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solvent-dependent_conductance_decay_constants_in_single_cluster_junctions

## Abstract: Single-molecule conductance measurements have focused primarily on organic molecular systems. Here, we carry out scanning tunneling microscope-based break-junction measurements on a series of metal chalcogenide Co 6 Se 8 clusters capped with conducting ligands of varying lengths. We compare these measurements with those of individual free ligands and find that the conductance of these clusters and the free ligands have different decay constants with increasing ligand length. We also show, through measurements in two different solvents, 1-bromonaphthalene and 1,2,4-trichlorobenzene, that the conductance decay of the clusters depends on the solvent environment. We discuss several mechanisms to explain our observations. ## Introduction Controlling charge transport through molecular junctions is critical to the realization of nanoscale electronic devices. 1,2 While numerous organic molecules have been studied as connecting wires for single-molecule junction studies, very little is known about the effect of metal complexes in these types of junctions. We recently reported that we could incorporate metal chalcogenide molecular clusters in single-molecule electrical circuits. 15 In this study, in order to determine how transport through such systems depends on molecular length, we connect these same clusters to conducting ligands of varying lengths. We have found that the inclusion of the cluster in the molecular circuit reduces the effect of ligand length on conductance decay with apparent molecular size. Moreover, we have found that the decay constant is impacted greatly by changing the solvent from 1,2,4-trichlorobenzene (TCB) to 1bromonaphthalene (BrN). Specifcally, the decay constant of the cluster is 0.04 1 in BrN, while it is 0.12 1 in TCB. We consider two possible mechanisms to explain these remarkable observations. Our work demonstrates, for the frst time, a molecular system where the tunneling decay constant can be modifed by altering the environment around the molecule. ## Results and discussion The single cluster circuits that we have designed, assembled, and studied consist of an atomically defned Co 6 Se 8 molecular cluster 16,17 (Fig. 1a) wired between nanoscale electrodes. The wiring is formed from bifunctional, conjugated ligands (Fig. 1b) that bind specifcally and directionally to the electrode and to the cluster. We employ an atomically defned segment of polyacetylene 18 that has an arylphosphine group on one terminus that coordinates to a cobalt atom on the clusters and an arylthiomethyl group on the other terminus that attaches to the Au electrode. 19,20 The mono-, di-, and triene ligands are L1, L2, and L3 and the corresponding clusters are 1, 2, and 3, respectively. Fig. 1c shows the molecular structure of 1 as determined by single crystal X-ray diffraction (SCXRD). 15 We measured the conductance of both the individual molecular clusters (1-3) and the free conducting ligands (L1-L3) using a scanning tunneling microscope-based break-junction (STM-BJ) technique. 21 In this technique, an Au STM tip and substrate are repeatedly brought into and out of contact to form and break Au-Au point contacts in solutions of the target compounds. During this process, a bias voltage is applied across the junction while current is measured in order to determine conductance (G ¼ I/V) of the junction. The measurements are repeated thousands of times, and the data is analyzed to reveal statistically signifcant results. The data is processed by compiling thousands of individual conductance traces into one-dimensional, logarithmically-binned conductance histograms. 22 We further generate two-dimensional (2D) histograms of the conductance versus displacement by aligning each conductance trace after the point contact ruptures (at a conductance of 0.5 G 0 ) and overlaying all conductance traces. In order to characterize transport through the molecular clusters and the free ligands, we measured the conductance of 1-3 and L1-L3 in two different solvents, BrN and TCB. These solvents were chosen taking into consideration the solubility of both the ligand and the cluster systems as well as for their varied affinity to gold electrodes. 23 Fig. 2a and b contain the onedimensional histograms for the measurements in BrN, and Fig. 2d and e show the same for the measurements in TCB. The 2D histograms for 1 and L1 in each solvent are insets in the respective fgures. The 2D histograms show a signifcant difference in length of the molecular feature for 1 and for L1. Moreover, the cluster junction lengths measured from the 2D histograms correlate with the molecular lengths of the cluster with the ligands fully extended (measured in BrN: 9 and 21 , and expected from SCXRD: 13 and 32 , for L1 and 1 respectively). Despite the additional complexity of the cluster system, we conclude that we are indeed probing transport through Au-ligand-cluster-ligand-Au junctions based on this large difference in the observed lengths. Furthermore, the histograms in Fig. 2a and d show shoulders, with an increasing prominence for the longer-ligand systems. Comparing the conductance of these shoulders with the ligand conductance in Fig. 2b and e, we attribute these shoulders to free ligands, that is, ligands that have detached from the clusters. We ft the peaks of all conductance histograms for both solvents with a Gaussian function and plot the peak conductance values versus the number of C]C units or "enes" in each molecule (Fig. 2c and f). In both solvents, and for both free ligand and cluster, we observe that the conductance decreases exponentially with increasing molecular length following the relationship G $ e bn , where n is the number of "ene" units in the backbone and b is the decay constant. We report the decay constant per Angstrom using a length of 2.48 per "ene" unit. The decay constant for the free ligand series is essentially independent of the solvent (b ¼ 0.15 1 in TCB and 0.17 1 BrN). The unexpected result is the factor of 3 difference in the decay constants of the cluster series in different solvents as can be seen comparing Fig. 2c and f. In TCB, the b of the cluster system is 0.12 1 , and in BrN it is 0.04 1 . We note that the difference between the decay constant of the ligand and that of the cluster is greater in BrN than in TCB. Furthermore, the absolute values of the conductance of the cluster series are signifcantly higher when measured in BrN than in TCB, with the conductance of 3 being almost an order of magnitude higher in BrN compared to TCB. Such a solvent-induced effect on the conductance has been observed in other systems, and this has been attributed to the solvent's ability to modulate the electrode work function. 23,24 These fndings are summarized: regardless of solvent the effect of C]C chain-length on conductance is less pronounced in 1-3 than in L1-L3. Furthermore, the conductance and the decay of L1-L3 are essentially insensitive to the choice of solvent, while the solvent signifcantly influences those of 1-3. To understand these results we consider several possible mechanisms of charge transport through these junctions. Charge transport can occur via a coherent off-resonance process through an orbital on the ligand-cluster-ligand assembly that is coupled to both electrodes. In that situation, the conductance depends on at least two related factors: (1) the energy of this conducting orbital relative to the metal E F , and (2) the coupling between this orbital and both electrodes. 25 As the length of the molecule increases, the HOMO-LUMO gap narrows, and if conductance were just related to energy level alignment, one would naively expect conductance to actually increase. However, transport through the junction is also related to how well the conducting orbital overlaps with the leads, and since the orbital is more delocalized over a longer conjugated molecule, this overlap decreases with increasing length. The conductance thus typically decays exponentially with increasing molecular length. Specifcally, as the conjugated backbone gets longer, the molecular orbital is delocalized over a longer molecule, and since the orbital is normalized, a smaller fraction of its amplitude resides on the sulfur atoms; therefore the coupling between the molecule and the electrodes decreases. If we assume that the conducting orbitals of the cluster and of the ligand for a given length are similar in both character and energy, we can develop a simple tight-binding model of the molecular junctions. The objective of this model is not to reproduce the experimental data but to examine and illustrate how the additional electronic structure of the cluster impacts transport through the system. Our tight-binding model is schematically presented in the insets of Fig. 3a and b for the ligand and the cluster respectively. For the conducting ligands, we assign a single energy level, 3, for each unit, and allow nearest neighbors to be coupled by d. The terminal units are coupled to the Au electrodes using an imaginary self-energy, iG/2. We apply a similar model for the cluster, adding an additional energy level, E 0 , between two ligands and coupling this site to its nearest neighbor ligand states with s. We compute the transmission functions for these model systems using a Green's function approach (see the ESI for a detailed description †). 