NH NMR Shifts of New, Structurally Characterized fac-[Re(CO)₃(polyamine)]ⁿ⁺ Complexes Probed via Outer-Sphere H-Bonding Interactions to Anions, Including the Paramagnetic [Re^IVBr₆]²⁻ Anion

fac-[Re^I(CO)₃L]ⁿ complexes serve as models for short-lived fac-[^99mTc^I(CO)₃L] imaging tracers (L = tridentate ligands forming two five-membered chelate rings defining the L face). Dangling groups on L, needed to achieve desirable biodistribution, complicate the NMR spectra, which are not readily understood. Using less complicated L, we found that NH groups (exo-NH) projecting toward the L face sometimes showed an upfield shift attributable to steric shielding of the exo-NH group from the solvent by the chelate rings. Our goal is to advance our ability to relate these spectral features to structure and to solution properties. To investigate whether exo-NH groups in six-membered rings exhibit the same effect and whether the presence of dangling groups alters the effect, we prepared new fac-[Re(CO)₃L]ⁿ complexes that allow direct comparisons of exo-NH shifts for six-membered vs. five-membered chelate rings. New complexes were structurally characterized with the following L: dipn (N-3-(aminopropyl)-1,3-propanediamine); N’-Medipn (3,3′-diamino-N-methyldipropylamine); N,N-Me₂dipn (N,N-dimethyldipropylenetriamine); aepn (N-2-(aminoethyl)-1,3-propanediamine); trpn (tris-(3-aminopropyl)amine); and tren (tris-(2-aminoethyl)amine). In DMSO-d₆, the upfield exo-NH signals were exhibited by all complexes, indicating that the rings sterically shield the exo-NH groups from bulky solvent molecules. This interpretation was supported by exo-NH signal shift changes caused by added halide and [ReBr₆]²⁻ anions, consistent with outer-sphere H-bond interactions between these anions and the exo-NH groups. For fac-[Re(CO)₃(dipn)]PF₆ in acetonitrile-d₃, the exo-NH signal shifted further downfield in the series, Cl⁻ > Br⁻ > I⁻, and the plateau in shift change required lower concentration for smaller anions. These results are consistent with steric shielding of the exo-NH groups by the chelate rings. Nevertheless, despite its size, the shape and the charge of [ReBr₆]²⁻ allowed the dianion to induce large upfield paramagnetic shifts of the exo-NH signal of fac-[Re(CO)₃(dipn)]PF₆. This dianion shows promise as an outer-sphere H-bonding paramagnetic shift reagent.

Introduction

fac-[Re(CO)₃L]ⁿ complexes have provided a good model system for interpreting the nature of the analogous fac-[^99mTc(CO)₃L]ⁿ imaging agents formed in tracer level preparations.^1,2 The convenient generation of the fac-[^99mTc(CO)₃(H₂O)₃]⁺ precursor^3,4 and the straightforward preparation of the fac-[Re(CO)₃(H₂O)₃]⁺ precursor⁵ have contributed toward developing new fac-[^99mTc(CO)₃L]ⁿ radiopharmaceuticals because fac-[Re(CO)₃(H₂O)₃]⁺ allows the simulation of the synthesis of ^99mTc complexes in aqueous media.² Recently Re complexes have been emerging as radiopharmaceuticals in their own right, owing to the possibility of utilizing the {^186/188Re(CO)₃}⁺ core for therapeutic purposes.^6,7 Additional evidence of the growing importance of this field is found in a recent report of a rapid and versatile microwave synthesis for preparing chelate complexes with the fac-{M^I(CO)₃}⁺ core (M = ^99mTc, Re).⁸

fac-[^99mTc(CO)₃L]ⁿ complexes bearing tridentate ligands (L) are rather robust,^6,9 and tridentate ligand systems bearing a dangling group with functional groups for conjugation to biomolecules or for directing the agent to a particular target are widely used.^9-13 Ligands with carboxyl groups on dangling chains are normally evaluated in renal tracer development because the interaction of the renal receptor with the carboxyl group is important for clearance of small peptides.^14-16 Tridentate ligands being investigated in bioconjugates or in tracers often have the dangling group attached to a central N anchoring the two chelate rings.^10,17-19 Thymidine derivatives functionalized at position N3 of the nucleobase and attached to ^99mTc or Re by a chain dangling from the central N of diethylenetriamine (dien) are recognized as substrates by human thymidine kinase 1, a promising target for noninvasive imaging and therapy of malignant cells.¹⁹ A recent report describes fac-[¹⁸⁸Re(CO)₃((bis(2-pyridylmethyl)amino)ethylamine)]Br, a ¹⁸⁸Re complex exhibiting promising biomedical properties and having a pyridyl-containing tridentate ligand with a dangling ethylamine group attached to the central N (Chart 1).¹⁸ Ligands named or used in this report are depicted in Chart 1. The H at the end of an abbreviation for a ligand name in Chart 1 or in the designation of a complex indicates the number of acidic hydrogens retained by the coordinated ligand, or in some cases, such as trenH (tris-(2-aminoethyl)amine), the H indicates that the coordinated ligand has become protonated.

Chart 1.

Highly functionalized fac-[Re(CO)₃L]ⁿ complexes are difficult to crystallize, and also the solution structures relevant to the likely structure of the tracer may differ from that in solution. For example, dangling uncoordinated carboxyl groups (which are negatively charged and deprotonated at physiological pH) usually become neutral protonated groups in procedures employed to crystallize the complex.^1,2,20-22 One goal of our study is to interpret how NMR spectra inform us about the solution structure of fac-[Re(CO)₃L]ⁿ complexes. We first became aware that an unusually wide shift range exists for NH signals at amine groups terminating chelate rings (i.e., amines not anchoring two chelate rings) in fac-[Re(CO)₃L]ⁿ complexes in a study of two fac-[Re(CO)₃(ENDACH)] isomers (ENDACH₂ ligand shown in Chart 1).²¹ For both isomers in the solid state, the coordinated carboxyl group is deprotonated, whereas the dangling carboxyl group is protonated. Two types of terminal NH’s were defined and unambiguously identified through the crystallography of the two isomers. In one isomer, the terminal amine has an endo-NH proton (defined as the proton projecting toward the carbonyl ligands, Figure 1) with a normal relatively downfield shift (5.84 ppm, DMSO-d₆) for a terminal secondary amine NH signal. In the other isomer, this amine has an exo-NH proton (defined as the proton projecting away from the carbonyl ligands, Figure 1).²¹ The signal of this terminal secondary amine exo-NH proton was observed at a rather upfield position (5.36 ppm, DMSO-d₆).

Figure 1.

Designation of endo and exo protons in 5-membered (left) and 6-membered (right) rings, as illustrated based on the molecular structure of [Re(CO)₃(aepn)]PF₆. The exo-NH or exo-CH protons point away from the carbonyl ligands and the endo-NH or endo-CH protons point toward the carbonyl ligands.

In later studies,^1,5,23 we found a relatively wide range of NH shifts also for terminal primary amine groups in fac-[Re(CO)₃L]⁺ complexes.^1,23 When L = lanthionine isomers as the tridentate ligand (LANH₂, Chart 1), the fac-[Re(CO)₃(LAN)]⁻ isomers exhibited NH signals differing in shift, but the shift range was not readily understood.¹ For some primary amine groups the two NH signals were well dispersed, whereas for others the shifts of both NH signals were similar.¹ Because the two deprotonated dangling carboxyl groups of the fac-[Re(CO)₃(LAN)]⁻ complex could be influencing shift, we examined fac-[Re(CO)₃L]⁺ complexes with such minimal prototypical ligands as dien or simple dien-related ligands (e.g., daes, Chart 1) to establish baseline chemical shift characteristics that define NMR parameters for fac-[Re(CO)₃L]ⁿ complexes.²⁴

For the prototypical fac-[Re(CO)₃L]⁺ complexes, with L lacking dangling groups and forming two 5-membered rings, downfield and upfield NH signals were observed and assigned to endo-NH and exo-NH protons, respectively.²⁴ We hypothesized that the shift differences might be attributable in part to the lower exposure to solvent of the exo-NH protons compared to the endo-NH protons. We reasoned that the chelate rings forming the face defined by L might provide a steric barrier that inhibits full access of the polyatomic solvent molecules to the exo-NH. As a result, the solvent cannot approach the exo-NH closely enough to allow formation of strong solvent to NH H-bonding interactions (an interaction causing downfield shifts).²⁴ Therefore, we evaluated the interaction of the small monoatomic Cl⁻ anion with these prototypical complexes.²⁴ We reasoned that the Cl⁻ anion would be attracted to the cationic complex, leading to an ion pair with the Cl⁻ anion H-bonded preferentially to the poorly solvated exo-NH groups. This interaction caused larger downfield shifts for the exo-NH signal than for the endo-NH signal, consistent with our hypothesis that solvent molecules are too large to access the exo-NH groups well. The extent of solvent accessibility to exo-NH groups might be altered by dangling groups on the ligands, by replacement of one of the groups with other donor types, by chelate ring size, as well as by other possible factors.

