Synthesis and Characterization of GaIII, InIII and LuIII Complexes of a Set of dtpa Bis-Amide Ligands

Article abstract of DOI:10.1002/ejic.201500436

The synthesis and characterization of five new diethylenetriaminepentaacetic acid (dtpa) ligands, (dtpa)-N,N"-bis(alkoxyphenylamide), and their complexation with Ga^III, In^III and Lu^III are reported. The procedures for the synthesis of all complexes in aqueous media are described as well as a synthetic pathway for the preparation of Ga^III complexes in chloroform. All substances were characterized by NMR spectroscopy, mass spectrometry, elemental analysis and HPLC. Single-crystal structure analysis was performed where applicable, which revealed the presence of hepta- and octa-coordinated isomers for In^III complexes and a nine-fold coordination of Lu^III ions in the solid state. Additional NMR experiments suggested a hepta-coordinated In^III species in solution, whereas the Ga^III complexes appear to be hexa-coordinated and the Lu^III complexes to be octa-coordinated. Both NMR and HPLC studies indicated the presence of a single isomer in every complex. The synthesis and characterization of new Ga^III, In^III and Lu^III complexes of five dtpa bis-amides are described. As determined by single-crystal structure analysis, the In^III complexes are hepta- or octa-coordinated, whereas the Lu^III are nona-coordinated in the solid state. NMR studies were undertaken to characterize the coordination behaviour of the complexes in solution.

Full text of DOI:10.1002/ejic.201500436

FULL PAPER
DOI:10.1002/ejic.201500436
Synthesis and Characterization of GaIII, InIII and LuIII
Complexes of a Set of dtpa Bis-Amide Ligands
Julia Greiser,[a] Tino Hagemann,[b] Tobias Niksch,[a]
Philipp Traber,[c] Stephan Kupfer,[c] Stefanie Gräfe,[c]
Helmar Görls,[b] Wolfgang Weigand,*[b] and Martin Freesmeyer*[a]
Keywords: N,O ligands / Amides / Gallium / Indium / Lutetium
The synthesis and characterization of five new diethylenetri-
aminepentaacetic acid (dtpa) ligands, (dtpa)-N,NЈЈ-bis(alk-
oxyphenylamide), and their complexation with GaIII, InIII and tion of LuIII ions in the solid state. Additional NMR experi-
cable, which revealed the presence of hepta- and octa-coor-
dinated isomers for InIII complexes and a nine-fold coordina-
LuIII are reported. The procedures for the synthesis of all
complexes in aqueous media are described as well as a syn-
thetic pathway for the preparation of GaIII complexes in chlo-
roform. All substances were characterized by NMR spec-
troscopy, mass spectrometry, elemental analysis and HPLC.
Single-crystal structure analysis was performed where appli-
ments suggested a hepta-coordinated InIII species in solution,
whereas the GaIII complexes appear to be hexa-coordinated
and the LuIII complexes to be octa-coordinated. Both NMR
and HPLC studies indicated the presence of a single isomer
in every complex.
trast agent, it does have its drawbacks. As an open-chain-
based GdIII complex it cannot be applied to patients in
cases of renal impairment or drug intolerance to this often
quite toxic agent. Additionally, MRI cannot be used for
patients with metallic MRI-incompatible implants (e.g.,
cardiac pacemakers) or claustrophobia.
dtpa derivatives structurally similar to EOB-dtpa might
be promising tracers for liver-specific molecular imaging
upon labelling with suitable radionuclides, therefore provid-
ing an alternative to MRI. The derivatization of dtpa usu-
ally involves either the introduction of structural moieties
into the ethylene or methylene groups of the backbone
structure[6,7] or the amidation of one or several of the five
carboxy groups.[8–11]
Although EOB-dtpa is only accessible through a multi-
step synthesis in which the lipophilic p-ethoxybenzyl moiety
is introduced in an early step,[12] dtpa amides can be synthe-
sized much more efficiently by using dtpa bis-anhydride as
the starting material. The variety of available anilines used
in the amidation step makes a diversity of dtpa bis-amides
accessible. Alterations of the amide moiety and the chain
length of substituents influence the lipophilicity of com-
plexes thereof and consequently their specificity to hepato-
cytes and suitability for hepatobiliary imaging. Therefore a
set of dtpa-N,NЈЈ-bis(alkoxyphenylamides) with a different
substitution pattern of the phenyl moiety and variable chain
lengths were designed and synthesized.
Introduction
Diethylenetriaminepentaacetic acid (dtpa) is a well-
known chelator that has been used since the 1960s as an
agent for treating heavy-metal poisoning and radioactive
contamination.[1–3] Its metal complexes are useful tools, one
major field of interest being medical imaging.
One approved contrast agent for MRI is gadoxetic acid,
also known as Eovist® or Primovist®, which was first de-
scribed in 1991.[4] It is the GdIII complex of EOB-dtpa, a
dtpa ligand bearing a p-ethoxybenzyl moiety on the diethyl-
enetriamine backbone that improves the lipophilicity of the
compound. This property results in a specific uptake of the
agent by liver hepatocytes by means of an organic anion
transporter.[5] The high liver specificity of gadoxetic acid
enables the localization of focal lesions and hepatic tumours
by MRI techniques. Although it is a frequently used con-
[a] University Hospital Jena, Clinic of Nuclear Medicine,
Bachstraße 18, 07743 Jena, Germany
E-mail: martin.freesmeyer@med.uni-jena.de
http://www.nuklearmedizin.uniklinikum-jena.de/Startseite.html
[b] Institute for Inorganic and Analytical Chemistry, Friedrich-
Schiller-University Jena,
Humboldtstraße 8, 07743 Jena, Germany
E-mail: wolfgang.weigand@uni-jena.de
http://www.chemgeo.uni-jena.de/Institute/
Institut+für+Anorganische+und+Analytische+Chemie/
Prof_+W_+Weigand+.html
[c] Institute for Physical Chemistry and Abbe Center of Photonics,
Friedrich-Schiller-University Jena,
dtpa amides are able to bind a variety of metal ions,
ranging from lanthanides[11,13–18] and d elements[19–22] to al-
kaline-earth metals,[23] pnictogens[24] as well as elements of
the boron group.[19,24–32] Among this last group, GaIII is of
Helmholtzweg 4, 07743 Jena, Germany
E-mail: s.graefe@uni-jena.de
http://www.ipc.uni-jena.de/Institut.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejic.201500436.
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particular interest due to its radioactive isotope 68Ga, which and the ligand either in an aqueous solution or in chloro-
is commonly used in positron emission tomography (PET). form. The syntheses in aqueous systems were performed at
GaIII complexes of dtpa and its derivatives are generally pH 3.3 for GaIII complexes using an acetate buffer solution
considered not suitable for medical applications due to a and at pH 7.5 for InIII and LuIII complexes (Scheme 2). Ow-
lack of kinetic inertness,[33–35] which may result in rapid ing to the poor solubility of the ligands in aqueous media,
trans-chelation to transferrin in vivo.[27,36–38] Nevertheless, the yields were improved by dissolving the dtpa bis-amides
some promising results in the field can be found. For exam- 2a–e in boiling water and then cooling to room temperature
ple, 68GaIII complexes of dtpa coupled to proteins through followed by the addition of the respective metal chloride.
an amide bond have been reported to be stable in vivo over
a period of hours.[29,30] A dtpa-conjugated chalcone deriva-
tive labelled with 68GaIII also showed only slow degradation
in human serum.[31]
Although the properties of the 68GaIII complexes of dtpa
amides have been intensively examined,[27,29–31] investi-
gations of the solution chemistry and the structural behav-
iour of non-radioactive equivalents are scarcer.[28] To pro-
vide new insights into this subject, this study focuses on the
synthesis and characterization of GaIII complexes of novel
dtpa bis-amide ligands. For means of comparison of their
solution chemistry and structural behaviour the respective
InIII and LuIII complexes have been synthesized as well.
Scheme 2. Synthesis of the GaIII (3a–e), InIII (4a–e) and LuIII com-
plexes (5a–e). Reagents and conditions: (i) GaCl3 (aq.), acetate
buffer, water, pH 3.3, 30 min; (ii) (nBu)4N+OH–, GaCl3, chloro-
Results and Discussion
form, room temp., 12 h; (iii) MIIICl3 (M = In, Lu), NaOH, water,
pH 7.5, room temp., 12 h.
Synthesis
The GaIII complexes 3a–e precipitated from the reaction
mixture and the crude products were isolated by filtration.
Despite a pH below 3.5, considerable amounts of hydrolysis
products formed, as proven by elemental analysis.
Recrystallization from boiling methanol afforded analyti-
cally pure compounds 3a–e in yields of 15–45%. The ab-
sence of free ligands 2a–e was additionally confirmed by
reversed-phase HPLC.
The dtpa-N,NЈЈ-bis(alkoxyphenylamides) were readily
synthesized by the addition of 2 equiv. of the respective an-
iline bearing the desired substituent to dtpa bis-anhydride
1 in dmf at room temperature (Scheme 1). After stirring for
24 h at room temperature and evaporation of the solvent,
recrystallization of the residue from ethanol gave com-
pounds 2a–e in yields of 57–82%.
Owing to the persistent presence of hydrolysed GaIII in
the crude product, other synthetic conditions were investi-
gated. Despite their poor solubility in organic solvents, bis-
amides 2a–e could be dissolved in chloroform after treat-
ment with 3 equiv. of a methanolic solution of tetra-n-but-
ylammonium hydroxide. Subsequent addition of GaIII
chloride in n-pentane resulted in the formation of the de-
sired compounds. Although 3e precipitated directly from
the reaction mixture within 12 h, the synthesis of com-
pounds 3a–3d demanded the precipitation by diffusion of
diethyl ether into the solution.
The InIII and LuIII species in aqueous media were syn-
thesized by using sodium hydroxide solution to adjust the
pH to 7.5. Separation of the metal complexes from inor-
ganic impurities represents a problem owing to the poor
solubility of the former in organic media and the rather
good solubility of both in water. For the InIII (4c–e) and
LuIII complexes (5c–e), the best results were obtained by
evaporation of the solvent from the reaction mixture in
vacuo and washing of the residue with minimum amounts
of water. After drying in vacuo, the complexes were ob-
tained analytically pure in yields of 39–74%. In contrast,
Scheme 1. Synthesis of ligands 2a–e; R = m-OCH3 (2a), o-
OCH2CH3 (2b), m-OCH2CH3 (2c), p-OCH2CH3 (2d) and p-
O(CH2)3CH3 (2e).
Complexes of compounds 2a–e were prepared by com- compounds 4a,b and 5a,b, which are readily soluble in
bining equimolar amounts of the respective metal chloride aqueous media, were purified by column chromatography
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on silica using highly polar solvents. However, this pro- sis of 4a revealed the presence of two species; both a hepta-
cedure provided lower yields of 15–26%.
and octa-coordinated isomer were identified, denoted
4ahepta and 4aocta, respectively (Figure 1).
Crystal Structures
All attempts to isolate suitable crystals of compounds
3a–e for single-crystal structure analysis usually yielded
needles lacking adequate thickness. Until now there was no
crystallographic evidence for any GaIII complex of dtpa de-
rivatives. Crystals of 4a suitable for single-crystal structure
analysis were obtained upon slow evaporation of a concen-
trated solution of the complex in a mixture of water/meth-
anol (1:1). Complexes 4c and 5c were crystallized by dis-
solving the compounds in hot water and subsequent slow
evaporation of the solvent. Selected crystallographic data
are listed in Table 1.
