Complexes possessing rare "tertiary" sulfonamide nitrogen-to-metal bonds of normal length: Fac -[Re(CO)3(N (SO 2R)dien)]PF6 Complexes with hydrophilic sulfonamide ligands

Article abstract of DOI:10.1021/ic4026987

Tertiary sulfonamide nitrogen-to-metal bonds of normal length are very rare. We recently discovered such a bond in one class of fac-[Re(CO) ₃(N(SO₂R)(CH₂Z)₂)]ⁿ complexes (Z = 2-pyridyl) with N(SO

Full text of DOI:10.1021/ic4026987

Article
pubs.acs.org/IC
Complexes Possessing Rare “Tertiary” Sulfonamide Nitrogen-to-
Metal Bonds of Normal Length: fac-[Re(CO)3(N(SO2R)dien)]PF6
Complexes with Hydrophilic Sulfonamide Ligands
Pramuditha L. Abhayawardhana, 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: Tertiary sulfonamide nitrogen-to-metal bonds
of normal length are very rare. We recently discovered such a
bond in one class of fac-[Re(CO)3(N(SO2R)(CH2Z)2)]n
complexes (Z = 2-pyridyl) with N(SO2R)dpa ligands derived
from di-(2-picolyl)amine (N(H)dpa). fac-[M(CO)3(N-
(SO2R)(CH2Z)2)]n agents (M = 186/188Re, 99mTc) could find
use as radiopharmaceutical bioconjugates when R is a targeting
moiety. However, the planar, electron-withdrawing 2-pyridyl
groups of N(SO2R)dpa destabilize the ligand to base and
create relatively rigid chelate rings, raising the possibility that
the rare M−N(sulfonamide) bond is an artifact of a restricted
geometry. Also, the hydrophobic 2-pyridyl groups could cause
undesirable accumulation in the liver, limiting future use in
radiopharmaceuticals. Our goal is to identify a robust, hydrophilic, and flexible N(CH2Z)2 chelate framework. New C2-symmetric
ligands, N(SO2R)(CH2Z)2 with (Z = CH2NH2; R = Me, dmb, or tol), were prepared by treating N(H)dien(Boc)2, a protected
diethylenetriamine (N(H)dien) derivative, with methanesulfonyl chloride (MeSO2Cl), 3,5-dimethylbenzenesulfonyl chloride
(dmbSO2Cl), and 4-methylbenzenesulfonyl chloride (tolSO2Cl). Treatment of fac-[Re(CO)3(H2O)3]+ with these ligands,
designated as N(SO2R)dien, afforded new fac-[Re(CO)3(N(SO2R)dien)]PF6 complexes. Comparing the fac-[Re-
(CO)3(N(SO2Me)dien)]PF6 and fac-[Re(CO)3(N(SO2Me)dpa)]PF6 complexes, we find that the ReI−N(sulfonamide) bonds
are normal in length and statistically identical and that the methyl 13C NMR signal has an unusually upfield shift compared to
that in the free ligand. We attribute this unusual upfield shift to the fact that the sulfonamide N undergoes an sp2-to-sp3
rehybridization upon coordination to ReI in both complexes. Thus, the sulfonamide N of N(SO2R)dien ligands is a good donor,
even though the chelate rings are conformationally flexible. Addition of the strongly basic and potentially monodentate ligand, 4-
dimethylaminopyridine, did not affect the fac-[Re(CO)3(N(SO2tol)dien)]PF6 complex, even after several weeks. This complex is
also stable to heat in aqueous solution. These results indicate that N(SO2R)dien ligands form fac-[Re(CO)3(N(SO2R)dien)]PF6
complexes sufficiently robust to be utilized for radiopharmaceutical development.
fac-[99mTc(CO)3L]n imaging agents.4,22−27 Moreover, fac-
[
INTRODUCTION
■
186/188Re(CO)3L]n agents themselves are emerging as
Many fac-[99mTc(CO)3L]n imaging agents with facially
coordinated tridentate ligands (L) have been studied1−8
because of the convenient generation of the fac-[99mTc-
(CO)3(H2O)3]+ precursor.9,10 Some of these imaging agents
have exhibited satisfactory results in human volunteers and in
early patient studies.4,7,8 Such fac-[99mTc(CO)3L]n agents are
more robust and have better pharmacokinetic properties than
agents with bidentate ligands.11 The γ-emitting 99mTc radio-
nuclide has ideal nuclear properties12,13 for diagnostic
applications in nuclear medicine.1,14−17
promising radiopharmaceuticals, owing to their potential
usefulness in radiotherapy.1,12,20,28
New types of tridentate ligands and ligand conjugation
methods will expand the likelihood of developing useful new
agents with the fac-[MI(CO)3]+ core (M = 99mTc,
186/188Re).10,29,30 Meeting such goals requires the identification
of suitable linker systems with high stability, small size, and core
ligands having a tridentate donor framework that does not
increase the number of isomers.31−34 Symmetrical linear
tridentate ligands with linkage at the center donor are thus
suitable candidates because the generation of racemic or
diastereoisomeric mixtures of radiopharmaceuticals can be
The development of 99mTc radiopharmaceutical agents
benefits from an understanding of the chemistry of their Re
analogues. The discovery of a straightforward preparation of the
fac-[Re(CO)3(H2O)3]+ precursor18 has led to significantly
improved aqueous synthetic methods for fac-[M(CO)3L]n
agents (M = various isotopes of Tc and Re).3,16,17,19−21 fac-
[Re(CO)3L]n complexes serve as excellent structural models for
Received: October 26, 2013
© XXXX American Chemical Society
A
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Article
avoided.35 Recent studies have reported promising biomedical
properties for fac-[Re(CO)3L]n complexes bearing a tridentate
L with three N donors having a substituent replacing the
proton at the central sp3 N.16,29,36,37 However, the conjugation
of biologically important groups in these complexes was limited
to groups attached via an N−C bond to the central N of ligands
with the N(CH2Z)2 tridentate ligand framework. Z is
commonly an N donor (e.g., 2-pyridyl)16,36 or a carboxyl
group.3 The use of a biologically compatible linking group that
did not create an N−C bond would greatly increase the chances
of discovering useful agents.
EXPERIMENTAL SECTION
■
Starting Materials. Methanesulfonyl chloride (MeSO2Cl), 3,5-
dimethylbenzenesulfonyl chloride (dmbSO2Cl), 4-methylbenzene-
sulfonyl chloride (tolSO2Cl), N,N,N-triethylamine, trifluoroacetic
acid (TFA), N(H)dien, 2-(tert-butoxycarbonyloxyimino)-2-(phenyl-
acetonitrile), 4-dimethylaminopyridine, and Re2(CO)10 were used as
received from Aldrich. Aqueous [Re(CO)3(H2O)3]OTf (OTf =
trifluoromethanesulfonate) was prepared by a known method.18
NMR Measurements. 1H NMR and 13C NMR spectra were
recorded on a 400 MHz Bruker spectrometer. Peak positions are
relative to TMS or to solvent residual peak, with TMS as reference. All
NMR data were processed with TopSpin and MestReNova software.
NMR data not presented in the Experimental Section can be found in
the Results Section or in Supporting Information.
Molecules containing a sulfonamide represent a very
important class of biologically active molecules with a wide
variety of applications.39−45 Therefore, we previously set out to
explore conjugation that utilizes an N−S bond with the central
N being the sulfonamide N.35 The reaction of various sulfonyl
chlorides (RSO2Cl) with di-(2-picolyl)amine (N(H)dpa)
afforded N(SO2R)dpa ligands.35 [Note that we use the normal
convention: an N (italic N) designates a substituent location on
nitrogen in the name of a compound. In this article, N
designates a substituent located on the central or anchoring
nitrogen atom of a tridentate ligand.] These N(SO2R)dpa
ligands readily added to fac-[Re(CO)3(H2O)3]+ to form fac-
[Re(CO)3(N(SO2R)dpa)]PF6 (or BF4) complexes. We learned
that these were the only examples of structurally characterized
complexes bearing an N-bound, open-chain tertiary sulfona-
mide linkage with a normal M−N bond length. These fac-
[Re(CO)3(N(SO2R)dpa)]PF6 complexes were the first exam-
ples of such structurally characterized complexes with a neutral
tertiary sulfonamide donor bound not only to the fac-
[ReI(CO)3]+ core but to any metal center.35 Although the
results in that report appeared to serve as proof of principle, the
tridentate framework, N(CH2Z)2 with Z = 2-pyridyl, is
relatively rigid, and the resulting geometric constraints could
possibly account for the observation of the M−N(sulfonamide)
bond of normal length, as found in cases when complicated
ligand ring structures fix the bond lengths.35 Thus, the study of
fac-[Re(CO)3(N(SO2R)(CH2Z)2)]n complexes with more
flexible chelate rings is of fundamental importance to
coordination chemistry.
