Macrocyclic Ligands with an Unprecedented Size-Selectivity Pattern for the Lanthanide Ions

Article abstract of DOI:10.1021/jacs.0c05217

Lanthanides (Ln3+) are critical materials used for many important applications, often in the form of coordination compounds. Tuning the thermodynamic stability of these compounds is a general concern, which is not readily achieved due to the similar coord

Full text of DOI:10.1021/jacs.0c05217

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Macrocyclic Ligands with an Unprecedented Size-Selectivity Pattern
for the Lanthanide Ions
Aohan Hu, Samantha N. MacMillan, and Justin J. Wilson*
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ABSTRACT: Lanthanides (Ln3+) are critical materials used for
many important applications, often in the form of coordination
compounds. Tuning the thermodynamic stability of these com-
pounds is a general concern, which is not readily achieved due to the
similar coordination chemistry of lanthanides. Herein, we report two
18-membered macrocyclic ligands called macrodipa and macrotripa
that show for the first time a dual selectivity toward both the light,
large Ln3+ ions and the heavy, small Ln3+ ions, as determined by
potentiometric titrations. The lanthanide complexes of these ligands
were investigated by NMR spectroscopy and X-ray crystallography,
which revealed the occurrence of a significant conformational toggle
between a 10-coordinate Conformation A and an 8-coordinate
Conformation B that accommodates Ln3+ ions of different sizes. The
origin of this selectivity pattern was further supported by density functional theory (DFT) calculations, which show the
complementary effects of ligand strain energy and metal−ligand binding energy that contribute to this conformational switch. This
work demonstrates how novel ligand design strategies can be applied to tune the selectivity pattern for the Ln3+ ions.
INTRODUCTION
■
The unique physical properties of the lanthanides (Ln3+) are
critical for use in magnets, superconductors, catalysts,
luminescent phosphors, and medicinal agents.1−6 Despite their
diverse magnetic and electronic properties, Ln3+ ions possess
similar chemical properties dictated by their strong preference
for the +3 oxidation state and tendency to engage in ionic
bonding.7,8 The major distinguishing feature among them is
their ionic radius, which decreases across the series, a
phenomenon known as the lanthanide contraction.9
For many applications of the Ln3+, a ligand is required to
chelate these ions to control and modify their chemical
properties. The availability of a range of chelators with different
affinities and selectivity patterns for the Ln3+ ions, measured by
the stability constant KLnL, is valuable for their implementa-
tion.10 Generally, most ligands possess a higher affinity for the
heavier, smaller Ln3+ ions because the increased charge density
on these smaller ions enhances metal−ligand electrostatic
interactions.11 Recent ligand design efforts, however, have led to
systems with other Ln3+-selectivity patterns. To date, three types
of selectivity patterns have been identified (Figure 1). As noted
above, the most common trend shows a systematic increase in
Figure 1. Stability constants of Ln3+ complexes formed with EDTA,
OBETA, and macropa plotted versus ionic radii.
Received: May 12, 2020
K
LnL across the lanthanide series (type I). This type I behavior is
observed for many well-known ligands including EDTA12
(Figure 1 and Chart 1), 1,4,7,10-tetraazacyclododecane-
1,4,7,10-tetraacetic acid (DOTA),13 and diethylenetriamine-
pentaacetic acid (DTPA).14,15
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A

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selectivity patterns is that they all have a maximum affinity for
only one Ln3+ ion.
Chart 1. Structures of Ligands Discussed in This Work
Inspired by macropa and our ongoing research efforts on
chelating agents for large metal ions of biomedical and industrial
relevance,21−24 we sought to explore other ligands containing
18-membered macrocycles. Specifically, we investigated an
isomer of macropa, called macrodipa, and a triaza-18-crown-6
ligand25,26 bearing three pendent picolinate donors, macrotripa
(Chart 1). Notably, these macrocycles are cyclic analogues of
the previously reported ligand OxyMepa27 (Chart 1) that
provides a similar albeit truncated set of donor atoms. Over the
course of our studies on their Ln3+ coordination chemistry, we
found that macrodipa and macrotripa undergo dramatic
conformational changes upon binding large versus small ions.