Table 1. Crystal data and refinement details for the X-ray structure
determinations of compounds 4a, 4c and 5c.
4a
4c
5c
Figure 1. ORTEP drawing of the two crystallized structural isomers
4ahepta (left) and 4aocta (right). Ellipsoids are drawn at the 35%
probability level. Solvent molecules and hydrogen atoms have been
omitted for the purpose of clarity. In 4ahepta, one of the methoxy
moieties shows a structural disorder in two positions, of which only
one isotropically refined group is depicted.
Formula
C
28H34InN5O10
·
C30H38InN5O10
4.5(H2O)
·
C30H40LuN5O11
8(H2O)
·
0.25(CH3OH)·
5.25(H2O)
768.47
–140(2)
monoclinic
P21/n
13.4668(2)
18.3357(3)
26.4406(5)
90
90.747(1)
90
6528.24(19)
8
1.564
7.96
52352
M [gmol–1
T [°C]
Crystal system
Space group
a [Å]
b [Å]
c [Å]
α [°]
β [°]
]
820.01
–140(2)
triclinic
965.77
–140(2)
triclinic
¯
P1
¯
P1
In the isomers, the respective donor atoms arrange com-
parably, forming a distorted mono- (4ahepta) or bicapped
(4aocta) trigonal-prismatic coordination sphere, which in the
case of 4aocta can also be interpreted as a strongly distorted
square antiprism. As none of the idealized polyhedra
matches satisfactorily and for reasons of comparability, the
distorted bicapped trigonal-prismatic structure is preferen-
tially discussed in this paper. In this structure, one triangu-
lar plane is formed by the three carboxylato moieties of
2a3–, O3, O5 and O7 (4ahepta) or O8 (4aocta), respectively.
The opposite plane is defined by an [N2O] donor set,
formed by the central (N3) and one terminal (N2) nitrogen
atom of the dtpa structure and the oxygen atom (O9) of the
distant amide group.
13.3851(3)
17.0855(5)
17.7590(5)
64.707(1)
78.872(2)
77.591(2)
3562.58(17)
4
1.529
7.38
25868
13332
7.9065(6)
10.0450(8)
25.268(2)
89.419(2)
89.515(3)
81.644(4)
1985.4(3)
2
1.616
25.68
8929
8109
γ [°]
V [Å3]
Z
Ρ [gcm–3
]
μ [cm–1
Measured data
]
Data with IϾ2σ(I) 13347
Unique data/Rint
wR2 (all data,
on F2)[a]
14832/0.0414
0.1163
14308/0.0252
0.1161
8929/0.0553
0.1254
R1 [IϾ2σ(I)][a]
S[b]
0.0501
1.136
0.0517
1.276
0.0505
1.131
The monocapped structure in 4ahepta is completed by the
coordination of the remaining nitrogen atom (N4) of the
dtpa structure and additional coordination of the second
amide oxygen atom (O2) completes the formation of the
bicapped trigonal prism in 4aocta. As expected, the distances
between the central InIII ion and the atoms in the capping
positions are elongated compared with the atoms forming
Max./min. resid.
1.502/–0.690
1.472/–0.584
1.330/–2.388
dens. [eÅ–3
]
Abs. method
Abs. corr. Tmin/Tmax 0.6912/0.7456
multi-scan
multi-scan
0.6767/0.7456
multi-scan
0.5261/0.7456
[a] Definition of R indices: R1 = (Σ||Fo| – |Fc||)/Σ|Fo|; wR2
=
2
2 2
{Σ[w(Fo – Fc ) ]/Σ[w(Fo2)2]}1/2 with w–1 = σ2(Fo2) + (aP)2 + bP; P
= [2Fc + max(Fo2)]/3. [b] s = {Σ[w(Fo – Fc ) ]/(No – Np)}1/2
.
2
2
2 2
[InIII(dtpa)] was the first complex found to contain an the trigonal prism (Table 2).
octa-coordinated InIII ion, which came as a surprise be-
A comparison of the bond lengths of 4ahepta and 4aocta
cause the ion had been considered too small to coordinate reveals that the additional coordination of the second
so many donors.[33] To the best of our knowledge, the only amide oxygen atom in 4aocta results in a weakening and
crystal structure determination of an open-chain dtpa bis- elongation of the oppositely arranged In–O5 bond to
amide to have been reported also revealed an octa-coordi- 2.240(3) Å from 2.170(3) Å in 4ahepta. The differences in
nated InIII complex.[9] In addition, an InIII complex of a bond lengths between InIII and the amide oxygen atoms O2
cyclic derivative crystallizing in a hepta-coordinated struc- and O9 in 4aocta, 2.565(3) Å compared with 2.247(3) Å, can
ture has also been reported.[10] In accordance with these be explained by the capping position of the O2 oxygen
previous studies, an octa-coordination was also expected for atom. In addition to that, the crowding of the central metal
4a. Much to our surprise, the single-crystal structure analy- ion and steric factors like packing effects might influence
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Table 2. Selected bond lengths for the hepta- and octa-coordinated (N1A···O7B). These bonds align the molecules in a two-
isomers of 4a.
dimensional network.
Bond length [Å][a]
The single-crystal structure analysis of 4c verifies the
presence of two symmetry-independent molecules in the
unit cell, both displaying an octa-coordinated complex
(Figure 3, left). The bond lengths between the InIII ion and
the surrounding donor atoms indicate that one In–N and
one In–O bond are remarkably longer than the respective
metal donor bonds (Table 3). As the coordination sphere
can be described as a bicapped trigonal prism, it is evident
that the corresponding atoms, N4 and O1, occupy the cap-
ping positions therein. The structure of the coordination
sphere is comparable to the one discussed for 4aocta, as is
4ahepta
4aocta
In1–N2
In1–N3
In1–N4
In1–O3
In1–O5
In1–O7/O8[b]
In1–O9
In1–O2
2.361(3)
2.398(3)
2.497(3)
2.171(3)
2.170(3)
2.194(3)
2.206(3)
3.083[c]
2.379(3)
2.382(3)
2.516(3)
2.178(3)
2.240(3)
2.194(3)
2.247(3)
2.565(3)
[a] Intramolecular bond lengths. [b] In1–O7 in 4ahepta and In1–O8
in 4aocta. [c] Non-bonding interatomic distance In···O2.
the structure in the solid state, as has been reported pre-
viously for the structure of [InIII(dtpa)].[33] However, the
differences in bond lengths and therefore in the bond
strengths might favour the dissociation of the amide oxygen
atom O2 in 4aocta in solution.
The supramolecular arrangement of the molecules is af-
fected by intermolecular hydrogen bonding between an
amide nitrogen atom and a carboxy oxygen atom of a
neighbouring molecule of the same isomer, resulting in the
formation of chains (Figure 2). The interatomic distances
were determined to be 2.756 Å (O4A···N5A) and 2.782 Å
(O4B···N5B) in the chains of 4ahepta and 4aocta, respectively,
which indicates strong hydrogen bonding in the solid state
with distances closer than the sum of the van der Waals
radii.[39] These chains are further interlinked by weak
hydrogen bonding between the second amide nitrogen atom
N1A of 4ahepta and two carboxy oxygen atoms of a mo-
lecule of 4aocta of a neighbouring chain with interatomic
distances of 3.035 Å (N1A···O8B) and 3.211 Å
Figure 3. ORTEP drawings of 4c (left, only one of the symmetry-
independent molecules is displayed) and the supramolecular ar-
rangement in the crystal (right). Ellipsoids (left) are drawn at the
35% probability level. Non-coordinating solvent molecules and
hydrogen atoms have been omitted for reasons of clarity. Hydrogen
bonding (right) is indicated by dotted lines.
Table 3. Selected bond lengths for 4c and 5c·H2O.
Bond length [Å][a]
4c[b]
5c·H2O
M–N2
M–N3
M–N4
M–O4
M–O6
M–O8
M–O1
M–O2
M–O11W
2.371(4), 2.337(4)
2.383(4), 2.363(4)
2.522(4), 2.517(4)
2.175(3), 2.190(3)
2.224(3), 2.230(3)
2.191(3), 2.159(3)
2.435(3), 2.481(6)
2.266(3), 2.283(3)
–
2.745(5)
2.553(5)
2.602(5)
2.228(4)
2.265(4)
2.299(4)
2.406(4)
2.401(4)
2.313(4)
Figure 2. ORTEP drawings of the supramolecular arrangement in
the crystal containing 4ahepta and 4aocta. Hydrogen bonding is indi-
cated by dotted lines. Owing to structural disorder, only one of
the isotropically refined methoxy moieties of 4ahepta is depicted.
To facilitate distinction, carbon atoms of molecules of 4ahepta are
coloured light grey, whereas the carbon atoms of 4aocta appear in
dark grey. Non-coordinating solvent molecules and hydrogen
atoms have been omitted for reasons of clarity.
[a] M = In (4c), Lu (5c·H2O). [b] Values for two symmetry-indepen-
dent molecules are given.
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the overall alignment of the donors. Although three carbox- capping position is occupied by the oxygen atom of the
ylato groups (O4, O6, O8) of 2c3– define one triangular water molecule, O11W. According to Caravan et al., this is
face, the other plane is formed by the central (N3) and one in accordance with the description of the cis isomer.[40]
terminal amine nitrogen atom (N2) and the distant amide
However, the coordination sphere in 5c might also be
oxygen atom (O2). Intermolecular hydrogen bonding (Fig- described as a distorted monocapped square antiprism in
ure 3, right) is observed between one terminal carboxylato which O2, N4, O8 and O11W define one square plane and
group and an amide nitrogen atom of an adjacent molecule, O1, O4, N3 and O6 form the other. In this way, the latter
resulting in the formation of chains. The interatomic dis- is capped by N2, which is in agreement with the respective
tances were determined to be 2.695 Å for O5A···N5B and bond (Lu–N2) being the longest in the coordination sphere.
2.739 Å for O5B···N5A and thus are a little shorter than This description is associated with the syn isomer, as de-
those observed in 4a. However, in contrast to 4a, no bond- scribed by Aime et al.[15]
ing between adjacent chains is observed.
The supramolecular arrangement is determined by inter-
In the solid state, the LuIII complex 5c·H2O displays a molecular hydrogen-bonding interactions between the water
nona-coordinated central metal ion, binding to all eight do- ligand and the uncoordinated terminal carboxy oxygen
nor sites of the ligand moiety and an additional water mo- atom O5 of an adjacent molecule (Figure 4). The in-
lecule (Figure 4). The bonds between Lu and the carbonyl teratomic distance O11W···O5 measures 2.624 Å. A second,
oxygen atoms of the amide moieties, O1 and O2, are the though weaker hydrogen bond measuring 2.846 Å is de-
longest Lu–O bonds of the coordination sphere (Table 3), tected between the oxygen atom O7 of the central carboxyl-
which suggests that the coordination of the amide pendant ato moiety and the amide nitrogen atom N5 of a neighbour-
arms to the metal centre is weaker than the carboxy oxygen ing molecule. These bonds cause a net-like structure in the
donors. The three Lu–N bonds are longer than all the Lu– crystal.
O bonds in the coordination sphere. It has been assumed
Furthermore, it should be mentioned that the phenyl
that the Lu–N bonds have lower bond strengths due to their rings of each molecule are almost coplanar, with the dihe-
lower polarity in comparison with the more ionic Lu–O dral angle of the averaged ring planes determined to be
bonds.[15] However, due to the impossibility of all three ni- 175.1°. However, this might solely be explained by packing
trogen atoms occupying capping positions in the trigonal effects, as neither sandwich nor parallel-displaced π–π
prism,[9,40] the nitrogen atom N3 occupies a corner and the stacking interactions could be detected.
