Magnetic Anisotropy in Functionalized Bipyridyl Cryptates

Article abstract of DOI:10.1021/acs.inorgchem.6b00591

The magnetic properties of molecular lanthanoid complexes are very important for a variety of scientific and technological applications, with the unique magnetic anisotropy being one of the most important features. In this context, a very rigid tris(bipyridine) cryptand was synthesized with a primary amine functionality for future bioconjugation. The magnetic anisotropy was investigated for the corresponding paramagnetic ytterbium cryptate. With the use of a combination of density functional theory calculations and lanthanoid-induced NMR shift analysis, the magnetic susceptibility tensor was determined and compared to the unfunctionalized cryptate analogue. The size and orientation of the axial and rhombic tensor components show remarkably great resilience toward the decrease of local symmetry around the metal and anion exchange in the inner coordination sphere. In addition, the functionalized ytterbium cryptate also exhibits efficient near-IR luminescence.

Full text of DOI:10.1021/acs.inorgchem.6b00591

Article
pubs.acs.org/IC
Magnetic Anisotropy in Functionalized Bipyridyl Cryptates
Elisabeth Kreidt,† Caroline Bischof,‡ Carlos Platas-Iglesias,*,§ and Michael Seitz*,†
†Institute of Inorganic Chemistry, University of Tubingen, Auf der Morgenstelle 18, 72076 Tubingen, Germany
̈
̈
‡Inorganic Chemistry I, Ruhr-University Bochum, 44780 Bochum, Germany
§Departamento de Química Fundamental, Universidade da Coruna, Campus da Zapateira-Rua da Fraga 10, 15008 A Coruna, Spain
́
̃
̃
S
* Supporting Information
ABSTRACT: The magnetic properties of molecular lanthanoid complexes are very
important for a variety of scientific and technological applications, with the unique
magnetic anisotropy being one of the most important features. In this context, a very rigid
tris(bipyridine) cryptand was synthesized with a primary amine functionality for future
bioconjugation. The magnetic anisotropy was investigated for the corresponding
paramagnetic ytterbium cryptate. With the use of a combination of density functional
theory calculations and lanthanoid-induced NMR shift analysis, the magnetic
susceptibility tensor was determined and compared to the unfunctionalized cryptate
analogue. The size and orientation of the axial and rhombic tensor components show remarkably great resilience toward the
decrease of local symmetry around the metal and anion exchange in the inner coordination sphere. In addition, the functionalized
ytterbium cryptate also exhibits efficient near-IR luminescence.
phenomenon overall. In addition, recent studies point to
somewhat unpredictable magnetic behavior even in DOTA
complexes with supposedly high symmetry9 and the extreme
sensitivity of the anisotropy toward exchange of additional,
axially coordinated ligands such as H2O or fluoride.10 One of
the alternatives to DOTA-derived ligand systems for lanthanoid
chelation are tris(2,2′-bpy)-based cryptands (2,2′-bpy = 2,2′-
bipyrdine) that have proven to be very valuable tools for
bioanalytical luminescence applications.11 Originally, they were
introduced by Lehn et al. in the form of the flexible cryptates 1-
Ln (Figure 1).12 Later development has shown the N,N′-
INTRODUCTION
■
The highly interesting physical properties of trivalent
lanthanoids have made them crucial components in innovative
scientific and technological applications.1 One of the most
prominent features in this respect is their unique magnetism,
which has been used in many different areas such as NMR shift
reagents,2 magnetic resonance imaging contrast agents,3 single-
molecule magnets,4 or paramagnetic tags in the structural
biology of proteins.5 One of the centrally important aspects of
lanthanoid magnetism is its often very pronounced and well-
defined anisotropy in the case of nonspherical f-electron
distributions, that is, for all paramagnetic Ln3+ except Gd3+. In
general, the magnitude and the spatial dependence of the
effects in molecular complexes are often very sensitive to the
composition and the symmetry of the inner coordination
sphere around the lanthanoid and the corresponding ligand
field splitting of the f-orbitals. Consequently, ligand architec-
tures that are able to provide a well-defined, unchanging
coordination environment would be the best choice if time-
invariant and predictable magnetic anisotropy is required. By
far the most prevalent ligand class for lanthanoid complexation
is based on 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic
acid (DOTA) and related systems.6 Despite the great success of
DOTA in fields related to lanthanoid magnetism, many DOTA-
derived lanthanoid complexes often exhibit typical exchange
processes that inherently affect magnetic anisotropy, for
example, configurational exchange between Δ and Λ stereo-
isomers through rotation of the pendant arms and conforma-
tional flexibility associated with the inversion of the macrocyclic
unit, which leads to interconversion between the square-
antiprismatic and twisted square-antiprismatic geometries.7
Some of these problems have been overcome with special
ligand modifications8 but remain a ubiquitous detrimental
Figure 1. 2,2′-Bipyridine-based cryptate scaffolds. Flexible 1-Ln12 vs
extremely rigid 2-Ln.13
dioxide analogues 2-Ln to be conformationally and configura-
tionally very stable on the NMR time scale, without any signs of
the detrimental exchange processes typically observed for
DOTA derivatives.13
Despite the great potential that cryptates of the type 2-Ln
have in this area, this class of ligands is virtually absent from the
field of lanthanoid magnetism. One of the major reasons for
this phenomenon is the somewhat underdeveloped and
sometimes cumbersome synthethic chemistry of cryptands, in
Received: March 8, 2016
© XXXX American Chemical Society
A
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contrast to the very mature synthetic methodology for the
preparation of tailor-made DOTA-derivatives. Especially
detrimental in this regard is the lack of cryptands with well-
behaved and stable magnetic anisotropy that also have the
possibility for covalent attachment via suitable, peripheral
functional groups to other chemical entities such as proteins. In
the past, there have been reports of a few monofunctionalized
lanthanoid cryptates such as cryptates 3-Ln14 with a peripheral
ester group or 4-Ln15 with a primary amine functionality for
bioconjugation (Figure 2, top row). Unfortunately, these
species are rather flexible and undergo the same unwanted
exchange processes as seen in DOTA.
Figure 3. Possibilities for the introduction of the peripheral group X in
the cryptate 2-Ln. Path A: Functionalization at the 2,2′-bpy unit; Path
B: Functionalization on the 2,2′-bpy-N,N′-dioxide moiety.
Figure 4. Unusual stereogenic element in cryptates 6-Ln due to the
topology of the macrobicyclic cryptand framework (the colors indicate
the fact that all three cryptate arms are different and one is
unsymmetric).
Figure 2. (top) Monofunctionalized lanthanoid cryptates 3-Ln14 and
4-Ln.15 (bottom) Rigid, monofuntionalized lanthanoid cryptate 5-Ln
developed for this study.
potential formation of diastereomeric cryptands. The diaster-
eomers of the corresponding paramagnetic lanthanoid com-
plexes would certainly have very different magnetic anisotropies
which would, of course, completely defeat the purpose outlined
in the introduction. The cryptates 7-Ln do not suffer from this
problem and are therefore ideal candidates for this study.
Cryptate Synthesis. The key building block for the
synthesis of the cryptates 5-Ln is the funtionalized 2,2′-
bipyridine derivative 10 (Scheme 1), which is known to be
In this study, we alleviate this problem with the introduction
of a new, monofunctionalized cryptate 5-Ln (Figure 2, bottom)
that is synthetically accessible on larger scales. For the
corresponding ytterbium cryptate 5-Yb, we investigate the
influence that the functionalization and the concomitant
reduction from C2 to C1 symmetry has on the magnetic
anisotropy and the photoluminescence properties.