These conformational changes manifest in a previously
unreported type IV selectivity pattern with one minimum and
two maxima of stability across the Ln3+ series. This work
demonstrates how novel ligand design strategies can be
employed to differentiate these ions in new ways.
RESULTS AND DISCUSSION
■
The syntheses of macrodipa and macrotripa (Schemes S1 and
S2) involve the assembly of the tosyl-protected 18-crown-6
macrocycles, deprotection of the tosyl groups, and subsequent
alkylation of the picolinate donor arms. They were characterized
by NMR spectroscopy, mass spectrometry, and HPLC (Figures
S1−S10).
Potentiometric titrations were performed to determine their
protonation constants (Ki, Table S1). To probe the thermody-
namic affinities of these ligands for Ln3+ ions, we conducted
potentiometric titrations to obtain their stability constants (KLnL
and KLnHL, Table 1). These protonation and stability constants
are defined in eqs 1−3, with the concentrations of all species at
chemical equilibrium.
Another less frequently observed trend, type II, has the
stability reach a maximum prior to dropping again. The ligands
OBETA16,17 (Figure 1 and Chart 1) and 1,4,7,10-tetrakis-
(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane
(TCMC)18 follow this pattern. The rarely observed behavior,
type III, occurs with ligands having reverse-size selectivity, an
unusual thermodynamic preference for large over small Ln3+
ions. This pattern has been observed in ligands containing the
large diaza-18-crown-6 macrocycle, such as macropa19 (Figure 1
and Chart 1) and 1,10-diaza-4,7,13,16-tetraoxacyclooctadecane-
N,N′-diacetic acid (dacda).20 A common feature of these three
Ki = [HiL]/[H+][Hi−1L]
(1)
KLnL = [LnL]/[Ln3+][L]
(2)
KLnHL = [LnHL]/[H+][LnL]
(3)
Table 1. Stability Constants of the Lanthanide Complexes Formed with Macrodipa, Macrotripa, OxyMepa, Macropa, EDTA, and
OBETA
a
a
b
c
d
e
macrodipa
macrotripa
log KLnL
OxyMepa
macropa
EDTA
OBETA
Ln3+
log KLnL
log KLnHL
log KLnL
log KLnL
log KLnHL
log KLnL
log KLnL
La3+
Ce3+
Pr3+
12.19(2)
12.50(4)
12.41(2)
12.25(3)
11.52(2)
10.93(1)
10.23(2)
9.68 (1)
9.36(2)
9.36(1)
12.57(1)
12.82(2)
12.65(1)
12.25(2)
11.41(1)
10.86(1)
10.19(2)
10.19(2)
10.49(3)
10.70(3)
11.05(3)
11.43(5)
11.80(3)
11.90(1)
3.67(2)
3.66(4)
3.65(2)
3.88(1)
3.99(1)
4.24(2)
4.51(1)
4.82(1)
4.86(2)
4.90(1)
4.92(4)
4.89(2)
4.88(1)
4.93(2)
9.93
10.74
11.25
11.49
12.13
12.15
12.02
12.17
12.18
12.10
12.00
12.05
12.14
12.21
14.99
15.11
14.70
14.36
13.80
13.01
13.02
11.79
11.72
10.59
10.10
9.59
2.28
2.07
2.96
2.08
2.70
1.97
2.48
2.91
2.42
15.46
15.94
16.36
16.56
17.10
17.32
17.35
17.92
18.28
18.60
18.83
19.30
19.48
19.80
16.89
17.34
Nd3+
Sm3+
Eu3+
Gd3+
Tb3+
Dy3+
Ho3+
Er3+
18.39
19.02
19.13
19.37
18.87
18.93
18.46
9.71(4)
Tm3+
Yb3+
Lu3+
10.13(1)
10.48(1)
10.64(4)
8.89
8.25
18.31
17.93
a
b
c
0.1 M KCl, this work. The values in the parentheses are one standard deviation of the last significant figure. 0.1 M KCl, ref 27. 0.1 M KCl, ref 19.