O11W of the water molecule is capping instead.
It has been agreed that the geometries of LuIII complexes
The coordination sphere around the central LuIII ion can of this nature range between the square-antiprismatic and
be described as a distorted tricapped trigonal prism, with the trigonal-prismatic description, although the latter is
O1, O2, O4 and O6, O8, N3 occupying the corners of a generally favoured.[9,15] A comparison of the dihedral
triangular plane, respectively. The bond length Lu–N2 and angles in both geometric arrangements assumed for 5c·H2O
Lu–N4 are the longest in the coordination sphere and there- with the respective values for idealized polyhedra shows
fore N2 and N4 occupy a capping position each. The third that a distorted tricapped trigonal prism is the best-match-
Figure 4. ORTEP drawing of 5c·H2O (left) and the supramolecular arrangement in the crystal (right). Ellipsoids (left) are drawn at the
35% probability level. Non-coordinating solvent molecules and hydrogen atoms have been omitted for reasons of clarity. Hydrogen
bonding (right) is indicated by dotted lines.
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ing description (Table 4). For comparison, the dihedral the complexes and are detected as two separated singlets in
1
angles determined for 4aocta and 4c are also given. In par- the H NMR spectra recorded in [D6]dmso. Although the
ticular, the angles between the neighbouring planes forming signals show very similar shifts in the spectra of 3a–e, 5c
the edges that connect the base and top face of the trigonal and 5d, indicative of a comparable chemical environment,
prism indicate that neither of the idealized polyhedra de- a remarkable difference is observed in the spectra of 4c and
scribes its structure adequately. For the sake of complete- 4d. This is suggestive of a hepta-coordinated InIII ion con-
ness, when assuming a square antiprismatic structure in taining both a coordinating and a non-coordinating amide
4aocta and 4c, one square plane is formed by the central and moiety, as observed in the solid state for 4a.
one terminal [NO] donor set, each formed by the amine
As expected, in nearly all the spectra of the complexes
nitrogen atom and carboxy oxygen atom. The opposite recorded in [D6]dmso, the amide protons are shifted to
square plane is spanned by the remaining terminal [NO] higher frequencies compared with the respective ligands by
donor set and both amide oxygen atoms.
about 0.3 ppm in 3a and 3c–e and 0.8 ppm in the LuIII spe-
cies 5c and 5d. This observation can be explained by non-
coordinating amide nitrogen donor atoms in the former and
the coordination of the amide moieties in the latter. This is
in good accordance with the expectation of hexa-coordi-
nated GaIII complexes and an increased coordination
number in the LuIII species. There is a third singlet merging
with the signals of the amide protons in 5c, which can be
assigned to the protons of a coordinated water ligand.
A summary of the NMR spectroscopic data assigned to
the moieties of the pendant arms (Figure 5) of 2c and its
three metal complexes is presented in Table 5. The following
discussion focuses on 3c–5c as representatives of the com-
plexes 3–5.
Table 4. Dihedral angles between trigonal faces in idealized polyhe-
dra and for the assumed trigonal prismatic structures of 4aocta, 4c
and 5c·H2O.
Dihedral angle [°]
Opposite planes[a]
Neighbouring planes[b]
Trigonal prism[c]
Square antiprism[c]
4aocta
4c
5c·H2O
180
163.5
26.4
0
168.7[d]
168.4, 167.8[f]
175.0[h]
14.5[e]
14.9,12.2[g]
27.3, 22.3, 16.8[i]
[a] Base and top face of the trigonal prismatic structure. [b] Planes
spanned by capping atom and two neighbouring atoms of an edge
of the trigonal prism connecting its base and top face. [c] Values
for respective idealized polyhedra, see ref.[40] [d] Є[(N2–N3–O9)
||(O8–O3–O5)]. [e] Є[(O2–O9–O8)||(O9–O8–N4)]. [f] Є[(O4–O6–
O8)||(N2–N3–O2)], values for two symmetry-independent mo-
lecules. [g] Є[(O2–O8–O1)||(O2–O8–N4)], values for two symmetry-
independent molecules. [h] Є[(O1–O2–O4)||(O6–O8–N3)]. [i] Dihe-
dral angles for Є[(N2–O1–O6)||(O11W–O1–O6)], Є[(O11W–O2–
O8)||(N4–O2–O8)] and Є[(N4–O4–N3)||(N2–O4–N3)], respectively.
NMR Spectroscopy
Figure 5. Atomic labelling of the aromatic moieties of 2c–5c.
In ligands 2a–e, the amide pendant arms are chemically
equal due to the symmetry of the molecules, exhibiting only
one set of signals for each moiety in all spectra. In the H
It is apparent that, in addition to the amide signals, the
aromatic structure and the ethoxy moiety of both pendant
arms exhibit a double set of signals in both the 1H and
13C{H} NMR spectra upon complexation. Structural moie-
ties positioned farther from the coordination centre may
still appear as only one signal set though (e.g., the CH3
moiety of the ethoxy chain in 3c and 5c). A comparison of
related signal sets shows that the differences in chemical
shifts between respective moieties are usually more pro-
1
NMR spectra, the amide and carboxylic protons appear as
singlets, and in the aliphatic region, the anticipated patterns
assigned to the dtpa backbone structure and the respective
alkoxy moieties could be detected in both the 1H and
13C{1H} NMR spectra.
Room-Temperature NMR Spectroscopy
As expected, the aliphatic protons of the dtpa backbone nounced in 4c. This observation is in accordance with a
1
of all the H NMR spectra of complexes 3–5 show a com- hepta-coordinated complex, in which the amide pendant
plex signal pattern with overlap of multiple couplings, that arms of 4c possess a clearly different chemical environment
3
is, 2JH,H and JH,H, induced by the chirality of the terminal compared with those in 3c and 5c, in which the double set
nitrogen atoms and the non-equivalence of the methylene of signals is likely caused by a different chemical environ-
and ethylene protons upon ligand complexation,. The inves- ment of the pendant arms due to the chirality of the com-
tigation of this spectral region did not allow reliable conclu- plex.
sions to be drawn on the conformation of the complexes in
The GaIII, InIII and LuIII complexes of the dtpa bis-
can exist in different diastereomeric
forms.[9,15,28,40,41] However, in every diastereomer the amide
1
solution. Thus, the following discussion focuses on the H amides
and 13C{1H} NMR signals of the amide pendant arms.
The amide protons serve as an expedient indicator for pendant arms may appear as a double set of signals due to
the prediction of the coordination environment of the cen- their different chemical environment. If several dia-
tral metal ions. The amide protons are inequivalent in all stereomers exist in solution and interconversion is slow
Eur. J. Inorg. Chem. 2015, 4125–4137
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Table 5. Selected NMR spectroscopic data of 2c–5c in [D6]dmso (600 MHz).
δ [ppm]
2c
3c
4c
5c
1H
–
13C{1H}
139.9
1H
–
13C{1H}
139.6
1H
–
13C{1H}
1H
–
13C{1H}
CH(1)
CH(2)
CH(3)
CH(4)
CH(5)
CH(6)
139.7
138.0
106.6
105.6
158.9
158.7
111.8
109.7
129.8
129.5
112.3
111.6
63.3
129.6
129.5
107.2
106.7
158.8
7.34
–
105.5
158.8
109.3
129.4
111.5
62.9
14.7
–
7.31 (s)
7.26 (s)
–
105.6
105.7
158.7
7.53 (s)
7.31 (s)
–
7.32 (s)
7.26 (s)
–
6.69 (d)
7.14 (dd)
7.18 (d)
6.64 (d)
109.8
109.5
129.5
6.77 (dd)
6.63 (dd)
6.76 (d)
6.73 (d)
7.27–7.23
7.25–7.22
110.3
110.1
138.7
138.4
112.7
112.4
63.1
7.21–7.18 (dd)
7.30–7.28 (dd)
7.21–7.18
7.13–7.12 (m)
7.09–7.08 (m)
4.10–4.05 (m)
4.00–3.97 (m)
1.34 (t)
7.12–7.11 (m)
7.09–7.07 (m)
3.98 (q)
111.5
111.4
62.9
7.38–7.37 (m)
7.32–7.30 (m)
4.04–4.00 (m)
4.02–3.98 (m)
1.30 (t)
OCH2CH3 3.96 (q)
OCH2CH3 1.30 (t)
62.9
14.6
14.5
–
63.0
14.6
1.32 (t)
14.6
–
1.32 (t)
11.44 (s)
10.31 (s)
1.29 (t)
10.81 (s)
10.78 (s)
NH–C=O
C=O
10.03
10.38 (s)
10.26 (s)
–
–
173.1
169.7
169.4
170.6
170.5
170.2
166.3
165.9
–
171.4
171.2
170.6
170.5
166.9
–
175.7
175.2
174.9
174.2
173.3
compared with the NMR timescale, more than one set of gion maintains some of its characteristic signal groups and
double signals should be observable for the pendant arms. coupling pattern, proving the integrity of the complex. Ap-
As this was not observed in the spectra of 3c–5c, only parently, at elevated temperatures the pendant arms of 3c
one detectable isomer for each complex may be present in become chemically equivalent. In the presumed octahedral
solution. Furthermore, the 13C{1H} NMR spectral assign- structure this might be due to a strong fluctuation of the
ment of the aliphatic carbon signals was performed for 3c– complex as well as interconversion between different con-
5c by using two-dimensional NMR spectroscopy. In no case formations, which might occur quickly compared with the
were more than nine carbon signals of the dtpa backbone NMR timescale. In contrast, a double set of aromatic pro-
detected. Additionally, only five signals for the carboxy and ton signals is observed in 4c at elevated temperatures. This
carbonyl carbon atoms were detected in total for 3c, con- double set of signals indicates that the complex maintains
trary to a previously reported similar complex.[28]
its hepta-coordinated structure even at 85 °C. Surprisingly,
1
However, it remains unknown whether the detection of in the H NMR spectra of 5c, the signals of the aromatic
a single isomer is caused by fast interconversion between protons 2-H, 5-H and 6-H show exceptionally strong over-
several conformers at room temperature or is due to the lap, which prevents definitive assignment. However, the
preference of a certain diastereomer in solution. Because proton 4-H is clearly detectable as a single doublet at these
coalescence might be reached at higher temperatures and elevated temperatures. Although the amide protons merge
1
abolished at lower temperatures, additional H NMR spec- into one singlet, the signal assigned to the water ligand is
troscopic studies of 3c–5c were performed at 85 and –50 °C. no longer detectable. The remarkable overlapping indicates
strong fluxional behaviour.
