Models for B12-conjugated radiopharmaceuticals. Cobaloxime binding to new fac-[Re(CO)3(Me2bipyridine)(amidine)]BF4 complexes having an exposed pyridyl nitrogen

Article abstract of DOI:10.1021/ic5016675

New mononuclear amidine complexes, fac-[Re(CO)₃(Me₂bipy)(HNC(CH₃)-(pyppz))]BF₄ [(4,4′-Me₂bipy (1), 5,5′-Me₂bipy (2), and 6,6′-Me₂bipy (3)] (bipy = 2,2′-bipyridine), were synthesized by treating the parent fac-[Re^I(CO)₃(Me₂bipy)(CH₃CN)]BF₄complex with the C₂-symmetrical amine 1-(4-pyridyl)piperazine (pyppzH). The axial amidine ligand has an exposed, highly basic pyridyl nitrogen. The reaction of complexes 1-3 with a B₁₂model, (py)Co(DH)₂Cl (DH = monoanion of dimethylglyoxime), in CH₂Cl₂ yielded the respective dinuclear complexes, namely, fac-[Re(CO)₃(Me₂bipy)(μ-(HNC(CH₃)(pyppz)))Co-(DH)₂Cl]BF₄ [(4,4′-Me₂bipy (4), 5,5′-Me₂bipy (5), and 6,6′-Me₂bipy (6)]. ¹H NMR spectroscopic analysis of all compounds and single-crystal X-ray crystallographic data for 2, 3, 5, and 6 established that the amidine had only the E configuration in both the solid and solution states and that the pyridyl group is bound to Co in 4-6. Comparison of the NMR spectra of 1-3 with spectra of 4-6 reveals an unusually large wrong-way upfield shift for the pyridyl H2/6 signal for 4-6. The wrong-way H2/6 shift of (4-Xpy)Co(DH)₂Cl (4-Xpy = 4-substituted pyridine) complexes increased with increasing basicity of the 4-Xpy derivative, a finding attributed to the influence of the magnetic anisotropy of the cobalt center on the shifts of the ¹H NMR signals of the pyridyl protons closest to Co. Our method of employing a coordinate bond for conjugating the fac-[Re^I(CO)₃] core to a vitamin B₁₂ model could be extended to natural B₁₂derivatives. Because B₁₂ compounds are known to accumulate in cancer cells, such an approach is a very attractive method for the development of ^99mTc and ^186/188Re radiopharmaceuticals for targeted tumor imaging and therapy. (Chemical Equation Presented).

Full text of DOI:10.1021/ic5016675

Article
pubs.acs.org/IC
Models for B12-Conjugated Radiopharmaceuticals. Cobaloxime
Binding to New fac-[Re(CO)3(Me2Bipyridine)(amidine)]BF4 Complexes
Having an Exposed Pyridyl Nitrogen
Nerissa A. Lewis, Patricia A. Marzilli, Frank R. Fronczek, and Luigi G. Marzilli*
Department of Chemistry, Louisiana State University, Baton Rouge, Louisiana 70803, United States
S
* Supporting Information
ABSTRACT: New mononuclear amidine complexes, fac-[Re(CO)3(Me2bipy)(HNC(CH3)-
(pyppz))]BF4 [(4,4′-Me2bipy (1), 5,5′-Me2bipy (2), and 6,6′-Me2bipy (3)] (bipy = 2,2′-
bipyridine), were synthesized by treating the parent fac-[ReI(CO)3(Me2bipy)(CH3CN)]BF4
complex with the C2-symmetrical amine 1-(4-pyridyl)piperazine (pyppzH). The axial amidine
ligand has an exposed, highly basic pyridyl nitrogen. The reaction of complexes 1−3 with a B12
model, (py)Co(DH)2Cl (DH = monoanion of dimethylglyoxime), in CH2Cl2 yielded the
respective dinuclear complexes, namely, fac-[Re(CO)3(Me2bipy)(μ-(HNC(CH3)(pyppz)))Co-
(DH)2Cl]BF4 [(4,4′-Me2bipy (4), 5,5′-Me2bipy (5), and 6,6′-Me2bipy (6)]. 1H NMR
spectroscopic analysis of all compounds and single-crystal X-ray crystallographic data for 2, 3,
5, and 6 established that the amidine had only the E configuration in both the solid and solution
states and that the pyridyl group is bound to Co in 4−6. Comparison of the NMR spectra of 1−
3 with spectra of 4−6 reveals an unusually large “wrong-way” upfield shift for the pyridyl H2/6
signal for 4−6. The wrong-way H2/6 shift of (4-Xpy)Co(DH)2Cl (4-Xpy = 4-substituted
pyridine) complexes increased with increasing basicity of the 4-Xpy derivative, a finding attributed to the influence of the
magnetic anisotropy of the cobalt center on the shifts of the 1H NMR signals of the pyridyl protons closest to Co. Our method of
employing a coordinate bond for conjugating the fac-[ReI(CO)3] core to a vitamin B12 model could be extended to natural B12
derivatives. Because B12 compounds are known to accumulate in cancer cells, such an approach is a very attractive method for the
development of 99mTc and 186/188Re radiopharmaceuticals for targeted tumor imaging and therapy.
We have recently been investigating the monodentate ligands
having a superbasic amidine donor group.4,19 In our first study,
we discovered that primary amines added to acetonitrile
complexes having bidentate substituted bipyridines, fac-
[ReI(CO)3(Me2bipy)(CH3CN)]BF4 (bipy = 2,2′-bipyridine),
form robust fac-[Re(CO)3(Me2bipy)(HNC(CH3)NHR)]BF4
complexes.19 Thus, amidine groups have potential as linkers
for the conjugation of the fac-[MI(CO)3] core (M = 99mTc and
186/188Re radionuclides) to bioactive targeting moieties.4,19 The
ReI amidine moiety, ReI−N3(H)−Cam(CH3)−N4(H)R, in
these reported complexes has two different substituents (H
and R) on the remote nitrogen (N4) and double-bond
character in the C−N bonds (Cam−N3 and Cam−N4).19
These features lead to the possibility of four configurations and
hence four conceivable isomers for fac-[Re(CO)3(Me2bipy)-
(HNC(CH3)NHR)]BF4 complexes (Figure 1).19 In some
solvents, as many as three isomers were found to exist and to
undergo interchange, properties limiting the application of such
amidines in radiopharmaceutical development. Bulky R groups
destabilized the Z and Z′ configurations.19
INTRODUCTION
■
Isotopes of rhenium and technetium are among the most
promising nuclides utilized in diagnostic and therapeutic
applications.1−3 Rhenium and technetium complexes bearing
the fac-[MI(CO)3] core have received much attention owing to
the many ideal properties of this core.4−7 Some fac-
[
99mTcI(CO)3L]n imaging agents have recently undergone
evaluations in humans,4,7,8 and fac-[186/188ReI(CO)3L]n agents
are emerging among the most promising radionuclides for
therapeutic applications.1−4
The concept of combining 99mTc and 186/188Re with bioactive
molecules to produce selective targeting agents is currently
receiving much attention.2−4,9−15 Investigations involving fac-
[ReI(CO)3L]n complexes prepared with naturally abundant
rhenium offer both guidance in the development of new
radiopharmaceuticals and deep insight into the chemistry and
biomedical characteristics of 186/188Re therapeutic agents and
99mTc diagnostic agents.1−3,7,10,16−18 We have been exploring
the chemistry of complexes containing the fac-[ReI(CO)3] core
to broaden the methods for linking [ReI(CO)3L]n complexes to
targeting molecules.4,16,19−21 We focus particularly on devel-
oping new chemistry in which the bioconjugation involves a
monodentate ligand rather than the multidentate ligands most
often used.15,16,21−24
Recently we overcame the “isomer problem” by forming the
amidines by using bulky C2-symmetrical saturated heterocyclic
Received: July 11, 2014
Published: October 6, 2014
© 2014 American Chemical Society
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Figure 2. Schematic structural representation of the cobalamins (Cbl):
cyanocobalamin (X = CN, vitamin B12, CNCbl), methylcobalamin (R
= CH3, MeCbl), and coenzyme B12 (R = 5′-deoxy-5′-adenosyl,
adenosylcobalamin, AdoCbl).
