Complexation of Ln3+ Ions with Cyclam Dipicolinates: A Small Bridge that Makes Huge Differences in Structure, Equilibrium, and Kinetic Properties

Article abstract of DOI:10.1021/acs.inorgchem.5b02627

The coordination properties toward the lanthanide ions of two macrocyclic ligands based on a cyclam platform containing picolinate pendant arms have been investigated. The synthesis of the ligands was achieved by using the well-known bis-aminal chemistry. One of the cyclam derivatives (cb-tedpa^2-) is reinforced with a cross-bridge unit, which results in exceptionally inert [Ln(cb-tedpa)]⁺ complexes. The X-ray structures of the [La(cb-tedpa)Cl], [Gd(cb-tedpa)]⁺, and [Lu(Me₂tedpa)]⁺ complexes indicate octadentate binding of the ligands to the metal ions. The analysis of the Yb³⁺-induced shifts in [Yb(Me₂tedpa)]⁺ indicates that this complex presents a solution structure very similar to that observed in the solid state for the Lu³⁺ analogue. The X-ray structures of [La(H₂Me₂tedpa)₂]³⁺ and [Yb(H₂Me₂tedpa)₂]³⁺ complexes confirm the exocyclic coordination of the metal ions, which gives rise to coordination polymers with the metal coordination environment being fulfilled by oxygen atoms of the picolinate groups and water molecules. The X-ray structure of [Gd(Hcb-tedpa)₂]⁺ also indicates exocyclic coordination that in this case results in a discrete structure with an eight-coordinated metal ion. The nonreinforced complexes [Ln(Me₂tedpa)]⁺ were prepared and isolated as chloride salts in nonaqueous media. However, these complexes were found to undergo dissociation in aqueous solution, except in the case of the complexes with the smallest Ln³⁺ ions (Ln³⁺ = Yb³⁺ and Lu³⁺). A DFT investigation shows that the increased stability of the [Ln(Me₂tedpa)]⁺ complexes in solution across the lanthanide series is the result of an increased binding energy of the ligand due to the increased charge density of the Ln³⁺ ion.

Full text of DOI:10.1021/acs.inorgchem.5b02627

Article
pubs.acs.org/IC
Complexation of Ln3+ Ions with Cyclam Dipicolinates: A Small Bridge
that Makes Huge Differences in Structure, Equilibrium, and Kinetic
Properties
Aurora Rodríguez-Rodríguez,†,‡ Martín Regueiro-Figueroa,† David Esteban-Gomez,† Raphael Tripier,*,‡
́
̈
Gyula Tircso,§,○,⊥ Ferenc Krisztian Kalman,§ Attila Csaba Benyei,∥ Imre Toth,§ Andres de Blas,†
́
́
́
́
́
́
́
Teresa Rodríguez-Blas,† and Carlos Platas-Iglesias*,†
†Grupo QUICOOR, Centro de Investigaciones Científicas Avanzadas (CICA) and Departamento de Química Fundamental,
Universidade da Coruna, Campus da Zapateira, Rua da Fraga 10, 15008 A Coruna, Spain
́
̃
̃
‡Universite
29238 Brest, Cedex 3, France
§Department of Inorganic and Analytical Chemistry, Faculty of Science and Technology, and Department of Pharmaceutical
Chemistry, University of Debrecen, Egyetem ter 1, H-4032 Debrecen, Hungary
○Centre de Biophysique Molec
ulaire, CNRS, rue Charles Sadron, 45071 Orleans, Cedex 2, France
⊥Le Studium, Loire Valley Institute for Advanced Studies, 1 Rue Dupanloup, 45000 Orlea
ns, France
́
de Bretagne Occidentale, UMR-CNRS 6521, UFR des Sciences et Techniques, 6 avenue Victor le Gorgeu, C.S. 93837,
∥
́
́
́
́
S
* Supporting Information
ABSTRACT: The coordination properties toward the
lanthanide ions of two macrocyclic ligands based on a cyclam
platform containing picolinate pendant arms have been
investigated. The synthesis of the ligands was achieved by
using the well-known bis-aminal chemistry. One of the cyclam
derivatives (cb-tedpa2−) is reinforced with a cross-bridge unit,
which results in exceptionally inert [Ln(cb-tedpa)]+ com-
plexes. The X-ray structures of the [La(cb-tedpa)Cl], [Gd(cb-
tedpa)]+, and [Lu(Me2tedpa)]+ complexes indicate octaden-
tate binding of the ligands to the metal ions. The analysis of
the Yb3+-induced shifts in [Yb(Me2tedpa)]+ indicates that this
complex presents a solution structure very similar to that
observed in the solid state for the Lu3+ analogue. The X-ray structures of [La(H2Me2tedpa)2]3+ and [Yb(H2Me2tedpa)2]3+
complexes confirm the exocyclic coordination of the metal ions, which gives rise to coordination polymers with the metal
coordination environment being fulfilled by oxygen atoms of the picolinate groups and water molecules. The X-ray structure of
[Gd(Hcb-tedpa)2]+ also indicates exocyclic coordination that in this case results in a discrete structure with an eight-coordinated
metal ion. The nonreinforced complexes [Ln(Me2tedpa)]+ were prepared and isolated as chloride salts in nonaqueous media.
However, these complexes were found to undergo dissociation in aqueous solution, except in the case of the complexes with the
smallest Ln3+ ions (Ln3+ = Yb3+ and Lu3+). A DFT investigation shows that the increased stability of the [Ln(Me2tedpa)]+
complexes in solution across the lanthanide series is the result of an increased binding energy of the ligand due to the increased
charge density of the Ln3+ ion.
Ln3+ ion is not released in vivo.4 Among the different
INTRODUCTION
■
polyaminopolycarboxylate ligands commonly used for Ln3+
complexation non-macrocyclic derivatives often form rather
labile complexes, while some macrocyclic ligands form
complexes with exceptionally high kinetic inertness.5
Complexes of the trivalent lanthanide ions (Ln3+) with
polyaminopolycarboxylate ligands are receiving increasing
attention due to their important medical and bioanalytical
applications. For instance, Gd3+ chelates are nowadays
commonly used by radiologists as contrast agents in magnetic
resonance imaging,1,2 while luminescent Ln3+ complexes are
used in bioanalytical applications and are being intensively
investigated as potential probes for optical imaging in vivo.3
These applications require a careful design of the ligand
structure to achieve a high thermodynamic stability and, more
importantly, a high kinetic inertness to ensure that the toxic
Cross-bridged tetraaza macrocyclic ligands based on 1,4,7,10-
tetraazacyclododecane (cyclen) or 1,4,8,11-tetraazacyclotetra-
decane (cyclam) platforms typically contain a linker connecting
two trans nitrogen atoms of the macrocycle (i.e., ethylene or
Received: November 13, 2015
© XXXX American Chemical Society
A
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propylene groups or linkers integrating additional donor
groups), which results in constrained positions of the four
nitrogen lone pairs of the macrocyclic cavity.6 The presence of
this linker increases the rigidity of the corresponding metal
complexes, which as a result are often very inert with respect to
complex dissociation.7,8 The first crossed-bridged cyclam
derivative was prepared by Weisman, who also reported its
unusual behavior as a proton sponge.9 Subsequently, Weisman
and Busch reported different transition metal complexes of
cross-bridged cyclam derivatives.10,11 Following these pioneer-
ing works, a wide range of cross-bridged metal complexes
functionalized with different pendant arms were reported (i.e.,
acetate,12 acetamide,13 picolinate,8 2-pyridylmethyl,14 methyl-
enephosphonate15). Many of the transition metal complexes
formed with cyclam cross-bridge derivatives were found to be
very inert, a property that in some cases was accompanied by
relatively fast complexation kinetics.8,16 These two properties
were important requisites for developing Cu2+-containing
radiopharmaceuticals for PET imaging.17
formation and dissociation kinetics of [Ln(cb-tedpa)]+
complexes precludes the determination of thermodynamic
stability constants. Thus, herein we report the nonreinforced
analogue H2Me2tedpa (Chart 1) and provide a detailed
comparison of the acid−base properties of the cb-tedpa2− and
Me2tedpa2− ligands. An analysis of the structure of the [Ln(cb-
tedpa)]+ and [Ln(Me2tedpa)]+ complexes in the solid state and
in aqueous solutions is also accomplished. Finally, the relative
stabilities of the two series of complexes and the stability trends
observed along the lanthanide series have been investigated by
using computational methods.
