Synthesis and characterization of nitrogen-rich macrocyclic ligands and an investigation of their coordination chemistry with lanthanum(III)

Article abstract of DOI:10.1021/ic501843c

Derivatives of the ligand 1,4,7,10-tetraazacyclododecane (cyclen) containing pendant N-heterocyclic donors were prepared. The heterocycles pyridine, pyridazine, pyrimidine, and pyrazine were conjugated to cyclen to give 1,4,7,10-tetrakis(pyridin-2-ylmethyl)-1,4,7,10-tetraazacyclododecane (L^py), 1,4,7,10-tetrakis(3-pyridazylmethyl)-1,4,7,10-tetraazacyclododecane (L^pyd), 1,4,7,10-tetrakis(4-pyrimidylmethyl)-1,4,7,10-tetraazacyclododecane (L^pyr), and 1,4,7,10-tetrakis(2-pyrazinylmethyl)-1,4,7,10-tetraazacyclododecane (L^pz), respectively. The coordination chemistry of these ligands was explored using the La³⁺ ion. Accordingly, complexes of the general formula [La(L)(OTf)](OTf)₂, where OTf = trifluoromethanesulfonate and L = L^py (1), L^pyd (2), L^pyr (3), and L^pz (4), were synthesized and characterized by NMR spectroscopy. Crystal structures of 1 and 2 were also determined by X-ray diffraction studies, which revealed 9-coordinate capped, twisted square-antiprismatic coordination geometries for the central La³⁺ ion. The conformational dynamics of 1-4 in solution were investigated by variable-temperature NMR spectroscopy. Dynamic line-shape and Eyring analyses enabled the determination of the activation parameters for the interconversion of enantiomeric forms of the complexes. Unexpectedly, the different pendant N-heterocycles of 1-4 give rise to varying values for the enthalpies and entropies of activation for this process. Density functional theory calculations were carried out to investigate the mechanism of this enantiomeric interconversion. Computed activation parameters were consistent with those experimentally determined for 1 but differed somewhat from those of 2-4.

Full text of DOI:10.1021/ic501843c

Article
pubs.acs.org/IC
Synthesis and Characterization of Nitrogen-Rich Macrocyclic Ligands
and an Investigation of Their Coordination Chemistry with
Lanthanum(III)
Justin J. Wilson,* Eva R. Birnbaum,* Enrique R. Batista, Richard L. Martin, and Kevin D. John
Los Alamos National Laboratory, P.O. Box 1663, Los Alamos, New Mexico 87545, United States
*
S Supporting Information
ABSTRACT: Derivatives of the ligand 1,4,7,10-tetraazacyclododecane
cyclen) containing pendant N-heterocyclic donors were prepared. The
(
heterocycles pyridine, pyridazine, pyrimidine, and pyrazine were conjugated
to cyclen to give 1,4,7,10-tetrakis(pyridin-2-ylmethyl)-1,4,7,10-tetraazacy-
clododecane (L ), 1,4,7,10-tetrakis(3-pyridazylmethyl)-1,4,7,10-tetraazacy-
clododecane (L ), 1,4,7,10-tetrakis(4-pyrimidylmethyl)-1,4,7,10-tetraaza-
cyclododecane (L ), and 1,4,7,10-tetrakis(2-pyrazinylmethyl)-1,4,7,10-
tetraazacyclododecane (L ), respectively. The coordination chemistry of
these ligands was explored using the La ion. Accordingly, complexes of the
py
pyd
pyr
pz
3
+
general formula [La(L)(OTf)](OTf) , where OTf = trifluoromethanesul-
2
py
pyd
pyr
pz
fonate and L = L (1), L (2), L (3), and L (4), were synthesized and
characterized by NMR spectroscopy. Crystal structures of 1 and 2 were also
determined by X-ray diffraction studies, which revealed 9-coordinate
capped, twisted square-antiprismatic coordination geometries for the central
3+
La ion. The conformational dynamics of 1−4 in solution were investigated by variable-temperature NMR spectroscopy.
Dynamic line-shape and Eyring analyses enabled the determination of the activation parameters for the interconversion of
enantiomeric forms of the complexes. Unexpectedly, the different pendant N-heterocycles of 1−4 give rise to varying values for
the enthalpies and entropies of activation for this process. Density functional theory calculations were carried out to investigate
the mechanism of this enantiomeric interconversion. Computed activation parameters were consistent with those experimentally
determined for 1 but differed somewhat from those of 2−4.
py
INTRODUCTION
Only recently has the lanthanide coordination chemistry of L
■
1
6−18
been explored for luminescence-sensitization applications.
The unique physical properties of lanthanide ions render them
useful for a number of biological applications. Complexes of
these ions are used as luminescent sensors, MRI contrast agents,
py
In this Article, new derivatives of L in which the pyridine is
replaced with pyridazine (L ), pyrimidine (L ), and pyrazine
(L ) are reported (Chart 1). Both the addition and location of
the additional nitrogen atoms in these newly prepared analogues
pyd
pyr
pz
1
−6
and radionuclide therapy and imaging agents.
To fully
maximize their potential, the design of ligands that are capable
of stabilizing these labile and easily hydrolyzable ions in aqueous
solution is necessary. Because lanthanides preferably attain high
coordination numbers, ligand design has focused on multi-
dentate ligands with an emphasis placed on those with eight or
more donor atoms.
A promising class of ligands are those based on 1,4,7,10-
tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) (Chart
). DOTA contains a macrocyclic cyclen base with four pendant
affect both their relative donor strength and chemical hardness.
3
+
The coordination chemistry of these ligands with the La ion
was explored. The interconversion of the La3+ complexes from
twisted square-antiprismatic geometries (TSAP) to square-
antiprismatic (SAP) geometries was probed by variable-temper-
ature NMR spectroscopy. Unexpectedly, the activation param-
eters for this interconversion process were found to depend
strongly on the ligand employed. Computational studies
investigating the mechanism of this interconversion process are
also presented.
7
1
carboxylate groups. The resulting anionic, octadentate lantha-
nide complexes of DOTA are incredibly stable. The success of
DOTA has motivated the synthesis of a wide range of analogues.
Among these is the ligand 1,4,7,10-tetrakis(pyridin-2-ylmethyl)-
RESULTS AND DISCUSSION
Ligand Synthesis and Characterization. Synthesis of Lpy
was carried out as previously reported by the reaction of slightly
py
■
1,4,7,10-tetraazacyclododecane (L ) (Chart 1), where the
pendant carboxylates are replaced with pyridines. This ligand
was first prepared to model the active sites of metalloenzymes
8
−11
and -proteins
and has subsequently been used to form
3
+
12−14
anticancer and antiviral Bi complexes
extract Na in the presence of competing alkali metal ions.
and to selectively
Received: July 29, 2014
+
15
©
XXXX American Chemical Society
A
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Article
Chart 1. Structures and Abbreviated Names of the Ligands Discussed and Investigated in This Article
a
Scheme 1. Synthesis of Ligands Described in This Article
a
Reaction conditions: refluxing CH CN and 20 equiv of Cs CO .
3
2
3
Figure 1. X-ray crystal structures of Lpyd (left), Lpyr (center), and L (right). Hydrogen atoms have been omitted for clarity. Ellipsoids are drawn at 50%
pz
probability levels.
excess Cs CO in CH CN. For the newly reported ligands Lpyd,
1
8
greater than 4 equiv of commercially available 2-picolyl chloride
with 1,4,7,10-tetraazacyclododecane (cyclen) in the presence of
2 3 3
pyr
pz
L , and L , the corresponding chloromethyl N-heterocycles,
B
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Figure 2. X-ray crystal structures of the complex cations of 1 (left) and 2 (right) from a side (top) and top-down view (bottom). The hydrogen atoms
have been omitted for clarity. In the top-down perspective, the coordinated triflate ligand has also been removed. Ellipsoids are drawn at 50% probability
levels.
which are not commercially available, were first prepared by the
treatment of the methyl N-heterocycles with 1/3 equiv of
trichloroisocyanuric acid in refluxing chloroform as previously
X-ray crystal structures of 1 and 2 are shown in Figure 2. The
coordination sphere of the La3+ ion is comprised of the eight
nitrogen donor atoms of the ligands arranged in a twisted square-
antiprismatic (TSAP) geometry and a triflate counterion, which
occupies the axial coordination site. Two additional triflate ions
are present in the outer sphere of both structures and balance the
charge of the complexes. Compound 1 is isomorphous to the
1
9
described. The chloromethyl N-heterocycles were used
immediately after purification by column chromatography for
the reaction with cyclen under conditions identical to those used
py
pyd pyr
pz
for L to afford L , L , and L in moderate yields (Scheme 1).