The new fac-[Re(CO)3(N(SO2R)dpa)]X complexes revealed
the feasibility of having a tridentate ligand anchored by a central
tertiary sulfonamide N. However, the two 2-pyridyl rings in a
potential fac-[M(CO)3(N(SO2R)dpa)]n imaging agent are
hydrophobic, an undesirable property in an imaging agent
because it is expected to promote liver uptake.12 Also, the 2-
pyridyl groups are electron withdrawing, facilitating decom-
position of coordinated N(SO2R)dpa ligands by strong base.35
With the goals of exploring fundamental coordination
chemistry of sulfonamides and of identifying ligands for use
in imaging agents, we have now explored a more hydrophilic
and more flexible ligand system that is suitable for our new
conjugation method. Here, we employ a prototypical triamine
ligand framework based on diethylenetriamine (N(H)dien).46
In the new N(SO2R)dien ligands, the aromatic 2-pyridyl groups
of the dpa moiety are replaced with hydrophilic −CH2NH2
groups. The new ligands are stable to base and have the
advantage of being small in size, a feature considered to be
desirable for bioconjugates.32,34 All of the new complexes
discussed below have the facial geometry, and thus from this
point onward, we omit the fac- designation when discussing
specific compounds.
Mass Spectrometric Measurements. High-resolution mass
spectra were recorded on a Bruker Ultraflex MALDI TOF mass
spectrometer and an Agilent 6210 ESI TOF LCMS mass
spectrometer.
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
with graphite-monochromated Mo Kα (λ = 0.71073 Å) radiation. Data
reduction included absorption corrections by the multiscan method,
with SADABS.47 The structures were determined by direct methods
and difference Fourier techniques and were refined by full-matrix least-
squares using SHELXL-97.48 All non-hydrogen atoms were refined
anisotropically. All H atoms were visible in difference maps but were
placed in idealized positions, except for N−H hydrogen atoms, for
which coordinates were refined. A torsional parameter was refined for
each methyl group. Compound 6 has two independent formula units
in the asymmetric unit.
Synthesis of N,N″-Bis(tert-butoxycarbonyl)diethylene-
triamine (N(H)dien(Boc)2). The N(H)dien(Boc)2 ligand was
prepared in 96% yield by a known method.49 1H NMR signals
(ppm) in CDCl3: 4.89 (br s, 1H, NH), 3.20 (m, 4H, 2CH2), 2.72 (t,
1
4H, 2CH2), 1.44 (s, 18H, 6CH3). These H NMR chemical shifts
matched the previously reported values.49
General Synthesis of N(SO2R)dien. The following general
procedure was employed to obtain the [N(SO2Me)dienH2]-
(CF3CO2)2 (1) and N(SO2R)dien (R = dmb (2), R = tol (3))
ligands: a solution of the sulfonyl chloride (2 mmol) in 30 mL of
dioxane was added dropwise over 2 h to a solution of N(H)dien(Boc)2
(0.61 g, 2 mmol) and triethylamine (0.28 mL, 2 mmol) in dioxane
(100 mL) at room temperature. The reaction mixture was stirred at
room temperature for 20 h and filtered to remove any precipitate. The
solvent was completely removed by rotary evaporation, water (50 mL)
was added to the resulting oil, and the product was extracted into
CH2Cl2 (2 × 25 mL). The CH2Cl2 extracts were combined and
washed again with water (2 × 25 mL) at pH ∼6. The organic layer was
dried with anhydrous Na2SO4, and the CH2Cl2 was removed by rotary
evaporation to yield an off-white solid. The Boc-protected
diensulfonamide, N(SO2R)dien(Boc)2, was purified if necessary by
column chromatography (silica gel column and a mixture of ethyl
acetate/hexane). After characterization by 1H NMR spectroscopy, this
N(SO2R)dien(Boc)2 product was then deprotected by dropwise
addition of trifluoroacetic acid (0.16−0.24 mL, 2−3 mmol) to a
CH2Cl2 solution (at ∼0 °C) of the compound (5 mL, 1 mmol). The
reaction mixture was allowed to warm to room temperature, stirred for
16 h at room temperature, and then filtered; the filtrate was taken to
dryness by rotary evaporation. Water at pH ∼8−9 (50 mL) was added
to the residue, and the product was extracted into CHCl3 (2 × 25
mL). The combined CHCl3 extracts were dried over anhydrous
Na2SO4, and the solvent was removed by rotary evaporation, leaving a
white/off-white powder or, when R = Me, a yellow oil.
General Synthesis of [Re(CO)3(N(SO2R)dien)]PF6. A solution of
the N(SO2R)dien ligand (0.1 mmol) in methanol (2 mL) was added
to an aqueous solution of [Re(CO)3(H2O)3]OTf (5 mL, 0.1 mmol).
Methanol (1−2 mL) was added to dissolve any precipitate that
formed. The pH of the reaction mixture was adjusted to ∼6−7 with
B
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Figure 1. General reaction scheme for the synthesis of N(SO2R)dien ligands (top) and [Re(CO)3(N(SO2R)dien)]+ complexes (bottom).
0.5 M NaOH if necessary, and the clear reaction mixture was heated at
reflux for 24 h. An excess (0.16 g, 1 mmol) of NaPF6 was added to the
clear solution, and the precipitate that formed within ∼30 min was
collected on a filter, washed with water, and air-dried.
H4), 5.19 (br s, 2H, NH), 3.32 (m, 4H, 2CH2), 3.18 (m, 4H, 2CH2),
2.38 (s, 6H, 2CH3), 1.45 (s, 18H, 6CH3).
Deprotection of N(SO2dmb)dien(Boc)2 (0.47 g, 1 mmol) with
trifluoroacetic acid (0.16 mL, 2 mmol), by the procedure described
above, afforded N(SO2dmb)dien (2) as a white powder (0.26 g, 98%
yield). 1H NMR signals (ppm) in CDCl3: 7.42 (s, 2H, H2/6), 7.20 (s,
H, H4), 3.15 (t, J = 6.4 Hz 4H, 2C(5/6)H2), 2.91 (t, J = 6.4 Hz, 4H,
2C(4/7)H2), 2.38 (s, 6H, 2CH3). ESI-MS m/z: [M + H]+ calcd for
C12H21O2N3S, 272.1427; found, 272.1431.
Synthesis of N(SO2tol)dien (3). The general procedure using
tolSO2Cl (0.44 g, 2 mmol) yielded N(SO2tol)dien(Boc)2 as a pale
yellow oil (0.78 g, 86% yield). 1H NMR signals (ppm) in CDCl3: 7.67
(d, J = 8.3 Hz, 2H, H2/6), 7.31 (d, J = 8.1 Hz, 2H, H3/5), 5.18 (br s,
2H, NH), 3.32 (m, 4H, 2CH2), 3.17 (m, 4H, 2CH2), 2.43 (s, 3H,
CH3), 1.45 (s, 18H, 6CH3).
Synthesis of [N(SO2Me)dienH2](CF3CO2)2 ([1H2](CF3CO2)2).
The use of MeSO2Cl (0.16 mL, 2 mmol) in the general method
described above yielded crude N(SO2Me)dien(Boc)2 as a brown oil
1
(0.65 g, 85% yield). H NMR signals (ppm) in DMSO-d6: 6.92 (br s,
2H, 2NH), 3.14 (m, 4H, 2CH2), 3.06 (m, 4H, 2CH2), 2.89 (s, 3H,
CH3), 1.37 (s, 18H, 6CH3).
