Transferred Overhauser DNP: A Fast, Efficient Approach for Room

Article pubs.acs.org/JPCB

Transferred Overhauser DNP: A Fast, Efficient Approach for Room Temperature 13C ODNP at Moderately Low Fields and Natural Abundance Arnab Dey, Abhishek Banerjee, and Narayanan Chandrakumar* MRI-MRS Centre and Deparment of Chemistry, Indian Institute of Technology Madras, Chennai 600036, Tamil Nadu, India S Supporting Information *

ABSTRACT: Overhauser dynamic nuclear polarization (ODNP) is investigated at a moderately low field (1.2 T) for natural abundance 13C NMR of small molecules in solution state at room temperature. It is shown that ODNP transferred from 1H to 13C by NMR coherence transfer is in general significantly more efficient than direct ODNP of 13C. Compared to direct 13C ODNP, we demonstrate over 4-fold higher 13C sensitivity (signal-to-noise ratio, SNR), achieved in one-eighth of the measurement time by transferred ODNP (t-ODNP). Compared to the 13C signal arising from Boltzmann equilibrium in a fixed measurement time, this is equivalent to about 1500-fold enhancement of 13C signal by tODNP, as against a direct 13C ODNP signal enhancement of about 45-fold, both at a moderate ESR saturation factor of about 0.25. This owes in part to the short polarization times characteristic of 1H. Typically, t-ODNP reflects the essentially uniform ODNP enhancements of all protons in a molecule. Although the purpose of this work is to establish the superiority of t-ODNP vis-à-vis direct 13C ODNP, a comparison is also made of the SNR in t-ODNP experiments with standard high resolution NMR as well. Finally, the potential of t-ODNP experiments for 2D heteronuclear correlation spectroscopy of small molecules is demonstrated in 2D 1H−13C HETCOR experiments at natural abundance, with decoupling in both dimensions.

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possible direct ODNP signal enhancements of 13C NMR, which relate to the ratio of the values of the electron γ and 13C γ, amount to −1308.5 in the dipolar limit and to +2617 in the scalar limit. Indeed, maximum observed 13C signal enhancements of several hundred-fold (with top magnitudes ranging between six hundred and nine hundred) have been reported in favorable cases,21,22 some of these measurements having been performed on 13C enriched samples. 13C ODNP measurements have been reported for a wide range of magnetic fields and ESR/NMR frequencies: in particular, at ca. 74, 176, 3400, 8000, 12000, and 21000−22000 G, and lately at 33600 G. This translates to ESR frequencies of ca. 207 MHz, 493 MHz, 9.5 GHz (X-band), 22.4 GHz (K-band), 34 GHz (Q-band), 60 GHz (V-band), and 94 GHz (W-band) respectively, the corresponding 13C NMR frequencies being ca. 80 kHz, 188 kHz, 3.6 MHz, 8.6 MHz, 12.8 MHz, 22.9 MHz, and 36 MHz. Although 13C Larmor frequencies of ca. 3.5 MHz and beyond would in principle be suitable for chemical shift resolved 13C NMR spectroscopy, this aspect has perhaps not quite received prime attention, the 13C line width in a recent report with impressive sensitivity enhancement, for example, being some 360 Hz (10 ppm at W-band).22

INTRODUCTION Dynamic nuclear polarization (DNP),1−6 which is one of the earliest and most well-known nuclear spin polarization techniques, has witnessed an energetic revival in recent years, especially in the solid state at low temperature. DNP in the solid state principally exploits the cross effect, the solid effect, or the Overhauser effect. The experiment may be directly employed for sensitivity enhancement of low temperature solid state MAS NMR.7−14 It may also be adapted to solution state NMR by suitable sample melting or dissolution strategies, following low temperature DNP by microwave irradiation for a duration that is typically several tens of minutes. The sample in solution state, following dissolution or melting, is then transferred to a standard NMR spectrometer (dissolution DNP, dDNP).15−18 However, dDNP is prone to relatively poor shim conditions owing to sudden sample injection.19,20 It also suffers from significant relaxation losses during melting and transfer of the sample. These losses affect, in particular, abundant nuclear spins with high magnetogyric ratio γ, whose relaxation rates are typically relatively high. This generally motivates “reverse” polarization transfer from low abundance, low γ spins to abundant high γ spins in dDNP experiments.19,20 Because 13C NMR signals at natural abundance are about 5900 times weaker than 1H NMR signals, Overhauser DNP (ODNP) enhancements of 13C NMR have been investigated since the early years of DNP experiments.21−29 The maximum © XXXX American Chemical Society