RESULTS AND DISCUSSION
■
Synthesis and Characterization of the Ligands. The
synthesis of H2cb-tedpa was described in a previous
communication.18 Single crystals of formula (H4cb-tedpa)
(ClO4)2 were obtained from an aqueous solution containing
equimolar amounts of the ligand and Lu(ClO4)3, which was
prepared in an attempt to form the Lu3+ complex. A view of the
structure of the H4cb-tedpa2+ unit is presented in Figure 1. The
In a recent communication we reported the cross-bridged
cyclam derivative containing picolinate pendant arms H2cb-
tedpa (Chart 1),18 which was rationally designed to provide
Chart 1. Chemical Structure of the Ligands Discussed in
This Work
Figure 1. View of the H4cb-tedpa2+ cation present in crystals of (H4cb-
tedpa) (ClO4)2. Hydrogen atoms bonded to carbon atoms and anions
are omitted for simplicity. The ORTEP plot is at the 30% probability
level.
X-ray structure indicates that protonation of the cyclam moiety
occurs on the two trans N atoms containing the picolinic acid
substituents. This reduces the electrostatic repulsion between
the two protonated sites, as the distance between these
nitrogen atoms (N3···N5 = 4.07 Å) is considerably longer than
that between the two nitrogen atoms linked by the ethylenic
bridge (N4···N2 = 2.83 Å). Each of the two protonated
nitrogen atoms are involved in hydrogen-bonding interaction
with a second nitrogen atom of the macrocycle: N2···N5
2.748(6) Å, N2−H2···N5 1.97 Å, N2−H2···N5 134.3°; N4···
N3 2.686(6) Å, N4−H4···N3 1.86 Å, N4−H4···N3 139.6°. The
structure of H4cb-tedpa2+ also shows that protonation of the
picolinate groups occurs at the oxygen atoms of the carboxylate
groups, as observed previously for (H4Me2dodpa)2+ (Chart
1).20
The synthesis of H2Me2tedpa was achieved by using the bis-
aminal chemistry,21 which provided a convenient access to
trans-substituted cyclam derivatives (Scheme 1). Thus, cyclam
was reacted with formaldehyde to give compound 2, which was
alkylated with MeI to yield the trans-disubstituted diammonium
salt 3 with a nearly quantitative yield. Hydrolysis of 3 in the
presence of a base afforded the unprotected cyclam derivative 4,
which was then alkylated with the 6-chloromethylpyridine
stable Ln3+ complexation in aqueous solution. Owing the high
coordination numbers often adopted by the Ln3+ ions in
solution (generally 8−9) the cross-bridged cyclam platform was
functionalized with two picolinate pendant arms to give a
potentially octadentate ligand. The corresponding Ln3+
complexes were found to form very slowly even in harsh
conditions, but once they were formed they were extremely
inert (i.e., they did not dissociate in 2 M HCl over a period of
several months). It has been reported that the Ln3+ complexes
of the octadentate cyclam-based ligand teta4‑ are considerably
less stable from both the thermodynamic and kinetic point of
view than the corresponding complexes of the cyclen-based
dota4− ligand,19 which suggests that the lack of dissociation of
the [Ln(cb-tedpa)]+ complexes in strongly acidic media is a
consequence of an extremely high kinetic inertness rather than
a high thermodynamic stability. However, the extremely slow
B
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are particularly well-suited for the coordination of small hard
metal ions as well as protons.11d,26 As stated earlier,27 the third
and fourth protonation constants can be assigned to the
carboxylate groups of the picolinate moieties, while the fifth
protonation process observed for Me2tedpa2− most likely
occurs on a third nitrogen atom of the macrocycle.
Scheme 1. Synthesis of H2Me2tedpa and Numbering Scheme
Used for NMR Spectral Assignment
a
Synthesis of Metal Complexes. Reaction of ligand
H2Me2tedpa with hydrated lanthanide chlorides in the presence
of an excess of trimethylamine in 2-propanol resulted in the
formation of compounds of formula [Ln(Me2tedpa)]Cl (Ln =
La, Eu, Gd, Tb, Yb, or Lu), which were isolated in 51−90%
yields (see the Experimental Section for full details). The high
resolution mass spectra (ESI+-MS) of the complexes showed
peaks due to the [Ln(Me2tedpa)]+ entities, thereby confirming
the formation of the desired compounds (Figures S3−S8,
Supporting Information).
The synthesis of compounds [Ln(cb-tedpa)]Cl (Ln = La, Eu,
Gd, Tb, or Yb) was reported in a preliminary communication.18
The formation of the complexes required rather harsh
conditions involving the use of a solvent with high boiling
point (n-butanol) and long reaction times (4 days).
Alternatively, the reaction times could be significantly
shortened with the use of microwave radiation. In detail,
reaction of H2cb-tedpa and EuCl3·6H2O in n-butanol in the
presence of diisopropylethylamine (DIPEA) under microwave
radiation (150 °C, 250 psi, maximum power 300 W) during
one hour provided a mixture composed of the [Eu(cb-tedpa)]+
complex (7%) and unreacted ligand (93%), as established by
1H NMR spectroscopy. Using identical conditions but longer
a
Reagents and conditions: (i) H2CO, H2O, 0 °C, 96%; (ii) MeI,
CH3CN, 98%; (iii) 3 M aqueous NaOH, 100%; (iv) K2CO3, CH3CN,
73%; (v) 6 M aqueous HCl, 98%.
derivative 522 to give precursor 6 in 73% yield. Finally,
deprotection of the methyl ester groups with 6 M HCl gave the
H2Me2tedpa ligand with an overall yield of 67% over the five
steps.
The protonation constants of Me2tedpa2− and cb-tedpa2−
were measured by using the standard pH-potentiometric
technique in 0.15 M NaCl. The ligand protonation constants
(Table 1) are defined as in eq 1 (where i = 1, 2, ..., 5):
1
reaction times (4 h) gave a mixture whose H NMR spectrum
[HiL]
[Hi−1L][H+]
KiH
=
revealed the absence of unreacted ligand and the presence of
two complex species with a 95:5 ratio (Figure 2). The major
(1)
1
species presented paramagnetically shifted H NMR signals in
The data shown in Table 1 indicate that the first protonation
constant of cb-tedpa2− is ca. 2.7 log units higher than that of
the range +11 to −11 ppm, while the minor species gave larger
shifts, with signals spreading over the range 39 to −17 ppm.
The HR-ESI+ spectrum of the mixture presented an intense
peak at m/z = 647.1835 that corresponded to the [Eu(cb-
tedpa)]+ complex (calculated value m/z = 647.1848), and a
weaker signal at m/z = 1143.4668 attributable to the [Eu(Hcb-
tedpa)2]+ entity (calculated value m/z = 1143.4652). Structural
evidence for the formation of this species was obtained from X-
ray crystallography (see below). The use of identical conditions
but employing a 100% excess of EuCl3·6H2O resulted in the
quantitative formation of the 1:1 species, which corresponded
to the [Eu(cb-tedpa)]+ complex. A close inspection of the
reaction mixtures obtained under conventional conditions (n-
butanol, reflux 4 days, 1:1 Eu3+:ligand ratio) revealed the
formation of both the 1:1 and 1:2 species in ∼95:5 ratio. These
results suggested that the 1:1 and 1:2 complex species were
both present once the thermodynamic equilibrium was
attained, while the use of an excess of Eu3+ shifted the
Me2tedpa2−, while the second protonation constant K2 is ca.
H
0.7 log units higher in Me2tedpa2−. We want to highlight that
even when the first protonation constant of cb-tedpa2− is rather
H
high (log K1 = 13.01(2)) under our experimental conditions
at pH 12.5 up to 25% of the ligand is in its deprotonated form,
and therefore this protonation constant could be determined to
a good accuracy. A similar trend, though less pronounced, is
observed upon comparison of the protonation constants
determined for cyclam and cb-cyclam (Table 1).23,24 The first
protonation constant of cb-te1pa− was also reported to be
considerably higher than that of te1pa−, although its value is too
high to be determined using potentiometric titrations.8,25 These
results indicate that the monoprotonated forms of the cross-
bridged derivatives are particularly stabilized by intramolecular
hydrogen-bonding interactions. A similar behavior has been
observed for other cross-bridged derivatives, and attributed to a
convergent disposition of the four nitrogen lone pairs, which
Table 1. Protonation Constants of Me2tedpa2− and cb-tedpa2− (25 °C, 0.15 M NaCl) and Values Reported in the Literature for
Related Systems
a
b
c
d
Me2tedpa2−
cb-tedpa2−
cyclam
cb-cyclam
te1pa−
cb-te1pa−
H
H
H
H
H
log K1
log K2
log K3
log K4
log K5
10.29(1)
10.28(2)
3.79(3)
2.85(3)
1.93(3)
13.01(2)
9.55(4)
3.27(4)
2.24(4)
11.29
10.19
1.61
12.42
10.20
1.39
11.55
10.11
2.71
1.7
e
10.13
2.42
<2
1.91
a
b
c
d
e
Reference 23. Reference 24. Reference 25. Reference 8. Too high to be determined experimentally.