Figure 1. All conceivable isomers of mononuclear fac-[Re-
(CO)3(Me2bipy)(HNC(CH3)(NHR))]BF4 complexes, in which
bidentate ligands (4,4′-Me2bipy, 5,5′-Me2bipy, or 6,6′-Me2bipy) are
denoted by the two N donor atoms connected by a curved line.
EXPERIMENTAL SECTION
■
secondary amines (HN(CH2CH2)2Y; Y = CH2, (CH2)2,
(CH2)3, NH, or O).4 Only two configurations (E and Z) are
possible when the two N4 substituents are equal, and the bulk
of two CH2CH2 chains attached to N4 was expected to
destabilize the Z configuration. Complexes of the type fac-
[Re(CO)3(Me2bipy)(HNC(CH3)N(CH2CH2)2Y)]BF4
(Me2bipy = 5,5′-Me2bipy or 6,6′-Me2bipy)4 were prepared and
found to be robust and to exist as only one isomer having the E
configuration.4
Starting Materials. Re2(CO)10, 4,4′-dimethyl-2,2′-bipyridine
(4,4′-Me2bipy), 5,5′-dimethyl-2,2′-bipyridine (5,5′-Me2bipy), 6,6′-
dimethyl-2,2′-bipyridine (6,6′-Me2bipy), pyridine (py), 4-cyanopyr-
idine (4-CNpy), 4-dimethylaminopyridine (4-Me2Npy), 4-methox-
ypyridine (4-MeOpy), 4-methylpyridine (4-Mepy), piperazine
(ppzH), 1-(4-pyridyl)piperazine (pyppzH), 1-(4-pyridyl)piperidine
(4-(CH2)5Npy), and AgBF4 were obtained from Sigma-Aldrich.
Known methods were employed to prepare the following: Re-
(CO)5Br,39 [Re(CO)3(CH3CN)3]BF4,20,40 [Re(CO)3(Me2bipy)-
(CH3CN)]BF4,19 and (py)Co(DH)2Cl.41
1
In the present study, we prepare analogues of the fac-
[Re(CO)3(L)(HNC(CH3)N(CH2CH2)2Y)]BF4 complexes,4
but with a novel dangling and potentially metal-ligating
donor group incorporated with Y. Such donors can coordinate
to metal centers with targeting or therapeutic potential, thereby
allowing us to use coordinate bonds in the approach to form
bioconjugates. We test our approach by using a pendant pyridyl
group and B12 model compounds. In contrast to healthy body
cells, rapidly dividing cells (such as those present at the site of
tumors or bacterial infections) have an increased demand for
cobalamins (also known as B12, Figure 2).25−35 The use of B12
for the targeted delivery of cytotoxic and radiotoxic agents to
tumor sites has therefore attracted much attention.25,28,34,36−38
Treatment of fac-[ReI(CO)3(Me2bipy)(CH3CN)]BF4 com-
plexes with the C2-symmetrical 1-(4-pyridyl)piperazine
(pyppzH) amine afforded new amidine complexes fac-[Re-
(CO)3(Me2bipy)(HNC(CH3)(pyppz))]BF4. As expected, the
amidine ligand has only the E configuration and contains an
exposed pyridyl nitrogen atom available to coordinate to a
target metal center. Treatment of the fac-[Re(CO)3(Me2bipy)-
(HNC(CH3)(pyppz))]BF4 complexes with a simple B12 model,
(py)Co(DH)2Cl (DH = monoanion of dimethylglyoxime),
produced dinuclear complexes fac-[Re(CO)3(Me2bipy)(μ-
(HNC(CH3)(pyppz)))Co(DH)2Cl]BF4, which have a direct
coordinate bond between the amidine ligand pyridyl ring N
atom and the cobalt atom. Because all of these new complexes
exhibit facial geometry, we shall omit the fac- designation below
when discussing the complexes.
NMR Measurements. H NMR spectra were recorded on a 400
MHz Bruker spectrometer. Peak positions are relative to tetrame-
thylsilane (TMS) or solvent residual peak, with TMS as reference. All
NMR data were processed with TopSpin and Mestre-Nova software.
For specific assignments of signals listed in the syntheses described
below, please see tables in the text and in Supporting Information.
X-ray Data Collection and Structure Determination. Intensity
data were collected at low temperature on a Bruker Kappa Apex-II
DUO CCD diffractometer fitted with an Oxford Cryostream cooler
and either graphite-monochromated Mo Kα (λ = 0.710 73 Å)
radiation or (for 2) Cu Kα (λ = 1.541 84 Å) radiation from an IμS
microfocus source with multilayer optics. Data reduction included
absorption corrections by the multiscan method, with SADABS.42 All
X-ray structures were determined by direct methods and difference
Fourier techniques and refined by full-matrix least-squares methods by
using SHELXL97.43
General Synthesis of [Re(CO)3(Me2bipy)(HNC(CH3)(pyppz))]-
BF4 Complexes. All of the mononuclear amidine complexes (Scheme
1) were synthesized by a slight modification of a known procedure.4
An acetonitrile solution (6 mL) of a [Re(CO)3(Me2bipy)(CH3CN)]-
BF4 complex (40 mg, 0.06 mmol) was treated with pyppzH (30 mg,
0.18 mmol); the reaction mixture was stirred at room temperature for
4 h and then reduced in volume to ∼1 mL by rotary evaporation. The
addition of diethyl ether to the point of cloudiness (∼5−10 mL)
produced a yellow crystalline material that was collected on a filter,
washed with diethyl ether, and dried.
[Re(CO)3(4,4′-Me2bipy)(HNC(CH3)(pyppz))]BF4 (1). The use of the
general method in the reaction of [Re(CO)3(4,4′-Me2bipy)-
(CH3CN)]BF4 with pyppzH afforded 32 mg (50% yield) of yellow
1
crystalline material. For H NMR data in CD2Cl2, see Table 1 and
Supporting Information. ESI-MS (m/z): [M + H]+ = 659.1780. Calcd
for [M + H]+ = 659.1780.
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the point of cloudiness produced a yellow crystalline material that was
collected on a filter, washed with diethyl ether, and dried.
[Re(CO)3(4,4′-Me2bipy)(μ-(HNC(CH3)(pyppz))(Co(DH)2Cl]BF4 (4).