Scheme 1. Synthesis of Sodium Cryptate 15
RESULTS AND DISCUSSION
■
Cryptate Design−Functionalization Strategy. The
specific placement and the nature of the peripheral functional
group onto the parent cryptate scaffold 2-Ln is of crucial
importance for achieving well-defined and stable complexes.
First, functionalization in the 4-position on a pyridine unit is
generally the most accessible from a synthetic perspective and
points away from the metal binding site, therefore avoiding
steric interferences with the nature of the core cryptate
geometry (Figure 3). Second, our choice for the functional
group fell on carboxylic acid derivatives (X in Figure 3) because
of literature precedence (cf. 3-Ln in Figure 2) and because of
the great synthetic versatility of this motif for further
modification/conjugation. Third and most importantly, the
functionalization must be located on the 2,2′-bpy-N,N′-dioxide
moiety (Figure 3, path B) and not on any of the pyridines of
the 2,2′-bpy units (Figure 3, path A) to avoid the potential
formation of diastereomeric cryptate species. Unfunctionalized
cryptates like 2-Ln already possess one stereogenic element in
the form of the fixed helical arrangement of the biaryl moieties.
Cryptates 6-Ln (Figure 3) with the peripheral group on the
bipyridines would feature a new and rather unusual stereogenic
element due to the special topology of the macrobicyclic
cryptand framework (Figure 4), which in turn would lead to the
accessible by either Stille16 or Negishi14 cross coupling. Both
reported procedures rely on chromatographic purification of
10, which makes its preparation rather cumbersome on larger
scales. We were therefore interested in developing an improved
purification protocol that avoids chromatography. Our
optimized approach utilizes the known Stille coupling16 of tin
precursor 8 and triflate 9 (Scheme 1). After the reaction,
product 10 can conveniently be isolated in analytically pure
form by a continuous liquid−liquid extraction using n-heptane
and CH3CN as the two liquid phases. So far, we successfully
validated this protocol on scales of up to 80 mmol of starting
B
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materials (8 and 9) giving product 10 in rather large amounts
(>13 g). The subsequent reactions to sodium cryptate 15 are
straightforward and start with the oxidation of 10 to the
corresponding N,N′-dioxide 11 using 3-chloroperbenzoic acid
(m-CPBA). This is followed by a one-pot Boekelheide
rearrangement/nucleophilic substitution sequence to benzylic
dibromide 12.17 After conversion of 12 to the N,N′-dioxide 13
using improved conditions (trifluoroacetic anhydride/urea
hydrogen peroxide) for the oxidation of electron-poor pyridine
derivatives,18 cryptate 15 can be obtained under standard
conditions (sodium template, high dilution) by macrocycliza-
tion reaction with aza-crown ether 14.19
luminescence in this spectral region.20 In addition to the
ytterbium cryptate 5-Yb, the analogue 5-Lu was also
synthesized as a diamagnetic and photoinactive reference
system. The metal exchange reaction of Ln3+ for Na+ was
performed similarly to the previously reported unfunctionalized
cryptates 2-Ln (Figure 1) but with the requirement for
extended reaction times (t > 40 h). The crude lanthanoid
cryptates with anions X− (X = Cl, Br, or OTf) were purified by
reversed-phase, preparative HPLC (H2O+1 vol % CF3COOH/
CH3CN). Under these harsh conditions, no decomposition of
the cryptates was observed, which is an indication of the
extremely high kinetic inertness of the complexes as has been
seen before for similar cryptates.11,13,15 The cryptate cations of
5-Ln have most likely the inner-sphere composition shown in
Figure 5. Because of the low pH (∼1) and the great excess of
In our first approach to transform the methyl ester in 15 into
a more suitable functional group for conjugation chemistry, we
were able to saponify the ester using NaOH to the
corresponding carboxylate in cryptate 16 (Scheme 2) in good
Scheme 2. Synthesis of Cryptates 16 and 5-Ln
Figure 5. Composition of the inner coordination sphere of 2-Ln13d
and 5-Ln.
trifluoroacetate anions in the HPLC eluent mixture, the
obtained cryptates 5-Ln are protonated at the primary amine
and feature exclusively trifluoroacetate as the counteranions.
From our previous studies on the corresponding unfunction-
alized cryptates 2-Ln, we know that there is exactly one
available binding site in the inner coordination sphere of the
lanthanoids. For example, if 2-Ln is synthesized from LnCl3·
6H2O and is not purified by HPLC, it features a chloride anion
directly bound to the lanthanoid in methanolic solution (Figure
5, right).13d In the case of 5-Yb, 19F NMR in CD3CN after
HPLC purification shows two singlet resonances, one at −76.4
ppm and another at −116.5 ppm in an integrated ratio of 3:1.
While the former signal is in the typical range for free
trifluoroacetate anions,21 we interpret the latter as originating
from a paramagnetically shifted inner-sphere trifluoroacetate.
Chemical Structure in SolutionNuclear Magnetic
Resonance/Density Functional Theory. The investigations
into the effects that structural variations of the core cryptate
scaffold 2-Yb have on the nature and spatial orientation of the
corresponding magnetic anisotropy were performed by
analyzing the lanthanoid-induced, paramagnetic 1H NMR
shifts. To assess these changes, we used the differences
outlined in Figure 5, that is, the introduction of the peripheral
functionalization in 5-Yb resulting in the reduction of overall
symmetry (from C2 in 2-Yb to C1) and the exchange of a
trifluoroacetate anion in 5-Yb for the inner-sphere chlorido
ligand in 2-Yb. Both effects could potentially have an enormous
impact on magnetic anisotropy as it has been documented
recently in DOTA-derived systems.9,10
yield. Unfortunately, the carboxylate group proved to be a very
sluggish reactant in peptide coupling reactions with primary
amines under a variety of standard conditions (e.g., DCC/
HOBt, HATU, PyBOP, etc). Because of these unexpected
difficulties, we turned our attention to alternative trans-
formations of the ester group of 15. After a number of
unsuccessful trials, we identified the reaction of 15 with an
excess neat ethylene diamine to the corresponding amide 5-Na
as a very efficient way to generate a universally useful primary
amine functionality for further conjugation chemistry (see
analogy to cryptate 4-Ln in Figure 2). Purification of this highly
polar compound on a preparative scale is possible by column
chromatography using silanized silica gel.
For the final complexation step, ytterbium was chosen as the
paramagnetic center for a number of reasons: First, the analysis
of its magnetic anisotropy is straightforward because of the
known fact that ytterbium-induced NMR shifts in molecular
complexes are overwhelmingly due to the dipolar, pseudocon-
tact shift mechanism with only minor interference from
corresponding contact shift contributions. This circumstance
makes the magnetic analysis of 5-Yb very convenient and the
obtained results highly reliable. Second, we have already
performed similar analyses of the magnetic anisotropies in the
unfunctionalized cryptate 2-Yb and similar species.13d,e Third
and finally, ytterbium is not only relevant for its magnetic
properties but it is also of considerable current interest in the
emerging field of near-IR bioimaging because of its efficient
1
The H NMR spectrum of 5-Yb in CD3CN (Figure 6b)
shows a set of 29 paramagnetically shifted but very well-defined
resonances corresponding to the immediate cryptate core
structure (i.e., aromatic and benzylic hydrogen atoms in 5-Yb).