In the present study, we investigate fac-[Re(CO)₃L]ⁿ⁺ complexes bearing polyamine ligands having 6-membered chelate rings to determine if some of the same unusual NH shifts are present in the ¹H NMR spectra of these compounds. Also, we test further our proposal that at least a significant factor influencing shift is solvent exposure by assessing the interaction of anions of increasing size along the series: Cl⁻, Br⁻, and I⁻. We also evaluated the large paramagnetic Re^IV anion, [ReBr₆]²⁻. This series of studies was designed to test the solvent exposure hypothesis that small species are expected to access the sterically hindered face of the octahedron defined by the tridentate ligand better than larger anions. Two-dimensional NMR NH signal assignment is more straightforward for fac-[Re(CO)₃L]ⁿ⁺ complexes bearing polyamine ligands having two 6-membered chelate rings than for fac-[Re(CO)₃L]ⁿ⁺ complexes bearing polyamine ligands having 5-membered chelate rings because ring pucker in the latter type of compounds is usually very fluxional and different for the two chelate rings.²⁴ From now on, we omit the fac- designation when discussing specific compounds because all the new compounds have this geometry.

Experimental Section

Starting Materials

Tris-(2-aminoethyl)amine (tren), N-3-(aminopropyl)-1,3-propanediamine (dipn), N-2-(aminoethyl)-1,3-propanediamine (aepn), 3,3′-diamino-N-methyldipropylamine (N’-Medipn), N,N-dimethyldipropylenetriamine (N,N-Me₂dipn), tris-(3-aminopropyl)amine (trpn), 1,4,7-triazacyclononane (tacn), and Re₂(CO)₁₀ from Aldrich were used as received. [Re(CO)₃(H₂O)₃]OTf (OTf = trifluoromethanesulfonate) and [Bu₄N]₂[ReBr₆] were prepared by known methods.^5,25

NMR Measurements

¹H (400 MHz) and ²H NMR (unlocked) spectra were recorded on Bruker spectrometers. Peak positions are relative to TMS by using TMS or in some cases solvent residual peak, referenced in turn to TMS. NMR data were processed with TopSpin and Mestre-C software.

X-ray Data Collection and Structure Determination

Intensity data were collected at 90.0(5) K on a Nonius Kappa CCD diffractometer fitted with an Oxford Cryostream cooler and graphite-monochromated MoKα (λ = 0.71073 Å) radiation. Data reduction included absorption corrections by the multi-scan method, with HKL SCALEPACK.²⁶

All X-ray structures were determined by direct methods and difference Fourier techniques and refined by full-matrix least squares, using SHELXL97.²⁷ All non-hydrogen atoms were refined anisotropically, except for those in the 6-membered chelate rings of 5, which were disordered into two conformations. Except for those on the water molecule in 1, all H atoms were visible in difference maps. H atoms on C and N were placed in idealized positions, except for the NH hydrogen atoms in 2, 4, and 6. A torsional parameter was refined for each methyl group. Compound 1 has three independent Re complexes in the asymmetric unit, two of which have disordered (CH₂)₃ groups. Compound 3 has two formula units in the asymmetric unit. Compound 7 crystallizes in a chiral conformation as an enantiopure crystal, as evidenced by Flack parameter x = 0.014(6).

Synthesis of fac-[Re(CO)₃L]PF₆ and fac-[Re(CO)₃L]BF₄ Complexes

An aqueous solution of [Re(CO)₃(H₂O)₃]OTf (5 mL, 0.1 mmol) was treated with the ligands, L (0.1 mmol). The pH was adjusted to ~6 (3 mL of methanol was added to dissolve any precipitate that formed), and the clear reaction mixture was heated at reflux for 16 h. The reaction mixture was allowed to cool to room temperature, treated with solid NaPF₆ or NaBF₄ (~15 mg), and then left undisturbed. X-ray quality crystals formed within 2-3 days. Specific procedures are detailed below.

[Re(CO)₃(dipn)]BF₄ (1)

Treatment of [Re(CO)₃(H₂O)₃]OTf with dipn (15 μL) as described above afforded [Re(CO)₃(dipn)]BF₄ as colorless crystals (17 mg, 35% yield) after the addition of NaBF₄. The product was characterized by single-crystal X-ray diffraction. ¹H NMR spectrum (ppm) in DMSO-d₆: 6.00 (b, 1H, NH), 5.23 (d, 2H, NH), 3.79 (b, 2H, NH), 3.20 (m, 2H, CH₂), 2.90 (m, 2H, CH₂), 2.68 (m, 2H, CH₂), 2.62 (m, 2H, CH₂), 1.88 (m, 2H, CH₂), 1.68 (m, 2H, CH₂). [Re(CO)₃(dipn)]PF₆. Treatment of [Re(CO)₃(H₂O)₃]OTf with dipn as described above afforded [Re(CO)₃(dipn)]PF₆ as colorless crystals (36 mg, 66% yield) after the addition of NaPF₆. The product could not be characterized by single-crystal X-ray diffraction because of twinning. ¹H NMR spectrum (ppm) in DMSO-d₆: identical to that of [Re(CO)₃(dipn)]BF₄.

[Re(CO)₃(N’-Medipn)]PF₆ (2)

Treatment of [Re(CO)₃(H₂O)₃]OTf with N’-Medipn (17 μL) as described above afforded [Re(CO)₃(N’-Medipn)]PF₆ as colorless crystals (18 mg, 32% yield) after the addition of NaPF₆. The product was characterized by single-crystal X-ray diffraction. ¹H NMR spectrum (ppm) in DMSO-d₆: 5.30 (d, 2H, NH), 3.80 (t, 2H, NH), 3.20 (m, 2H, CH₂), 3.02 (m, 2H, CH₂), 2.98 (s, 3H, CH₃), 2.65 (m, 4H, CH₂), 1.90 (m, 2H, CH₂), 1.88 (m, 2H, CH₂).

[Re(CO)₃(N,N-Me₂dipn)]BF₄ (3)

Treatment of [Re(CO)₃(H₂O)₃]OTf with N,N-Me₂dipn (18 μL) as described above afforded [Re(CO)₃(N,N-Me₂dipn)]BF₄ as colorless crystals (29 mg, 56% yield) after the addition of NaBF₄. The product was characterized by single-crystal X-ray diffraction. ¹H NMR spectrum (ppm) in DMSO-d₆: 6.34 (s, 1H, NH), 5.53 (d, 1H, NH), 3.78 (t, 1H, NH), 3.24 (m, 1H, CH₂), 3.01 (s, 3H, CH₃), 2.90 (m, 3H, CH₂), 2.80 (m, 1H, CH₂), 2.71 (m, 3H, CH₂), 2.62 (s, 3H, CH₃), 1.94 (m, 1H, CH₂), 1.86 (m, 1H, CH₂), 1.62 (m, 2H, CH₂).