25,26 Sample computed transmission functions are shown in Fig. 3a and b using the same values for 3, d and G for the ligand and the cluster series. The transmission functions display resonances at energy values corresponding to the molecular orbitals of the system where the probability of an electron being transmitted through the system is unity. The transmission function for L1 contains one resonance at energy 3, while longer ligands have resonances equal to the number of sites in the corresponding model. As the length of the molecule increases, the frontier resonance moves closer to E F but also narrows, which is a consequence of the frontier orbital being delocalized over a longer molecular backbone. Upon comparing the transmission functions for the ligands with those of the clusters, we see that the clusters contain resonances that are closer to E F than their ligand counterparts, but with narrower full widths at half max (i.e. they are more poorly coupled to the leads). This observation leads to a lower transmission at E F ; more importantly, it also leads to a conductance that is more sensitive to the exact location of the E F . In Fig. 3c, we show the conductances that are determined from the tight-binding model for each molecule versus the number of ligand levels in the molecule (using the same model parameter values for both series). From the ft to these values, it is clear that the predicted decay constants are essentially the same for the ligand and cluster series. We use one set of E 0 and s values to calculate the representative transmission/conductance functions shown in Fig. 3a and b. Regardless of what value is assigned to E 0 and s, we fnd that this model predicts very similar decay constants for the two systems (Fig. 3d). Our tight-binding calculations suggest that the addition of a cluster level E 0 between two ligands cannot explain the observed change in b. In other words, the ligand and cluster series should have the same b values, unless the energy alignment of the cluster resonance is altered relative to the electrode Fermi level in this model. We have three sets of observations that are consistent with a change in E F : (1) b of the cluster in BrN is signifcantly lower than in TCB, (2) b values measured in both solvents are almost the same for the ligand series, and (3) b of the cluster is lower than that of the ligand in both solvents. The steeper transmission curves of the cluster series in Fig. 3 indicate that the resonance energies are closer to E F . Within this coherent transport model, we can see that a small change in E F will result in a large shift in b for the cluster relative to the ligand. For instance, changing E F by 0.5 eV shifts the b value to 0.1 1 for the clusters while a similar change in E F for the ligand changes b to 0.3 1 . These results, when viewed in light of the known ability of solvent-binding to produce changes in E F , 23 point to BrN shifting E F closer to resonance relative to TCB. This effect is compounded by the sensitivity of the metal. The free ligand and the cluster have very different characteristics (e.g., size, steric hindrance, redox behaviour, dielectric constant polarizability and binding ability) that will result in different shifts in E F . We also consider a hopping mechanism for charge transfer, a process generally mediated by an activation-controlled reaction (e.g., a thermally induced conformational change or an electron transfer reaction). 27,28 We frst rule out the possibility that such a conformational change can occur within the ligand. 3 We also refute the process involving a direct through-space charge transfer from the electrode to an unoccupied molecular level on the cluster through a resonant transfer process. 14 In this picture, the cluster does not have to be chemically attached to the electrodes to form a conducting junction and the charge transfer efficiency depends on the core-electrode spacing. We discount this mechanism based on a previously published study in which we demonstrated that our clusters form molecular junctions by bonding their terminal thiomethyl groups to the Au electrodes. 15 By varying the substitution pattern or removing the aurophilic functionality, we can modulate or completely shut down the conductivity of these molecular junctions, suggesting that there is an orbital pathway for the transport of charge in these cluster systems. These fndings refute the idea of direct through-space charge transfer mediated by an orbital localized on the core. We are left with a hopping mechanism in which the charge tunnels from the source electrode across the ligand to the cluster core and then transfers to the drain electrode through a second coherent tunneling process. Such a transport process requires that the cluster can reversibly change its oxidation state with each charge transfer. Since the applied bias in these measurements is not small ($0.5 V) and the cluster core Co 6 Se 8 is redox active, it is plausible that such a hopping process is at play. In this case, the activation energy arises from the charge transfer process reorganization energy, which can be strongly influenced by the solvent. This mechanism is consistent with our observation that b changes with solvent. Within our experimental constraints, it is therefore difficult to conclusively establish which process (off-resonance tunneling or hopping) is at work in our single cluster junction system. ## Conclusions In summary, we measured charge transport through molecular clusters with ligands of different lengths and showed that the conductance decay depends on the solvent used for these measurements. Our results illustrate a novel effect that allows the environment to alter the conductance decay constants. This study opens up the possibility to carry out conductance measurements in which clusters can be controllably gated by changing the environment. 20 While the conducting ligands alone are limited to a one-dimensional system, the threedimensional architecture of the metal chalcogenide cluster allows us to envision novel electronic devices where a molecular cluster is contacted by electrodes at multiple locations.

chemsum

{"title": "Solvent-dependent conductance decay constants in single cluster junctions", "journal": "Royal Society of Chemistry (RSC)"}

characterization_of_frequency-chirped_dynamic_nuclear_polarization_in_rotating_solids

## Abstract: Continuous wave (CW) dynamic nuclear polarization (DNP) is used with magic angle spinning (MAS) to enhance the typically poor sensitivity of nuclear magnetic resonance (NMR) by orders of magnitude. In a recent publication we show that further enhancement is obtained by using a frequency-agile gyrotron to chirp incident microwave frequency through the electron resonance frequency during DNP transfer. Here we characterize the effect of chirped MAS DNP by investigating the sweep time, sweep width, center-frequency, and electron Rabi frequency of the chirps. We show the advantages of chirped DNP with a tritylnitroxide biradical, and a lack of improvement with chirped DNP using AMUPol, a nitroxide biradical. Frequency-chirped DNP on a model system of urea in a cryoprotecting matrix yields an enhancement of 142, 21% greater than that obtained with CW DNP. We then go beyond this model system and apply chirped DNP to intact human cells. In human Jurkat cells, frequency-chirped DNP improves enhancement by 24% over CW DNP. The characterization of the chirped DNP effect reveals instrument limitations on sweep time and sweep width, promising even greater increases in sensitivity with further technology development. These improvements in gyrotron technology, frequency-agile methods, and incell applications are expected to play a significant role in the advancement of MAS DNP. ## Introduction Dynamic nuclear polarization (DNP) is commonly used to improve the inherent insensitivity of nuclear magnetic resonance (NMR) spectroscopy . Typically, only continuous wave (CW) microwave methods have been employed with magic angle spinning (MAS) DNP. The solid effect and the cross effect are the primary DNP mechanisms used in moderate magnetic field