The deprotection process described in the general method above
afforded N(SO2Me)dien (1) as a pale-yellow, oily substance (yield:
1
0.004 g, 18%). H NMR signals (ppm) in CDCl3: 3.25 (t, J = 6.3 Hz,
4H, 2C(5/6)H2), 2.93 (s, 3H, CH3), 2.90 (t, J = 6.4 Hz, 4H, 2C(4/
7)H2); in acetonitrile-d3: 3.14 (t, J = 6.5 Hz, 4H, 2C(5/6)H2), 2.86 (s,
3H, CH3), 2.76 (t, J = 6.5 Hz, 4H, 2C(4/7)H2); in DMSO-d6: 3.08
(broad t, 4H, 2C(5/6)H2), 2.91 (s, 3H, CH3), 2.67 (broad t, 4H,
2C(4/7)H2). 13C NMR signals (ppm) in CDCl3: 51.59 (C5/6), 40.70
(C4/7), 37.60 (CH3).
Deprotection of N(SO2tol)dien(Boc)2 (0.45 g, 1 mmol) with
trifluoroacetic acid (0.16 mL, 2 mmol) afforded N(SO2tol)dien (3) as
a white powder (0.23 g, 92% yield). 1H NMR signals (ppm) in CDCl3:
7.70 (d, J = 8.2 Hz, 2H, H2/6), 7.31 (d, J = 8.0 Hz, 2H, H3/5), 3.15
(t, J = 6.4 Hz, 4H, 2C(5/6)H2), 2.91 (t, J = 6.4 Hz, 4H, 2C(4/7)H2),
2.43 (s, 3H, CH3); in acetonitrile-d3: 7.69 (d, J = 8.4 Hz, 2H, H2/6),
7.39 (d, J = 7.9 Hz, 2H, H3/5), 3.07 (t, J = 6.4 Hz, 4H, 2C(5/6)H2),
2.79 (t, J = 6.5 Hz, 4H, 2C(4/7)H2), 2.41 (s, 3H, CH3). ESI-MS m/z:
[M + H]+ calcd for C11H19O2N3S, 258.1271; found, 258.1277.
Synthesis of [Re(CO)3(N(SO2Me)dien)]PF6 (4). The general
method above, with the [1H2](CF3CO2)2 ligand (0.04 g, 0.1 mmol)
and [Re(CO)3(H2O)3]OTf (5 mL, 0.1 mmol), afforded [Re-
(CO)3(N(SO2Me)dien)]PF6 (4) as a white crystalline precipitate
(0.036 g, 60% yield) after the addition of NaPF6 (∼16 mg). (The pH
of the acidic reaction mixture was adjusted to ∼7 with 0.5 M NaOH
Compared to ligands with other R groups, isolation for R = Me
produced a low yield, owing to the more hydrophilic nature of
N(SO2Me)dien. To increase the amount of material available for
synthesis of the complex, the general deprotection process was
modified by adding a slight excess of trifluoroacetic acid to obtain the
protonated ligand [N(SO2Me)dienH2](CF3CO2)2 ([1H2]-
(CF3CO2)2). A mixture of N(SO2Me)dien(Boc)2 (0.38 g, 1 mmol)
and trifluoroacetic acid (0.24 mL, 3 mmol) was stirred at room
temperature for 16 h, and the resulting mixture was filtered; the white
precipitate that was collected on a filter paper was washed several
times with CH2Cl2 and air-dried. The precipitate was then dissolved in
methanol (3 mL), and the solution was filtered. CH2Cl2 (∼10 mL)
was added to the filtrate until cloudiness was observed. After 24 h, the
undisturbed solution yielded thin, colorless, needle-like crystals of the
trifluoroacetate salt of the protonated ligand [N(SO2Me)dienH2]-
1
before the solution was heated at reflux.) H NMR signals (ppm) in
DMSO-d6: 5.65 (m, 2H, NH), 4.27 (m, 2H, NH), 3.57 (s, 3H, CH3),
3.45 (m, 2H, CH2), 3.22 (m, 2H, CH2), 3.10 (m, 2H, CH2), 2.97 (m,
4H, 2CH2). 1H NMR signals (ppm) of the R group in acetone-d6: 3.62
1
1
(CF3CO2)2 ([1H2](CF3CO2)2) (0.29 g, 72% yield). H NMR signals
(s, 3H, CH3); in acetonitrile-d3: 3.33 (s, 3H, CH3). Chelate ring H
(ppm) in DMSO-d6: 7.81 (br s, 6H, 2+NH3), 3.37 (t, J = 6.2 Hz, 4H,
2CH2), 3.04 (s, 3H, CH3), 3.00 (t, J = 6.3 Hz, 4H, 2CH2). ESI-MS m/
z: [M + H]+ calcd for C5H15O2N3S, 182.0958; found, 182.0957.
Synthesis of N(SO2dmb)dien (2). The use of dmbSO2Cl (0.40 g,
2 mmol) according to the general synthetic procedure above yielded a
pale yellow oil, which was purified by dissolving the oil in a minimum
(∼1 mL) of ethyl acetate and loading the solution onto a silica gel
column. A 1:5 mixture of ethyl acetate:hexane was used to elute the
remaining dmbSO2Cl starting material (UV−vis). The product (UV−
vis) was then eluted with a 2:3 (v/v) mixture of ethyl acetate/hexane.
Thin-layer chromatography was used to determine the progress of
separation. Removal of solvent by rotary evaporation yielded
N(SO2dmb)dien(Boc)2 as a pale yellow powder (0.87 g, 92% yield).
1H NMR signals (ppm) in CDCl3: 7.65 (s, 2H, H2/6), 7.21 (s, H,
NMR signals for 4−6 in these solvents are reported in the Results and
Discussion. 13C NMR signals (ppm) in DMSO-d6: 55.91 (C5/6),
44.86 (C4/7), 32.50 (CH3). 13C NMR signals (ppm) in acetone-d6:
55.11 (C5/6), 44.46 (C4/7), 30.97(CH3). MALDI-TOF m/z: [M+]
calcd for C8H15O5N3SRe, 452.029; found, 452.158.
Synthesis of [Re(CO)3(N(SO2dmb)dien)]PF6 (5). The use of the
general procedure with N(SO2dmb)dien (2) (0.03 g, 0.1 mmol)
afforded [Re(CO)3(N(SO2dmb)dien)]PF6 (5) as a white precipitate
(0.047 g, 69% yield) after the addition of NaPF6 (∼16 mg). 1H NMR
signals (ppm) in DMSO-d6: 7.72 (s, 2H, H2/6), 7.57 (s, H, H4), 5.72
(m, 2H, NH), 4.28 (m, 2H, NH), 3.41 (m, 2H, CH2), 3.14 (m, 2H,
CH2), 3.00 (m, 2H, CH2), 2.65 (m, 2H, CH2), 2.42 (s, 6H, 2CH3). 1H
NMR signals (ppm) of the R group in acetone-d6: 7.77 (s, 2H, H2/6),
7.60 (s, H, H4), 2.46 (s, 6H, 2CH3); in acetonitrile-d3: 7.65 (s, 2H,
C
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H2/6), 7.55 (s, H, H4), 2.44 (s, 6H, 2CH3). 13C NMR signals (ppm)
in acetone-d6: 142.30 (dmb ring C1), 139.54 (dmb ring C4), 130.93
(dmb ring C2/6), 126.71(dmb ring C3/5), 57.83 (C5/6), 46.93 (C4/
7), 22.09 (2CH3). MALDI-TOF m/z: [M+] calcd for C15H21O5N3SRe,
542.076; found, 542.155.
Table 1. Crystal Data and Structure Refinement for
[Re(CO)3(N(SO2Me)dien)]PF6 (4) and
[Re(CO)3(N(SO2tol)dien)]PF6 (6)
4
6
Synthesis of [Re(CO)3(N(SO2tol)dien)]PF6 (6). The use of
N(SO2tol)dien (3) (0.02 g, 0.1 mmol) as described in the general
synthesis afforded [Re(CO)3(N(SO2tol)dien)]PF6 (6) as a white
precipitate (0.056 g, 84% yield) after the addition of NaPF6 (∼16 mg).
