Second Harmonic 527-GHz Gyrotron for DNP-NMR: Design and Experimental Results.

We report the design and experimental demonstration of a frequency tunable terahertz gyrotron at 527 GHz built for an 800 MHz Dynamic Nuclear Polarization enhanced Nuclear Magnetic Resonance (DNP-NMR) spectrometer. The gyrotron is designed at the second harmonic (ω = 2ω c) of the electron cyclotron frequency. It produces up to 9.3 W continuous microwave (CW) power at 527.2 GHz frequency using a diode type electron gun operating at V = 16.65 kV, Ib = 110 mA in a TE11,2,1 mode, corresponding to an efficiency of ~0.5%. The gyrotron is tunable within ~ 0.4 GHz by combining voltage and magnetic field tuning. The gyrotron has an internal mode converter that produces a Gaussian-like beam that couples to the HE11 mode of an internal 12 mm i.d. corrugated waveguide periscope assembly leading up to the output window. An external corrugated waveguide transmission line system is built including a corrugated taper from 12 mm to 16 mm i.d. waveguide followed by 3 m of the 16 mm i.d. waveguide The microwave beam profile is measured using a pyroelectric camera showing ~ 84% HE11 mode content.

High frequency dynamic nuclear polarization.

During the three decades 1980-2010, magic angle spinning (MAS) NMR developed into the method of choice to examine many chemical, physical, and biological problems. In particular, a variety of dipolar recoupling methods to measure distances and torsion angles can now constrain molecular structures to high resolution. However, applications are often limited by the low sensitivity of the experiments, due in large part to the necessity of observing spectra of low-γ nuclei such as the I = 1/2 species (13)C or (15)N. The difficulty is still greater when quadrupolar nuclei, such as (17)O or (27)Al, are involved. This problem has stimulated efforts to increase the sensitivity of MAS experiments. A particularly powerful approach is dynamic nuclear polarization (DNP) which takes advantage of the higher equilibrium polarization of electrons (which conventionally manifests in the great sensitivity advantage of EPR over NMR). In DNP, the sample is doped with a stable paramagnetic polarizing agent and irradiated with microwaves to transfer the high polarization in the electron spin reservoir to the nuclei of interest. The idea was first explored by Overhauser and Slichter in 1953. However, these experiments were carried out on static samples, at magnetic fields that are low by current standards. To be implemented in contemporary MAS NMR experiments, DNP requires microwave sources operating in the subterahertz regime, roughly 150-660 GHz, and cryogenic MAS probes. In addition, improvements were required in the polarizing agents, because the high concentrations of conventional radicals that are required to produce significant enhancements compromise spectral resolution. In the last two decades, scientific and technical advances have addressed these problems and brought DNP to the point where it is achieving wide applicability. These advances include the development of high frequency gyrotron microwave sources operating in the subterahertz frequency range. In addition, low temperature MAS probes were developed that permit in situ microwave irradiation of the samples. And, finally, biradical polarizing agents were developed that increased the efficiency of DNP experiments by factors of ∼4 at considerably lower paramagnet concentrations. Collectively, these developments have made it possible to apply DNP on a routine basis to a number of different scientific endeavors, most prominently in the biological and material sciences. This Account reviews these developments, including the primary mechanisms used to transfer polarization in high frequency DNP, and the current choice of microwave sources and biradical polarizing agents. In addition, we illustrate the utility of the technique with a description of applications to membrane and amyloid proteins that emphasizes the unique structural information that is available in these two cases.

Corrugated Waveguide Mode Content Analysis Using Irradiance Moments.

We present a novel, relatively simple method for determining the mode content of the linearly polarized modes of a corrugated waveguide using the moments of the intensity pattern of the field radiated from the end of the waveguide. This irradiance moment method is based on calculating the low-order irradiance moments, using measured intensity profiles only, of the radiated field from the waveguide aperture. Unlike the phase retrieval method, this method does not use or determine the phase distribution at the waveguide aperture. The new method was benchmarked numerically by comparison with sample mode mixtures. The results predict less than ±0.7% error bar in the retrieval of the mode content. The method was also tested using high-resolution experimental data from beams radiated from 63.5 mm and 19 mm corrugated waveguides at 170 and 250 GHz, respectively. The results showed a very good agreement of the mode content retrieved using the irradiance moment method versus the phase retrieval technique. The irradiance moment method is most suitable for cases where the modal power is primarily in the fundamental HE11 mode, with <8% of the power in high-order modes.

Design and optimization of THz coupling in zirconia MAS rotors for dynamic nuclear polarization NMR.