C
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Figure 3. View of the [La(cb-tedpa)Cl] entity present in crystals of
[La(cb-tedpa)Cl]·5H2O. Hydrogen atoms are omitted for simplicity.
The ORTEP plot is at the 30% probability level.
Figure 2. 1H NMR and HR-ESI+ spectra of the crude mixture
obtained upon reaction of equimolar EuCl3 and H2cb-tedpa in n-
butanol in the presence of diisopropylethylamine (DIPEA) under
microwave radiation (150 °C, 250 psi, maximum power 300 W,
reaction time 4 h).
equilibrium to the exclusive formation of the 1:1 species. The
counterion employed for the synthesis of the complex was also
found to play an important role, as replacing EuCl3 by
Eu(OTf)3 lead to the nearly exclusive formation of the
[Eu(Hcb-tedpa)2]+ species (>95%).
X-ray Structures of [La(cb-tedpa)Cl]·5H2O, [Gd(cb-
tedpa)](PF6)·2.5H2O, and [Lu(Me2tedpa)]Cl·6H2O. Single
crystals with formula [La(cb-tedpa)Cl]·5H2O and [Lu-
(Me2tedpa)]Cl·6H2O were obtained by slow evaporation of
aqueous solutions of the complexes at neutral pH, while those
of [Gd(cb-tedpa)](PF6)·2.5H2O were grown by addition of an
excess of KPF6 to a solution of the complex in water. The latter
compound crystallized in the orthorhombic Pbca space group
and it was isomorphous with respect to the Eu3+ complex
reported in our previous communication.18 Bond distances of
the metal coordination environments are given in Table 2,
while views of the structures of the complexes are presented in
Figures 3−5.
Figure 4. View of the [Gd(cb-tedpa)]+ cation present in crystals of
[Gd(cb-tedpa)](PF6)·2.5H2O. Hydrogen atoms and anions are
omitted for simplicity. The ORTEP plot is at the 30% probability level.
Table 2. Bond Distances (Å) of the Metal Coordination
Environments in [La(cb-tedpa)Cl], [Gd(cb-tedpa)]+, and
[Lu(Me2tedpa)]+ Complexes
[La(cb-tedpa)Cl]
[Gd(cb-tedpa)]+
[Lu(Me2tedpa)]+
Figure 5. View of the [Lu(Me2tedpa)]+ cation present in crystals of
[Lu(Me2tedpa)]Cl·6H2O. Hydrogen atoms and anions are omitted for
simplicity. The ORTEP plot is at the 30% probability level.
La1−N1
2.601(2)
2.705(2)
2.771(2)
Gd1−N1 2.497(6) Lu1−N1 2.3657(12)
Gd1−N2 2.614(6) Lu1−N2 2.4767(12)
Gd1−N3 2.573(6) Lu1−N3 2.5907(12)
La1−N2
La1−N3
La1−O1
2.4695(17) Gd1−N4 2.616(6) Lu1−O1 2.2359(10)
La1−Cl1 3.0004(9)
Gd1−N5 2.554(6)
Gd1−N6 2.486(5)
Gd1−O1 2.309(5)
Gd1−O3 2.318(5)
our discussion on the complex unit containing Gd1. The metal
ions in [Gd(cb-tedpa)]+ and [Lu(Me2tedpa)]+ are eight-
coordinated, being directly bound to two oxygen atoms of
the carboxylate groups, the nitrogen atoms of the pyridyl units,
and the four nitrogen atoms of the macrocyclic entities. The
metal ion in [La(cb-tedpa)Cl] is also directly coordinated to
the eight donor atoms of the ligand, nine coordination being
completed by the presence of a coordinated chloride anion.
However, the La1−Cl1 distance (3.0004(9) Å) is considerably
longer than those observed for different nine-coordinate La3+
complexes,28 which points to a weak coordination of the
The [La(cb-tedpa)Cl] and [Lu(Me2tedpa)]+ complexes
possess a crystallographically imposed C2 symmetry. On the
other hand, crystals of the Gd3+ complex contain two [Gd(cb-
tedpa)]+ complex entities in the asymmetric unit with only
slightly different bond distances and angles of the metal
coordination environment. Thus, in the following we will focus
D
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chloride anion in the [La(cb-tedpa)Cl] complex. The bond
distances of the metal coordination environment in [Lu-
(Me2tedpa)]+ are very similar to those reported for the eight-
coordinate macrocyclic complexes [Lu(Me2dodpa)]+ and
[Lu(bp12c4)]+22,29 and slightly shorter than the ones observed
for eight-coordinate Lu3+ complexes containing picolinate
pendant arms.30 The bond distances of the Gd3+ coordination
sphere in [Gd(cb-tedpa)]+ are similar or even slightly shorter
than those observed for the eight-coordinate [Ln(teta)]−
complexes (Ln = Eu, Tb).31
The distances between the Lu3+ ion and the amine nitrogen
atoms of the macrocyclic unit functionalized with the picolinate
pendants in [Lu(Me2tedpa)]+ (N2) are ∼0.11 Å shorter than
those involving the nitrogen atoms containing methyl
substituents. In the case of [La(cb-tedpa)Cl] the distances to
the nitrogen donor atoms linked by the ethylenic bridge are
also longer than the La1−N2 distances. However, this situation
is reversed in the [Gd(cb-tedpa)]+ complex, as the Gd1−N3
and Gd1−N5 distances are ca. 0.04−0.06 Å shorter than the
Gd1−N2 and Gd1−N4 bonds. The different pattern observed
for the bond distances involving the nitrogen atoms of the
macrocycle in [La(cb-tedpa)Cl] and [Gd(cb-tedpa)]+ is likely
related to the presence of the chloride anion in the former,
which results in a considerably more open angles defined by the
donor atoms of the pyridine units and the metal ion (N1−
La1−N1i = 138.24(8)°, N1−Gd1−N6 = 116.06(18)°).
Figure 6. View of the [La(H2Me2tedpa)3(H2O)4]3+ entity present in
crystals of [La(H2Me2tedpa)2](PF6)3·8H2O. Hydrogen atoms bonded
to carbon atoms and anions are omitted for simplicity. The ORTEP
plot is at the 30% probability level.
with La−O distances of ca. 2.49−2.56 Å (Table 3). In the Yb3+
complex the metal ion is coordinated to four different
Table 3. Bond Distances (Å) of the Metal Coordination
Environments in [La(H2Me2tedpa)3(H2O)4]3+,
[Yb(H2Me2tedpa)4(H2O)2]3+, and [Gd(Hcb-tedpa)2]+
Entities
The coordination of the macrocyclic unit to the Ln3+ ions
introduces two sources of chirality in the complexes, one
related to the layout of the picolinate pendant arms (absolute
configurations Δ or Λ), and the second associated to the
conformations of the two ([Lu(Me2tedpa)]+) or three ([La(cb-
tedpa)Cl] and [Gd(cb-tedpa)]+) five-membered chelate rings
formed upon coordination of the macrocyclic ethylenediamine
moieties (absolute configuration δ or λ). Inspection of the
crystal data shows that the three complexes are present in the
solid state as racemic mixtures containing the Δ(λλ)/Λ(δδ) or
Δ(λλλ)/Λ(δδδ) enantiomeric pairs. The cyclam unit in
[Lu(Me2tedpa)]+ adopts a trans-I configuration, while the
presence of the bridging unit in [La(cb-tedpa)Cl] and [Gd(cb-
tedpa)]+ dictates a cis-V-folded configuration that provides four
convergent nitrogen atoms for metal ion coordination. The six-
membered chelate rings in [La(cb-tedpa)Cl] and [Gd(cb-
tedpa)]+ adopt chair conformations. The bicyclo[6.6.2] ligand
backbones of the cross-bridge derivatives present [2233]/
[2233] conformations, while complexes of smaller metal ions
with cross-bridge derivatives often present [2323]/[2323]
conformations.32 However, the six-membered chelate rings of
[Lu(Me2tedpa)]+ present twist-boat conformations, which is in
contrast with the chair conformations observed for [Ln(teta)]−
complexes (Ln = Eu, Tb).31
X-ray Structures of [La(H2Me2tedpa)2](PF6)3·8H2O,
[Yb(H2Me2tedpa)2](PF6)3·4H2O, and [Gd(Hcb-tedpa)2]Cl·
5H2O. Addition of an excess of KPF6 to aqueous solutions of
the [Ln(Me2tedpa)]+ complexes gives crystals of formula
[Ln(H2Me2tedpa)2](PF6)3·xH2O (Ln = La, x = 8; Ln = Yb, x =
4). In both compounds the Ln3+ ion presents an exocyclic
coordination involving oxygen atoms of the carboxylate groups
of the ligand. In the case of the La3+ derivative (Figure 6), two
carboxylate groups of different H2Me2tedpa entities provide a
slightly asymmetrical bidentate coordination to the metal ion,
while a third H2Me2tedpa unit gives monodentate coordination
through O4. Nine coordination around the metal ion is
completed by the presence of four coordinated water molecules
[La(H2Me2tedpa)3(H2-
O)4]3+
[Yb(H2Me2tedpa)4(-
H2O)2]3+
[Gd(Hcb-tedpa)2]+
La1−O1
La1−O2
La1−O4
La1−O5
La1−O6
La1−O9
La1−O10
La1−O11
La1−O12
2.647(4)
2.574(4)
2.418(4)
2.509(3)
2.606(4)
2.564(4)
2.498(4)
2.556(4)
2.564(4)
Yb1−O1
Yb1−O2
Yb1−O3
Yb1−O4
Yb1−O5
Yb1−O7
Yb1−O9
2.323(3)
2.282(3)
2.395(3)
2.358(3)
2.134(3)
2.236(3)
2.142(3)
Gd1−O1
Gd1−O3
Gd1−O5
Gd1−O7
Gd1−N1
Gd1−N6
Gd1−N7
Gd1−N12
2.305(2)
2.287(2)
2.280(2)
2.292(2)
2.664(3)
2.674(2)
2.643(2)
2.681(2)
carboxylate groups, one providing a bidentate coordination
and three of them being monodentated (Figure 7).
