Journal of Magnetic Resonance 264 (2016) 88–98

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Instrumentation for solid-state dynamic nuclear polarization with magic angle spinning NMR Melanie Rosay a, Monica Blank b, Frank Engelke c,⇑ a

Bruker-Biospin, 15 Fortune Drive, Billerica, MA 01730, USA Communications and Power Industries, 811 Hansen Way, Palo Alto, CA 94304, USA c Bruker-Biospin, Silberstreifen 4, 76287 Rheinstetten, Germany b

a r t i c l e

i n f o

Article history: Received 25 September 2015 Revised 17 December 2015

Keywords: Dynamic nuclear polarization Nuclear magnetic resonance Gyrotrons NMR DNP probes DNP sample preparation DNP radicals Instrumentation

a b s t r a c t Advances in dynamic nuclear polarization (DNP) instrumentation and methodology have been key factors in the recent growth of solid-state DNP NMR applications. We review the current state of the art of solid-state DNP NMR instrumentation primarily based on available commercial platforms. We start with a general system overview, including options for microwave sources and DNP NMR probes, and then focus on specific developments for DNP at 100 K with magic angle spinning (MAS). Gyrotron microwave sources, passive components to transmit microwaves, the DNP MAS probe, a cooling device for lowtemperature MAS, and sample preparation procedures including radicals for DNP are considered. Ó 2016 Elsevier Inc. All rights reserved.

1. Introduction The last two decades have witnessed an impressive development and renewed interest in dynamic nuclear polarization (DNP) in liquids and solids. The present article will focus on developments in the field of DNP NMR in solids with a particular focus on activities to provide a unique platform for magic angle spinning (MAS) DNP NMR. The availability of advanced instrumentation for that field, pioneered by the group of Griffin [1–4] at the Massachusetts Institute of Technology (MIT), has achieved a sophisticated level of instrumentation and contributed significantly to the propagation and new applications of solid-state DNP NMR. This progress in instrumentation and methodology is still continuing such that the present article can only give a summary of the state-of the art with a brief overview of some achievements and prospective outlook. In this publication we focus on solid-state NMR enhanced by DNP. The active field of Dissolution DNP is not included within the present article: although the DNP step in dissolution DNP is also in solid-state (at lower temperature), the applications are aimed at MRI and liquid-state NMR. This highly interesting field is covered by several other articles in this special perspectives journal issue. ⇑ Corresponding author. E-mail addresses: [email protected] (M. Rosay), monica.blank@cpii. com (M. Blank), [email protected] (F. Engelke). http://dx.doi.org/10.1016/j.jmr.2015.12.026 1090-7807/Ó 2016 Elsevier Inc. All rights reserved.

The discovery of DNP in the 1950’s by Carver and Slichter [5] in solid-state samples (metals) was followed by many studies of DNP in low temperature physics and liquids and solids NMR [6–8]. The initial applications of DNP for NMR applications were performed by the groups of Wind, Schaefer and Yannoni [6,7,58,59] at relatively low NMR and microwave frequency (40 GHz). In the mid1990’s Griffin [1–3] started to develop solid-state DNP in solids at low temperatures using gyrotrons as microwave sources operating beyond 100 GHz. More than one decade later, commercial companies such as Bruker/CPI and Gycom started to build gyrotrons for DNP, manufactured, for example, by Bruker with CPI [9], Osaka University [10–12], and Gycom [13,14]. There is a straightforward reason to use microwave sources which enable relatively high power (on the order of 10 watts) for frequencies far above 100 GHz, as compared to EPR: NMR DNP probes need to be optimized for sample size, radio frequency (rf) irradiation, and microwave irradiation. This leads to the requirement, in particular for MAS probes, that the samples and MAS rotors have geometric dimensions on the order of or larger than the wavelength (say, about 1 mm at 263 GHz) and therefore the MAS sample ‘‘cavity” is overmoded with a relatively low Q factor for millimeter waves. From the instrumentation and methodological point of view four fields of relevance should be considered: (a) DNP microwave sources that fulfill the high demands for spectroscopic techniques, like gyrotrons, klystrons, or solid-state sources (b) microwave transmission from the gyrotron to the DNP NMR probe, (c)