0.1 M ionic strength, ref 12. 0.1 M KCl, refs 16 and 17.
d
e
B
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Figure 2 shows a plot of log KLnL versus the Ln3+ ionic radius28
for both macrodipa and macrotripa, which reveals them to be the
The log KLnHL values, which represent the protonation of LnL
complex, are also noteworthy. These values were not found for
Ln3+-macrodipa complexes but were observed for Ln3+-macro-
tripa complexes. Comparing the chemical structures of macro-
dipa and macrotripa and their complexes (vide infra), it can be
reasonably inferred that this protonation event occurs on the
third picolinate arm in macrotripa. The KLnHL values of the
macrotripa complexes remain steady from La3+ to Pr3+, but then
increase abruptly from Nd3+ to Tb3+, before leveling off from
Dy3+ to Lu3+. The sudden change in log KLnHL implies that a
conformational change may be present for Ln3+-macrotripa
complexs when crossing the Ln3+ series.
To gain insight on the type IV selectivity of macrodipa and
macrotripa, we analyzed their complexes of the largest and
smallest lanthanides, La3+ and Lu3+, by NMR spectroscopy.
These diamagnetic La3+ and Lu3+ complexes were characterized
1
by H, 13C{1H}, and 2D (HSQC, HMBC, COSY, ROESY)
NMR spectroscopy in D2O at pD = 7 (Figures 3 and S41−S80).
The 1H NMR spectra of all four complexes indicate that a single
species is present in solution. However, significant differences
are apparent in comparing the La3+ and Lu3+ complexes. For
example, the La3+-macrodipa complex is 2-fold symmetric,
Figure 2. Stability constants of Ln3+ complexes formed with macrodipa
and macrotripa plotted versus ionic radii.
1
indicated by one-half the number of H and 13C resonances
relative to the asymmetric Lu3+-macrodipa complex.
first known ligands that exhibit type IV selectivity. In comparing
the log KLnL values between Ln3+-macrodipa and Ln3+-
macrotripa systems, they are similar for early lanthanides,
La3+−Gd3+. Ln3+-macrodipa reaches a minimum for Dy3+ and
Ho3+, whereas for macrotripa the minimum occurs earlier in the
series, between Gd3+ and Tb3+. For late lanthanides, the
macrotripa complexes are significantly more stable than those of
macrodipa.
Additionally, the hydrogen resonances from the methylene
groups linking the crown and picolinate donors (H-13, H-20 for
macrodipa, and H-13, H-20, H-27 for macrotripa; Chart 1),
which are informative due to their proximities to the picolinate
donors, are significantly different between the La3+ and Lu3+
complexes. For example, the peaks for the diastereotopic H-27′
and H-27″ in the La3+-macrotripa case are well-separated,
Figure 3. 1H NMR spectra of macrodipa and macrotripa complexes formed with La3+ and Lu3+ (600 MHz, D2O, pD = 7, 25 °C). Selected peaks are
labeled using the numbering scheme in Chart 1.
C
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Figure 4. Crystal structures of (a) [La(macrodipa)]+, (b) [Lu(macrodipa)(OH2)]+, and (c) [La(macrotripa)]+ complexes. Thermal ellipsoids are
drawn at the 50% probability level. Solvent, counterions, and nonacidic hydrogen atoms are omitted for clarity. Only one of the two [La(macrodipa)]+
complexes in the asymmetric unit is shown.
whereas for Lu3+-macrotripa they have near-identical chemical
shifts. Collectively, these NMR data suggest that there is a
significant conformational difference between the La3+ and Lu3+
complexes of these ligands.
structures are highly comparable to those found for the acyclic
ligand OxyMepa,27 which displays type I selectivity, indicating
that the complete 18-crown-6 macrocycles of macrodipa and
macrotripa are critical for their unique Ln3+-selectivity profiles.