Received: May 25, 2017 Revised: June 28, 2017 Published: June 28, 2017 A

DOI: 10.1021/acs.jpcb.7b05081 J. Phys. Chem. B XXXX, XXX, XXX−XXX

Article

The Journal of Physical Chemistry B Here we report practical ODNP-enhanced, 1H-decoupled high resolution 13C NMR with line widths down to about 10 Hz, working at Q-band at room temperature. It is shown on a 13 C enriched sample with ODNP transferred from 1H to the coupled 13C that even a modest ESR saturation factor (s) on the order of 0.25 (as inferred from a study of the microwave power dependence of the 1H enhancement), leads to over 4fold higher 13C sensitivity in one-eighth the measurement time, compared to direct 13C ODNP. This approach may be termed as transferred-ODNP (t-ODNP). Compared to the signal generated directly from 13C spins at Boltzmann equilibrium in a given measurement time, t-ODNP leads to about 1500-fold 13C signal enhancement, as against a direct 13C ODNP signal enhancement of about 45-fold. As an initial demonstration of the practical capability of this approach, we report t-ODNP enhanced 2D 1 H−13C correlation spectroscopy (HETCOR)30−32 experiments at Q-band at natural 13C abundance, the 2D spectra being decoupled in both dimensions. It may be noted that in all these cases it is impractical to measure the natural abundance 13C spectra under Boltzmann conditions, as may be judged from the fact that 256 scans were required to acquire the direct equilibrium 13C signal from 99% 13Cenriched CH3OH.

To appreciate the scope of t-ODNP, we recall here the variation of the ODNP coupling parameter ξ as a function of ωτ (the product of the electron Larmor frequency ω and the motional correlation time τ).4,5 The early general models (eg. the Hubbard model4) employed to generate analytical solutions, and therefrom, graphical plots, are isotropic random motional models, where translational and rotational motions are separable for two-spin systems. More recent molecular dynamics (MD) simulations (eg. on the TEMPO/H2O, TEMPOL/H2O, and TEMPONE/H2O systems) suggest that the approach of the radical to the substrate molecule could have an orientational preference.35−37 While, in summary, the recent MD simulations suggest that the coupling parameter could be higher than predicted based on the Hubbard model, especially at higher frequencies (with a frequency dependence possibly as favorable as ω−1), the latter has the merit of presenting what may be viewed as the general solution for the “worst case scenario”, and we adopt this approach for our purposes here. In the Hubbard model, as is well-known, translational dipolar interactions of the radical with the substrate molecule lead to substantial enhancements at considerably higher frequencies (with an ω−3/2 freqeuency dependence), compared to the rotational model (which has an ω−2 frequency dependence). For a translational correlation time of 40 ps, 1H ODNP, which is predominantly controlled by translational dipolar interactions of the substrate molecule with the free radical, already falls on the Hubbard model at Q-band to a coupling parameter of about 0.12 (vide Figure 1 and Table 1), as against its maximum value

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PRINCIPLES The ODNP enhancement is given by the well-known expression: γ ⟨Iz⟩ − ⟨I0⟩ = ξfs S ⟨I0⟩ γI

(1)

Here, I denotes the nuclear spin and S, the electron spin; the coupling parameter ξ is the ratio of the electron−nuclear cross relaxation rate and the nuclear auto relaxation rate; f is the leakage factor, which measures the deviation from 1 of the ratio of the nuclear spin T1 in the presence and in the absence of free radical; s is the ESR saturation factor; and γS is the magnetogyric ratio of the electron spin, while γI is that of the nucleus in question. While direct ODNP of 13C in solution state is well-known since long as stated earlier, it suffers in general from the requirement of rather long polarization times (tens of seconds), and further results in differential enhancements, i.e., site specific positive or negative enhancements in the same molecule. Direct 13C enhancements are also influenced by three-spin effects,29,33,34 especially at low radical concentrations. Differential enhancements and three-spin effects could both be of interest if the purpose were investigation of molecular dynamics or spin interaction dynamics. However, these characteristics would not, on the other hand, be conducive to sensitivity enhanced NMR for structure elucidation purposes. In this work, we adopt a quite different approach, relying on relatively rapid ODNP buildup of 1H spins at the molecular periphery (which typically takes no longer than a second), followed by NMR polarization transfer to 13C at natural abundance. Typically, eight or more such t-ODNP scans are possible in the time it takes for a single scan with direct 13C ODNP. It may be noted that at such a short 1H polarization time, direct 13C polarization hardly takes effect, thereby avoiding the complications of differential 13C enhancements. While we intend to examine t-ODNP at multiple fields (especially at 0.35, 1.2, and 3.36 T), the present report focuses on work at 1.2 T.