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microwave irradiation of the sample in the DNP NMR probe, (d) DNP sample preparation including suitable radicals/biradicals particularly adapted to the DNP mechanisms. A commercial solid DNP platform, as sketched in Fig. 1, contains an NMR spectrometer (including the NMR magnet), a microwave source for example a gyrotron tube with dedicated magnet plus control unit with high voltage power supply and gyrotron cooling system, the transmission line for microwave propagation from the source to the NMR sample, the DNP NMR probe and a cooling unit providing cryogenic gases for cooling the sample and operating MAS at low temperature. Although there have been attempts to apply DNP to solid-state NMR experiments at room temperature [6,7], the majority of solid-state DNP NMR experiments are run at low temperature below 120 K. The main reason for that is the prolonged electron spin relaxation time at low temperature, a prerequisite to obtain high DNP enhancement factors. A variety of components for DNP systems are available from companies such as Revolution NMR with probes operating according to the cooling principle as introduced by Tycko et al. utilizing nitrogen gas for sample rotation and cold helium gas for sample cooling [15–17]. Further Bridge-12 [18] and Swissto12 [19], offer DNP waveguide components, for example, corrugated waveguides, tapers, miterbends, and polarization grids. Gyrotrons (with more than 10 W output power) are available from Bruker/CPI, described in following section, Fukui University [20–22], Gycom [13,14], and within a research project at EPFL, from Thales [23]. Lower-power millimetre-wave sources, in particular 263 GHz klystron (ca. 1 W) [24,25] and even solid-state sources at 140–263 GHz [4,16,26,27], have been also demonstrated for applications at heliumcryogenic temperatures. Virginia Diodes, for example, can provide about 90 mW of cw output power from a solid-state source at 263 GHz [27]. The strong increase of interest in solid-state DNP NMR instrumentation manifests itself also in patent filing activities. Seeking protection of IP in that field is not restricted to commercial companies such as Swiss-to-12 [28–31], Bridge-12 [32], Doty [33], or Bruker [34,35], also academic institutions contribute IP like the patent applications of CNR Roma [36–38], EPFL in Lausanne in collaboration with Swiss-to-12, and CEA Grenoble [39– 41]. In parallel to the publication records of scientific papers this shows impressively the potential of DNP instrumentation for solid-state NMR today.

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In the following sections we focus on a DNP NMR system working with a gyrotron source, operating at frequencies of either 263 GHz, 395 GHz, or 527 GHz (for 400, 600 and 800 MHz NMR) with the DNP NMR probe at temperatures around 100 K, including MAS. First, in Section 2 an overview of vacuum electron devices (gyrotron and klystron) is presented followed by a detailed description and characterization of a gyrotron designed for DNP applications. The transmission of the microwave beam from its source to the probe and the characteristics of that beam are also described. In Section 3 we describe the specifics of solid-state DNP NMR probes, in particular involving MAS and address briefly cooling techniques and equipment. The success of DNP NMR crucially depends on the DNP radical used as the source of electron spin polarization – Section 4 is dedicated to questions related to DNP radicals and sample preparation for different application areas. In Section 5 we provide an outlook on near-future prospectives in solid-state DNP NMR. 2. Microwave sources for solid-state DNP NMR Solid-state and vacuum electronic device sources are available for DNP systems. Vacuum electronic devices capable of producing the powers, frequencies, and stability suitable for DNP applications can be broken into two categories, fast-wave and slow-wave devices. For both fast and slow-wave vacuum electronic sources, energy is transferred from an unbound electron beam to an electromagnetic wave. In order for this transfer to occur, synchronism between the beam and wave must be achieved. In fast-wave devices, such as the gyrotron [42,43], the phase velocity of the electromagnetic wave is equal to or greater than the speed of light and in slow-wave devices, such as klystrons or helix traveling-wavetubes, the phase velocity of the wave is less than the speed of light. Gyrotrons, also known as cyclotron resonance masers, take advantage of the cyclotron resonance maser instability to transfer energy from an electron beam to an electromagnetic wave. In the interaction, an annular electron beam, composed of mildly relativistic electrons traveling in helical paths, interacts with the electromagnetic fields of a circuit or cavity in the presence of an applied axial magnetic field. In cyclotron resonance masers, the synchronism between the electron beam electromagnetic fields of the circuit is achieved by choosing the applied magnetic field such that the

Fig. 1. Schematics of a solid-state DNP NMR system with a gyrotron microwave source (gyrotron tube in red), microwave transmission line (cyan) and low-temperature NMR probe (green). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