Slow evaporation of a solution of the compound in acetone produced
colorless, X-ray quality, needle-shaped crystals. 1H NMR signals
(ppm) in DMSO-d6: 7.99 (d, J = 8.5 Hz, 2H, H2/6), 7.61 (d, J = 8.1
Hz, 2H, H3/5), 5.70 (m, 2H, NH), 4.28 (m, 2H, NH), 3.40 (m, 2H,
CH2), 3.14 (m, 2H, CH2), 3.01 (m, 2H, CH2), 2.66 (m, 2H, CH2),
∼2.5, overlapped (s, 3H, CH3). 1H NMR signals (ppm) of the R group
in acetone-d6: 8.05 (d, 2H, H2/6), 7.65 (d, 2H, H3/5), 2.53 (s, 3H,
CH3); in acetonitrile-d3: 7.91(d, 2H, H2/6), 7.58 (d, 2H, H3/5), 2.51
(s, 3H, CH3). 13C NMR signals (ppm) in DMSO-d6: 147.80 (tol ring
C4), 132.07 (tol ring C2/6), 131.00 (tol ring C3/5), 125.98 (tol ring
C1), 56.20 (C5/6), 44.80 (C4/7), 21.69 (CH3). 13C NMR signals
(ppm) in acetone-d6: 148.88 (tol ring C4), 132.70 (tol ring C2/6),
131.58 (tol ring C3/5), 127.05 (tol ring C1), 56.94 (C5/6), 46.00
(C4/7), 21.74 (CH3). MALDI-TOF m/z: [M+] calcd for
C14H19O5N3SRe, 528.060; found, 528.001.
empirical formula
fw
C8H15N3O5ReS·PF6
596.46
C14H19N3O5ReS·PF6
672.55
crystal system
space group
unit cell dimensions
a (Å)
monoclinic
P21/c
monoclinic
P21/c
12.822(3)
8.8089(19)
14.026(3)
94.373(10)
1579.6(6)
100
26.0233(14)
13.0607(7)
12.2147(7)
95.831(3)
4130.1(4)
100
b (Å)
c (Å)
β (deg)
V (Å3)
T (K)
Z
4
8
ρcalc (Mg/m3)
2.508
2.163
abs coeff (mm−1
)
8.02
6.15
2θmax (°)
R indices
70
71.2
a
0.018
0.029
b
wR2 = [I > 2σ (I)]
data collected, Rint
data/param
0.044
0.055
Challenge Reactions of [Re(CO)3(N(SO2tol)dien)]PF6 (6). Two
5 mM solutions of 6 in DMSO-d6 (500 μL) were treated separately
with 10 molar equiv (0.6 μL, 50 mM) or 2 molar equiv (0.12 μL, 10
28379, 0.034
51479, 0.033
6953/239
18802/585
2
a
b
R = (∑∥Fο| − |Fc∥)/∑|Fο|. wR2 = [∑[w(Fο − Fc2)2]/
1
mM) of diethylenetriamine and monitored over time by H NMR
2
2
∑[w(Fο )2]]1/2, in which w = 1/[σ2(Fο ) + (dP)2 + (eP)] and P =
spectroscopy. Another challenge experiment was carried out with a 5
mM solution of 6 in DMSO-d6 by first adding 1 molar equiv of 4-
dimethylaminopyridine (4-Me2Npy) and then increasing the 4-
Me2Npy to 10 molar equiv.
2
(Fο + 2Fc2)/3.
carbonyl ligands occupying one face; the remaining three
coordination sites are occupied by the three nitrogen atoms of
the tridentate ligand.
RESULTS AND DISCUSSION
■
Synthesis of N(SO2R)dien and [Re(CO)3(N(SO2R)dien)]-
PF6. N(SO2Me)dien (1), N(SO2dmb)dien (2), and N(SO2tol)-
dien (3) were synthesized by coupling N(H)dien with the
respective sulfonyl chloride (Figure 1). In this case, unlike in
the synthesis of N(SO2R)dpa ligands,35 additional steps are
required to synthesize the N(SO2R)dien ligands (1−3), owing
to the possibility of attack by the terminal N(H)dien amino
groups on the sulfur atom of the sulfonyl chloride. Thus, the
N(H)dien terminal amine groups were protected with Boc
groups. The products were obtained in good yield and purity,
as indicated by 1H NMR spectral data. Reaction of the
deprotected ligands with an aqueous solution of [Re-
(CO)3(H2O)3]OTf afforded [Re(CO)3(N(SO2Me)dien)]PF6
(4), [Re(CO)3(N(SO2dmb)dien)]PF6 (5), and [Re-
(CO)3(N(SO2tol)dien)]PF6 (6) in 60−84% yields. All three
Selected bond distances and angles of complexes 4 and 6 are
presented in Table 2. The Re−C bond distance of the CO
group trans to the sulfonamide group is not significantly
different from those of the two cis Re−CO bonds, indicating
the absence of any trans influence. All Re−N bond distances in
6 are generally similar to the Re−N(sp3) distances observed in
[Re(CO)3L]+ complexes with prototypical NNN donor
ligands, which range from ∼2.21 to 2.29 Å as the bulk of
substituents on the N atoms increases.46,50 However, the
distances from Re to the central N2 (2.2763(14) Å in 4 and
2.2686(19) Å in 6) are significantly longer than the Re−N1
distances (2.2377(14) Å for 4 and 2.221(2) Å for 6) and Re−
N3 distances (2.2072(15) Å for 4 and 2.216(2) Å for 6) (Table
2). These Re−N2 distances in 4 and 6 are significantly longer
46
than the Re−N2 distance in [Re(CO)3(N(H)dien)]PF6
1
complexes were characterized by H and 13C NMR spectros-
(2.201(3) Å), but they are comparable to the Re−N2 distance
of [Re(CO)3(N(Me)dien)]PF6.46 The Re−N2 distance in the
latter complex (2.250(4) Å) is not statistically different from
the Re−N2 distance in [Re(CO)3(N(SO2tol)dien)]PF6 (6,
Table 2), suggesting that the bond lengthening in 6 is caused
chiefly by steric effects, not electronic effects. Furthermore, the
good overlap of the three donor N atoms observed when the
three carbonyl carbon (C1, C2, and C3) and Re atoms in the
structure of 6 are superimposed with the corresponding atoms
copy and by mass spectrometry (Experimental Section).
X-ray quality crystals of 4 and 6 were grown by slowly
cooling a 5 mM solution of the compound in warm water.
Crystals of 5 (grown by slow evaporation of a 5 mM acetone
solution) suffered from twinning, space-group ambiguity, and
disorder problems in the molecule, which prevented refinement
within acceptable values. However, the structural character-
ization of 5 (using the same procedures as for 4 and 6)
confirmed that all three N atoms of N(SO2dmb)dien are
coordinated to Re.
Structural Results. Crystal data and structural refinement
details for [Re(CO)3(N(SO2Me)dien)]PF6 (4) and [Re-
(CO)3(N(SO2tol)dien)]PF6 (6) are summarized in Table 1,
and the ORTEP plots appear in Figure 2 (see Figure 1 for the
numbering scheme used to describe the solid-state data). Both
4 and 6 exhibit a pseudo octahedral structure, with the three
46
in [Re(CO)3(N(Me)dien)]PF6 (Supporting Information,
Figure S1) demonstrates the lack of any large effect of having
a tertiary sulfonamide nitrogen instead of a typical sp3 nitrogen
serve as the central anchor of the tridentate ligand.
The lengthening of the Re−N2 bond in 4 and 6 versus
[Re(CO)3(N(H)dien)]PF6 is similar to that observed in
[Re(CO)3(N(SO2R)dpa)]PF6 complexes (e.g., R = Me and
tol) versus the parent [Re(CO)3(N(H)dpa)]Br complex.30,35
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Figure 2. ORTEP plots of the cations in [Re(CO)3(N(SO2Me)dien)]PF6 (4) (left) and Re(CO)3(N(SO2tol)dien)]PF6 (6) (right). Thermal
ellipsoids are drawn with 50% probability.