Figure 1. ODNP relative enhancement curves4,5 at s = 1 and f = 1, in units of γirr/γobs, as a function of ωτ for dipolar and scalar cross relaxation, the latter with various values of the weightage factor k for “leakage” nuclear relaxation mechanisms. ω is the electron Larmor frequency, while τ is the motional correlation time; the nuclear Larmor frequency is approximated to 0 to obtain these general plots, which have been generated for a motional correlation time of 40 ps.

of 0.5. This implies that the maximum magnitude of the 1H enhancement at Q-band would be only about (−)80, which would be attained for an ESR saturation parameter of 1, and a leakage factor also of 1. On the other hand, at X-band the maximum 1H enhancement would be about (−)200 for this motional correlation time (vide Figure 1 and Table 1), and about (−)23 at W-band. Dipolar 1H enhancements are essentially uniform across different sites of small molecules since these interactions are not site specific; minor intramolecular variations of motional characteristics, for example at methyl groups, lead to changes of a few percent in enhancement. In contrast, direct 13C enhancements would B


The Journal of Physical Chemistry B

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EXPERIMENTAL SECTION Polarization of the sample is achieved directly in solution state in situ by irradiating the ESR transition of an added free radical; this is then followed by acquisition of the NMR spectrum also in situ, without transferring the sample to a different magnet. Our experiments were all carried out on a spectrometer system with coil-in-cavity configuration that is doubly resonant to radiofrequency (RF) and microwaves. It may be noted that the instrumentation includes the capability of two-way triggering between a Bruker ELEXSYS microwave system and a Bruker AV III NMR acquisition server. In particular, microwave (MW) irradiation, used to saturate the electron spin transitions prior to NMR excitation, is triggered from the NMR pulse sequence. The duration of MW irradiation may be directly controlled, or altered in units of a loop counter in the pulse sequence, using a basic loop duration; at the end of MW irradiation, control is handed back to the NMR pulse sequence. The maximum microwave power output available was ca. 2.5 W with 100% duty cycle at Q-band. A stream of nitrogen was passed through the cavity to maintain temperature. 1H and 13C 90° RF pulse widths were 5 μs @ 30 W and 11 μs @ 30 W respectively. All experiments were performed with a Bruker SQFT ENDOR resonator. For NMR sensitivity and nuclear isotope selectivity, two-channel tuning and matching boxes (1H and 13C) were employed along with relevant filters (high pass filter for 1H/19F, and low pass filter for 13C). A Bruker 10″ electromagnet was employed, with 12 kW power supply. While this approach avoids complexities and problems associated with other contemporary DNP modalities, care is to be exercised in handling samples with high dielectric constants and/or high molecular dipole moments; besides, sample sizes are limited by the microwave resonator dimensions. Sample Preparation. For polarization transfer from the unpaired electron to 1H using ODNP, TEMPO was employed in the present studies, samples being prepared with the TEMPO free radical at typically 20 mM concentration. Samples were sonicated and degassed by bubbling pure, dry nitrogen gas through them to remove dissolved oxygen. The experiments were performed at room temperature (ca. 27 °C) in 1.6 mm o.d. sample tubes at Q-band (i.d. 1.1 mm), dry nitrogen being continuously passed through the cavity. A 0.9 mm o.d. sample tube was used for the 13CH3OH study (0.5 mm i.d.); single scan direct 13C ODNP enhancements on this enriched sample remained stable over several individual scans with polarization time of 15 s and interscan delay of 120−150 s.