[Re(CO)₃(trenH)](PF₆)₂ (4)

Treatment of [Re(CO)₃(H₂O)₃]OTf with tren (16 μL) as described above afforded [Re(CO)₃(trenH)](PF₆)₂ as colorless crystals (34 mg, 47% yield) after the addition of NaPF₆. The product was characterized by single-crystal X-ray diffraction. ¹H NMR spectrum (ppm) in DMSO-d₆: 7.70 (b, 3H, NH), 5.62 (b, 2H, NH), 4.22 (b, 2H, NH), 3.57 (m, 2H, CH₂), 3.18 (m, 2H, CH₂), 3.09 (m, 2H, CH₂), 2.91 (m, 6H, CH₂).

[Re(CO)₃(trpnH)](PF₆)₂ (5)

Treatment of [Re(CO)₃(H₂O)₃]OTf with trpn (20 μL) as described above afforded [Re(CO)₃(trpnH)](PF₆)₂ as colorless crystals (34 mg, 45% yield) after the addition of NaPF₆. The product was characterized by single-crystal X-ray diffraction. ¹H NMR spectrum (ppm) in DMSO-d₆: 7.69 (b, 3H, NH), 5.39 (b, 2H, NH), 3.72 (b, 2H, NH), 3.10 (m, 4H, CH₂), 2.85 (m, 4H, CH₂), 2.75 (m, 4H, CH₂), 1.96 (m, 6H, CH₂).

[Re(CO)₃(aepn)]PF₆ (6)

Treatment of [Re(CO)₃(H₂O)₃]OTf with aepn (13 μL) as described above afforded [Re(CO)₃(aepn)]PF₆ as colorless crystals (30 mg, 56% yield) after the addition of NaPF₆. The product was characterized by single-crystal X-ray diffraction. ¹H NMR spectrum (ppm) in DMSO-d₆: 6.47 (b, 1H, NH), 5.50 (d, 1H, NH), 5.24 (d, 1H, NH), 4.08 (b, 1H, NH), 3.50 (t, 1H, NH), 3.25 (m, 1H, CH₂), 3.04 (m, 1H, CH₂), 2.97 (m, 1H, CH₂), 2.63 (m, 3H, CH₂), 2.57 (m, 1H, CH₂), 2.43 (m, 1H, CH₂), 1.94 (m, 1H, CH₂), 1.74 (m, 1H, CH₂).

[Re(CO)₃(tacn)]PF₆ (7)

Treatment of [Re(CO)₃(H₂O)₃]OTf with tacn (13 mg) as described above afforded [Re(CO)₃(tacn)]PF₆ as colorless crystals (30 mg, 55% yield) after the addition of NaPF₆. The product was characterized by single-crystal X-ray diffraction. ¹H NMR spectrum (ppm) in DMSO-d₆: 7.06 (b, 3H, NH), 2.96 (m, 6H, CH₂), 2.88 (m, 6H, CH₂).

Cl⁻ Titration of [Re(CO)₃L]PF₆ Complexes

A 5 mM solution of the desired fac-[Re(CO)₃L]PF₆ complex in DMSO-d₆ or acetonitrile-d₃ (600 μL) was treated with increasing amounts of Et₄NCl (1 to 125 mM), and the solution was monitored by ¹H NMR spectroscopy after each Cl⁻ aliquot was added. All Et₄NCl stock solutions were prepared by using a 5 mM solution of the complex to keep the complex concentration constant throughout the titration. Similar experiments were performed with [Re(CO)₃(dipn)]PF₆ in acetonitrile-d₃ by using Et₄NBr (1 to 125 mM) and Et₄NI (1 to 50 mM, owing to low solubility).

Preparation of [Re(CO)₃(dipn-d₅)]PF₆

The NH NMR signals of a 5 mM solution of [Re(CO)₃(dipn)]PF₆ in acetonitrile-d₃ (600 μL) disappeared within ~40 min after addition of D₂O (5 μL) and K₂CO₃ (2 mg). Therefore, the NH groups of [Re(CO)₃(dipn)]PF₆ (8 mg) in CH₃CN (3 mL) were exchanged by using D₂O (70 μL) and K₂CO₃ (8 mg). The reaction mixture was taken to dryness, the residue dissolved in CH₃CN, and the solution filtered to remove K₂CO₃. The filtrate was taken to dryness, and the residue was re-dissolved in CH₃CN (3 mL) to give a 5 mM [Re(CO)₃(dipn-d₅)]PF₆ stock solution for use in ²H NMR-monitored titrations. Later, [Re(CO)₃(dipn-d₅)]PF₆ was prepared more conveniently by using the volatile Et₃N instead of K₂CO₃.

Addition of [Bu₄N]₂[ReBr₆] to [Re(CO)₃(dipn-d₅)]PF₆

A 5 mM solution of [Re(CO)₃(dipn-d₅)]PF₆ in CH₃CN (600 μL) was treated with increasing amounts of [Bu₄N]₂[ReBr₆] (1 to 12 mM), and the solution was monitored by ²H NMR spectroscopy after each [ReBr₆]²⁻ aliquot was added. An analogous ¹H NMR experiment was performed with [Re(CO)₃(dipn)]PF₆ in acetonitrile-d₃. The [Re(CO)₃(dipn-d₅)]PF₆ concentration was kept constant throughout the titrations as described above.

Results and Discussion

Synthesis

A [Re(CO)₃(H₂O)₃]OTf aqueous solution⁵ (pH ~6) was used to prepare all the complexes crystallized and structurally characterized in this study (Scheme 1). All complexes are new except for the tacn complex, which was not previously characterized as a PF⁻₆ salt.^28,29 This salt was needed for our NMR studies.

Scheme 1.

X-ray Crystallography

All complexes possess a distorted octahedral structure, with the three carbonyl ligands occupying one face. The three remaining coordination sites are occupied by amine nitrogen atoms (Figures 2-4). Crystal data and details of the structural refinement for these complexes are summarized in Table 1. Ligands and their abbreviations are depicted in Chart 1. The complexes have chelate rings of different sizes: two 6-membered chelate rings ([Re(CO)₃(dipn)]BF₄ (1), [Re(CO)₃(N’-Medipn)]PF₆ (2), [Re(CO)₃(N,N-Me₂dipn)]BF₄ (3), and ([Re(CO)₃(trenH)](PF₆)₂ (4)); 6- and 5-membered chelate rings ([Re(CO)₃(aepn)]PF₆) (6)); two 5-membered rings ([Re(CO)₃(trenH)](PF₆)₂) (5)); or three 5-membered rings ([Re(CO)₃(tacn)]PF₆) (7)). For all complexes except [Re(CO)₃(tacn)]PF₆ (7), N1 and N3 refer to bound terminal nitrogen atoms of the ligand, and N2 denotes the central nitrogen; for [Re(CO)₃(trenH)](PF₆)₂ (4) and [Re(CO)₃(trpnH)](PF₆)₂ (5), the nitrogen atom of the dangling NH₃⁺ group is designated as N4 (Chart 1).

Figure 2.

ORTEP plots of the cations of [Re(CO)₃(dipn)]BF₄ (1), [Re(CO)₃(N’-Medipn)]PF₆ (2), [Re(CO)₃(N,N-Me₂dipn)]BF₄ (3), and [Re(CO)₃(aepn)]PF₆ (6). Thermal ellipsoids are drawn with 50% probability. Only one of the independent molecules is shown for 1 (Z’ = 3) and for 3 (Z’ = 2).

Figure 4.

ORTEP plot of the cation of [Re(CO)₃(tacn)]PF₆) (7). Thermal ellipsoids are drawn with 50% probability.

Table 1.

