Formation of a metal-to-nitrogen bond of normal length by a neutral sufonamide group within a tridentate ligand. A new approach to radiopharmaceutical bioconjugation

Article abstract of DOI:10.1021/ic302180t

We demonstrate that a tertiary sulfonamide group, N(SO₂R) R′₂, can rehybridize to form a M-N bond of normal length even when the group is in a linear tridentate ligand, such as in the new tridentate N(SO₂R)dpa ligands derived from di-(2-picolyl)amine (N(H)dpa). N(SO₂R)dpa ligands were used to prepare fac-[Re(CO) ₃(N(SO₂R)dpa)](PF₆ or BF₄) complexes. Structural characterization of the new complexes established that the tertiary sulfonamide nitrogen atom binds to Re with concomitant sp ²-to-sp³ rehybridization, facilitating facial coordination. The new fac-[Re(CO)₃(N(SO₂R)dpa)]X structures provide the only examples for any metal with the sulfonamide as part of a noncyclic linear tridentate ligand and with a normal metal-to- nitrogen(tertiary sulfonamide) bond length. Rare previous examples of such normal M-N bonds have been found only in more constrained situations, such as with tripodal tetradentate ligands. Our long-term objectives for the new tridentate N(SO₂R)dpa ligands are to develop the fundamental chemistry relevant to the eventual use of the fac-[M^I(CO) ₃]⁺ core (M = ^99mTc, ^186/188Re) in imaging and therapy. The sulfonamide group uniquely contributes to two of our goals: expanding ways to conjugate the fac-[M^I(CO)₃] ⁺ core to biological molecules and also developing new symmetrical tridentate ligands that can coordinate facially to this core. Tests of our conjugation method, conducted by linking the fac-[Re^I(CO) ₃]⁺ core to a new tetraarylporphyrin (T(N(SO ₂C₆H₄)dpa)P) as well as to a dansyl (5-(dimethylamino)naphthalene-1-sulfonyl) group, demonstrate that large molecular fragments can be tethered via a coordinated tertiary sulfonamide linkage to this core.

Full text of DOI:10.1021/ic302180t

Article
pubs.acs.org/IC
Formation of a Metal-to-Nitrogen Bond of Normal Length by a
Neutral Sufonamide Group within a Tridentate Ligand. A New
Approach to Radiopharmaceutical Bioconjugation
Theshini Perera, Pramuditha 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: We demonstrate that a tertiary sulfonamide group,
N(SO2R)R′2, can rehybridize to form a M−N bond of normal
length even when the group is in a linear tridentate ligand, such
as in the new tridentate N(SO2R)dpa ligands derived from di-(2-
picolyl)amine (N(H)dpa). N(SO2R)dpa ligands were used to
prepare fac-[Re(CO)3(N(SO2R)dpa)](PF6 or BF4) complexes.
Structural characterization of the new complexes established that
the tertiary sulfonamide nitrogen atom binds to Re with
concomitant sp2-to-sp3 rehybridization, facilitating facial coordi-
nation. The new fac-[Re(CO)3(N(SO2R)dpa)]X structures
provide the only examples for any metal with the sulfonamide
as part of a noncyclic linear tridentate ligand and with a normal
metal-to-nitrogen(tertiary sulfonamide) bond length. Rare
previous examples of such normal M−N bonds have been found only in more constrained situations, such as with tripodal
tetradentate ligands. Our long-term objectives for the new tridentate N(SO2R)dpa ligands are to develop the fundamental
chemistry relevant to the eventual use of the fac-[MI(CO)3]+ core (M = 99mTc, 186/188Re) in imaging and therapy. The
sulfonamide group uniquely contributes to two of our goals: expanding ways to conjugate the fac-[MI(CO)3]+ core to biological
molecules and also developing new symmetrical tridentate ligands that can coordinate facially to this core. Tests of our
conjugation method, conducted by linking the fac-[ReI(CO)3]+ core to a new tetraarylporphyrin (T(N(SO2C6H4)dpa)P) as well
as to a dansyl (5-(dimethylamino)naphthalene-1-sulfonyl) group, demonstrate that large molecular fragments can be tethered via
a coordinated tertiary sulfonamide linkage to this core.
serving as models that allow insight into the chemistry and
biomedical characteristics of these short-lived radioactive 99mTc
imaging agents.4,15−20
INTRODUCTION
■
Improved methods of ligand design are needed for the
synthesis of radiopharmaceuticals containing the fac-
Symmetrical linear tridentate ligands that do not induce
asymmetry at the metal center are desirable for avoiding
racemic or diastereoisomeric mixtures of radiopharmaceuticals.
For example, di-(2-picolyl)amine (N(H)dpa) forms a sym-
metrical complex, fac-[Re(CO)3(N(H)dpa)]X.21 Promising
biomedical properties have been reported for fac-[Re-
(CO)3(N(R)dpa)]n complexes bearing a substituent linked by
a C−N bond at the central sp3 N, replacing the amine proton of
N(H)dpa.10,22,23 In referring to such ligands in this article, we
use N(substituent)dpa, with the italic N designating the central
nitrogen. Ligand design requires that the central donor of the
tridentate ligand, such as the central sp3 N in N(H)dpa or
N(R)dpa, accommodates facial coordination. A thioether sulfur
atom achieves this geometry,16,24,25 but substituents imparting
[
99mTcI(CO)3]+ core; such agents have received widespread
attention in the past two decades.1−6 Many factors have
contributed to this interest, including the convenient
generation of the fac-[99mTc(CO)3(H2O)3]+ precursor,7,8 the
stability and kinetic inertness of fac-[99mTc(CO)3L]n imaging
agents when L is a facially coordinated tridentate ligand,1,4,9 and
the potential that novel ligands bound to this core will lead to
agents with new or superior clinical utility.10 Such fac-
[
99mTc(CO)3L]n agents have been shown to possess desirable
biological characteristics in human volunteers,4,11 with fac-
99mTc(CO)3(NTA)]2‑ (NTA = nitrilotriacetate)11 showing
[
promise as a renal imaging agent in early patient studies.12
Historically, the study of nonradioactive Re analogues has
played an important role in guiding ligand design and in
providing a basis for understanding the chemistry of 99mTc
diagnostic agents and 186/188Re therapeutic agents.1,13,14 Like-
wise, many fac-[Re(CO)3L]n analogues have more recently
facilitated the fac-[99mTc(CO)3L]n biomedical studies by
Received: October 6, 2012
© XXXX American Chemical Society
A
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Scheme 1. Synthesis of fac-[Re(CO)3(N(SO2R)dpa)]+
Complexes
desirable biodistribution or targeting characteristics cannot be
attached at a central sulfur donor atom.
Full exploitation of the fac-[MI(CO)3]+ (M = 99mTc, Re)
core relies on new types of tridentate ligands and ligand
conjugation methods.8,21,23 In this study, we explore con-
jugation utilizing an N−S bond by preparing new N(SO2R)dpa
ligands (R = Me, tmb, dmb, and Me2Nnap; see Figure 1 for
agents in humans because the more traditional peptides
coordinate with a deprotonated nitrogen, which enforces the
meridional coordination mode.4 The sulfonamide group
explored here has an additional advantage over the thioether
or peptide N-donor groups in being able to serve as a juncture
point for conjugation. We validated the versatility of the
sulfonamide method by conjugating the dansyl group or a
tetraarylporphyrin biological targeting group to the fac-
[ReI(CO)3]+ core. (From this point on, we omit the fac-
designation when discussing specific compounds because all
compounds have this geometry.)