High-Temperature NMR Spectroscopy
Low-Temperature NMR Spectroscopy
There are three types of isomerism in dtpa amide com-
plexes, induced by “wagging” of the diethylenetriamine
Fast interconversion between several conformers might
backbone, “shuffling” of the two [NO2] donor sets or inver- result in the observed detection of a single double set of
sion at the two terminal nitrogen atoms.[8] Even at elevated signals suggesting the presence of only one diastereomer.
temperatures, no coalescence of the signals of InIII or LuIII However, more signals might evolve at low temperatures.
complexes was reported and therefore it was concluded that Therefore the NMR spectra of 3c–5c were recorded at
even at high temperatures, inversion of the terminal nitro- –50 °C in [D7]dmf as solvent.
gen donors occurs slowly compared with the NMR times-
For comparison, NMR spectra were also recorded at
cale.[9,15] It should be noted that these NMR measurements room temperature in the same solvent, and were compar-
were performed in D2O whereas we had to use [D6]dmso. able to the spectra recorded in [D6]dmso. Double sets of
Therefore the results should be compared with caution.
signals can be seen for the pendant arms of 3c and 4c,
At 85 °C, only one set of proton signals was detected for whereas in 5c remarkable overlap and broadening of the
the amide pendant arms of 3c. However, the aliphatic re- signals are observed. The differences in the chemical shifts
Eur. J. Inorg. Chem. 2015, 4125–4137
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FULL PAPER
between respective signal groups of the pendant arms are dant arms in aqueous solution. Furthermore, the dissoci-
again most pronounced in 4c.
ation might be followed by association of water ligands,
No additional signal sets appeared in any of the spectra making the InIII complexes even slightly more hydrophilic
of 3c–5c at –50 °C. The protons of the pendant arms main- than the respective GaIII species.
tain their pattern of double signal sets, and there are still
only nine signals detected for the dtpa backbone structure
in the 13C{1H} NMR spectra. One could assume that even
Conclusions
at these low temperatures interconversion might still occur
We have successfully synthesized and characterized five
easily enough to result in only one isomer being detectable.
dtpa bis(alkoxyphenyl)amides and their GaIII, InIII and
But these results rather corroborate our assumption, that
LuIII complexes. Elemental analysis, mass spectrometry and
only one diastereomer is present in solution, in contrast to
NMR spectroscopy confirmed that one ligand chelates one
previous research of similar metalIII complexes in which
metal ion. The NMR spectra indicated the existence of
usually several diastereomers were detected by NMR spec-
hexa-coordinated GaIII species. We found that the InIII
troscopy.[9,15,28]
complex 4a crystallizes in both a hepta- and octa-coordi-
Additionally, quantum chemical calculations performed
on 3c did not yield precise information on the existence
nated form, whereas the NMR spectra revealed the exclus-
ive existence of the hepta-coordinated species. The LuIII ion
of a preferred structure of the complex because the energy
coordinates a water molecule in addition to the eight donor
differences between the isomers were all within the error
atoms of the ligands to form a nona-coordinated complex.
range. Detailed data are given in the Supporting Infor-
Although the results of quantum-chemical calculations
mation.
on 3c indicated that several isomers may exist in solution,
the results of our NMR and HPLC analyses strongly indi-
cate the sole existence of a single diastereomer in solution
HPLC Analysis
for all complexes.
Although theoretically complexes of the type 3–5 may
exist as diastereomers, their respective HPLC chromato-
Experimental Section
grams show only a single peak. This is in accordance with
previous observations and was associated with fast in-
terconversion between different diastereomers.[9,41] Al-
though this would require the inversion of a terminal nitro-
gen atom, which was acknowledged to occur slowly even at
high temperatures on the basis of NMR studies, the low
concentrations of the complexes during HPLC analysis
were considered to facilitate the process due to dissociation
of the [NO2] donor set.[9] As supported by our previous
NMR studies, we assume the exclusive existence of one dia-
stereomer for the described metal complexes.
General: All reagents were purchased from commercial sources and
used without further purification. dmf was distilled from sodium
prior to use and stored under nitrogen over molecular sieves (4 Å).
Diethyl ether was stored over KOH plates. dtpa bis-anhydride 1
and the dtpa bis-amides 2 were synthesized under nitrogen using
standard vacuum-line and Schlenk techniques.
GaIII chloride (1.42 g) was dissolved in 0.3 m acetate buffer
(100 mL) to prepare a stock solution with a pH of 1.9. For the
syntheses in chloroform, a 0.5 m solution of GaIII chloride in n-
pentane was used.
The InIII compounds 4a–d show lower retention than the
For the HPLC analyses a system equipped with a binary pump
corresponding GaIII compounds 3a–d, whereas 4e shows (HP 1100, G1312A), UV/Vis detector (HP 1100, G1315A) and col-
umn (ACE C18-PFP; 150ϫ3 mm) was used. Reported values indi-
cate the purity of the compounds as detected by means of their UV
absorbance at 220 nm. The following gradient was used: 0–3 min
80% A, 3–6 min 80% AǞ0% A, 6–10 min 0% A [A: water/tri-
fluoroacetic acid (99.9%/0.1%); B: acetonitrile/trifluoroacetic acid
(99.9%/0.1%)].
higher retention than 3e. However, the differences are only
0.1–0.3 min, and the compounds therefore exhibit a com-
parable degree of lipophilicity. For comparison, LuIII com-
plexes 5a–e show an additional prolonged retention of ap-
proximately 0.5 min and thus are more lipophilic. Owing to
the fact that all the complexes are uncharged, the relative
lipophilicity is mostly affected by the nature of the coordi-
nation sphere of the central metal ion.
It has been noted before that uncoordinated amide moie-
ties possess the ability to form hydrogen bonds with water
molecules from the solvent, resulting in increased hydrophi-
licity.[9,41] This is in agreement with the fact that the LuIII
complexes most likely feature strong bonding of the amide
moieties and are therefore the most lipophilic species. Ap-
parently, the GaIII and InIII complexes have more similar
coordination spheres than the respective LuIII complexes.
As the GaIII complexes most likely show a hexa-coordi-
nated central metal ion, we suppose that the InIII complexes
Unless stated otherwise, 1H and 13C{1H} NMR spectra were re-
corded at room temperature with either a Bruker AVANCE 400 or
600 spectrometer. The NMR spectra of the ligands were recorded
in deuterated dmso, which had been dried prior to use over 4 Å
molecular sieves and stored under nitrogen. The NMR spectra of
the complexes were recorded in [D6]dmso or [D4]MeOH. Addition-
ally, the NMR spectra of complexes 3c–5c were recorded at 85 °C
in [D6]dmso and at room temperature as well as –50 °C in deuter-
iated anhydrous [D7]dmf (Ն99.5%). In these spectra some of the
proton signals of the complexes merge with the signal of residual
water in the solvent. The residual peaks of the solvents were used
as internal reference.
Mass spectra were recorded with either a Finnigan SSQ 710 (DEI,
also show at least partial dissociation of the two amide pen- FAB) or a MAT 95 XL (ESI) spectrometer. Elemental analyses
Eur. J. Inorg. Chem. 2015, 4125–4137
4132
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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FULL PAPER
3
were performed as single determinations using a Vario EL III
7.01–6.97 (m, 4 H, HAr), 6.89–6.86 (m, 2 H, HAr), 4.01 (q, JH,H
=
CHNS instrument (Elementaranalysensystem GmbH, Hanau, Ger-
many).
7.0 Hz, 4 H, OCH2CH3), 3.40 (s, 4 H, CH2C=O), 3.29 (s, 4 H,
CH2C=O), 3.28 (s, 2 H, CH2COOcentral), 2.79–2.76 (m, 4 H,
3
NCH2CH2N), 2.71–2.69 (m, 4 H, NCH2CH2N), 1.33 (t, JH,H
=
Structure Determinations: The intensity data of the compounds
were collected with a Nonius–KappaCCD diffractometer using
graphite-monochromated Mo-Kα radiation. Data were corrected
for Lorentzian and polarization effects and absorption was taken
into account on a semi-empirical basis using multiple scans.[42–44]
7.0 Hz, 6 H, OCH2CH3) ppm. 13C{1H} NMR (100.6 MHz, [D6]-
dmso): δ = 172.2 (C=O), 172.0 (C=O), 169.0 (C=O), 147.5 (O-CAr),
127.4 (N-CAr), 123.6 (CAr), 120.4 (CAr), 118.9 (CAr), 111.8 (CAr),
63.9 (OCH2CH3), 59.4 (CH2C=O, NCH2CH2N), 55.5 (CH2C=O,
NCH2CH2N), 54.6 (CH2C=O, NCH2CH2N), 52.8 (CH2C=O,
The structures were solved by direct methods (SHELXS[45]) and
NCH2CH2N),
52.7
(CH2C=O,
NCH2CH2N),
14.7
2
(OCH2CH3) ppm. MS (DEI): calcd. for [M]+ 631 ; found 632 [M
+ H]+, 614 [M – H2O]+. C30H41N5O10·H2O (649.30): calcd. C
55.46, H 6.67, N 10.78; found C 55.23, H 6.64, N 10.69.
refined by full-matrix least-squares techniques against Fo
(SHELXL-97[45]). The hydrogen atoms of the amine groups N1A
and N1B of compound 4c were located by difference Fourier syn-
thesis and refined isotropically. All other hydrogen atoms were in-
cluded at calculated positions with fixed thermal parameters. All
non-disordered non-hydrogen atoms were refined anisotropi-
cally.[45] The crystallographic data as well as structure solution and
refinement details are summarized in Table 1.
dtpa-N,NЈЈ-Bis(m-ethoxyphenylamide) (2c): Prepared from m-
ethoxyaniline (1.49 mL, 1.54 g, 11.2 mmol), yield 2.79 g (4.4 mmol,
79%). 1H NMR (400.1 MHz, [D6]dmso): δ = 11.93 (br. s, 1.7 H,
COOH), 10.02 (s, 2 H, NH-CO), 7.73 (s, 2 H, HAr), 7.18–7.11 (m,
3
4 H, HAr), 7.59–7.57 (m, 2 H, HAr), 3.95 (q, JH,H = 7.0 Hz, 4 H,
CCDC-1048431 (for 4a), -1048432 (for 4c) and -1048433 (for 5c)
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_requ-
est/cif.
OCH2CH3), 3.52 (s, 2 H, CH2COOcentral), 3.43 (s, 4 H, CH2C=O),
3.42 (s, 4 H, CH2C=O), 3.03–3.01 (m, 4 H, NCH2CH2N), 2.94–
3
2.92 (m, 4 H, NCH2CH2N), 1.29 (t, JH,H = 7.0 Hz, 6 H,
OCH2CH3) ppm. 13C{1H} NMR (100.6 MHz, [D6]dmso): δ =
173.5 (C=O), 170.1 (C=O), 169.8 (C=O), 159.2 (O-CAr), 140.3 (N-
CAr), 129.8 (CAr), 111.9 (CAr), 109.8 (CAr), 106.0 (CAr), 63.3
(OCH2CH3), 58.8 (CH2C=O, NCH2CH2N), 55.8 (CH2C=O,
NCH2CH2N), 55.5 (CH2C=O, NCH2CH2N), 52.7 (CH2C=O,
Synthesis of dtpa Bis-anhydride 1: This compound was synthesized
according to a literature procedure.[46] Under nitrogen, dtpa (49 g,
125 mmol) was suspended in dry pyridine (62 mL, 770 mmol) and
acetic anhydride (53 mL, 560 mmol) and stirred at 65 °C for 24 h.
The precipitate was filtered and washed three times with diethyl
ether to afford a colourless solid, yield 42 g (117.5 mmol, 94%). 1H
NCH2CH2N),
51.5
(CH2C=O,
NCH2CH2N),
15.1
(OCH2CH3) ppm. MS (DEI): calcd. for [M]+ 631; found 632 [M +
H]+. C30H41N5O10·H2O (649.30): calcd. C 55.46, H 6.67, N 10.78;
NMR (400.1 MHz, [D6]dmso): δ = 3.71 [s, 8 H, N(CH2CO)2O], found C 55.25, H 6.62, N 10.71.