Table 1. Field/Frequency Dependence of the Coupling Parameter ξ for Different Modes of Intermolecular Electron Nuclear Interaction (Motional Correlation Time: 40 ps), on the Isotropic Stochastic Model different modes of electron−nuclear interaction

value of coupling parameter for multiband DNP X

dipolar interaction

scalar interaction with leakage (weightage k)

Q

W

translational motion rotational motion k=0

−1

−1

−1

k k k k k

−0.939 −0.748 −0.592 −0.231 −0.13

−0.578 −0.2169 −0.1248 −0.0327 −0.0114

−0.1602 −0.0398 −0.022 −0.0114 −0.0079

= = = = =

0.01 0.05 0.1 0.5 1

0.2998

0.123

0.0351

0.1763

0.0204

0.0028

Article

not be easily predictable, owing to mixed dipolar and scalar interactions. While 13C enhancement due to dipolar cross relaxation with the unpaired electron would behave similarly as for 1H, 13C enhancements due to scalar cross relaxation of the first kind are inherently field independent, but also do tail off in practice at high frequencies, as a function of the contribution of leakage relaxation. It is to be noted especially that competition between scalar and dipolar effects could result in partial cancellation of direct 13C ODNP enhancements. It follows that t-ODNP, i.e., ODNP of 1H followed by 1 H−13C transfer, reflects the essentially uniform dipolar negative enhancements characteristic of 1H ODNP; however, relatively minor variation could occur in internuclear polarization transfer (PT) efficiency (e.g., INEPT, refocused INEPT, DEPT, or JCP) owing to a distribution of heteronuclear coupling constant values. This latter effect may be minimized by applying suitable composite pulse strategies,38,39 if required. The experimental pulse sequence for our t-ODNP work is shown in Figure 2. Experimental details including sample preparation are given in the Experimental section, which follows.

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RESULTS AND DISCUSSION For direct comparison of enhancement efficiencies, we have employed solutions of 13CH3OH with about 40 mM TEMPO dissolved in them. The signal enhancement in each case of ODNP has been obtained, in accordance with eq 1, from the integral of the signal, taking its ratio to the single scan signal integral under the Boltzmann condition (which is calculated by scaling the experimental multiscan Boltzmann signal integral by the number of scans), and subtracting 1 from this ratio. It may be noted that signal integration, which measures the area under the peak, renders the result essentially independent of any line width changes, and scales in direct proportion to the number of scans. An error of the order of 10% is associated with the signal enhancements tabulated below. As a measure of more direct practical relevance, the SNR is also given in each case. The

Figure 2. Pulse sequence diagram for ODNP enhanced 2D heteronuclear correlation experiments (HETCOR). The EPR transition of the added free radical is first irradiated at its microwave resonance frequency, followed by a standard 2D HETCOR pulse sequence. Here δ1 and δ2 are dephasing and rephasing delays ((2J)−1 and ca. (3J)−1 respectively), while CPD indicates composite pulse decoupling during signal acquisition. Other standard 2D sequences for heteronuclear correlation may be similarly implemented, both for direct and indirect detection work, employing either laboratory frame or rotating frame coherence transfer modules. C