Crystal Data and Structure Refinement for [Re(CO)₃(dipn)]BF₄ (1), [Re(CO)₃(N’-Medipn)]PF₆ (2), [Re(CO)₃(N,N-Me₂dipn)]BF₄ (3), [Re(CO)₃(trenH)](PF₆)₂ (4), [Re(CO)₃(trpnH)](PF₆)₂ (5), [Re(CO)₃(aepn)]PF₆ (6), and [Re(CO)₃(tacn)]PF₆ (7)

	1	2	3	4	5	6	7
empirical formula	C9H17N3O3Re· BF4·0.33(H2O)	C10H19N3O3Re· PF6	C11H21N3O3Re· BF4	C9H19N4O3Re· (PF6)2·H2O	C12H25N4O3Re· (PF6)2	C8H15N3O3Re· PF6	C9H15N3O3 Re·PF6
fw	494.27	560.45	516.32	725.44	749.50	532.40	544.41
space group	P21/c	$P\stackrel{‒}{1}$	Pbca	P21/n	Pnma	Pbca	P21
a (Å)	21.2819(15)	8.3290(10)	14.546(2)	7.8157(5)	29.620(2)	13.2550(15)	8.1859(10)
b (Å)	13.1010(5)	8.4008(10)	13.335(2)	13.7565(10)	9.5359(5)	12.756(2)	12.5249(15)
c (Å)	16.0615(10)	11.8149(15)	34.811(6)	18.9670(15)	7.9455(5)	17.512(3)	8.3319(10)
α (°)	90	87.892(7)	90	90	90	90	90
β (°)	94.218(2)	84.975(6)	90	91.516(4)	90	90	117.085(4)
γ (°)	90	89.380(7)	90	90	90	90	90
V (Å3)	4466.0(5)	822.93(17)	6752.3(18)	2038.6(3)	2244.2(2)	2960.9(8)	760.57(16)
T (K)	90	90	90	90	90	90	90
Z	12	2	16	4	4	8	2
ρcalc (g/m3)	2.205	2.262	2.032	2.364	2.218	2.389	2.377
abs coeff (mm−1)	8.22	7.56	7.25	6.25	5.68	8.40	8.18
2θmax (°)	71.4	66.4	57.6	72.6	71.2	65.8	82.0
R indicesa	0.035	0.026	0.034	0.023	0.023	0.036	0.025
wR2 = [I> 2σ(I)]b	0.077	0.055	0.094	0.057	0.057	0.080	0.056
data/param	20482/652	6238/231	8645/419	9583/317	5413/185	5417/215	9584/209

^aR = (ΣǁF_oǀ − ǀF_cǁ)/ΣǀF_oǀ

^bwR2 = [Σ[w(F_o ² - F_c ²)₂]/Σ[w(F_o ²)₂]]½, in which w = 1/[σ²(F_o²) + (dP) ² + (eP)] and P = (F_o ² + 2F_c ²)/3, d = 0.0356, 0.0245, 0.0412, 0.0241, 0.0294,0.0225, and 0.0131, and e = 7.9046, 0.3934, 0.4422, 3.894, 2.1227, 2.1782, and 1.8054 for complexes 1-7, respectively.

Selected Re–N bond lengths and the N–Re–N bond angles are summarized in Table 2. The Re–N bond lengths and N–Re–N bond angles are consistent with those found in similar fac-[Re(CO)₃L]⁺ complexes.^23,24 It is useful to compare the N–Re–N angles for two terminal amine groups of [Re(CO)₃(dien)]PF₆ (87.14(12)°), which has two 5-membered chelate rings,²⁴ with those of [Re(CO)₃(aepn)]PF₆ (86.74(15)°), which has 5- and 6-membered chelate rings (Figure 2), and [Re(CO)₃(dipn)]BF₄ (84.67(10)°), which has two 6-membered rings (Figure 2). The N–Re–N angle relating two terminal N’s decreases significantly as the ring size increases (Table 2). The non-bonded distances between N1 and N3 are mostly similar for complexes 1-6, ranging from 3.01-3.14 Å (Table 3) regardless of the size of the chelate ring.

Table 2.

Selected Bond Distances (Å) and Angles (deg) for [Re(CO)₃(dipn)]BF₄ (1), [Re(CO)₃(N’-Medipn)]PF₆ (2), [Re(CO)₃(N,N-Me₂dipn)]BF₄ (3), [Re(CO)₃(trenH)](PF₆)₂ (4), [Re(CO)₃(trpnH)](PF₆)₂ (5), [Re(CO)₃(aepn)]PF₆ (6), and [Re(CO)₃(tacn)]PF₆ (7)

	1	2	3	4	5	6	7
bond distances
Re–N1	2.235(3)	2.249(2)	2.306(4)	2.2218(17)	2.218(4)	2.210(4)	2.194(4)
Re–N2	2.244(3)	2.299(2)	2.245(4)	2.2687(16)	2.281(2)	2.229(4)	2.208(2)
Re–N3	2.236(3)	2.226(2)	2.215(4)	2.2173(17)	2.275(4)	2.234(4)	2.209(2)
bond angles
N1–Re–N2	84.72(10)	91.47(8)	91.82(14)	78.55(6)	83.62(13)	77.42(14)	77.10(11)
N2–Re–N3	85.57(10)	84.63(8)	81.80(15)	77.35(6)	86.11(12)	83.90(14)	77.14(8)
N1–Re–N3	84.67(10)	84.32(9)	87.88(14)	88.04(7)	88.80(18)	86.74(15)	77.34(11)

Table 3.

Selected Non-bonded Distances (Å) [Re(CO)₃(dipn)]BF₄ (1), [Re(CO)₃(N’-Medipn)]PF₆ (2), [Re(CO)₃(N,N-Me₂dipn)]BF₄ (3), [Re(CO)₃(trenH)](PF₆)₂ (4), [Re(CO)₃(trpnH)](PF₆)₂ (5), [Re(CO)₃(aepn)]PF₆ (6), and [Re(CO)₃(tacn)]PF₆ (7)

	1	2	3	4	5	6	7
non-bonded distances
N1,N2	3.018	3.257	3.269	2.843	3.000	2.776	2.744
N2,N3	3.043	3.047	2.920	2.804	3.110	2.983	2.755
N1,N3	3.012	3.005	3.137	3.085	3.143	3.052	2.751
exo-NH, exo-NH	2.112	2.475		2.571	2.336	2.314

The presence of a methyl group on N2 of [Re(CO)₃(N’-Medipn)]PF₆ (2) is reflected in a longer Re–N2 bond distance for 2 (2.299(2) Å) than for [Re(CO)₃(dipn)]BF₄ (1) (2.244(3) Å) (Table 2). A similar difference in the Re–N2 bond distance is found for the corresponding complexes with two 5-membered rings (L = dien and N’-Medien, Chart 1).²⁴ Thus, in [Re(CO)₃L]ⁿ complexes containing either 6- or 5-membered chelate rings, having a methyl substituent on N2 increases the Re–N2 bond distance by a similar small extent. This same conclusion appears to apply when data for [Re(CO)₃(trenH)](PF₆)₂ (4) and [Re(CO)₃(trpnH)](PF₆)₂ (5) are considered. The central N in 4 and 5 bears a CH₂CH₂NH₃⁺; the greater bulkiness of this dangling group does not appear to cause any greater lengthening of the Re–N2 bond than does the methyl group.

Chelate Ring Conformation

In the next subsection on NMR signal assignments, we discuss the use of COSY NMR spectra and chelate ring torsion angles, which depend on chelate ring conformation. Thus, it is useful to consider chelate ring conformations in the new structures and to compare these to conformations found in previous studies.^23,24 From Scheme 1, it can be seen that all of the new complexes except 3 and 6 will have a time-averaged plane of symmetry. However, none have such a plane in the solid state (Figures 2 and 3).

Figure 3.

ORTEP plots of the cations of [Re(CO)₃(trenH)](PF₆)₂ (4) and [Re(CO)₃(trpnH)](PF₆)₂ (5). Thermal ellipsoids are drawn with 50% probability.

The N2,N3 6-membered rings in compounds 1, 2, 3, and 6 (Figure 2) all have a very similar chair conformation (Chart 2). However, the conformation of the N1,N2 ring differs; this ring has the twist boat conformation in 1 (Chart 2), the sofa conformation in 2 and 3 (Chart 2), and five members in 6 (see below).^30,31

Chart 2.

When the two chelate rings are not equivalent (as in 3 and 6), L has a ‘head’ and a ‘tail’ (htL), and thus the complex is chiral. Also, one of the htL rings may dictate the conformation of the other ring. For 3, in which both rings are 6-membered and flexible, such conformational control of one ring by the other ring is not evident.