Characterization data for the ligands are given in the
Experimental Section and in Figures S1−S12 in the Supporting
Information (SI).
3+
3+
py 18
corresponding Nd and Eu complexes of L . The sum of the
interatomic distances comprising the inner coordination sphere
3+
3+
of 1 is 24.187(6) Å, whereas the Nd and Eu complexes have
values of 23.78(2) and 23.51(4) Å, respectively. These decreases
in interatomic distances upon population of the 4f orbitals in the
The ligands were also characterized structurally in the solid
state by single-crystal X-ray diffraction. The crystal structures are
shown in Figure 1. Despite similar geometric requirements, all
ligands crystallize with distinct unit cell parameters. As previously
3
+
3+
Nd and Eu structures are consistent with the effects of the
20,21
well-known lanthanide contraction.
Analogous to the lanthanide complexes of DOTA,
2
2,23
py 18
pyd
pz
two
reported for L , both L and L are centrosymmetric, as
dictated by crystallographic inversion centers that reside in the
stable diastereomers are possible for this class of ligands. The
chirality of the helical twist of the pendant carboxylate groups of
DOTA and pendant N-heterocycles of the ligands studied here is
denoted by Δ and Λ, respectively (Figure 3). The chirality of
each of the four 5-membered chelate rings formed by the cyclen
macrocycle is indicated by lowercase δ or λ (Figure 3). On the
basis of these two sources of chirality, two stable diastereomers
exist, namely Λ(λλλλ) and Λ(δδδδ), with the corresponding
enantiomers Δ(δδδδ) and Δ(λλλλ). Complexes of Λ(λλλλ)/
Δ(δδδδ) stereochemistry obtain a TSAP geometry. The twist
angle (ϕ), which is the angle between the plane of the four
nitrogen atoms on the cyclen macrocycle and the plane of the
four pendant donor atoms, ranges from 20 to 30° for the TSAP
isomer. For complexes of Λ(δδδδ)/Δ(λλλλ) stereochemistry, a
square-antiprismatic (SAP) geometry is given, where the twist
angle ranges from 36 to 45° (Figure 3). For DOTA and related
ligands, the TSAP isomer is energetically preferred for the earlier
lanthanide ions. The SAP geometry is stabilized in the mid to late
pyr
middle of the 12-membered cyclen macrocycle. In contrast, L
crystallizes in a puckered conformation, where the four
pyrimidine heterocycles sit on the same face of the 12-membered
macrocycle.
Lanthanum(III) Complex Synthesis and Character-
ization. To investigate the coordination chemistries of the
3+
four ligands, La complexes were prepared. The reaction of
La(OTf) in MeOH with the ligands at 40 °C afforded complexes
3
1, 2, 3, and 4, which are characterized by the general formula,
[
La(L)(OTf)](OTf) , where OTf = trifluoromethanesulfonate
2
py
pyd
pyr
pz
and L = L , L , L , and L , respectively. Complex 4
crystallizes out of solution directly, whereas the other three
complexes are soluble in methanol. The complexes were
characterized by Fourier transform infrared (FTIR) spectrosco-
py and elemental analysis (EA). The IR spectra (Figures S13−
S16, SI) possess similar vibrational features among the four
complexes, consistent with their analogous compositions. EA is
consistent with the molecular formulas as well.
23
lanthanide ions, which have smaller ionic radii. The two
diastereomers give rise to complexes that can have substantially
C
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Inorganic Chemistry
Article
2+
this range, are [La(DOTAM-glycol)Cl] and [La(THED)-
3
+
(
[
OH )] , as indicated in Table 1. The large twist angle of
2
2
+
La(DOTAM-glycol)Cl] arises as a consequence of its
existence in the solid state as the SAP isomer. The structure
of [La(THED)(OH )] reveals a uniquely small twist angle,
26
3+
2
which gives rise to a structure in which the pendant alcohol
donor groups nearly eclipse the nitrogen atoms of the
27
macrocycle. For 1 and 2, La−N distances are not significantly
different, ranging from 2.66 to 2.75 Å. However, the average La−
N
distances are slightly larger than the average La−N
3+
cyclen
pendant
distances for both complexes. The related La complex,
LaL2 (OCH )] , in which the pendant N-heterocycles of
quin
2+ 28
[
3
1
and 2 are replaced by 2-quinoline, is structurally similar.
28
Notably, the La−N
distances (average 2.889(3) Å) of this
pendant
complex are substantially greater than those of 1 and 2, which
may possibly be a consequence of the greater steric hindrance of
the quinoline arms or the strong electron-donating properties of
the anionic methoxide axial ligand. The La−OTf distance of 2 is
marginally smaller than that of 1. An additional intramolecular
interaction is observed in the structure of 2 as well. The two
noncoordinating oxygen atoms of the triflate ligand are in close
contact with the noncoordinating nitrogen atoms of the pendant
pyridazine ligands (2.96 and 3.04 Å) (Figure 2). This interaction
is expected to be repulsive because both nitrogen and oxygen
atoms carry partial negative charges.
Figure 3. Schematic depiction of the sources of chirality and
diastereomerism of the complexes prepared in this work.
Crystals of 3 and 4 were also obtained. However, the quality of
data afforded by these crystals was poor due to low resolution,
weak intensity of reflections, and the presence of multiple twin
domains. Despite these limitations, the structures could still be
solved, unambiguously identifying the atomic connectivity of the
complexes. In both structures, the La3+ ion is complexed in a
TSAP fashion to the octadentate ligands and also directly
coordinated to a triflate ligand in the axial position. The
Supporting Information contains the measured unit cell
parameters and figures depicting the atomic connectivity
(Table S1 and Figures S18 and S19, SI). Although a more
detailed analysis of the interatomic distances and angles cannot
be carried out, these results indicate that the solid state structures
of 1−4 are similar despite the systematic modification of the
pendant N-heterocycle donor.
2
4,25
different water-exchange rates.
Therefore, knowledge of the
relative populations of these diastereomers and their rates of
interconversion is crucial for the design of lanthanide complexes
for luminescence and MRI sensing.
The crystal structures of 1 and 2 reveal the exclusive presence
of the TSAP geometry in the solid state. Enantiomers Λ(λλλλ)
and Δ(δδδδ) are both present in the centrosymmetric crystal
lattices of 1 and 2. In Figure 2, the Λ(λλλλ) enantiomer of 1 and
the Δ(δδδδ) enantiomer of 2 are shown. TSAP geometry is
expected on the basis of the large ionic radius of La . The heavier
lanthanide ions, which have small ionic radii due to the
lanthanide contraction, form complexes of L with SAP
3
+
py
1
8
3+
geometry. Specific structural data for 1, 2, and related La
complexes are given in Table 1. The structures and abbreviations
of ligands described are given in Figure S17 of the SI. The twist
angles for 1 and 2 are nearly identical (24 and 25°, respectively)
and are within the expected range for TSAP geometries. La3+
complexes, which have twist angles that deviate significantly from
1
13
1
NMR Spectroscopy. H and C{ H} NMR spectra of 1−4
in D O (Figures S20−S27, SI) in the temperature range of
2
5−95 °C reveal the presence of a single diastereomer. Based on
literature precedence, X-ray crystallography (vide supra), and
Table 1. Selected Structural Parameters for 1, 2, and Related La3+ Complexesa
ϕ,
average La−N
average La−N/O
axial La
La−N (cyclen)
La−O /N (pendant)
4 4
cyclen
distance, Å
pendant
4
b
complex
deg
distance, Å
distance, Å
centroid, Å
centroid, Å
0.83
ref
this
1
2
23.9
2.713(4)
2.699(4)
2.5374(18)
1.71
work
this
work
28
24.9
2.74(1)
2.69(1)
2.498(5)
1.76
0.71
LaL2quin(OCH )]
2+
c
24.4
23.0
2.780(3)
2.794(3)
2.769(3)
2.718(3)
2.788(4)
2.69(1)
2.889(3)
2.493(3)
2.492(3)
2.423(3)
2.501(3)
2.38(2)
2.149(4)
2.568(5)
2.537(5)
N/A
1.82
1.835
1.810
1.63
1.81
1.68
0.71
0.70
0.73
1.23
0.54
0.95
[
3
Na[La(HDOTA)La(DOTA)]
29
2
4.5
3+
d
[
[
[
La(DOTAM′)]
La(DOTAM-glycol)Cl]
La(THED)(OH )]3+
26.7
37.7
13.3
30
26
27
2+
e
2.811(3)
2.57(3)
f
2
a
b
c
2quin
See Figure S17 in the SI for the structures of the ligands. Twist angle; see Figure 3. L
= 1,4,7,10-tetrakis(2′-quinolylmethyl)-1,4,7,10-
e
d
tetraazacyclododecane. DOTAM′ = 1,4,7,10-tetrakis(2-carbamoylethyl)-l,4,7,10-tetraazacyclododecane. DOTAM-glycol = 2,2′,2″,2‴-(1,4,7,10-
tetraazacyclododecane-1,4,7,10-tetrayl)-tetrakis[N-[2-(2-hydroxyethoxy)ethyl]acetamide]. THED = 1,4,7,10-tetrakis(2-hydroxyethyl)-1,4,7,10-
f
tetraazacyclododecane.