The signals for the C−H moieties in the peripheral ethylene
diamine unit could not be identified unambiguously because of
C
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following the previously reported methodology,13d,22 assuming
that they are dominated by the pseudocontact contribution
(δpc), which can be expressed as a linear combination of the five
components of the magnetic susceptibility tensor χ:23
2
2
2
2
⎛
⎞
⎟
⎠
⎛
⎞
⎛
⎞
⎟
x − y
1
3
3z − r
δpc = χzz
−
Trχ
+ (χ − χyy )⎜
⎜
⎜
⎝
⎟
⎠
xx
r5
r5
⎝
⎠
⎝
⎛
⎜
⎞
⎛
⎜
⎞
⎟
⎛
⎜
⎞
⎟
4yz
r5
4E
4xz
r5
⎟
⎠
+ χxy
+ χxz
+ χyz
withr
5
⎝
⎝
⎠
⎝
⎠
r
=
x2 + y2 + z2
Here, x, y and z represent the Cartesian coordinates of the
observed nuclei with the paramagnetic ion placed at the origin.
In the principal magnetic axis system, the tensor is diagonalized,
so that χxy = χxz = χyz = 0. Thus, the pseudocontact shifts were
analyzed by using a five-parameter least-squares search that
minimizes the difference between the experimental and
calculated pseudocontact shifts. These five parameters are (χzz
− 1/3Trχ), (χzz − χyy), and a set of Euler angles that relate the
principal magnetic axis system to the molecular coordinate
system. Given the small chemical shift differences introduced
by the absence of C2-symmetry in 5-Yb, we carried out this
analysis using averaged chemical shifts (Table 1). The 1H NMR
1
Figure 6. H NMR spectra of (a) unfunctionalized 2-Yb (CD3OD,
400 MHz)13d with chloride in the inner coordination sphere and (b)
functionalized 5-Yb (CD3CN, 500 MHz) with trifluoroacetate bound
to the lanthanoid.
overlap with strong residual solvent signals. Overall, the spectral
features are similar to the ones observed for 2-Yb in CD3OD
(Figure 6a).13d Typically, signals that could be observed as
singlets with an integral of two protons, in the case of 2-Yb,
split into two singlets for 5-Yb with an integral of one proton
each (see, e.g., the signals between −60 and −80 ppm in Figure
6). The shifts of the signals of the formerly equivalent protons
show small separations, but the differences do not exceed 3.5
ppm. As in the case of the parent compound 2-Yb, no exchange
processes on the NMR time scale are observable for 5-Yb.
Density functional theory (DFT) calculations in CH3CN
were performed on the cryptate cation of 5-Yb to get a deeper
understanding of the spatial structure of the cryptate. To keep
the sizable computational demands as low as possible, we used
a simplified model system with a water molecule bound to
ytterbium instead of the actually present inner-sphere
trifluoroacetate (cf. Figure 5). The obtained structure (Figure
7) shows great similarity to the calculated structure for 2-Yb13d
1
Table 1. Comparison of Experimental and Calculated H
a
NMR Shifts for 5-Yb in Acetonitrile
b
c
proton
H1o
δiexp
δiavg
δiavg,cald
−69.35/−65.97
21.63/22.55
12.79/10.88
0.02
−67.66
22.09
−68.46
25.89
H2o
H3o
H4o
H5o
H1b
H2b
H3b
H4b
H5b
H6b
H7b
H8b
H9b
H10b
11.84
12.73
0.02
2.11
−13.19/−14.55
−13.87
153.49
61.59
−13.96
148.05
63.50
d
153.49
61.82/61.35
−3.18/-4.07
−12.82/-13.72
−15.59/-15.85
12.04/11.97
34.09/33.97
69.10/68.99
−3.63
−13.27
−15.72
12.01
−2.65
−11.88
−15.06
10.63
34.01
33.32
69.05
68.81
d
113.22
113.22
134.62
0.0321
114.63
137.96
135.27/133.96
e
AFj
ppm Å3
ppm Å3
χzz
χxx − χyy
−
13 Trχ
2740 62
−8601 138
b
a
See Figure 8 for numbering scheme. Averaged chemical shifts.
c
Values obtained from the analysis of the paramagnetic shifts assuming
Figure 7. Calculated structure of 5-Yb optimized in CH3CN solution
at the TPSSh/LCRECP/6-31G(d,p) level and bond distances of the
metal coordination environment (Å).
d
that the paramagnetic shifts are purely pseudocontact in origin. Only
exp
cal)2/∑ ( exp)2]1/2
δi
,
e
one signal is observed.
where δei xp and δei xp represent the experimental and calculated values
of a nucleus i, respectively.
AF [∑ (δi
=
−
δi
j
i
i
(DFT) and the crystallographically determined one previously
reported for the structurally related cryptate 2-Lu.13b The
optimized geometry for 5-Yb retains a nearly undistorted, local
C2 symmetry in the immediate coordination sphere around the
metal, where the symmetry axis contains the oxygen atoms of
the coordinated water molecule and the Yb(III) ion. The
general arrangement of the biaryl units remains virtually
unaffected by the functionalization of the ligand.
chemical shifts of the unfunctionalized lutetium cryptate 2-
Lu13d were used to estimate the diamagnetic contributions. The
DFT structure of 5-Yb (Figure 7) optimized in acetonitrile
solution provides very good agreement between the exper-
imental and calculated Yb-induced shifts, with an agreement
factor AFj = 0.032 (Figure 8, Table 1). The excellent match
between experiment and theory unambiguously proves that our
DFT calculations provide a very accurate description of the
Lanthanoid-Induced NMR Shift Analysis. The para-
1
magnetic H NMR shifts of the cryptate 5-Yb were analyzed
D
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Figure 8. Experimental 1H NMR spectrum (CD3CN, 500 MHz) of 5-
Yb, plot of experimental versus calculated shifts, and numbering
scheme for the hydrogen atoms in 5-Yb (protons that would be related
by the pseudo C2 symmetry in the unfunctionalized cryptate have the
same name). The solid line represents a perfect fit between
experimental and calculated values.
Figure 9. Graphical representation of 5-Yb (without the bound water
molecule) and the pseudocontact shift isosurface (light green: +12
ppm, dark green: −12 ppm; negative shifts correspond to shifts to
lower field) corresponding to the magnetic susceptibility tensor χ. The
green line illustrates the effective C2 symmetry axis.25
structure of this complex, as much higher agreement factors AFj
≈ 0.06−0.09 have been considered to be acceptable for
different nonaxial Yb(III) complexes.24
Magnetic Anisotropy. Multiple studies in the past have
shown that magnetic anisotropy and hence the induced
pseudocontact NMR shifts of Yb(III) complexes can be
profoundly different upon subtle changes in the lanthanoid
coordination environment.9,10 For the purpose of this study, we
can compare two factors governing the magnetic anisotropy in
the related cryptates 2-Yb and functionalized 5-Yb, the
reduction in symmetry from C2 to C1 and the exchange of
inner-sphere monodentate ligands (Figure 5: chloride vs
trifluoroacetate). As expected given the similarity of the
measured chemical shifts of 2-Yb and 5-Yb (see Figure 6),
the calculated axial (χzz − 1/3Trχ = 2740 ppm Å3) and
rhombic (χxx − χyy = −8601 ppm Å3) components of the
magnetic susceptibility tensor in 5-Yb (Table 1) are very similar
to those obtained previously for the unfunctionalized cryptate
2-Yb (χzz − 1/3Trχ = 2197 ppm Å3; χxx − χyy = −7916 ppm
Å3).13d Figure 9 shows a schematic representation of the core
cryptate 5-Yb surrounded by an isosurface of the induced
pseudocontact shifts.