Figure 1. Ligands mentioned or used in this study: di(2-picolyl)amine
(N(H)dpa); N,N-di(2-picolyl)methanesulfonamide (N(SO2Me)dpa);
N,N-di(2-picolyl)-2,4,6-trimethylbenzenesulfonamide (N(SO2tmb)-
dpa); N,N-di(2-picolyl)-3,5-dimethylbenzenesulfonamide
(N(SO2dmb)dpa); N,N-di(2-picolyl)-4-methylbenzenesulfonamide
(N(SO2tol)dpa); and N,N-di(2-picolyl)-5-(dimethylamino)-
naphthalene-1-sulfonamide (N(SO2Me2Nnap)dpa).
EXPERIMENTAL SECTION
ligand sketches and abbreviations). We show that treatment of
fac-[Re(CO)3(H2O)3]+ with such open-chain tridentate
N(SO2R)dpa ligands affords fac-[Re(CO)3(N(SO2R)dpa)]X
complexes (Scheme 1), although the central N-donor atom is
part of a tertiary sulfonamide group (N(SO2R)R′2). X-ray
structural characterization shows that this nitrogen atom is a
strong donor to Re. Our study of fac-[Re(CO)3(N(SO2R)-
dpa)]X complexes provides the only examples of structurally
characterized complexes with a tertiary neutral sulfonamide
donor bound to the fac-[ReI(CO)3]+ core. Furthermore, these
compounds are the only examples of metal complexes in which
any such open-chain tertiary sulfonamide linear tridentate
ligand possesses a M−N(sulfonamide) bond of normal length,
regardless of the metal center. Indeed, these are among the very
few crystallographically characterized complexes containing
tertiary sulfonamide N donors with any metal.26−33 In
previously reported sulfonamide complexes, the bound
sulfonamide is either constrained within a ring system or has
elongated bonds.26−33
In the design of new ligands, the nature of the geometric
constraints induced by the central donor atoms is an important
factor. The ligand should be able to coordinate facially. As an
example, the propensity of thioethers to enforce a facial
coordination mode34,35 was utilized in designing renal agents,
including agents bearing lanthionine dipeptide ligands.4,16,17,36
These NSN-donor dipeptides with amino acids linked via a
thioether group were used to study small fac-[99mTc(CO)3L]n
■
Starting Materials. Methanesulfonyl chloride (MeSO2Cl), 2,4,6-
trimethylbenzenesulfonyl chloride (tmbSO2Cl), 3,5-dimethylbenzene-
sulfonyl chloride (dmbSO2Cl), 4-methylbenzenesulfonyl chloride
(tolSO2Cl), 5-(dimethylamino)naphthalene-1-sulfonyl chloride
(Me2NnapSO2Cl, dansyl chloride), di-(2-picolyl)amine (N(H)dpa),
and Re2(CO)10 were used as received from Aldrich. [Re-
(CO)3(H2O)3]OTf (OTf = trifluoromethanesulfonate) was prepared
by a known method.36 [Re(CO)3(CH3CN)3]BF4 and meso-tetrakis(4-
chlorosulfonylphenyl)porphyrin (TClSO2PP) were synthesized as
described elsewhere,37,38 and their 1H NMR spectra were in agreement
with those reported.
NMR Measurements. 1H NMR spectra were recorded on a
Bruker 400 MHz spectrometer. Peak positions are relative to
tetramethylsilane (TMS) or solvent residual peak with TMS as
reference. All NMR data were processed with TopSpin and Mestre-C
software.
X-ray Data Collection and Structure Determination. Intensity
data were collected at low temperature on a Nonius Kappa CCD
diffractometer fitted with an Oxford Cryostream cooler and graphite-
monochromated Mo Kα (λ = 0.71073 Å) radiation. Data were
collected at 90 K for 1 and 2, but for 4 (T = 200 K) and 5 (T = 220
K), higher temperatures were chosen to avoid phase changes that
occurred with twinning. Data reduction included absorption
corrections by the multiscan method, using HKL SCALEPACK.39
All X-ray structures were determined by direct methods and difference
Fourier techniques and refined by full-matrix least-squares by using
SHELXL97.40 All non-hydrogen atoms were refined anisotropically.
All H atoms except those on water molecules in 2 and 5 were visible in
difference maps, but were placed in idealized positions. Those on
B
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Figure 2. ORTEP plots of the cations in [Re(CO)3(N(SO2Me)dpa)]PF6 (1), [Re(CO)3(N(SO2tmb)dpa)]PF6 (2), [Re(CO)3(N(SO2tol)dpa)]PF6
(4), and [Re(CO)3(N(SO2Me2Nnap)dpa)]BF4 (5). Thermal ellipsoids are drawn with 50% probability.
water were not located and are likely disordered. A torsional parameter
was refined for each methyl group. For 1, the PF6 anion was
in the asymmetric unit, only one of which is shown in Figure 2. Crystal
data and refinement details are included in Table 1.
−
Synthesis of [Re(CO)3L]PF6 and [Re(CO)3L]BF4 Complexes.
The following general procedure was employed to obtain the
N(SO2R)dpa ligands: a solution of the sulfonyl chloride (0.9−1.5 g,
5 mmol) in 25 mL of dioxane was added dropwise over a period of 2 h
to a solution of N(H)dpa (1.80 mL, 10 mmol) in 100 mL of dioxane
disordered into two positions treated with equal populations. For 5,
the BF4 anion site exhibited both substitutional and orientational
−
disorder. The site was occupied by bromide with 6.8(3)% population,
−
and the BF4 had two orientations with relative population
59(3):34(3)%. Structure 2 contains two independent formula units
C
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Table 1. Crystal Data and Structure Refinement for [Re(CO)3(N(SO2Me)dpa)]PF6 (1), [Re(CO)3(N(SO2tmb)dpa)]PF6 (2),
[Re(CO)3(N(SO2tol)dpa)]PF6 (4), and [Re(CO)3(N(SO2Me2Nnap)dpa)]BF4 (5)
a
1
2
4
5
empirical formula
fw
C16H15N3O5ReS·PF6
692.54
C24H23N3O5ReS·PF6·H2O
814.70
C22H19N3O5ReS·PF6
768.63
C27H24N4O5ReS·0.93(BF4)·0.07(Br)·4H2O
861.58
crystal system
space group
unit cell dimensions
a (Å)
monoclinic
C2/c
triclinic
monoclinic
C2/c
monoclinic
C2/c
P1
̅
20.549(2)
20.297(2)
12.5771(10)
90
14.353(2)
15.010(2)
16.028(3)
110.298(8)
115.806(7)
96.429(9)
2770.6(7)
90
15.102(2)
10.4922(15)
34.186(4)
90
33.684(4)
8.1471(10)
23.635(3)
90
b (Å)
c (Å)
α (deg)
β (deg)
123.039(4)
90
100.598(4)
90
97.278(6)
90
γ (deg)
V (Å3)
4397.5(7)
90
5324.5(12)
200
6433.8(14)
220
T (K)
Z
8
4
8
8
ρcalc (g/cm3)
2.092
1.953
1.918
1.779
abs coeff (mm−1
)
5.78
4.61
4.78
4.01
2θmax (deg)
71.2
55.8
55.0
52.2
b
R
[I > 2σ(I)]
0.026
0.048
0.029
0.037
c
wR2
res. dens (e Å−3
0.055
0.105
0.087
0.088
)
−1.36, 1.58
10038/332
−1.29, 1.41
13140/764
−1.10, 1.20
5756/353
−0.96, 1.09
6317/456
data/param
a
−
The asymmetric unit of 1 contains one [Re(CO)3(N(SO2Me)dpa)]+ cation and half of two crystallographically independent PF6 anions; one
b
c
anion lies on an inversion center, and the other anion lies on a 2-fold axis and is disordered. R = (∑||Fο| − |Fc||)/∑|Fο|. wR2 = [∑[w(Fο2 − Fc2)2]/
∑[w(Fο )2]]1/2, in which w = 1/[σ2(Fο ) + (dP)2 + (eP)] and P = (Fο + 2Fc2)/3; d = 0.021, 0.0463, 0.041, and 0.0399, and e = 0.6452, 0, 0, and
2
2
2
2.129 for 1, 2, 4, and 5, respectively.