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cyclotron frequency of the electrons is nearly equal to the desired microwave frequency of the device. The benefits of gyrodevices are derived from the combination of the cyclotron resonance interaction and the fast-wave interaction circuit. In fast-wave circuits, the electromagnetic field strength can be quite high, independent of the proximity of the metallic circuit structure. This enables the electron beam to be situated in regions of high field, for optimum coupling, without necessarily placing the beam too close to the circuit. The interaction mode is selected by the magnitude of the applied magnetic field, which determines the electron cyclotron frequency, and the placement of the electron beam. If a highorder waveguide or cavity mode is selected, the transverse dimensions of the interaction structure can be several times the freespace wavelength. The larger interaction structure enhances the ability of the device to generate high output powers and increasingly greater frequencies. However, the necessity of a superconducting magnet to generate the magnetic field required for interactions at frequencies above 30 GHz can be construed as a disadvantage of the device. DNP gyrotrons have been developed from 140 to 527 GHz with output power of 10–100 W [1–4,9,10–14,46– 48]. In traditional slow-wave devices, such as klystrons [44,45], the interaction circuits are designed to reduce the phase velocity of the electromagnetic wave to values below the speed of light so that synchronism between the beam and wave can be maintained. The electric field strength falls off rapidly with distance from the circuit structure. Typical transverse circuit dimensions required to effectively slow the phase velocity of the wave are on the order of 10% of the free space wavelength. These small circuit sizes, necessary to achieve the interaction in a slow-wave device, severely limit the peak and average power capabilities, particularly at millimeter wave frequencies. Klystrons have been developed for DNP applications at up to 263 GHz with 1–2 W of cw output power [24,25]. Similarly to gyrotrons, klystrons are driven by high voltage power supplies with substantial beam energy (kilowatts) and associated cooling requirements. Solid-state sources are compact, easy to use, and require no special facility requirements. A low frequency synthesizer (typically 9–20 GHz) is followed by set of multipliers and amplifier to reach target frequency and power. Several sources can be combined for higher power, but mixers at 263 GHz frequency have high insertion loss and component heating is one of the challenges in extending to higher power. Solid-state sources have been used for DNP experiments at helium temperature [4,16,26] and are commonly used in EPR spectrometers, however to date, the output power of solidstate sources has not been sufficient for MAS DNP experiments above 77 K. Continuous wave (CW) gyrotron oscillators capable of producing 50 W at 263 GHz and 395 GHz, and 20 W 527 GHz have been developed by Bruker and CPI for 400 MHz, 600 MHz, and 800 MHz NMR systems, respectively. In Fig. 2, a solid model and photograph of a typical DNP gyrotron are shown. An annular electron beam is produced by a single-anode magnetron injection gun operating at cathode voltages in the 14–18 kV range with cathode currents up to 200 mA. The magnetic field required for the gyrotron interaction at the second harmonic of the electron cyclotron frequency, approximately 5 T, 7 T, and 10 T for the 263 GHz, 395 GHz, and 527 GHz devices, respectively, is produced by a cryogen-free superconducting magnet, which is not shown in the figure. The electron beam is accelerated toward the anode, which is at ground potential, and travels in a tapered beam tunnel region as its diameter is compressed by the increasing magnetic field. The interaction cavity is located at the peak of the axial magnetic field where the beam diameter is at its minimum. The high-order transverse electric (TE) interaction mode is carefully selected based on several criteria including the electron beam