3
3.31 (s, 2 H, NCH2COOH), 2.75 (t, JH,H = 6.0 Hz, 4 H,
dtpa-N,NЈЈ-Bis(p-ethoxyphenylamide) (2d): Prepared from p-ethox-
3
NCH2CH2N), 2.60 (t, JH,H = 6.0 Hz, 4 H, NCH2CH2N) ppm.
yaniline (1.45 mL, 1.54 g, 11.2 mmol), yield 2.89 g (4.6 mmol,
82%). 1H NMR (400.1 MHz, [D6]dmso): δ = 11.86 (br. s, 0.7 H,
COOH), 9.91 (s, 2 H, NH-CO), 7.53 (d, 3JH,H = 9.0 Hz, 4 H, HAr),
13C{1H} NMR (150.9 MHz, [D6]dmso): δ = 171.9 (COOH), 165.8
[N(CH2CO)2O], 54.6 (CH2COOH), 52.6 ppm.
3
3
General Procedure for the Preparation of dtpa-N,NЈЈ-Bis(alkoxy-
phenylamides) 2a–e:[47,48] Under nitrogen, dtpa bis-anhydride 1 (2 g,
5.6 mmol) was dissolved in dry dmf (50 mL), the respective aniline
(11.2 mmol) was added and the solution was stirred for 24 h at
room temperature. The solvent was removed in vacuo and the resi-
due was recrystallized from hot ethanol to yield dtpa bis-amides
2a–e as colourless solids.
6.80 (d, JH,H = 9.0 Hz, 4 H, HAr), 3.93 (t, JH,H = 6.9 Hz, 4 H,
OCH2CH3), 3.50 (s, 2 H, CH2COOcentral), 3.43 (s, 4 H, CH2C=O),
3.40 (s, 4 H, CH2C=O), 3.03–3.01 (m, 4 H, NCH2CH2N), 2.93–
3
2.90 (m, 4 H, NCH2CH2N), 1.28 (t, JH,H = 6.9 Hz, 6 H,
OCH2CH3) ppm. 13C{1H} NMR (100.6 MHz, [D6]dmso): δ =
173.0 (C=O), 169.5 (C=O), 168.7 (C=O), 154.5 (O-CAr), 131.8 (N-
CAr), 120.8 (CAr), 114.2 (CAr), 63.0 (OCH2CH3), 58.2 (CH2C=O,
NCH2CH2N), 55.3 (CH2C=O, NCH2CH2N), 52.3 (CH2C=O,
dtpa-N,NЈЈ-Bis(m-methoxyphenylamide) (2a): Prepared from m-
NCH2CH2N),
51.0
(CH2C=O,
NCH2CH2N),
14.7
methoxyaniline (1.25 mL, 1.38 g, 11.2 mmol), yield 2.67 g
(OCH2CH3) ppm. MS (ESI, + mode): calcd. for [M]+ 631; found
654 [M + Na]+, 632 [M + H]+. C30H41N5O10·H2O (649.30): calcd.
C 55.46, H 6.67, N 10.78; found C 55.86, H 6.54, N 10.87.
1
(4.4 mmol, 79%). H NMR (600.1 MHz, [D6]dmso): δ = 11.92 (br.
4
s, 1.5 H, COOH), 10.03 (s, 2 H, NH-CO), 7.35 (t, JH,H = 1.9 Hz,
2 H, HAr), 7.19–7.14 (m, 4 H, HAr), 6.61–6.59 (m, 2 H, HAr), 3.70
(s, 6 H, OCH3), 3.53 (s, 2 H, CH2COOcentral), 3.44 (s, 4 H,
CH2C=O), 3.42 (s, 4 H, CH2C=O), 3.02 (m, 4 H, NCH2CH2N),
2.93 (m, 4 H, NCH2CH2N) ppm. 13C{1H} NMR (100.6 MHz,
[D6]dmso): δ = 173.1 (C=O), 169.7 (C=O), 169.4 (C=O), 159.5 (O-
CAr), 139.9 (N-CAr), 129.4 (CAr), 111.6 (CAr), 108.8 (CAr), 105.1
(CAr), 58.3 (CH2C=O, NCH2CH2N), 55.4 (CH2C=O,
NCH2CH2N), 55.3 (CH2C=O, NCH2CH2N), 55.0 (OCH3), 52.3
(CH2C=O, NCH2CH2N), 51.1 (CH2C=O, NCH2CH2N) ppm. MS
(DEI): calcd. for [M]+ 603; found 604 [M + H]+, 587 [M – OH]+,
164 [H3C–O–C6H4 – NHCO – CH2]+·. C28H37N5O10·0.5H2O
(612.26): calcd. C 54.89, H 6.25, N 11.43; found C 54.55, H 6.35,
N 11.11.
dtpa-N,NЈЈ-Bis(p-butoxyphenylamide) (2e): Prepared from p-butox-
yaniline (1.85 g, 11.2 mmol), yield 2.20 g (3.2 mmol, 57%). 1H
NMR (400.1 MHz, [D6]dmso): δ = 11.50 (br. s, 0.3 H, COOH),
3
9.91 (s, 2 H, NH-CO), 7.52 (d, JH,H = 9.0 Hz, 4 H, HAr), 6.80 (d,
3
3JH,H = 9.0 Hz, 4 H, HAr), 3.87 (t, JH,H = 6.5 Hz, 4 H,
OCH2CH2CH2CH3), 3.53 (s, 2 H, CH2COOcentral), 3.43 (s, 4 H,
CH2C=O), 3.41 (s, 4 H, CH2C=O), 3.04 (m, 4 H, NCH2CH2N),
2.92 (m, 4 H, NCH2CH2N), 1.65 (m, 4 H, OCH2CH2CH2CH3),
3
3
1.40 (m, JH,H = 7.5 Hz, 4 H, OCH2CH2CH2CH3), 0.91 (t, JH,H
=
7.5 Hz,
6
H, OCH2CH2CH2CH3) ppm. 13C{1H} NMR
(100.6 MHz, [D6]dmso): δ = 173.0 (C=O), 169.5 (C=O), 168.8
(C=O), 154.7 (O-CAr), 131.8 (N-CAr), 120.8 (CAr), 114.3 (CAr), 67.2
(OCH2CH2CH2CH3), 58.2 (CH2C=O, NCH2CH2N), 55.3
(CH2C=O, NCH2CH2N), 55.0 (CH2C=O, NCH2CH2N), 52.3
dtpa-N,NЈЈ-Bis(o-ethoxyphenylamide) (2b): Prepared from o-ethox-
yaniline (1.47 mL, 1.54 g, 11.1 mmol), yield 2.82 g (4.5 mmol,
80%). 1H NMR (600.1 MHz, [D6]dmso): δ = 12.31 (br. s, 2.8 H, (CH2C=O, NCH2CH2N), 51.0 (CH2C=O, NCH2CH2N), 30.8
COOH), 9.75 (s, 2 H, NH-CO), 8.20 (d, 3JH,H = 8.0 Hz, 2 H, HAr), (OCH2CH2CH2CH3),
18.8
(OCH2CH2CH2CH3),
13.7
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FULL PAPER
(OCH2CH2CH2CH3) ppm. MS (ESI, + mode): calcd. for [M]+ 687;
found 710 [M + Na]+, 688 [M + H]+. C34H49N5O10·1.5H2O
(714.37): calcd. C 57.13, H 7.33, N 9.80; found C 57.28, H 7.30, N
9.77.
General Procedure for the Preparation of GaIII Complexes 3a–e: Two
procedures, one in aqueous and one in organic media, have been
developed. Either method is suitable for all the described GaIII
complexes.
[D6]dmso): δ = 170.7 (C=O), 170.6 (C=O), 170.1 (C=O), 166.4
(C=O), 166.0 (C=O), 150.2 (O-CAr), 149.5 (O-CAr), 126.5 (N-CAr
,
CAr), 126.4 (N-CAr, CAr), 125.6 (N-CAr, CAr), 125.1 (N-CAr, CAr),
124.0 (N-CAr, CAr), 123.1 (CAr), 120.0 (CAr), 112.4 (CAr), 63.8
(OCH2CH3), 61.4 (CH2C=O, NCH2CH2N), 60.0 (CH2C=O,
NCH2CH2N), 57.2 (CH2C=O, NCH2CH2N), 56.7 (CH2C=O,
NCH2CH2N), 54.5 (CH2C=O, NCH2CH2N), 54.3 (CH2C=O,
NCH2CH2N), 53.9 (CH2C=O, NCH2CH2N), 51.5 (CH2C=O,
NCH2CH2N), 14.6 (OCH2CH3) ppm. MS (ESI, + mode): calcd.
for [M(71Ga)]+, 699, [M(69Ga)]+ 697; found m/z (%) = 723 (25)
[M(71Ga) + 1 + Na]+, 722 (76) [M(71Ga) + Na]+, 721 (36) [M(69Ga)
+ 1 + Na]+, 720 (100) [M(69Ga) + Na]+. C30H38GaN5O10·2 H2O
(734.40): calcd. C 49.06, H 5.76, N 9.54; found C 49.37, H 5.74, N
9.54.
Procedure A: Acetate buffer (100 mL, 0.3 m, pH 4.5) was added to
GaIII chloride (1.42 g, 8.2 mmol)to give a stock solution of GaIII
(82 mm, pH 1.9). An aliquot of the stock solution was transferred
into a flask, followed by the addition of 1 equiv. of ligand, which
had been dissolved in hot deionized water. The more lipophilic 2e
did not dissolve completely, resulting in a suspension that could be
used for the reaction without remarkably affecting the reaction
yield. A stirrer and pH electrode was added to the clear solution
or suspension. At room temperature, a solution of 0.3 m acetate
buffer (pH 4.5) was added dropwise to raise the pH to 3.2–3.3 upon
which a colourless precipitate formed immediately. The solution
was stirred at room temperature for 30 min with the pH increasing
to 3.5 at most. The precipitate was filtered off and washed thor-
oughly with deionized water to remove buffer and inorganic salts.
The solid was dried in vacuo. Subsequent recrystallization from hot
methanol yielded the complexes as colourless solids.
[GaIII{dtpa-N,NЈЈ-bis(m-ethoxyphenylamide)}] (3c): Prepared fol-
lowing procedure A from GaIII chloride (2.6 mL, 0.21 mmol) and
2c (130 mg, 0.21 mmol), yield 22 mg (0.03 mmol, 15%). HPLC:
4.8 min, 94.5%. 1H NMR (600.1 MHz, [D6]dmso, 22 °C): δ = 10.38
(s, 1 H, NH-CO), 10.26 (s, 1 H, NH-CO), 7.31–7.26 (m, 2 H, HAr),
7.21–7.18 (m, 2 H, HAr), 7.12–7.07 (m, 2 H, HAr), 6.64–6.63 (m, 2
H, HAr), 4.00–3.96 (m, 4 H, OCH2CH3), 4.10–2.82 (m, 18 H,
3
CH2CO, NCH2CH2N), 1.32
9
(t, JH,H
=
7.0 Hz,
6
H,
OCH2CH3) ppm. 1H NMR (600.1 MHz, [D6]dmso, 85 °C): δ =
10.12 (s, 2 H, NH-CO), 7.27 (s, 2 H, HAr), 719 (t, JH,H = 8.1 Hz,
2 H, HAr), 7.11–7.10 (m, 2 H, HAr), 6.66 (dd, JH,H = 8.1, JH,H
2.1 Hz, 2 H, HAr), 4.03 (q, JH,H = 7.0 Hz, 4 H, OCH2CH3), 3.97–
3
3
4
=
Procedure B: In a flask 1 equiv. of ligand was added to 3 equiv. of a
solution of tetra-n-butylammonium hydroxide in methanol (1.0 m).