In addition to the size of the tensor components being
similar in 2-Yb and 5-Yb, the relative spatial orientation of the
two different tensors are also remarkably similar. Figure 10
clearly shows that the pseudocontact isosurfaces as a
manifestation of the underlying tensors are almost indistin-
guishable apart from very small differences in size and virtually
none in terms of orientation. This result underscores the very
robust nature of the tensors in these cryptates with a
remarkable degree of tolerance for functionalization and
inner-sphere substitution of monodentate ligands.
Figure 10. Graphical representation of the size and orientations of the
pseudocontact shift isosurfaces of the functionalized and unfunction-
alized cryptate along the three different Cartesian coordinate axes
(rows) − Right column: 2-Yb;13dLeft column: 5-Yb; Middle column:
Overlay of 2-Yb and 5-Yb.
(antenna effect), the energy is usually transferred to the
lanthanoid from the ligand-centered excited triplet level. From
the low-temperature (77 K) steady-state emission spectrum of
the photoinactive lutetium cryptate 5-Lu (Figure 11), we could
obtain an estimate for the zero-phonon T1 → S0 transition
energy E(T1) ≈ 20 400 cm−1, which is virtually identical to the
values previously found for 2-Lu13b and 2-Gd.26 Like 2-Yb,
functionalized 5-Yb shows rather strong steady-state photo-
luminescence after excitation at λex = 305 nm in CD3OD
(Figure 12) with an almost identical band shape of the
transition 2F5/2 → 2F7/2 compared to the spectrum for 2-Yb.13c
In addition, the observed monoexponential luminescence decay
(Figure 13) with a lifetime of τobs = 10.8 μs is also very similar
Luminescence Properties. The unfunctionalized parent
compound 2-Yb has very favorable photoluminescence proper-
ties, especially after perdeuteration of the cryptand scaf-
fold,13b,d,e which could be very interesting for bioanalytical
applications using the new functionalized cryptates.20 There-
fore, we also measured the luminescence of 5-Yb to see
whether we could find any detrimental effect of functionaliza-
tion on the photophysical properties. In the case of the indirect
lanthanide sensitization via the surrounding organic ligand
E
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applications where stable magnetic properties are key and
where DOTA-derived systems still suffer from fluxional
magnetic behavior due to conformational and configurational
exchange processes in the ligand backbone.
EXPERIMENTAL SECTION
■
General. Solvents were dried by standard procedures (tetrahy-
drofuran (THF), xylenes: Na; CH2Cl2; CaH2), dry dimethylforma-
mide (DMF) was used as purchased. Air-sensitive reactions were
performed under a dry, dioxygen-free atmosphere of N2 using Schlenk
technique. Column chromatography was performed with silica gel 60
(Merck KGaA, 0.063−0.200 mm) or for cryptate 5-Na with silanized
silica gel 60 (Merck KGaA, 0.063−0.200 mm). Analytical thin layer
chromatography (TLC) was done on silica gel 60 F254 plates (Merck,
coated on aluminum sheets). Electrospray ionization (ESI) mass
spectrometry was measured using Bruker Daltonics Esquire 3000plus
or Bruker Daltonics APEX II FT-ICR (FAB). NMR spectra were
measured on a Bruker AVII+500 (1H: 500 MHz), AVII+400 (1H: 400
MHz), DPX-250 (1H: 250 MHz, 13C: 62.9 MHz), and DPX-200 (1H:
200 MHz, 13C: 50 MHz).
Figure 11. Low-temperature steady-state emission spectra (λexc = 315
nm, T = 77 K) for 5-Lu in a glassy CH3OH/EtOH matrix (1:1, v/v).
Density Functional Theory Calculations. All calculations were
performed employing DFT within the hybrid meta generalized
gradient approximation, with the TPSSh exchange-correlation func-
tional,27 and the Gaussian 09 package (Revision D.01).28 Full
geometry optimizations of 5-Yb were performed in acetonitrile
solution by using the large-core relativistic effective core potential
(LCRECP) of Dolg et al. and the related [5s4p3d]-GTO valence basis
set for Yb,29 and the standard 6-31G(d,p) basis set for C, H, N, and O
atoms. No symmetry constraints were imposed during the
optimizations. The default values for the integration grid (“fine”)
and the self-consistent field energy convergence criteria (1 × 10−8)
were used. The stationary points found on the potential energy
surfaces as a result of the geometry optimizations were tested to
represent energy minima rather than saddle points via frequency
analysis. Solvent effects (acetonitrile) were taken into account by using
the integral equation formalism variant of the polarizable continuum
model as implemented in Gaussian 09.30
Figure 12. Normalized steady-state emission spectra for 5-Yb (black)
and for 2-Yb (red)13c in solution (CD3OD, λexc = 305 nm, emission
path: long pass filter RG780).
Luminescence Spectroscopy. Steady-state emission spectra were
acquired on a PTI Quantamaster QM4 spectrofluorimeter using 1.0
cm quartz cuvettes. The excitation light source was a 75 W continuous
xenon short arc lamp. Emission was monitored at 90° using a PTI
P1.7R detector module (Hamamatsu PMT R5509−72 with a
Hamamatsu C9525 power supply operated at −1500 V and a
Hamamatsu liquid N2 cooling unit C9940 set to −80 °C). For the
near-IR steady-state emission measurements, a long-pass filter RG-780
(Schott, 3.0 mm thickness, transmission >83% between 800 and 850
nm and >99% between 850 and 1700 nm) was used in the emission
channel to avoid higher-order excitation light. Low-temperature
spectra were recorded on frozen glasses of solutions of 5-Lu
(MeOH/EtOH 1:1, v/v) using a dewar cuvette filled with liquid N2
(T = 77 K). Spectral selection was achieved by single grating
monochromators (excitation: 1200 grooves/mm, blazed at 300 nm;
near-IR emission: 600 grooves/mm, blazed at 1200 nm). Lumines-
cence lifetimes were determined with the same instrumental setup
without the use of the long-pass filter. The light source for these
measurements was a xenon flash lamp (Hamamatsu L4633; 10 Hz
repetition rate, pulse width ca. 1.5 μs full width at half-maximum).
Lifetime data analysis (deconvolution, statistical parameters, etc.) was
performed using the software package FeliX32 from PTI. Lifetimes
were determined by deconvolution fitting of the decay profiles with
the instrument response function, which was determined using a dilute
aqueous dispersion of colloidal silica (Ludox AM-30). The estimated
uncertainties in τ are 10%.
Figure 13. Luminescence decay profile of 5-Yb (black) and
monoexponential fit in red (CD3OD, λexc = 305 nm, λem = 970 nm).
to the behavior observed for 2-Yb (τobs = 12.3 μs) under
identical conditions. Taken together, the excellent photo-
luminescence properties documented previously for the
unfunctionalized cryptate 2-Yb are completely retained in the
functionalized cryptates 5-Yb.