diameter in the cavity, the power loading on the cavity walls, and competition with other cavity modes. Low-order cylindrical cavity modes, such as the TE11 or TE01 modes, are not practical because of the small-diameter electron beam that would be required for the interaction as well as the small diameter cavity that would lead to large ohmic power densities on the cavity walls and would be difficult to effectively cool. Higher order modes offer the possibility of larger cavities with lower power densities on the cavity walls excited by larger diameter electron beams. The interaction modes for the 263 GHz, 395 GHz and 527 GHz gyrotrons are the TE11,2, the TE10,3, and TE14,3 modes, respectively. Because these high-order interaction modes are not suitable for efficient transmission in smooth or corrugated waveguides, an internal mode converter is used to transform the interaction mode to a Gaussian beam. The mode converter consists of a helically cut launcher with specially designed wall-perturbations to increase the Gaussian mode content of the launched beam, as well as four or five mirrors that serve to both shape the Gaussian beam so that the waist is the suitable size for transmission through the vacuum window and steer the beam to the window. The final mirror has the capability of being moved radially and tilted in the horizontal and vertical directions to ensure that the beam exits through the center of the single-disk alumina vacuum window and is travelling perpendicular to the window plane. The internal converter also serves to separate the generated electromagnetic wave from the electron beam, which is guided by the magnetic field and continues along the gyrotron axis until it is incident on the walls of the collector. The cryogen-free gyrotron magnet design allows for more compact magnet and shorter path from microwave cavity to output window than previous generation liquid cooled 263 GHz gyrotron [9]. The vacuum is maintained by a 2 l/s vac ion pump that uses the fringing field of the superconducting magnet rather than the more typically employed permanent magnet. Rigorous tests of each gyrotron are performed to demonstrate the required performance characteristics including a output power, the ability to tune power smoothly from 50 W to less than 3 W, the power and frequency stability, and the Gaussian output beam characteristics and quality. Typical measured results for a 395 GHz gyrotron are shown in Fig. 3, where the output power and frequency as a function of cathode voltage is plotted. As seen in the figure, the power can be smoothly varied from 60 W to 3 W by reducing the cathode voltage from 15.7 kV to 14.2 kV and leaving all other parameters fixed. Output power can also be adjusted by varying the electron beam current. Fig. 4 shows infrared (IR) images of the output beam from a 395 GHz gyrotron. The output beam is incident on a target that can be moved in a plane perpendicular to the window. Images at distances 51, 61, 71, and 81 cm from the gyrotron output window are shown in the figure. The cross hairs represent the position of the window center and the circle shown overlaying each image is 5 cm in diameter. As seen in the figure, the output beam is a high-quality Gaussian beam which is centered on the window and travelling perpendicular to the window plane. A modal decomposition of the measured output beam shows greater than 97% overlap with the beam that is ideal for injection into the 17 mm diameter corrugated waveguide. The beam waist expansion is plotted as a function of target distance and shows good match to theoretical expansion of gaussian beam in free space. As part of the experimental demonstration, the output beam from the window is injected into the first section of corrugated waveguide and additional IR images of the beam exiting the guide are made. Images of the beam from the corrugated guide typically show greater than 98% overlap between the measured beam and the HE11 waveguide mode. The gyrotron output beam is transmitted to the NMR probe via corrugated waveguide to retain high gaussian beam purity and minimize power losses in the transmission line [49]. The corruga-

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Cathode Voltage (kV) Fig. 3. Measured output power (blue diamonds) and frequency (red squares) as a function of cathode voltage for a 395 GHz gyrotron. All parameters other than cathode voltage are held fixed. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

tions (1/4 k depth and width with 1/3 k period) are cut for 263 GHz or 440 GHz with the later used on the 395 and 527 GHz assembly due to the broadband nature of corrugated waveguide. The waveguide inner diameter (ID) is 19.3 mm at 263 GHz and 17 mm at 440 GHz. Three 90 degrees miter bends are included to complete the path from gyrotron window to NMR probe base with a corrugated taper at the probe base to transition to the probe waveguide (7.6 mm ID for 263 GHz and 7.7 mm ID for 395 and 527 GHz). A directional coupler in the transmission line allows for power and frequency measurements during DNP experiments. Low-loss beam transmission has been confirmed with power measurements at the

gyrotron output waveguide, NMR probe base and end of probe waveguide. For example, at 395 GHz just 10% loss was measured over 3030 mm total length of 17 mm ID waveguide and 3 miter bends. An additional 20% power loss is measured across the taper, 700 mm length of probe waveguide and two miter bends by the sample. Similar results are obtained at 263 and 527 GHz. Fig. 5 shows the DNP signal enhancement at 395 GHz on a standard sample with AMUPOL polarizing agent as a function of microwave power. In this case, 15 W of microwave power is sufficient to reach saturation point. Samples with different dielectric constants, microwave penetration depth, polarizing agents, sample temperature, and MAS frequency can vary in their power requirement to reach the plateau. 3. Solid-state DNP NMR probes and cryogenic MAS The dominant technique and accompanying instrumentation in solid-state NMR requires fast sample spinning at the magic angle (MAS). Henceforth in our excursion we will focus on MAS NMR probes suitable for low-temperature and DNP, in the following abbreviated as LT.MAS DNP probes. There are applications with static but oriented samples, e.g. oriented biomembranes, which aim at DNP NMR as well [50–52]. Much of the principal probe design, for example, the corrugated wave guide inside the probe, the miter bends and the radial irradiation scheme has been derived from earlier work in the Griffin group [46–48]. The microwave beam arrives at the bottom of the LT.MAS DNP probe (cf. Fig. 1) is reflected by a 90° miterbend, propagates upwards through a