The use of the general method for the reaction of [Re(CO)3(4,4′-
Me2bipy)(HNC(CH3)(pyppz))]BF4 with (py)Co(DH)2Cl afforded
21 mg (66% yield) of yellow crystalline material. For 1H NMR data in
CD2Cl2, see Table 1 and Supporting Information. ESI-MS(m/z): [M +
H]+ = 983.1884. Calcd for [M + H]+ = 983.1816.
Scheme 1. Synthesis of Mononuclear Amidine Complexes,
Showing the Numbering Systems for Ligands in the Reaction
of [Re(CO)3(Me2bipy)(CH3CN)]BF4 with pyppzH
a
[Re(CO)3(5,5′-Me2bipy)(μ-(HNC(CH3)(pyppz)))Co(DH)2Cl]BF4 (5).
The use of the general method for the reaction of [Re(CO)3(5,5′-
Me2bipy)(HNC(CH3)(pyppz))]BF4 with (py)Co(DH)2Cl afforded
24 mg (75% yield) of yellow crystalline material. For 1H NMR data in
CD2Cl2, see Table 1 and Supporting Information. X-ray quality crystals
were obtained from a solution of the material (10 mg/1 mL of
CH2Cl2) in a lightly stoppered container after the addition of 8 mL of
diethyl ether.
[Re(CO)3(6,6′-Me2bipy)(μ-(HNC(CH3)(pyppz)))Co(DH)2Cl]BF4 (6).
The use of the general method for the reaction of [Re(CO)3(6,6′-
Me2bipy)(HNC(CH3)(pyppz))]BF4 with (py)Co(DH)2Cl afforded
25 mg (78% yield) of yellow crystalline material. For 1H NMR data in
CD2Cl2, see Table 1 and Supporting Information. X-ray quality crystals
were obtained from a solution of the material (10 mg/1 mL of
CH2Cl2) in a lightly stoppered container after the addition of 10 mL of
diethyl ether.
a
Me2bipy = 4,4′-, 5,5′-, or 6,6′-Me2bipy.
[Re(CO)3(5,5′-Me2bipy)(HNC(CH3)(pyppz))]BF4 (2). The use of the
general method in the reaction of [Re(CO)3(5,5′-Me2bipy)-
(CH3CN)]BF4 with pyppzH afforded 39 mg (61% yield) of yellow
RESULTS AND DISCUSSION
■
1
crystalline material. For H NMR data in CD2Cl2, see Table 1 and
Synthesis. Treatment of [Re(CO)3(Me2bipy)(CH3CN)]-
BF4 (Me2bipy = 4,4′-Me2bipy, 5,5′-Me2bipy, and 6,6′-Me2bipy)
with pyppzH in acetonitrile at room temperature afforded good
yields (usually 50−60%) of new mononuclear amidine
complexes, [Re(CO)3(Me2bipy)(HNC(CH3)(pyppz))]BF4
[Me2bipy = 4,4′-Me2bipy (1), 5,5′-Me2bipy (2), and 6,6′-
Me2bipy (3)], as illustrated in Scheme 1.
Supporting Information. X-ray quality crystals grew from a solution of
the crystalline material (10 mg/1 mL of CH2Cl2) in a lightly stoppered
container after the addition of 8 mL of diethyl ether.
[Re(CO)3(6,6′-Me2bipy)(HNC(CH3)(pyppz))]BF4 (3). The use of the
general method in the reaction of [Re(CO)3(6,6′-Me2bipy)-
(CH3CN)]BF4 with pyppzH afforded 33 mg (51% yield) of yellow
1
crystalline material. For H NMR data in CD2Cl2, see Table 1 and
Supporting Information. X-ray quality crystals grew from a solution of
the material (10 mg/1 mL of CH2Cl2) in a lightly stoppered container
after the addition of 10 mL of diethyl ether.
General Synthesis of [Re(CO)3(Me2bipy)(μ-(HNC(CH3)-
(pyppz)))Co(DH)2Cl]BF4 Dinuclear Complexes. The [Re-
(CO)3(Me2bipy)(HNC(CH3)(pyppz))]BF4 complex (30 mg, 0.04
mmol) was dissolved in CH2Cl2 (6 mL) and treated with
(py)Co(DH)2Cl (16 mg, 0.04 mmol), and the reaction mixture was
stirred at room temperature for 24 h. The volume was reduced to ∼1
mL by rotary evaporation. Addition of diethyl ether (∼5−10 mL) to
Numerous similarities in the chemical and physical properties
exist between simple pseudo-octahedral cobaloximes
LCoIII(DH)2(monoanion) [L = neutral ligand, DH =
monoanion of dimethylglyoxime, and monoanion = an
inorganic (X) or an alkyl (R) ligand] and B12.44−46 The well-
defined relationships between the structural and spectroscopic
properties revealed by the study of simple B12 model
compounds facilitate the interpretation of spectral trends (or
1
Table 1. H NMR Chemical Shifts (ppm) of [Re(CO)3(Me2bipy)(HNC(CH3)(pyppz))]BF4 and [Re(CO)3(Me2bipy)(μ-
(HNC(CH3)(pyppz)))Co(DH)2Cl]BF4 Complexes in CD2Cl2 at 25 °C
1
2
3
4
5
6
4,4′-Me2bipy
5,5′-Me2bipy
6,6′-Me2bipy
4,4′-Me2bipy
5,5′-Me2bipy
6,6′-Me2bipy
N3H
4.70
2.37
4.73
2.38
5.14
1.95
4.69
2.33
4.70
2.35
5.03
1.89
CamCH3
pyppz signals
8.20
H2/6
8.17
6.54
3.34
3.34
8.18
6.53
3.34
3.34
7.53
6.32
3.32
3.32
7.54
6.32
3.34
3.34
7.54
6.35
3.33
3.33
H3/5
6.54
H8/12
H9/11
3.34
3.34
Me2bipy signals
8.20
H3/3′
H4/4′
H5/5′
H6/6′
CH3
8.32
8.33
8.02
8.25
8.27
7.99
8.21
8.03
7.54
8.06
7.41
8.74
2.63
7.56
7.39
8.71
2.61
8.73
2.51
8.70
2.49
3.06
3.05
oxime signals
CH3
2.31
2.31
2.31
OH···O
18.40
18.39
18.37
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structural data) observed for the larger, more complicated
cobalamins.46−49
Selected bond lengths and bond angles are presented in
Table 3. In all complexes studied, the Re atom has a pseudo-
octahedral geometry, with the three carbonyl ligands
coordinated facially. The Re coordination sphere is completed
by two nitrogen atoms of the bidentate Me2bipy ligand and by
one nitrogen atom (N3) of the neutral monodentate amidine
ligand (Figures 3 and 4). For the purposes of this discussion,
the coordination plane defined by Re, Me2bipy, and the two
CO groups trans to Me2bipy will be called the equatorial plane;
the other CO and the amidine ligand in the complex are
referred to as axial ligands. The Re−C bond distances for the
axial and equatorial CO ligands (Figures 3 and 4) are generally
not significantly different. This finding is consistent with
structural data reported for recently synthesized amidine
complexes of the type [Re(CO)3(Me2bipy)(HNC(CH3)N-
(CH2CH2)2Y)]BF4.4 In the Re,Co binuclear complexes 5 and
6, the cobalt center has a distorted octahedral geometry, with
the four equatorial positions occupied by the nitrogen donor
atoms of the two monoanionic DH ligands. The axial positions
are occupied by Cl and the pyridyl N of the pyppz moiety of
the amidine ligand.