D
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Figure 4. Variable-temperature 13C{ H} NMR spectra of 1 in D O (pD between 6 and 7, unadjusted) showing the broadening and coalescence of the
1
2
resonances from the ethylenic carbon atoms on the cyclen macrocycle (left). The simulated data and corresponding rate constants are shown on the
right.
E
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density functional theory (DFT) calculations (vide infra), this
diastereomer is most likely the TSAP isomer. The aromatic
1
13
1
regions of both the H and C{ H} NMR spectra for all
complexes contain a single set of resonances for the pendant N-
heterocycles, indicating that the complexes attain C symmetry in
4
solution. The signals arising from the aliphatic protons, however,
exhibit different line widths and diastereotopic splitting among
the four complexes, which suggest different degrees of
conformational rigidity that depend on the nature of the ligand.
1
3
Additionally, in the C NMR spectra at 5 °C, the resonances
arising from the cyclen backbone are not equivalent, further
indicating that the complexes are locked into a single
conformation.
The overall complex stability in aqueous solution was also
assessed by NMR spectroscopy (Figures S28−S31, SI). At
ambient temperature (22−25 °C) in D O (pD between 6 and 7,
2
1
unadjusted), the H NMR spectra were measured after 1, 7, and
2
4 h. Complex 1 remains stable at 24 h, with no signs of
decomposition or ligand loss. Similarly, 2 displays only minor
Figure 5. Eyring plot for the conformational changes observed in 1 in
D O.
2
decomposition (<5%) after 24 h, as evidenced by the presence of
free ligand in the H NMR spectra. Although complexes 3 and 4
1
are generally stable after 1 h, as indicated by less than 5%
decomposition, after longer time periods substantial decom-
position is observed. At 7 h, only 86% of 3 and 67% of 4 remain
intact. After 24 h, these values drop to 66% and 50% for 3 and 4,
respectively. These data indicate that the relative long-term
limited temperature range for 3 and 4. Complete decomposition
of 4 was observed upon ramping the temperature up to 95 °C,
whereas approximately 67% decomposition of 3 was observed
under the same conditions. Hence, the Eyring analyses for 3 and
4 were carried out only in the temperature range of 5−45 °C,
temperatures at which <10% complex decomposition was
observed. In contrast, complex 1 was entirely stable, and 2
exhibited only 6−10% complex degradation when the temper-
ature was increased to 95 °C.
These activation parameters correspond to interconversion of
the carbon atoms on the cyclen macrocycle. Because the SAP
isomers of the complexes investigated here are not observed in
appreciable amounts, interconversion of the carbon atoms
observed at higher temperatures must correspond to a process
that interconverts the two enantiomeric pairs of the TSAP
isomer, Δ(δδδδ) and Λ(λλλλ). This enantiomerization process
can occur only through the sequential operation of two distinct
processes. A ring inversion, the sequential change of the four 5-
membered chelate rings from δ to λ, must take place along with
stability of the complexes correlates with the pK of the pendant
a
donor arm. Pyridine, the most basic arm, stabilizes complex 1
effectively, whereas pyrazine, the least basic arm, gives rise to
poorly stable complex 4.
Variable-temperature NMR spectroscopy was carried out to
probe the conformational dynamics of the complexes in greater
detail. When the temperature was increased from 5 to 95 °C, the
1
multiplets of 1−4 in the aliphatic region of the H NMR broaden
1
3
1
and then coalesce (Figures S32−S35, SI). In the C{ H} NMR
spectra, the two resonances near 53 and 60 ppm, which
correspond to the ethylenic carbon atoms of the cyclen
macrocycle, broaden and cleanly coalesce into a single peak as
shown in Figure 4 for 1 (and Figures S36−S38 for 2−4,
respectively, SI). Line-shape analysis of this simple coalescence
event enables extraction of first-order rate constants at different
temperatures for the interconversion of these two carbon atoms.
The resulting data can be evaluated with an Eyring analysis, as
shown in eq 1, where k is the rate constant, T is the temperature
concerted arm rotation of the pendant donors from Δ to Λ to
13
interconvert the enantiomers. Line-shape analyses of the
C
resonances presented here enable us to probe only the highest
energy rate-determining step between both mechanisms. For
complexes that form both isomers in solution, the distinct energy
barriers for the arm-rotation and ring-inversion processes can be
ascertained. These analyses have been carried out on diamagnetic
in kelvin, R is the gas constant, k is the Boltzmann constant, and
B
h is Planck’s constant, to yield a straight line from which the
⧧
⧧
enthalpy and entropy of activation (ΔH and ΔS , respectively)
can be calculated. A representative Eyring plot for 1 is shown in
Figure 5, and those for 2−4 are given in Figures S39−S41,
13
complexes via line-shape analyses of C resonances including
⧧
⧧
respectively, of the SI. From the ΔH and ΔS values, the free
31
1
those of the SAP isomer and by line-shape analyses of H NMR
⧧
energy of activation (ΔG ) and the first-order rate constant at
98 K were calculated according to eqs 2 and 3. These values are
32
spectra. Additionally, two-dimensional EXSY NMR spectros-
2
copy of paramagnetic lanthanide complexes has proven valuable
for the determination of activation parameters for each
collected in Table 2.
2
2,24,33,34
−ΔH⧧
ΔS⧧
R
process.
The unobservable population of the SAP
k
T
+ ln k
B
ln
=
+
isomer for the complexes studied here, however, limits our
analysis to only the highest energy barrier between both
processes, corresponding to enantiomerization of the TSAP
RT
h
(1)
(2)
⧧
⧧
⧧
ΔG = ΔH − TΔS
35−40
isomer, as described in earlier studies.
⧧
The ΔG values at 298 K vary among the four complexes from
k T
h
⧧
B
−ΔG /RT
⧧
⧧
k =
e
60 to 66 kJ/mol. The changes in ΔH and ΔS vary more widely.
(3)
⧧
Decreases in ΔH , however, are compensated for by more
⧧
Because of the different stabilities of the complexes studied,
however, line-shape analysis could be carried out only over a
negative values of ΔS , leading to the relatively modest
⧧
⧧
differences of ΔG across the series. The ΔG value for the
F
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Table 2. Rate Constants and Activation Parameters for the Conformational Fluxionality of 1−4
1
2
3
4
⧧
−1
ΔH , kJ mol
60 ± 1
−20 ± 4
66 ± 2
17
51 ± 1
−30 ± 4
60 ± 2
191
51 ± 2
−40 ± 6
63 ± 3
57
34 ± 3
−93 ± 11
62 ± 4
102
ΔS , J K mol−1
⧧
−1
⧧
−1
ΔG at 298 K, kJ mol
a
−1
k
b
at 298 K, s
calcd
−1
k at 298 K, s
33
214
52
94
a
b
Obtained from combining eqs 2 and 3 and the activation parameters derived from the Eyring analysis. Average value obtained from two
independent line-shape analyses on two independently prepared samples.
Table 3. DFT-Calculated Structural Parameters for the TSAP Isomers of 1H2O−4H2O and 1′−4′
average La−N
average La−N/O
H O−La
La−N (cyclen) centroid
La−N (pendant) centroid
cyclen
distance, Å
pendant
2
4
4
a
complex ϕ, deg
distance, Å
distance, Å
distance, Å
distance, Å
1H2O
2H2O
3H2O
4H2O
22.1
18.1
21.5
21.7
2.7785
2.846
2.785
2.7705
2.731
2.822
2.730
2.721
2.747
2.718
2.7435
2.7695
2.690
2.605
2.692
2.712
2.680
2.488
2.698
2.682
1.762
1.826
1.758
1.742
1.677
1.785
1.655
1.656
0.888
0.826
0.881
0.917
1.062
0.859
1.068
1.102
1
2
3
4
′
′
′
′
19.24
17.06
18.70
18.50
a
Twist angle; see Figure 3.