CONCLUSION
■
In summary, we have developed a practical synthetic route to
rigid lanthanoid cryptates 5-Ln (Ln = Yb, Lu) with a peripheral
primary amino group for future conjugation chemistry to
biomolecules. These species are highly stable in solution and
can even be purified by reversed-phase HPLC. In addition, the
functionalized ytterbium cryptate retains all excellent physical
properties found in the unfunctionalized parent cryptate 2-Yb,
such as well-defined, time-invariant magnetic anisotropy and
efficient photoluminescence in solution. Particularly remarkable
is the great apparent resilience of its magnetic anisotropy
toward changes in symmetry and anion exchange in the inner-
coordination sphere. These findings show that this type of
lanthanoid cryptate will be a very good candidate in future
Synthesis. 6,6′-Dimethyl-2,2′-bipyridine-4-carboxylic Acid Meth-
yl Ester (10). Under N2, a two-neck Schlenk flask equipped with a
reflux condenser was charged with 2-methyl-6-(trifluoromethylsulfo-
nyloxy)-isonicotinic acid methyl ester (9)16 (11.97 g, 40.00 mmol, 1.0
equiv), 2-methyl-6-(tributylstannyl)pyridin (8)16 (15.29 g, 40.00
mmol, 1.0 equiv), and PPh3 (1.05 g, 4.00 mmol, 0.1 equiv) in dry
F
DOI: 10.1021/acs.inorgchem.6b00591
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
xylene (300 mL, isomeric mixture). The solution was degassed by one
freeze−pump−thaw cycle before solid [PdCl2(PPh3)2] (1.40 g, 2.00
mmol, 0.05 equiv) was added. After two additional freeze−pump−
thaw cycles, the yellow suspension was heated to reflux for 24 h. The
reaction mixture was allowed to come to ambient temperature and was
poured into a saturated, aqueous solution of Na2H2EDTA (300 mL).
The aqueous phase was extracted with CH2Cl2 (3 × 300 mL), and the
combined organic phases were dried (MgSO4) and concentrated
under reduced pressure. The remaining residue was dissolved in
CH3CN, and the solution was extracted continuously in a liquid−
liquid extractor with n-heptane for 24 h. The pale yellow product,
which crystallized from the extract after standing overnight at room
temperature, was collected, washed with n-heptane, and dried in vacuo
(6.78 g, 70%). The analytical data were in complete agreement with
the literature.14,16
and stirred overnight (15 h). A saturated solution of sodium
thiosulfate pentahydrate (10 mL) and water (200 mL) was added,
and the mixture was stirred for 30 min. The phases were separated,
and the aqueous phase was extracted with CH2Cl2 (2 × 75 mL). The
combined organic layers were dried (MgSO4) and concentrated. The
isolated crude product was purified by column chromatography (SiO2,
CH2Cl2/MeOH 100:1 → 25:1, preloading onto SiO2) to give the title
compound as a colorless solid (5.85 g, 78%).
1H NMR (200 MHz, CDCl3): δ = 8.23 (d, J = 2.5 Hz, 1 H), 8.14 (d,
J = 2.4 Hz, 1 H), 7.67 (dd, J = 2.0, 7.5 Hz, 1 H), 7.59−7.50 (m, 1 H),
7.34 (t, J = 7.9 Hz, 1 H), 4.73 (s, 2 H), 4.70 (s, 2 H), 3.96 (s, 3 H)
ppm. 13C NMR (126 MHz, CDCl3): δ = 163.7, 148.4, 148.2, 143.6,
142.7, 128.0, 127.9, 127.8, 127.5, 125.3, 124.7, 53.1, 25.4, 25.1 ppm.
MS (ESI+): m/z (%) = 454.73 (100, [M + Na]+, Br2-pattern). TLC: Rf
= 0.22 (SiO2, CH2Cl2/MeOH 25:1, detection: UV).
Sodium Cryptate 15. Under N2, macrocycle 1419 (0.48 g, 1.22
mmol, 1.0 equiv) and the dibromide 13 (0.53 g, 1.22 mmol, 1.0 equiv)
were dissolved in CH3CN (500 mL, HPLC grade), and Na2CO3 (1.29
g, 12.2 mmol, 10 equiv) was added. The mixture was heated under
reflux for 40 h, cooled to ambient temperature, and filtered. The
filtrate was concentrated under reduced pressure, and the resulting
residue was subjected to column chromatography (SiO2, gradient:
CH2Cl2/MeOH 15:1 → 9:1) to yield the title compound as a light-
yellow solid (0.30 g, 31%).
1H NMR (200 MHz, CDCl3): δ = 8.72 (s, 1 H), 8.20 (d, J = 7.8 Hz,
1 H), 7.71 (s, 1 H), 7.68 (d, J = 7.8 Hz, 1 H), 7.18 (d, J = 7.8 Hz, 1 H),
3.98 (s, 3 H), 2.72 (s, 3 H), 2.69 (s, 3 H) ppm.
6,6′-Dimethyl-4-methyloxycarbonyl-2,2′-bipyridine N,N′-dioxide
(11). With cooling in an ice bath, a solution of m-chloroperoxybenzoic
acid (32.35 g of 77 wt %, 24.90 g of pure, 144 mmol, 2.4 equiv) in
CH2Cl2 (750 mL) was added dropwise to a solution of 6,6′-dimethyl-
2,2′-bipyridine-4-carboxylic acid methyl ester (10) (14.57 g, 60.1
mmol, 1.0 equiv) in CH2Cl2 (600 mL) over the course of 1.5 h. The
pale yellow solution was allowed to reach room temperature over ca. 3
h and was stirred overnight. After extraction of the reaction mixture
with aq. NaHCO3 solution (pH 8, 2 × 300 mL) and water (300 mL),
the organic layer was dried over MgSO4, and the solvent was removed
under reduced pressure (bath temperature <35 °C). The crude
product was purified by column chromatography (SiO2, CH2Cl2/
MeOH 100:1 → 24:1) to afford the title compound as an off-white
solid (13.85 g, 84%).
1H NMR (200 MHz, CDCl3): δ = 8.26−8.18 (m, 1 H), 8.10−8.02
(m, 1 H), 8.01−7.92 (m, 1 H), 7.88−7.60 (m, 8 H), 7.58−7.33 (m, 4
H), 4.32 (d, J = 12.0 Hz, 1 H), 4.29 (d, J = 11.7 Hz, 1 H), 4.08−3.31
(m, 13 H) ppm. 13C NMR (50.3 MHz, CDCl3): δ = 163.6, 158.8,
158.4 157.8, 157.6, 157.1, 157.0, 156.4, 156.2, 148.6, 148.5, 145.5,
144.0, 138.32, 138.30, 130.2, 128.6, 126.9, 126.8, 125.4, 125.3, 124.74,
124.68, 122.2, 122.1, 121.3, 121.2, 60.9, 60.70, 60.66, 60.62, 54.6, 54.3,
53.1 ppm. MS (ESI, pos. mode): m/z (%) = 687.20 (100, [M]+).TLC:
Rf = 0.45 (SiO2, CH2Cl2/MeOH 9:1, detection UV + I2 vapor). Anal.
Calcd (Found) for C38H32BrN8NaO4·2 H2O (Mr = 803.64): C, 56.79
(56.61); H, 4.52 (4.28); N, 13.94 (13.73).