Table 2. Selected Bond Distances (Å) and Angles (deg) for [Re(CO)3(N(SO2Me)dien)]PF6 (4) and
[Re(CO)3(N(SO2tol)dien)]PF6 (6)
4
6
4
6
bond distance
Re−N1
bond angle
2.2377(14)
2.2763(14)
2.2072(15)
1.9128(16)
1.9109(18)
1.9136(19)
1.4273(13)
1.4324(13)
1.7434(13)
2.221(2)
2.2686(19)
2.216(2)
1.913(2)
1.911(2)
1.917(3)
1.4280(18)
1.4339(17)
1.759(2)
N1−Re−N2
N1−Re−N3
N2−Re−N3
C2−Re−N1
C3−Re−N1
C2−Re−N3
C1−Re−N3
Re−N2−S1
Re−N2−C5
Re−N2−C6
S1−N2−C5
S1−N2−C6
C5−N2−C6
C1−Re−N2
C3−Re−N2
C1−Re−C2
C3−Re−C2
C1−Re−C3
77.07(5)
86.53(6)
77.80(5)
95.72(6)
92.31(6)
96.60(7)
93.12(6)
111.07(7)
105.93(9)
110.01(10)
109.13(10)
108.52(10)
112.19(13)
99.98(6)
97.91(6)
87.25(7)
87.62(7)
87.83(7)
77.54(7)
Re−N2
Re−N3
Re−C1
Re−C2
Re−C3
S1−O5
S1−O4
S1−N2
85.83(8)
77.86(7)
92.70(9)
94.99(9)
98.29(9)
91.92(9)
111.35(9)
106.14(13)
109.86(13)
108.82(14)
108.18(13)
112.52(18)
100.55(8)
96.81(8)
nonbonded distance
N1−N3
N1−N2
3.046(2)
2.812(2)
2.816(2)
3.021(3)
2.812(3)
2.818(3)
N2−N3
a
deviation of N2
0.513(1)
0.514(2)
89.08(10)
87.29(10)
87.10(10)
a
Distance to the sulfonamide N from the plane defined by the S and the two C atoms attached to N2 (average of two independent molecules for 6).
The similarity of the central Re−N bond distances of the
analogous [Re(CO)3(N(SO2R)dpa)]PF6 complexes (average =
∼2.277 Å) and in 4 and 6 (average = ∼2.272 Å) indicates that
the donating ability of the sulfonamide N is similar for both
ligands.35 Furthermore, all three donor N atoms show good
overlap when the C1, C2, C3, and Re atoms in [Re-
(CO)3(N(SO2tol)dien)]PF6 and [Re(CO)3(N(SO2tol)dpa)]-
PF6 are superimposed (Figure 3). The central Re−N bond
distance of the [Re(CO)3(N(SO2Me)dpa)]PF6 complex
(2.2826(16) Å) is not significantly different from this distance
in 4. Thus, the normal length of the Re−N(sulfonamide) bonds
in [Re(CO)3(N(SO2R)dpa)]PF6 complexes is not a conse-
quence of the rigidity of the five-membered dpa chelate rings.
The sulfonamide nitrogen of the N(SO2tol)dpa ligand in a
PdII complex is not bound to PdII and all bond angles around
the sulfonamide nitrogen of the N(SO2tol)dpa ligand in the
bidentate binding mode are close to 120°, indicating sp2
hybridization for this N atom.52 In contrast, in 4 and 6, all
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the sulfonamide N from the plane defined by the S and the two
C atoms attached to N typically ranges from 0.47−0.52 Å.35
Such values are larger than those for the corresponding distance
in complexes with an unbound sulfonamide N atom (0.06−
0.26 Å).35 In the new complexes, [Re(CO)3(N(SO2Me)dien)]-
PF6 (4) and [Re(CO)3(N(SO2tol)dien)]PF6 (6), this distance
(Table 2) is in the range characteristic of a M−N bond.
Most of the known complexes with tertiary sulfonamide
ligands exhibit relatively long M−N(sulfonamide) bond
distances and short S−N distances, features attributed to the
resonance contribution of the lone pair on the sulfonamide N
and to the poor electron donation of the sulfonamide N to the
metal.54,55 Thus, both the comparatively short Re−N-
(sulfonamide) bond distance [2.2763(14) for 4 and
2.2686(19) Å for 6] and the long S−N bond distance in
these complexes [1.7434(13) for 4 and 1.759(2) Å) for 6]
indicate that the sulfonamide N is a relatively strong donor.
Only one other structurally characterized complex in which a
diethylenetriamine derivative is bound to a metal (LaIII) via a
sulfonamide bond through the N has been reported;56 the
sulfonamide group in that complex, however, is part of a cyclic
heptadentate ligand. Thus, the sulfonamide complexes reported
here are the first structurally characterized metal complexes in
which the metal is coordinated by the central tertiary
sulfonamide N in a linear, highly flexible tridentate ligand.
We have previously discussed at length chelate ring pucker λ
or δ chirality and the consequences on structure and NMR
spectra of [Re(CO)3(polyamine)]X complexes.38,46,50 The
cation of [Re(CO)3(N(SO2Me)dien)]PF6 (4) and one of the
cations of [Re(CO)3(N(SO2tol)dien)]PF6 (6) (the one shown
in Figure 2) have five-membered chelate rings of different
chirality (λ or δ). However, the other independent cation in the
asymmetric unit of 6 (not shown) has chelate rings of the same
chirality. The relative frequency of observing the same or
different chiralities in the two chelate rings with a central
Figure 3. Overlay of Re, C1, C2, and C3 atoms of [Re-
(CO)3(N(SO2tol)dien)]PF6 (6) (blue) and [Re(CO)3(N(SO2tol)-
dpa)]PF6 (magenta) complexes. (The SO2R groups have been
35
omitted for clarity.)
bond angles around the sulfonamide N (N2) are ∼109° (Table
2). This observation, which is consistent with data for
[Re(CO)3(N(SO2R)dpa)]PF6 complexes,35 indicates that the
sulfonamide nitrogen changes from sp2 to sp3 hybridization
upon tridentate binding to ReI.35 This conclusion is confirmed
by the fact that the C5−N2 (average = 1.511 Å) and C6−N2
(average = 1.512 Å) bond distances are longer than an average
C−N(sp2) distance (∼1.28 Å).53 Data for all of the bond angles
and distances involving the sulfonamide N indicate that it is sp3
hybridized.
In [Re(CO)3(N(SO2R)dpa)]PF6 and other complexes that
have metal-bound tertiary sulfonamide groups, the distance to
1
Figure 4. H NMR spectra of [Re(CO)3(N(SO2R)dien)]PF6 complexes (4−6) in acetone-d6 at 25 °C.
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Chart 1. Front (Left) and Side (Right) Views of [Re(CO)3(N(SO2tol)dien)]PF6 (6), Showing the Designation of endo- and exo-
CH and endo- and exo-NH Protons
tertiary sulfonamide N donor (4 and 6) suggests that structures
in which the chirality of the rings differs may be slightly more
stable than structures having rings of the same chirality. Thus,
our finding agrees with cases in which the central N is a classical
sp3 N donor, namely, that examples in which the chirality of the
rings in a given structure differs (λδ or δλ) occur more
frequently than those in which the chirality is the same (λλ or
δδ).46
NMR Spectroscopy. The N(SO2R)dien ligands and the
[Re(CO)3(N(SO21R)dien)]PF6 complexes reported here were
characterized by H NMR (1−6) and 13C NMR (1, 3−6)
spectroscopy, usually in one or more of several solvents
(CDCl3, acetone-d6, acetonitrile-d3, and DMSO-d6). NMR
signals were assigned by analyzing the splitting pattern,
integration, and data from 2D NMR experiments.
giving rise to a multiplet. For example, the methylene group 1H
NMR signals observed in acetonitrile-d3 changed from two
triplets (at 3.07 and 2.79 ppm) for the N(SO2tol)dien ligand
(3) to four multiplets [at 3.51, 3.16 (two overlapped), and 2.59
ppm; see the Experimental Section and Supporting Informa-
tion, Figure S4] for [Re(CO)3(N(SO2tol)dien)]PF6 (6). The
least amount of overlap of the multiplets for complexes 4−6
was found in acetone-d6 (Figure 4). Thus, as expected, the
apparent magnetic equivalence of methylene protons in the free
ligands is lost in 4−6. Similar changes in signals for methylene
protons upon coordination of ligands have been reported for
[Re(CO)3(N(SO2R)dpa)]PF6 complexes35 and for [Re-
(CO)3(N(H)dien)]PF6.46
We designate the magnetically distinct protons in −CH2− or
−NH2 groups as endo-H or exo-H protons, on the basis of the
orientation of the proton either toward (endo) or away (exo)
from the carbonyl ligands (Chart 1). Note that the chelate rings
in these complexes are puckered, and the corresponding
protons in the two chelate rings are not equivalent in the solid
state. However, the chelate rings are fluxional, and time
averaging leads to only one signal for each type of CH or NH
The two methylene 1H NMR signals in N(SO2R)dien
ligands (1−3) are triplets integrating to four protons in CDCl3
(Experimental Section and Figure S2). Selected data were
obtained in acetonitrile-d3 or in DMSO-d6 (Experimental
Section and Figure S3). The C(5/6)H2 triplet for 2 (R = dmb)
and for 3 (R = tol) is slightly upfield from the C(5/6)H2 triplet
for 1 (R = Me) in CDCl3 (Figure S2). Shift values for the C(4/
7)H2 triplet are similar for all three ligands. These observations
are attributed to the anisotropic sulfonamide aromatic groups,
which are close to the C(5/6)H2 groups but far from the C(4/
7)H2 groups. Similar results were obtained for 1 and 3 in
acetonitrile-d3. The two protons in each methylene group are
not sterically similar because the sulfonamide N lies out of the
plane defined by the S and the two C atoms attached to N; the
apparent magnetic equivalence in the NMR spectra indicates
that inversion at the sulfonamide nitrogen leads to time
averaging, as discussed previously for the N(SO2R)dpa
ligands.35
1
proton, or six H NMR signals for the N(C(5/6)H2−C(4/
7)H2−NH2)2 tridentate framework moiety.