Coordination number seven is completed by the presence of
two inner-sphere water molecules. In both [La-
(H2Me2tedpa)3(H2O)4]3+ and [Yb(H2Me2tedpa)4(H2O)2]3+
entities the carboxylate groups of the ligands are deprotonated,
while two of the nitrogen atoms of the macrocyclic fragment
are protonated. The protonated amine nitrogen atoms are
involved in hydrogen bonding interaction with the nitrogen
atoms of the pyridine units (Table S1, Supporting Informa-
tion). The Ln3+−O distances involving oxygen atoms of
bidentate carboxylates are longer than those comprising
monodentate groups.
Crystals of formula [Gd(Hcb-tedpa)2]Cl·5H2O have been
obtained from a solution of GdCl3 and H2cb-tedpa prepared in
an attempt to synthesize the [Gd(cb-tedpa)]+ complex (Figure
8). The metal ion is directly bound to the nitrogen and oxygen
donor atoms of the picolinate pendant arms of two Hcb-tedpa
entities, which results in an eight-coordinate complex. One of
the nitrogen atoms of each ligand is protonated, while the
carboxylate groups of the ligand are deprotonated. The
coordination polyhedron around the metal ion can be described
as a twisted square antiprism with square faces defined by O3,
E
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Article
stable in aqueous solution and thus experience dissociation.
The 1H NMR spectrum of the [Ln(Me2tedpa)]+ complex
shows paramagnetically shifted resonances spreading over the
range ∼170 to −80 ppm at 25 °C, which testifies the existence
of the complex in solution. However, the signals of the free
ligand are also clearly visible, indicating partial dissociation of
the complex (∼45% of the overall ligand is in the uncomplexed
form). A similar situation holds for the Lu3+ complex, which
also shows 1H NMR signals corresponding to both the complex
and the free ligand. These results indicate that the [Ln-
(Me2tedpa)]+ complexes with the large Ln3+ ions display a very
low stability in aqueous solution, while for the heaviest Ln3+
ions the low stability of the complexes still leads to partial
dissociation. The relaxometric method20 confirmed that the
Gd3+ complex presents a very low thermodynamic stability, as
at pH 7.0 only ca. 15% of the metal ion is in the complexed
form. Different experiments were carried out to obtain accurate
stability constants of this complex, including the use of different
competitor ligands to prevent the formation of hydroxide
species at the relatively high pH values required for Gd3+
complexation. In spite of our efforts, an accurate stability
constant could not be obtained, but nevertheless these studies
allowed us to obtain a rough estimate of the stability constant
of the [Gd(Me2tedpa)]+ complex, which falls in the range log K
= 8.0−8.5.
Figure 7. View of the [Yb(H2Me2tedpa)4(H2O)2]3+ entity present in
crystals of [Yb(H2Me2tedpa)2](PF6)·4H2O. Hydrogen atoms bonded
to carbon atoms and anions are omitted for simplicity. The ORTEP
plot is at the 30% probability level.
The Yb3+-induced paramagnetic 1H NMR shifts are generally
dominated by the pseudocontact contribution, which is the
result of the dipolar coupling between the magnetic moments
of the unpaired electrons and the observed nucleus.35 The
pseudocontact shift can be approximated by using eq 2:36
2
2
2
2
⎛
⎜
⎝
⎞
⎟
⎠
⎛
⎞
⎛
⎞
⎟
x − y
1
3
3z − r
dip
⎜
δ
= χzz
−
Trχ
+ (χ − χyy)
xx
⎜
⎝
⎟
⎠
ij
r5
r5
⎝
⎠
(2)
Figure 8. View of the [Gd(Hcb-tedpa)2]+ entity present in crystals of
[Gd(Hcb-tedpa)2]Cl·5H2O. Water molecules and hydrogen atoms
bonded to carbon atoms and anions are omitted for simplicity. The
ORTEP plot is at the 30% probability level.
with
r = x2 + y2 + z2
(3)
where [χzz − 1/3(χxx + χyy + χzz)] and (χxx − χyy) are
respectively the axial and rhombic anisotropies of the magnetic
susceptibility tensor (χ), and x, y, and z are the Cartesian
coordinates of the nucleus under study with the lanthanide at
the origin. Following our previous studies on related systems,37
we used the molecular structure of the [Yb(Me2tedpa)]+
complex obtained with density functional theory calculations
(DFT) at the TPSSh/LCRECP/6-31G(d) level to assess the
agreement between the observed paramagnetic shifts and those
O5, N6, and N7 (mean deviation from planarity 0.091 Å) and
O1, O7, N1, and N12 (mean deviation from planarity 0.072 Å).
These square faces are nearly parallel (1.5°) and display a mean
twist angle of 28.4°, which is relatively close to the ideal value
for a twisted square antiprism (22.5°).
Diprotonated species in which oxygen atoms of carboxylate
groups are involved in coordination to the Ln3+ ion have been
proposed as intermediates in the formation and dissociation of
complexes with dota-like ligands.33 Structural evidence for the
formation of such diprotonated intermediates was provided in
some cases using X-ray diffraction measurements.34 The X-ray
structures reported in this section suggest that the reaction
intermediates responsible for the formation and dissociation of
the [Yb(Me2tedpa)]+ complexes are diprotonated. Further-
more, the higher rigidity and degree of preorganization of the
cross-bridge derivative results in the formation of a rather stable
[Ln(Hcb-tedpa)2]+ intermediates that in the case of Eu3+ could
1
calculated with eq 2. The assignment of the H NMR signals
1
was achieved using line-width analysis and the H−1H COSY
spectrum, which presented cross-peaks relating H11ax−H11eq,
1
H8ax−H8eq, H8ax−H9ax, and H9ax−H9eq. The H NMR
spectrum recorded at 298 K revealed the position of 15 of the
16 signals expected for an effective C2 symmetry of the complex
in solution, while all 16 signals could be located at 278 K
(Figure 9, see also Table S2, Supporting Information). The
agreement between the experimental and calculated shifts of
[Yb(Me2tedpa)]+ is excellent (Figure 9, see also Table S2,
Supporting Information), with deviations between the exper-
imental and calculated data in the range 0.6−6.1 ppm.
Furthermore, the agreement factor AFj = 0.05738 is similar to
those reported for other Yb3+ complexes analyzed using this
methodology.39,40 This confirms that our DFT calculations
provide an adequate description of the solution structure of the
1
be detected by H NMR spectroscopy and mass spectrometry.