35
La3+ complex of DOTA is 60.7 kJ/mol, which is within the
higher temperatures limited the Eyring analysis to temperatures
below the fast-exchange limit. Although the parameters
determined from independent variable-temperature runs were
reproducible, some additional error in the entropy of activation is
most likely present, which may contribute to the large negative
values observed.
⧧
3+
range of the compounds studied here. The ΔG value of the La
complex of an analogous ligand containing two pendant
carboxylate and imidazole donors is 61.5 kJ/mol, similar to
40
3+
that of the DOTA complex. La complexes of ligands that have
neutral pendant donors, such as alcohols or amides, generally
have smaller energy barriers, which range from 52 to 58.8 kJ/
DFT Calculations. Structures of the aqueous analogues of 1−
4, in which the inner-sphere triflate ligand is replaced by a
coordinated water molecule (1H2O−4H2O), were optimized in the
gas phase at the B3LYP/6-31G*/SDD(La) level of theory for
both the TSAP and SAP diastereomers. The triflate ligand was
replaced with a water molecule to model the most likely
configuration of the complex in aqueous solution. In agreement
with the crystal structure analysis, the TSAP isomers are
thermodynamically preferred by 15−25 kJ/mol. This large
stabilization of the TSAP isomer is consistent with our inability
to observe the SAP isomer by NMR spectroscopy. Additionally,
derivatives of 1−4 with no axial ligands, 1′−4′, were also
optimized at the same level of theory. For these analogues, the
TSAP isomers were stabilized to a larger degree, as indicated by
free energy differences ranging from 26.6 to 33.6 kJ/mol.
Selected structural parameters of the DFT-optimized TSAP
3
6−39
mol.
Although 1−4 contain neutral pendant donors, the
energy barriers found for these complexes are more similar to
those with anionic donors. This observation suggests that the
steric hindrance of the large aromatic heterocycles may
compensate for their lack of anionic character in enforcing
more rigid conformations of the macrocyclic ligand.
⧧
⧧
A systematic decrease in both ΔH and ΔS occurs in the
order of 1 > 2 > 3 > 4. This sequence also follows that of the
relative pK values of the pendant heterocycles, as pyridine is the
a
most basic (pK 5.23), followed by pyridazine (pK 2.33),
a
a
pyrimidine (pK 1.30), and pyrazine (pK 0.65). The large
a
a
−1
−1
negative entropy of activation of 4, −93 ± 11 J K mol , is
particularly noteworthy. The La complex of the pendant
alcohol donor ligand THED (1,4,7,10-tetrakis(2-hydroxyethyl)-
,4,7,10-tetraazacyclododecane) exhibited a ΔS of −58 J K
mol , and the Lu complex of a derivative of DOTA, where
3
+
⧧
−1
1
−1
39
3+
diastereomers of 1H2O−4
and 1′−4′ are given in Table 3.
H2O
the anionic carboxylate arms are replaced by neutral pendant N-
In comparison to data obtained from X-ray crystallography for
[
2-(2-hydroxyethoxy)ethyl]acetamide donors, possessed similar
1 and 2, the average La−N distances computed by DFT are
⧧
activation parameters as well, with ΔH = 33 ± 3 kJ/mol and
overestimated by about 0.06 Å for 1
and up to 0.1 Å for 2
.
H2O
H2O
⧧
−1
−1 26
ΔS = −109 ± 7 J K mol . The observance of such a large
The root-mean-square deviations (RMSD) of the calculated
structures overlaid with the experimentally determined struc-
tures with the axial ligand omitted are 0.1014 Å for 1 and 1H2O
and 0.2854 Å for 2 and 2H2O. The larger deviations observed for
the DFT structure of 2H2O are most likely the result of
intramolecular hydrogen bonds between the hydrogen atoms of
the coordinated water molecule and the nitrogen atoms in the
ortho position of the pendant pyridazine donors (Figure S42,
SI). The importance of these intramolecular hydrogen bonds is
most likely diminished in aqueous solution in which the water-
exchange rate for lanthanide complexes occurs with lifetimes
ranging from nano- to microseconds and where the presence of
⧧
and negative ΔS for what should be an intramolecular process
was not fully explained or understood for these complexes. These
⧧
ΔS values may signify an increase in symmetry in the transition
state. However, the transition state also encompasses the
surrounding solvent molecules whose reorganization may also
significantly contribute to the overall activation parameters
4
1
observed. The presence of additional nitrogen atoms in the
pendant heterocycles of 2−4 provides hydrogen-bond donors
for interactions with water, which may alter the secondary
solvation shell of the transition state more drastically than for that
of 1. It should also be noted that decomposition of 3 and 4 at
G
dx.doi.org/10.1021/ic501843c | Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
outer-sphere water molecules can effectively hydrogen bond to
both the coordinated water molecule and the pyridazine nitrogen
atoms. The RMSD values for the overlaid structures of the
structures calculated without axial ligands are 0.2199 Å for 1 and
1
′ and 0.3573 Å for 2 and 2′. These substantially larger deviations
indicate that the presence of axial ligands has a dramatic effect on
the coordination geometries of the La complexes.
3
+
The activation barriers for enantiomerization of the TSAP
isomers via sequential arm rotation and ring inversion of 1H2O
−
4H2O were also investigated. The computational approach used
was similar to that developed by other researchers to investigate
the solution dynamics of lanthanide complexes of DOTA and
1
8,26,32,42−45
related cyclen-based macrocycles.
The ring-inversion
mechanism, in which the chirality of each 5-membered chelate
ring sequentially switches from the δ to λ configuration, was
successfully modeled with DFT calculations. The relative free
energies of the intermediates and transition states along this
pathway in the gas phase are shown in Figure 6 for 1H2O and in
Figure 7. Relative free energies for intermediates and transition states of
the ring-inversion and arm-rotation processes for 1′ in the gas phase.
imately 10 kJ/mol. The concerted arm-rotation mechanism for
2
′−4′, however, is energetically competitive with the ring
inversion of 2 −4 . In contrast, the free energy barrier of
H2O
H2O
this process for 1′ is over 10 kJ/mol greater than that for the ring
inversion of 1 . Notably, the arm-rotation mechanism for 2′
H2O
has a barrier substantially smaller than that of any of the
⧧
complexes studied; the computed ΔG value at 298 K is only
4
4.9 kJ/mol. This small barrier may arise, in part, because of the
absence of hydrogen atoms in the ortho position of the pendant
heterocycle, which diminishes the unfavorable steric interactions
in the transition state of the concerted arm rotation.
Unfortunately, because the transition state for the arm-rotation
mechanism of the hydrated complexes could not be located,
these energies, which may be rate-limiting, cannot be included in
this discussion.
Figure 6. Relative free energies for intermediates and transition states of
the ring-inversion process for 1H2O in the gas phase.
The role of the dielectric continuum of water on the energies
of all intermediates and transition states was investigated next.
Attempts to optimize structures in the presence of the implicit
solvation models were generally unsuccessful except for several
cases. Hence, single-point calculations employing the SMD
Figures S43−S45 in the SI for 2 −4H2O, respectively. For the
H2O
ring-inversion mechanism, the complexes can pass through an
intermediate of either Δ(δλδλ) or Δ(δδλλ) stereochemistry. The
highest energy barriers, however, were found to correspond to
TS4 (Figure 6), suggesting that preceding intermediates of both
stereochemistries are accessible during the interconversion
process. Attempts to find a transition state corresponding to an
arm-rotation mechanism in which the overall complex helicity
switches from Δ to Λ were not successful. Therefore, the
activation barriers for the complexes lacking axial ligands (1′−4′)
were also computed. Transition states corresponding to the
concerted arm-rotation mechanism were located in addition to
those for the sequential ring-inversion mechanism. The relative
gas-phase free energies of these species are shown in Figure 7 for
46
solvation model were carried out on gas-phase-optimized
geometries. Thermochemical corrections from the gas-phase
calculations were applied to solution-phase SCF energies to
estimate thermodynamic values in solution. The relative free
energies in solution for 1H2O and 1′ are shown in Figures 8 and 9,
respectively; the energies for 2H2O−4
and 2′−4′ are displayed
H2O
in Figures S49−S54, respectively, in the SI. The pathways
between the TSAP and SAP diastereomers in solution are
qualitatively similar to those in the gas phase; however,
intermediates and transition states are systematically destabilized
in the presence of the dielectric continuum of water. The highest
energy barrier in solution for the ring-inversion process is the
same as that in the gas phase, TS4. Thermodynamic activation
barriers for TS4 and the arm-rotation TS for 1′−4′ are given in
Table 5. Polarization of the solvent systematically increases the
1
′ and Figures S46−S48 in the SI for 2′−4′, respectively. In
Table 4, the calculated activation parameters for the highest
energy barriers are reported. The highest energy barrier for all
complexes in the ring inversion was found to be TS4.