Structural Features of the Me2Bipy Equatorial Ligand.
The tilting of the plane of the 6,6′-Me2bipy ligand out of the
equatorial coordination plane in 3 and 6 (Figure 5 and
Supporting Information, Figure S1) is expected,4,19,20 because
otherwise the methyl groups of the 6,6′-Me2bipy ligand and the
two equatorial CO ligands would clash. The tilting typically
moves the methyl groups toward the axial CO.4,19,20,54 As can
be seen in Supporting Information, Figures S2 and S3, the 5,5′-
Me2bipy ligand in 2 is tilted in the same direction but less
acutely than is the 6,6′-Me2bipy ligand in 3 and 6. In contrast,
the 5,5′-Me2bipy ligand in amidine complexes4,19 normally is
not tilted (Supporting Information, Figure S2). Furthermore,
the 5,5′-Me2bipy ligand is tilted in 5 also (Supporting
Information, Figures S4 and S5), but in the direction opposite
to that in 2, 3, and 6. Despite the tilting, the Re−N bond
lengths (in the equatorial plane) for 2, 3, 5, and 6 (Table 3) are
all comparable to typical Re−N (sp2) bond lengths, which
range from 2.15 to 2.21 Å.4,19,55,56
Analytically pure cobaloximes, LCoIII(DH)2X, prepared by
the usual procedure involving air oxidation,41 contain traces
(<0.1%) of LCoII(DH)2.50,51 These traces of LCoII(DH)2
catalyze a rapid ligand-exchange reaction (eq 3) that proceeds
by the mechanism described by eqs 1−3.50−53 The time for the
reaction depends on the amount of trace CoII present.
fast: LCoII(DH)2 + L′ ↔ L′CoII(DH)2 + L
(1)
slow: LCoIII(DH)2X + L′CoII(DH)2 → L′CoIII(DH)2X + LCoII(DH)2
(2)
LCoIII(DH)2X + L′ → L′CoIII(DH)2X + L
(3)
The rate-determining step (2) is shown as being irreversible
because in past studies as well as in this study, ordinarily L′ is a
much better ligand than L. All evidence indicates that step 2
involves an inner-sphere electron-transfer process.50−52 The
activated complex for this step, LCoIII(DH)2−X−CoII(DH)2L′,
has a bridging chloro ligand.50−52
We utilized this facile exchange process by treating
(py)Co(DH)2Cl with complexes 1−3 (Scheme 2) to produce
Scheme 2. Synthesis of Re,Co Dinuclear Complexes by the
Reaction of [Re(CO)3(Me2bipy)(HN(CH3)2(pyppz))]BF4
(Me2bipy = 4,4′-, 5,5′-, or 6,6′-Me2bipy) with
(py)Co(DH)2Cl
Amidine Ligand Structural Features and Relation to
the Me2Bipy Equatorial Ligand. The Re−N and C−N bond
distances and the C−N−C and N−C−N bond angles (Table
3) all confirm that 2, 3, 5, and 6 possess very similar rhenium-
bound amidine ligands. The Re−N3 bond lengths (Table 3)
showed no significant difference and are comparable to those of
similar amidine and iminoether complexes.4,19,20
For 2, 3, 5, and 6, the C16−N bond lengths (Table 3) of the
amidine ligand are all closer to the average sp2 CN bond
length (∼1.28 Å) than to the average sp3 C−N bond length
(∼1.47 Å).4,19 Also, the very slightly shorter C16−N3 bond
distances indicate that the C16−N3 bond has more double-
bond character than the C16−N4 bond.4,19 The sp2-like C16−
N4−C18, C16−N4−C21, and N3−C16−N4 bond angles, all
close to 120° (Table 3), confirm the electron delocalization
within the amidine group.4,19,20,57−59
The orientation of the amidine ligand (specified by the
projection of the amidine plane, defined by the N3, C16, and
N4 atoms, onto the equatorial plane) is similar for 2, 3, and 6
(Figures 3 and 4). This orientation, with the two N−Re−C
angles in the equatorial plane bisected by the plane of the
amidine ligands, has also been found for other amidine
complexes.4,19 From 2, 3, 6, and structures in previous
studies,4,19 we can conclude that this “normal” orientation of
Re,Co dinuclear [Re(CO)3(Me2bipy)(μ-(HNC(CH3)-
(pyppz)))Co(DH)2Cl]BF4 complexes (Me2bipy = 4,4′-
Me2bipy (4), 5,5′-Me2bipy (5), and 6,6′-Me2bipy (6)) in
1
65−80% yields. H NMR spectroscopic data (Table 1, see also
Supporting Information) and structural characterization by
single-crystal X-ray crystallography show that the new
mononuclear and dinuclear amidine complexes all contain
only one detectable isomer, with the amidine in the E
configuration (Figure 1), consistent with previous findings on
related compounds.4
Structural Results. Overall Aspects. The crystal data and
details of the structural refinement for complexes 2, 3, 5, and 6
are summarized in Table 2. The ORTEP plots of the cations of
2, 3, 5, and 6 are shown in Figures 3 and 4, along with the
numbering scheme used to describe the solid-state data.
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Table 2. Crystal Data and Structural Refinement for [Re(CO)3(Me2bipy)(HNC(CH3)(pyppz))]BF4 and [Re(CO)3(Me2bipy)(μ-
(HNC(CH3)(pyppz)))Co(DH)2Cl]BF4 Complexes
2 (5,5′-Me2bipy)
3 (6,6′-Me2bipy)
5 (5,5′-Me2bipy)
6 (6,6′-Me2bipy)
empirical formula
C26H28N6O3Re·BF4
745.55
C26H28N6O3Re·BF4
745.55
C34H42ClCoN10O7Re·CH2Cl2·BF4
1155.09
C34H42ClCoN10O7Re·C4H10O·BF4
1144.29
triclinic
fw
crystal system
space group
a (Å)
monoclinic
P21/n
monoclinic
P21/n
orthorhombic
P212121
P1
̅
8.6106(4)
8.8914(10)
26.195(3)
12.5039(15)
14.963(2)
16.604(2)
17.856(2)
10.997(3)
14.686(3)
16.078(4)
105.787(15)
105.748(15)
102.678(14)
2281.1(10)
90
b (Å)
31.9058(13)
30.2319(13)
c (Å)
α
β (deg)
γ
V (Å3)
93.653(2)
110.199(5)
8288.7(6)
90
2733.2(5)
90
4436.2(9)
90
T (K)
Z
12
4
4
2
ρcalcd (Mg/m3)
abs. coeff. (mm−1
θmax. (deg)
1.792
9.20
1.812
4.51
1.729
3.36
1.666
)
3.15
67.9
30.6
25.4
27.6
a
R [I > 2σ(I)]
0.041
0.113
14 122/1099
0.025
0.053
8368/377
2.12, −1.32
0.036
0.075
7646/559
1.32, −1.02
0.050
b
wR2
0.122
data/parameters
10 019/605
res. dens (e Å−3
)
1.63, −1.27
3.49, −1.47
a
b
R = (∑∥Fo| − |Fc∥)/∑|Fo|. wR2 = [∑w(Fo2 − Fc2)2]/∑w(Fo2)2]1/2, in which w = 1/[σ2(Fο2) + (dP)2 + (eP)] and P = (Fο2 + Fc2)/3.