Sodium Cryptate 16. Compound 15 (71.0 mg, 88.3 μmol, 1.0
equiv) was dissolved in MeOH (8 mL), and a solution of NaOH (18.5
mg, 462 μmol, 5.2 equiv) in water (2 mL) was added dropwise. The
solution was stirred at 40 °C (bath temperature) for 3 h. The solvents
were removed, and the residue was subjected to column chromatog-
raphy (SiO2, CH2Cl2/MeOH 2:1, detection: UV). The product was
obtained as a colorless solid (51 mg, 76%).
1H NMR (250 MHz, CDCl3): δ = 8.01 (br s, 2 H), 7.49−7.30 (m, 3
H), 3.94 (s, 3 H), 2.64 (s, 3 H), 2.61 (s, 3 H) ppm. 13C NMR (62.9
MHz, CDCl3): δ = 164.1, 150.2, 150.0, 143.7, 143.2, 127.3, 126.8,
125.7, 125.5, 125.3, 124.9, 52.7, 17.97, 17.94. MS (FAB, pos. mode):
m/z (%) = 275.1 (100, [M + H]+), 259.1 (13). TLC: Rf = 0.08 (SiO2,
CH2Cl2/MeOH 24:1, detection: UV). mp:190−192 °C (decomp).
6,6′-Bis(bromomethyl)-2,2′-bipyridine-4-carboxylic Acid Methyl
Ester (12).17 Under N2, (CF3CO)2O (44.1 mL, 66.6 g, 317 mmol, 12
equiv) was added dropwise via syringe to a yellow solution of 11 (7.25
g, 26.4 mmol, 1.0 equiv) in dry CH2Cl2 (80 mL). The brown reaction
mixture was heated under reflux for 1.5 h before the volatiles were
removed in vacuo. Under N2, the obtained orange residue was
dissolved in a mixture of dry DMF/THF (40 mL, 1:1, v/v). Under N2
and with ice-cooling, anhydrous LiBr (18.4 g, 211 mmol, 8.0 equiv)
was dissolved in dry THF (50 mL), and the cold solution was added
dropwise to the reaction mixture. After it was stirred at room
temperature for 12 h, the solvents were removed under reduced
pressure (bath temperature 40 °C). The brown residue was dissolved
in CH2Cl2/water (400 mL, 1:1, v/v), and the aqueous phase was
adjusted to pH ≈ 6 with saturated aqueous Na2CO3. The organic layer
was washed with additional water (2 × 150 mL), dried (MgSO4), and
concentrated to dryness. The crude product was purified by column
chromatography (SiO2, CH2Cl2/MeOH 100:1, preloading onto SiO2)
to give the product as a yellow solid (7.00 g, 66%).
1H NMR (200 MHz, CD3OD): δ = 8.22 (d, J = 2.3 Hz, 1 H), 8.14
(d, J = 2.3 Hz, 1 H), 7.99−7.73 (m, 10 H), 7.66−7.36 (m, 5 H), 4.30
(d, J = 11.8 Hz, 2 H), 3.95−3.75 (m, 4 H), 3.64−3.34 (m, 6 H) ppm.
13C NMR (50.3 MHz, CD3OD): δ = 169.5, 160.1, 159.3, 159.2,
157.91, 157.88, 150.2, 149.5, 146.6, 145.9, 139.5, 139.3, 131.0, 130.6,
128.5, 128.4, 128.1, 125.61, 125.56, 125.51, 123.13. 123.11, 122.34,
122.31, 61.81, 61.73, 61.69, 55.63, 55.55 ppm. MS (ESI, pos. mode):
m/z (%) = 673.21 (66, [M + H]+), 695.17 (100, [M + Na]+). Rf = 0.17
(SiO2, CH2Cl2/MeOH 2:1, detection: UV). Anal. Calcd (Found) for
C37H29N8NaO4·5H2O (Mr = 762.74): C, 58.26 (57.96); H, 5.15
(4.94); N, 14.69 (14.72).
Sodium Cryptate 5-Na. Under N2 and with ice-cooling, 15 (250.7
mg, 0.327 mmol, 1.0 equiv) was added as a solid to freshly dried and
distilled ethylenediamine (3.5 mL, 3.15 g, 52.4 mmol, 150 equiv). The
slightly red suspension was allowed to warm to room temperature and
stirred for 2 d before the volatiles were removed in vacuo. The crude
product was subjected to column chromatography (silanized SiO2,
CH2Cl2/MeOH 24:1, preloading onto silanized SiO2) to give pure 5-
Na as an off-white solid (197 mg, 76%).
1H NMR (200 MHz, CDCl3): δ = 8.97−8.84 (m, 1 H), 8.47−8.33
(m, 1 H), 8.08−7.96 (m, 1 H), 7.90 (t, J = 7.8 Hz, 1 H), 7.59−7.47
(m, 1 H), 4.73 (s, 2 H), 4.69 (s, 2 H), 4.02 (s, 4 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 165.4, 157.6, 156.6, 156.4, 154.4, 139.9, 138.5,
124.4, 123.1, 121.0, 120.2, 53.0, 33.6, 33.4 ppm. MS (ESI, pos. mode):
m/z (%) 258.99 (42), 336.88 (46), 400.74 (100, [M + H]+), 422.69
(100, [M + K]+). TLC: Rf = 0.64 (SiO2, CH2Cl2/MeOH 100:1,
detection UV).
6,6′-Bis(bromomethyl)-4-methyloxycarbonyl-2,2′-bipyri-dine
N,N′-dioxide (13).18 Under N2 and with cooling in an ice bath, urea/
H2O2 adduct (3.77 g, 40.1 mmol, 2.3 equiv) was added in portions to a
suspension of 3 (6.97 g, 17.4 mmol, 1.0 equiv) in dry CH2Cl2 (300
mL). Then, (CF3CO)2O (5.6 mL, 8.42 g, 40.1 mmol, 2.3 equiv) was
added slowly; the mixture was allowed to warm to room temperature
1H NMR (250 MHz, CD3OD): δ = 8.48 (d, J = 2.3 Hz, 1 H), 8.35
(d, J = 2.6 Hz, 1 H), 7.96−7.82 (m, 9 H), 7.79 (dd, J = 2.0, 7.8 Hz, 1
H), 7.62−7.53 (m, 1 H), 7.51−7.42 (m, 4 H), 4.43−4.30 (m, 2 H),
4.02−3.85 (m, 4 H), 3.83−3.60 (m, 4 H), 3.59−3.39 (m, 4 H), 3.30−
3.20 (m, 2 H) ppm. 13C NMR (62.9 MHz, CD3OD): δ = 166.3, 160.1,
159.3, 159.2, 158.3, 157.8, 150.25, 150.23, 146.2, 146.0, 139.6, 139.4,
131.9, 131.4, 128.71, 128.69, 126.8, 125.7, 123.2, 122.4, 61.9, 61.82,
61.75, 61.6, 55.5, 55.4, 41.0, 39.4 ppm. MS (ESI, pos. mode): m/z (%)
357.99 (34), 715.10 (100, [M]+). Anal. Calcd (Found) for
G
DOI: 10.1021/acs.inorgchem.6b00591
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
C39H36BrN10NaO3·4 H2O (Mr = 867.72): C, 53.98 (53.85); H, 5.11
(4.92); N, 16.14 (16.00). TLC: Rf = 0.48 (SiO2, CH2Cl2/MeOH 4:1,
detection UV + ninhydrin).