Given the fast water-exchange rate of lanthanide complexes in
aqueous solution, enantiomerization of the TSAP isomer could
conceivably occur through complexes lacking axial ligands if
these complexes provided an overall lower energy pathway. The
activation barriers for the ring-inversion process of 1H2O−4
H2O
and 1′−4′ by 14−24 and 12−20 kJ/mol, respectively. In
⧧
contrast, the ΔG values for the arm-rotation mechanism of 1′,
3′, and 4′ decrease substantially due to stabilization of the
transition state in a dielectric continuum. Stabilization of this
transition state in solution is correlated with the dipole moment
⧧
calculated ΔG values for 1′−4′ for the ring-inversion process
are consistently greater than those of 1 −4
by approx-
H2O
H2O
H
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Inorganic Chemistry
Article
Table 4. Activation Parameters in the Gas Phase for the Highest Energy Transition State (TS4) of the Ring-Inversion Mechanism
of 1H2O−4H2O and 1′−4′ and for the Transition State of the Arm-Rotation Mechanism of 1′−4′
ring inversion
arm rotation
1H2O
2H2O
3H2O
4H2O
1′
2′
3′
4′
1′
2′
3′
4′
⧧
−1
ΔH , kJ mol
68.9
78.2
5.1
70.8
−9.6
73.7
69.5
−10
72.5
84.8
−3.8
85.9
82.6
−2.6
83.4
85.5
−3.0
86.4
85.2
−2.9
86.1
81.9
51.2
21.2
44.9
70.2
−7.2
72.4
74.5
−9.5
77.3
⧧
−1
−1
ΔS , J K mol
−15.7
73.6
−12.3
85.5
⧧
−1
ΔG , kJ mol
76.7
of the molecule; the solution-phase dipole moments of 1′, 3′, and
4
′ of this transition state are more than a debye larger than those
for the other intermediates and transition states along the ring-
inversion pathway. In contrast, the dipole moment of the
transition state for 2′ is smaller than that of the other species on
the ring-inversion pathway, and therefore addition of the
dielectric continuum minimally alters the energy barrier to arm
⧧
rotation. The low ΔG values, all less than 60 kJ/mol, suggest
that synchronous arm rotation is not the rate-limiting process for
the enantiomerization process of the TSAP diastereomer. The
lower energy of the ring-inversion pathway in the hydrated
compared to the water-free complexes suggests that enantiome-
rization may occur with an axial water ligand.
The solution-phase values presented in Table 5 are generally in
poorer agreement with experimental values and previously
47
calculated values for similar systems than the gas-phase
calculations given in Table 4. The larger discrepancy observed
by introducing solvent effects is counterintuitive. Structures of
Figure 8. DFT-calculated relative free energies of transition states and
intermediates for the ring-inversion process of 1H2O with the SMD
solvation model applied.
the TSAP, Δ(δδδλ), and Δ(δλδλ) isomers of 1
were
H2O
successfully optimized in the polarizable continuum model
PCM), along with transition states TS2A and TS3A. Other
(
ground and transition state structures would not converge in the
presence of the PCM. The calculated free energies of the PCM-
optimized structures relative to the TSAP isomer are 27.8, 35.2,
6
3.2, and 66.9 kJ/mol for Δ(δδδλ), Δ(δλδλ), TS2A, and TS3A,
respectively. These values are in good agreement with the gas-
phase calculations in which the respective values are 31.5, 31.0,
6
2.5, and 71.3 kJ/mol. The solution-phase energies of the gas-
phase-optimized structures are, as noted above, greater than both
of these sets of values at 41.9, 45.5, 74.1, and 77.3 kJ/mol for the
Δ(δδδλ), Δ(δλδλ), TS2A, and TS3A structures, respectively.
Therefore, it appears that because the geometries were not
allowed to relax in the potential energy surface of the PCM, a
systematic error is introduced, which manifests in the larger than
expected barriers and energy values relative to the TSAP isomer.
The decrease in the energy of the transition state of the arm-
rotation mechanism, however, is a significant insight that is
granted only by the introduction of the solvation model. Thus,
the use of these single-point solvation energy calculations is still
capable of giving valuable qualitative insights.
Figure 9. DFT-calculated relative free energies of transition states and
intermediates for the ring-inversion and arm-rotation processes of 1′
with the SMD solvation model applied.
The experimentally determined activation parameters for 1
⧧
⧧
−1
−1
(
ΔH = 60 kJ/mol, ΔS = −20 J K mol ) are in close
agreement with the calculated solution-phase ring-inversion
Table 5. Activation Parameters in Water Using the SMD Solvation Model for the Highest Energy Transition State (TS4) of the
a
Ring-Inversion Mechanism of 1H2O−4H2O and 1′−4′ and for the Transition State of the Arm-Rotation Mechanism of 1′−4′
ring inversion
arm rotation
1H2O
2H2O
3H2O
4H2O
1′
2′
3′
4′
1′
2′
3′
4′
⧧
−1
ΔH , kJ mol
82.7
99.1
5.1
82.8
−9.6
85.6
93.9
−10
96.9
104.7
−3.8
105.8
93.9
−2.6
94.6
104.2
−3.0
105.1
104.0
−2.9
104.8
50.8
63.0
21.2
56.7
44.7
−7.2
46.8
44.9
−9.5
42.1
⧧
−1
−1
ΔS , J K mol
−15.7
87.4
−12.3
54.5
⧧
−1
ΔG , kJ mol
97.6
a
Entropy and enthalpy corrections were used from the corresponding gas-phase calculations.
I
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Inorganic Chemistry
Article
⧧
barrier of 1H2O and arm rotation of 1′. The ΔS values are of the
standard errors of the least-squares fit to the linear equation. Eyring
analyses of 3 and 4 were complicated by the observation of significant
complex decomposition at temperatures greater than 45 °C. Therefore,
line-shape analysis was carried out only in the 5−45 °C range. Because
this narrow temperature range precludes the analysis of rate constants
near and above the coalescence temperature, a greater error was
associated with the Eyring analyses of these two complexes as reflected
by poorer linear fits.
expected sign and magnitude. In contrast, the larger, more
negative ΔS values determined experimentally for 2−4 are not
matched well by the DFT calculations. This poor agreement may
arise from a lack of consideration for explicit solvent molecules,
which may be the determining factors in the entropy of activation
values.
⧧
1
,4,7,10-Tetrakis(3-pyridazylmethyl)-1,4,7,10-tetraazacyclo-
pyd
dodecane (L ). To a mixture of 233 mg (1.35 mmol) of cyclen and
SUMMARY AND CONCLUSIONS
■
8
3
.8 g (27 mmol) of Cs CO in 6 mL of CH CN was added a solution of
-(chloromethyl)pyridazine·3.6EtOH (1.67 g, 6.57 mmol) in 9 mL of
2 3 3
A series of nitrogen-rich macrocyclic ligands were prepared. The
pendant donors were systematically varied to provide a series of
structurally homologous yet electronically distinct ligands. The
CH CN in a dropwise manner. The resulting suspension was then
heated to reflux for 16 h. The dark orange-brown mixture was filtered
through a pad of Celite while still hot. The solid residue, remaining on
the Celite pad, was washed with 5 × 5 mL of boiling CH CN until the
eluate was colorless. The combined filtrate and washings were
evaporated to dryness under reduced pressure at 40 °C, leaving a
brown residue. The residue was taken up in 3 mL of CH CN. The red-
brown supernatant was carefully separated from the beige solid with a
Pasteur pipet, and the solid was washed an additional three times with 3
mL of CH CN. The solid was then dissolved in 10 mL of boiling
3
3
+
coordination chemistry of these ligands with La revealed that
subtle modifications of the ligand donors gave rise to differing
degrees of conformational rigidity and thermal stability of the
resulting complexes in solution. More basic pendant donors gave
rise to more thermally stable complexes. This parameter,
however, did not correlate with the conformational rigidity of
the complexes in solution. DFT calculations, employed to
investigate the conformational dynamics of these complexes in
solution, were carried out. These calculations in the gas phase
reveal good agreement with experimental data, implicating the
ring-inversion mechanism as the rate-determining step for
enantiomerization. The broader utility of this new class of
nitrogen-rich octadentate ligands for the chelation of medical
radioisotopes is currently under investigation.