Figure 3. ORTEP plots of the cations of [Re(CO)3(5,5′-Me2bipy)(HNC(CH3)(pyppz))]BF4 (2) (left) and [Re(CO)3(6,6′-Me2bipy)(HNC-
(CH3)(pyppz))]BF4 (3) (right). Thermal ellipsoids are drawn with 50% probability.
the amidine ligand in the solid state is not very dependent on
either the substitution pattern of the Me2bipy ligand or the size
and shape of the amidine ligand.4,19 However, there are
occasional exceptions, and the orientation of the amidine ligand
in 5 (Figure 4) is one such exception. In 5 the plane of the
amidine ligand bisects the C13−Re−C14 and N1−Re−N2
angles.
For 2, 3, and 6 (Figures 3 and 4), which have the normal
amidine orientation, the bond angles from the equatorial N
atoms to the axial N3 atom (N1−Re−N3 and N2−Re−N3) are
statistically different (Table 3), as also observed in previous
studies.4,19,20 Previously the larger N−Re−N3 bond angle was
thought to be caused by steric repulsion between the methyl
group of the axial amidine4,19 or axial iminoether20 ligand and
the closest atoms of the equatorial ligands. For example, we
found for [Re(CO)3(Me2bipy)(HNC(CH3)N(CH2CH2)2Y]-
BF4 complexes4 that the average of the larger of the two N−
Re−N3 bond angles was greater in the 5,5′-Me2bipy complexes
than in the 6,6′-Me2bipy complexes. Furthermore, the differ-
ence between the two angles was usually larger for the 5,5′-
Me2bipy complexes than for the 6,6′-Me2bipy complexes.4 The
space near the axial amidine coordination site (trans to the axial
CO) was assessed by using the nonbonded distances from N3
to the Me2bipy carbon and nitrogen atoms.4,20 It was concluded
that the tilting of the 6,6′-Me2bipy ligand results in a significant
decrease in the interactions between the methyl group of the
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Figure 4. ORTEP plots of the cations of [Re(CO)3(5,5′-Me2bipy)(μ-(HNC(CH3)(pyppz)))Co(DH)2Cl]BF4 (5) (upper) and [Re(CO)3(6,6′-
Me2bipy)(μ-(HNC(CH3)(pyppz)))Co(DH)2Cl]BF4 (6) (lower). Thermal ellipsoids are drawn with 50% probability.
axial iminoether or amidine ligand and the equatorial Me2bipy
ligand in the 6,6′-Me2bipy complexes versus the 5,5′-Me2bipy
analogue.4
from N3 to C1 or C10 have relatively small differences (Table
4).
The back-side nonbonded distances from N3 to C4 and C7
average ∼0.7 Å shorter in 6 than in 5. These differences are
somewhat greater than the respective ∼0.5 Å differences found
for the close analogues [Re(CO)3(Me2bipy)(HNC(CH3)N-
(CH2CH2)2NH)]BF4, in which the amidine was derived from
piperazine (Supporting Information).4 The larger differences
are attributed to the unusual opposite-direction tilting of the
5,5′-Me2bipy ligand in 5 (Supporting Information, Figure S4).
This tilting increases the nonbonded distances. In contrast to
these large differences between 6 and 5, the “back-side”
nonbonded distances from N3 to C4 and C7 average only ∼0.2
Å shorter in 3 than in 2, a difference smaller than for the
[Re(CO)3(Me2bipy)(HNC(CH3)N(CH2CH2)2NH)]BF4 ana-
logues. The smaller differences in nonbonded distances in 3
than in 2 (as compared to the analogues) are chiefly the result
of the normal-direction tilting of the 5,5′-Me2bipy ligand in 2
(Supporting Information, Figure S3). Such tilting is unusual for
a 5,5′-Me2bipy analogue.
However, unlike previous findings,4,19,20 the size of the larger
of the two N−Re−N3 (N2−Re−N3) bond angles in the 6,6′-
Me2bipy complex (3) is greater than the larger corresponding
N2−Re−N3 bond angle in the 5,5′-Me2bipy complex (2)
(Table 3). The difference between the two N−Re−N3 bond
angles in 2, while significant, is very small (∼1°). In 6, however,
the N2−Re−N3 bond angle is much larger (>4°) than the
N1−Re−N3 angle (Table 3). The plane of the 6,6′-Me2bipy
ligand in 6 is tilted out of the equatorial plane as expected
(Figure 5 and Supporting Information, Figure S1).
The differences in the relative sizes of the N3−Re−N angles
found here compared to such differences found in previous
studies led us to compare the space near the amidine ligand in
2, 3, 5, and 6 to that present in related complexes.4,20 In this
method, the Me2bipy ligand is viewed as having an interior or
“front side” (atoms C1, N1, N2, C10) and an exterior or “back
side” (atoms C3, C4, C7, C8), according to the numbering
scheme in Figures 3 and 4. The front-side nonbonded distances
We attribute the structural differences in this report as
compared to those for previously studied Me2bipy amidine
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Table 3. Selected Bond Distances (Å) and Angles (deg) for [Re(CO)3(Me2bipy)(HNC(CH3)(pyppz))]BF4 and
[Re(CO)3(Me2bipy)(μ-(HNC(CH3)(pyppz)))Co(DH)2Cl]BF4 Complexes
2 (5,5′-Me2bipy)
3 (6,6′-Me2bipy)
5 (5,5′-Me2bipy)
6 (6,6′-Me2bipy)
bond distances
1.910(3)
1.924(3)
1.914(3)
2.207(2)
2.199(2)
2.171(2)
1.302(3)
1.355(3)
Re−C13
Re−C14
Re−C15
Re−N1
Re−N2
Re−N3
1.933(5)
1.935(6)
1.922(6)
2.185(4)
2.179(5)
2.177(5)
1.310(7)
1.344(7)
1.902(7)
1.914(8)
1.905(6)
2.169(5)
2.168(6)
2.165(5)
1.291(8)
1.352(8)
1.946(5)
1.891(6)
1.896(6)
1.885(6)
1.876(6)
2.2391(18)
1.365(7)
1.353(8)
1.357(7)
1.349(7)
1.268(9)
1.289(9)
1.295(8)
1.305(9)
1.922(6)
1.894(7)
1.933(8)
2.196(5)
2.202(5)
2.190(5)
1.307(8)
1.342(8)
1.947(5)
1.875(5)
1.896(5)
1.912(5)
1.905(5)
2.2272(17)
1.344(7)
1.322(7)
1.325(7)
1.356(6)
1.292(8)
1.306(8)
1.302(8)
1.293(7)
C16−N3
C16−N4
Co−N6
Co−N7
Co−N8
Co−N9
Co−N10
Co−Cl
N7−O4
N8−O5
N9−O6
N10−O7
C27−N7
C28−N8
C31−N9
C32−N10
bond angles
74.51(8)
78.61(8)
84.45(8)
96.55(10)
89.81(8)
108(2)
N1−Re−N2
N1−Re−N3
N2−Re−N3
75.01(17)
79.49(17)
81.06(16)
95.8(2)
74.30(19)
82.90(2)
86.2(2)
75.90(18)
78.87 (18)
84.42 (18)
98.0 (3)
89.1(2)
N3−Re−C13
N3−Re− C14
Re−N3−H3N
Re−N3−C16
C16−N3−H3N
N3−C16−N4
N3−C16−C17
N4−C16−C17
C16−N4−C18
C16−N4−C21
N6−Co−Cl
98.7(3)
94.7(2)
93.9(3)
113(5)
120(5)
99(4)
134.2(4)
112(5)
137.71(19)
112(2)
133.5(5)
106(5)
137.4(5)
123(4)
123.3(5)
120.2(5)
116.5(5)
123.6(5)
124.5(5)
122.3(2)
119.8(2)
117.8(2)
123.7(2)
122.5(2)
124.1(6)
119.5(6)
116.4(6)
121.5(6)
123.5(6)
178.00(18)
124.3(8)
122.6(7)
123.8(7)
122.5(7)
122.8(6)
119.6(6)
117.5(6)
124.7(6)
126.9(7)
177.32(15)
122.8(7)
123.4(7)
122.6(6)
124.4(6)
N7−C27−C29
N8−C28−C30
N9−C31−C33
N10−C32−C34
complexes4 to the influence on solid-state packing by the
elongated axial amidine ligands in this work. Because tilting can
be assessed from the NMR data (see below), we can determine
if this is indeed a solid-state effect.