In contrast, when one htL ring is 5-membered, the conformation of the ring may be influenced by the other ring. The conformation of 5-membered rings is described by ring pucker (λ or δ) (Figure 5). One ring pucker (λ or δ) may be favored. In cases such as [Re(CO)₃(tmbSO₂-dien)], in which both rings of the htL are 5-membered, this chirality will determine the favored ring pucker of each ring (λ or δ).²³ The common pucker designation (λ or δ) is not useful for interpreting NMR data. Instead, we designate the 5-membered ring conformations as endo-C and exo-C, where the ring carbon bound to the terminal N projects toward and away, respectively, from the carbonyl ligands (Figure 5). This designation can also be used for 6-membered rings (Figure 5). Please note: the ring carbon has both an endo-CH and an exo-CH, regardless of whether or not the carbon is an endo-C or an exo-C. For example, in Figure 1, the 6-membered ring shown has an endo-C with its two hydrogens labeled as endo-CH and exo-CH.

Figure 5.

Designations of the exo-C and endo-C conformations for 5- and 6-membered rings of fac-[Re(CO)₃L]ⁿ complexes. Re is directed away from the viewer and the nitrogens are blue. The terminal N of the ring of interest is on the right, the central N is on the left, and the terminal N (but not the chain methylene groups) of the other ring is in the axial position. Note that for 5-membered rings, the chirality of the ring pucker is also designated.

NMR Spectroscopy

Complexes 1–7 were characterized by NMR spectroscopy in DMSO-d₆ (Figures 6 and S1, Supporting Information), acetonitrile-d₃, and acetone-d₆ at 25 °C (Table 4). COSY experiments performed for most of the complexes at 25 °C in DMSO-d₆, together with torsion angles obtained from the respective molecular structures, were useful in assigning NMR signals.

Figure 6.

¹H NMR spectra of [Re(CO)₃(dipn)]PF₆ (1), [Re(CO)₃(aepn)]PF₆ (6), and [Re(CO)₃(dien)]PF₆ (top) in DMSO-d₆ at 25 °C (* water peak). Full spectra for 1 and 6 are presented in Figure S1 in Supporting Information.

Table 4.

Selected ¹H NMR Chemical Shifts (ppm) of [Re(CO)₃(dipn)]BF₄ (1), [Re(CO)₃(N’- Medipn)]PF₆ (2), [Re(CO)₃(N,N-Me₂dipn)]BF₄ (3), [Re(CO)₃(trenH)](PF₆)₂ (4), [Re(CO)₃(trpnH)](PF₆)₂ (5), [Re(CO)₃(aepn)]PF₆ (6), and [Re(CO)₃(tacn)]PF₆ (7) at 25 °C ^a

	1	2	3	4	5	6	7
DMSO-d6
exo-NH	3.78	3.80	3.78	4.22	3.72	4.07, 3.50 c
endo-NH	5.22	5.30	5.53	5.62	5.39	5.50, 5.24 c
central-NH	6.01		6.34	7.70 b	7.69 b	6.47	7.06
acetonitrile-d3
exo-NH	2.83	2.85	2.83	3.36	2.76	3.15, 2.53 c
endo-NH	4.18	4.22	4.36	4.44	4.27	4.37, 4.17 c
central-NH	4.76		4.99	6.34 b	6.22 b	5.10	5.57
acetone-d6
exo-NH	3.83	3.90	3.76	4.36	3.76	4.14, 3.64 c
endo-NH	5.11	5.17	5.38	5.50	5.22	5.38, 5.10 c
central-NH	5.67		5.98	4.49 b	4.05 b	6.13	6.62

^aCOSY spectra were used to assign the NH signals of 1-6 in DMSO-d₆ and 4 in acetone-d₆.

^bFor 4 and 5, the chemical shift of the dangling NH₃⁺ group is listed in the rows containing central-NH values.

^cThe second entry is for the 6-membered ring.

In our previous work, the assignment by COSY or other means of an NH signal to an exo-NH or endo-NH proton was possible either because the complex contained only one of these types of protons in a secondary amine or because there was only one NH₂ group in a unique 5-membered chelate ring (the ligand was an htL).²³ For example, the ring with the terminal amine in [Re(CO)₃(tmbSO₂-dien)] has an exo-C conformation in the solid, and the endo-NH exhibited a strong COSY cross-peak to the exo-CH. In [Re(CO)₃(aepn)]PF₆ (6), the 5-membered chelate ring has an endo-C conformation, and the exo-NH signal exhibited a strong COSY cross-peak to the endo-CH signal of the endo-C.

For a symmetric (non-htL) complex with two identical ethylene chains such as [Re(CO)₃(dien)]⁺, the 5-membered chelate rings undergo rapid change in pucker, with both rings λ (λ,λ) or both δ (δ,δ).²⁴ Over time, any given CH₂ group in these rings is alternately endo or exo with respect to the carbonyl ligands. This rapid conformational interchange process averages the torsion angles such that endo-NH and exo-NH to CH couplings average. This averaging is found for each of the NH signals to both CH signals (unpublished data). COSY data cannot be used to assign the signals. However, the position in conformational space of the NH groups moves just slightly as the slight rotation about the Re–N bond occurs during the dynamic process. Thus, the exo-NH signal remains upfield to the endo-NH signal.²⁴

The conformations of 6-membered rings are more diverse than those of 5-membered rings (Chart 2), as discussed above. However, the chair conformation is most commonly found for the 6-membered rings in the new structures, and we assume that the solution structures will be dominated by this conformation, even in those symmetrical compounds in which the rings undergo conformational interchange. As will be seen, this assumption is justified by its utility in interpreting the NMR data. In the chair conformation, the exo-NH is related to the endo-CH by the largest H–N–C–H torsion angle (Table S1, Figure S2, Supporting Information); thus, for the 6-membered ring(s) in 1, 2, 3, and 6 (which exhibit similar COSY NH-CH cross-peaks), the NH-CH cross-peak having the highest intensity will be the exo-NH-endo-CH cross-peak (see below and Supporting Information).

We begin our discussion with [Re(CO)₃(N,N-Me₂dipn)]BF₄ (3, Figure 2), a chiral complex with an unsymmetrical coordinated htL in which dynamic motion cannot interchange the rings. The ring with the terminal NH₂ group has the chair conformation. The expected three NH signals (central NH and terminal NH₂) were observed for 3 in DMSO-d₆ (Table 4, Figure S3, Supporting Information). COSY studies discussed in Supporting Information establish that, although the chelate ring has six members, the exo-NH shift is upfield, as found for 5-membered chelate rings. However, the exo-NH-endo-CH COSY cross-peak is larger than the endo-NH-exo-CH COSY cross-peak, unlike the case of the 5-membered chelate ring of [Re(CO)₃(tmbSO₂-dien)] in a previous study in which the largest H-N-C-H torsion angle was ~157° for a ring in the exo-C conformation (Figure 5). For this compound, the endo-NH-exo-CH cross-peak was the strongest HN-CH cross-peak.²³

As found for 3, COSY data for [Re(CO)₃(dipn)]BF₄ (1) in DMSO-d₆ (Supporting Information) allowed us to establish that the exo-NH signal is upfield. Furthermore, unlike the case for symmetrical complexes with two 5-membered rings, the NH signals of the complexes with two 6-membered rings can be assigned unambiguously by COSY to either exo-NH or endo-NH. A COSY experiment on [Re(CO)₃(aepn)]PF₆ (6) in DMSO-d₆ showed NH-CH correlations (Supporting Information) which leave no doubt about the assignment of the NH signals (Figure 6) of the 6-membered ring. NMR results indicate that 6-membered rings in 1, 2, 3, and 6 have an endo-C conformation (Figure 5).

The COSY spectrum of 6 establishes that pucker of the 5-membered ring is endo-C in solution, the same conformation as in the solid. Thus the 6-membered ring induces a preferred endo-C conformation in the 5-membered ring in both the solution and solid states. Note that the ring bearing the tmbSO₂ group in the case of [Re(CO)₃(tmbSO₂-dien)] also induces a preferred ring conformation in both states, but this conformation is exo-C.²³

For [Re(CO)₃(trenH)](PF₆)₂ (4), both 5-membered chelate rings will time average between endo-C and exo-C conformations in solution. Thus, as expected for a symmetrical complex with two 5-membered rings, the NH-CH COSY cross-peaks in DMSO-d₆ have similar intensity and do not allow assignment of the signals to a specific proton (Figure S4, Supporting Information). However, we can use the clear pattern that the upfield NH signal arises from the exo-NH to assign the NH signals of 4 (Table 4).