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Fig. 4. Output beam characterization of the 395 GHz gyrotron output beam. (a) Infrared images: the cross hairs represent the position of the window center and the circle is 5 cm in diameter. (b) Beam expansion: the solid line represents the theoretical expansion of the TEM00 mode from a 17 mm diameter corrugated guide and the red diamonds and green squares show the measured vertical and horizontal beam radii. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

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Microwave Power (W) Fig. 5. 395 GHz DNP signal enhancement as a function of microwave power at the end of the probe waveguide. Sample of 1 M 13C Urea in glycerol d8/D2O/H2O (60/30/ 10) with 10 mM AMUPOL at 108 K, 12 kHz MAS, 3.2 mm sapphire rotor.

taper and cylindrical corrugated wave guide, changes direction through one or more miterbends and finally enters the MAS system with the NMR coil, MAS rotor and sample inside orthogonal to the rotor axis (radial irradiation scheme). Other schemes, for example an axial irradiation scheme are principally also possible. Both schemes have their own advantages and disadvantages. The axial scheme, i.e., the microwave beam is incident along the rotor axis [20,21,34], is very sensitive against coupling conditions and geometric constraints imposed by the MAS air bearing system. The radial scheme, as discussed in the following, depends on the geometry of the rf coil, the latter acting as a diffraction grating, and the geometry and material properties of the MAS rotor. There are quite a few probe designs and microwave irradiation schemes reported in the literature. Revolution NMR offers the commercialization of probes [72] according to the Thurber-Tycko design [15–17], where MAS is run with cryogenic nitrogen and the sample is cooled with cryogenic helium. Doty [22,33] has proposed probe designs addressing cold NMR coils and cold or warm samples including DNP capabilities in such a probe for a wide sample temperature range from 30 K to 300 K and higher. At MIT probes have been build based on a balanced rf transmission line that allow remote tuning and matching [53]. Last but not least Maly et al. at Bridge-12 [54,55] came up with the idea to incorporate NMR DNP probe and gyrotron within the same cryomagnet in such a way to arrive at a very compact system.

In order to successfully design, construct, and build NMR DNP MAS probes and equipment to efficiently cool the NMR sample to cryogenic temperatures under MAS, several technological challenges have to be overcome. The cooling system must produce cold gas flows for MAS with typical gas flow rates on the order of 30– 100 standard liters per minute, depending on the MAS system and the MAS speed. With gaseous nitrogen temperatures down to ca. 90 K can be achieved, depending on the gas pressures for bearing and drive and the MAS spinning rate applied. The heat exchanger design needs to address these boundary constraints. An example for such a heat exchanger suitable for MAS at low temperature has been described in the NMR literature in [56]. The possibility to lower the temperature below the condensation point of liquid nitrogen by using cryogenic helium is even more promising for many DNP applications. This requires heat exchangers for helium to operate for MAS conditions, which are different from those for nitrogen. An early example is Potter’s proposal [57]. MAS with cryogenic helium has been accomplished by Yannoni and coworkers [58,59]. Samoson reported on MAS with cryogenic helium [60] as well as Levitt et al. in [61]. These experiments were conducted with helium heat exchangers that did not form a closedloop system and consequently very high helium consumption. Doty [62] described a heat exchanger system that works over a wide variable temperature range. Thurber et al. [15–17] linked DNP and cryogenic helium MAS. Fujiwara et al. [63,64] went one step further and introduced a closed-loop system for cryogenic helium MAS. For such a closed-loop helium system much effort has been spent also at CEA Grenoble in the group of dePaepe et al. [65] demonstrating MAS DNP at cryogenic temperatures using a closed-loop helium system allowing much higher MAS speeds than previously possible at cryogenic nitrogen temperatures or with similar setups with closed-loop helium MAS described in Refs. [63,64] . From the NMR rf side, MAS DNP NMR probes are very similar to regular solid-state MAS probes. They are equipped with two or three channels, one tuned to 1H, the other two to heteronuclei like 13 C, 15N, 29Si, 27Al. The particularity of DNP MAS probes consists of the specific design to enable the irradiation of the sample by millimeter waves (high-frequency microwaves) of a given polarization of the electric field. The DNP NMR enhancement factors, measured by the ratio of NMR signal amplitudes between cw microwave irradiation switched on and off, critically depend on the local microwave field amplitude at the site of unpaired electron spins inside the sample. The MAS system with its NMR rf coil, the rotor and