comparison to unambiguous assignments reported for [Re-
(CO)3(Me2bipy)(HNC(CH3)N(CH2CH2)2Y)]BF4 com-
plexes.4 The atom-numbering system used in this discussion
is shown in Scheme 1.
The axial N6−Co−Cl bond angles in 5 and 6 and the Co−N
and Co−Cl axial bond distances (Table 3) are very similar to
those of (py)Co(DH)2Cl.60 There are no noteworthy structural
differences between the Co(DH)2Cl moiety in (py)Co-
(DH)2Cl and in 5 and 6.60
[Re(CO)3(Me2bipy)(HNC(CH3)(pyppz))]BF4 Mononu-
clear Complexes. Selected H NMR signals of complexes
1
1−3 in CD2Cl2 (Table 1) reveal that the CamCH3 signal of 3
(1.95 ppm) is more upfield (by ∼0.4 ppm) than that of 1 (2.37
ppm) and 2 (2.38 ppm); this finding is attributed to the
anisotropic effect of the 6,6′-Me2bipy aromatic rings.4 The
distance from the CamCH3 methyl carbon to the centroid of the
closer bipyridine ring in 3 (3.4 Å) is significantly shorter than in
2 (4.0 Å). This shorter distance results from the tilting in the
6,6′-Me2bipy ligand, which moves the back side of the 6,6′-
Me2bipy ring up toward the amidine ligand (Supporting
Information, Figure S1). The bipyridine rings thus exert a
1
NMR Spectroscopy. Complexes were characterized by H
NMR spectroscopy in CD2Cl2 (1−6) and CD3CN (2, 3, 5, and
6) (Table 1 and Supporting Information). The 1H NMR
spectra of all of the new [Re(CO)3(Me2bipy)(HNC(CH3)-
(pyppz))]BF4 complexes indicate that only the E isomer is
1
present in solution. H NMR signals of the Me2bipy ligand
were assigned from the splitting pattern, the integration, and by
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[Re(CO)3(Me2bipy)(μ-(HNC(CH3)(pyppz)))Co(DH)2Cl]-
BF4 Dinuclear Complexes. Except for the pyridyl ring signals
1
(see below), the H NMR signals of corresponding protons in
both mononuclear and dinuclear complexes have similar shifts
in both CD2Cl2 (Table 1) and CD3CN (Supporting
Information). Thus, spectra for 4−6 can be interpreted as
discussed above for complexes 1−3. In CD2Cl2, for example,
the ∼0.4 ppm more upfield CamCH3 signal of 6 versus those of
4 and 5 is a result of the anisotropic effect of the tilted 6,6′-
Me2bipy ligand in 6, as discussed above for 3.
The oxime CH3 signals of complexes 4−6 all have the same
shift, 2.31 ppm in CD2Cl2 (Table 1), a value very similar to that
of (py)Co(DH)2Cl (2.35 ppm) (Supporting Information,
Table S1). This finding is expected because shifts of the
oxime CH3 signals of cobaloximes (LCo(DH)2Cl) are
essentially independent of L when L is a planar N-donor
heterocyclic aromatic ligand.47 The O−H···O signals were
easily assigned because they appeared farthest downfield as
broad singlets integrating to two protons. The chemical shifts of
the O−H···O signals for 4−6 (∼18.4 ppm, Table 1) are very
similar to that of (py)Co(DH)2Cl (18.37 ppm, Supporting
Information, Table S1).
Figure 5. Overlay (root mean square = 0.137) of the Re and the O1,
O2, and O3 atoms of the carbonyl ligands of [Re(CO)3(5,5′-
Me2bipy)(HNC(CH3)(pyppz))]BF4 (2) (purple) and [Re-
(CO)3(6,6′-Me2bipy)(HNC(CH3)(pyppz))]BF4 (3) (green). The
structures are depicted with the equatorial coordination plane
perpendicular to the plane of the paper in a side view (left) and a
front view (right) with the CO ligands toward the viewer.
The shift changes (Δδ) of the pyridyl ring H2/6 signals were
upfield following the coordination of 1, 2, or 3 to form 4, 5, and
6 (Table 1). The upfield direction of Δδ for the H2/6 signals of
(py)Co(DH)2(monoanion) complexes is expected because it is
known that the through-space shielding effect of the cobalt
anisotropy on the signals of protons on the axial ligand closest
to cobalt more than offsets the through-bond electron-
withdrawing inductive deshielding effect of the positive metal
ion.41,47,61,62 The ∼0.5−0.6 ppm Δδ values observed (Table 1)
were larger than those typically found in CDCl3.41,47,61,62
However, the Δδ = 0.39 ppm observed upon (py)Co(DH)2Cl
formation in CD2Cl2 (Supporting Information, Table S1) is
relatively normal and similar to that found in CDCl3 (0.34 ppm,
Table 5). Thus, the only unusual NMR findings involved the
H2/6 signals of the pyridyl group.
greater anisotropic upfield-shifting effect on the CamCH3 signal
for 3 than for 1 and 2. As mentioned above, NMR shifts are
sensitive to Me2bipy tilting.4 The shift of the CamCH3 signal for
2 is similar to that for 1, indicating that the 5,5′-Me2bipy ligand
is not tilted in either complex. In addition, the shift for this
signal for the related analogue [Re(CO)3(5,5′-Me2bipy)(HNC-
(CH3)N(CH2CH2)2NH)]BF4, which has no tilted 5,5′-
Me2bipy ligand in the solid state, is at 2.12 ppm in CD3CN.4
For 2, the shift in CD3CN (Supporting Information, Table S2)
is even slightly more downfield at 2.18 ppm, further establishing
that the tilting in 2 (Supporting Information, Figure S2) is a
solid-state effect.