We present 3D electromagnetic simulations of the coupling of a 250 GHz beam to the sample in a 380 MHz DNP NMR spectrometer. To obtain accurate results for magic angle spinning (MAS) geometries, we first measured the complex dielectric constants of zirconia, sapphire, and the sample matrix material (DNP juice) from room temperature down to cryogenic temperatures and from 220 to 325 GHz with a VNA and up to 1 THz with a THz TDS system. Simulations of the coupling to the sample were carried out with the ANSYS HFSS code as a function of the rotor wall material (zirconia or sapphire), the rotor wall thickness, and the THz beam focusing (lens or no lens). For a zirconia rotor, the B1 field in the sample was found to be strongly dependent on the rotor wall thickness, which is attributed to the high refractive index of zirconia. The optimum thickness of the wall is likely due to a transmission maximum but is offset from the thickness predicted by a simple calculation for a flat slab of the wall material. The B1 value was found to be larger for a sapphire rotor than for a zirconia rotor for all cases studied. The results found in this work provide new insights into the coupling of THz radiation to the sample and should lead to improved designs of future DNP NMR instrumentation.

Frequency-swept dynamic nuclear polarization.

Dynamic nuclear polarization (DNP) improves the sensitivity of NMR spectroscopy by the transfer of electron polarization to nuclei via irradiation of electron-nuclear transitions with microwaves at the appropriate frequency. For fields > 5 T and using g ∼ 2 electrons as polarizing agents, this requires the availability of microwave sources operating at >140 GHz. Therefore, microwave sources for DNP have generally been continuous-wave (CW) gyrotrons, and more recently solid state, oscillators operating at a fixed frequency and power. This constraint has limited the DNP mechanisms which can be exploited, and stymied the development of new time domain mechanisms. We report here the incorporation of a microwave source enabling facile modulation of frequency, amplitude, and phase at 9 T (250 GHz microwave frequency), and we have used the source for magic-angle spinning (MAS) NMR experiments. The experiments include investigations of CW DNP mechanisms, the advantage of frequency-chirped irradiation, and a demonstration of an Overhauser enhancement of ∼25 with a recently reported water-soluble BDPA radical, highlighting the potential for affordable and compact microwave sources to achieve significant enhancement in aqueous samples, including biological macromolecules. With the development of suitable microwave amplifiers, it should permit exploration of multiple new avenues involving time domain experiments.

Measurement of Time Dependent Reflection, Transmission, and Absorption in Laser Driven Silicon and GaAs Switches for 250 GHz Radiation.

The reflectance (R) and transmittance (T) of Si and GaAs wafers irradiated by a 6 ns pulsed, 532 nm laser have been studied for s- and p-polarized 250 GHz radiation as a function of laser fluence and time. The measurements were carried out using precision timing of the R and T signals, allowing an accurate determination of the absorptance (A) where A=1-R-T. Both wafers had a maximum reflectance above 90% for a laser fluence ≥8 mJ/cm2. Both also showed an absorptance peak of ~50% lasting ~2 ns during the risetime of the laser pulse. Experimental results were compared with a stratified medium theory using the Vogel model for the carrier lifetime and the Drude model for permittivity. Modeling showed that the large absorptance at the early part of the rise of the laser pulse was due to the creation of a lossy, low carrier density layer. For Si, the measured R, T and A were in very good agreement with theory on both the nanosecond time scale and the microsecond scale. For GaAs, the agreement was very good on the nanosecond scale but only qualitatively correct on the microsecond scale. These results may be useful for planning applications of laser driven semiconductor switches.

Mode Content Determination of Terahertz Corrugated Waveguides Using Experimentally Measured Radiated Field Patterns.

This work focuses on the accuracy of the mode content measurements in an overmoded corrugated waveguide using measured radiated field patterns. Experimental results were obtained at 250 GHz using a vector network analyzer with over 70 dB of dynamic range. The intensity and phase profiles of the fields radiated from the end of the 19 mm diameter helically tapped brass waveguide were measured on planes at 7, 10, and 13 cm from the waveguide end. The measured fields were back propagated to the waveguide aperture to provide three independent estimates of the field at the waveguide exit aperture. Projecting that field onto the modes of the guide determined the waveguide mode content. The three independent mode content estimates were found to agree with one another to an accuracy of better than ±0.3%. These direct determinations of the mode content were compared with indirect measurements using the experimentally measured amplitude in three planes, with the phase determined by a phase retrieval algorithm. The phase retrieval technique using the planes at 7, 10, and 13 cm yielded a mode content estimate in excellent agreement, within 0.3%, of the direct measurements. Phase retrieval results using planes at 10, 20, and 30 cm were less accurate due to truncation of the measurement in the transverse plane. The reported measurements benefited greatly from a precise mechanical alignment of the scanner with respect to the waveguide axis. These results will help to understand the accuracy of mode content measurements made directly in cold test and indirectly in hot test using the phase retrieval technique.

Phase Measurements of a 140-GHz Confocal Gyro-Amplifier.