3
3
3
CH CN, and the resulting orange solution was filtered through a
3
column of Celite while still hot to remove some solid impurities. The
filtrate was stored at −20 °C for 5 h, giving rise to pale-orange crystals of
the desired compound. The supernatant was decanted from the crystals,
which were washed sequentially with 3 × 5 mL of cold (−20 °C)
CH CN and 3 × 5 mL of Et O and then dried in air. Yield: 315 mg, 43%.
3
2
1
H NMR (400 MHz, CDCl , 25 °C): δ 9.04 (4H, d), 7.65 (4H, d), 7.35
3
13
1
(4H, dd), 3.78 (8H, s), 2.75 (16H, s). C{ H} NMR (100 MHz,
−1
CDCl , 25 °C): δ 161.9, 150.5, 127.0, 126.6, 59.6, 53.3. IR (ATR, cm ):
3
EXPERIMENTAL SECTION
Materials and Methods. Solvents used were of analytical grade.
■
2938 w, 2824 m, 2785 m, 5179 m, 1555 w, 1453 s, 1431 s, 1399 s, 1371 s,
1355 s, 1307 s, 1288 s, 1265 s, 1250 s, 1185 m, 1152 m, 1133 s, 1094 s,
1079 s, 1068 s, 1046 s, 1008 s, 996 s, 961 m, 923 s, 844 w, 823 s, 780 s,
749 s. APCI-MS (positive ion mode, MeOH) m/z: 541.5; calcd for [M +
H] , 541.3. Anal. Calcd for C28H N12 (L ): C, 62.20; H, 6.71; N,
31.09. Found: C, 62.34; H, 6.75; N, 30.96.
Cs CO was purchased from Acro
̈
s Organics, and cyclen and La(OTf)3
2
3
py
were procured from Strem Chemicals. The ligand L was synthesized as
18
+
pyd
previously reported. The chloromethyl N-heterocycles were synthe-
sized by the reaction of trichloroisocyanuric acid and the methyl N-
36
heterocycle and were purified by SiO gel column chromatography,
1,4,7,10-Tetrakis(4-pyrimidylmethyl)-1,4,7,10-tetraazacyclo-
2
pyr
eluting with either 100% ethyl acetate or 100% diethyl ether (stabilized
dodecane (L ). To a mixture of 517 mg (3.00 mmol) of cyclen and
19
with 1−2% ethanol) as previously described. The residual solvent
content in these products, which are viscous oils, was quantified by
NMR spectroscopy and incorporated in the molecular weight used for
calculating proper stoichiometric quantities. Reactions were carried out
under normal atmospheric conditions with no efforts to exclude
atmospheric moisture or oxygen.
20.5 g (62.9 mmol) of Cs
solution of 4-(chloromethyl)pyrimidine·0.75EtOAc (2.45 g, 12.6
mmol) in 10 mL of CH CN in a dropwise manner. The resulting
2 3 3
CO in 15 mL of CH CN was added a
3
suspension was then heated to reflux for 16 h. The dark red-orange
mixture was filtered through a pad of Celite while still hot. The pale-
brown solid residue, remaining on the Celite pad, was washed with 5 × 5
Physical Measurements. Fourier transform infrared (FTIR)
spectra were acquired with a Thermo Scientific Nicolet iS10
spectrometer in the attenuated total reflectance (ATR) mode with a
diamond ATR crystal accessory. Relative peak intensities are reported as
very strong (vs), strong (s), medium (m), weak (w), or very weak (vw).
APCI-MS data were acquired with a Varian 500-MS Ion Trap Mass
Spectrometer with the capillary and needle voltages set to 95 and 4055
V, respectively. Elemental analyses (CHN) were performed by ALS
Environmental (Tucson, AZ). NMR spectra were acquired with a
Bruker Avance III HD 400 MHz Spectrometer interfaced with TopSpin
v3.2 software. In deuterated organic solvents, chemical shifts were
referenced internally to residual protic solvent peaks. For NMR spectra
mL of boiling CH CN until the eluate was colorless. The combined
3
filtrate and washings were evaporated to dryness under reduced pressure
at 40 °C, leaving a red oily residue. The residue was taken up in 5 mL of
CH
separated from the dark red solution by decanting. The remaining solid
CN and then dissolved in 16 mL of
CN and cooled in an ice bath for 15 min. A pale-orange solid was
3
was washed with 2 × 5 mL of CH
3
boiling CH CN. The orange-red solution was filtered through a column
3
of Celite while still hot and then stored at −20 °C for 16 h. A pale-orange
crystalline solid deposited, which was separated from the orange
supernatant by decanting. The solid was washed sequentially with 3 × 2
mL of cold (−20 °C) CH CN and 3 × 2 mL of Et O and then dried in
3
2
1
air. Yield: 594 mg, 37%. H NMR (400 MHz, CDCl , 25 °C): δ 9.08
(4H, s), 8.51 (4H, d), 7.69 (4H, d), 3.62 (8H, s), 2.78 (16H, s). C{ H}
3
1
3
1
acquired in D O, shifts were referenced internally to either residual
2
1
13
acetonitrile (δ H = 2.22 ppm, δ C (CH ) = 1.97 ppm) or a small
amount of added 1,4-dioxane (δ H = 3.75 ppm, δ C = 67.19 ppm).
For variable-temperature experiments, the temperatures were corrected
NMR (100 MHz, CDCl , 25 °C): δ 168.8, 158.7, 157.1, 120.1, 60.9,
3
3
1
13
48
−1
53.8. IR (ATR, cm ): 2794 m, 1578 vs, 1548 s, 1471 m, 1436 m, 1384 s,
1360 s, 1307 m, 1293 s, 1248 m, 1158 w, 1108 s, 1071 w, 994 m, 973 m,
49
using an ethylene glycol chemical shift thermometer. Correction
902 s, 869 s, 834 s, 798 s, 777 s, 739 s, 677 m. APCI-MS (positive ion
+
factors were generally less than 1 K. Samples of 1−4 were prepared in
mode, MeOH) m/z: 541.2; calcd for [M + H] , 541.3. Anal. Calcd for
pyr
D O at concentrations of 25−50 mM. The pD values of the solutions
C H N (L ): C, 62.20; H, 6.71; N, 31.09. Found: C, 61.88; H, 6.78;
2
28 36 12
were not adjusted but were found to be consistently between 6.0 and 7.0
N, 30.75.
13
with pH paper. Line-shape analysis of the two coalescing C resonances
was carried out using the DNMR module of Bruker’s TopSpin v3.2
software. Variable-temperature runs were carried out two times with
independently prepared samples. The data from the two runs were
combined on a single Eyring plot. Errors quoted are derived from the
1,4,7,10-Tetrakis(2-pyrazinylmethyl)-1,4,7,10-tetraazacyclo-
pz
dodecane (L ). To a mixture of 333 mg (1.93 mmol) of cyclen and
13.0 g (39.9 mmol) of Cs CO in 15 mL of CH CN was added a
2
3
3
solution of 2-(chloromethyl)pyrazine·0.13EtOH (1.14 g, 8.48 mmol) in
10 mL of CH CN in a dropwise manner. The resulting suspension was
3
J
dx.doi.org/10.1021/ic501843c | Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
Table 6. X-ray Crystallographic Data Collection and Refinement Parameters
Lpyd
Lpyr
Lpz
1·0.5Et O
2·H O
2
2
formula
fw
C H N
C H N
C H N
C H F LaN O9.50S3
C H F LaN O S
33 39 9 13 10 3
2
8
36 12
28 36 12
28 36 12
41 51
9
10
540.69
P1
540.69
540.69
1242.01
1183.86
space group
a, Å
̅
Pna21
P2 /n
1
Pbcn
P2 /n
1
8.8576(5)
9.6141(6)
9.6564(6)
106.408(4)
91.713(4)
115.409(4)
701.61(7)
1
16.343(5)
12.689(4)
13.491(4)
11.6230(15)
10.0308(13)
11.6987(15)
34.084(5)
13.3725(19)
21.967(3)
12.945(4)
27.498(8)
13.200(4)
b, Å
c, Å
α, deg
β, deg
99.7720(10)
91.262(4)
γ, deg
V, Å3
2797.8(14)
4
1344.1(3)
2
10012(2)
8
4698(2)
4
Z
ρcalcd, g cm3
1.280
1.284
140(2)
0.083
2.03−25.12
25569
4970
1.336
140(2)
0.086
2.28−27.48
14616
3055
1.648
140(2)
1.076
1.85−27.24
106007
11193
675
1.674
140(2)
1.145
1.48−25.13
53829
8352
636
T, K
140(2)
0.083
−
1
μ (Mo Kα), mm
θ range, deg
total data
unique data
parameters
restraints
2.23−28.87
16845
3637
181
361
181
0
1
0
38
25
completeness, %
99.0
99.9
99.5
99.8
99.2
a
R , %
5.09
3.24
3.69
3.17
6.41
1
b
wR , %
9.40
6.93
9.28
7.34
15.83
1.060
2
c
GoF
1.011
1.033
0.160, −0.168
1.039
0.301, −0.244
1.051
max, min peaks, e Å−
3
0.276, −0.237
1.436, −0.843
1.709, −1.096
a
R = ∑∥F | − |F ∥/∑|F | for I > 2σ. wR = {∑[w(F − F ) ]/∑[w(F ) ]} for I > 2σ. GoF = {∑[w(Fo − F ) ]/(n − p)}1/2, where n is the
b
2
o
2
2
2
o
2
1/2
c
2
2 2
c
1
o
c
o
2
c
number of data points and p is the number of refined parameters.