strengths of 5-14 Tesla (T) . While CW approaches can significantly increase NMR sensitivity, they have limitations. Except in certain model systems , the solid effect and cross effect are inefficient at room temperature due to short longitudinal electron relaxation times. To perform CW DNP, samples are commonly cooled to <120 K, which adds complexity not only to the instrumentation, but also often leads to a loss of spectral resolution . Arrested molecular motion at these temperatures can cause substantial line broadening in most samples [3, . The cross effect and solid effect also exhibit worse performance at higher magnetic field, with cross effect efficiency decreasing as 1/B0 and that of solid effect as 1/B0 2 . Therefore new mechanisms will be required for efficient DNP at magnetic fields of 28 T and higher. Frequency-chirped DNP techniques, such as the frequency-swept integrated solid effect (FS-ISE) , nuclear orientation via electron spin locking (NOVEL) , and timeoptimized pulsed (TOP) DNP show promise to perform well both at high magnetic field and room temperature. For instance, ISE yields DNP enhancements of ~150 at room temperature and is predicted to be unaffected by the strength of the external magnetic field . However, these experiments have been performed without MAS and at magnetic fields <3 T , primarily due to the difficulty of implementing MAS with the microwave resonators required to generate considerable electron nutation frequencies. Frequency-swept DNP at higher magnetic fields has also been shown to improve DNP performance , but has only recently been implemented with MAS . MAS improves the sensitivity and resolution of solid-state NMR by partially averaging anisotropic interactions of the magnetic resonance Hamiltonian, and is a crucial aspect of applying DNP to systems of interest. Here we characterize the behavior of frequency-chirped DNP experiments performed with MAS, expanding on our recent work . We optimize frequency chirps from a custom-built frequency-agile high-power gyrotron to produce large gains in intensity beyond those obtained with CW DNP. In addition to measuring its performance on a model system, we conduct optimized chirped experiments on intact human Jurkat cells to demonstrate frequency-chirped DNP in a biologically complex environment. ## NMR Experiments MAS DNP NMR experiments were performed using a custom-built DNP spectrometer at a magnetic field of 7.1584 T . 13 C and 1 H Larmor frequencies were 75.4937 MHz and 300.1790 MHz, respectively. A CPMAS, rotor synchronized, Hahn echo sequence with TPPM decoupling was used for all experiments (Fig. 1a). The initial magnetization of 1 H and 13 C spins was destroyed using a saturation train. 1 H and 13 C pulses were performed with nutation frequencies of 77 kHz and 100 kHz, respectively. The Hartmann-Hahn matching condition (γB1) for 1 H and 13 C was 30 kHz. Frequency chirps were applied over the DNP polarization period (τpol), and CW microwaves were employed over the rest of the experiment. The spinning frequency was 4.5 kHz for all experiments, and the sample temperature was 90 K. Typical polarization times (τpol) for optimized spectra were 5-times the T1 of the sample in the absence of microwaves, in order to remove contamination of the data by differences in the nuclear T1 and the T1DNP. Microwaves were generated using a frequency-agile gyrotron, whose output frequency was adjusted by varying the electron acceleration potential at the electron gun anode. An arbitrary waveform generator (AWG) integrated into the NMR spectrometer (Redstone, Tecmag Inc. Houston, TX) was used to generate a waveform, which ramped the output frequency of the gyrotron in a linear fashion through 197.670 GHz, the frequency of maximum DNP enhancement of the TEMTriPol-1 radical . The frequency chirps were a triangular waveform, which was repeated over the entire polarization period. For frequency chirp optimization the incident microwave power, the center DNP microwave frequency, and the sweep width and sweep time of the individual chirps were varied. The center frequency of the sweeps was varied by changing the voltage at the gyrotron anode with the AWG amplified by a high-voltage amplifier (TREK, Inc. Lockport, NY). The sweep width corresponded to the frequency range of one sweep/chirp (either up or down) in MHz, and sweep time was the time to complete a sweep/chirp. Microwave power was attenuated from full power by inserting copper foil with slits cut in it into a gap in the waveguide to partially pass the microwave beam. The optimal power of 7 W incident on the sample was used for most experiments, which provided an estimated electron Rabi frequency of 0.43 MHz . ## 7 The 13 C carbonyl resonance was fit using DMfit to determine resulting enhancement increases. For all optimization spectra, the magnitude of the Hahn echo was used to calculate the percent increase in intensity. All experiments were repeated four times to acquire adequate error values for the measurements. ## Sample Preparation Experiments were performed on 4 M [U-13 C, 15 N] urea mixed with 5 mM TEMTriPol-1 or 5 mM AMUPol in a cryoprotecting matrix consisting of 60% d8 glycerol, 30% D2O, and 10% H2O by volume. Intact Jurkat cells (ATCC, Manassas, VA) were cultured in [U- 13 C, 98%; U-15 N, 98%] BioExpress-6000 mammalian cell growth medium (Cambridge Isotope Laboratories, Tewksbury, MA) at a concentration of 3 × 10 6 cells/mL in a six-well plate at 37°C and 5% CO2 for 48 hr. 3.6 × 10 7 cells were collected, spun at 170 g for 5 min, washed with 1× phosphate-buffered saline (PBS), and spun again at 170 g for 5 min to remove extracellular NMR labels (g = 9.8 m/s 2 ). 40 µL of 20 mM TEMTriPol-1 in 1×PBS with 10% DMSO was added to a cell pellet containing 36 million Jurkat cells. This suspension was centrifuged directly into the 3.2 mm zirconia rotor at 800 g for 30 s and immediately frozen in liquid nitrogen as detailed in our previous work . ## Results and Discussion Frequency-chirped DNP refers to a change in the microwave frequency or intensity throughout the course of an experiment. The frequency-chirped DNP pulse sequence is shown in Fig. 1A. Frequency chirps (represented by the rainbow gradient) are applied over the DNP polarization period and the resulting NMR signal is detected through a cross polarization (CP) Hahn echo sequence. We emphasize that microwave frequency chirps result in better manipulation of the electron spin polarization, yet the active DNP mechanism is still the cross effect. Selection of appropriate radicals for frequency-chirped DNP is crucial due to drastic differences in electron spin g-anisotropy and relaxation properties. In our previous demonstrations of electron decoupling using chirped microwave pulses with MAS, we employed trityl rather than nitroxide radicals . Those successes led us to explore the use of trityl-nitroxide biradicals, with the rational that the narrow trityl resonance would be easier to manipulate and the tethered nitroxide would provide greater DNP enhancements through the cross effect mechanism. TEMTriPol-1 is such a biradical, consisting of a Finland trityl radical covalently linked to a 4-amino TEMPO radical, which is used for cross effect DNP . TEMTriPol-1 improves cross effect efficiency at high magnetic fields. Where other biradicals, such as AMUPol, depolarize nuclear spins at 100 K in the absence of microwave irradiation, TEMTriPol-1 preserves nuclear polarization . ## Frequency-chirped DNP on a Model System CW DNP CPMAS experiments were performed at various microwave frequencies to record a 1 H DNP enhancement profile with TEMTriPol-1 . The enhancement profile shows the trityl resonance frequency as the optimal frequency for CW DNP enhancement. This will be the target for the center of the frequency chirps. In a 7.1584 T magnetic field, the microwave frequency for maximum CW DNP enhancement was 197.670 GHz (Fig. 1B). Experiments were performed to determine the effect of frequency-chirped microwave pulses during the polarization period of MAS DNP (Fig. 2). For comparison, cross effect DNP experiments were performed with CW microwave irradiation. CW DNP experiments on a model system of urea with TEMTriPol-1 resulted in an enhancement of 118 (Fig. 2, red). Enhancements herein are defined as the NMR signal intensity recorded with DNP compared to that without DNP . For frequency-chirped DNP experiments, the microwave frequency was linearly chirped with a triangular waveform over 197.670 GHz, with a 28 µs sweep time and a 120 MHz sweep width. These optimized chirps yielded a 21% increase over CW DNP and an enhancement of 142 (Fig. 2, blue). Polarization times of 53 s (5×T1DNP, Fig. S1) were used to ensure that >99% of the polarization had built up for both experiments, allowing for direct comparison of the