at 20 °C. The reaction mixture was stirred at room temperature for 24
h and then filtered to remove any precipitate before the dioxane was
completely removed by rotary evaporation. Water (30 mL, pH ∼5)
was added to the resulting oil, and the product was extracted into
CH2Cl2 (2 × 25 mL). The CH2Cl2 extracts were combined, washed
with water (2 × 25 mL), and taken to dryness to yield an oil, which
was used to synthesize [Re(CO)3L]PF6 and [Re(CO)3L]BF4 in the
general procedure outlined here. The preparation utilized 0.1 mmol of
the reactants. An aqueous solution of the ligand (0.1 mmol in 2 mL)
was treated with aqueous [Re(CO)3(H2O)3]+ (0.1 mmol in 3 mL).
Methanol (2−3 mL) was added to dissolve any precipitate that
formed, and the clear reaction mixture was heated at reflux for 12 h. A
slight excess of NaPF6 or NaBF4 was added to the clear solution, and
the resulting precipitate was collected on a filter, washed with water,
and air-dried. (If the pH of the final reaction mixture was below 6, it
was adjusted to 7 before the addition of NaPF6 or NaBF4. For
N(SO2tmb)dpa and N(SO2Me2Nnap)dpa, methanol (∼1 mL) was
used initially to dissolve the ligand).
[Re(CO)3(N(SO2Me)dpa)]PF6 (1). The general ligand preparative
method described above, with MeSO2Cl (0.39 mL) and N(H)dpa
(1.80 mL), yielded the crude N(SO2Me)dpa ligand as a deep red oil
(1.40 g, 76% yield). 1H NMR signals (ppm) in DMSO-d6: 8.50 (d, J =
6.5 Hz, 2H, H6/6′), 7.75 (t, J = 7.6 Hz, 2H, H4/4′), 7.34 (d, J = 7.8
Hz, 2H, H3/3′), 7.27 (t, J = 6.5 Hz, 2H, H5/5′), 4.48 (s, 4H, CH2),
3.11 (s, 3H, CH3). In the 0.1 mmol preparative method described
above, N(SO2Me)dpa (28 mg) was used. [Re(CO)3(N(SO2Me)-
dpa)]PF6 formed as a white precipitate (38 mg, 54% yield) after the
addition of NaPF6 (∼15 mg). Slow evaporation of a solution of this
compound in acetone produced colorless, needle-like crystals that
were characterized crystallographically. 1H NMR signals (ppm) in
DMSO-d6: 8.89 (d, J = 5.4 Hz, 2H, H6/6′), 8.09 (t, J = 6.7 Hz, 2H,
H4/4′), 7.57 (d, 2H, H3/3′), 7.53 (t, J = 6.5 Hz, 2H, H5/5′), 5.44 (d,
J = 15.8 Hz, 2H, CH2), 5.13 (d, J = 15.8 Hz, 2H, CH2), 3.87 (s, 3H,
CH3).
signals (ppm) in DMSO-d6: 8.43 (d, J = 6.4 Hz, 2H, H6/6′), 7.65 (t, J
= 7.9 Hz, 2H, H4/4′), 7.22 (t, J = 6.1 Hz, 2H, H5/5′), 7.09 (d, J = 7.8
Hz, 2H, H3/3′), 6.97 (s, 2H, H3/5), 4.53 (s, 4H, CH2), 2.53 (s, 6H,
CH3), 2.23 (s, 3H, CH3). In the 0.1 mmol preparative method,
N(SO2tmb)dpa (38 mg) afforded [Re(CO)3(N(SO2tmb)dpa)]PF6 as
a white precipitate (51 mg, 64% yield) after the addition of NaPF6
(∼15 mg). Slow evaporation of a solution of the compound in CHCl3
produced colorless, block-shaped crystals that were characterized
crystallographically. 1H NMR signals (ppm) in DMSO-d6: 8.90 (d, J =
5.4 Hz, 2H, H6/6′), 8.05 (t, J = 7.8 Hz, 2H, H4/4′), 7.64 (d, J = 7.8
Hz, 2H, H3/3′), 7.49 (t, J = 6.6 Hz, 2H, H5/5′), 7.46 (s, 2H, H3/5),
5.22 (d, J = 15.9 Hz, 2H, CH2), 4.53 (d, J = 15.9 Hz, 2H, CH2), 2.78
(s, 6H, CH3), 2.43 (s, 3H, CH3).
[Re(CO)3(N(SO2dmb)dpa)]BF4 (3). The general method described
above, with dmbSO2Cl (1.02 g) and N(H)dpa (1.80 mL), yielded
1
N(SO2dmb)dpa as a pale orange oil (1.45 g, 86% yield). H NMR
signals (ppm) in DMSO-d6: 8.37 (d, J = 5.6 Hz, 2H, H6/6′), 7.67 (t, J
= 6.8 Hz, 2H, H4/4′), 7.35 (s, 2H, H2/6), 7.28 (d, J = 7.8 Hz, 2H,
H3/3′), 7.21 (s, 1H, H4), 7.19 (t, J = 5.9 Hz, 2H, H5/5′), 4.54 (s, 4H,
CH2), 2.29 (s, 6H, CH3). In the 0.1 mmol preparative method,
N(SO2dmb)dpa (37 mg) afforded [Re(CO)3(N(SO2dmb)dpa)]BF4 as
a white precipitate (55 mg, 67% yield) after the addition of NaBF4
1
(∼15 mg). H NMR signals (ppm) in DMSO-d6: 8.88 (d, J = 5.4 Hz,
2H, H6/6′), 8.02 (t, J = 7.7 Hz, 2H, H4/4′), 7.96 (s, 2H, H2/6), 7.72
(s, 1H, H4), 7.51 (d, J = 8.4 Hz, 2H, H3/3′), 7.46 (t, J = 6.4 Hz, 2H,
H5/5′), 5.25 (d, J = 16.2 Hz, 2H, CH2), 4.55 (d, J = 16.2 Hz, 2H,
CH2), 2.51 (s, 6H, CH3, overlap with solvent residual peak). Anal.