Factors Influencing Shifts of NH Signals for Six- vs. Five-Membered Rings

Assignments and shifts of NH signals of new complexes in several solvents are summarized in Table 4. Spectra are shown in Figure 6 and in Supporting Information. An important goal of the current study is to understand factors influencing NH shifts for 6-membered rings. Our interest focuses on the dependence of shifts on through-space and solvent effects, and thus we must factor out the through-bond inductive effect on shift of the extra methylene group in the 6-membered rings vs. 5-membered rings of fac-[Re(CO)₃L]ⁿ complexes. The through-bond inductive effect is best assessed by considering the shift of the signal of the central NH group.

As illustrated in Figure 6, the central NH signal of [Re(CO)₃(dipn)]⁺ in DMSO-d₆, is more upfield (6.01 ppm, Table 4) than that of [Re(CO)₃(dien)]⁺ (6.98 ppm).²⁴ The more upfield shift of the NH signal of a central N joining 6-membered rings than for an N joining 5-membered rings²⁴ can also be observed in acetonitrile-d₃ and acetone-d (Table 4). Furthermore, the shift of the central NH of [Re(CO)₃(aepn)]⁺ is 6.47 ppm; thus, the shift for the compound with one 5- and one 6-membered ring is almost exactly between the shifts for the 5,5- and 6,6- compounds. This relationship is also found for the central NH signal of [Re(CO)₃(N,N-Me₂dipn)]⁺ (6.34 ppm) vs. that of its corresponding dien analogue, [Re(CO)₃(N,N-Me₂dien)]⁺ (7.02 ppm).²⁴ Thus, there is an inductive through-bond, upfield-shifting effect of ~0.3 to 0.5 ppm for every 5- to 6-membered ring change. This finding is also true for acetone-d₆ and acetonitrile-d₃, even though the specific values quoted above are for DMSO-d₆.

If this inductive effect alone were influencing the shifts of the exo-NH and endo-NH signals, then these also would be shifted upfield by ~0.3 to 0.5 ppm for every 5- to 6-membered ring change (Figure 6). For [Re(CO)₃(dipn)]⁺, in DMSO-d₆, the upfield exo-NH signal (3.78 ppm) is more upfield than the exo-NH signal for [Re(CO)₃(dien)]⁺ (4.14 ppm),²⁴ and the endo-NH signal (5.22 ppm) is also more upfield than for [Re(CO)₃(dien)]⁺ (5.43 ppm).²⁴ A comparison of NH shifts in DMSO-d₆ for this pair of complexes (Figure 6) and several more pairs of complexes [trpnH vs. trenH (Supporting Information); N’-Medipn vs. N’-Medien;²⁴ and N,N-Me₂dipn vs. N,N-Me₂dien²⁴] indicates that the exo-NH signal is upfield by an average of ~0.4 ppm and the endo-NH signal is upfield by an average of ~0.2 ppm for complexes with two 6-membered rings vs. those with two 5-membered rings. We attribute these differences to the inductive effect and suggest that the effect on signals of terminal amine proton signals is smaller than on central secondary amine NH signals. At present not enough information exists to interpret the causes of these small differences, but it is clear that the shifts of the NH₂ signals of one chelate ring depend slightly on the features of the other chelate ring (cf. Figure 6).

The NH protons of [Re(CO)₃(tacn)]⁺ (7) may be considered to resemble closely the central NH protons of Re tricarbonyl complexes containing 5-membered rings such as [Re(CO)₃(dien)]⁺. These NH protons are directed toward solvent, away from the hydrophobic pocket. The ¹H NMR shifts of the NH signals of [Re(CO)₃(tacn)]⁺ in DMSO-d₆ (7.06 ppm), acetonitrile-d₃ (5.57 ppm), and acetone-d₆ (6.62 ppm) are very similar to those of [Re(CO)₃(dien)]⁺ (6.98, 5.57, and 6.57 ppm in DMSO-d₆, acetonitrile-d₃, and acetone-d₆, respectively).²⁴ Because [Re(CO)₃(tacn)]⁺ lacks competing exo-NH and endo-NH protons, we use [Re(CO)₃(tacn)]⁺ as a control to help interpret the effect of Cl⁻ upon the central NH signals of the new complexes in the studies to be described next.

Interaction of exo-NH Groups with the Cl⁻ Anion

The effects of Cl⁻ addition on NH shifts for 5 mM solutions of several complexes in DMSO-d₆ were assessed. Upon the addition of Et₄NCl, the observed shift changes, Δδ, of the exo-NH signals of 1, 2, 4, 5 and 6 (Figures 7-9 and S5 and S6, Supporting Information) were downfield (+ values). (The smaller Δδ’s for the endo-NH and the central NH signals are discussed below.)

Figure 7.

Effect of Cl⁻ on Δδ of the NH signals of [Re(CO)₃(dipn)]PF₆ (1) and [Re(CO)₃(tacn)]PF₆ (7) (designated as tacn-NH) in DMSO-d₆ at 25 °C.

Figure 9.

Effect of Cl⁻ on Δδ of the NH signals of [Re(CO)₃(aepn)]PF₆ (6) in DMSO-d₆ at 25 °C. A COSY spectrum was used to assign the NH signals.

For [Re(CO)₃(dipn)]⁺ (1), the shift changes of the exo-NH signal (Δδ = ~1.4 ppm, plateau at [Cl⁻] of ~75 mM, Figure 7) were comparable to those for [Re(CO)₃(dien)]⁺ (Δδ = ~1.2 ppm, plateau at [Cl⁻] of ~100 mM).²⁴ Following a reported treatment of the Δδ data,²⁴ we calculated the equilibrium constant for ion-pairing ([Re(CO)₃L]ⁿ⁺ + X^m− ↔ [Re(CO)₃L]ⁿ⁺,X^m−) in DMSO-d₆ at 25 °C. A value of 168 ± 26 M⁻¹ was calculated for the equilibrium constant for [Re(CO)₃(dipn)]⁺ + Cl⁻ ↔ [Re(CO)₃(dipn)]⁺,Cl⁻. This value is comparable to that reported for [Re(CO)₃(dien)]⁺ (93 ± 11 M⁻¹).²⁴ The non-bonded distance between the two exo-NH’s in [Re(CO)₃(N’-Medipn)]PF₆ (2), a complex with two representative 6-membered conformations, is 2.475 Å, a value similar to the 2.509 Å distance in [Re(CO)₃(dien)]PF₆,²⁴ a representative compound with two 5-membered chelate rings.

The standard method for calculating ion-pairing equilibrium constants in DMSO-d₆ gave values for the [Re(CO)₃(aepn)]⁺,Cl⁻ equilibrium of 210 ± 12 M⁻¹ (exo-N1H Δδ plateau = 1.33 ppm) and 188 ± 13 M⁻¹ (exo-N3H Δδ plateau = 1.49 ppm) for the NH’s. In the molecular structure of 6 (Figure 2), the distance between the two exo-NH’s is 2.314 Å. For [Re(CO)₃(trenH)]²⁺ (4), this distance is 2.571 Å, and Cl⁻ ion-pairing caused a large Δδ for the exo-NH (1.2 ppm). For [Re(CO)₃(trpnH)]²⁺ (5), the distance between the exo-NH’s is 2.336 Å, and the exo-NH Δδ plateau = 1.5 ppm. However, the ion-pairing equilibrium constant could not be determined well, possibly because of the extra charge and the dangling charged group (see below).

The new results on exo-NH signals reported in this section are consistent with our previous interpretations as follows: the chloride ion interacts with the two exo-NH groups; this interaction involves the formation of H-bonds to chloride; and the two chelate rings sterically impede access of the solvent to the exo-NH’s.