The signal of the proton on the coordinated amidine N
donor, N3H, is easily assigned because the peaks are broad
singlets integrating to one proton. The signal is sensitive to tilt
and also to the amidine substituent. The more downfield shift
(∼0.4 ppm) (Table 1) of the N3H signal of the 6,6′-Me2bipy
complex (3) than for complexes with other Me2bipy isomers (1
and 2) is consistent with results for similar amidine complexes.4
For 2 in CD3CN, the N3H shift is 4.86 ppm (Supporting
Information, Table S2), very similar to the corresponding shift
(4.84 ppm) found for [Re(CO)3(5,5′-Me2bipy)(HNC(CH3)-
N(CH2CH2)2NH)]BF4, with an untilted 5,5′-Me2bipy ligand.4
Effect of Basicity on the H2/6 1H NMR Signals of
LCo(DH)2Cl. To determine if the unusual effect on H2/6 Δδ
values arises from the appended [Re(CO)3(Me2bipy)(μ-
(HNC(CH3)] moiety or from the basicity of the pendant
pyridyl of 1, 2, and 3, we examined the Δδ values of the H2/6
1H NMR signals for a series of LCo(DH)2Cl complexes, with L
= a 4-substituted pyridine (4-Xpy). We employed 4-Xpy
possessing varying electron-donating properties (estimated
Table 4. Selected Non-Bonded Distances (Å) for [Re(CO)3(Me2bipy)(HNC(CH3)(pyppz))]BF4 and [Re(CO)3(Me2bipy)(μ-
(HNC(CH3)(pyppz)))Co(DH)2Cl]BF4 Complexes
2
3
5
6
(5,5′-Me2bipy)
(6,6′-Me2bipy)
(5,5′-Me2bipy)
(6,6′-Me2bipy)
N3−N1
N3−N2
C1−N3
2.789(6)
2.831(6)
3.628(7)
4.862(7)
4.259(7)
4.237(7)
4.880(7)
3.709(7)
2.774(3)
2.937(3)
3.694(3)
4.647(4)
3.970(4)
4.084(5)
4.875(4)
3.957(3)
2.870(9)
2.962(8)
3.602(9)
5.37(1)
2.790(8)
2.947(9)
3.64(1)
4.64(1)
4.03(1)
4.28(1)
5.00(1)
3.928(9)
a
C3−N3
C4−N3
C7−N3
C8−N3
b
b
a
4.901(9)
4.827(9)
5.33(1)
C10−N3
3.696(9)
a
There is a small difference in these distances (average = 0.1 Å) for 2 and 3, but for the analogues derived from piperazine the differences average
∼0.3 Å.4 For 5 and 6, the differences average 0.5 Å. Differences in these distances for 2 and 3 average ∼0.2 Å, but for the analogues derived from
b
piperazine this difference is ∼0.45 Å.4 For 5 and 6, the differences average 0.7 Å.
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(py)Co(DH)2Cl. These points lie off the lines shown, most
likely because of the absence of a substituent at the 4 position.
Inclusion of the points causes only slight differences in both the
slopes and correlation coefficients, see Supporting Informa-
tion.]
In conclusion, the large Δδ values for the H2/6 signal
accompanying the coordination of 1, 2, and 3 to form 4, 5, and
6 are consistent with the expected strong electron-donating
properties of 1, 2, and 3 as ligands, and the appended Re
moiety does not exert any unusual effect.
Table 5. pKa and H2/6 NMR Shift (δ, ppm) of py and 4-Xpy
Ligands in CDCl3 at 25 °C. Changes in H2/6 Shift (Δδ) on
Formation of (py)Co(DH)2Cl and (4-Xpy)Co(DH)2Cl
Complexes
a
L
pKa
L H2/6 δ LCo(DH)2Cl H2/6 δ H2/6 Δδ
4-CNpy
py
2.1068
5.2569
5.9870
6.4771
8.82
8.61
8.47
8.43
8.23
8.22
8.54
8.27
8.06
8.00
7.58
7.63
0.28
0.34
0.41
0.43
0.65
0.59
4-Mepy
4-MeOpy
4-(CH2)5Npy
4-Me2Npy
b
9.6
9.6172
Robustness of the Co−N Bond in the Dinuclear
Complex, [Re(CO)3(5,5′-Me2bipy)(μ-(HNC(CH3)(pyppz)))-
Co(DH)2Cl]BF4 (5). A 5 mM solution of (4-Me2Npy)Co-
(DH)2Cl was treated with a molar equivalent of [Re-
(CO)3(5,5′-Me2bipy)(HNC(CH3)(pyppz))]BF4 (2), and the
exchange reaction to form [Re(CO)3(5,5′-Me2bipy)(μ-(HNC-
a
b
pKa value obtained from refs 68−72. Estimated.
from basicity as reflected in pKa values) and chose the solvent
used widely for NMR studies of cobaloximes, CDCl3.49,63−67
With increasing basicity of the free 4-Xpy ligands (4-CNpy < 4-
Mepy < 4-MeOpy < 4-(CH2)5Npy ≈ 4-Me2Npy), the shifts of
the H2/6 signal were observed to be more upfield for both the
ligand and its complex (Table 5). A linear plot for the shift
dependence on basicity of the H2/6 signal of the (4-
Xpy)Co(DH)2Cl complexes has a steeper slope than the
corresponding slope for the free ligand (Figure 6). Thus, the
1
(CH3)(pyppz)))Co(DH)2Cl]BF4 (5) was monitored by H
NMR spectroscopy in CDCl3. Small 1H NMR signals
corresponding to the “free” 4-Me2Npy ligand and to 5 were
detectable after 30 min. The intensity of these new signals
gradually increased with time as the intensity of signals of (4-
Me2Npy)Co(DH)2Cl and 2 decreased (Figure 8 and
Figure 6. Plot of shift (ppm) of the H2/6 NMR signals of 4-Xpy
ligands both free (blue line) and coordinated (red line) in (4-
Xpy)Co(DH)2Cl vs the pKa value of the free ligands. The values for
free 4-(CH2)5Npy and 4-Me2Npy overlap.
Figure 8. Aromatic 1H NMR signals (in CDCl3, 25 °C) for the
exchange reaction of a 5 mM solution of (4-Me2Npy)Co(DH)2Cl with
a molar equivalent of [Re(CO)3(5,5′-Me2bipy)(HNC(CH3)-
(pyppz))]BF4 (2) to form [Re(CO)3(5,5′-Me2bipy)(μ-(HNC(CH3)-
(pyppz)))Co(DH)2Cl]BF4 (5) and free 4-Me2Npy. More complete
traces are shown in Supporting Information, Figure S8, which includes
a 24 h spectrum essentially identical to the 2 h spectrum shown here.
Δδ values (0.28−0.65 ppm) correlate nonlinearly with the
electron-donating properties of the pyridine ligands (Figure 7).
[Figures 6 and 7 do not contain data for free py and
Supporting Information, Figure S8). The intensities of the
H2/6 and H3/5 signals of (4-Me2Npy)Co(DH)2Cl were
approximately twice as large as for 5 at 24 h, indicating that the
4-Me2Npy ligand is about twice as strong a donor as 2.
We also examined the exchange reaction between [Re-
(CO)3(5,5′-Me2bipy)(μ-(HNC(CH3)(pyppz)))Co(DH)2Cl]-
BF4 (5) and 4-Me2Npy to form (4-Me2Npy)Co(DH)2Cl in
1
CDCl3. When a 5 mM solution was monitored by H NMR
1
spectroscopy, new H NMR signals corresponding to both (4-
Me2Npy)Co(DH)2Cl and “free” 2 were immediately observed.