Chloroform (20 mL) was added to the mixture to give a clear solu-
tion. A stirrer and 1 equiv. of a solution of GaIII chloride in n-
pentane (0.5 m) was added to the mixture at room temperature. The
mixture was stirred at room temperature overnight. Complex 3e
precipitated from the solution as a colourless solid and could be
isolated by filtration, followed by washing with chloroform and
drying in vacuo. Slow diffusion of diethyl ether into the reaction
mixture afforded precipitation of compounds 3a–d.
3
3
3.23 (m, 18 H, CH2CO, NCH2CH2N), 1.33 (t, JH,H = 7.0 Hz, 6
H, OCH2CH3) ppm. 13C{1H} NMR (150.9 MHz, [D6]dmso, room
temp.): δ = 170.6 (C=O), 170.5 (C=O), 170.2 (C=O), 166.3 (C=O),
165.9 (C=O), 158.7 (O-CAr), 139.6 (N-CAr), 129.5 (CAr), 111.5
(CAr), 111.3 (CAr), 109.8 (CAr), 109.8 (CAr), 105.5 (CAr), 62.9
(OCH2CH3), 61.3 (CH2C=O, NCH2CH2N), 60.2 (CH2C=O,
NCH2CH2N), 60.1 (CH2C=O, NCH2CH2N), 57.1 (CH2C=O,
NCH2CH2N), 56.5 (CH2C=O, NCH2CH2N), 54.7 (CH2C=O,
NCH2CH2N), 54.3 (CH2C=O, NCH2CH2N), 54.0 (CH2C=O,
[GaIII{dtpa-N,NЈЈ-bis(m-methoxyphenylamide)}] (3a): Prepared fol-
lowing procedure A from GaIII chloride (3.7 mL, 0.30 mmol) and
2a (183 mg, 0.30 mmol), yield 90 mg (0.13 mmol, 45%). HPLC:
NCH2CH2N),
51.7
(CH2C=O,
NCH2CH2N),
14.6
(OCH2CH3) ppm. MS (ESI, + mode): calcd. for [M(71Ga)]+ 699,
[M(69Ga)]+ 697; found m/z (%) = 723 (25) [M(71Ga) + 1 + Na]+,
722 (76) [M(71Ga) + Na]+, 721 (36) [M(69Ga) + 1 + Na]+, 720 (100)
[M(69Ga) + Na]+. C30H38GaN5O10·2 H2O (734.40): calcd. C 49.06,
H 5.76, N 9.54; found C 48.98, H 5.51, N 9.63.
1
4.3 min, 96.8%. H NMR (600.1 MHz, [D6]dmso): δ = 10.40 (s, 1
H, NH-CO), 10.28 (s, 1 H, NH-CO), 7.32–7.27 (m, 2 H, HAr),
7.23–7.20 (m, 2 H, HAr), 7.14–7.09 (m, 2 H, HAr), 6.66–6.65 (m, 2
H, HAr), 4.06–2.81 (m, 18 H, CH2C=O, NCH2CH2N), 3.72 (s, 6
H, OCH3) ppm. 13C{1H} NMR (150.9 MHz, [D6]dmso): δ = 170.7
(C=O), 170.5 (C=O), 170.2 (C=O), 166.3 (C=O), 165.9 (C=O),
159.5 (O-CAr), 129.6 (N-CAr), 111.6 (CAr), 111.5 (CAr), 109.2 (CAr),
108.9 (CAr), 105.1 (CAr), 61.3 (CH2C=O, NCH2CH2N), 60.2
(CH2C=O, NCH2CH2N), 60.1 (CH2C=O, NCH2CH2N), 57.1
(CH2C=O, NCH2CH2N), 56.5 (CH2C=O, NCH2CH2N), 55.0
(OCH3), 54.7 (CH2C=O, NCH2CH2N), 54.3 (CH2C=O,
NCH2CH2N), 54.0 (CH2C=O, NCH2CH2N), 51.7 (CH2C=O,
NCH2CH2N) ppm. MS (ESI, + mode): calcd. for [M(71Ga)]+ 671,
[M(69Ga)]+ 669; found m/z (%) = 695 (22) [M(71Ga) + 1 + Na]+,
694 (74) [M(71Ga) + Na]+, 693 (33) [M(69Ga) + 1 + Na]+, 692 (100)
[M(69Ga) + Na]+. C28H34GaN5O10·H2O (688.33): calcd. C 48.86,
H 5.27, N 10.17; found C 48.53, H 5.28, N 10.06.
[GaIII{dtpa-N,NЈЈ-bis(p-ethoxyphenylamide)}] (3d): Prepared follow-
ing procedure A from GaIII chloride solution (2.6 mL, 0.21 mmol)
and 2d (135 mg, 0.21 mmol), yield 35 mg (0.05 mmol, 23%).
HPLC: 4.7 min, 95.6%. 1H NMR (600.1 MHz, [D6]dmso): δ =
10.27 (s, 1 H, NH-CO), 10.16 (s, 1 H, NH-CO), 7.51–7.47 (m, 4 H,
3
HAr), 6.97 (d, JH,H = 8.7 Hz, 4 H, HAr), 3.99–3.96 (m, 4 H,
OCH2CH3), 4.04–2.84 (m, 18 H, CH2CO, NCH2CH2N), 1.31–1.29
(m, 6 H, OCH2CH3) ppm. 13C{1H} NMR (100.6 MHz, [D6]dmso):
δ = 170.7 (C=O), 170.5 (C=O), 168.7 (C=O), 165.3 (C=O), 154.7
(O-CAr), 154.6 (O-CAr), 131.6 (N-CAr), 122.7 (CAr), 120.8 (CAr),
114.7 (CAr), 114.4 (CAr), 63.3 (OCH2CH3), 63.1 (OCH2CH3), 60.0
(CH2C=O, NCH2CH2N), 57.8 (CH2C=O, NCH2CH2N), 54.7
(CH2C=O, NCH2CH2N), 54.4 (CH2C=O, NCH2CH2N), 14.7
(OCH2CH3), 14.6 (OCH2CH3) ppm. MS (ESI, + mode): calcd. for
[M(71Ga)]+ 699, [M(69Ga)]+ 697; found m/z (%) = 723 (25)
[M(71Ga) + 1 + Na]+, 722 (76) [M(71Ga) + Na]+, 721 (36) [M(69Ga)
+ 1 + Na]+, 720 (100) [M(69Ga) + Na]+. C30H38GaN5O10·2.5H2O
(743.41): calcd. C 48.47, H 5.84, N 9.42; found C 48.09, H 5.40, N
9.31.
[GaIII{dtpa-N,NЈЈ-bis(o-ethoxyphenylamide)}] (3b): Prepared follow-
ing procedure A from GaIII chloride (3 mL, 0.25 mmol) and 2b
(150 mg, 0.24 mmol), yield 33 mg (0.05 mmol, 20%). HPLC:
4.6 min, 96.6%. 1H NMR (600.1 MHz, [D6]dmso): δ = 9.66–9.60
(m, 2 H, NH-CO), 7.85–7.72 (m, 2 H, HAr), 7.11–7.09 (m, 2 H,
HAr), 7.04–7.03 (m, 2 H, HAr), 6.91–6.89 (m, 2 H, HAr), 4.07 (m,
4 H, OCH2CH3), 4.14–2.85 (m, 18 H, CH2C=O, NCH2CH2N), [GaIII{dtpa-N,NЈЈ-bis(p-butoxyphenylamide)}] (3e): Prepared follow-
1.41–1.36 (m, 6 H, OCH2CH3) ppm. 13C{1H} NMR (150.9 MHz, ing procedure B from GaIII chloride solution (0.6 mL, 0.32 mmol),
Eur. J. Inorg. Chem. 2015, 4125–4137
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FULL PAPER
tetra-n-butylammonium hydroxide solution (0.87 mL, 0.87 mmol)
and 2e (200 mg, 0.29 mmol), yield 120 mg (0.16 mmol, 55%).
HPLC: 5.6 min, 95.0%. 1H NMR (600.1 MHz, [D6]dmso): δ =
[InIII{dtpa-N,NЈЈ-bis(o-ethoxyphenylamide)}] (4b): Prepared follow-
ing procedure B from InIII chloride (52 mg, 0.24 mmol) and 2b
(150 mg, 0.24 mmol). Purification by column chromatography (sil-
10.26 (s, 1 H, NH-CO), 10.14 (s, 1 H, NH-CO), 7.51–7.46 (m, 4 H, ica, MeOH/H2O, 2:1) followed by flash chromatography (silica,
HAr), 6.86 (m, H, HAr), 4.02–2.84 (m, 18 H, CH2CO, MeOH), yield 36 mg (0.05 mmol, 20%). HPLC: 4.2 min, 95.6%.
NCH2CH2N), 3.90 (t, JH,H = 6.5 Hz, 4H OCH2CH2CH2CH3), 1H NMR (400.1 MHz, [D4]MeOH): δ = 8.01–7.80 (m, 2 H, HAr),
1.68–1.62 (m, H, OCH2CH2CH2CH3), 1.41 (m, H, 7.42–6.77 (m, H, HAr), 4.15–2.89 (m, 22 H, CH2C=O,
4
3
4
4
6
OCH2CH2CH2CH3), 0.91 (m, 6 H, OCH2CH2CH2CH3) ppm. NCH2CH2N, OCH2CH3), 1.44–1.39 (m, 6 H, OCH2CH3) ppm.
13C{1H} NMR (100.6 MHz, [D6]dmso): δ = 170.7 (C=O), 170.6 13C{1H} NMR (100.6 MHz, [D4]MeOH): δ = 175.8 (C=O), 175.6
(C=O), 170.3 (C=O), 165.8 (C=O), 165.3 (C=O), 155.0 (O-CAr),
(C=O), 172.1 (C=O), 169.1 (C=O), 152.0 (O-CAr), 151.5 (O-CAr),
154.9 (O-CAr), 131.5 (N-CAr), 120.9 (CAr), 120.8 (CAr), 114.5 (CAr), 128.7 (N-CAr, CAr), 127.3 (N-CAr, CAr), 127.2 (N-CAr, CAr), 125.9
67.3 (OCH2CH2CH2CH3), 61.3 (CH2C=O, NCH2CH2N), 60.2 (N-CAr, CAr), 125.6 (N-CAr, CAr), 124.7 (N-CAr, CAr), 121.7 (CAr),
(CH2C=O, NCH2CH2N), 56.7 (CH2C=O, NCH2CH2N), 54.7 121.4 (CAr), 113.3 (CAr), 113.1 (CAr), 65.5 (OCH2CH3), 65.4
(CH2C=O, NCH2CH2N), 51.7 (CH2C=O, NCH2CH2N), 30.8 (OCH2CH3), 61.7 (CH2C=O, NCH2CH2N), 60.9 (CH2C=O,
(OCH2CH2CH2CH3),
(OCH2CH2CH2CH3) ppm. MS (ESI,
[M(71Ga)]+ 755, [M(69Ga)]+ 753; found m/z (%) = 755 (29)
18.8
(OCH2CH2CH2CH3),
13.8 NCH2CH2N), 58.1 (CH2C=O, NCH2CH2N), 57.2 (CH2C=O,
–
mode): calcd. for
NCH2CH2N), 56.3 (CH2C=O, NCH2CH2N), 53.1 (CH2C=O,
NCH2CH2N), 15.1 (OCH2CH3), 15.0 (OCH2CH3) ppm. MS (ESI,
[M(71Ga) + 1 – H]–, 754 (76) [M(71Ga) – H]–, 753 (40) [M(69Ga) + + mode): calcd. for [M(115In)]+ 743, [M(113In)]+ 741; found m/z (%)
1 – H]–, 752 (100) [M(69Ga) – H]–. C34H46GaN5O10·2H2O (790.50): = 767 (34) [M(115In) + 1 + Na]+, 766 (100) [M(115In) + Na]+, 764
calcd. C 51.66, H 6.38, N 8.86; found C 51.46, H 6.08, N 8.68.