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the sample inside the rotor have a geometry which is not close to a structure which would be ideal for a single fundamental mode of a resonant cavity. The system is highly overmoded and for that reason it is still essential to obtain a fairly detailed picture of the microwave field amplitude distribution. It is difficult to achieve that in situ with the complete MAS system and rf coil involved, though simulations of the electromagnetic field distribution turn out to be very beneficial. It is nevertheless required to validate such simulations by experiment, at least to verify simulation data vs. experimental data for a simplified system. Such a validation is shown in Fig. 6, which represents the forward scattering of a millimeter wave incident through an aperture on an 3.2 mm NMR rf solenoidal coil. The coil acts like a grating and leads to multiple diffraction of the wave behind the coil. The figure shows on the left the experimentally measured electric field amplitude of the propagating wave in two orthogonal planes behind the coil, on the right side an electromagnetic simulation using the simulation software CST Microwave Studio (CST GmbH, Darmstadt). Details on the measurements of field maps and the simulations of such can be found in [66]. There is earlier work on electromagnetic simulations of mm wave propagation and reflection of other coil geometries [67] and millimeter wave propagation through radially irradiated MAS rotors [68], the latter demonstrating the diffractive influence of the MAS rotor material (zirconia ceramics or sapphire). In a study by Nanni et al. [69] the millimeter wave field distribution in a complete MAS system was investigated. In the following some of the subtleties in the millimeter wave field distribution inside a real MAS system are discussed. The system studied by electromagnetic simulations using CST Microwave Studio (CST GmbH, Darmstadt) is shown in Fig. 7. On the left side a photograph of the upper part of a widebore 3.2 mm MAS DNP probe is displayed, on the right side the corresponding axial cross section through the MAS system. As indicated, for the 3.2 mm MAS system, the millimeter wave beam enters through an aperture, propagates radially through the NMR rf coil and the MAS rotor. Fig. 8 demonstrates more examples of field distributions shown as snapshots for three different frequencies – 263 GHz, 395 GHz, and 527 GHz. It becomes apparent that the mm wave field is far from being spatially homogeneous, rather it appears periodic, depending on the wavelength, the dielectric material, the detailed diffraction pattern, and reflection of the beam. Standing waves occur generated by forward beam propagation and backward propagation caused by reflection. These standing wave patterns represent one possibility to improve the millimeter wave amplitude inside the sample. Further, if one keeps in mind that the MAS rotor spins with several kHz it becomes clear that an unpaired electron spin at a given spatial position inside the rotor experiences a time dependent electromagnetic field on two time scales – the fast one given by the resonant microwave frequency and a slow one given by MAS. When one detects the DNP NMR enhancement one measures an ensemble average of spins and microwave fields over the sample volume and an additional slow modulation time average by MAS. With this perspective it becomes difficult to postulate simple straightforward relationships between local features in the sample and the millimeter wave field. It is rather the millimeter wave field average over the sample that is important. In a recent article, Kubicki et al. [70] reported that the DNP enhancement factor of frozen solutions of glycerol/water or TCE with various radicals (TekPol, bCtbK, bTbK, AMUPOL, TOTAPOL) and a dispersion of dielectric particles (powdered KBr, Sapphire, NaCl, PTFE, CaF2) embedded in the frozen solution significantly increases as compared to the bulk solution (without dielectric particles). It could be excluded that the effect originates from different microwave heating characteristics when comparing frozen bulk solutions and solutions with particles. Since the increase of DNP enhancement factors strongly depends on the kind of dielectric