1
1H NMR Assignments. H NMR signals of the protons in
the terminal NH2 groups of previously reported [Re-
(CO)3(L)]n compounds (L = simple tridentate ligands similar
to diethylenetriamine with two terminal −NH2 groups)46,50 are
well-resolved. The endo-NH signal has a more downfield
chemical shift than the exo-NH signal; solvent has access to the
exposed endo-NH protons, but solvent access to the exo-NH
protons is impeded by the chelate rings.46,50 The signal of the
exposed endo-NH protons is shifted downfield by NH-solvent
H-bonding. Both the shifts and the characteristic shift
separation between these signals (Δ = ∼1.5 ppm in DMSO-
d6) are useful for assigning such NH NMR signals.46,50
The spectra of the respective complexes, on the other hand,
are consistent with each of the four protons in the chelate ring
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In this work, two broad 1H NMR signals of [Re-
(CO)3(N(SO2tol)dien)]PF6 (6) (5 mM) in DMSO-d6 at
4.28 and 5.70 ppm decreased in size when D2O was added,
indicating that they are NH signals. The signals are connected
by a strong COSY cross-peak, as expected for an NH2 group
(Figure S5). The downfield signal at 5.70 ppm and the
relatively upfield signal at 4.28 ppm, each integrating to two
protons with Δ = ∼1.5 ppm, can be assigned as endo-NH and
exo-NH signals, respectively.46,50
Similar Δ values of ∼1.5 ppm (DMSO-d6), ∼1.1 ppm
(acetone-d6), and ∼1.0 ppm (acetonitrile-d3) were observed
between the downfield and upfield NH signals for all three
complexes studied here (Table 3). This consistency aided in
1
Table 3. H NMR Shifts (ppm) of exo- and endo-NH and
exo- and endo-CH Signals for [Re(CO)3(N(SO2R)dien)]PF6
Complexes in Various Solvents at 25 °C
signal
R = Me (4)
DMSO-d6
R = dmb (5)
R = tol (6)
exo-NH
4.27
5.65
3.45
3.23
3.10
2.97
4.28
5.72
3.41
3.14
3.00
2.65
4.28
5.70
3.42
3.14
3.01
2.66
endo-NH
endo-C(5/6)H
exo-C(4/7)H
endo-C(4/7)H
exo-C(5/6)H
1
Figure 5. H NMR spectra of [Re(CO)3(N(SO2tol)dien)]PF6 (6),
illustrating the relative position of NH signals observed at 25 °C in (a)
acetonitrile-d3, (b) acetone-d6, and (c) DMSO-d6.
acetone-d6
exo-NH
4.45
5.54
4.40
5.52
3.81
3.58
3.50
3.02
4.40
5.51
3.81
3.55
3.52
3.02
specific endo-CH or exo-CH proton (Chart 1), we use
[Re(CO)3(N(SO2tol)dien)]PF6 (6) in acetone-d6 because of
the low degree of overlap of signals for the ethylene group
(Figure 4). The atom-numbering system used in this discussion
appears in Figure 1. Cross-peaks in COSY spectra (Supporting
Information, Figure S5) and ROESY spectra (Figure 6 and
Supporting Information, Figure S6) identify a multiplet as a
endo-NH
endo-C(5/6)H
exo-C(4/7)H
endo-C(4/7)H
exo-C(5/6)H
3.85
3.69
∼3.50
∼3.50
acetonitrile-d3
exo-NH
3.44
4.46
3.41
4.52
3.37
4.51
endo-NH
endo-C(5/6)H
exo-C(4/7)H
endo-C(4/7)H
exo-C(5/6)H
3.50
3.52
3.51
∼3.18
∼3.18
3.00
∼3.16
∼3.16
2.60
∼3.16
∼3.16
2.59
assigning the endo-NH and exo-NH signals in complexes 4−6
(Table 3, Figure 4). Although X-ray quality crystals for
1
compound 5 have not been isolated, the H NMR patterns
and shifts of its chelate ring signals in all solvents used match
1
the corresponding H NMR data for the crystallographically
1
characterized compound 6 (Table 3 and Figure 4). These H
NMR chemical shifts provide strong evidence that 5 has a
structure very similar to that of 6. The NH signals of 6 in
different solvents (Figure 5) are shifted downfield as the H-
bonding ability of the solvent increases. Thus, significant
downfield chemical shifts are observed in acetone-d6 and
DMSO-d6, in contrast to the relatively upfield chemical shifts
observed in acetonitrile-d3 (Table 3 and Figure 5), owing to the
weak interactions of that solvent with the NH groups. The
highest Δ value (∼1.5 ppm) occurs in DMSO-d6 because it has
the greatest H-bonding ability among the three solvents.
1
The endo-NH and exo-NH H NMR signals’ assignments
provide a starting point that allows us to exploit our structural
data to achieve complete and unambiguous assignment of the
1
1
Figure 6. H−1H ROESY spectrum of [Re(CO)3(N(SO2tol)dien)]-
ethylene H NMR signals, which are rarely well-resolved for
coordinated ligands having such chelate rings.50 To demon-
strate our assignment strategy of assigning the multiplets to a
PF6 (6) in acetone-d6 at 25 °C. An expanded version of this figure is in
Supporting Information (Figure S6).
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C(4/7)H or C(5/6)H signal. In the solid state, the endo-NH
protons have a shorter average distance to the endo-C(4/7)H
protons (2.20 Å) than to the exo-C(4/7)H protons (2.71 Å),
and the exo-NH protons have a shorter average distance to the
exo-C(4/7)H protons (2.22 Å) than to the endo-C(4/7)H
protons (2.43 Å). Thus, from NH−CH NOE cross-peak
intensities, the CH multiplets at 3.52 ppm and 3.55 ppm are
assigned to the endo- and exo-C(4/7)H protons, respectively.
The average distance from the exo-C(4/7)H protons is shorter
to the exo-C(5/6)H protons (2.30 Å) than to the endo-C(5/6)
H protons (2.85 Å). In the ROESY spectrum, a strong NOE
cross-peak from the exo-C(4/7)H multiplet to the most upfield
multiplet at 3.02 ppm thus assigns the multiplet to the exo-
C(5/6)H protons. Similarly, an NOE cross-peak from the endo-
C(4/7)H multiplet to the most downfield multiplet at 3.81
ppm assigns this multiplet to the endo-C(5/6)H protons. The
tosyl methyl singlet (2.53 ppm) of 6 has an NOE cross-peak to
the tosyl doublet at 7.65 ppm, unambiguously assigning it to
the tosyl H3/5 protons and the other tosyl doublet to H2/6.
The latter is more downfield (8.05 ppm), consistent with the
proximity of the H2/6 protons to the sulfonamide group,
shown in previous work on the [Re(CO)3(N(SO2tol)dpa)]PF6
complexes with assigned signals for us to interpret the factors
influencing shift, but the upfield shift may be caused by the SO2
group anisotropy. Also, although the reaction of free amines
with acetone prevents comparison using acetone-d6, in DMSO-
d6 (the other solvent rather different from acetonitrile-d3 that
we used for the complexes), the same pattern of shift changes
was observed upon coordination of 1 to form 4, including the
slight upfield shift of the exo-C(5/6)H signal (Figure S3). Thus,
solvent effects are probably not causing the unexpected upfield
shift.