Calcd for C23H21BF4N3O5ReS: C, 38.10; H, 2.92; N, 5.80. Found: C,
37.87; H, 2.83; N, 5.88.
[Re(CO)3(N(SO2tol)dpa)]PF6 (4). The general method described
above, with tolSO2Cl (0.95 g) and N(H)dpa (1.80 mL), yielded
1
N(SO2tol)dpa as a deep brown oil (1.52 g, 86% yield). H NMR
signals (ppm) in DMSO-d6: 8.35 (d, J = 4.8 Hz, 2H, H6/6′), 7.70 (d, J
= 8.2 Hz, 2H, H2/6), 7.65 (t, J = 7.7 Hz, 2H, H4/4′), 7.36 (d, J = 8.0
Hz, 2H, H3/5), 7.25 (d, J = 7.8 Hz, 2H, H3/3′), 7.19 (t, J = 4.9 Hz,
2H, H5/5′), 4.49 (s, 4H, CH2), 2.39 (s, 3H, CH3). In the 0.1 mmol
preparative method, N(SO2tol)dpa (35 mg) afforded [Re-
[Re(CO)3(N(SO2tmb)dpa)]PF6 (2). The general method described
above, with tmbSO2Cl (1.10 g) and N(H)dpa (1.80 mL), yielded
1
N(SO2tmb)dpa as a pale orange oil (1.75 g, 92% yield). H NMR
D
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Scheme 2. Synthesis of T(N(SO2C6H4)dpa)P
(CO)3(N(SO2tmb)dpa)]PF6 as a white precipitate (50 mg, 65% yield)
after the addition of NaPF6 (∼15 mg). Slow evaporation of a solution
of the compound in CHCl3 produced colorless, block-shaped crystals
that were characterized crystallographically. 1H NMR signals (ppm) in
DMSO-d6: 8.87 (d, J = 5.4 Hz, 2H, H6/6′), 8.21 (d, J = 8.4 Hz, 2H,
H2/6), 8.02 (t, J = 7.8 Hz, 2H, H4/4′), 7.76 (d, J = 8.4 Hz, 2H, H3/
5), 7.48 (d, J = 7.9 Hz, 2H, H3/3′), 7.47 (t, 2H, H5/5′), 5.58 (d, J =
16.0 Hz, 2H), 4.53 (d, J = 16.0 Hz, 2H), 2.57 (s, 3H, CH3).
then reduced to dryness by rotary evaporation. The maroon residue
obtained was quickly washed with CH2Cl2, dissolved in acetone, and
the resultant solution layered with hexane to give a maroon precipitate
(15 mg, 40% yield). 1H NMR signals (ppm) in DMSO-d6: 9.19 (s, 8H,
βH), 9.01 (d, J = 5.4 Hz, 8H, H6/6′), 8.84 (s, 16H, o and mH), 8.14
(t, J = 7.9 Hz, 8H, H4/4′), 7.71 (d, J = 8.0 Hz, 8H, H3/3′), 7.58 (t, J =
6.8 Hz, 8H, H5/5′), 5.98 (d, J = 16.4 Hz, 8H, CH2), 4.97 (d, J = 16.4
Hz, 8H, CH2), −2.81 (s, 2H, NH).
[Re(CO)3(N(SO2Me2Nnap)dpa)]BF4 (5). The general method
described above, with dansyl chloride (1.42 g) and N(H)dpa (1.8
mL), yielded N(SO2Me2Nnap)dpa as a pale orange oil (1.96 g, 91%
yield). 1H NMR signals (ppm) in DMSO-d6: 8.44 (d, J = 8.5 Hz, 1H),
8.37 (d, J = 4.5 Hz, 2H, H6/6′), 8.20 (d, J = 8.6 Hz, 1H), 8.16 (d, J =
7.3 Hz, 1H), 7.58 (t, 2H, H4/4′), 7.54 (m, 2H), 7.23 (d, J = 7.6 Hz,
1H), 7.18 (t, 2H, H5/5′), 7.12 (d, J = 7.8 Hz, 2H, H3/3′), 4.72 (s, 4H,
CH2), 2.82 (s, 6H, CH3). In the 0.1 mmol preparative method,
N(SO2Me2Nnap)dpa (43 mg) afforded [Re(CO)3(N(SO2Me2Nnap)-
dpa)]BF4 as yellow block-like crystals (38 mg, 44% yield) after the
addition of NaBF41 (∼15 mg). The product was characterized
crystallographically. H NMR signals (ppm) in DMSO-d6: 8.90 (m,
3H), 8.71 (d, J = 7.7 Hz, 1H), 8.58 (d, J = 8.7 Hz, 1H), 7.98 (t, J = 8.1
Hz, 2H, H4/4′), 7.92 (t, J = 7.9 Hz, 1H), 7.78 (t, J = 8.2 Hz, 1H), 7.47
(t, J = 6.6 Hz, 2H, H5/5′), 7.42 (d, J = 7.6 Hz, 2H, H3/3′), 7.39 (d, J
= 7.9 Hz, 1H), 5.64 (d, J = 15.7 Hz, 2H), 4.53 (d, J = 15.8 Hz, 2H,
CH2), 2.91 (s, 6H, CH3).
RESULTS AND DISCUSSION
■
Synthesis of N(SO2R)dpa and [Re(CO)3(N(SO2R)dpa)]X
(X = PF6 or BF4). Potentially tridentate ligands with R = Me,
tmb, dmb, tol, and Me2Nnap groups at the central N (Figure 1)
were synthesized in good yield by coupling N(H)dpa with the
relevant sulfonyl chloride. NMR spectral data indicated that the
products were uncontaminated with byproducts and could be
used without further purification (cf. Experimental Section and
Supporting Information, Figure S1). Aqueous [Re-
(CO)3(H2O)3 ]OTf36 was used to prepare [Re-
(CO)3(N(SO2R)dpa)]X complexes 1−5 (Scheme 1). NMR
spectra of the new complexes are illustrated below or in the
Supporting Information, Figure S2. No change was observed in
the 1H NMR signals of 1 and 4 (5 mM, DMSO-d6), even after
6 months.
Synthesis of the Porphyrin, T(N(SO2C6H4)dpa)P, and
the 4:1 Re Adduct, [[Re(CO)3]4T(N(SO2C6H4)dpa)P](BF4)4.