CW and frequency-chirped experiments. To determine the necessity of a narrow-line radical, such as trityl, for frequency-chirped DNP, experiments were performed on a sample containing the nitroxide-nitroxide biradical, AMUPol. The frequency chirps were centered at 197.674 GHz (maximum with 1 H-enhancement for AMUPol) the previously optimized sweep time of 28 µs and sweep width of 120 MHz were used. Frequency chirps over the polarization period resulted in a decrease in signal intensity of 3% compared to CW DNP (Fig. 3). These frequency chirps do not yield the same improved electron spin control over the nitroxide biradical, AMUPol, as they do over TEMTriPol-1. This implies that a narrow-line radical is required for implementation of frequency-chirped DNP. ## Frequency-chirped DNP in Intact Jurkat Cells The performance of frequency-chirped DNP was then examined within intact human Jurkat cells (Fig. 4). Frequency chirps improved the NMR signal by 24%, yielding an enhancement of 6 (versus 4.8 for CW DNP). These results display the application of frequency-chirped DNP to more complex samples of biological interest. ## Power Dependence of CW and Frequency-chirped DNP To determine the dependence of CW and frequency-chirped enhancement on microwave power, CPMAS experiments were performed with varying microwave attenuation on the TEMTriPol-1/urea sample (Fig. 5). For frequency-chirped DNP the optimized triangle waveform (28 µs sweep time and 120 MHz sweep width) was repeated over a polarization time of 20 s. 35 W of microwave power incident on the sample (Rabi frequency of 0.95 MHz) produced a 123% increase in signal with frequency-chirped DNP compared to CW, yielding enhancements of 17 and 8, respectively (Fig. 5a, b). We note that such high microwave powers place the cross effect in the oversaturated regime, leading to less overall enhancement. 7 W of microwave power resulted in the highest sensitivity and an improvement of 25% with frequency-chirped DNP compared to CW. Higher microwave power yielded greater improvements with frequency-chirped DNP over CW DNP, but the overall signal intensity obtained was suboptimal due to saturation of the cross effect . ## Characterization of Frequency-chirped DNP The effects of sweep time, sweep width, and center frequency on the improvement with frequencychirped DNP over CW irradiation are shown in Fig. 6. For this dependence the polarization time was 20 s; the sweep width was held constant at 80 MHz, the incident microwave power at 7 W, and the center frequency at 197.670 GHz. Shorter sweep times increased the sensitivity to a greater extent than longer sweep times, with the greatest improvement over CW (15%) occurring with a 20 μs sweep time (Fig. 6a). Sweep times below 20 μs were not achievable with the current microwave frequency agility circuit, as the frequency output waveform became distorted. A sweep time of 150 µs resulted in only a 1% improvement in signal intensity over CW. We suspect that at longer sweep times electron spin saturation is lost through relaxation mechanisms. The dependence of frequency-chirped DNP sensitivity on the sweep width of the frequency chirps is shown in Fig. 6b. For this dependence the polarization time was 20 s; the sweep time was held constant at 28 μs, the incident microwave power at 7 W, and the center frequency at 197.670 GHz. The improvement from the frequency chirps increased as the sweep width increased. A 120 MHz sweep width resulted in an improvement of 21%, while the signal intensity decreased by 1% with a sweep width of 10 MHz. Due to instrument limitations, sweep widths greater than 120 MHz could not be attained. This width is roughly that of the base of the trityl lineshape in the enhancement profile (Fig. 1b). We previously reported a similar optimal sweep width in electron decoupling experiments involving the Finland trityl radical . Larger sweep widths provide microwave irradiation that is resonant with a greater number of trityl electron spins, enabling better electron spin control and improving the efficiency of frequency-chirped DNP. During characterization it is important to consider multiple points on the enhancement profile. Fig. 6d provides a clear picture of the effect of frequency chirping, whereas Fig. 6c shows the potential for misinformation. The choice of irradiation frequency can lead to suspiciously high improvements due to difference in positive and negative enhancement regions between CW and frequency-chirped DNP. The CW enhancement profile shows maximum positive and negative enhancements at 197.670 GHz and 197.850 GHz, respectively (Fig. 6d). Frequency chirping at microwave frequencies lower than 197.750 GHz (positive enhancement), yielded greater enhancements than CW (Fig. 6d). However, at frequencies greater than 197.750 GHz (negative enhancement), the frequency-chirped DNP provided lower signal intensity than CW DNP. Note that at this point we have simply demonstrated the methodology of performing frequencychirped DNP experiments with TEMTriPol-1. To compare the sensitivity of the experiments with TEMTriPol-1 and AMUPol, we can divide the signal-to-noise from each experiment by the square root of the polarization time for the respective experiments. In doing so, we obtain a sensitivity of 79 with AMUPol (Fig. 3) and 73 with TEMTriPol-1 (Fig. 2). Thus, while the sensitivity of the experiments performed on each radical are similar at this stage, advances in instrumentation that enable greater sweep times and sweep widths will make frequency-chirped DNP experiments with TEMTriPol-1 more sensitive than AMUPol, and thus more feasible for sensitivity-demanding, multidimensional experiments. ## Conclusion To date, frequency-chirped DNP experiments, such as FS-ISE, NOVEL, and TOP DNP, have been largely restricted to static samples due to the difficulties of housing microwave resonators with the instrumentation required for magic angle spinning (MAS). Here, we have characterized the optimal experimental conditions for frequency-chirped MAS DNP. At a magnetic field of 7 T and with 7 W of microwave power, frequency-chirped microwaves over the polarization period improved DNP enhancements by 21%. Greater microwave powers resulted in up to 123% improvements with frequency-chirped DNP, but saturation of the cross effect resulted in less overall signal intensity. These optimized frequency-chirped experiments were applied to a more biologically complex sample: intact Jurkat cells. This resulted in an improvement in signal intensity of 24% over CW DNP. Characterization of the parameters of frequency-chirped DNP revealed areas for further improvements to elicit even greater sensitivity. More powerful gyrotrons with larger frequency bandwidths, and gating mechanisms for chirps can be developed to increase sweep widths and shorten the sweep times, thus improving electron spin control. To take full advantage of frequencychirped DNP at high power and high electron Rabi frequencies, duty cycling of the microwaves can be implemented to reduce dielectric heating . We expect optimization of the waveform, with respect to both intensity and phase, to result in improved frequency-chirped DNP MAS performance. Future studies could analyze the effect of the spinning frequency on the enhancement achieved by frequency chirped DNP over CW DNP. Both the solid effect and cross effect are driven by interactions between the spin system, the microwave field, and the spinning rotor. Understanding these effects will prove crucial in the future development of DNP, as MAS frequencies and magnetic fields are pushed to ever higher values. New radicals composed of tethered broad and narrow line radicals are currently being investigated with useful electronic properties such as long longitudinal relaxation times. Longer relaxation times will afford even more electron spin control with frequency-chirped DNP. Although the precise mechanism governing the improvement in sensitivity will require further investigation, it is possible that it is governed by an adiabatic process. As such, future experiments could focus on maintaining a constant sweep rate by simultaneously varying the sweep time and sweep width in an inverse manner. This could prove important, as adiabatic processes often show a remarkable resilience to microwave inhomogeneities and frequency offsets arising from difference in molecular orientation and conformations in a solid sample. These techniques can be paired with other advances in instrumentation such as higher power microwave sources and microwave lenses for improved microwave intensity and high frequency MAS for 1 H detected spectra in future experiments. These could allow for the implementation of pulsed DNP mechanisms such as electron-nuclear cross polarization at high magnetic fields in the foreseeable future.