1
The methyl H NMR signal of N(SO2Me)dien (1) shifted
downfield upon coordination of 1 to form [Re-
(CO)3(N(SO2Me)dien)]PF6 (4) in both acetonitrile-d3 (0.47
ppm) and DMSO-d6 (0.66 ppm) (Experimental Section and
Supporting Information, Figure S3). These downfield shifts can
be attributed to the ReI inductive effect. We previously
attributed a similar downfield shift (∼0.76 ppm) observed for
[Re(CO)3(N(SO2Me)dpa)]PF6 to the ReI inductive effect.35 A
slightly greater downfield shift (∼1.03 ppm) relative to the free
ligand reported for the [Re(CO)3(N(Me)dien)]PF6 complex in
46
DMSO-d6 can be explained by the transmission of the
analogue to have an electron-withdrawing inductive effect.35
A
inductive effect through just two bonds (N−C and C−H)
versus three bonds in 4 (N−S, S−C, and C−H).
strong H2/6-to-endo-C(5/6)H NOE cross-peak and a very
weak H2/6-to-exo-C(5/6)H cross-peak is consistent with the
shorter H2/6-to-endo-C(5/6)H average distance (2.60 Å)
compared to the H2/6-to-exo-C(5/6)H average distance
(2.81 Å), thus confirming the assignment of the endo-C(5/
6)H and exo-C(5/6)H signals (Table 3).
1
13C NMR Shift Interpretation. Unlike H NMR signals,
the shifts of 13C NMR signals are not very dependent on
solvent effects (e.g., as discussed for the NH signals) or on
aromatic ring anisotropic effects (e.g., as discussed for exo-C(5/
6)H signals). Instead, 13C NMR signals are influenced more
significantly by other factors, with signals of aliphatic carbons
most frequently being shifted downfield by metal inductive
effects. Analysis of 13C NMR shifts can often provide insight
into the effect of a diamagnetic metal center on the ligand.
Therefore, we undertook the unambiguous assignment of the
13C NMR signals of selected ligands and complexes, as
described in Supporting Information. The 13C NMR signals
of the chelate ring carbons shift downfield, as expected, by 4 to
5 ppm upon coordination of the tridentate ligands 1 and 3 to
form complexes 4 and 6, and the shifts for the C4/7 and C5/6
signals of 4 are very similar to the shifts for these signals of 6
(data for acetonitrile-d3 are reported in Table S1).
1H NMR Shift Interpretation. The exo-C(5/6)H signal is
more upfield for 5 and 6 than for 4 in acetone-d6 (Figure 4). In
6 (Figure 2 and Chart 1), the relative average distance from the
centroid of the tosyl ring to the exo-C(5/6)H protons (which
point toward the center of the ring) is shorter (3.45 Å) than the
distance (4.09 Å) to the endo-C(5/6)H protons (Chart 1).
Thus, the anisotropic effect of the aromatic ring of the R group
explains the unusual upfield shift of the exo-C(5/6)H multiplet
at 3.02 ppm in acetone-d6 for 5 and 6. This explanation is
supported by the fact that the exo-C(5/6)H signal is not so
upfield for 4, a complex in which R lacks an aromatic ring. This
same trend, with the methylene endo-CH signal downfield from
the exo-CH signal and the latter signal appearing more upfield
when R has an aromatic ring (tol) than when R = Me, was
reported for the [Re(CO)3(N(SO2R)dpa)]X complexes.35
The methyl group 13C NMR signal for the free N(SO2Me)-
dien ligand (1) appears at 37.87 ppm, but it is shifted
considerably upfield for [Re(CO)3(N(SO2Me)dien)]PF6 (4)
(33.02 ppm, Table S1 in Supporting Information). The almost
5 ppm upfield change in shift when 1 forms 4 is unusual in that
13C NMR shifts are influenced mainly by through-bond effects,
such as the metal inductive effect expected to produce a
downfield shift. For example, a significant ∼14 ppm downfield
13C NMR shift was observed for the methyl group of
[Re(CO)3(N(Me)dien)]PF6 (56.48 ppm) compared to the
methyl group in the free N(Me)dien ligand (42.72 ppm) in
acetonitrile-d3.51 Because of the unexpected upfield direction of
the shift change of the methyl 13C NMR signal of 4, we
measured the 13C NMR shift of the methyl signal of
[Re(CO)3(N(SO2Me)dpa)]PF6 in DMSO-d6 (32.88 ppm), a
value ∼6.5 ppm upfield compared to the methyl signal in the
free N(SO2Me)dpa ligand (39.24 ppm).51 We attribute the
observed unusual upfield shift for 4 to the fact that the
sulfonamide N undergoes an sp2-to-sp3 rehybridization upon
coordination to ReI in both 4 and [Re(CO)3(N(SO2Me)-
dpa)]PF6.
1
Coordination of a ligand normally leads to downfield H
NMR shift changes attributable to the metal inductive effect.
Upon coordination to ReI of the free N(SO2R)dien ligands 1
and 3 in acetonitrile-d3, the downfield shift for signals of the
C4/7 protons is ∼0.4 ppm. For example, the C(4/7)H2 triplet
for 1 shifts from 2.76 ppm downfield to ∼3.18 ppm for the
overlapping C(4/7)H signals of [Re(CO)3(N(SO2Me)dien)]-
PF6 (4). A corollary of the relationships of the distance of the
exo-C(5/6)H protons to the aromatic groups mentioned above
for 6 is that the endo-C(5/6)H protons are farther from R, and
the shift of the endo-C(5/6)H signal for 4 and 6 is not
influenced by the R group. Hence, compared to the C(5/6)H2
triplets of 1 and 3, the endo-C(5/6)H signals of 4 and 6 are
shifted downfield (∼0.4 ppm to ∼3.5 ppm in acetonitrile-d3).
Remarkably, upon coordination of N(SO2Me)dien to form 4,
the exo-C(5/6)H signal (expected to shift downfield by ∼0.4
ppm owing to inductive effects) is shifted slightly upfield (0.14
ppm) compared to the free ligand triplet, even though R = Me
is not anisotropic. Presently, there are not enough other
I
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Inorganic Chemistry
Article
Challenge Reactions of [Re(CO)3(N(SO2tol)dien)]PF6
(6) in DMSO-d6. No change was observed in the H NMR
extent much greater than is required for radiopharmaceuticals
and that 6 is robust even in a hot aqueous solution.
Furthermore, another experiment conducted using 5 mg of 6
1
signals of 6 (5 mM), even after 6 months, indicating that 6 is
robust. However, addition of diethylenetriamine to 5 mM
solutions of 6 to create solutions that were 50 mM or 10 mM in
diethylenetriamine led to the elimination of all peaks for 6 by
the next day and after about 6 days (t1/2 ∼28 h), respectively. In
1
also showed complete dissolution (observed visibly and by H
NMR spectroscopy) of 6 in a 450 μL:20 μL of D2O/DMSO
mixture (95.7%:4.3%). In contrast, similar NMR experiments
carried out using the previously reported [Re-
(CO)3(N(SO2Me)dpa)]PF6 complex35 show that even the
[Re(CO)3(N(SO2R)dpa)]PF6 complex having the smallest R
group is insoluble in D2O or in D2O/DMSO (95.7%:4.3%).
1
both cases, the final H NMR spectrum exhibits peaks for the
N(SO2tol)dien ligand (3) and for the known [Re(CO)3(N(H)-
dien)]PF6 complex.46 No signals indicating any intermediates
were observed. The complete displacement of the coordinated
N(SO2tol)dien ligand of 6 by 10 mM diethylenetriamine
establishes that although the Re−N bonds involving the central
donor of N(SO2R)dien ligands have normal lengths, the donor
ability of the central sulfonamide nitrogen atom is lower than
that of the central nitrogen atom of diethylenetriamine.