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particles embedded, it seems plausible that this dielectric effect comes from the diffractive behavior of the incident millimeter wave beam inside the frozen solution/particles, such that the diffraction (strongly depending on the spatial distribution of the dielectric properties) and scattering/reflection should be dependent on the dielectric constant of the particles. The simulated magnetic field magnitude distribution as shown in Fig. 9a reveals that this is indeed the case. For a given filling factor of 0.63 it becomes evident, that locally the magnetic field magnitude may increase, caused by the random diffraction, reflection, and superposition of mm waves by the dielectric particles. But it is not only the local field distributions that change. As exemplified in Fig. 9b also the spatially averaged magnetic mm field magnitude becomes dependent on the dielectric constant of the embedded particles and of the filling factor. For dielectric constants larger than 2.5 and up to 11 one finds a systematic increase of the millimeter magnetic field by a factor of ca. 2 in accordance to and as an explanation for the increased DNP enhancement factors observed experimentally. As we have discussed now with case studies, some example results shown in Figs. 6–9, there are several important geometry and material factors that determine the performance of DNP experiments: (i) coupling geometry of the millimeter wave beam into the MAS system, (ii) propagation of the millimeter wave beam through NMR rf coil and MAS rotor materials, (iii) the dielectric properties of the sample itself, and (iv) the radical molecules used as source of electron spin polarization. These factors should be known since they appear as boundary conditions when one investigates the detailed microscopic mechanisms of DNP. 4. DNP radicals and DNP sample preparation Samples for DNP experiments must contain a paramagnetic center, an EPR-active spin often referred to as the polarizing agent, which is either added to the sample or an endogenous species. The first demonstration of DNP in frozen aqueous media with a focus toward biological applications was demonstrated by the Griffin group using 4-amino TEMPO nitroxide radical in a mixture of water and glycerol [73], a common EPR solvent. The water/glycerol solution forms a cryogenic glass which is beneficial for microwave transmission and required for keeping the polarizing agent well dispersed upon freezing. The water/glycerol/nitroxide matrix was demonstrated to be applicable to soluble proteins [74] and extended to membrane proteins and virus particles [75]. The polarizing agents themselves have greatly evolved since the original 4amino TEMPO experiments. Another ground-breaking step by the Griffin group was the introduction of biradical polarizing agents [76], two covalently bound nitroxides, allowing for much higher DNP efficiency and at a lower total paramagnetic concentration. These biradical polarizing agents have been further investigated and optimized by the groups of Griffin and Swager at MIT [77] and Tordo at the University of Aix-Marseille [78,79]. A particular challenging category of biological samples has been lipid bilayers which often show low DNP efficiency; recent progress with spinlabeled lipids offers a promising outlook [80,81]. The ultimate goal in DNP experiments for solid state NMR applications is sensitivityper-unit-time and additional factors such as polarization build-up time, paramagnetic quenching [82], and depolarization upon MAS [83,84] must also be considered. Another set of key contributions, this time toward material science applications, were made by the group of Emsley at ENS Lyon who demonstrated the first applications of DNP on porous materials [85] introducing incipient wetness impregnation and the use of organic solvents for sample preparation [86], and optimized biradicals [87]. The fields of biological and materials applications are covered in details in several other articles in this perspective JMR issue.

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Fig. 6. Experimental vs. simulated millimeter wave forward scattering field amplitude distribution at 263 GHz revealing the field amplitude in two different planes as indicated. The comparison serves for validating the simulation result (simulation data Armin Purea, Bruker Biospin 2012).

Fig. 7. Left – upper part of the interior of an LT.MAS DNP probe with MAS system, miter-bended waveguide upper end and pneumatic sample insert/eject system. Right – Axial cross section through a 3.2 mm MAS system showing the plane of the incident millimeter-wave front and the interior of an MAS system constructed for millimeterwave irradiation in direction along the rotor radius (radial irradiation).

We conclude, as we transition to outlook, with a brief mention of recent work on polarizing agents for applications at high field (800 MHz, 527 GHz), where the DNP efficiency of traditional cross effect experiments with nitroxide biradicals drops severely [88]. Narrow-line radicals, such as bdpa and trityl, with the Overhauser mechanism offer opportunities for more favorable scaling with increasing frequency and reduced microwave power requirements [89]. The introduction of trityl/nitroxide biradicals has yielded the highest DNP signal enhancements at 527 GHz to date, with DNP sig-

nal enhancements actually increasing with frequency, and provided valuable insight into the factors contributing to efficient DNP [90].

