 2017, 2, 3669−3680.
[29] M. V. Rekharsky, Y. Inoue, Chem. Rev. 1998, 98, 18751917.
[30] L. Liu, Q.-X. Guo, Chem. Rev. 2001, 101, 673695.
[31] D. W. Smith, J. Chem. Ed. 1977, 54, 540-542.
[32]
R. W. Young, J. Cell Biol. 1973, 57, 175189.
[33] D. W. Schindler, Science 1988, 239, 149157.
[34] B. A. Moyer, R. Custelcean, B. P. Hay, J. L. Sessler, K. Bowman-James, V. W. Day, S.-O.
Kang, Inorg. Chem. 2013, 52, 34733490.
[35] M. A. Yawer, V. Havel, V. Sindelar, Angew. Chem. 2015, 127, 278281; Angew. Chem., Int.
Ed. 2015, 54, 276−279.
[36] M. Lisbjerg, B. M. Jessen, B. Rasmussen, B. E. Nielsen, A. Ø. Madsen, M. Pittelkow, Chem.
Sci. 2014, 5, 2647−2650.
[37] M. Lisbjerg, B. E. Nielsen, B. O. Milhøj, S. P. A. Sauer, M. Pittelkow, Org. Biomol. Chem.
2015, 13, 369−373.
[38] AFFINImeter: https://www.affinimeter.com/site/resources/
[39] G. Gran, Analyst 1952, 77, 661671.
[40] ‘Hyperquad 2013’ package; P. Gans, A. Sabatini, A. Vacca, Talanta 1996, 43, 17391753;
http://www.hyperquad.co.uk/HQ2013.htm
[41] SAINT Software Reference Manual, Version 6; Bruker AXS Inc.: Madison, WI, 2003.
This article is protected by copyright. All rights reserved.

10.1002/chem.201800067
Chemistry - A European Journal
15
[42] L. Krause, R. Herbst-Irmer, G. M. Sheldrick, D. Stalke, D. J. Appl. Crystallogr. 2015, 48,
3−10.
[43]
A. Altomare, M. C. Burla, M. Camalli, G. L. Cascarano, C. Giacovazzo, A. Guagliardi, A. G.
G. Moliterni, G. Polidori, R. Spagna, J. Appl. Crystallogr. 1999, 32, 115−119.
[44] G. M. Sheldrick, Acta Crystallogr. 2015, C71, 38.
This article is protected by copyright. All rights reserved.

10.1002/chem.201800067
Chemistry - A European Journal
16
FULL PAPER
Massimo Boiocchi, Marco
Selectivity is no longer a molecular
H° < 0
H° > 0
property: the dicopper((II) bicyclam
Bonizzoni,*, Carlo Ciarrocchi, Luigi
Fabbrizzi,*, Michele Invernici, and
Maurizio Licchelli*
TS° < 0
TS° > 0
receptor [CuII (L)]4+ includes in water
2
[CuII (L)I]3+
[CuII (L)SO4]3+
2
2
ambidentate anions (halides, sulfate)
with a poor selectivity, which derives
from conflicting enthalpy and entropy
contributions: the more favourable
the one, the less favourable the
other. This points toward the major
role of solvational terms (mainly
anion dehydration), which mitigate
the contribution of the metal-anion
coordinative interaction.
2
O
O
O
Anion Recognition in Water,
Including Sulfate, by a bicyclam
Bimetallic Receptor, a Process
Governed by the Enthalpy/Entropy
Compensatory Relationship
I
S
O
N
H
N
H
NH
HN
NH
HN
NH
N
H
[CuII (L)]4+
2
This article is protected by copyright. All rights reserved.