We have utilized our synthetic approach reported for
T(R1R2NSO2C6H4)P [R1 = N-py-n-CH2 (n = 2 or 4) and R2
= alkyl)]41 to prepare T(N(SO2C6H4)dpa)P, a porphyrin
bearing four tertiary N(SO2)dpa moieties (Scheme 2). Because
the porphyrin is not soluble in water, we employed the
[Re(CO)3(CH3CN)3]BF4 precursor37 to form [[Re(CO)3]4T-
(N(SO2C6H4)dpa)P](BF4)4. In this 4:1 adduct, each fac-
[ReI(CO)3]+ moiety is coordinated to three N-donor atoms
(of a peripheral tertiary dpa moiety) linked to the porphyrin
aryl group. In previous work, Alessio and co-workers utilized
the [Re(CO)3(DMSO)3]+ precursor to synthesize [Re-
(CO)3(bipyridine)(DMSO)]+,42 which was then used to
prepare 1:1 and 4:1 adducts between ReI(CO)3(bipyridine)
T(N(SO2C6H4)dpa)P. A solution of TClSO2PP (0.4 g, 0.39 mmol) in
CH2Cl2 (50 mL) was treated with N(H)dpa (3.7 mL, 1.98 mmol), and
the reaction mixture was stirred at room temperature for 24 h.
Impurities in this mixture were then extracted with water (3 × 25 mL);
the organic layer was dried over anhydrous Na2SO4 and the solvent
removed under vacuum. The purple residue was crystallized from
CH2Cl2/hexane, and the purple crystals were washed with hexane
(0.32 g, 49% yield). 1H NMR signals (ppm) in DMSO-d6: 8.87 (s, 8H,
βH), 8.55 (d, J = 4.1 Hz, 8H, H6/6′), 8.37 (d, J = 8.3 Hz, 8H, oH),
8.24 (d, J = 8.4 Hz, 8H, mH), 7.83 (t, 8H, H4/4′), 7.49 (d, J = 7.9 Hz,
8H, H3/3′), 7.34 (t, J = 6.2 Hz, 8H, H5/5′), 4.90 (s, 16H, CH2),
−2.96 (s, 2H, NH). ESI-MS (m/z): [M + H]+ = 1660.4881, [M +
2H]2+ = 830.7465. Calcd for [M + H]+ = 1660.4886, [M + 2H]2+
830.7443.
=
[[Re(CO)3]4T(N(SO2C6H4)dpa)P](BF4)4 (6). [Re(CO)3(CH3CN)3]-
BF4 (28 mg, 0.058 mmol) was added to a solution of T(N(SO2C6H4)-
dpa)P (20 mg, 0.012 mmol) in a mixture of chloroform/acetone (25
mL/5 mL). The reaction mixture was heated at reflux for 16 h and
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Table 2. Selected Bond Distances (Å) and Angles (deg) for [Re(CO)3(N(SO2Me)dpa)]PF6 (1) and
[Re(CO)3(N(SO2tmb)dpa)]PF6 (2), [Re(CO)3(N(SO2tol)dpa)]PF6 (4), and [Re(CO)3(N(SO2Me2Nnap)dpa)]BF4 (5)
1
2
4
5
Bond Distances
2.175(5)
2.279(5)
2.175(5)
1.909(7)
1.893(7)
1.936(8)
1.433(5)
1.428(4)
1.755(5)
Bond Angles
76.98(18)
86.49(19)
73.96(18)
100.3(3)
90.4(2)
Re−N1
Re−N2
Re−N3
Re−C1
Re−C2
Re−C3
S1−O5
S1−O4
S1−N2
2.1736(17)
2.2826(16)
2.1948(18)
1.928(2)
2.179(3)
2.275(3)
2.173(3)
1.937(4)
1.907(5)
1.938(5)
1.416(3)
1.437(3)
1.752(3)
2.170(4)
2.272(4)
2.181(4)
1.925(6)
1.900(6)
1.945(6)
1.425(4)
1.420(3)
1.776(4)
1.905(2)
1.936(2)
1.4288(17)
1.4299(15)
1.7552(17)
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−C9
Re−N2−C10
S1−N2−C9
S1−N2−C10
C9−N2−C10
77.16(6)
80.12(7)
76.25(6)
94.33(8)
96.45(8)
96.55(8)
96.18(8)
111.00(8)
107.70(11)
108.47(12)
109.69(13)
108.22(12)
111.8(2)
75.86(12)
78.85(12)
77.58(11)
96.83(16)
95.52(15)
97.25(17)
96.56(14)
111.68(15)
104.1(2)
110.1(2)
109.5(2)
109.8(3)
111.5(3)
78.08(14)
78.42(16)
76.37(15)
95.53(19)
96.96(19)
96.5(2)
94.6(3)
96.1(2)
97.37(19)
111.91(19)
108.3(3)
106.5(3)
109.1(3)
109.4(3)
111.5(4)
109.8(2)
109.4(3)
104.1(3)
110.9(4)
113.5(4)
108.9(5)
units and meso-tetrakis(4-pyridyl)porphyrin (TpyP(4)).43 In
these Re-porphyrin adducts, only one Re−N bond, involving a
peripheral meso-pyridyl group, links the Re moiety to the
porphyrin. The [[Re(CO)3]4T(N(SO2C6H4)dpa)P](BF4)4 ad-
duct prepared in this study is expected to maintain its integrity
better because each Re moiety is linked by three donor atoms.
Structural Results. Crystal data and details of the structural
refinement for complexes 1, 2, 4, and 5 are summarized in
Table 1. The Re complexes reported here exhibit a pseudo
octahedral structure (Figure 2), with the three carbonyl ligands
occupying one face. The remaining three coordination sites are
occupied by three nitrogen atoms of the tridentate ligands. The
atom numbering systems in Figure 2 are used to describe the
solid-state data.
The unusual and most interesting structural features of these
complexes involve the sulfonamide containing the central
nitrogen (N2), which is bound to Re. First, we present
information on other structural aspects, beginning with a
consideration of bond lengths. In [Re(CO)3L]+ complexes with
prototypical NNN donor ligands, Re−N(sp3) bond distances
(generally ∼2.23−2.29 Å)44,45 are longer than Re−N(sp2)
bond distances (generally 2.14−2.18 Å).37,46,47 The Re−N(sp2)
bond distances involving the pyridyl groups (N1 and N3,
Figure 2) of [Re(CO)3(N(SO2Me)dpa)]PF6 (1), [Re-
(CO)3(N(SO2tmb)dpa)]PF6 (2), [Re(CO)3(N(SO2tol)dpa)]-
PF6 (4), and [Re(CO)3(N(SO2Me2Nnap)dpa)]BF4 (5) are
similar and fall within a normal range (Table 2). For the most
part, the Re−N(pyridyl) bond distances are not significantly
different from the values reported for [Re(CO)3(N(H)dpa)]Br
(2. 177(5) and 2. 183(5) Å)2 1 and for [Re-
(CO)3(N(CH2CO2Et)dpa)]Br (2.161(6) and 2.174(5) Å).21
In addition, superimposing the donor N and the Re atoms in
[Re(CO)3(N(CH2CO2Et)dpa)]Br with the corresponding
atoms in 1 reveals very good overlap of the dpa moieties of
both compounds (Supporting Information, Figure S3). Thus,
any effect of having a tertiary sulfonamide nitrogen, rather than
a traditional sp3 nitrogen, anchoring the two chelate rings is
minimal.