(5) [M(113In) + Na]+. C30H38InN5O10·3.5H2O (806.52): calcd. C
44.68, H 5.62, N 8.68; found C 44.30, H 5.16, N 8.41.
General Procedure for the Preparation of the InIII and LuIII Com-
plexes 4a–e and 5a–e: dtpa-N,NЈЈ-bis(alkoxyphenyl)amide 2a–d
(1 equiv.) was dissolved or, in the case of 2e, suspended in hot water,
cooled to room temperature and an aqueous solution of InIII chlor-
ide (1 equiv.) or LuIII chloride hexahydrate (1 equiv.) was added,
respectively. The pH of the mixture was raised to 7.5 by the drop-
wise addition of 2.0 m NaOH solution. The solution was stirred at
room temperature overnight and the solvent was evaporated.
[InIII{dtpa-N,NЈЈ-bis(m-ethoxyphenylamide)}] (4c): Prepared follow-
ing procedure A from InIII chloride (122 mg, 0.55 mmol) and 2c
(350 mg, 0.55 mmol), yield 230 g (0.31 mmol, 55%). HPLC:
4.5 min, 98.8%. 1H NMR (600.1 MHz, [D6]dmso, 25 °C): δ = 11.44
(s, 1 H, NH-CO), 10.31 (s, 1 H, NH-CO), 7.54 (s, 1 H, HAr), 7.31–
7.27 (m, 2 H, HAr), 7.18 (m, 1 H, HAr), 7.12–7.10 (m, 2 H, HAr),
3
4
3
6.77 (dd, JH,H = 8.2, JH,H = 1.7 Hz, 1 H, HAr), 6.62 (dd, JH,H
=
4
8.2, JH,H = 1.7 Hz, 1 H, HAr), 4.10–2.61 (m, 22 H, CH2C=O,
NCH2CH2N, OCH2CH3), 1.35–1.30 (m, 6 H, OCH2CH3) ppm. 1H
NMR (600.1 MHz, [D6]dmso, 85 °C): δ = 10.11 (s, 0.3 H, NH-CO),
7.48 (s, 0.5 H, HAr), 7.33–7.09 (m, 5.5 H, HAr), 6.77 (s, 1 H, HAr),
6.65 (s, 1 H, HAr), 4.13–2.39 (m, 22 H, CH2C=O, NCH2CH2N,
OCH2CH3), 1.38–1.31 (m, 6 H, OCH2CH3) ppm. 13C{1H} NMR
(150.9 MHz, [D6]dmso): δ = 171.4 (C=O), 171.2 (C=O), 170.5,
(C=O) 170.4 (C=O), 166.9, 158.9 (O-CAr), 158.7 (O-CAr), 139.7 (N-
CAr), 138.0 (N-CAr), 129.7 (CAr), 129.5 (CAr), 112.3 (CAr), 111.8
(CAr), 111.6 (CAr), 109.7 (CAr), 106.6 (CAr), 105.6 (CAr), 63.3
(OCH2CH3), 62.9 (OCH2CH3), 60.8 (CH2C=O, NCH2CH2N), 60.0
(CH2C=O, NCH2CH2N), 59.6 (CH2C=O, NCH2CH2N), 56.2
(CH2C=O, NCH2CH2N), 55.3 (CH2C=O, NCH2CH2N), 55.1
(CH2C=O, NCH2CH2N), 54.5 (CH2C=O, NCH2CH2N), 52.0
(CH2C=O, NCH2CH2N), 50.5 (CH2C=O, NCH2CH2N), 14.6
(OCH2CH3), 14.5 (OCH2CH3) ppm. MS (ESI, + mode): calcd. for
[M(115In)]+ 743, [M(113In)]+ 741; found m/z (%) = 767 (34)
[M(115In) + 1 + Na]+, 766 (100) [M(115In) + Na]+, 764 (5) [M(113In)
+ Na]+, 744 (115) [M(115In) + H]+. C30H38InN5O10·H2O (761.57):
calcd. C 47.32, H 5.29, N 9.20; found C 47.52, H 5.06, N 9.20.
Procedure A: The residue was suspended in deionized water and
washed thoroughly with water to remove all traces of soluble inor-
ganic salts. The colourless solids were dried in vacuo.
Procedure B: The complexes with a higher solubility in water were
redissolved in a small amount of hot methanol and purified by
silica column chromatography. The colourless solids were dried in
vacuo.
[InIII{dtpa-N,NЈЈ-bis(m-methoxyphenylamide)}] (4a): Prepared fol-
lowing procedure B from InIII chloride (127 mg, 0.58 mmol) and
2a (350 mg, 0.58 mmol). Purification by column chromatography
(silica, MeOH/H2O, 1:1), yield 100 mg (0.14 mmol, 24%). HPLC:
1
4.2 min, 99.0%. H NMR (400.1 MHz, [D4]MeOH): δ = 7.38–6.58
(m, 8 H, HAr), 4.12–2.78 (m, 24 H, CH2C=O, NCH2CH2N,
OCH3) ppm. 13C{1H} NMR (100.6 MHz, [D4]MeOH): δ = 177.0
(C=O), 176.5 (C=O), 176.0 (C=O), 175.9 (C=O), 175.8 (C=O),
175.7 (C=O), 175.5 (C=O), 175.4 (C=O), 170.3 (C=O), 168.5
(C=O), 161.6 (O-CAr), 161.5 (O-CAr), 161.4 (O-CAr), 140.3 (N-
CAr), 140.2 (N-CAr), 130.9 (CAr), 130.8 (CAr), 130.6 (CAr), 114.4
(CAr), 113.7 (CAr), 113.5 (CAr), 113.4 (CAr), 113.1 (CAr), 111.2
(CAr), 111.1 (CAr), 110.9 (CAr), 107.9 (CAr), 107.3 (CAr), 107.2
[InIII{dtpa-N,NЈЈ-bis(p-ethoxyphenylamide)}] (4d): Prepared follow-
(CAr), 106.7 (CAr), 63.5 (CH2C=O, NCH2CH2N), 62.3 (CH2C=O, ing procedure A from InIII chloride (127 mg, 0.58 mmol) and 2d
NCH2CH2N), 61.6 (CH2C=O, NCH2CH2N), 61.1 (CH2C=O, (350 mg, 0.58 mmol), yield 168 mg (0.23 mmol, 39%). HPLC:
1
NCH2CH2N), 60.7 (CH2C=O, NCH2CH2N), 60.3 (CH2C=O, 4.7 min, 96.7%. H NMR (600.1 MHz, [D6]dmso): δ = 11.47 (s, 1
3
NCH2CH2N), 59.8 (CH2C=O, NCH2CH2N), 59.6 (CH2C=O, H, NH-CO), 10.22 (s, 1 H, NH-CO), 7.59 (d, JH,H = 7.5 Hz, 2 H,
3
3
NCH2CH2N), 57.9 (CH2C=O, NCH2CH2N), 57.6 (CH2C=O, HAr), 7.50 (d, JH,H = 8.9 Hz, 2 H, HAr), 6.96 (d, JH,H = 8.9 Hz,
3
NCH2CH2N), 57.2 (CH2C=O, NCH2CH2N), 57.1 (CH2C=O, 2 H, HAr), 6.86 (d, JH,H = 8.9 Hz, 2 H, HAr), 4.03–2.66 (m, 22 H,
NCH2CH2N), 57.0 (CH2C=O, NCH2CH2N), 56.7 (CH2C=O, CH2C=O, NCH2CH2N, OCH2CH3), 1.32–1.28 (m,
6
H,
NCH2CH2N), 56.3 (CH2C=O, NCH2CH2N), 55.8–55.7 OCH2CH3) ppm. 13C{1H} NMR (150.9 MHz, [D6]dmso): δ =
(OCH3) ppm. MS (ESI, + mode): calcd. for [M(115In)]+ 715, 171.4 (C=O), 171.1 (C=O), 170.7 (C=O), 196.3 (C=O), 166.3
[M(113In)]+ 713; found m/z (%) = 739 (34) [M(115In) + 1 + Na]+,
738 (100) [M(115In) Na]+, 736 (5) [M(113In) Na]+.
(C=O), 164.8 (C=O), 156.0 (O-CAr), 154.7 (O-CAr), 131.6 (N-CAr),
129.8 (N-CAr), 122.0 (CAr), 120.9 (CAr), 114.6 (CAr), 114.3 (CAr),
+
+
C28H34InN5O10·H2O·0.5CH3OH (749.45): calcd. C 45.67, H 5.11, 62.2 (OCH2CH3), 63.1 (OCH2CH3), 60.6 (CH2C=O, NCH2CH2N),
N 9.34; found C 45.94, H 4.88, N 9.03. The content of methanol
was established from its X-ray structure.
59.9 (CH2C=O, NCH2CH2N), 59.5 (CH2C=O, NCH2CH2N), 56.3
(CH2C=O, NCH2CH2N), 55.2 (CH2C=O, NCH2CH2N), 55.1
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(CH2C=O, NCH2CH2N), 54.5 (CH2C=O, NCH2CH2N), 52.1 CAr, CAr), 126.5 (N-CAr, CAr), 126.4 (N-CAr, CAr), 126.1 (N-CAr
,
(CH2C=O, NCH2CH2N), 50.5 (CH2C=O, NCH2CH2N), 14.7 CAr), 126.0 (N-CAr, CAr), 125.2 (N-CAr, CAr), 121.6 (CAr), 121.3
(OCH2CH3), 14.6 (OCH2CH3) ppm. MS (ESI, + mode): calcd. for
[M(115In)]+ 743, [M(113In)]+ 741; found m/z (%) = 767 (34)
[M(115In) + 1 + Na]+, 766 (100) [M(115In) + Na]+, 764 (5) [M(113In)
(CAr), 113.4 (CAr), 113.1 (CAr), 68.1 (CH2C=O, NCH2CH2N), 65.5
(OCH2CH3), 65.4 (OCH2CH3), 63.8 (CH2C=O, NCH2CH2N), 63.4
(CH2C=O, NCH2CH2N), 63.0 (CH2C=O, NCH2CH2N), 60.0
+ Na]+, 744 (8) [M(115In) + H]+. C30H38InN5O10·3H2O (797.51): (CH2C=O, NCH2CH2N), 59.7 (CH2C=O, NCH2CH2N), 57.4
calcd. C 45.18, H 5.56, N 8.78; found C 45.02, H 5.30, N 8.64.
(CH2C=O, NCH2CH2N), 57.2 (CH2C=O, NCH2CH2N), 15.1
(OCH2CH3), 15.0 (OCH2CH3) ppm. MS (ESI, + mode): calcd. for
[M]+ 821, [M – H2O]+ 803; found m/z (%) = 826 (100) [M – H2O,
+ Na]+. C30H38LuN5O10·2.5H2O (848.66): calcd. C 42.46, H 5.11,
N 8.25; found C 42.57, H 4.95, N 7.94.