5. Outlook We close our survey of instrumentation aspects of solid-state DNP by taking a tentative look to the next-future developments with some of these conclusions resulting from our own work at

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Fig. 8. Simulation of the microwave magnetic field magnitude distribution in a radial plane (top) and an axial plane (bottom) inside a 3.2 mm MAS system for three different frequencies of an incident mm wave beam (incident from the right side) with the mm wave E field polarized parallel to the rotor axis (simulation data Armin Purea, Bruker Biospin 2014).

present time. Without the intention of putting any strategic priority to the order of items in the following list, the present and nearfuture development of instrumentation for solid-state DNP MAS NMR might include: (i) Faster MAS at low temperature by adapting the small diameter MAS systems to the cryogenic environment necessary for solid-state DNP. (ii) MAS at cryogenic temperatures below 77 K with closed-loop or low helium consumptions systems. The first steps in that direction have already been taken or are presently in progress by various groups [15–17,63–65,71,72]. (iii) Dedicated probe hardware for DNP on static oriented biomembrane samples [50–52] taking into account the peculiarity of sample geometry and structure of typical oriented bio-membrane samples. (iv) Solid-state MAS DNP employing microwave sources with powers lower than gyrotron power levels (10–50 W) to provide lower-cost, economic instrumentation solutions also with reduced infrastructure requirements. The first steps have also been taken in this area with klystrons and solidstate sources as presented in the introduction. (v) MAS DNP at fields even higher than 800 MHz/527 GHz. (vi) Improvement and optimization of the coupling of the incident microwave field to the MAS NMR sample by applying more sophisticated resonator designs and principles from quasioptical systems. (vii) Solid-state DNP with microwave sources capable of short (nanosecond to microsecond timescale) phase coherent pulses, development of pulsed DNP methods, and/or the availability of sweepable magnets. (viii) New developments and optimizations in the field of DNP radicals.

Faster MAS (i) is almost self-explanatory for solid-state NMR spectroscopists – the reasons for it are the same as for solid-state NMR close to room temperature: higher spectral resolution. These developments are based on 1.3 and 1.9 mm MAS systems and preliminary results already show good prospect for DNP MAS applications, with high DNP signal enhancement obtained at spinning speeds at 25 kHz and higher. MAS with cryogenic helium at temperatures below 77 K (ii) has three aspects. First, experiments at these low temperatures promise even higher DNP enhancement factors. Second, spinning with helium gas offers the potential for faster spinning than with cold nitrogen gas. Third, the microwave power requirements at lower temperature become less severe such that lower-power sources (iv) could be used. Solid-state NMR of oriented biomembranes are very often characterized by a notoriously low signal-to-noise ratio, thus in this particular subfield (iii) the benefits of successful DNP experiments can hardly be overestimated. The search and development of microwave sources different from the gyrotron with smaller power levels (iv) has mainly economic reasons, nevertheless for wider adoption also depends on the possibilities to go to lower temperatures (ii), the accomplishments of probe developments (vi), and research in radical chemistry (viii). The quest for ever higher static NMR fields (v) applies to DNP NMR as it does to NMR without DNP, very often driven by the need of higher spectral resolution. Probe developments (vi) have been so far in their ‘‘infant stage”. With the current requests for higher MAS speeds, lower temperatures, and improved microwave coupling there is more to be expected in the next few years. Coherent pulse capability (vii) in DNP NMR appears to be the ambition of genuine NMR/ESR/DNP spectroscopists with the potential to truly unify ESR and NMR. This field is covered by another contribution in this special issue. Last but not least, DNP takes polarization from electron spins and transfers it to the nuclear spin system. Thus the chemistry of radicals (viii) providing

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Fig. 9. (a) Magnitude distribution of the millimeter wave magnetic field inside a 3.2 mm MAS rotor filled with frozen solution of H2O/D2O/glycerol (left) and filled with frozen solution and dielectric particles embedded, filling factor 0.63 (right three panels). The frozen solution has a real part of the dielectric constant equal to 2.5 (left), the dielectric constant of the particles is varied from 2.5 to 11 (right three panels). (b) Spatially averaged millimeter wave magnetic field magnitude for a frozen solution with dielectric constant of 2.5 and dielectric particles with dielectric constants varied from values of 1 to 11 for various filling factors. The solid curves are meant to guide the eye (simulation data: Armin Purea, Bruker Biospin, 2014).

the spin polarization appears as one of the most important molecular engineering tools for efficacious DNP NMR experiments.

[3]

Acknowledgments [4]

The authors are indebted to Dr. Werner Maas, Leo Tometich, Patrick Saul, Bryce Smith, Christian Reiter, Dr. Armin Purea, Dr. Kevin Felch, and Philipp Borchard.

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