chemsum

{"title": "Characterization of Frequency-chirped Dynamic Nuclear Polarization in Rotating Solids", "journal": "ChemRxiv"}

physico-chemical_properties_and_catalytic_activity_of_the_sol-gel_prepared_ce-ion_doped_lamno3_perov

## Abstract: Ce-doped LaMno 3 perovskite ceramics (La 1−x Ce x Mno 3 ) were synthesized by sol-gel based coprecipitation method and tested for the oxidation of benzyl alcohol using molecular oxygen. Benzyl alcohol conversion of ca. 25-42% was achieved with benzaldehyde as the main product. X-ray diffraction (XRD), thermogravimetric analysis (TGA), BET surface area, transmission electron microscopy (teM), X-ray photoelectron spectroscopy (Xps), temperature-programmed reduction (H 2 -tpR), temperature-programmed oxidation (o 2 -tpo), Ft-IR and UV-vis spectroscopic techniques were used to examine the physiochemical properties. XRD analysis demonstrates the single phase crystalline high purity of the perovskite. the Ce-doped LaMno 3 perovskite demonstrated reducibility at low-temperature and higher mobility of surface o 2 -ion than their respective un-doped perovskite. the substitution of Ce 3+ ion into the perovskite matrix improve the surface redox properties, which strongly influenced the catalytic activity of the material. The LaMnO 3 perovskite exhibited considerable activity to benzyl alcohol oxidation but suffered a slow deactivation with time-on-stream. Nevertheless, the insertion of the A site metal cation with a trivalent Ce 3+ metal cation led to an enhanced in catalytic performance because of atomic-scale interactions between the A and B active site. La 0.95 Ce 0.05 Mno 3 catalyst demonstrated the excellent catalytic activity with a selectivity of 99% at 120 °C. Presently, perovskite-based materials are gaining immense popularity in the field of material science due to their extraordinary optical, electro-magnetic properties. Perovskite materials mostly applied for removing common exhaust pollutants including carbon monoxide, hydrocarbon, ammonia oxidation, water dissociation, and NOx, etc. . Amongst different perovskite, Mn-containing oxide materials have been growing a considerable interest from the researchers because of the large specific external area, high thermo-chemical durability and extraordinary catalytic performance even at environmental conditions . These excellent physicochemical properties of Mn-based perovskite materials made them an ideal candidate for their applications in the decomposition of customary use pollutants including carbon monoxide, NOx, and poisonous hydrocarbons. In this regard, various types of catalytic conversion technologies were developed 4,5,8,10,11 . Besides that, in order to make the catalytic combustion widely applicable, the development of reliable technologies is highly desirable. Amongst various catalytic active perovskite materials, lanthanide (Ln 3+ ) ion substituted perovskite demonstrated superior activities 10,12 . Such materials revealed higher catalytic activity and superior thermal stability for hydrocarbon combustion than their respective un-substituted perovskites 2,7,10 . Owing to the outstanding catalytic activity of perovskite-type oxide ABO 3 , where A is 12 coordinated and larger cation in size, whereas B is 6 fold coordination and smaller cation in size with oxygen anion. The partial co-doping of the A-site by the transition metal ions with dissimilar valance generate a structural defect because of bond stretching and amend the valence of the B-site to meet the chemical charge balance of the perovskite structure; actually, it is the prime origin for extraordinary catalytic oxidation performance of the ABO 3 based oxides. Therefore, doping of similar valence state ions at A or B sites might be altered the crystal structure, geometrical symmetry and disturb the oxidation states of the cations without altering the structure. Besides that, the variation of Mn 4+/ Mn 3+ ratio has the main effect on the catalytic activities of ABO 3 materials. The partial doping of Ce 3+ ion into LaMnO 3 altered the catalytic activity because of an increase in specific surface area, surface defects, oxygen mobility, and redox ability. Ceria has the capability to absorb and release the oxygen vacancies, and these oxygen species play a crucial role in the overall catalytic activities of the CeO 2 -based perovskites . Owing to the oxidation state transformation behavior of ceria between Ce 3+ and Ce 4+ dependent on the O 2 partial pressure in the nearby atmosphere 13,14 . Usually, the redox behavior of Ce 3+ is determined by morphology, size, and dissemination of oxygen species as the utmost appropriate surface defects 13 . This unique property of Ce 3+ revealed high thermo-chemical robustness and large O 2 species movement, and thus displays improved performance in catalytic oxidation of hydrocarbons and nitrogen oxides. So far, nonstoichiometric perovskite materials demonstrated some specific physical properties including evolution in surface defects, oxygen ion mobility, and redox property. In this article, we proposed the synthesis of Ce 3+ ion substituted LaMnO 3 nanoparticles via sol-gel based co-precipitation process. We inspected the impact of Ce 3+ ion doping in LaMnO 3 nanoparticles on physiochemical properties and oxidation performance of C 6 H 5 CH 2 OH to C 6 H 5 CHO. For characterization various techniques were applied including X-ray diffraction pattern (XRD), transmission electron microscope (TEM), energy dispersive x-ray analysis (EDX), N 2 adsorption, Fourier transform infrared (FTIR), optical absorption (UV-Vis), thermogravimetric analysis (TGA), temperature program reduction (TPR), temperature program oxidation (TPO) and X-ray photoelectron spectroscopy (XPS) techniques. These techniques revealed the role of Ce 3+ ion substitution on the crystal structure, crystallinity, surface properties, thermal stability, optical, redox behavior, oxygen adsorption properties and catalytic activities of the as-prepared nonstoichiometric LaMnO 3 materials. experimental section synthesis of perovskites (La 1−x Ce x Mno 3 ). Analytical grade chemicals were procured and used directly without any extra distillation. In a typical synthesis of LaMnO 3 perovskite, 4.3 g La(NO 3 ) 3 .6H 2 O (99.99%), and 2.4 g Mn(NO 3 ) 3 .3H 2 O (99.99%, BDH Chemicals Ltd, UK), were dissolved in 50 ml H 2 O along with C 6 H 8 O 7 .H 2 O (E-Merck, Germany). Citric acid was used as a chelating agent for complexation with lanthanum and manganese nitrates. The resulting mixed aqueous solution was magnetically stirred on a hot plate at 100 °C until the transparent solution was achieved. Aqueous ammonia solution was quickly added to precipitation under constant mechanical stirring. The occurrence of the willing product was dried at 100 °C for overnight and further annealed at 700 °C in the air for 5 hrs. A similar procedure was repeated for synthesis of La 1−x Ce x MnO 3 oxides (x = 0.05, 0.07 and 0.10 mol %). ## Catalyst characterization. Powder X-ray diffraction measurement was performed on a PANalytical X'PERT (X-ray diffractometer) furnished with Ni filter and using CuKα (λ = 1.5406 ). Morphology was obtained from Field emission Transmission Electron Microscope (FE-TEM, JEM-2100F JEOL, Japan) furnished with energy dispersive x-ray analysis (EDX) functioned at an accelerating voltage of 200 kV. Thermal analysis was measured on (TGA/DTA Mettler, Toledo, AG, Analytical CH-8603, Schwerzenbach, Switzerland). UV/Vis absorption spectra were measured by using Perkin-Elmer Lambda-40 Spectrophotometer. Fourier transforms Infrared (FT-IR) spectra were recorded on Perkin-Elmer 580B IR spectrometer. Temperature program reduction (TPR) and Temperature program oxidation (TPO) spectra were recorded on chemisorption Micromeritics AutoChem model 2910 analyzer furnished with a thermal conductivity indicator. Before the experiment, 100 mg material sample was treated with 10 vol % O 2 /He stream at 500 °C for 30 min to get complete oxidation. Then materials were cooled at room temperature and a mixture of 10 vol% H 2 /Ar gas with flow