Article


stabilize the field during experiments. Nevertheless, short-term fluctuations of the field could not be arrested. We may mention here that our ODNP enhanced HETCOR studies have been performed with rather small amounts of sample in the range from 25 μmol to a maximum of 70 μmol for the samples investigated at natural abundance, and ca. 30 μmol for 13C enriched methanol. Such a low sample requirement could be especially useful in sample limited cases such as measurements on natural products. We have also carried out measurements on some small perfluorinated molecules in t-ODNP mode, with similar attendant advantages. It may be recalled that 19F ODNP also exhibits rapid polarization build-up rates, but could in general exhibit mixed scalar and dipolar interactions, leading again to differential ODNP enhancements at different sites in the same molecule. However, we anticipate that redistribution of ODNP-enhanced 19F polarization by homonuclear isotropic mixing (eg. with an ASAP-type module40) would result in more uniform polarization across the molecule, and would minimize the impact of differential enhancements on subsequent 19F−13C transfer. 19F ODNP is known to exhibit significant field and radical dependence; however, negative (dipolar) enhancements are common at X-band, while positive (scalar) enhancements are common at W-band; we have achieved 19F spectral line widths of the order of 5−10 Hz at both bands.41 Comparison of t-ODNP with Standard High Resolution NMR. While our present studies clearly establish the superiority of t-ODNP relative to direct 13C ODNP, we would also like to place these in situ ODNP measurements that employ an EPR spectrometer with coil-in-cavity arrangement, together with an NMR acquisition server, in context vis-à-vis standard high resolution 13C NMR work. To this end, we have measured a 1H decoupled single scan spectrum of methanol with 13C at natural abundance at 11.75 T, and compared the 13 C SNR obtained from the corresponding single scan t-ODNP experiment at 1.2 T using a 99% 13C-enriched sample. The resulting SNR values are respectively 128 and 53, the spin count being a factor 2.8 smaller in the t-ODNP experiment. Since our present saturation factor is only ca. 0.25, it may be anticipated that a sensitivity figure of about 128 would however be readily achieved for t-ODNP at this spin count (a further factor of 2.4fold enhancement, corresponding to a saturation factor of ca. 0.6), e.g., in conjunction with an arbitrary microwave waveform generator (AWG).42,43 In the present case where TEMPO is the polarizer, 15N-TEMPO would also help improve the saturation factor,22 because of a hyperfine doublet rather than the triplet from normal 14N-TEMPO. Clearly, the single scan t-ODNP SNR anticipated with the AWG and/or 15N-TEMPO would thus be a factor of 90 below the standard 13C sensitivity on a 500 MHz high resolution NMR spectrometer (not counting the disparity in spin count, which actually makes it a factor of just over 32). We briefly

relevant 13C NMR spectra are displayed in Figure 3, and the experiments are summarized in Table 2.

Figure 3. 13C spectra of 13C enriched methanol with 1H decoupling. For the refocused INEPT module of t-ODNP, the refocusing delay was optimized to the 1H−13C coupling constant (141 Hz). 40 mM TEMPO was used as the source of polarization. For direct 13C ODNP and t-ODNP, the optimal polarizing time was 15 and 1 s, respectively. For the Boltzmann signal a 16 s recycle delay was used, and the spectrum is scaled down to the same noise level as the DNP spectrum.

All other experiments reported here have been performed at natural 13C abundance. Figure 4 displays typical 2D HETCOR spectra obtained on: (a) a 2:1 v/v mixture of n-pentane and benzene, (b) toluene, (c) n-propylbenzene, and (d) p-xylene, each with 20 mM TEMPO. The sample volume in each case was ca. 8 μL. Unshimmed line widths of enhanced 13C signals are typically of the order of 10 Hz. These experiments cover a reasonable 13C chemical shift range (of about 130 ppm) and it has proved possible to resolve rather closely spaced 13C signals, e.g., those acquired from the aromatic region of toluene (see inset to Figure 4b). As anticipated, close lying 1H signals are also usefully spread out in the second dimension. All the experiments were carried out in a 10 in. electromagnet employing an ESR Teslameter lock and ESR FF lock (ESR field frequency lock, but no NMR field frequency lock), to

Table 2. 13C Enhancement Values of Enriched 13C Methanol with 40 mM TEMPO experiment Boltzmann direct ODNP, decoupled t-ODNP, decoupled

no. of scans

signal to noise ratio (SNR) per scan

signal integral per scan

signal enhancement, [(/ )−1]

MW irradiation time (s)