then heated to reflux for 16 h. The yellow-brown mixture was filtered
through a pad of Celite while still hot. The pale brown solid residue,
remaining on the Celite pad, was washed with 3 × 5 mL of boiling
concentrated to dryness under vacuum at 40 °C to give an oily orange
residue. The residue was dissolved in 1.5 mL of CH CN and filtered.
3
Slow vapor diffusion of Et O at room temperature into this solution
2
CH CN. The combined orange filtrate and washings were stored at −20
afforded a pale yellow crystalline solid. This solid was dispersed in 1 mL
3
°C for 4 h. The mix was then filtered to collect the product as an off-
of CH CN and then centrifuged. The solid, now white in color, was
3
white crystalline solid. The solid was washed sequentially with 3 × 5 mL
separated from the yellow supernatant, washed with 1.5 mL of CH CN
3
of cold (−20 °C) CH CN and 3 × 5 mL of Et O and then dried in air.
and 3 × 1 mL of Et O, and dried in vacuo. Et O was allowed to vapor
3
2
2
2
1
Yield: 639 mg, 61%. H NMR (400 MHz, CDCl , 25 °C): δ 8.78 (4H, s),
diffuse into the yellow supernatant, affording an additional crop of white
3
.43 (8H, d+d), 3.65 (8H, s), 2.76 (16H, s). 13C{ H} NMR (100 MHz,
1
crystalline product, which was washed with 3 × 1 mL of Et O, and dried
8
2
−1
1
CDCl , 25 °C): δ 155.3, 145.7, 143.8, 143.2, 59.6, 53.6. IR (ATR, cm ):
in vacuo. Yield: 40 mg (first crop) + 26 mg (second crop), 36%. H
3
2
947 w, 2802 m, 1479 w, 1455 m, 1430 m, 1397 s, 1369 s, 1353 s, 1308
vs, 1295 m, 1233 w, 1154 m, 1134 s, 1081 vs, 1064 m, 1049 m, 1013 s,
24 s, 859 s, 830 s, 803 m, 749 w, 660 w. APCI-MS (positive ion mode,
NMR (400 MHz, D O, 5 °C): δ 8.98 (4H, t), 7.94 (8H, d+d), 4.57 (4H,
2
13
1
br d), 4.02 (8H, br t), 3.52 (4H, br t), 2.80 (8H, br d). C{ H} NMR
(100 MHz, D O, 5 °C): δ 162.6, 152.7, 132.3, 131.1, 120.2 (q, J = 316
Hz), 59.0, 53.71 (br), 51.43 (br). IR (ATR, cm ): 3069 w, 2862 w, 1616
w, 1595 m, 1560 w, 1483 w, 1443 m, 1415 w, 1367 vw, 1251 vs, 1221 s,
1151 s, 1076 m, 1027 vs, 1007 s, 967 m, 904 w, 839 m, 815 m, 772 w, 756
w, 745 w. Anal. Calcd for C H N F LaO S (2·H O): C, 32.52; H,
3.35; N, 14.68. Found: C, 32.47; H, 3.59; N, 14.59.
[LaL (OTf)](OTf) ·MeOH (3·MeOH). A solution of L (100 mg,
0.18 mmol) in 3 mL of MeOH was added in a dropwise manner to a
1
9
2
CF
+
−1
MeOH) m/z: 541.5; calcd for [M + H] , 541.3. Anal. Calcd for
C H N (L ): C, 62.20; H, 6.71; N, 31.09. Found: C, 62.24; H, 6.78;
pz
2
8
36 12
N, 30.88.
py
py
[LaL (OTf)](OTf) (1). A solution of L (46 mg, 0.086 mmol) in 5
2
31 38 12
9
10
3
2
mL of MeOH was added in a dropwise manner to a solution of
pyr
pyr
La(OTf) (50 mg, 0.085 mmol) in 5 mL of MeOH. The combined
3
2
reagents were then heated at 40 °C for 3 h. The colorless solution was
concentrated to dryness under vacuum at 40 °C to give a white oily
solution of La(OTf) (108 mg, 0.18 mmol) in 3 mL of MeOH. The
3
residue. The residue was dissolved in 1 mL of CH CN. The slow vapor
combined reagents were then heated at 40 °C for 6 h and then allowed to
3
diffusion of Et O at room temperature into this solution afforded
cool to room temperature. Vapor diffusion of Et O at room temperature
2
2
needle-like colorless crystals of the desired compound. The crystals were
into the resulting yellow solution afforded a white crystalline solid. The
supernatant was decanted, and the solid was washed with 3 × 2 mL of
washed with 3 × 1 mL of Et O and then dried in vacuo. Yield: 71 mg,
2
1
1
7
(
4%. H NMR (400 MHz, D O, 5 °C): δ 8.12 (4H, t), 7.84 (4H, d), 7.68
Et O and dried in vacuo. Yield: 130 mg, 62%. H NMR (400 MHz, D O,
2
2
2
4H, d), 7.43 (4H, t), 4.54 (4H, d), 4.01 (4H, t), 3.85 (4H, d), 3.33 (4H,
5 °C): δ 9.03 (4H, d), 8.55 (4H, s), 7.86 (4H, d), 4.64 (4H, d), 4.04 (8H,
13
1
13
1
t), 2.71 (8H, t). C{ H} NMR (100 MHz, D O, 5 °C): δ 157.9, 149.4,
m), 3.26 (4H, t), 2.81 (8H, m). C{ H} NMR (100 MHz, D O, 5 °C):
2
2
1
1
1
42.8, 126.8, 125.8, 120.6 (q, J = 315 Hz), 60.6, 53.4, 51.9. IR (ATR,
δ 166.7, 161.7, 158.3, 123.8, 120.2 (q, J = 315 Hz), 59.8, 53.6, 51.3. IR
(ATR, cm ): 2873 w, 1593 s, 1554 m, 1483 w, 1460 w, 1400 m, 1312 m,
CF
CF
−1
−1
cm ): 2867 w, 1607 m, 1571 m, 1483 m, 1444 m, 1380 w, 1313 m, 1254
s, 1209 s, 1153 s, 1076 m, 1024 vs, 974 m, 907 w, 839 w, 812 m, 780 m,
1253 vs, 1207 s, 1155 s, 1075 m, 1026 vs, 1002 m, 966 m, 906 s, 839 w,
7
58 s, 731 w. Anal. Calcd for C H N F LaO S (1): C, 37.44; H, 3.59;
812 w, 779 w, 740 w, 688 m. Anal. Calcd for C H N F LaO S (3·
35
40
8
9
9
3
32 40 12
9
10 3
N, 9.98. Found: C, 37.11; H, 3.87; N, 9.80.
MeOH): C, 33.17; H, 3.48; N, 14.50. Found: C, 33.73; H, 3.74; N,
14.81.
pyd
pyd
[
LaL (OTf)](OTf) ·H O (2·H O). A solution of L (87 mg, 0.16
2 2 2
pz
pz
mmol) in 2 mL of MeOH was added in a dropwise manner to a solution
[LaL (OTf)](OTf) ·MeOH (4·MeOH). L (50 mg, 0.092 mmol) was
2
of La(OTf) (94 mg, 0.16 mmol) in 3 mL of MeOH. The combined
dissolved in 2 mL of MeOH by heating the mixture to 50 °C. The
3
pz
reagents were then heated at 40 °C for 6 h. The pale yellow solution was
resulting solution of L was added to La(OTf) (54 mg, 0.092 mmol)
3
K
dx.doi.org/10.1021/ic501843c | Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
dissolved in 0.5 mL of MeOH. After the solution had sat at room
temperature for 16 h without being stirred, colorless plate-like crystals of
the desired compound deposited. The supernatant was carefully
removed with a Pasteur pipet, and the crystals were washed sequentially
(those with exponential constants <0.05). Geometries of both stable
structures and transition states were optimized in the gas phase.