rate 20 mL/min was introduced and the reactor was heated from ambient temperature to 900 °C and maintained this temperature up to 20 min. For the O 2 -TPO experiments, helium(He, 30 mL/min) gas was applied for drying the perovskite samples at 150 °C and cooled down to room temperature, followed by an increase of temperature under O 2 /He (30 mL/min) flow with a temperature slope of 10 °C/min to 900 °C on the same instrument. The textural properties of the perovskites were recorded on a Micromeritics TriStar 3000 BET Analyzer, taking a value of 0.162 nm 2 for the cross-sectional area of the N 2 molecule adsorbed at 77 K. Powder samples were dried and degassed by heating gently to 90 °C for 1 h, then at 200 °C for 3 h under flowing N 2 before measurement. The free space in each sample tube was determined with He, which was assumed not absorb. Catalytic studies. Liquid-phase oxidation of benzyl alcohol was carried out in a glass vessel equipped with a magnetic stirrer, reflux condenser, and thermometer. Briefly, a mixture containing benzyl alcohol (2 mmol), toluene (10 mL) and the perovskite (0.3 g) was vigorously stirred in a three-necked round-bottomed flask (100 mL) and then heated up to 120 °C. The O 2 -gas was introduce in the reaction mixture through bubbling to start the oxidation experiment with a 20 mL/min flow rate. After completion of reaction solid catalyst extracted from the solution by centrifugation and reaction mixture was analyzed by gas chromatography to examine the conversion of the alcohol and product selectivity by (GC, 7890 A) Agilent Technologies Inc, equipped with a flame ionization detector (FID) and a 19019S-001 HP-PONA column. The specific activity of the catalyst was calculated using the equation ## Specific activity Moles of substrate (mmol) Product formed/Amount of catalyst(g) Reactiontime(h) The turnover number and turnover frequency of the catalyst were calculated using ## Results and Discussion Crystallographic and morphological structure. Figure 1 demonstrates the XRD pattern to observe the chemical composition, crystallographic structure and grain size of the as-synthesized perovskite. As observed in Fig. 1. the distinct diffraction lines of perovskite in XRD pattern can be assigned to the (012), (110), (104), (202), (024), (122), (116), (214), (018), ( 208) and (128) lattice planes, which are attributed to the hexagonal structure of LaMnO 3 nanoparticles(Fig. 1) (JCPDS card No. 032-0484) 6,19 . Any other diffraction line associated with MnO or CeO 2 is not identified over the whole XRD range specifies the homogeneous dispersion into the crystal lattice and formation of perfect single phase LaMnO 3 perovskite. An observed diffraction line at 30.27° corresponds to La 2 O 3 , which is weaker than the reflection lines of LaMnO 3 perovskite. All diffractograms of the perovskite materials revealed the similar trigonal symmetry in the crystallographic space group with marginally dissimilar cell parameters. As shown in Fig. 1 diffraction lines in trivalent Ce 3+ substituted perovskite are slightly shifted towards longer angle along with reduced intensity in respect to the un-substituted LaMnO 3 perovskite, it could be due to the effect of Ce 3+ ion doping into the crystal matrix. Owing to the small radius of Ce 3+ ions, they are highly mobile and easily migrate from surface to crystal lattice within the crystal matrix of perovskite materials at environment conditions 13,14,20 . The broadening of reflection lines in perovskite materials suggested the nanocrystalline nature of the as-prepared nanomaterials. As shown in Fig. 1, on substituted of small radius Ce 3+ (1.25 ) in place of La(1.27 ), the reflection lines slightly shifted to higher 2θ, signifying that the crystal arrangement becomes distorted 13,21 , resulting the transformation is occurring in the symmetry of crystallographic structure 7,10,22 . The experimentally calculated lattice parameters for LaMnO 3 , La 0.95 Ce 0.05 MnO 3 , La 0.93 Ce 0.07 MnO 3, and La 0.90 Ce 0.10 MnO 3 are a = 5.527 , 5.463 , 5.449 and 5.436 , respectively, are decreased on increasing the substitution concentrations of the Ce 3+ ion into the LaMnO 3 crystal lattice in respect to un-substituted LaMnO 3 perovskite. These variations in lattice parameters and shifts in peak positions endorse the substitution of modified ions into the crystal lattice structure. TEM micrograph clearly shows the irregular hexagonal structure, smooth surface, uncontrolled size, highly aggregated, well-distributed nanoparticles. Figure 2a illustrates the typical image of Ce 3+ ion substituted LaMnO 3 perovskite nanoproduct with size ranging from 25-31 nm. Energy dispersive x-ray analysis in Fig. 2b revealed the existence of all substituted elements including La 3+ , Mn 3+ , Ce 3+ and oxygen elements in the as-prepared LaMnO 3 perovskite. The appearance of intense peaks of Cu 2+ and C belong to the carbon coated copper grid. It confirmed the efficacious doping of Ce 3+ into the crystal matrix. textural properties and thermal stability. The structural parameters after calcination of Ce substituted LaMnO 3 catalysts, Specific surface area (BET), pore volume (PV) and average pore size (PD) are summarized in Table 1. The PV and PD were obtained from the adsorption branch of the respective N 2 isotherm by put on the BJH method. Surface area (Single point BET and Multipoint BET), PV and PD drop with increasing Ce ion concentrations from 5 to 10 mol% (Table 1). Thermogravimetric (TGA) analysis of the as-prepared LaMnO 3 perovskite and Ce-substituted materials exhibit a similar decomposition trend in all thermograms (Fig. 3). TGA spectra were recorded from 0-900 °C in N 2 -atmosphere with a heating rate of 10 °C/min (Fig. 3). First big exothermic peak (DTA) in all samples are observed at around 400 °C resemble the crystalline H 2 O molecules or complexation form surface attached organic impurities. The surface attached OH groups or organic moieties are coordinated to the central metal ion in different attachment form in the existing complex precursor system 23,24 . Generally, -OH groups attached on the surface of metal ions in two forms either terminal Ln-OH or in the bridge from Ln-(OH)-Mn 25 . In both cases, the dissociation of surface OH groups contrasts from each other depending on the surrounding chemical environment. So that, the reduction ii molar mass occurs in a rather varied range of temperature. No decomposition peaks signifying further crystallization are found in TGA, specifying that the perovskite materials are in crystalline form, as verified by XRD results. All four thermograms illustrate the sluggish weight loss (~6-8%) in between 400-900 °C, which is assigned to the removal or combustion of carbon dioxide at high temperature. optical properties. Figure 4 displays the infrared spectra of the as-synthesized LaMnO 3 and different Ce ion substituted LaMnO 3 perovskite nanoparticles. All samples exhibited a diffused band in between 3160-3653 cm −1 assigned to the νO-H stretching vibration originating from surface adsorbed H 2 O molecules (Fig. 4) 25 . Two additional strong intensity infrared bands are observed positioned at 1486 and 1375 cm −1 attributed to the δOH and γOH vibrational modes of H 2 O molecules. These observed infrared spectral results are in accord with TGA observations. The observed infrared band at 644 cm −1 is allotted to the νM-O stretching vibrational mode which certified the formation of metal oxide framework 26,27 . www.nature.com/scientificreports www.nature.com/scientificreports/ Optical absorption spectra were carried out to determine the optical characteristics of the as-synthesized perovskites (Fig. 5a,b). The direct energy band gap (E g ) is estimated by fitting the absorption spectral data to the straight transition equation by extrapolating the linear portions of the curve into αhν = A(hν − E g )½, where α is optical absorption coefficient, hν is the photon energy, E g is the direct bandgap and A is constant (Fig. 5b) 25,28,29 . The experimentally assessed direct energy band gaps of all perovskite