The phase stability of a 140GHz, 1kW pulsed gyro-amplifier system and the phase dependence on the cathode voltage were experimentally measured. To optimize the measurement precision, the amplifier was operated at 47 kV and 1 A, where the output power was ∼ 30W. The phase was determined to be stable both pulse-to-pulse and during each pulse, so far as the cathode voltage and electron beam current are constant. The phase variation with voltage was measured and found to be 130±30°/kV, in excellent agreement with simulations. The electron gun used in this device is non-adiabatic, resulting in a steep slope of the beam pitch factor with respect to cathode voltage. This was discovered to be the dominant factor in the phase dependence on voltage. The use of an adiabatic electron gun is predicted to yield a significantly smaller phase sensitivity to voltage, and thus a more phase-stable performance. To our knowledge, these are the first phase measurements reported for a gyro-amplifier operating at a frequency above W-band.

In Situ Characterization of Pharmaceutical Formulations by Dynamic Nuclear Polarization Enhanced MAS NMR.

A principal advantage of magic angle spinning (MAS) NMR spectroscopy lies in its ability to determine molecular structure in a noninvasive and quantitative manner. Accordingly, MAS should be widely applicable to studies of the structure of active pharmaceutical ingredients (API) and formulations. However, the low sensitivity encountered in spectroscopy of natural abundance APIs present at low concentration has limited the success of MAS experiments. Dynamic nuclear polarization (DNP) enhances NMR sensitivity and can be used to circumvent this problem provided that suitable paramagnetic polarizing agent can be incorporated into the system without altering the integrity of solid dosages. Here, we demonstrate that DNP polarizing agents can be added in situ during the preparation of amorphous solid dispersions (ASDs) via spray drying and hot-melt extrusion so that ASDs can be examined during drug development. Specifically, the dependence of DNP enhancement on sample composition, radical concentration, relaxation properties of the API and excipients, types of polarizing agents and proton density, has been thoroughly investigated. Optimal enhancement values are obtained from ASDs containing 1% w/w radical concentration. Both polarizing agents TOTAPOL and AMUPol provided reasonable enhancements. Partial deuteration of the excipient produced 3× higher enhancement values. With these parameters, an ASD containing posaconazole and vinyl acetate yields a 32-fold enhancement which presumably results in a reduction of NMR measurement time by ∼1000. This boost in signal intensity enables the full assignment of the natural abundance pharmaceutical formulation through multidimensional correlation experiments.

Low-Loss Transmission Lines for High-Power Terahertz Radiation.

Applications of high-power Terahertz (THz) sources require low-loss transmission lines to minimize loss, prevent overheating and preserve the purity of the transmission mode. Concepts for THz transmission lines are reviewed with special emphasis on overmoded, metallic, corrugated transmission lines. Using the fundamental HE(11) mode, these transmission lines have been successfully implemented with very low-loss at high average power levels on plasma heating experiments and THz dynamic nuclear polarization (DNP) nuclear magnetic resonance (NMR) experiments. Loss in these lines occurs directly, due to ohmic loss in the fundamental mode, and indirectly, due to mode conversion into high order modes whose ohmic loss increases as the square of the mode index. An analytic expression is derived for ohmic loss in the modes of a corrugated, metallic waveguide, including loss on both the waveguide inner surfaces and grooves. Simulations of loss with the numerical code HFSS are in good agreement with the analytic expression. Experimental tests were conducted to determine the loss of the HE(11) mode in a 19 mm diameter, helically-tapped, three meter long brass waveguide with a design frequency of 330 GHz. The measured loss at 250 GHz was 0.029 ± 0.009 dB/m using a vector network analyzer approach and 0.047 ± 0.01 dB/m using a radiometer. The experimental results are in reasonable agreement with theory. These values of loss, amounting to about 1% or less per meter, are acceptable for the DNP NMR application. Loss in a practical transmission line may be much higher than the loss calculated for the HE(11) mode due to mode conversion to higher order modes caused by waveguide imperfections or miter bends.

Dynamic nuclear polarization at 700 MHz/460 GHz.

We describe the design and implementation of the instrumentation required to perform DNP-NMR at higher field strengths than previously demonstrated, and report the first magic-angle spinning (MAS) DNP-NMR experiments performed at (1)H/e(-) frequencies of 700 MHz/460 GHz. The extension of DNP-NMR to 16.4 T has required the development of probe technology, cryogenics, gyrotrons, and microwave transmission lines. The probe contains a 460 GHz microwave channel, with corrugated waveguide, tapers, and miter-bends that couple microwave power to the sample. Experimental efficiency is increased by a cryogenic exchange system for 3.2 mm rotors within the 89 mm bore. Sample temperatures ≤85 K, resulting in improved DNP enhancements, are achieved by a novel heat exchanger design, stainless steel and brass vacuum jacketed transfer lines, and a bronze probe dewar. In addition, the heat exchanger is preceded with a nitrogen drying and generation system in series with a pre-cooling refrigerator. This reduces liquid nitrogen usage from >700 l per day to <200 l per day and allows for continuous (>7 days) cryogenic spinning without detrimental frost or ice formation. Initial enhancements, ε=-40, and a strong microwave power dependence suggests the possibility for considerable improvement. Finally, two-dimensional spectra of a model system demonstrate that the higher field provides excellent resolution, even in a glassy, cryoprotecting matrix.