SUMMARY AND CONCLUSIONS
■
From the present results with [Re(CO)3(N(SO2R)dien)]PF6
complexes, in which the chelate rings are less rigid, we conclude
that the M−N bond of normal length observed was not a result
of the rigid tridentate framework in the [Re(CO)3(N(SO2R)-
dpa)]X35 complexes. In both series of complexes, the methyl
13C NMR signal of the R = Me member of the series exhibited a
very unusual upfield shift for an aliphatic carbon signal upon
coordination of the ligand. This result, attributed to the similar
sp2-to-sp3 rehybridization of the sulfonamide N upon
coordination to ReI in both series of complexes, further
establishes that coordination of the sulfonamide N is not
influenced by the rigidity of the N(SO2R)dpa chelate rings. The
decomposition of the [Re(CO)3(N(SO2R)dpa)]X complexes
by base35 led us to hypothesize that base was attacking the
coordinated N(SO2R)dpa ligand, most likely by deprotonating
the CH2 group, and that the low electrophilicity of the Z =
CH2NH2 group of the N(CH2CH2NH2)2 framework would
confer stability toward base. The stability of the new
[Re(CO)3(N(SO2R)dien)]PF6 complexes toward base sup-
ports these hypotheses and allowed us to conduct a challenge
reaction study with the basic N(H)dien ligand. N(H)dien
replaced the coordinated N(SO2tol)dien ligand in [Re-
(CO)3(N(SO2tol)dien)]PF6, indicating that the neutral
sulfonamide N central donor in N(SO2tol)dien is a somewhat
weaker donor than the central traditional sp3 N donor in
N(H)dien. Nevertheless, the new [Re(CO)3(N(SO2R)dien)]-
PF6 complexes are long-lived, even in the presence of base, and
are relatively robust to heat treatment. As expected, the
moderately hydrophilic character of the Z = CH2NH2 group of
the N(CH2CH2NH2)2 framework also confers water solubility
on the [Re(CO)3(N(SO2R)dien)]PF6 complexes. The aqueous
solubility of the new ligands and complexes is much higher than
necessary for radiopharmaceutical kit formulation. Also, there
are perceived advantages in using small chelate ligands when
constructing bioconjugates, and the N(CH2CH2NH2)2 frame-
work is relatively small. Thus, the results obtained here suggest
that N(SO2R)dien ligands should be explored in the develop-
ment of radiopharmaceuticals, including bioconjugates.
A related study38 was reported for the neutral Re-
(CO)3(tmbSO2-dien) complex. The coordinated unsymmet-
rical monoanionic NNN donor ligand, tmbSO2-dien− (Chart
2), employed in that study has a 2,4,6-trimethylbenzenesulfonyl
Chart 2. tmbSO2-dien− Monoanionic Ligand.38
(tmbSO2) group linked to one of the terminal N atoms of
diethylenetriamine. The terminal donor of the free ligand prior
to coordination is a secondary sulfonamide of the type
(RSO2)R′NH. When 10 molar equiv of diethylenetriamine
was added to a solution of Re(CO)3(tmbSO2-dien) (3 mM,
DMSO-d6), no coordinated tmbSO2-dien− ligand was dis-
placed, even after the solution was heated at ∼60 °C.38 Thus,
the deprotonated monoanionic tmbSO2-dien− ligand is clearly a
better ligand than neutral N(SO2tol)dien.
If the central tertiary sulfonamide donor in N(SO2tol)dien
were coordinated weakly enough to the Re in [Re-
(CO)3(N(SO2R)dien)]PF6 complexes, a good monodentate
ligand might be able to substitute for the coordinated
sulfonamide group. Therefore, we conducted a challenge
experiment in which the strongly basic, potentially mono-
dentate 4-Me2Npy ligand was added to [Re(CO)3(N(SO2tol)-
1
dien)]PF6 (6). No H NMR spectral changes were observed
over many days, even with a 10-fold excess of 4-Me2Npy. Such
evidence indicates that the central sulfonamide bond is strong
enough to stay coordinated to Re, even in the presence of an
excess of a strong monodentate ligand. Also, the results show
that the [Re(CO)3(N(SO2tol)dien)]PF6 complex is resistant to
strong base, an advantage over [Re(CO)3(N(SO2Me)dpa)]PF6,
which decomposes readily in the presence of base.35
Solubility of [Re(CO)3(N(SO2tol)dien)]PF6 (6) in Water.
A mixture of 5 mg of [Re(CO)3(N(SO2tol)dien)]PF6 (6) and
450 μL of D2O gave a clear solution when heated in a boiling
water bath for 30 min. The 1H NMR spectrum of this solution,
which compares favorably with spectra of 6 in other solvents
(Figure 4), has four methylene multiplets, whereas the
N(SO2tol)dien ligand has two methylene triplets in D2O.
These results established that 6 dissolved unchanged to an
ASSOCIATED CONTENT
■
S
* Supporting Information
Crystallographic data for [Re(CO)3(N(SO2Me)dien)]PF6 (4)
and [Re(CO)3(N(SO2tol)dien)]PF6 (6), in CIF format; figure
illustrating overlay of the Re, C1, C2, and C3 atoms of 6 and
1
[Re(CO)3(N(Me)dien)]PF6; H NMR spectra of ligands 1−3
in CDCl3; 1H NMR spectra of 1 and 4 in DMSO-d6; 1H NMR
spectra of [Re(CO)3(N(SO2R)dien)]PF6 complexes (4−6) in
acetonitrile-d3; COSY spectrum of 6 in acetone-d6; ROESY
spectrum of 6 in acetone-d6; 13C NMR spectrum of 6 and
assignment of 13C NMR signals of 6 in acetone-d6; aromatic
J
dx.doi.org/10.1021/ic4026987 | Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
(22) Alberto, R.; Schibli, R.; Schubiger, A. P.; Abram, U.; Pietzsch, H.
J.; Johannsen, B. J. Am. Chem. Soc. 1999, 121, 6076−6077.
(23) He, H.-Y.; Lipowska, M.; Xu, X.; Taylor, A. T.; Marzilli, L. G.
Inorg. Chem. 2007, 46, 3385−3394.
region of the HMBC spectrum of 6 in acetone-d6; HSQC
spectrum of 6 in acetone-d6; and a comparison of 13C NMR
shifts of ligands (1 and 3) and complexes (4 and 6) in
acetonitrile-d3. This material is available free of charge via the
Internet at http://pubs.acs.org.
(24) He, H.-Y.; Lipowska, M.; Christoforou, A. M.; Marzilli, L. G.;
Taylor, A. T. Nucl. Med. Biol. 2007, 34, 709−716.
(25) Kyprianidou, P.; Tsoukalas, C.; Chiotellis, A.; Papagiannopolu,
D.; Raptopolou, C. P.; Terzis, A.; Pelecanou, M.; Papadopoulos, M.;
Pirmettis, I. Inorg. Chim. Acta 2011, 370, 236−242.
AUTHOR INFORMATION
■
Corresponding Author
(26) Boros, E.; Hafeli, U. O.; Patrick, B. O.; Adam, M. J.; Orvig, C.
̈
*E-mail: lmarzil@lsu.edu.
Bioconjugate Chem. 2009, 20, 1002−1009.
Notes
(27) Klenc, J.; Lipowska, M.; Marzilli, L. G.; Taylor, A. T. Eur. J.
Inorg. Chem. 2012, 4334−4344.
The authors declare no competing financial interest.
(28) Schibli, R.; Schwarzbach, R.; Alberto, R.; Ortner, K.; Schmalle,
H.; Dumas, C.; Egli, A.; Schubiger, P. A. Bioconjugate Chem. 2002, 13,
750−756.
ACKNOWLEDGMENTS
■
This work was supported in part by the National Institutes of
Health (R37 DK038842-22). An upgrade of the diffractometer
was made possible by Grant No. LEQSF (2011−2012)-ENH-
TR-01, administered by the Louisiana Board of Regents.
L.G.M. thanks the RAYMOND F. SCHINAZI INTERNA-
TIONAL EXCHANGE PROGRAMME between the Univer-
sity of Bath, U.K., and Emory University, Atlanta, GA, U.S.A.,
for a Faculty Fellowship.
(29) Xia, J.; Wang, Y.; Li, G.; Yu, J.; Yin, D. J. Radioanal. Nucl. Chem.
2009, 279, 245−252.
(30) Banerjee, S. R.; Levadala, M. K.; Lazarova, N.; Wei, L.; Valliant,
J. F.; Stephenson, K. A.; Babich, J. W.; Maresca, K. P.; Zubieta, J. Inorg.
Chem. 2002, 41, 6417−6425.
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Johannsen, B. Bioconjugate Chem. 2000, 11, 414−424.
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