NMR Studies. The 1H NMR spectra recorded upon
dissolution of the [Ln(Me2tedpa)]Cl complexes (Ln = La or
Eu) in D2O at pH 7.0 show the signals corresponding to the
free ligand, which in the case of the Eu3+ complex are somewhat
broader due to the paramagnetism of the metal ion. This
indicates that these complexes are not thermodynamically
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Scheme 2. Thermodynamic Cycle Used for the Analysis of
Complex Stabilities along the Lanthanide Series
ligands. Thus, the unfavorable term corresponding to the
hydration free energies of the Ln3+ ions (ΔGsol(La3+) −
ΔGsol(Ln3+) > 0) is compensated by the increasingly negative
ΔGg(1) values. According to our calculations this trend is more
pronounced for [Ln(Me2tedpa)]+ complexes, which probably
reflects the ability of the flexible Me2tedpa2− ligand to
accommodate Ln3+ ions with different size. These results are
in qualitative agreement with the NMR studies performed for
[Ln(Me2tedpa)]+ complexes, which demonstrated that only the
complexes with the heaviest Ln3+ ions are thermodynamically
stable in aqueous solution. It is also worth noting that the
solvation free energies of the complexes become significantly
less negative on proceeding to the right across the series, which
is related to a significant decrease of the dipole moment across
the 4f period (Table 4 and Tables S6 and S7, Supporting
Information).
Figure 9. 1H NMR (300 MHz, 278 K) spectrum of [Yb(Me2tedpa)]+
recorded in D2O solution (∼30 mM, pH = 7.0) and plot of the
experimental shifts versus those calculated with the DFT optimized
geometry and pseudocontact contributions. The solid line represents a
perfect fit between experimental and calculated values.
[Yb(Me2tedpa)]+ complex, which is very similar to that
observed in the solid state for the Lu3+ analogue.
The components of the susceptibility tensor obtained from
Table 4. Thermodynamic Data (kcal mol−1, Scheme 3)
Obtained with DFT Calculations at the TPSSh/LCRECP/6-
31G(d) Level for [Ln(Me2tedpa)]+ and [Ln(cb-tedpa)]+
Complexes
1
the analysis of the Yb3+-induced paramagnetic H NMR shifts
of [Yb(Me2tedpa)]+ at 278 K ([χzz − 1/3(χxx + χyy + χzz)] =
3974 43 ppm Å3 and (χxx − χyy) = −2178 79 ppm Å3)
define a rhombic susceptibility tensor, as observed previously
for [Yb(teta)]− ([χzz − 1/3(χxx + χyy + χzz)] = 3237 ppm Å3
and (χxx − χyy1) = −2526 ppm Å3).41 Thus, the Yb3+-induced
paramagnetic H NMR shifts of these complexes show sizable
contributions from both the axial and rhombic components,
although the axial contribution dominates the observed
paramagnetic shifts as a consequence of the prolate magnetic
susceptibility tensor. On the contrary, [Yb(cb-tedpa)]+ presents
an oblate magnetic susceptibility tensor dominated by the
rhombic contribution ([χzz − 1/3(χxx + χyy + χzz)] = 90 ppm Å3
and (χxx − χyy) = 3018 ppm Å3.18
Assessment of the Thermodynamic Stabilities. The
bond distances of the metal coordination environments
calculated for [Ln(Me2tedpa)]+ and [Ln(cb-tedpa)]+ com-
plexes at the TPSSh/LCRECP/6-31G(d) level decrease
quadratically along the lanthanide series (Figures S11−S14,
Tables S3−S5 Supporting Information), in line with previous
experimental and computational studies.42,43 This is typical of
complexes presenting an increased stability across the series, as
attenuated44 or even reversed45 stability trends have been
related to the weakening of some of the Ln3+-donor bonds.
Following our recently developed methodology, the
evolution of the stability of [Ln(Me2tedpa)]+ and [Ln(cb-
tedpa)]+ complexes in aqueous solution has been evaluated by
using DFT calculations with the aid of the thermodynamic
cycle presented in Scheme 2.43
ΔGsol([Ln(cb-
a
b
b
Ln ΔGg(2)
tedpa)]+)
ΔGsol([Ln(Me2tedpa)]+) ΔGaq(2)cald
La
−12.29
−77.14
−74.13
−70.63
−69.18
−67.68
−67.33
−70.66
−68.15
−65.46
−64.12
−62.48
−62.09
−16.51
−15.55
−13.88
−13.29
−12.68
−12.61
Nd
Gd
Dy
Yb
Lu
−11.84
−10.98
−10.49
−9.75
−9.64
a
Basis set superposition error (BSSE) corrections taken into account
b
with the counterpoise method. ΔGsol(LnL) were calculated in
aqueous solution using the structures optimized in vacuo at the
TPSSh/LCRECP/6-31G(d) level.
The relative thermodynamic stabilities of the [Ln-
(Me2tedpa)]+ and [Ln(cb-tedpa)]+ complexes were inves-
tigated by using the thermodynamic cycle presented in Scheme
3.
The calculated ΔGg(2) and ΔGaq(2) values (Figure 10, see
also Table 4) are negative, which indicates that the [Ln(cb-
tedpa)]+ complexes are more stable than the [Ln(Me2tedpa)]+
counterparts both in the gas-phase and in solution. The
calculated ΔGg(2) values range between −12.3 and −9.6 kcal
mol−1 and become steadily less negative across the series. This
can be explained by the values of ΔGg(1) calculated for [Ln(cb-
tedpa)]+ and [Ln(Me2tedpa)]+ complexes, as they become
more negative for the latter as the ionic radius of the metal ion
decreases (Tables S6 and S7, Supporting Information). In
solution the [Ln(cb-tedpa)]+ complexes are stabilized with
respect to the [Ln(Me2tedpa)]+ analogues, which is a
consequence of the more negative hydration free energies of
the cross-bridge derivatives (Table 4), as the hydration free
energies of the ligands are very similar (−168.0 and −170.2 kcal
As expected, the ΔGg(1) values become more negative on
proceeding to the right across the lanthanide series for the two
series of complexes (Tables S6 and S7, Supporting
Information) as a consequence of the increased charge density
of the metal ion. In aqueous solution the ΔGaq(1) values also
get more negative, which is the most common situation
observed for Ln3+ complexes with polyaminocarboxylate
G
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Scheme 3. Thermodynamic Cycle Used for the Analysis of the Relative Stabilities of [Ln(Me2tedpa)]+ and [Ln(cb-tedpa)]+
Complexes
mol−1 for Me2tedpa2− and cb-tedpa2−). The calculated ΔGaq(2)
values can be used to estimate equilibrium constants using the
relationship ΔGaq(2) = −RT ln K, which in turn provide the
difference between the stability constants of [Ln(cb-tedpa)]+
and [Ln(Me2tedpa)]+ complexes. According to the results of
our calculations the Δlog K = log K[Ln(cb‑tedpa)] − log
K[Ln(Me2tedpa)] values range between 11.4 (Ln = La) and 9.2
(Ln = Lu). This results suggest that the [Ln(cb-tedpa)]+
complexes are several orders of magnitude more stable than
the [Ln(Me2tedpa)]+ ones, which is likely related to the higher
basicity of the cross-bridge derivative evidenced by the
potentiometric measurements described above. Although our
computational results should be taken with some caution, a
stability constant of log K ∼ 8.0 for [Gd(Me2tedpa)]+ (see
above) yields according to our DFT studies log K ∼ 18.0 for
[Gd(cb-tedpa)]+. The latter value is very similar to that
determined for [Gd(Me2dodpa)]+ complex (log K = 17.6).20
Figure 10. Gibbs free energies calculated in the gas phase (ΔGg(2),
blue squares) and in aqueous solution phase (ΔGaq(2), green circles)
according to Scheme 3. The solid lines are only a guide for the eye.
Table 5. Crystal Data and Refinement Details
a
b
c
(H4cb-tedpa) (ClO4)2
[La(cb-tedpa)Cl]
[Gd(cb-tedpa)](PF6)
[Gd(Hcb-tedpa)2]Cl
formula
CCDC number
MW
C26H38Cl2N6O12
1436890
697.52
C26H44ClLaN6O9
1434304
759.03
C52H78F12Gd2N12O13P2
1434305
1683.70
orthorhombic
Pbca
C52H80ClGdN12O13
1434308
1273.98
monoclinic
P21/n
crystal system
space group
T/K
monoclinic
P21/n
monoclinic
C2/c
100(2)
8.838(3)
18.252(7)
18.672(7)
90
100(2)
100(2)
100(2)
a/Å
13.5447(6)
16.3852(6)
14.1598(6)
90
13.9271(8)
21.5806(12)
41.373(2)
90
16.0360(4)
16.4812(4)
22.7258(6)
90
b/Å
c/Å
α/deg
β/deg
99.33(2)
90
102.195(2)
90
90
107.432(2)
90
γ/deg
V/Å3
90
2972.1(19)
1464
3071.6(2)
1552
12435.0(12)
6752
5730.4(3)
2644
F(000)
Z
4
4
8
4
λ/Å (Mo Kα)
0.71073
1.559
0.71073
1.641
0.71073
1.799
0.71073
1.477
D
calc/g cm−3
μ/mm−1
0.294
1.539
2.274
1.276
θ range/deg
Rint
2.211 to 26.372
0.1204
2.49 to 25.10
0.0407
8.631 to 24.411
0.2041
1.816 to 30.033
0.0731
reflns measd
unique reflns
reflns obsd
GOF on F2
16855
14091
116346
9752
128809
5775
2743
16768
2926
2548
6520
11698
1.003
1.056
1.026
1.037
d
R1
0.0797
0.0230
0.0468
0.0382
e
wR2 (all data)
largest differences peak and hole/e Å−3
0.2086
0.0528
0.1035
0.0933
0.496/−0.641
0.720/−1.061
0.907/−0.826
1.614/−0.979
a
b
c
d
Full formula [La(cb-tedpa)Cl]·5H2O. Full formula [Gd(cb-tedpa)](PF6)·2.5H2O. Full formula [Gd(Hcb-tedpa)2]Cl·5H2O. R1 = ∑||Fo| − |Fc||/
e
4
∑|Fo|. wR2 = {∑[w(||Fo|2 − |Fc|2)2]/∑[w(Fo )]}1/2
.