Consistent with a rehybridization of the sulfonamide N atom
from sp2 to sp3, the Re−N2(sp3) bond distance involving the
central sulfonamide group is significantly longer than the Re−
N1(sp2) and Re−N3(sp2) bond distances involving the pyridyl
groups for all four compounds (Table 2). The Re−N2 bond
distance (2.2826(16) Å) of [Re(CO)3(N(SO2Me)dpa)]PF6
(1) (Figure 2) is comparable to that of the unquestionably
sp3-hybridized N atom (2.232(4) Å) of the central donor group
of [Re(CO)3(N(CH2CO2Et)dpa)]Br.21 These bond distances
are slightly longer than that (2.187(4) Å) of the parent
complex, [Re(CO)3(N(H)dpa)]Br,21 indicating that replacing
the NH proton with a larger substituent leads to bond
lengthening. This result is attributable mainly to steric rather
than electronic effects. Thus, these comparisons clearly indicate
that the sulfonamide N is a relatively strong electron donor
because the SO2 group on N2 in 1 is more bulky than the CH2
group on N2 in [Re(CO)3(N(CH2CO2Et)dpa)]Br.
In [Re(CO)3(N(SO2Me)dpa)]PF6 (1) (Figure 2), the angles
of the sulfonamide nitrogen are close to 109.5° (Table 2),
another result clearly illustrating that the hybridization of the
sulfonamide nitrogen has changed from sp2 to sp3 upon binding
to Re. Similar conclusions apply to the other structurally
characterized complexes in Figure 2. However, the bond angles
of [Re(CO)3(N(SO2tmb)dpa)]PF6 (2, Table 2) show on
average a greater deviation from values for other complexes,
and this deviation appears to be clearly attributable to the
stacking of the tmb rings (3.8−3.9 Å contact distances) in the
crystal (Supporting Information, Figure S4). This result and
features of structures in the literature (see below) suggest that
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the angles of the sulfonamide group are quite pliable, a feature
that can lead to ligands which exhibit coordinative flexibility.27
Fewer than 20 complexes are known in which tertiary
sulfonamides have been shown to bind to metals;26−33 in all of
these reported compounds the sulfonamide N is positioned
advantageously by ligand rings. The evidence for angles close to
109.5° (Table 2) clearly indicates that binding to ReI results in
sp2-to-sp3 rehybridization of the tertiary sulfonamide nitrogen.
This finding that all angles are close to the tetrahedral value is a
common feature in the complexes of many metals in various
oxidation states (NiII, CoII, MnII, CuII, LaIII)26,27,32,33 with a
bound sulfonamide. One useful approach to appreciating the
sp3 nature of the sulfonamide nitrogen is to determine the
distance by which the N lies out of the plane defined by the S
atom and the two C atoms attached to N. For complexes 1, 2,
4, and 5, this out-of-the-plane distance ranges from 0.486−
0.515 Å. Likewise, for complexes with other metals and
differing widely in the ligands and geometries, values of 0.38−
0.51 Å are typically found.26,27,32,33 In contrast, for complexes
in which the sulfonamide nitrogen is not bound, the out-of-the-
plane distances in reported structures typically range from
0.06−0.125 Å.26,27
spectroscopy in DMSO-d6 (NMR data and assignments are
presented in the Experimental Section). In the free N(SO2R)-
dpa (R = Me, tmb, dmb, tol, and Me2Nnap) ligands, the signal
for the methylene groups is a singlet (Figure 3 and Supporting
New complexes 1, 2, 4, and 5 are the only examples of
complexes with a tridentate ligand having a coordinated tertiary
sulfonamide with a typical M−N(sp3) distance. In almost all
cases, the metal-bound tertiary sulfonamide nitrogen and the
donors of the adjacent chelate rings occupy the face of an
octahedron26,28,33 or have a similar arrangement in complexes
with other geometries.29,30 In other words, these three N-donor
atoms and the metal atom typically do not define a common
plane. However, because the sulfonamide group is pliable, when
the R group attached to sulfur possesses a suitably positioned
donor atom, the ligand can coordinate in a tripodal tetradentate
fashion.27 In fact, only in such rare cases is the M−
N(sulfonamide) bond length as short as a typical M−N(sp3)
distance.27 In these rare tripodal tetradentate cases, the
sulfonamide N and the two flanking N donor atoms linked
to it coordinate meridionally, not facially.27 In the only other
case of meridional coordination, the M−N(sulfonamide) bond
length is long (2.298 Å).27 A ten-coordinate square
antiprismatic LaIII complex with one macrocyclic ligand derived
from cyclen, having one sulfonamide N donor and three amine
N donors, has a long LaIII−N(sulfonamide) bond, and the
coordination mode is between facial and meridional.32
For compounds 1, 2, 4, and 5, the relatively short metal-to-
nitrogen(sulfonamide) bond (adjusting for the ReI character-
istics) correlates with a relatively long N−S bond. The N−S
distances found in this work are 1.755−1.776 Å. In the rare
examples in which the M−N(sulfonamide) bond length reflects
a strong bond (enforced by the tripodal nature of the ligand),
the N−S distance is ∼1.73−1.76 Å.27 For more common cases
in which the M−N(sulfonamide) bond length is much longer
than the typical value for the M−N distance of that metal in its
oxidation state, the N−S distance is shorter, ∼1.7 Å or less.27
For complexes in which the sulfonamide is not coordinated, the
N−S distance is about 1.62−1.64 Å.27 Thus, although the bond
angles appear to reflect sp2-to-sp3 rehybridization of the
sulfonamide nitrogen, weakly coordinated or noncoordinated
sulfonamide groups have N−S bonds possessing considerable
double-bond character.27 The N−S bond length in the square
antiprismatic LaIII complex32 is consistent with this relationship.
NMR Spectroscopy. T(N(SO2C6H4)dpa)P and all com-
plexes and ligands reported here were characterized by NMR
Figure 3. Comparison of the 1H NMR spectra of ligands
(N(SO2Me)dpa (a), N(SO2Me2Nnap)dpa (c)) and the corresponding
Re complexes ([Re(CO)3(N(SO2Me)dpa)]PF6 (1) (b), [Re-
(CO)3(N(SO2Me2Nnap)dpa)]BF4 (5) (d)) in DMSO-d6 at 25 °C.
Information, Figure S1). The protons in each group are
magnetically equivalent because the sulfonamide group can
achieve a time-averaged planar geometry with both methylene
groups in the pseudo plane.
The methylene groups of [Re(CO)3(N(SO2R)dpa)]X
complexes 1−5 are related by a mirror plane. However, unlike
the case of the free ligand, the two protons on each methylene
group are not magnetically equivalent (cf. Figure 2); they
project toward and away from the carbonyl ligands and are
designated as endo- and exo-CH protons, respectively (Chart
1). The methylene protons give rise to two doublets (Figure 3
and Supporting Information, Figure S2) rather than one singlet,
as found for the free ligand (Figure 3 and Supporting
Information, Figure S1).
Bidentate coordination of the N(SO2R)dpa ligand via the
two pyridyl N atoms also prevents the tertiary sulfonamide
group from achieving a time-averaged planar geometry.
Methylene doublets for N(SO2R)dpa ligands in the bidentate
binding mode were observed for the pseudo square planar
48
complexes, PdII(N(SO2tol)dpa)Cl2 and PtII(N(SO2R)dpa)-
Cl2.49 (These PtII complexes contain the N(SO2R)dpa ligands
used in the current study, Figure 1.) The geminal coupling
constants also were similar; for example, J = 15.8 Hz for 1 and J
= 15.0 Hz for Pt(N(SO2Me)dpa)Cl2. Furthermore, no trend
1
was observed in the shifts of the methylene H NMR signals.