Transition-state structures were obtained using the synchronous transit-
6
1,62
guided quasi-Newton method.
Intermediates and transition states
with 3 × 2 mL of hot (40 °C) MeOH and 3 × 2 mL of Et O. The
were characterized by frequency calculations, which gave zero-point
energy-corrected thermodynamic values. Intermediates possessed no
imaginary frequencies, which verified their position at a local minimum
on the potential energy surface. Transition states contained a single
imaginary frequency. The imaginary frequency was visualized with
GaussView5 to confirm that it traversed the proper reaction coordinates
between two intermediates. Solution energies in water were calculated
2
remaining solid was dried in vacuo at room temperature. Yield: 27 mg,
1
2
5%. H NMR (400 MHz, D O, 5 °C): δ 8.67 (4H, s), 8.64 (4H, d), 8.17
2
(
(
1
4H, unresolved d), 4.44 (4H, d), 3.92 (8H, d), 3.22 (4H, br t), 2.66
8H, br t). C{ H} NMR (100 MHz, D O, 5 °C): δ 152.8, 147.0, 145.7,
44.5, 120.2 (q, J = 315 Hz), 57.8, 53.1, 51.0. IR (ATR, cm ): 2862
13
1
2
1
−1
CF
w, 1481 w, 1458 w, 1420 w, 1374 w, 1255 vs, 1222 m, 1150 s, 1080 m,
4
6
1
027 vs, 1007 m, 968 w, 902 w, 855 w, 840 w, 803 w, 774 w, 752 w, 676
using the implicit SMD solvation model. Single-point energy
calculations of gas-phase-optimized structures were carried out in the
dielectric continuum. The thermochemical correction factors obtained
from gas-phase frequency analyses were applied to the SCF energy of the
same structure in solution to estimate thermodynamic parameters. The
thermal correction to Gibbs free energy was modified for a pressure of
1354 atm on the basis of the experimental density of liquid water prior to
w. Anal. Calcd for C H N F LaO S (4·MeOH): C, 33.17; H, 3.48;
N, 14.50. Found: C, 32.70; H, 3.95; N, 14.59.
32
40 12
9
10 3
X-ray Crystallography. Single crystals of Lpyd and Lpyr were
obtained by the slow evaporation of methanolic solutions, whereas
pz
crystals of L were grown by vapor diffusion of Et O into a
2
dimethylformamide solution. Vapor diffusion of Et O into CH CN
2
3
6
3
solutions of 1 and 2 afforded X-ray quality crystals. Weakly diffracting
and highly twinned crystals of 3 and 4 were obtained by the vapor
adjustment of the SCF energy in solution. Gas-phase thermochemical
calculations employed a pressure of 1 atm. All free energy values cited
throughout the Article are calculated at 298 K unless otherwise stated.
For two transition state structures, those of the arm-rotation mechanism
of 2′ and of TS4 of 3′, stationary points were not found with the default
optimization criteria of Gaussian09. Whereas the maximum force and
RMS converged, the maximum displacement and its RMS remained
above the convergence criteria. Calculating exact force constants at each
step, decreasing the optimization step size, and carrying out the
optimization in Cartesian coordinates failed to give geometries that
satisfied the maximum displacement convergence criteria. Variations in
electronic energies during the optimizations of the arm-rotation
transition state of 2′ and TS4 of 3′ were only 0.00015 hartree (0.4
kJ/mol) and 0.0004 hartree (1 kJ/mol), respectively. Frequency
calculations on the final geometries obtained after exceeding the
maximum number of steps were carried out. Only a single imaginary
frequency corresponding to the desired reaction coordinate was
obtained for both structures. The thermochemical data for these
incompletely optimized structures were used for the analysis described
above. Coordinates and energies for both the gas phase and in solution
of all optimized structures are given in Tables S2−S101 in the SI.
diffusion of Et O into a methanolic solution and directly from the
2
methanol reaction solvent, respectively.
Single crystals were mounted on a nylon loop in n-paratone oil and
cooled with a Bruker Kryoflex nitrogen cold stream. A Bruker D8
diffractometer with a graphite monochromatized Mo Kα X-ray source (λ
5
0
=
0.71073 Å) controlled by the APEX2 software package was used for
51
data collection. Data were integrated with SAINT and subsequently
corrected for absorption with SADABS. The SHELXTL software
51
5
2,53
package
was employed for structure solution and refinement against
2
F . Heavy atoms were located on the difference Fourier map and refined
anisotropically. Hydrogen atoms were placed at calculated positions and
given isotropic thermal parameters equal to either 1.5 (terminal CH3
groups) or 1.2 times that of the thermal parameter of the atom to which
they were attached. For the ligands L , L , and L , the locations of the
nitrogen atoms on the heterocycles were assigned by careful analysis of
the difference Fourier map prior to hydrogen atom placement. No
electron density corresponding to hydrogen atoms was located at the
atoms assigned as nitrogens, whereas the other atoms on the heterocycle
pyd pyr
pz
pyr
clearly displayed residual density arising from hydrogens. L
crystallized in the noncentrosymmetric space group Pna2 . Because of
1
pyr
the lack of heavy atoms in the structure of L , the absolute structure was
ASSOCIATED CONTENT
Supporting Information
X-ray crystallographic data in CIF format, complete character-
ization data, Eyring analyses, and DFT energies and optimized
coordinates. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
not refined. In the structure of 1, the oxygen atom of a disordered
molecule of diethyl ether was located on a crystallographic 2-fold axis.
The geometries of the disordered components were refined with
similarity restraints (SADI, default values), and the sum of the
occupancy of the components was constrained to unity. The thermal
displacement parameters of this disordered molecule were also
restrained to have similar size and shape (SIMU and DELU, default
values). For 2, after all species in the asymmetric unit had been identified
and assigned, several peaks of residual electron density remained. The
electron density was refined as four water molecules, disordered spatially
within this void. The sum of the occupancy of the four oxygen atoms was
constrained to unity. The thermal ellipsoids of the oxygen atoms were
restrained to be spherical (ISOR, default values) and constrained to be
identical (EADP). Because of the low occupancy of each oxygen atom,
hydrogen atoms were neither located on the difference Fourier map nor
included in the final model. X-ray crystallographic data collection and
refinement parameters are collected in Table 6, and CIF files can be
found in the SI. The poor quality data sets afforded from crystals of 3 and
*
S
AUTHOR INFORMATION
Corresponding Authors
E-mail: jjwilson@lanl.gov.
E-mail: eva@lanl.gov.
■
*
*
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Ben Davis for assistance with and use of a mass
spectrometer. J.J.W. acknowledges funding support via the
LANL/LDRD program through a Seaborg Institute Postdoctoral
Research Fellowship. The research described in this paper was
funded by the United States Department of Energy Office of
Science via funding from the Isotope Development and
Production for Research and Applications subprogram in the
Office of Science, Nuclear Physics, and through the Heavy
Element Chemistry Program of BES (R. L. Martin and E. R.
Batista). The content of this Article has been reviewed and
approved for public release as LA-UR-14-25841.
4
were not amenable to satisfactory structure refinement. Structure
solution, however, was carried out, and basic atomic connectivity could
be resolved. The unit cell parameters and space groups used for
resolution of these structures are given in Table S1 of the SI.
DFT Calculations. DFT calculations were carried out with the
5
4
55,56
Gaussian09 software package. The hybrid functional B3LYP
was
was assigned to atoms
other than La. For La, the quasi-relativistic 28-electron Stuttgart/
5
7,58
used, and the Pople-style basis set 6-31G(d)
59
Dresden (SDD) effective core potential was employed. The associated
segmented SDD basis set was modified for computational efficiency by
60
removing the g functions and removing the most diffuse functions
L
dx.doi.org/10.1021/ic501843c | Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
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36) Morrow, J. R.; Chin, K. O. A. Inorg. Chem. 1993, 32, 3357.
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dx.doi.org/10.1021/ic501843c | Inorg. Chem. XXXX, XXX, XXX−XXX