Because there were no significant differences between the first
1
(∼5 min) and last (24 h) H NMR spectra recorded, we
Figure 7. Plot of Δδ (ppm) [H2/6 NMR shift of free 4-Xpy ligand
minus the shift of the corresponding ligand in (4-Xpy)Co(DH)2Cl] vs
the pKa value of the ligand.
assumed that the exchange reaction was complete before the
first spectrum was recorded. As shown in Figure 9 (see also
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Figure 9. Aromatic region of 1H NMR spectra (in CDCl3, 25 °C) for
the exchange reaction of a 5 mM solution of [Re(CO)3(5,5′-
Me2bipy)(μ-(HNC(CH3)(pyppz)))Co(DH)2Cl]BF4 (5) with a molar
equivalent of 4-Me2Npy to form (4-Me2Npy)Co(DH)2Cl and free
[Re(CO)3(5,5′-Me2bipy)(HNC(CH3)(pyppz))]BF4 (2). More com-
plete traces are shown in Supporting Information, Figure S9.
1
Figure 10. Aromatic H NMR signals (in CDCl3, 25 °C) for the
exchange reaction of a 5 mM solution of (4-Me2Npy)Co(DH)2Cl with
a molar equivalent of pyppzH to form (pyppzH)Co(DH)2Cl and free
4-Me2Npy. More complete traces are shown in Supporting
Information, Figure S10, which includes spectra recorded at 1 h and
at 24 h, both essentially identical to the 2 h spectrum shown here.
Supporting Information), the results are generally very similar
to those obtained for the exchange reaction of (4-Me2Npy)-
Co(DH)2Cl and 2 and can thus confirm that 4-Me2Npy is
about twice as good a donor as 2, consistent with 2 being a
strong donor ligand.
To determine whether the appended [Re(CO)3(Me2bipy)-
(μ-(HNC(CH3)] moiety in [Re(CO)3(5,5′-Me2bipy)(HNC-
(CH3)(pyppz))]BF4 (2) exerts an effect on the donor ability of
1
the 4-pyridyl ring in pyppzH, we monitored by H NMR
spectroscopy the exchange reactions in CDCl3 of pyppzH with
(4-Me2Npy)Co(DH)2Cl and also of pyppzH with [Re-
(CO)3(5,5′-Me2bipy)(μ-(HNC(CH3)(pyppz)))Co(DH)2Cl]-
BF4 (5). When a 5 mM solution of (4-Me2Npy)Co(DH)2Cl
was treated with a molar equivalent of pyppzH, small 1H NMR
signals corresponding to the free 4-Me2Npy ligand and
(pyppzH)Co(DH)2Cl were observed immediately. The inten-
sity of these new signals gradually increased but remained
constant after 1 h (Figure 10, see also Supporting Information).
The intensities of the H2/6 and H3/5 signals of (4-
Me2Npy)Co(DH)2Cl were slightly greater than those of
(pyppzH)Co(DH)2Cl even after 24 h. These results indicate
that 4-Me2Npy and pyppzH have similar donor ability,
although 4-Me2Npy is the slightly stronger donor. The
exchange reaction between pyppzH and 5 to form (pyppzH)-
Co(DH)2Cl was also monitored. New 1H NMR signals
corresponding to (pyppzH)Co(DH)2Cl and free 2 emerged
immediately and grew gradually with time (Figure 11, see also
Supporting Information). The intensities of the H2/6 and H3/
5 signals of (pyppzH)Co(DH)2Cl were approximately twice as
large as for 5 at 24 h, thus confirming that the pyppzH ligand is
also about twice as good a donor as 2. We can therefore
conclude that the donor ability of the 4-pyridyl ring in pyppzH
is lowered slightly when the proton on the nitrogen of the
piperazine ring is replaced by the Re(CO)3(5,5′-Me2bipy)-
(HNC(CH3)− moiety (in 2).
1
Figure 11. Aromatic H NMR signals (in CDCl3, 25 °C) for the
exchange reaction of a 5 mM solution of [Re(CO)3(5,5′-Me2bipy)(μ-
(HNC(CH3)(pyppz)))Co(DH)2Cl]BF4 (5) with a molar equivalent
of pyppzH to form (pyppzH)Co(DH)2Cl and [Re(CO)3(5,5′-
Me2bipy)(HNC(CH3)(pyppz))]BF4 (2). More complete traces are
shown in Supporting Information, Figure S11, which includes spectra
recorded at 1 h and at 24 h, both essentially identical to the 2 h
spectrum shown here.
between the bulky −C(CH3)(pyppz) moiety of the axial
amidine ligands and the equatorial Me2bipy ligands highly favor
the amidine ligand E configuration.
Mixtures of the B12 model (py)Co(DH)2Cl complex with
[Re(CO)3(Me2bipy)(HNC(CH3)(pyppz))]BF4 complexes
formed [Re(CO)3(Me2bipy)(μ-(HNC(CH3)(pyppz)))Co-
(DH)2Cl]BF4 complexes readily. The appended [Re-
(CO)3(Me2bipy)(μ-(HNC(CH3)] moiety appears to cause
only a slight lowering of the donor ability of the 4-pyridyl ring
as compared to pyppzH. (The latter exhibits a donor ability
very similar to that of the excellent 4-Me2Npy donor ligand.)
The findings of this study confirm that the amidine linkage can
be used as a juncture for the conjugation of the fac-[MI(CO)3]
core (M = 99mTc and 186/188Re radionuclides) to biomedical
targeting molecules such as B12 derivatives. Such a strategy may
provide a successful method for the development of delivery
CONCLUSIONS
■
All of the new [Re(CO)3(Me2bipy)(HNC(CH3)(pyppz))]BF4
and [Re(CO)3(Me2bipy)(μ-(HNC(CH3)(pyppz)))Co-
(DH)2Cl]BF4 complexes exist as only one isomer both in
solution and in the solid state because steric interactions
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Inorganic Chemistry
Article
systems for the targeted B12-mediated delivery of radiophar-
maceuticals.
AUTHOR INFORMATION
Corresponding Author
*E-mail: lmarzil@lsu.edu.
Notes
■
The amidine ligands in the present work differ from those
derived from heterocyclic amines studied previously4 in that the
second ring (pyridyl group) elongates the amidine, and this
elongation is further increased by the Co(DH)2Cl moiety in the
dinuclear complexes. We hypothesized that, in the solid state,
packing forces distort structural features of the complex cations.
For example, packing effects appear to counteract to some
degree interligand repulsions in determining the relative sizes of
the N−Re−N3 angles. In addition, in the solid state the 5,5′-
Me2bipy ligand is tilted in opposite directions in [Re-
(CO)3(5,5′-Me2bipy)(HNC(CH3)(pyppz))]BF4 (2) and [Re-
(CO)3(5,5′-Me2bipy)(μ-(HNC(CH3)(pyppz)))Co(DH)2Cl]-
BF4 (5), whereas no similar tilting was observed in previous
studies.4 This conclusion that solid-state effects influence the
5,5′-Me2bipy ligand tilting and N−Re−N3 angle distortions is
supported by NMR data.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
L.G.M. thanks Prof. Michael Threadgill, University of Bath, for
useful discussions and the Raymond F. Schinazi International
Exchange Programme between the University of Bath, UK and
Emory University, Atlanta, USA for a Faculty Fellowship which
provided support during the time that this research project was
conceived.Upgrade of the diffractometer was made possible
through Grant No. LEQSF(2011-12)-ENH-TR-01, adminis-
tered by the Louisiana Board of Regents.
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ASSOCIATED CONTENT
■
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* Supporting Information
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