Thus, the methylene signals of the coordinated N(SO2Me)dpa
ligand are not useful for assessing binding mode (bidentate or
tridentate).
1
The methyl H NMR signal of [Re(CO)3(N(SO2Me)dpa)]-
PF6 (1) is shifted downfield by 0.76 ppm relative to the
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to the methylene doublet at 5.13 ppm than to the doublet at
5.44 ppm (not shown). In the molecular structure of 1,
nonbonded distances of ∼2.44 and 2.45 Å between the pyridyl
H3/3′ and the exo-CH protons are shorter than the nonbonded
distances of 3.02 and 3.09 Å between H3/3′ and the endo-CH
protons. This information, combined with the size of the NOE
cross-peaks, indicates that the more upfield signal (5.13 ppm) is
the exo-CH doublet for 1.
Chart 1. Designation of the Methylene Group endo-CH and
exo-CH Protons in Complexes 1−6
Except for the distorted [Re(CO)3(N(SO2tmb)dpa)]PF6 (2)
complex, all of the nonbonded distances from the pyridyl H3/
3′ protons of structurally characterized complexes are shorter to
the exo-CH protons (∼2.5 Å) than to the endo-CH protons
(∼3.0 Å). In a ROESY spectrum of [Re(CO)3(N(SO2dmb)-
dpa)]PF6 (3) in DMSO-d6 (Supporting Information, Figure
S7), an NOE cross-peak from the CH doublet at 4.55 ppm to
the H3/3′ signal assigns this doublet to the exo-CH protons.
An NOE cross-peak between the dmb H2/6 signal (7.96 ppm)
and the CH doublet at 5.25 ppm assigns this doublet to the
endo-CH signal. Thus, the exo-CH and endo-CH assignments
are mutually confirmed because the nonbonded distances from
the H2/6 protons in [Re(CO)3(N(SO2tol)dpa)]PF6 (4) to the
exo-CH and endo-CH protons are 3.06 and 2.59 Å, respectively.
Changes in the NMR signals in DMSO-d6 for T-
(N(SO2C6H4)dpa)P on formation of [[Re(CO)3]4T-
(N(SO2C6H4)dpa)P](BF4)4 (6) (Figure 4) establish beyond
N(SO2Me)dpa ligand; however, this signal shifted downfield by
only 0.10 ppm for Pt(N(SO2Me)dpa)Cl2.49 The downfield shift
for 1 can be explained best by the inductive effect resulting
from a direct N−Re bond (Figure 2) compared to the absence
of a N−Pt bond in Pt(N(SO2Me)dpa)Cl2. Thus, for the
1
N(SO2Me)dpa complexes, the methyl group H NMR shift
appears to provide a good spectroscopic handle for assigning
binding mode.
COSY spectra were useful in assigning the aromatic signals of
the free N(SO2Me)dpa ligand and [Re(CO)3(N(SO2Me)-
dpa)]PF6 (1) in DMSO-d6 (Supporting Information, Figures
S5 and S6). All of the aromatic signals for 1 were shifted more
downfield than the corresponding signal of the free ligand. For
example, the most downfield doublet (8.50 ppm) of the free
N(SO2Me)dpa ligand is the pyridyl H6/6′ signal (consistent
with the close proximity of the H6/6′ protons to a pyridyl
nitrogen); the H6/6′ signal has an even more downfield shift
(8.89 ppm) in 1, as expected from the ReI electron-withdrawing
inductive effect on the coordinated pyridyl group. The pyridyl
H6/6′ signal (9.24 ppm) of Pt(N(SO2Me)dpa)Cl2 is even
more downfield than that of 1. The same trend in H6/6′ shifts
is seen when comparing the spectra of [Re(CO)3(N(SO2tmb)-
dpa)]PF6 (2) and Pt(N(SO2tmb)dpa)Cl2. We attribute the
greater downfield shifts in the Pt complexes to a greater
electron-withdrawing inductive effect of PtII as compared to
ReI. In DMSO-d6 for L = 3-(4′-methylpyridin-2′-yl)-5,6-
dimethyl-1,2,4-triazine,50 the pyridyl H6 signal appeared more
downfield for PtLCl2 (9.35 ppm)50 than for [Re(CO)3L-
(CH3CN)]BF4 (8.97 ppm),49 a result indicating that PtII does
indeed have a generally greater inductive effect than ReI. This
greater effect for PtII than for ReI adds further confidence to our
1
Figure 4. Comparison of H NMR spectra of T(N(SO2C6H4)dpa)P
(bottom) and [[Re(CO)3]4T(N(SO2C6H4)dpa)P](BF4)4 (6) (top) in
DMSO-d6 at 25 °C.
question that the formulation of 6 is correct. The methylene
group singlet for T(N(SO2C6H4)dpa)P becomes two doublets
in 6. In the ROESY spectrum in DMSO-d6 (not shown), an
NOE cross-peak from the doublet at 4.97 ppm to the pyridyl
H3/3′ signal assigns that doublet to the exo-CH protons, and
the NOE cross-peak from the other methylene doublet (5.97
ppm) to the phenylene signal (8.84 ppm) assigns this doublet
to the endo-CH protons (Chart 1).
Coordination of the four Re moieties to T(N(SO2C6H4)dpa)
P leads to the apparent singlet signal (8.84 ppm, Figure 4) for
the clearly inequivalent phenylene ortho and meta protons of 6
(Scheme 2). We attribute this interesting spectral feature to a
similar chemical shift of the signals of the phenylene group,
leading to non-first-order spectral features in this aromatic
region. Binding of the porphyrin sulfonamide groups to Re
leads to a larger downfield shift change (by 0.60 ppm) of the m-
H (H2/6) signal (for the phenylene protons closest to Re)
versus the smaller downfield shift change (by 0.37 ppm) of the
phenylene o-H (H3/5) signal. This result fully supports the
proposed structure.
1
analysis that the small downfield shift for the Me H NMR
signal for Pt(N(SO2Me)dpa)Cl2 compared to that for 1
indicates that the sulfonamide N binds to ReI but not to PtII;
otherwise, the Me 1H NMR signal for the PtII compound would
be more downfield than that for the ReI compound.
For [Re(CO)3(N(SO2Me)dpa)]PF6 (1), we could not use
the weak NOE cross-peaks from the methyl signal to both
methylene doublets to assign unambiguously the doublets to
exo-CH and endo-CH protons (Chart 1). However, the NOE
cross-peak from the pyridyl H3/3′ signal (7.57 ppm) was larger
H
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1
The H NMR spectrum of [[Re(CO)3]4T(N(SO2C6H4)-
Summary and Conclusions. The [Re(CO)3(N(SO2R)-
dpa)]X (X = PF6 or BF4) complexes synthesized and
characterized as a prelude to radiopharmaceutical studies with
novel N(SO2R)dpa ligands provide structural evidence
establishing that the Re−N bond formed between a tertiary
sulfonamide N and Re can have a normal length. Because there
are distinctive NMR spectral features associated with such
binding in the N(SO2R)dpa ligands, it is clear that the tertiary
sulfonamide N binds to Re even in cases such as [Re-
(CO)3(N(SO2dmb)dpa)]PF6 (3), for which an X-ray structure
could not be obtained.
dpa)P](BF4)4 (6) in DMSO-d6 (Figure 4) reveals other effects
of Re coordination to the pyridyl nitrogen. The 1H NMR signal
for the pyrrole βH (Scheme 2) is ∼0.3 ppm more downfield
than the βH signal of the free T(N(SO2C6H4)dpa)P ligand.