H
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Table 6. Crystal Data and Refinement Details
a
b
c
[Lu(Me2tedpa)]Cl
[La(H2Me2tedpa)2](PF6)3
[Yb(H2Me2tedpa)2](PF6)3
formula
CCDC number
MW
C26H48ClLuN6O10
1434303
815.12
C52H92F18LaN12O16P3
1434306
1715.19
monoclinic
P21/n
C52H84F18N12O12P3Yb
1434307
1677.26
crystal system
space group
T/K
monoclinic
C2/c
triclinic
P1
̅
100(2)
100(2)
100(2)
a/Å
17.7491(5)
15.1219(4)
12.1887(3)
90
15.2720(8)
25.6660(13)
19.5730(10)
90
10.7944(4)
11.6488(4)
28.2797(12)
85.196(2)
87.336(3)
74.556(2)
3414.4(2)
1706
b/Å
c/Å
α/deg
β/deg
103.7850(10)
90
111.425(3)
90
γ/deg
V/Å3
3177.22(15)
1656
7141.9(7)
3520
F(000)
Z
4
4
2
λ, Å (Mo Kα)
0.71073
1.704
0.71073
1.595
0.71073
1.631
D
calc/g cm−3
μ/mm−1
3.254
0.782
1.554
θ range/deg
Rint
3.20 to 28.36
0.0274
2.259 to 24.412
0.1842
2.01 to 24.71
0.0959
reflns measd
unique reflns
reflns obsd
GOF on F2
20762
163636
11737
82045
3973
11598
3829
7856
9710
1.055
1.032
1.038
d
R1
0.0141
0.0531
0.0366
e
wR2 (all data)
largest differences peak and hole/e Å−3
0.0374
0.1309
0.0809
0.521/−0.702
0.926/−0.633
1.288/−0.882
a
b
c
d
Full formula [Lu(Me2tedpa)]Cl·6H2O. Full formula [La(H2Me2tedpa)2](PF6)3·8H2O. Full formula [Yb(H2Me2tedpa)2](PF6)3·4H2O. R1 = ∑||
e
4
Fo| − |Fc||/∑|Fo|. wR2 = {∑[w(||Fo|2 − |Fc|2)2]/∑[w(Fo )]}1/2
.
Due to the slow formation kinetics of metal complexes with
cross-bridge derivatives, there are only a few examples of metal
complexes whose thermodynamic stabilities are known for the
cross-bridge ligand and the nonreinforced analogue.6e,26 In the
latter cases it was found that the stability of the Cu2+ and Zn2+
complexes with the cross-bridge ligands was smaller than that
of the nonreinforced derivatives. Our results suggest however
that this situation might be reversed for the Ln3+ ions.
dissociation of this family of complexes. The computational
study presented in this work suggests that the [Ln(cb-tedpa)]+
complexes are considerably more stable thermodinamically
than the [Ln(Me2tedpa)]+ analogues.
EXPERIMENTAL SECTION
■
Chemicals, Starting Materials, and General Procedures.
Chemicals were purchased from commercial sources and used without
further purification. Compounds 1,4,8,11-tetraazatricyclo[9.3.1.14,8]-
hexadecane (2), 1,8-dimethyl-1,4,8,11-tetraazatricyclo[[9.3.1.14,8]-
hexadecane-1,8-diium iodide (3), and 1,8-dimethyl-1,4,8,11-tetraaza-
cyclotetradecane (4) were prepared following the published
procedures.21 Preparative medium pressure liquid chromatography
was carried out using a CombiFlash Rf system using neutral Al2O3
RediSepRf columns (column size 48 g, particle size 40−63 μm, pore
CONCLUSIONS
■
The comparison of the coordination properties of the cross-
bridge cb-tedpa2− ligand and the nonreinforced analogue
Me2tedpa2− allows rationalizing the origin of the exceptional
stability of the [Ln(cb-tedpa)]+ complexes. Both ligands
provide octadentate binding to the Ln3+ ions both in the
solid state and in solution, the [Ln(cb-tedpa)]+ and [Ln-
(Me2tedpa)]+ complexes presenting similar structures. The
formation of the [Ln(cb-tedpa)]+ complexes is very slow and
requires a slight excess of Ln3+ ion to avoid the formation of
exocyclic [Ln(Hcb-tedpa)2]+ intermediates. In aqueous sol-
utions the [Ln(Me2tedpa)]+ complexes are not stable from the
thermodynamic point of view, except in the case of the smallest
Ln3+ ions, which were found to dissociate partially. Crystals of
the exocyclic [Ln(H2Me2tedpa)2]3+ (Ln = La or Yb) complexes
were obtained from aqueous solutions prepared upon
dissolution of the corresponding [Ln(Me2tedpa)]Cl salts.
Furthermore, the [Eu(Hcb-tedpa)2]+ species was characterized
using 1H NMR and mass spectrometry during the formation of
the [Eu(cb-tedpa)]+ complex. Thus, these exocyclic derivatives
can be regarded as key intermediates in the formation and
1
size 60 Å). H and 13C NMR spectra were recorded at 25 °C on
Bruker Avance 300 or Bruker Avance 500 spectrometers. ESI-TOF
mass spectra were recorded using a LC-Q-q-TOF Applied Biosystems
QSTAR Elite spectrometer in the positive mode. Elemental analyses
were carried out on a ThermoQuest Flash EA 1112 elemental analyzer.
IR spectra were recorded using a Bruker Vector 22 spectrophotometer
equipped with a Golden Gate Attenuated Total Reflectance (ATR)
accessory (Specac). The longitudinal relaxation times (T1) of water
protons were measured at 20 MHz with a Bruker Minispec MQ-20
NMR Analyzer at 25.0 0.2 °C.
Dimethyl 6,6′-((4,11-Dimethyl-1,4,8,11-tetraazatricyclo-
tetradecane-1,8-diyl)bis(methylene))dipicolinate (6). A mixture
of compound 4 (0.438 g, 1.92 mmol) and Na2CO3 (1.330 g, 9.62
mmol) in dry acetonitrile (40 mL) was stirred for 30 min, and then a
solution of compound 5 (0.750 g, 4.04 mmol) in acetonitrile (15 mL)
was added dropwise. The mixture was stirred at 45 °C for a period of 3
days, and then the excess Na2CO3 was filtered off. The filtrate was
concentrated to dryness and the yellow oil was partitioned between a
I
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2:5 H2O:CH2Cl2 mixture (70 mL). The aqueous phase was further
extracted with CH2Cl2 (2 × 50 mL). The organic phase was dried over
MgSO4, filtered, and evaporated to dryness to give an oily residue that
was purified by preparative medium pressure liquid chromatography
(neutral Al2O3 with a CH2Cl2/MeOH mixture as the eluent; gradient
0−10%) to give 6 (0.740 g) as a yellow oil. Yield: 73%. MS (ESI+, %
BPI): m/z 527,33 (100) ([C28H43N6O4]+). IR (ATR): 2977, 2955,
[Tb(Me2tedpa)]Cl. The preparation of the white solid followed the
same procedure as that described for [La(Me2tedpa)]Cl by using
H2Me2tedpa·5HCl·3H2O (0.066 g, 0.090 mmol), triethylamine (0.077
g, 0.763 mmol) and TbCl3·6H2O (0.034, 0.090 mmol). Yield 0.043 g,
70%. Anal. calcd. for C26H36ClN6O4Tb: C, 45.19; H, 5.25; N, 12.16%.
