Six-coordinate Iron(II) and Cobalt(II) paraSHIFT Agents for Measuring Temperature by Magnetic Resonance Spectroscopy

Abstract

Paramagnetic Fe(II) and Co(II) complexes are utilized as the first transition metal examples of (1)H NMR shift agents (paraSHIFT) for thermometry applications using Magnetic Resonance Spectroscopy (MRS). The coordinating ligands consist of TACN (1,4,7-triazacyclononane) and CYCLEN (1,4,7,10-tetraazacyclododecane) azamacrocycles appended with 6-methyl-2-picolyl groups, denoted as MPT and TMPC, respectively. (1)H NMR spectra of the MPT- and TMPC-based Fe(II) and Co(II) complexes demonstrate narrow and highly shifted resonances that are dispersed as broadly as 440 ppm. The six-coordinate complex cations, [M(MPT)](2+) and [M(TMPC)](2+), vary from distorted octahedral to distorted trigonal prismatic geometries, respectively, and also demonstrate that 6-methyl-2-picolyl pendents control the rigidity of these complexes. Analyses of the (1)H NMR chemical shifts, integrated intensities, line widths, the distances obtained from X-ray diffraction measurements, and longitudinal relaxation time (T1) values allow for the partial assignment of proton resonances of the [M(MPT)](2+) complexes. Nine and six equivalent methyl protons of [M(MPT)](2+) and [M(TMPC)](2+), respectively, produce 3-fold higher (1)H NMR intensities compared to other paramagnetically shifted proton resonances. Among all four complexes, the methyl proton resonances of [Fe(TMPC)](2+) and [Co(TMPC)](2+) at -49.3 ppm and -113.7 ppm (37 °C) demonstrate the greatest temperature dependent coefficients (CT) of 0.23 ppm/°C and 0.52 ppm/°C, respectively. The methyl groups of these two complexes both produce normalized values of |CT|/fwhm = 0.30 °C(-1), where fwhm is full width at half-maximum (Hz) of proton resonances. The T1 values of the highly shifted methyl protons are in the range of 0.37-2.4 ms, allowing rapid acquisition of spectroscopic data. These complexes are kinetically inert over a wide range of pH values (5.6-8.6), as well as in the presence of serum albumin and biologically relevant cations and anions. The combination of large hyperfine shifts, large temperature sensitivity, increased signal-to-noise ratio, and short T1 values suggests that these complexes, in particular the TMPC-based complexes, show promise as paraSHIFT agents for thermometry.

Figure 1

ORTEP plots of two structural diastereomers of [Fe(MPT)](CF₃SO₃)₂ presented by A) Fe4 – Λ(λλλ) and B) Fe3 – Λ(δδδ) isomers. ORTEP plot of [Co(MPT)](NO₃)₂ shows C) Λ(λλλ) isomer. Hydrogen atoms, solvent molecules and counter ions are omitted for clarity. Ellipsoids are set at 50%. Twist angles (θ) are shown for the projections of two triangles formed by three donor atoms each when viewed down the C₃-axis of symmetry.

Figure 2

ORTEP plots of (A) [Fe(TMPC)](CF₃SO₃)₂ and (B) [Co(TMPC)]Cl₂ that both have Λ(δδδδ) configuration. Hydrogen atoms, solvent molecules and counter ions are omitted for clarity. Ellipsoids are set at 50%. Twist angles (θ) are shown for the projections of two triangles formed by three donor atoms each when viewed down the quasi-C₃ axis of symmetry perpendicular to the C₂-axis of symmetry.

Figure 3

¹H NMR spectra of [Fe(MPT)]²⁺ (A) and [Co(MPT)]²⁺ (B) in D₂O, pD 7.0–7.6, at 25 °C. Insert B shows expanded region of the [Co(MPT)]²⁺ spectra around solvent peak. Solvent peaks are labeled “s”.

Figure 4

¹H NMR spectra of (A) [Fe(TMPC)]²⁺ and (B) [Co(TMPC)]²⁺ in D₂O, pD 7.0–7.4, at 25 °C. Inserts show expanded diamagnetic regions. Solvent peaks are labeled “s”.

Figure 5

(A) ¹H NMR temperature dependence of α-CH₃ chemical shift of [Fe(MPT)]²⁺ (●), [Co(MPT)]²⁺ (○), [Fe(TMPC)]²⁺ (▼) and [Co(TMPC)]²⁺ (Δ). Solid lines represent linear fits of the data. (B) ¹H NMR overlaid plot: Temperature dependence of α-CH₃ chemical shift of [Co(TMPC)]²⁺ in the range 37–41 °C.

Scheme 1