Rigid orthogonal bis-TEMPO biradicals with improved solubility for dynamic nuclear polarization

Abstract

The synthesis and characterization of oxidized bis-thioketal-trispiro dinitroxide biradicals that orient the nitroxides in a rigid, approximately orthogonal geometry are reported. The biradicals show better performance as polarizing agents in dynamic nuclear polarization (DNP) NMR experiments as compared to biradicals lacking the constrained geometry. In addition, the biradicals display improved solubility in aqueous media due to the presence of polar sulfoxides. The results suggest that the orientation of the radicals is not dramatically affected by the oxidation state of the sulfur atoms in the biradical, and we conclude that a biradical polarizing agent containing a mixture of oxidation states can be used for improved solubility without a loss in performance.

Figure 1

Effect of sulfur oxidation on geometry. (A) Stick model of X-ray structure of biradical 7. (B) Stick model of X-ray structure of biradical 4. (C) Equilibrium geometry model of the trans, trans-tetrasulfoxide version of biradical 1.

Figure 2

9 GHz EPR spectra of biradical 4. (A) Room temperature liquid-state EPR spectra of 1 mM biradical 4 in DMSO/H2O (50/50 v/v). The spectrum was recorded with a 0.1 mT modulation amplitude. Simulations were performed using the EasySpin package using a correlation time of τ_c = 15 ns. (B) Low-temperature EPR spectrum taken at 77 K in d₈-THF. The spectrum was recorded using a modulation amplitude of 0.2 mT.

Figure 3

9 GHz EPR spectra of biradicals 8 and 7. (A) Spectrum of dinitroxide disulfoxide 8 in toluene at room temperature (J ≪ a_iso(¹⁴N)). (B) Spectrum of dinitroxide 7 in toluene at room temperature (J ≈ a_iso(¹⁴N)).

Figure 4

140 GHz EPR spectrum of biradical 4 in toluene recorded at 20 K. Top: absorption spectrum. Bottom: pseudo-modulated spectrum using a modulation amplitude of 0.4 mT, to remove high-frequency noise the spectrum was smoothened using a binominal weighted moving average function. Particular care was taken to not mask any spectral features. The spectrum was recorded using a three-pulse echo sequence with equally spaced pulses (π/2-τ-π/2-τ-π/2) giving overlap of the Hahn echo and stimulated echo for additional sensitivity. The π/2 pulse lengths were 120 ns, and the delay between pulses was 400 ns. 801 field points were acquired, with 300 shots per point, and 10 ms between shots.

Figure 5

140 GHz DNP enhancement profile and EPR spectrum of biradical 1. Top: 140 GHz EPR spectrum. Bottom: ¹H-detected DNP enhancement profile of biradical 1, biradical 8, bTbk, and TOTAPOL (data for bTbk and TOTAPOL taken from ref. 7). T = 90 K, t_p(π/2) = 3 μs. All enhancement profiles are recorded under similar experimental conditions.

Figure 6

DNP enhancements of TOTAPOL versus 1. The enhancement in the ¹³C-NMR signal of urea when biradical 1a (blue) is used as the polarizing agent is 10% greater than when TOTAPOL (red) is used under the same conditions. The signal in the absence of DNP enhancement is show at the bottom in black (magnified 10-times).

Figure 7

Microwave power dependent enhancement factors of Biradical 1 (blue), Biradical 8 (green) and TOTAPOL (red) for comparison. All polarizing agent solutions were prepared from the same glycerol/water mixture in order to maximize comparability. Enhancement factors were determined by recording a full build-up curve at each power level, and dividing the pre-exponential factor (Signal intensity at infinite time) of an exponential fit by the respective factor of a build-up curve recorded without mw irradiation for each biradical (off-signal). All experiments were performed at ~84 K.

Scheme 1

Synthesis of biradical 4.

Scheme 2

Synthesis of biradicals 7 and 8.

Scheme 3

Oxidation of 2b to biradical 1.

CHART 1