Effect on endo-NH and Central NH Signals of Cl⁻ Anion Interaction with the exo-NH and Central NH Groups. DMSO-d₆ As Solvent

The plots of NH signal shift vs. Cl⁻¹ concentration (Figures 7-9 and in Figures S5 and S6, Supporting Information) are revealing. As the Cl⁻ concentration is increased, particularly beyond the concentration at which the large Δδ of the exo-NH signal plateaus, the endo-NH signals (and sometimes the central NH signal) shift upfield (−Δδ). At higher Cl⁻ concentration the shift changes reverse and the signal may shift downfield slightly (+Δδ) from the upfield-shifted position. These Δδ are not large (<0.2 ppm and usually < 0.1 ppm), but similar trends were found both in acetonitrile, see below, and in earlier studies.²⁴ Previously no attempt was made to explain the small shifts, but it is now clear that these small Δδ’s are real and are interpretable.

The Δδ for endo-NH and central NH signals can be explained by invoking two counteracting factors, one upfield-shifting and the other downfield-shifting. One or the other factor prevails in some cases, and the two nearly cancel each other in the other cases.

The downfield shifting factor arises from Cl⁻ H bonding with the NH group as discussed above. However, both the endo-NH and central NH groups are H-bonded to solvent and are downfield; thus the the Δδ’s are small in comparison to the Δδ observed for the less solvated exo-NH groups, which have upfield signals in the absence of Cl⁻ and exhibit large downfield Δδ’s in the presence of Cl⁻.

The upfield-shifting factor arises from the fact that Cl⁻ H-bonding with an NH group will result in the release of electron density from the N-H bond into the N-Re and N-C bonds. In the present study, the exo-NH bonds of the terminal amines are affected by this H-bonding. In turn, the electron density in the endo-NH bonds (and less so in the central NH bond) will increase, causing an upfield shift change (−Δδ). This explanation, which we believe is compelling, adds additional evidence that the ion-pairing at the exo-NH site involves H-bonding. Because the interaction of Cl⁻ at the exo-NH site is favorable, this upfield-shifting factor is most likely to prevail over the downfield-shifting factor at low Cl⁻ concentration. This reasoning explains the shift changes shown in Figures 7 to 9 and S5 to S9.

For [Re(CO)₃(dipn)]⁺ (1) and [Re(CO)₃(aepn)]⁺ (6) (Figure 2), the shift patterns of the two endo-NH signals DMSO-d₆ (Figures 7 and 9) are informative. At low Cl⁻ concentration the two endo-NH signals shift upfield. We believe this behavior is clear evidence for the preferred ion-pairing of the Cl⁻ to the exo-NH protons, which causes the electron density to increase near the endo-NH protons and the consequent upfield shift.

For [Re(CO)₃(dipn)]⁺ (1), as the Cl⁻ concentration is increased and the ion-pairing at the exo-NH site is saturated, the Cl⁻ added to the solution then builds to a sufficient concentration to interact detectably with the central NH, as can be deduced from the reversal of the direction of shift changes of the central NH signal (Figure 7). This H-bonding of the central NH begins to reverse the direction of the shift change around the plateau Cl⁻ concentration.

For [Re(CO)₃(dipn)]⁺ the endo-NH Δδ is ~ −0.1 ppm. However, for complexes in which the central N has an alkyl group, the endo-NH signal upfield shift change is smaller, such as for [Re(CO)₃(N’-Medipn)]⁺ (2) (Δδ ~ −0.03 ppm, Figure 8), [Re(CO)₃(trenH)]²⁺ (4) (Δδ ~ −0.04 ppm, Figure S5, Supporting Information), and [Re(CO)₃(trpnH)]²⁺ (5) (Δδ ~ −0.07 ppm, Figure S6, Supporting Information). This finding is readily explained by the fact that the central NH H-bonding site is absent. Thus, after the first anion to interact binds at the preferred exo-NH binding site, the next anion to interact with this ion pair necessarily forms an H-bond to the endo-NH proton. As a result, the changes in shift from the two factors (upfield shift from electron density changes from exo-NH interaction and downfield shift from endo-NH H-bonding) nearly cancel, and only very small endo-NH Δδ values are observed (Figure 8 and Figures S5 and S6, Supporting Information).

Figure 8.

Effect of Cl− on Δδ of the NH signals of [Re(CO)₃(N’-Medipn)]PF₆ (2) in DMSO-d₆ at 25 °C.

[Re(CO)₃(aepn)]⁺ (6) in DMSO-d₆ exhibits interesting behavior as the Cl⁻ concentration increases (Figure 9). The secondary Cl⁻ anion interaction with the central NH shifts this signal downfield. This is the same shift behavior we observed previously with [Re(CO)₃(dien)]⁺.²⁴ As we suggested above, the extra methylene group of the 6-membered rings leads to electron donation to the NH groups. Thus, the central NH is more electron-rich when attached to a 6-membered ring. The lower electron density of a 5-membered ring of [Re(CO)₃(aepn)]⁺ (6) is also indicated by the slight downfield shift of the upfield-shifted 5-membered ring endo-NH signal (Figure 9). No such Δδ is exhibited by the 6-membered ring endo-NH signal for [Re(CO)₃(aepn)]⁺ (6) (Figure 9).

When Cl⁻ was added to a 5 mM solution of [Re(CO)₃(tacn)]⁺ (7) in DMSO-d₆, only downfield shifting of the NH signal was observed (maximum Δδ = 0.17 ppm, light blue full circles, Figure 7). As mentioned above, the NH protons of 7 are directed toward solvent (Figure 4). Also, our analysis above comparing central NH shifts to the [Re(CO)₃(tacn)]⁺ NH shift indicates clearly that the NH groups in [Re(CO)₃(tacn)]⁺ are like the central NH of linear triamines. Thus, the downfield shift observed supports our interpretation that at high Cl⁻ concentration, the central NH groups form H bonds to added Cl⁻ anion.

For [Re(CO)₃(trenH)]²⁺ (4), the Cl⁻ ion-pairing caused a large Δδ for the exo-NH (1.2 ppm) and a small negative Δδ for the endo-NH (−0.04 ppm) signal (Figure S5, Supporting Information). This behavior is similar to that of other complexes without the dangling groups, such as [Re(CO)₃(N’-Medipn)]⁺ (2). This similarity suggests no synergism involving the dangling NH₃⁺ (Δδ = 0.8 ppm). Indeed, the protons of the dangling NH ⁺₃ group of [Re(CO)₃(trenH)]²⁺ cannot come close enough to interact with the Cl⁻ hydrogen bonded to the exo-NH groups in the 1:1 ion pair. After rotation of torsion angles using Chem3D software, the closest distance between endo-NH and NH₃⁺ protons is ~3.65 Å. Both protons could interact with a Cl⁻ anion in an ion pair. However, this type of synergistic ion-pair interaction appears to be unfavorable because neither plateauing of Δδ at low added Cl⁻ anion concentration nor significant endo-NH Δδ values were observed. Similar results were obtained for [Re(CO)₃(trpnH)]²⁺ (5) (Figure S6, Supporting Information).

Interaction of Cl⁻, Br⁻ and I– Anions with [Re(CO)₃(dipn)]⁺. Acetonitrile-d₃ As Solvent

In order to compare the effect of halide size on ion-pairing interactions with [Re(CO)₃(dipn)]⁺, the halide titration experiments were performed in acetonitrile-d₃, because we were concerned that the larger halide anions might bind too weakly in DMSO-d₆.

As expected from past studies with Et₄NCl,^24,32 the weakness of the interactions of acetonitrile with the NH as compared to DMSO facilitate Cl⁻ interaction with the exo-NH groups, leading to larger Δδ and lower Cl⁻ ion concentration for leveling off of Δδ (Δδ = 3 ppm, plateau at ~10 mM Cl⁻, Figure S7 Supporting Information). As found previously,²⁴ the sharpness of the shift changes makes the NMR method for determining ion pairing equilibrium constants inaccurate.