Found: C, 44.99; H, 5.43; N, 12.22%. MS (ESI+, %BPI): m/z 655.21
(100) ([C26H36N6O4Tb]+). HS-MS (ESI+): m/z 655.2044; calcd. for
[C26H36N6O4Tb]+ 655.2046. IR (ATR): 1568 cm−1 (CN)py.
[Yb(Me2tedpa)]Cl. The preparation of the white solid followed the
same procedure as that described for [La(Me2tedpa)]Cl by using
H2Me2tedpa·5HCl·3H2O (0.053 g, 0.072 mmol), triethylamine (0.062
g, 0.613 mmol), and YbCl3·6H2O (0.028, 0.072 mmol). Yield 0.030 g,
59%. Anal. calcd. for C26H36ClN6O4Yb: C, 44.29; H, 5.15; N, 11.92%.
Found: C, 44.08; H, 5.31; N, 11.75%. MS (ESI+, %BPI): m/z 670.22
(100) ([C26H36N6O4Yb]+). HS-MS (ESI+): m/z 670.2176; calcd. for
[C26H36N6O4Yb]+ 670.2181. IR (ATR): 1632 cm−1 (CO).
[Lu(Me2tedpa)]Cl. The preparation of the white solid followed the
same procedure as that described for [La(Me2tedpa)]Cl by using
H2Me2tedpa·5HCl·3H2O (0.052 g, 0.071 mmol), triethylamine (0.061
g, 0.601 mmol) and LuCl3·6H2O (0.028, 0.071 mmol). Yield 0.026 g,
51%. Anal. calcd. for C26H36ClLuN6O4: C, 44.17; H, 5.13; N, 11.89%.
Found: C, 43.88; H, 5.41; N, 11.66%. MS (ESI+, %BPI): m/z 671.22
(100) ([C26H36LuN6O4]+). HS-MS (ESI+): m/z 671.2204; calcd. for
[C26H36LuN6O4]+ 671.2200. IR (ATR): 1633 (CO), 1575 cm−1
(CN)py.
1
2931, 2781 (C-H), 1733 (CO), 1588 cm−1 (CN)py. H NMR
(CDCl3, 300 MHz, 25 °C, TMS): δ 7.98 (dd, 3J = 7.4 Hz, 4J = 1.3 Hz,
2H, py), 7.89−7.83 (m, 2H, py), 7.78 (t, 3J = 7,7 Hz, 2H, py), 3.98 (s,
6H, OCH3), 3.82 (s, 4H, CH2 arm), 2.71−2.58 (m, 8H, α-CH2
cyclam), 2.55−2.35 (m, 8H, α-CH2 cyclam), 2.08 (s, 6H, Me), 1.72−
1.58 ppm (m, 4H, β-CH2 cyclam). 13C NMR (CDCl3, 75.5 MHz, 25
°C): δ 166.1 (CO), 161.8, 147.2, 137.2, 126.5, 123.6 (py), 61.1 (CH2
arm), 54.9 (OCH3), 54.7, 53.0, 52.0 (α-CH2 cyclam), 51.7 (Me), 43.2
(α-CH2 cyclam), 24.5 ppm (β-CH2 cyclam).
6,6′-((4,11-Dimethyl-1,4,8,11-tetraazacyclotetradecane-1,8-
diyl)bis(methylene))dipicolinic acid (H2Me2tedpa). The dimethyl
ester 6 (1.121 g, 2.13 mmol) was dissolved in a 6 M HCl aqueous
solution (20 mL). The mixture was heated to reflux with stirring for 24
h, and then the solvents were removed in a rotary evaporator to give a
dark oil. This was dissolved in H2O (10 mL) and the solvent was
evaporated. This process was repeated twice, and then the residue was
dried under vacuum to give 1.538 g of the expected compound as a
white solid. Yield: 98%. Anal. Calcd. for C26H38N6O4·5HCl·3H2O: C
42.49, H 6.72, N 11.43%. Found: C 42.42, H 6.61, N 10.88%. MS
(ESI+, %BPI): m/z 250.16 (100) ([C26H40N6O4]2+), 499.31 (30)
([C26H39N6O4]+). IR (ATR): 2582, 2487 (C-H), 1750 (CO), 1649
pH-Potentiometric Titrations of the Ligands. The protonation
constants of the ligands were determined by using pH-potentiometric
titrations with Methrohm 888 Titrando and a 785 DMP titrator
systems and Metrohm-6.0233.100 combined electrode. For the pH-
calibration of the electrode KH-phthalate (pH = 4.005) and borax (pH
= 9.180) buffers obtained from commercial sources (Merck certified
standard reference materials for pH measurements) were used.46 The
titrated solutions (6.00 mL) were thermostatted at 25 °C and kept
under inert gas atmosphere (N2) to avoid the effect of CO2. The
concentrations of the ligands in the samples were set to 2.35 and 4.24
mM for Me2tedpa2− and cb-tedpa2−, respectively. In the pH-
potentiometric titrations 284 to 440 mL−pH data pairs were recorded
in the pH range of 1.7−12.5. The calculation of [H+] from the
measured pH values was performed with the use of the method
proposed by Irving et al.47 by titrating a 0.01 M HCl solution (I = 0.15
M NaCl) with a standardized (cNaOH = 0.2190 M) NaOH solution.
The differences between the measured and calculated pH values were
used to obtain the [H+] concentrations from the pH data obtained in
the titrations. The ion product of water was determined from the same
experiment in the pH range 11.4−12.0 and was found to be 13.81(1),
which is acceptably close to the value referred in the literature (pKw =
13.78 in 0.15 M NaCl at 25 °C). The protonation and stability
constants were calculated from the titration data with the PSEQUAD
program.48
Single Crystal X-ray Diffraction Measurements. Single crystals
of formula (H4cb-tedpa)(ClO4)2 were obtained from an aqueous
solution containing equimolar amounts of Lu(ClO4)3 and the ligand,
prepared in an attempt to form the Lu3+ complex (pH ∼ 6.0). Partial
complex formation (i.e., out-of-cage complexes) likely lowered the pH
of the mixture, as the ligand crystallized in its tetraprotonated form.
Crystals of [La(H2Me2tedpa)2](PF6)3·8H2O, [Yb(H2Me2tedpa)2]-
(PF6)3·4H2O, and [Gd(cb-tedpa)](PF6)·2.5H2O were obtained by
dissolving small amounts of the isolated [Ln(Me2tedpa)]Cl (Ln = La,
Yb) or [Gd(cb-tedpa)]Cl complexes in water and addition of an excess
of KPF6. Crystals of [La(cb-tedpa)Cl]·5H2O and [Lu(Me2tedpa)]Cl·
6H2O were obtained by slow evaporation of aqueous solutions of the
complexes at neutral pH. Crystals of [Gd(Hcb-tedpa)2]Cl·5H2O were
obtained by reacting the ligand (∼30 mg) and equimolar GdCl3 in 5
mL of n-butanol in the presence of DIPEA as a base under microwave
irradiation (8−10 W to set the temperature to 140−145 °C) for nearly
40 h. The crystals were obtained upon storing the resulting solution at
room temperature for a few days.
1
cm−1 (CN)py. H NMR (D2O, pD = 0.73, 500 MHz, 25 °C): δ
3
8.20−8.12 (m, 4H, py), 7.76 (d, J = 7.7 Hz, 2H, py), 4.25−3.95 (m,
4H, CH2 arm), 3.75−2.78 (m, 16H, α-CH2 cyclam), 2.80 (s, 6H, Me),
2.10−1.90 (m, 4H, β-CH2 cyclam). 13C NMR (D2O, pD = 0.73, 125.8
MHz, 25 °C): 165.93 (CO), 154.94, 146.26, 142.50, 128.20, 125.29
(py), 57.03 (CH2 arm), 52.21, 51.70, 51.07, 47.33 (α-CH2 cyclam),
41.88 (Me), 21.20 (β-CH2 cyclam).