*E-mail: carlos.platas.iglesias@udc.es. (C.P.-I.)
Notes
The authors declare no competing financial interest.
Synthesis of Ln Complexes 5-LnGeneral Procedure. The
sodium cryptate 5-Na (1.0 equiv) and Ln(X)3·nH2O (1.7 equiv)
were suspendend in CH3CN (HPLC grade), and the mixture was
heated under reflux for at least 40 h. The solvent was removed in
vacuo, and the remaining residue was taken up in a minimum of
CH3CN/H2O (1:1, v/v) and subjected to preparative reversed-phase
HPLC (Lichrospher RP-18e, 250× 10 mm-10 μm, flow rate: 3.0 mL
min−1, UV detection: 300 nm) with H2O (+1% TFA, v/v) as mobile
Phase A, CH3CN (HPLC grade) as mobile Phase B, and the following
gradient: 0 min: 85%A/15%B; 5 min 85%A/15%B; 19 min: 45%A/
55%B; 25 min: 45%A/55%B; 40 min: 85%A/15%B; 50 min: 85%A/
15%B.
ACKNOWLEDGMENTS
■
Financial support is gratefully acknowledged from DFG (Emmy
Noether and Heisenberg Fellowships for M.S., Research Grant
SE 1448/6-1), German National Academic Foundation
(predoctoral fellowship for E.K.), and Int. Max Planck Research
School in Chemical Biology (predoctoral fellowship for C.B.).
C.P.-I. thanks Centro de Supercomputacio
(CESGA) for providing the computer facilities.
́
n de Galicia
The composition of the collected fractions was checked by
analytical, reversed-phase HPLC (Lichrospher RP-18e, 125 × 4 mm-
5 μm, flow rate: 1 mL min−1, UV detection: 300 nm), using the same
mobile phase mixture and gradient (see Supporting Information for
HPLC traces). Fractions containing pure lanthanoid complexes 5-Ln
were combined (retention times tr ≈ 12.6−12.7 min) and evaporated
to dryness at room temperature. The complexes were isolated as off-
white or faintly yellow solids.
REFERENCES
■
(1) The Rare Earth Elements - Fundamentals and Applications;
Atwood, D. A., Ed.; Wiley: Chichester, U.K., 2012.
(2) Geraldes, C. F. G. C. Lanthanide Shift Reagents. In The Rare
Earth Elements - Fundamentals and Applications; Atwood, D. A., Ed.;
Wiley: Chichester, U.K., 2012; p 501.
(3) The Chemistry of Contrast Agents in Medical Magnetic Resonance
Imaging, 2nd ed.; Merbach, A. S., Helm, L., Toth, E., Eds.; Wiley:
Chichester, U.K., 2013.
(4) (a) Habib, F.; Murugesu, M. Chem. Soc. Rev. 2013, 42, 3278.
(b) Woodruff, D. N.; Winpenny, R. E. P.; Layfield, R. A. Chem. Rev.
2013, 113, 5110. (c) Liddle, S. T.; van Slageren, J. Chem. Soc. Rev.
2015, 44, 6655.
(5) (a) Su, X.-C.; Otting, G. J. Biomol. NMR 2010, 46, 101.
(b) Otting, G. Annu. Rev. Biophys. 2010, 39, 387. (c) Liu, W.-M.;
Overhand, M.; Ubbink, M. Coord. Chem. Rev. 2014, 273−274, 2.
(6) Selected review: Stasiuk, G. J.; Long, N. J. Chem. Commun. 2013,
49, 2732 and references cited therein..
(7) Selected reviews: (a) Parker, D.; Dickins, R. S.; Puschmann, H.;
Crossland, C.; Howard, J. A. K. Chem. Rev. 2002, 102, 1977.
(b) Platas-Iglesias, C. Eur. J. Inorg. Chem. 2012, 2012, 2023.
(8) Selected examples: (a) Martins, A. F.; Eliseeva, S. V.; Carvalho,
H. F.; Teixeira, J. M. C.; Paula, C. T. B.; Hermann, P.; Platas-Iglesias,
C.; Petoud, S.; Toth, E.; Geraldes, C. F. G. C. Chem. - Eur. J. 2014, 20,
14834. (b) Polasek, M.; Rudovsky, J.; Hermann, P.; Lukes, I.; Vander
Elst, L.; Muller, R. N. Chem. Commun. 2004, 2602. (c) Keizers, P. H.
J.; Desreux, J. F.; Overhand, M.; Ubbink, M. J. Am. Chem. Soc. 2007,
129, 9292.
Ytterbium Cryptate 5-Yb. 5-Na (30 mg, 38 μmol, 1.0 equiv) and
YbCl3·6 H2O (25 mg, 63 μmol, 1.7 equiv) in 15 mL of CH3CN
(HPLC grade). Yield: 14 mg.
1H NMR (500 MHz, CD3CN): δ = 153.5 (H1b, 2 H), 135.3/134.0
(H10b, 2 H), 113.2 (H9b, 2 H), 69.1/69.0 (H8b, 2 H), 61.8/61.4
(H2b, 2 H), 34.1/33.9 (H7b, 2H), 22.6/21.6 (H2o, 2H), 12.8/10.9
(H3o, 2 H), 12.04/11.97 (H6b, 2 H), 0.02 (H4o, 1 H), −3.2/−4.1
(H3b, 2 H), −12.8/−13.7 (H4b, 2 H), −13.2/−14.6 (H5o, 2 H),
−15.6/−15.9 (H5b, 2 H), −66.0/−69.4 (H1o, 2H) ppm. Remarks:
(a) The signals representing the four protons of the ethylene group
could not be identified unambigiously, as in the respective region of
the spectrum there are several solvent signals; (b) The numbering
scheme uses the same name for protons that would be symmetry-
related in the unfunctionalized cryptate, see Figure 8. 19F NMR (376
MHz, CD3CN): δ = −76.4 (s, 9 F), −116.5 (s, 3 F) ppm. 19F NMR
(376 MHz, CD3OD): δ = −77.0 (s, 9 F), −114.4 (s, 3 F) ppm. MS
(ESI, pos. mode): m/z (%) = 489.7 (100, {[Yb(II)(L)] +
CF3COO}2+), 560.8 (58). Analytical HPLC: tr = 12.7 min (see Figure
S13 in the Supporting Information).
Lutetium Cryptate 5-Lu. 5-Na (20 mg, 25 μmol, 1.0 equiv) and
Lu(OTf)3 (27 mg, 43 μmol, 1.7 equiv) in 15 mL of CH3CN (HPLC
grade). Yield: 18 mg.
1H NMR (400 MHz, CD3CN): δ = 10.0 (t, J = 4.6 Hz, 1 H), 8.90
(d, J = 2.3 Hz, 1 H), 8.70 (d, J = 2.4 Hz, 1 H), 8.48 (dd, J = 1.7, 7.8
Hz, 1 H), 8.33−8.28 (m, 2 H), 8.23−8.05 (m, 8 H), 7.62−7.55 (m, 4
H), 4.79−4.71 (m, 4 H), 4.13−3.93 (m, 6 H), 3.84 (d, J = 13.1 Hz, 1
H), 3.80−3.64 (m, 5 H), 3.23 (t, J = 5.3 Hz, 2 H) ppm. MS (ESI, pos.
mode.): m/z (%) = 360. (87), 478.3 (79), 561.3 (84), 697.3 (100).