As a further validation on the proposed intramolecular
hydrogen bond in [Lu(macrotripa)(OH2)], we optimized its
structure (Figure S98) using validated DFT methods (vide
infra) and carried out a topological analysis of the electron
density using the quantum theory of atoms in molecules
(QTAIM).29 Specifically, we found all bond critical points
(BCP) with the Multiwfn30 program (Figure S99). A BCP was
located between a hydrogen atom of the coordinated water
molecule and the oxygen atom of the pendent picolinate group.
At this BCP, the magnitude of its local electron density (ρ) is
0.079 au, and the Laplacian of the electron density (∇2ρ) is 0.16
au. The positive value for ∇2ρ reflects a closed-shell hydrogen
bond, and the magnitude of ρ suggests that this interaction is
strong, comparable to that found between OH− and H2O.31−33
This analysis supports the proposed intramolecular hydrogen-
bonding interaction present in [Lu(macrotripa)(OH2)].
On the basis of the NMR and X-ray crystallographic data, it is
clear that macrodipa and macrotripa attain distinct conforma-
tions depending on whether they bind large or small Ln3+ ions
(Scheme 1). Large ions, like La3+, attain Conformation A, in
which the ion is fully encapsulated by the macrocycle, whereas
small ions, like Lu3+, sit in Conformation B, held by only part of
the macrocycle. The ability of these ligands to drastically alter
their conformations to match the sizes of metal ions accounts for
the type IV selectivity pattern. The structures may also explain
To further explore these different conformations, we
characterized these complexes by X-ray crystallography. Crystal
structures of [La(macrodipa)]+, [Lu(macrodipa)(OH2)]+, and
[La(macrotripa)]+ are shown in Figure 4. A weakly diffracting
and partially twinned crystal of [Lu(macrotripa)(OH2)] was
also obtained, but the connectivity information was reliably
ascertained (Figure S89). Confirming the NMR spectroscopic
data, the La3+ complexes attain a significantly different
conformation than do the Lu3+ complexes. In both La3+
structures, this ion is encapsulated into the 18-membered
macrocyclic core, which interacts with all of its six donor atoms.
Moreover, the pendent picolinate groups bind to La3+ from two
opposite faces of the macrocycle, resulting in 10-coordinate
complexes. The third picolinate donor of macrotripa does not
participate in coordination. Consistent with its NMR spectra,
[La(macrodipa)]+ attains a slightly distorted C2 symmetry. By
contrast, both Lu3+ structures show significantly different
coordination environments. Specifically, only two tertiary
nitrogens and one ethereal oxygen from the macrocycle act as
donors. The coordination sphere is completed with the four
donor atoms from two picolinate groups and an inner-sphere
water molecule, yielding 8-coordinate Lu3+ centers. In [Lu-
(macrotripa)(OH2)], the third unbound picolinate donor is
positioned to interact with the bound water molecule through
hydrogen bonding. Except for the macrocycle, these Lu3+
D
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take the solvent effects into consideration. The ΔG° for the
conformational equilibrium:
Scheme 1. Depiction of the Conformational Toggle Present
in Ln3+-Macrodipa and Ln3+-Macrotripa Complex Systems
[Ln(macrodipa)]+ (Conformation A, aq) + H2O (l)
F [Ln(macrodipa)(OH2)]+ (Conformation B, aq)
(4)
was calculated for Ln3+-macrodipa complexes. The ΔG° (Figure
5) is positive for light Ln3+ and negative for heavy Ln3+. This
the difference in thermodynamic stability of macrodipa and
macrotripa for the late, but not early, Ln3+ (Figure 2). Both
ligands give rise to identical coordination spheres for the large
early lanthanides, like La3+, and therefore exhibit only minor
differences in their thermodynamic stabilities. However, for the
small late lanthanides, like Lu3+, the inner coordination spheres
are nearly identical between macrodipa and macrotripa, but the
outer sphere differs due to the hydrogen-bonding interaction
with the coordinated water molecule. Thus, the differences in
thermodynamic stability between the macrodipa and macrotripa
complexes of the late lanthanides are most likely a consequence
of the hydrogen bonding of the pendent picolinate donor arm.