Synthesis of [La(Me2tedpa)]Cl Complex Salt. A mixture of
H2Me2tedpa·5HCl·3H2O (0.053 g, 0.072 mmol) and triethylamine
(0.062 g, 0.615 mmol) in 2-propanol (7 mL) was heated to reflux for
30 min, and then a solution of LaCl3·6H2O (0.026, 0.072 mmol) in 2-
propanol (3 mL) was added dropwise. The mixture was heated to
reflux for a period of 2 days. After this, the reaction was allowed to
cool to room temperature and then concentrated to dryness. The
addition of chloroform (4 mL) resulted in the formation of a white
precipitate, which was isolated by filtration. The solid was washed with
chloroform (3 × 7 mL), diethyl ether (1 × 7 mL) and dried under
vacuum. Yield 0.044 g, 90%. Anal. Calcd. for C26H36ClLaN6O4: C,
46.54; H, 5.41; N, 12.53%. Found: C, 46.80; H, 5.69; N, 12.66%. MS
(ESI+, %BPI): m/z 499.30 (100) ([C26H39N6O4]+), 559.23 (62)
([C26H37KN6NaO4]+), 537.25 (28) ([C26H38KN6O4]+), 521.28 (18)
([C26H38N6NaO4]+), 635.18 (7) ([C26H36LaN6O4]+). HS-MS (ESI+):
m/z 635.1843; calcd. for [C26H36LaN6O4]+ 635.1856. IR (ATR): 1612
(CO), 1568 cm−1 (CN)py.
[Eu(Me2tedpa)]Cl. The preparation of the white solid followed the
same procedure as that described for [La(Me2tedpa)]Cl by using
H2Me2tedpa·5HCl·3H2O (0.067 g, 0.091 mmol), triethylamine (0.078
g, 0.775 mmol) and EuCl3·6H2O (0.033, 0.091 mmol). Yield 0.050 g,
80%. Anal. calcd. for C26H36ClEuN6O4: C, 45.65; H, 5.31; N, 12.29%.
Found: C, 45.54; H, 5.66; N, 12.31%. MS (ESI+, %BPI): m/z 649.19
(100) ([C26H36EuN6O4]+). HS-MS (ESI+): m/z 649.1984; calcd. for
[C26H36EuN6O4]+ 649.2005. IR (ATR): 1613 (CO), 1568 cm−1
(CN)py.
[Gd(Me2tedpa)]Cl. The preparation of the white solid followed the
same procedure as that described for [La(Me2tedpa)]Cl by using
H2Me2tedpa·5HCl·3H2O (0.070 g, 0.095 mmol), triethylamine (0.081
g, 0.805 mmol) and GdCl3·6H2O (0.035, 0.095 mmol). Yield 0.047 g,
72%. Anal. calcd. for C26H36ClGdN6O4: C, 45.30; H, 5.26; N, 12.19%.
Found: C, 44.91; H, 5.06; N, 12.18%. MS (ESI+, %BPI): m/z 654.20
(100) ([C26H36GdN6O4]+). HS-MS (ESI−): m/z 654.2045; calcd. for
[C26H36GdN6O4]+ 654.2034. IR (ATR): 1614 (CO), 1568 cm−1
(CN)py.
Three dimensional X-ray data were collected on Bruker-Nonius X8
APEX Kappa CCD or Bruker Kappa APEXII CCD ([Gd(Hcb-
tedpa)2]Cl·5H2O) diffractometers. Data were corrected for Lorentz
J
DOI: 10.1021/acs.inorgchem.5b02627
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
and polarization effects and for absorption by semiempirical methods49
based on symmetry-equivalent reflections. Complex scattering factors
were taken from the programs SHELX9750 running under the WinGX
program system.51 The structures were solved by Patterson methods
with DIRDIF200852 ([Lu(Me2tedpa)]Cl and [Yb(H2Me2tedpa)2]-
(PF6)3) and with SHELXS9750 ([La(cb-tedpa)Cl] and [Gd(cb-
tedpa)](PF6)). The other three structures were solved by direct
methods with SIR 200453 ([La(H2Me2tedpa)2](PF6)3) or SIR201154
((H4cb-tedpa) (ClO4)2 and [Gd(Hcb-tedpa)2]Cl·5H2O). All the
structures were refined50 by full-matrix least-squares on F2. The
hydrogen atoms were included in calculated positions and refined in
riding mode, with the following exceptions: Hydrogen atoms of water
molecules were located in a difference electron-density map and the
distances restrained (DFIX 0.84(1) DANG 1.34(2)). In the case of the
[Lu(Me2tedpa)]Cl hydrogen atoms bonded to O1W were refined
freely and those bonded to O2W and O3W were refined with all the
positional parameters fixed. For [Gd(Hcb-tedpa)2]Cl·5H2O the N−H
distances involving N3 and N9 were refined, H91 an H92 (bonded to
O9) were refined freely and finally the position of H122, H141, and
H142 had to be fixed to achieve convergence. Three of the crystals
present positional disorder; Crystals of [Gd(cb-tedpa)](PF6) contain
two disordered water molecules with occupation factors for the main
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.5b02627.
■
S
1H and 13C NMR spectra, HR-ESI+ mass spectra,
calculated bond distances of the metal coordination
environments, quadratic fits of the average bond
distances of the metal coordination environments,
1
hydrogen-bonding data, experimental and calculated H
NMR shifts of [Yb(Me2tedpa)]+, thermodynamic data
obtained using DFT calculations according to Scheme 2,
basis set superposition errors, \ optimized Cartesian
coordinates obtained with DFT calculations (PDF)
Crystallographic data (CIF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail address: carlos.platas.iglesias@udc.es (C.P.-I.).
*E-mail address: Raphael.Tripier@univ-brest.fr (R.T.).
■
−
positions of O3W and O5W of 0.81(1). One noncoordinated PF6
anion also shows positional disorder with occupational factors of
0.810(9) for F8A, F9A, F10A, and F11A, so that 16 restraints had to
be applied in order to reach convergence. Crystals of [Yb-
(H2Me2tedpa)2](PF6)3 contain one disordered perchlorate with
occupation factors for O9, O11, and O12 of 0.679(5). The refinement
converged with anisotropic displacement parameters for all non-
hydrogen atoms in all the cases. Two water molecules present in the
crystal of [Gd(Hcb-tedpa)2]Cl·5H2O show positional disorders into
three positions that have been solved. The total occupancy factor was
restrained initially with SUMP to 2 but finally the occupancy factors
had to be fixed to 0.68 for O12, 0.62 for O13, and 0.50 for O14 in
order to achieve convergence. Crystal data and details on data
collection and refinement are summarized in Tables 5 and 6.
Computational Details. All calculations presented in this work
were performed employing the Gaussian 09 package (Revision
D.01).55 Full geometry optimizations of the [Ln(cb-tedpa)]+ and
[Ln(Me2tedpa)]+ systems (Ln = La, Pr, Nd, Eu, Gd, Dy, Ho, Yb, or
Lu) were conducted employing DFT within the hybrid meta
generalized gradient approximation (hybrid meta-GGA), with the
TPSSh exchange-correlation functional.56 Geometry optimizations
were carried out by using the large-core quasirelativistic effective core
potential (LCECP) of Dolg and co. and its associated [5s4p3d]-GTO
valence basis set,57 while the ligand atoms were described by using the
standard 6-31G(d) basis set. Input geometries were taken from our
previous computational studies in the case of [Ln(cb-tedpa)]+
complexes.18 No symmetry constraints have been imposed during
the optimizations. The stationary points found on the potential energy
surfaces as a result of geometry optimizations were tested to represent
energy minima rather than saddle points via frequency analysis. Gibbs
free energies were obtained at T = 298.15 K within the harmonic
approximation. The ΔGg values reported in this work include basis-set
superposition errors, which were estimated using the Counterpoise
method of Boys and Bernardi (Table S8, Supporting Information).58
The default values for the integration grid (75 radial shells and 302
angular points) and the SCF energy convergence criteria (10−8) were
used in all calculations.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors are indebted to Centro de Supercomputacion
Galicia (CESGA) for providing the computer facilities. A.R.-R.,
M.R.-F., D.E.-G., A.deB., T.R.-B., and C.P.-I. thank Ministerio
■
́
de
́
de Economia y Competitividad (CTQ2009-10721-PPQ) for
generous financial support. G.T., F.K.K., and I.T. thank the
Hungarian Scientific Research Fund (OTKA K-84291 and K-
109029) for their financial support. This work was also
́
supported by the Janos Bolyai Research Scholarship (G.T. and
F.K.K.) of the Hungarian Academy of Sciences. A.R.-R., G.T.,
F.K.K., I.T., and C.P.-I. gratefully acknowledge support from
the COST CM1006 “European F-Element Network (EuFen)”
and COST TD1004 “Theragnostics Imaging and Therapy: An
Action to Develop Novel Nanosized Systems for Imaging-
Guided Drug Delivery” Actions. A.R.-R. thanks the Ministerio
de Educacion
fellowship. R.T. acknowledges the Minister
Superieur et de la Recherche, the Centre National de la
́
y Ciencia (FPU program) for a predoctoral
̀
e de l′Enseignement
́
Recherche Scientifique, and the “Service Commun” of NMR
facilities of the University of Brest. C.P.-I. acknowledges the
University of Brest for his invited Professor position.
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