The above titration was repeated with a “buffering” amount of 50 mM Et₄NPF₆. Aliquots of a stock solution of 150 mM Et₄NCl and 5 mM [Re(CO)₃(dipn)]⁺ were added into a 5 mM [Re(CO)₃(dipn)]⁺ / 50 mM Et₄NPF₆ acetonitrile-d₃ solution. The Δδ values obtained (Figure S7 (right), Supporting Information) were almost identical to those obtained without added PF₆⁻ (Figure S7 (left), Supporting Information).

When the Et₄NBr salt was used, the final Δδ (2.5 ppm) was slightly less than for Et₄NCl; the plateau occurred at ~10 mM Br⁻ (Figure S8, Supporting Information). A much higher Et₄NI concentration (~15 mM) was required to reach a plateau (Δδ = 1.5 ppm) (Figure S9, Supporting Information). The interaction of halide ions with the exo-NH groups thus decreases in the order, Cl⁻ > Br⁻ > I⁻ (Figure 10).

Figure 10.

Effect of Cl⁻, Br⁻, and I⁻ on Δδ of the exo-NH signals of [Re(CO)₃(dipn)]PF₆ (1) in acetonitrile-d₃ at 25 °C.

Of some interest, the two counteracting factors (H-bonding-induced electron density changes at the proton and anion H-bonding) influencing Δδ of the endo-NH signal and the central NH signal in DMSO-d₆ also explain the Δδ of these NH signals in acetonitrile-d₃. In particular, as shown in Figure S9, Supporting Information, the endo-NH signal of [Re(CO)₃(dipn)]⁺ in acetonitrile-d₃ shifts upfield rather little (Δδ = −0.1 ppm) with added I⁻ compared to the effect of Cl⁻ (Δδ = −0.4 ppm). A small upfield shift could be caused by the downfield shifting effect of direct I⁻ interaction with the endo-NH. However, I⁻ has a very small direct effect. Thus, the smallness of the upfield shift undoubtedly arises from the weakness of the interaction of I⁻ with the endo-NH group. The interaction of I⁻ causes very little change in electron density at the endo-NH proton. The results fully support our conclusions above.

Interaction of the Paramagnetic Anion, [ReBr₆]²⁻, with [Re(CO)₃(dipn)]⁺

When [Bu₄N]₂[ReBr₆] was added to a 5 mM solution of [Re(CO)₃(dipn)]⁺ in acetonitrile-d₃, upfield shift changes (negative Δδ) for the NH signals were observed. At 1.65 mM [ReBr₆]²⁻, Δδ for the exo-NH (−3.6 ppm) was much greater than for the endo-NH (−1 ppm). However, during the titration, the exo-NH signal of 1 was often lost under CH₂ multiplets (both from 1 and from [Bu₄N]⁺ ions) in the ¹H NMR spectral region of 1-3.5 ppm.

We reasoned that by exchanging the NH’s to ND’s to obtain [Re(CO)₃(dipn-d₅)]⁺, and by performing ²H NMR spectroscopy on the sample in normal solvent (CH₃CN), we should be able to obtain exact Δδ values throughout the titration. Accordingly, ²H NMR experiments were performed on [Re(CO)₃(dipn-d₅)]⁺ (5 mM, 600 μL) in CH₃CN, and upfield Δδ were noted upon each addition of aliquots of a 30 mM stock solution of [Bu₄N]₂[ReBr₆] containing 5 mM [Re(CO)₃(dipn-d₅)]⁺. Figure 11 shows a plot of Δδ vs. [ReBr₆]²⁻ concentration. At a final [ReBr₆]²⁻ concentration of 10 mM, no further upfield shift was observed for the exo-ND signal, and the maximum Δδ was −6.1 ppm. For the endo-ND signal, the maximum Δδ was only ca. −1.8 ppm. For the central ND signal, the Δδ was negligible (0.03 ppm). Thus, the greater sensitivity of the exo-ND signal of 1 to the large paramagnetic [ReBr₆]²⁻ anion indicates clearly that this anion interacts with the exo-ND groups. The NMR data indicate strong interactions, and we estimate the ion-pairing constant to be greater than 1,000 M⁻¹. However, accurate constants cannot be obtained. We further note that the large negative Δδ values leave no doubt that [ReBr₆]²⁻ is acting as an outer-sphere paramagnetic shift reagent.

Figure 11.

Effect of [ReBr₆]²⁻ on Δδ of the ND signals of [Re(CO)₃(dipn-d₅)]PF₆ in DMSO-d₆ at 25 °C.

A preliminary investigation using [Re(CO)₃(N,N-Me₂dipn)]⁺ showed that the exo-NH group did not interact strongly with the [ReBr₆]²⁻ anion. This result is consistent with our interpretation of the nature of the anion interactions. Namely, we propose that the anions interact simultaneously with two exo-NH groups. Alternatively, the exo-NMe group could sterically prevent the anion from closely approaching the exo-NH.

Conclusions

The introduction of a third CH₂ group, changing a dimethylene chain bridging the donor atoms in a 5-membered chelate ring to a trimethylene chain, does not significantly alter the exposure of the exo-NH groups of fac-[Re(CO)₃L]ⁿ complexes to solvent. The exo-NH signal is relatively upfield for both 5- and 6-membered chelate rings. Adding the third CH₂ group affects chiefly the ring conformation and the electron richness of the central NH group anchoring the two chelate rings in fac-[Re(CO)₃L]ⁿ complexes.

The 6-membered chelate rings favor the chair conformation in both the solid and solution states. Specifically the most common conformations are designated as being endo-C. Thus, COSY data allow unambiguous assignment of the exo-NH and endo-NH signals, even when L is a symmetrical ligand. In contrast, the conformational interchange between the λ,λ and δ,δ conformations (or as we designate pucker, between the endo-C,exo-C and exo-C,endo-C conformations) precludes the use of COSY to assign NH₂ signals when L is a symmetrical ligand with two 5-membered rings. However, at least for L in which there are no dangling groups or in which the dangling group is on the central N, the signals can be assigned by recognizing that the upfield NH signal of the NH₂ group is the exo-NH signal.

The electron richness of the central NH group resulting from the third CH₂ group leads to upfield shifts of the NH signal, with the upfield-shifting inductive effect increasing along the series: two 5-membered rings < one 5- and one 6-membered ring < two 6-membered rings. Consistent with this trend, the interaction of the Cl⁻ anion with this central NH group (as assessed with ¹H NMR shift changes) decreases along this series, as would be expected from the increase in electron density at the proton. The latter observation reveals the utility of the use of the Cl⁻ anion in combination with ¹H NMR shift changes to probe the properties of the NH groups of complexes. Our work focuses on fac-[Re(CO)₃L]ⁿ complexes of potential radiopharmaceutical utility. However, the anion probe method to assess the solvation around complexes and the variation in electron distribution should apply to other types of compounds, including complexes of other metals. Indeed, the [ReBr₆]²⁻ anion appears to be a promising H-bonding outer-sphere paramagnetic shift reagent, which complements the halide ions used in this study and earlier.^24,32

The small upfield shifts observed for the endo-NH signal support the concept that two exo-NH groups simultaneously form H-bonds to the anion in the ion pair. These upfield endo-NH shifts are best understood as arising from the increase of electron density in the endo-N-H bond resulting from the interaction of the two exo-NH groups with the anion. Larger halide anions form H-bonds in the ion pair, but the interaction is weaker. The alteration of the electronic properties of L decreases with increasing halide size. Ion-pair stability decreases with halide size. However, the dianionic charge of the large [ReBr₆]²⁻ anion overcomes this instability problem to a large extent, and the increased stability provides another reason that this anion should be explored more fully in future as an outer-sphere shift reagent.

Synopsis.

New, structurally characterized fac-[Re(CO)₃L]ⁿ complexes with L = R₂N(CH₂)_nNR(CH₂)_nNH₂ (n = 2 or 3, R = Me or H) exhibit upfield-shifted NH signals for protons projecting into the L face. The use of anions as probes, including the new use of the [ReBr₆]²⁻ anion as a paramagnetic outer-sphere H-bonding shift reagent, establishes that these NH protons are not well solvated. Lack of solvation, induced by chelate ring bulk, accounts for the upfield shift.