measurement time

256 1

0.2356 (−)11.9

0.0039 (−)0.1701

0 (−)45

− 15

68 min (16 s per scan) 16 s

(−)52.3

(−)0.725

(−)187

1

1

D

2s DOI: 10.1021/acs.jpcb.7b05081 J. Phys. Chem. B XXXX, XXX, XXX−XXX

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Figure 4. t-ODNP enhanced 13C−1H 2D 1H decoupled HETCOR spectrum of different samples. (a) n-pentane:benzene (2:1 v/v), no. of scans = 32, 1TD = 64, polarization time = 1 s, spectral width in F1, SW1 = 3.5 kHz, spectral width in F2, SW2 = 5 kHz, experiment time = 1.19 h; (b) toluene, no. of scans = 32, 1TD = 64, polarization time = 1 s, SW1 = 2.5 kHz, SW2 = 3.8 kHz, experiment time = 1.2 h; (c) n-propylbenzene, no. of scans = 48, 1TD = 64, polarization time = 1.5 s, SW1 = 2.0 kHz, SW2 = 5 kHz, experiment time = 2.2 h; (d) p-xylene; no of scans = 64, 1TD = 64, polarization time = 1 s, SW1 = 4 kHz, SW2 = 3.8 kHz, experiment time = 2.42 h. In all cases, the polarizing radical used was 20 mM TEMPO except in in part c, 25 mM. A value of 150 Hz was used for the 1H−13C coupling constant in all cases except p-xylene (145 Hz). For long 2D experiments run in conventional mode, we normally polarize for a time shorter than the time at which maximum enhancement is reached, typically settling for about 80% of the maximum enhancement.

The maximum improvement in t-ODNP SNR at Q-band visà-vis standard high resolution 13C NMR on a 500 MHz spectrometer could thus reach an order of magnitude with an ESR saturation factor approaching 1 and with complete compensation of the disparity in the parameters noted above.

summarize the origins of this loss of SNR and point out that this may be overcome with some simple measures. The SNR scales as a function of a number of parameters, as described in detail by Doty.44 In particular, the linear dependence of SNR on the number of spins per unit volume (ns) and on the source spin magnetogyric ratio (γS), as well as its square root dependence on the apparent T2*, filling factor (ηf), sample volume (VS) and probe Q-factor (QL), and finally its three-halves power dependence on the detected resonance frequency (ω) are to be noted: SNR ∝ nsγS T2*ηf VSQ Lω3

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CONCLUSIONS

In summary, we have established that in terms of reproducible enhancements and performance t-ODNP is a robust technique for 2D heteronuclear correlation work on small molecules at 1.2 T. Although the resolution in the 1H dimension remains limited given the limited chemical shift range and also the line width in the presence of radicals, the technique proves to be robust in terms of sensitivity and the resolution in the 13C dimension. It may also be noted that such improved sensitivity comes without incurring any penalty in excitation, decoupling or detection efficiency since the RF bandwidth requirements remain modest, compared to the requirements of standard 500 MHz high resolution NMR. Several factors that would lead to further improvement of the ODNP enhancement factors reported in this work have been pointed out in the discussion. A variety of applications of this approach may be anticipated.

(2)

Excluding the operating frequency, the four factors that are responsible for the loss of t-ODNP SNR are the larger NMR signal line width, the smaller sample filling factor and volume, as well as the lower probe Q-factor. In the present case, they contribute respectively factors of 3.06, 3.42, 15.88, and 2.55 to the loss in SNR; taken together, they thus contribute a factor of about 424 to the loss in SNR. Quite clearly, remediation in respect of these four parameters could result in a t-ODNP SNR that significantly outstrips the SNR of the 500 MHz measurement, by a factor of ca. 4.7. Further SNR advantage is to be anticipated for multiscan t-ODNP, typically by a factor of at least 1.35, compared to the standard multiscan high resolution NMR experiment, the latter employing the Ernst optimal flip angle. E


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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpcb.7b05081. Single scan spectra of ODNP enhanced 1H spectrum, coupled 13C t-ODNP spectrum, and coupled direct ODNP 13C spectrum of 13C enriched CH3OH; t-ODNP enhanced 1D 13C spectrum of p-xylene at natural abundance; t-ODNP enhanced 13 C− 19 F 2D 19 F decoupled HETCOR spectrum of 1,4-difluorobenzene and hexafluorobenzene (2:1, v/v); ODNP relative enhancement curves and table for a motional correlation time of 20 ps; and table for experimental parameters used for 13C sensitivity comparison between standard high field NMR and moderately low field NMR (PDF)

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AUTHOR INFORMATION

Corresponding Author

*(N.C.) Fax: (+) 91-2257-4202. E-mail: chandrakumar.iitm@ gmail.com; [email protected]. ORCID

Narayanan Chandrakumar: 0000-0002-7089-3823 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS A.D. acknowledges the grant of an HTRA fellowship by IIT Madras. A.B. acknowledges a Fast Track Young Scientist Project Grant from SERB, India. N.C. acknowledges a spectrometer grant by SERB, and the J. C. Bose National Fellowship awarded by SERB.

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REFERENCES

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