This result highlights how modifying the outer coordination
sphere of lanthanide complexes fine-tunes their thermodynamic
properties.
As a further test of this conformational toggle, we investigated
the complexes of Y3+, a diamagnetic Ln3+ analogue with an ionic
radius comparable to that of Ho3+,7,28 by NMR spectroscopy.
The 1H and 13C{1H} NMR spectra of Y3+-macrodipa and Y3+-
macrotripa were acquired in D2O at pD = 7 (Figures S81−S88).
Both Conformations A and B are detected for Y3+-macrodipa, in
a molar ratio of 1:15. For the Y3+-macrotripa complex, only
Conformation B is observed. The 90-pm ionic radius of Y3+
places its macrodipa complex near the local minimum of log
Figure 5. DFT-computed standard free energies for the conformational
equilibrium (eq 4) of Ln3+-macrodipa complexes.
observation is consistent with the experimental results with La3+-
macrodipa and Lu3+-macrodipa complexes attaining Conforma-
tions A and B, respectively. Additionally, ΔG° changes its sign
between Gd3+ and Tb3+, which indicates the switch of favored
conformation. This crossover suggests that the type IV behavior
of macrodipa is a consequence of the significant conformational
changes that occur when binding Ln3+ ions of different sizes.
Furthermore, ΔG° for this conformational change can be
broken into three contributors. Specifically, it can be expressed
as the sum of the relative ligand strain energies (ΔΔGS°),
relative metal−ligand binding energies (ΔΔGB°), and relative
solvation energies (ΔΔGsolv°) between Conformations A and B,
as described in the Supporting Information. As shown in Figure
5, ΔΔGsolv° is positive for all Ln3+ complexes, which reveals that
Conformer A and the noncoordinated water ligand are better
solvated in aqueous solution than is Conformer B. Likewise,
ΔΔGB° is positive for all Ln3+, which indicates that
Conformation A is better suited to neutralize the electrostatic
charges of these ions than is Conformation B. This observation
can be rationalized by the fact that Conformation A interacts
with the Ln3+ with two more donor atoms. However, ΔΔGB°
decreases as the Ln3+ gets smaller, which suggests that
Conformation A is less effective at binding the smaller ions.
By contrast, ΔΔGS° is negative across the entire series, which
shows that Conformation B requires less ligand strain than does
Conformation A. Among the three values, ΔΔGS° shows the
most significant changes as a function of the Ln3+ ionic radius,
and it becomes more negative for smaller ions. Importantly, the
strain energy is the only exothermic term for the switch from
Conformation A to B, and thus it is the driving factor in the
conformational switch of macrodipa. This result suggests that
modifications of this ligand scaffold to alter the strain energy
term could lead to a significant shift in the Ln3+-stability pattern
for this ligand class.
K
LnL, but its macrotripa complex is placed rather far from the
minimum (Figure 2). Thus, these NMR data show that the
conformational switch occurs for complexes of ions with their
radii near the minimum of stability; larger and smaller ions show
preferences for Conformations A and B, respectively.