nanomaterials are 1.15, 1.31, 1.34 and 1.32 eV for LaMnO 3 , La 0.95 Ce 0.05 MnO 3 , La 0.93 Ce 0.07 MnO 3 , and La 0.90 Ce 0.10 MnO 3 perovskites, respectively. An observed increase band gap energy with increasing the Ce 3+ ion substitution quantity into the LaMnO 3 crystal lattice, which is attributable to the Burstein-Moss effect 28, . ## Redox properties (tpR/tpo). Redox properties of the as-prepared LaMnO 3 perovskite and their Ce 3+ ion substituted LaMnO 3 perovskites are determined by H 2 -TPR and the observed results are presented in Fig. 6a and tabulated in Table 2. TPR and TPO studies are performed to examine the role of Ce 3+ ion-doping on redox behavior of LaMnO 3 perovskite within the range from 50-800 °C. The TPR spectra were recorded within the temperature range from 50 to 800 °C temperature. TPR spectra exhibited two typical characteristic reduction peaks, first one in between 280-600 °C and second started from 645 °C5 . The observed peak at low reduction temperature (280-600 °C) is correspond to the reduction of Mn 4+ to Mn 3+ and elimination of surface adsorbed oxygen vacancies, and the second reduction band is observed at a higher temperature (645 °C), which correspond to the reduction of Mn 3+ to Mn 2+ 4,6,7,33,34 . The first broadband occurred at lower reduction temperature indicate the largest H 2 -consumption, it suggesting the better initiative catalytic activities of LaMnO 3 perovskite at a lower temperature. The higher oxidation state of Mn 3+/4+ ions is accountable for more oxygen species because of lacking ligand amounts of Mn 3+/4+ ion. The occurrence of Mn 4+ ion is associated with the fact that Mn 3+ has a permitted electron, and have the ability to adsorb molecular O 2 and convert it into an electrophilic form 6 . Reversed transformation of manganese ion oxidation states is observed by the TPO analysis (Fig. 6b), in which the oxidation peak www.nature.com/scientificreports www.nature.com/scientificreports/ at low temperature (205-310 °C) suggest the transition of Mn 2+ to Mn 3+ and the oxidation peak at 445-717 °C exhibit the oxidation from Mn 3+ to Mn 4+ . These observations are in accord with published reports 4,5,34 . Additionally, the H 2 -TPR profile shape of LaMnO 3 is altered after doping of different Ce 3+ ion concentrations into the LaMnO 3 crystal lattice as seen in Fig. 6a. The incorporation of Ce 3+ ion into the LaMnO 3 matrix strongly modified the reduction behavior of LaMnO 3 perovskite. As shown in Fig. 6a, the Ce 3+ ions-substituted sample revealed three peaks at 330-345, 440-450 and ~800 °C, the first band looks very minute and the second band occurs very robustly 35 . The occurrence of two peaks in Ce 3+ ion substituted LaMnO 3 TPR profiles indicates the existence of at least two species in the LaMnO 3 crystal lattice, which became stronger and shifted towards high temperature after increasing the doping concentrations of Ce 3+ . An observed band between 330-345 °C, ascribed to the replacement of Mn 2+ by Ce 3+ in LaMnO 3 crystal matrix. Because of this charge disparity lattice alteration would arise that promote to the construction of La-O-Mn-O-Ce solid solution form, resulting the reactive O 2 vacancies are produced that may be reduced simply at low temperature. Generally, the elimination of oxygen vacancies at low temperatures associated with higher oxygen mobility (oxygen reacts more easily) and oxygen reactivity 4,6 . An observed reduction band at 448 °C ascribed to the dissociation of powerfully interactive MnO 2 type with Ce 3+ supports, whereas weak intensity reduction band observed at ~800 °C consigned to the high-temperature dissociation band because of bulk MnO 2 24 . Owing to the variation in balance of both metal (Mn 3+/4+ and Ce 3+/4+ ) cations from 4+ to 3+ or from 3+ to 2+, the up-down swings of O 2 imperfections escorted with valence alteration is observed 6,35 . Therefore, the high O 2 storage capacity of 10 mol% Ce substituted LaMnO 3 perovskite because of the simultaneous occurrence of transportable O 2 vacancies and analogous (Mn 2+/3+/4+ /Ce 3+/4+ ) redox couples. Consequently, the La 0.90 Ce 0.10 MnO 3 sample revealed an excellent catalytic activity at a lower temperature, so that, the highest redox properties, these results are in accord with previous literature reports 7,24,33 . Comparatively the intensity of the high-temperature components is remarkably varied on increasing the Ce ion concentrations, whereas peak positions (decomposition temperature) are almost similar. It suggested the similar type of species is reduced at the same temperature, which enhanced by Ce 3+ ion substitution. As shown in Fig. 6a, La 0.90 Ce 0.10 MnO 3 sample revealed high reducibility at high temperature. So that, the replacement of La 3+ by Ce 3+ ion would effect in enhanced concentrations of Mn 3+ ions and oxygen vacancies because of charge discrepancy accomplished by oxidation of Mn 2+ to Mn 3+ and by the construction of an oxygen-deficient perovskite La 0.90 Ce 0.10 MnO 3 , which would enhance the reducibility character of the perovskite. These observations are well consistent with XRD and XPS results, in which non-Ce ion substituted Mn 2+ species are oxidized and transform into Mn 3+ valence states. It inferred that the reducibility behavior of the perovskites in the following sequence LaMnO 3 ≤ La 0.95 Ce 0.05 MnO 3 ≤ La 0.90 Ce 0.10 MnO 3 ≤ La 0.90 Ce 0.10 MnO 3 , according to the H 2 consumption at 446 °C and 800 °C. Generally, oxygen species are attached with metal ion into two different bonding forms including non-crystalline and crystalline bonding forms. In the non-crystalline bonding form, the oxygen species are present in the outer coordination sphere and is referred to as surface adsorbed oxygen species. Whereas in case of crystalline bonding form, the oxygen species entered into the inner coordination sphere and compensate its valence state. These crystalline form oxygen species can be typically eliminated in metal oxide products at higher temperature 36,37 . Temperature program oxidation or desorption was performed to evaluate the catalytic affinity towards oxygen. Figure 6b illustrates the TPO profile of the as-prepared LaMnO 3 and different Ce 3+ ion concentration substituted LaMnO 3 perovskites. The TPO-profile of blank LaMnO 3 perovskite in Fig. 6b, illustrate three oxygen desorption regions, at three different temperatures including 266, 533 and ~799 °C, respectively. An observed first band at 266 °C is attributed to the weakest oxygen vacancies (superficial O 2 species), which are physiochemically adsorbed/chemisorbed O 2 species and are eliminated at low-temperature. The appearance of broadband between 350-725 °C assigned to the non-stoichiometric oxygen (interfacial oxygen) vacancies and reduction of Mn 4+ to Mn 3+ , which are desorbed at high temperature. Whereas the oxygen vacancies desorbed at a higher temperature (≥725 °C) can be attributed to the relocation of lattice O 2 in the bulk perovskite phase and reduction of Mn 3+ to Mn 2+ 7,10,33,35 . Generally, surface adsorbed O 2 vacancies desorbed at low temperatures and interfacial oxygen in non-stoichiometric form desorbing at high temperature 33,35,36,38 . As seen in Fig. 6b, when the Ce 3+ ion is replaced in the La 3+ site of LaMnO 3 perovskite a charge balance is desired to attain the neutrality of the perovskite. It can either achieved by O 2 defects or the swing of the Mn ion towards higher valance states (Mn 3+ to Mn 4+ ). As illustrated in Fig. 6b, on the substitution of 5 mol% Ce 3+ ion doping the strong low-temperature peak is shifted towards slightly higher temperature, which corresponds to surface desorbed oxygen species. While high-temperature peak assigned to interfacial oxygen species is split into two peaks observed at 390 and 490 °C. However, on increasing the substitution concentration of Ce 3+ ion in LaMnO 3 crystal lattice, the low temperature desorption peaks are moved towards higher temperature with significant enhanced integral area, indicating the homogeneous substitution of Ce 3+ ion into crystal lattice