Analytical HPLC: tr = 12.6 min (see Figure S14 in the Supporting
Information).
(9) (a) Boulon, M.-E.; Cucinotta, G.; Luzon, J.; Degl’Innocenti, C.;
Perfetti, M.; Bernot, K.; Calvez, G.; Caneschi, A.; Sessoli, R. Angew.
Chem., Int. Ed. 2013, 52, 350. (b) Cucinotta, G.; Perfetti, M.; Luzon, J.;
Etienne, M.; Car, P. E.; Caneschi, A.; Calvez, G.; Bernot, K.; Sessoli, R.
Angew. Chem., Int. Ed. 2012, 51, 1606.
(10) (a) Blackburn, O. A.; Chilton, N. F.; Keller, K.; Tait, C. E.;
Myers, W. K.; McInnes, E. J. L.; Kenwright, A. M.; Beer, P. D.;
Timmel, C. R.; Faulkner, S. Angew. Chem., Int. Ed. 2015, 54, 10783.
(b) Liu, T.; Nonat, A.; Beyler, M.; Regueiro-Figueroa, M.; Nchimi
Nono, K.; Jeannin; Camerel, O. F.; Debaene, F.; Cianfer
́
ani-Sanglier,
ASSOCIATED CONTENT
■
S.; Tripier, R.; Platas-Iglesias, C.; Charbonniere, L. J. Angew. Chem., Int.
̀
S
* Supporting Information
Ed. 2014, 53, 7259. (c) Blackburn, O. A.; Edkins, R. M.; Faulkner, S.;
Kenwright, A. M.; Parker, D.; Rogers, N. J.; Shuvaev, S. Dalton Trans.
2016, 45, 6782.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.6b00591.
(11) Review: Zwier, J. M.; Bazin, H.; Lamarque, L.; Mathis, G. Inorg.
Chem. 2014, 53, 1854.
NMR spectra of the compounds 10, 11, 12, 13, 15, 16,
5-Na, and 5-Lu. HPLC traces for 5-Ln. Cartesian
coordinates for the structure of 5-Yb as obtained by
DFT calculations. (PDF)
(12) Alpha, B.; Lehn, J.-M.; Mathis, G. Angew. Chem., Int. Ed. Engl.
1987, 26, 266.
(13) (a) Lehn, J.-M.; Roth, C. O. Helv. Chim. Acta 1991, 74, 572.
(b) Doffek, C.; Alzakhem, N.; Molon, M.; Seitz, M. Inorg. Chem. 2012,
51, 4539. (c) Doffek, C.; Seitz, M. Angew. Chem., Int. Ed. 2015, 54,
9719. (d) Doffek, C.; Alzakhem, N.; Bischof, C.; Wahsner, J.; Guden-
̈
AUTHOR INFORMATION
■
Silber, T.; Lugger, J.; Platas-Iglesias, C.; Seitz, M. J. Am. Chem. Soc.
̈
Corresponding Authors
*E-mail: michael.seitz@uni-tuebingen.de. (M.S.)
2012, 134, 16413. (e) Guden-Silber, T.; Doffek, C.; Platas-Iglesias, C.;
̈
Seitz, M. Dalton Trans. 2014, 43, 4238.
H
DOI: 10.1021/acs.inorgchem.6b00591
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Inorganic Chemistry
Article
(14) (a) Havas, F.; Danel, M.; Galaup, C.; Tisnes, P.; Picard, C.
Tetrahedron Lett. 2007, 48, 999. (b) Havas, F.; Leygue, N.; Mestre, B.;
Galaup, C.; Picard, C. Tetrahedron 2009, 65, 7673.
(15) (a) Lamarque, L.; Bazin, H.; Blanche, E. (Cisbio International).
Patent WO 2010/070232, June 24, 2010. (b) Ansanay, H.; Fink, M.;
Mathis, G.; Maurel, D.; Trinquet, E.; Pin, J.-P. (Cisbio International).
Patent WO 2006/085040, August 17, 2006.
(16) Mathieu, J.; Marsura, A. Synth. Commun. 2003, 33, 409.
(17) In analogy to: Psychogios, N.; Regnouf-de-Vains, J.-B.; Stoeckli-
Evans, H. M. Eur. J. Inorg. Chem. 2004, 2004, 2514.
(18) In analogy to: Caron, S.; Do, N. M.; Sieser, J. E. Tetrahedron
Lett. 2000, 41, 2299.
(19) Newkome, G. R.; Pappalardo, S.; Gupta, V. K.; Fronczek, F. R. J.
Org. Chem. 1983, 48, 4848.
(20) Selected reviews: (a) Bunzli, J.-C. G. J. Lumin. 2016, 170, 866.
̈
(b) Bunzli, J.-C. G.; Eliseeva, S. V. J. Rare Earths 2010, 28, 824.
̈
(c) Comby, S.; Bunzli, J.-C. G. In Handbook on the Physics and
Chemistry of Rare Earths; Gschneidner, K. A., Jr., Bunzli, J.-C. G.,
Pecharsky, V. K., Eds.; Elsevier: Amsterdam, 2007; Vol. 37, pp 217.
(21) Emsley, J. W.; Phillips, L. Prog. Nucl. Magn. Reson. Spectrosc.
1971, 7, 1.
̈
̈
́
(22) Rodríguez-Rodríguez, A.; Esteban-Gomez, D.; de Blas, A.;
Rodríguez-Blas, T.; Fekete, M.; Botta, M.; Tripier, R.; Platas-Iglesias,
C. Inorg. Chem. 2012, 51, 2509.
(23) Forsberg, J. H.; Delaney, R. M.; Zhao, Q.; Harakas, G.;
Chandran, R. Inorg. Chem. 1995, 34, 3705.
(24) Lisowski, J.; Sessler, J. L.; Lynch, V.; Mody, T. D. J. Am. Chem.
Soc. 1995, 117, 2273. (b) Lima, L. M. P.; Lecointre, A.; Morfin, J.-F.;
de Blas, A.; Visvikis, D.; Charbonnier
R. Inorg. Chem. 2011, 50, 12508. (c) del C. Fernan
Bastida, R.; Macías, A.; Perez-Lourido, P.; Platas-Iglesias, C.; Valencia,
̀
e, L. J.; Platas-Iglesias, C.; Tripier,
́
dez-Fernandez, M.;
́
́
L. Inorg. Chem. 2006, 45, 4484.
(25) Graphical representation calculated using the program Mayavi 2:
Ramachandran, P.; Varoquaux, G. Comput. Sci. Eng. 2011, 13, 40.
(26) Prodi, L.; Maestri, M.; Balzani, V.; Lehn, J.-M.; Roth, C. Chem.
Phys. Lett. 1991, 180, 45.
(27) Tao, J. M.; Perdew, J. P.; Staroverov, V. N.; Scuseria, G. E. Phys.
Rev. Lett. 2003, 91, 146401.
(28) Frisch, M. J. et al. Gaussian 09, Revision D.01; Gaussian, Inc:
Wallingford, CT, 2009.
(29) Dolg, M.; Stoll, H.; Savin, A.; Preuss, H. Theor. Chim. Acta 1989,
75, 173.
(30) Tomasi, J.; Mennucci, B.; Cammi, R. Chem. Rev. 2005, 105,
2999.
I
DOI: 10.1021/acs.inorgchem.6b00591
Inorg. Chem. XXXX, XXX, XXX−XXX