DFT has been extensively used to investigate the properties of
Ln3+ coordination compounds.34−36 In this study, we took
advantage of this powerful tool to help understand the origin of
the type IV selectivity pattern of these ligands. We focused
exclusively on the Ln3+-macrodipa system. These complexes lack
the third noncoordinated picolinate arm of the Ln3+-macrotripa
and therefore provide a straightforward system to model the
inner coordination spheres of these complexes. DFT calcu-
lations were executed using Gaussian 0937 with the ωB97XD
functional.38,39 This functional, which is long-range corrected
and includes dispersion corrections, has been shown to give
accurate geometries of Ln3+ complexes.40 Because of the
importance of relativistic effects in Ln3+ ions,41 we used the
large-core relativistic effective core potential (LCRECP) by
Dolg42 to account for these effects in a computationally efficient
manner. For light atoms, the 6-31G(d,p) basis set43,44 was
applied. The SMD solvation model45,46 was implemented to
E
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from the College of Arts and Sciences at Cornell University and
by the National Institute of Biomedical Imaging and
Bioengineering of the National Institutes of Health under
award number R21EB027282. The content is solely the
responsibility of the authors and does not necessarily represent
the official views of the National Institutes of Health. This
research was also supported by a Cottrell Research Scholar
Award from the Research Corporation for Science Advance-
ment. This research made use of the NMR Facility at Cornell
University, which is supported, in part, by the U.S. National
Science Foundation under award number CHE-1531632.
CONCLUSION
■
In summary, this work describes two ligands that display an
unprecedented type IV selectivity pattern with one minimum
and two maxima of KLnL across the Ln3+ series. This novel
selectivity pattern may have key applications in Ln3+ separations
and nuclear medicine, where it is often desirable to stably chelate
a range of metal ions with disparate ionic radii. Our structural
data by NMR spectroscopy and X-ray crystallography show that
both macrodipa and macrotripa undergo a significant conforma-
tional shift in moving from a large to small Ln3+ ion, which allows
for high thermodynamic stability for both early and late Ln3+. In
comparing macrodipa and macrotripa, we have shown that one
can modify these ligands to tune the position of the minimum
and the overall magnitude of thermodynamic stability. Our DFT
calculations further support the presence of this conformational
toggle and show that the ligand strain and metal−ligand binding
energies are complementary factors contributing to the
conformational switch. Between them, we believe that the
ligand strain energy is more easily modified, for example, by
including groups in the macrocyclic backbone that prevent
conformational flexibility, which thus presents a path for tuning
these ligands for different applications. This work demonstrates
how the incorporation of conformational flexibility in ligands
can be used to satisfy the coordination environments of different
metal ions, a principle of great value for chelator design efforts.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c05217.
■
sı
Experimental procedures and supplementary data for
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AUTHOR INFORMATION
Corresponding Author
Justin J. Wilson − Department of Chemistry and Chemical
Biology, Cornell University, Ithaca, New York 14853, United
States; orcid.org/0000-0002-4086-7982; Email: jjw275@
cornell.edu
■
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Authors
Aohan Hu − Department of Chemistry and Chemical Biology,
Cornell University, Ithaca, New York 14853, United States;
orcid.org/0000-0002-9720-3159
Samantha N. MacMillan − Department of Chemistry and
Chemical Biology, Cornell University, Ithaca, New York 14853,
United States; orcid.org/0000-0001-6516-1823
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c05217
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C.; Benyei, A. C.; Bodnar, J.; Vagner, A.; Botta, M. Lower Denticity
Leading to Higher Stability: Structural and Solution Studies of
Ln(III)−OBETA Complexes. Inorg. Chem. 2014, 53, 12499−12511.
(18) Voss, D. A., Jr.; Farquhar, E. R.; Horrocks, W. D., Jr.; Morrow, J.
R. Lanthanide(III) Complexes of Amide Derivatives of DOTA Exhibit
an Unusual Variation in Stability across the Lanthanide Series. Inorg.
Chim. Acta 2004, 357, 859−863.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This research was supported in part by seed funding from the
Academic Integration grant program at Cornell University and
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