Endeavor toward Redox-Responsive Transition Metal Contrast Agents Based on the Cross-Bridge Cyclam Platform

Abstract

We present the synthesis and characterization of a series of Mn(III), Co(III), and Ni(II) complexes with cross-bridge cyclam derivatives (CB-cyclam = 1,4,8,11-tetraazabicyclo[6.6.2]hexadecane) containing acetamide or acetic acid pendant arms. The X-ray structures of [Ni(CB-TE2AM)]Cl₂·2H₂O and [Mn(CB-TE1AM)(OH)](PF₆)₂ evidence the octahedral coordination of the ligands around the Ni(II) and Mn(III) metal ions, with a terminal hydroxide ligand being coordinated to Mn(III). Cyclic voltammetry studies on solutions of the [Mn(CB-TE1AM)(OH)]²⁺ and [Mn(CB-TE1A)(OH)]⁺ complexes (0.15 M NaCl) show an intricate redox behavior with waves due to the Mn^III/Mn^IV and Mn^II/Mn^III pairs. The Co(III) and Ni(II) complexes with CB-TE2A and CB-TE2AM show quasi-reversible features due to the Co^III/Co^II or Ni^II/Ni^III pairs. The [Co(CB-TE2AM)]³⁺ complex is readily reduced by dithionite in aqueous solution, as evidenced by ¹H NMR studies, but does not react with ascorbate. The [Mn(CB-TE1A)(OH)]⁺ complex is however reduced very quickly by ascorbate following a simple kinetic scheme (k₀ = k₁[AH^-], where [AH^-] is the ascorbate concentration and k₁ = 628 ± 7 M^-1 s^-1). The reduction of the Mn(III) complex to Mn(II) by ascorbate provokes complex dissociation, as demonstrated by ¹H nuclear magnetic relaxation dispersion studies. The [Ni(CB-TE2AM)]²⁺ complex shows significant chemical exchange saturation transfer effects upon saturation of the amide proton signals at 71 and 3 ppm with respect to the bulk water signal.

Chart 1. Ligands Discussed in This Work.

Figure 1

ORTEP view of the structure of the [Ni(CB-TE2AM)]²⁺ (left) and [Mn(CB-TE1AM)(OH)]²⁺ (right) complexes (50% ellipsoid probability). Hydrogen atoms and water molecules are omitted for simplicity.

Figure 2

Absorption spectra of the [Mn(CB-TE1A)(OH)]⁺ complex recorded as a function of pH. The blue trace corresponds to pH 8.35 and the red trace corresponds to pH 2.18. The inset shows the variation of the molar extinction coefficient at 397 nm with pH.

Figure 3

¹H NMR spectrum (500 MHz) of the [Co(CB-TE2AM)]²⁺ complex recorded in D₂O solution, pH 3.76. The Co(II) complex was generated by adding an ascorbate excess to a solution of the Co(III) complex in a glovebox, employing a screw-cap NMR tube. The presence of traces of oxygen results in very fast oxidation to the Co(III) complex. The sharp signals close to the residual HDO solvent peak are due to partial oxidation of the complex.

Figure 4

Z-spectra of the 7 mM [Ni(CB-TE2AM)]²⁺ complex acquired at 298 K (top) and 310 K (bottom) recorded using different saturation powers B₁ (11.75 T, saturation time 2 s, pH 7.0).

Figure 5

Cyclic voltammograms of the Co(III) (a) and Ni(II) (b) complexes recorded from ca. 2 mM aqueous solutions (0.15 M NaCl, pH 7.1, scan rate 0.01 V s^–1).

Figure 6

Cyclic voltammograms of the Mn(III) complex of CB-TE1A^– recorded at different pH values (0.15 M NaCl, scan rate 0.25 V s^–1).

Figure 7

Pseudo-first-order rate constants for the reaction of [Mn(CB-TE1A)(OH)]⁺ with ascorbate ([Tris]_tot = 0.050 M; I = 0.15 M NaCl) at pH 8.55 (green squares) and pH 7.70 (blue circles). The red line corresponds to the linear fit of the data to k₀ = k₁[AH^–] with k₁ = 628 ± 7 M^–1 s^–1.

Figure 8

¹H NMRD profiles recorded for the [Mn(CB-TE1A)(OH)]⁺ complex in the absence of ascorbic acid at different temperatures [283 K (blue ◆), 298 K (◆), and 310 K (red ◆) and in the presence of an excess (5 equiv) of ascorbate (298 K (●))].