[InIII{dtpa-N,NЈЈ-bis(p-butoxyphenylamide)}] (4e): Prepared follow-
ing procedure A from InIII chloride (112 mg, 0.51 mmol) and 2e
(350 mg, 0.51 mmol), yield 170 mg (0.21 mmol, 41%). HPLC:
1
5.8 min, 95.5%. H NMR (600.1 MHz, [D4]MeOH): δ = 7.60–6.69
(m, 8 H, HAr), 3.94–2.75 (m, 22 H, CH2C=O, NCH2CH2N, [LuIII{dtpa-N,NЈЈ-bis(m-ethoxyphenylamide)}] (5c): Prepared fol-
OCH2CH2CH2CH3), 1.76–1.61 (m, 4 H, OCH2CH2CH2CH3), lowing procedure A from LuIII chloride hexahydrate (215 g,
1.52–1.37 (m, 4 H, OCH2CH2CH2CH3), 0.99–0.88 (m, 6 H, 0.55 mmol) and 2c (350 mg, 0.55 mmol), yield 325 mg (0.40 mmol,
OCH2CH2CH2CH3) ppm. 13C{1H} NMR (150.9 MHz, [D4]- 74%). HPLC: 5.3 min, 98.6%. 1H NMR (600.1 MHz, [D6]dmso,
MeOH): δ = 177.1 (C=O), 175.9 (C=O), 175.6 (C=O), 173.9
(C=O), 169.3 (C=O), 157.7 (O-CAr), 157.5 (O-CAr), 157.0 (O-CAr),
25 °C): δ = 10.82–10.77 (m, 2 H, NH-CO, H2Oligand), 7.38–7.16 (m,
6 H, HAr), 6.77–6.72 (m, 2 H, HAr), 4.24–4.21 (m, 0.8 H), 4.25–
131.9 (N-CAr), 129.0 (N-CAr), 123.2 (CAr), 122.7 (CAr), 118.2 (CAr), 2.27 (m, 22 H, CH2CO, NCH2CH2N, OCH2CH3), 1.31–1.28 (m, 6
1
116.6 (CAr), 115.6 (CAr), 115.2 (CAr), 68.9 (OCH2CH2CH2CH3), H, OCH2CH3) ppm. H NMR (600.1 MHz, [D6]dmso, 85 °C): δ =
68.8 (OCH2CH2CH2CH3), 57.0 (CH2C=O, NCH2CH2N), 56.8 10.45 (s, 1.2 H, NH-CO), 7.29–7.23 (m, 6 H, HAr), 6.75–6.74 (m,
3
(CH2C=O, NCH2CH2N), 56.7 (CH2C=O, NCH2CH2N), 56.4 2 H, HAr), 4.04 (q, JH,H = 7.1 Hz, 4 H, OCH2CH3), 4.16–2.38
3
(CH2C=O, NCH2CH2N), 55.7 (CH2C=O, NCH2CH2N), 55.3 (m, 18 H, CH2CO, NCH2CH2N), 1.31 (t, JH,H = 7.1 Hz, 6 H,
(CH2C=O, NCH2CH2N), 55.2 (CH2C=O, NCH2CH2N), 53.5 OCH2CH3) ppm. 13C{1H} NMR (150.9 MHz, [D6]dmso): δ =
(CH2C=O, NCH2CH2N), 52.8 (CH2C=O, NCH2CH2N), 32.7 175.7 (C=O), 75.2 (C=O), 174.9 (C=O), 173.3 (C=O), 158.8 (O-
(OCH2CH2CH2CH3),
(OCH2CH2CH2CH3),
32.5
20.2
(OCH2CH2CH2CH3),
(OCH2CH2CH2CH3),
20.3 CAr), 138.7 (N-CAr), 138.4 (N-CAr), 129.6 (CAr), 129.5 (CAr), 112.7
14.2 (CAr), 112.4 (CAr), 110.4 (CAr), 110.1 (CAr), 107.2 (CAr), 106.7
(OCH2CH2CH2CH3) ppm. MS (ESI,
+
mode): calcd. for (CAr), 66.6 (CH2C=O, NCH2CH2N), 63.1 (OCH2CH3), 63.0
[M(115In)]+ 799, [M(113In)]+ 797; found m/z (%) = 822 (14)
[M(115In) + Na]+, 801 (34) [M(115In) + 1 + H]+, 800 (100) [M(115In)
+ H]+. C34H46InN5O10·3H2O (853.70): calcd. C 47.84, H 6.14, N
8.20; found C 47.71, H 5.78, N 8.01.
(OCH2CH3), 62.3 (CH2C=O, NCH2CH2N), 62.2 (CH2C=O,
NCH2CH2N), 62.0 (CH2C=O, NCH2CH2N), 58.1 (CH2C=O,
NCH2CH2N), 57.9 (CH2C=O, NCH2CH2N), 55.9 (CH2C=O,
NCH2CH2N),
55.0
(CH2C=O,
NCH2CH2N),
14.6
(OCH2CH3) ppm. MS (ESI, + mode): calcd. for [M]+ 821, [M –
H2O]+ 803; found m/z (%) = 826 (100) [M – H2O + Na]+, 804 (26)
[M – H2O + H]+. C30H38LuN5O10·3H2O (875.66): calcd. C 42.01,
H 5.17, N 8.17; found C 41.89, H 5.10, N 8.09.
[LuIII{dtpa-N,NЈЈ-bis(m-methoxyphenylamide)}] (5a): Prepared fol-
lowing procedure B from LuIII chloride hexahydrate (225 mg,
0.58 mmol) and 2a (350 g, 0.58 mmol), yield 120 mg (0.15 mmol,
26%). HPLC: 4.7 min, 99.0%. 1H NMR (600.1 MHz, [D4]MeOH):
δ = 7.38–7.18 (m, 6 H, HAr), 6.81–6.74 (m, 2 H, HAr), 3.84–3.43 [LuIII{dtpa-N,NЈЈ-bis(p-ethoxyphenylamide)}] (5d): Prepared follow-
(m, 24 H, CH2CO, NCH2CH2N, OCH3) ppm. 13C{1H} NMR ing procedure from LuIII chloride hexahydrate (215 mg,
A
(150.9 MHz, [D4]MeOH): δ = 181.3 (C=O), 180.6 (C=O), 180.4 0.55 mmol) and 2d (350 mg, 0.55 mmol), yield 196 mg (0.24 mmol,
(C=O), 180.1 (C=O), 177.0 (C=O), 175.4 (C=O), 175.3 (C=O), 44%). HPLC: 5.1 min, 97.0%. 1H NMR (600.1 MHz, [D6]dmso):
161.8 (O-CAr), 161.6 (O-CAr), 139.3 (N-CAr), 139.1 (N-CAr), 131.0 δ = 10.79 (s, 2 H, NH-CO), 7.71–7.58 (m, 4 H, HAr), 6.95–6.86 (m,
(CAr), 130.9 (CAr), 130.8 (CAr), 114.4 (CAr), 114.3 (CAr), 112.4
4 H, HAr), 4.22–2.57 (m, 22 H, CH2C=O, NCH2CH2N,
(CAr), 112.0 (CAr), 108.2 (CAr), 108.1 (CAr), 68.2 (CH2C=O, OCH2CH3), 1.34–1.30 (m, 6 H, OCH2CH3) ppm. 13C{1H} NMR
NCH2CH2N), 68.0 (CH2C=O, NCH2CH2N), 64.0 (CH2C=O, (100.6 MHz, [D6]dmso): δ = 175.8 (C=O), 175.3 (C=O), 175.6
NCH2CH2N), 63.5 (CH2C=O, NCH2CH2N), 63.2 (CH2C=O, (C=O), 175.0 (C=O), 173.7 (C=O), 173.0 (C=O), 172.5 (C=O),
NCH2CH2N), 60.0 (CH2C=O, NCH2CH2N), 59.8 (CH2C=O, 155.6 (O-CAr), 155.3 (O-CAr), 130.7 (N-CAr), 130.4 (N-CAr), 121.9
NCH2CH2N), 57.4 (CH2C=O, NCH2CH2N), 57.2 (CH2C=O, (CAr), 121.8 (CAr), 121.6 (CAr), 114.5 (CAr), 114.4 (CAr), 114.3
NCH2CH2N), 56.0 (CH2C=O, NCH2CH2N), 55.9 (OCH3), 55.8 (CAr), 66.7 (CH2C=O, NCH2CH2N), 63.2 (OCH2CH3), 63.1
(OCH3) ppm. MS (ESI, + mode): calcd. for [M]+ 793, [M – (OCH2CH3), 62.6 (CH2C=O, NCH2CH2N), 62.3 (CH2C=O,
H2O]+ 775; found m/z (%) = 798 (100) [M – H2O + Na]+, 776 (15) NCH2CH2N), 61.6 (CH2C=O, NCH2CH2N), 58.1 (CH2C=O,
[M – H2O + H]+. C28H34LuN5O10·4H2O (847.62): calcd. C 39.68,
H 4.99, N 8.26; found C 39.68, H 4.58, N 8.22.
NCH2CH2N), 55.8 (CH2C=O, NCH2CH2N), 55.1 (CH2C=O,
NCH2CH2N), 14.6 (OCH2CH3) ppm. MS (ESI, + mode): calcd.
for [M]+ 821, [M – H2O]+ 803; found m/z (%) = 826 (100) [M –
H2O + Na]+, 804 (5) [M – H2O, + H]+. C30H38LuN5O10·4H2O
(875.68): calcd. C 41.15, H 5.29, N 7.98; found C 41.45, H 5.12, N
8.00.
[LuIII{dtpa-N,NЈЈ-bis(o-ethoxyphenylamide)}] (5b): Prepared follow-
ing procedure
B
from LuIII chloride hexahydrate (111 mg,
0.29 mmol) and 2b (180 mg, 0.29 mmol), yield 35 mg (0.04 mmol,
15%). Purification by column chromatography (silica, MeOH/H2O,
1
2:1). HPLC: 5.2 min, 96.5%. H NMR (400.1 MHz, [D4]MeOH):
[LuIII{dtpa-N,NЈЈ-bis(p-butoxyphenylamide)}] (5e): Prepared follow-
δ = 7.95–7.69 (m, 2 H, HAr), 7.27–6.82 (m, 6 H, HAr), 4.16–2.43 ing procedure
A
from LuIII chloride hexahydrate (198 g,
(m, 22 H, CH2CO, NCH2CH2N, OCH2CH3), 1.45–1.30 (m, 6 H, 0.51 mmol) and 2e (350 g, 0.51 mmol), yield 225 mg (0.26 mmol,
OCH2CH3) ppm. 13C{1H} NMR (100.6 MHz, [D4]MeOH): δ = 51%). HPLC: 6.1 min, 95.5%. 1H NMR (600.1 MHz, [D4]MeOH):
181.2 (C=O), 180.6 (C=O), 180.4 (C=O), 180.3 (C=O), 180.1 δ = 7.58–7.45 (m, 4 H, HAr), 6.91–6.78 (m, 4 H, HAr), 4.00–2.46
(C=O), 177.3 (C=O), 175.8 (C=O), 169.9 (C=O), 152.8 (O-CAr),
151.6 (O-CAr), 128.7 (N-CAr, CAr), 128.2 (N-CAr, CAr), 128.0 (N-
(m, 22 H, CH2C=O, NCH2CH2N, OCH2CH2CH2CH3), 1.78–1.68
(m, H, OCH2CH2CH2CH3), 1.55–1.44 (m, H,
4
4
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Received: April 21, 2015
Published Online: July 23, 2015
Eur. J. Inorg. Chem. 2015, 4125–4137
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim