Research ArticlePHYSICS

Direct and cost-efficient hyperpolarization of long-lived nuclear spin states on universal 15N2-diazirine molecular tags

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Science Advances  25 Mar 2016:
Vol. 2, no. 3, e1501438
DOI: 10.1126/sciadv.1501438
  • Fig. 1 The hyperpolarization mechanism.

    (A) The precatalyst, 15N2-diazirine substrate, and p-H2 are mixed, resulting in the activated species depicted in (B). (B) Both p-H2 and the free 15N2-diazirine [2-cyano-3-(D3 methyl-15N2-diazirine)-propanoic acid] are in reversible exchange with the catalytically active iridium complex. The catalyst axial position is occupied by IMes [1,3-bis(2,4,6-trimethylphenyl)-imidazolium] and Py (pyridine) as nonexchanging ligands. The structure shown is a local energy minimum of the potential energy surface based on all-electron DFT calculations and the dispersion-corrected PBE density functional. In the complex, hyperpolarization is transferred from the parahydrogen (p-H2)–derived hydrides to the 15N nuclei (white, hydrogen; gray, carbon; blue, nitrogen; red, oxygen).

  • Fig. 2 Experimental and spectral distinction between magnetization and singlet spin order.

    (A) Experimental procedure. The sample is hyperpolarized by bubbling parahydrogen (p-H2) through the solution in the NMR tube for 5 min and subsequently transferred into the high-field magnet for detection. If the hyperpolarization/bubbling is performed in a magnetic shield at ~6 mG, z-magnetization is created (black). If the hyperpolarization/bubbling is performed in the laboratory field anywhere between ~0.1 and ~1 kG, singlet order is created (blue). (B) Z-magnetization and singlet spin order can easily be distinguished based on their spectral appearance. a.u., arbitrary units. Z-magnetization produces an in-phase quartet (black). Singlet order gives an anti-phase quartet (blue). The spin system parameters for the 15N2 two-spin system are JNN = 17.3 Hz and Δδ = 0.58 parts per million.

  • Fig. 3 Hyperpolarization buildup in the form of magnetization or singlet order.

    (A) Magnetization and singlet order as a function of magnetic field. The graph shows signal intensity after 5 min of bubbling. Magnetization is produced only at low magnetic fields inside the magnetic shield ideally at ~6 mG. Singlet order is obtained at any other magnetic field up to ~1 kG. (B) Spin systems and resonance conditions for forming magnetization versus singlet order. The condition for forming magnetization is field-dependent, whereas the condition for forming singlet order is not field-dependent, explaining the experimental observations of (A). (C) Polarization buildup as a function of bubbling time. Magnetization builds up faster, because the resonance condition can be matched exactly and T1 is shorter, whereas singlet order builds up slower because the matching condition is not met exactly and TS is longer. The measurements are performed with a methanol-d4 solution containing 12 mM 15N2-diazirine, 0.5 mM [IrCl(COD)(IMes)], 4 mM Py, and 960 mM D2O.

  • Fig. 4 Maximum enhancement levels and decay time constants observed for magnetization and singlet order.

    (A) Single-shot SABRE-SHEATH spectra obtained from a methanol-d4 solution containing 3 mM 15N2-diazirine, 0.125 mM [Ir(COD)(IMes)(Py)][PF6], and 240 mM D2O. Enhancements are obtained by comparison to the displayed thermal reference spectrum of the 15N2-diazirine [2-cyano-3-(D3-methyl-15N2-diazirine)-propanoic acid] in D2O. (In D2O, the chemical shift difference between the 15N nuclei is smaller than that in MeOH, and therefore, only one peak is observed.) (B) Representative T1 and TS decay measurements. T1 is measured at 120 G (12 mT) from a methanol-d4 solution containing 12 mM 15N2-diazirine, 0.125 mM [IrCl(COD)(IMes)], 1 mM Py, and 960 mM D2O. TS is measured at 3 G (0.3 mT) from a solution containing 12 mM 15N2-diazirine, 0.05 mM [IrCl(COD)(IMes)], and 0.4 mM Py. (C) The z-magnetization and singlet-order components are extracted from the data sets in (B) and fit to a single exponential (see the Supplementary Materials for further details).

Supplementary Materials

  • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/2/3/e1501438/DC1

    Synthesis of 15N2-diazirine and iridium precatalyst

    Theoretical derivation of resonance conditions for hyperpolarization transfer

    Spin dynamics during low- to high-field sample transfer

    MD simulations of possible transitions states for hyperpolarization transfer

    Sample preparation and setup to obtain well-controlled milligauss fields

    Hyperpolarization buildup dynamics, lifetimes, and enhancements in detail

    Appendix

    Fig. S1. Synthesis of 2-cyano-3-(3′-(methyl-d3)-3′H-diazirine-3′-yl-1′,2′-15N2)propanoic acid using modified literature procedures.

    Fig. S2. Spin system for polarization transfer.

    Fig. S3. Eigenstates of a J-coupled two-spin system as a function of magnetic field.

    Fig. S4. Simulated spectra for magnetization and singlet order.

    Fig. S5. Three candidate conformations of 2-cyano-3-(D3-methyl-15N2-diazirine)-propanoic acid as identified by DFT PBE + TS calculations, as used to construct likely catalytically active structures producing hyperpolarization attached to the SABRE catalyst.

    Fig. S6. First-principles derived candidate conformations of catalytic species that drive hyperpolarization transfer.

    Fig. S7. Experimental SABRE-SHEATH setup.

    Fig. S8. Decay time constants, buildup constants, and enhancements as a function of magnetic field and concentrations.

    Fig. S9. The effect of continued singlet-polarization buildup after stopping p-H2 bubbling.

    Table S1. Relative energies of the diazirine attachment modes tested in this work for the case of two different ligands that are simultaneously present: two equatorial hydrides, axial IMes, axial pyridine, one equatorial pyridine, and diazirine in an equatorial position.

    Table S2. Relative energies of the diazirine attachment modes tested in this work for the case of two diazirine molecules that are simultaneously present.

    Table S3. Magnetization lifetimes, T1, under varying catalyst concentrations and holding fields.

    Table S4. Singlet lifetimes, TS, under varying catalyst concentrations and holding fields.

    Table S5. Magnetization buildup times, Tb1, at 6 mG under varying catalyst concentrations.

    Table S6. Singlet buildup times, TbS, under varying catalyst concentrations and magnetic fields.

    Table S7. Enhancements, ε, under varying concentrations of catalyst [IrCl(COD)(IMes)] (1a), [Ir(COD)(IMes)(Py)][PF6] (1b), diazirine substrate (2), pyridine (3), and D2O (4).

    References (5569)

  • Supplementary Materials

    This PDF file includes:

    • Synthesis of 15N2-diazirine and iridium precatalyst
    • Theoretical derivation of resonance conditions for hyperpolarization transfer
    • Spin dynamics during low- to high-field sample transfer
    • MD simulations of possible transitions states for hyperpolarization transfer
    • Sample preparation and setup to obtain well-controlled milligauss fields
    • Hyperpolarization buildup dynamics, lifetimes, and enhancements in detail
    • Appendix
    • Fig. S1. Synthesis of 2-cyano-3-(3′-(methyl-d3)-3′H-diazirine-3′-yl-1′,2′-15N2) propanoic acid using modified literature procedures.
    • Fig. S2. Spin system for polarization transfer.
    • Fig. S3. Eigenstates of a J-coupled two-spin system as a function of magnetic field.
    • Fig. S4. Simulated spectra for magnetization and singlet order.
    • Fig. S5. Three candidate conformations of 2-cyano-3-(D3-methyl-15N2-diazirine)-propanoic acid as identified by DFT PBE + TS calculations, as used to construct likely catalytically active structures producing hyperpolarization attached to the SABRE catalyst.
    • Fig. S6. First-principles derived candidate conformations of catalytic species that drive hyperpolarization transfer.
    • Fig. S7. Experimental SABRE-SHEATH setup.
    • Fig. S8. Decay time constants, buildup constants, and enhancements as function of magnetic field and concentrations.
    • Fig. S9. The effect of continued singlet-polarization buildup after stopping p-H2 bubbling.
    • Table S1. Relative energies of the diazirine attachment modes tested in this work for the case of two different ligands that are simultaneously present: two equatorial hydrides, axial IMes, axial pyridine, one equatorial pyridine, and diazirine in an equatorial position.
    • Table S2. Relative energies of the diazirine attachment modes tested in this work for the case of two diazirine molecules that are simultaneously present.
    • Table S3. Magnetization lifetimes, T1, under varying catalyst concentrations and holding fields.
    • Table S4. Singlet lifetimes, TS, under varying catalyst concentrations and holding fields.
    • Table S5. Magnetization buildup times, Tb1, at 6 mG under varying catalyst concentrations.
    • Table S6. Singlet buildup times, TbS, under varying catalyst concentrations and magnetic fields.
    • Table S7. Enhancements, ε, under varying concentrations of catalyst IrCl(COD)(IMes) (1a), Ir(COD)(IMes)(Py)PF6 (1b), diazirine substrate (2), pyridine (3), and D2O (4).
    • References (55–69)

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