The pyridyl H6/6′ signal (J = 5.4 Hz) of 6 appears at 9.01 ppm
versus 8.55 ppm for T(N(SO2C6H4)dpa)P. The 1H NMR shifts
of the pyridyl signals of 6 are very similar to those of the
crystallographically characterized complex 1, another indication
of the presence of a Re−N(pyridyl) bond. Furthermore, the
two methylene doublets for 6 have J = 16.4 Hz, a value very
similar to that for 1 (J = 15.8 Hz). As is true for the smaller
complexes, the two doublets for [[Re(CO)3]4T(N(SO2C6H4)-
dpa)P](BF4)4 can be attributed to the fact that the CH2−
N(SO2R)−CH2 grouping cannot achieve the time-averaged
planarity required for magnetic equivalence.
In general, the relatively downfield and upfield methylene
doublets are assigned to the endo-CH and the exo-CH signals,
respectively, for complexes 1−6. However, there is some
variability in the exact shift values (cf. Experimental Section,
Supporting Information). The shift dependence on the nature
of R is complicated, but we can explain the shift dependence
within the series of R groups that have methyl-substituted
benzene rings (tol, dmb, and tmb). The exo-CH signals all have
nearly identical shifts (Supporting Information, Figure S2) and
the endo-CH signals for tol and dmb also have nearly identical
shifts. However, the endo-CH signal for the tmb complex is
relatively upfield. The two ortho methyl groups of tmb appear
to position the ring so that it has an anisotropic shielding of the
endo-CH proton. This positioning is found in the molecular
structure and may be the reason for the stacking interactions
found in the solid (Supporting Information, Figures S4 and
S8).
Effects of Bases. As mentioned above, these complexes are
stable for long periods in DMSO-d6. However, when basic
ligands were added to a 5 mM solution of [Re-
(CO)3(N(SO2Me)dpa)]PF6 in acetonitrile-d3 (4-dimethylami-
nopyridine, 4-methylimidazole, or 3,5-lutidine) or in DMSO-d6
(4-dimethylaminopyridine), complicated 1H NMR spectral
changes attributable to a decomposition reaction were
observed. For 4-dimethylaminopyridine, decomposition was
observed in the first spectrum (recorded after 15 min);
however, for 3,5-lutidine, decomposition was first noticeable in
a spectrum recorded after 24 h. When triethylamine (a strong
base but a very poor ligand) was added to a similar 5 mM
solution of [Re(CO)3(N(SO2Me)dpa)]PF6, immediate decom-
position was observed. All spectra contained a very similar set
of peaks attributable to decomposition products. These results
are consistent with base-catalyzed decomposition of the
coordinated N(SO2Me)dpa ligand. In contrast, adding 1
molar equiv of triethylamine to a 5 mM acetonitrile-d3 solution
of the N(SO2Me)dpa ligand itself produced no changes in the
1H NMR spectrum, even after 2 weeks. These observations
suggest that the ligand decomposition is promoted by the
electron-withdrawing inductive effect of the ReI(CO)3 metal
center.
Monodentate tertiary sulfonamides do not bind metals.
Thus, as illustrated in the examples here and in previous
reports,28−31 tertiary sulfonamides bind metals via the N atom
only when geometrical restraints are enforced by the ligand so
as to place the N atom in a favorable position to form a bond.
The tertiary sulfonamide nitrogen adopts stereochemical and
structural features consistent with sp3 hybridization. As a result,
the N atom accommodates a facial tridentate geometry when
the sulfonamide anchors two chelate rings. Of note,
sulfonamide binding in the [ReI(CO)3L]+ complexes described
in this study is facilitated by sp2-to-sp3 rehybridization of the
sulfonamide nitrogen. In such complexes, the tertiary
sulfonamide appears to be a relatively good donor, as judged
by the near-normal Re−N bond length and the relatively long
N−S bond. In most cases reported in the literature, the M−N
bond is long, and the N−S bond is relatively short.26,27,32
The conjugation approach described here has potentially
wide applications. This prospect is supported by our results
showing that a sulfonamide can be used to conjugate the fac-
[ReI(CO)3]+ core unit to a dansyl group or a porphyrin. We
anticipate no limitation in conjugating other molecules to such
a core or in extending this chemistry to 99mTc analogues. Our
results demonstrate that the tertiary sulfonamide linkage may
be utilized for tethering biologically important molecules, and
we are confident that the chemistry with the fac-[ReI(CO)3]+
core reported here can be readily extended to the fac-
[
99mTcI(CO)3]+ core.
ASSOCIATED CONTENT
■
S
* Supporting Information
Crystallographic data for [Re(CO)3(N(SO2Me)dpa)]PF6 (1),
[Re(CO)3(N(SO2tmb)dpa)]PF6 (2), [Re(CO)3(N(SO2tol)-
dpa)]PF6 (4), and [Re(CO)3(N(SO2Me2Nnap)dpa)]BF4 (5)
in CIF format; 1H NMR spectra in DMSO-d6 of complexes 1 to
5 and of the N(SO2R)dpa ligands used to form these
complexes; figure illustrating the overlay of Re, N1, N2 and
N3 atoms of 1 and [Re(CO)3(N(CH2CO2Et)dpa)]Br; figure
depicting stacking of tmb rings in 2; COSY spectra of
N(SO2Me)dpa and 1; ROESY spectrum of [Re-
(CO)3(N(SO2dmb)dpa)]BF4 (3) in DMSO-d6; and an
informative side view of [Re(CO)3(N(SO2tmb)dpa)]PF6 (2).
This material is available free of charge via the Internet at
http://pubs.acs.org.
The absence of any need to protect the two terminal pyridyl
donor nitrogens is an advantage of using the dpa framework for
bioconjugation; however, the electron-withdrawing pyridyl
group may contribute to the base-catalyzed decompostion.
We have thus redesigned the ligand framework for future
studies.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: lmarzil@lsu.edu.
Notes
The authors declare no competing financial interest.
I
dx.doi.org/10.1021/ic302180t | Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
(28) Klingele, M. H.; Moubaraki, B.; Murray, K. S.; Brooker, S.
Chem.Eur. J. 2005, 11, 6962−6973.
ACKNOWLEDGMENTS
■
This work was supported in part by the National Institutes of
Health (R37 DK038842-22). Purchase of the diffractometer
was made possible by Grant LEQSF (1999-2000)-ENH-TR-13,
administered by the Louisiana Board of Regents. L.G.M. thanks
the RAYMOND F. SCHINAZI INTERNATIONAL EX-
CHANGE PROGRAMME between the University of Bath,
U.K., and Emory University, Atlanta, GA, U.S.A., for a Faculty
Fellowship.
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