which increase the oxygen ion mobility of both surface (superficial) oxygen species and non-stoichiometric (interfacial) lattice oxygen species, it could be due to the effect of small ionic size Ce 3+ ion substitution 13,24,25 . As observed previously, the Ce 3+/4+ ions have high oxygen species motilities because of their multiple oxidation states. The high-temperature O 2 desorption of LaMnO 3 is typically denoted to as the removal of non-stoichiometric surplus oxygen. It could be due to the creation of Mn 3+ in LaMnO 3 to reduce the Jahn-Teller distortion, although the charge stability advocates that Mn should be in 3+ oxidation state. In La 0.90 Ce 0.10 MnO 3 the Mn 3+ state is highly stable because of the existence of Ce 3+ ions in the crystal lattice (charge compensation) 33 . Xps studies. The surface chemical components, phase purity, and their oxidation states are inspected by XPS analysis. Figures 7 and 8 demonstrated the XPS spectra of La(3d & 4d), Mn(2p) and O(1 s) for the different Ce ion concentration substituted perovskites. XPS spectra of the La 3d in the LaMnO 3 and La x Ce 1−x MnO 3 displayed two binding energies (BE) bands located at 844 and 860 eV which correspond to the La 3d 5/2 and La 3d 3/2 , respectively. The existence of these valence band indicates that lanthanum in La 3+ ion form(Fig. 7a) 1 . Additionally, each band has additional satellite band along with core band, owing to the relocation of electrons from O2p to the vacant orbital of La 5 f orbital. These observations are similar to the previous values observed for La 2 O 3 1,39 , it suggested www.nature.com/scientificreports www.nature.com/scientificreports/ the trivalent state of La 3+ ions in the perovskite materials. The increased La 4d binding energy is interpreted as due to the displacement of the electron density toward nearest neighbors. The oxygen (O1s) signal in XPS spectra shows two peaks, the first one is centered at 531 eV and second at around 436 eV in La 0.95 Ce 0.05 MnO 3 sample (Fig. 7b). As shown in Fig. 7b, the low BE band is due to the lattice oxygen, whereas broader band with high BE band is associated with the surface adsorbed oxygen or surface hydroxyl groups. Peng et al. observed that the surface adsorbed O 2 is the most active oxygen because of higher mobility in respect of lattice oxygen, which plays a crucial role in conversion process through migration from the surface to lattice sites 1,3,13 . As seen in Fig. 7b, on increasing the dopant concentration (Ce 3+ ions) the peaks are varied along with broadening, it indicates the existence of several types of oxygen vacancies such as oxygen of hydroxyl (-OH − )/carbonate(-CO 3 2− ) groups on the surface of matrices 2,7,8,10 and it is in accord with the TPO results. According to the TPO results the observed low-temperature desorption band(surface O 2 species) is directly related to the quantity of O 2 species are in very small, while the high quantity of O 2 species evolved at a higher temperature(chemisorbed O 2 species). An observed an increase in core-level binding energy indicates that all of the cations in the samples (La, Ce, and Mn) are bonded to the oxygen. Most importantly, we are unable to observe the Ce ion peak in the current perovskites matrixes due to the Ce ion in LaCeMnO 3 perovskites are mostly in the tetravalent state 40 . An observed XPS peak located at around 655 eV is assigned to 2p 1/2 of Mn ions, although the band of Mn 2p 3/2 is composed of multiple bands it implies the presence of multivalence states such as Mn 2+ (641), Mn 3+ (644) and Mn 4+ (648) (Fig. 8) . Qureshi et al. observed that the splitting in Mn 2p peak is due to the asymmetric nature of the metal, which suggests Mn exists in the mixed valence state 46,47 . However, satellite structure at higher BE divided by ~4 eV, it could be due to the strong columbic interaction in between hybridization of Mn 3d electrons and other valence sub-shells 42,44,47 . No Mn 2p 3/2 band for Mn (~639 eV) is detected in the spectrum, it implies that no metallic form of Mn is presented in the as-prepared perovskites (Fig. 8). The impact of the catalytic activity on MnOx is related to its oxidation states which are MnO 2 > Mn 2 O 3 > MnO as reported by Thirupathi & Smirniotis 4,10,48,49 . According to them, MnO 2 is a highly reactive compound in all Mn-based compounds including MnO 2 , Mn 5 O 8 , Mn 2 O 3 , and Mn 3 O 4 . Therefore, Mn 4+ has higher catalytic performance, and this resembled the finest catalytic denitration activity of La 90 Ce 10 MnO 3 . The peaks of the Mn 2p 1/2 and Mn 2p 3/2 of the applied materials are moved towards longer BE, observed at ~2 eV and 3 eV, respectively. As shown in Fig. 8, the binding energies are significantly varied upon increasing the Ce ion concentration into the perovskite matrix, it indicates the variation in valence states of Mn ions. ## Catalytic reaction. The prepared materials were exposed to catalytic assessment and the conversion of benzyl alcohol into benzaldehyde is taken up as a typical reaction. It was observed that the prepared catalysts are active against the substrate benzyl alcohol. Adding Ce in the LaMnO 3 catalyst is found to impact on catalytic aerobic oxidation of benzyl alcohol due to the synergetic effect between Ce 3+/4+ and Mn 3+/4+ ions. The C 6 H 5 CHO is the core constituent, with an insignificant quantity of C 6 H 5 COOH as a byproduct. The perovskite LaMnO 3 is found to yield a 29% benzaldehyde within 12 hours, while conversion yield is improved on increasing the Ce ion substitution concentration in the perovskite, as shown in Table 3 (Fig. 9). As demonstrated in Fig. 9, on the substitution of 0.05% Ce in the La 0.95 Ce 0.05 MnO 3 catalyst yielded 10% more benzaldehyde i.e. 40% which is better than their parent or blank perovskite. Further modification of the catalyst with further increase in the percentage content of Ce in the catalytic system, yielded La 0.93 Ce 0.07 MnO 3 and La 0.9 Ce 0.1 MnO 3 respectively, it indicates that the catalytic activity decreases as the % of Ce 3+ ion concentration increase in the catalyst composition. The catalyst La 0.93 Ce 0.07 MnO 3 and La 0.9 Ce 0.1 MnO 3 yielded 37% and 32% oxidation product, i.e. benzaldehyde, respectively. Furthermore, the selectivity towards benzaldehyde was found to be >99% in all the cases. The graphical representation of the results obtained for all the catalysts tested is given in Fig. 9. When the catalytic activity is compared to the external area of the as-synthesized perovskite, it was observed that the catalyst La 0.95 Ce 0.05 MnO 3 which displayed the best catalytic performance has a surface area of 7.7922 m 2 /g, and it found to be lower than the surface area of the perovskite LaMnO 3 i.e. 8.3410 m 2 /g, which yielded a 29% benzaldehyde within 12 hours lower than the catalyst La 0.95 Ce 0.05 MnO 3 which yielded a 40% benzaldehyde. However, as the % of Ce in the catalyst composition is increased in the perovskites i.e. La 0.93 Ce 0.07 MnO 3 and La 0.9 Ce 0.1 MnO 3 the surface area further decreases to 7.7554 and 6.9371 respectively and the catalytic performance also depreciates. This indicates that the catalytic activity is not only dependent on the specific surface area it also depends on the doping concentration of the Ce 3+ ion in the materials. An un-doped perovskite possesses Mn in +3 state, while upon the inclusion of the Ce 3+ ions and the Mn oxidation state +4 (excess) and +2 is obtained as indicated by the XPS. Noticeably, Ce 3+ ion concentration plays a crucial part in the enhancement of the catalytic performance as it induces a high surface oxygen mobility than their un-doped perovskite, and the Mn oxidation state +4 (excess) and +2 is obtained, which enhances the surface redox properties of the perovskites as confirmed by the XPS. However, further increase of the Ce 3+ ions in the perovskite was found to result in the diminution in the catalytic performance, it specifies may be the depreciation in Mn 4+ and Mn 2+ sites and increase in the Mn 3+ ion. Apart from the oxidation states of Mn, the decrease in the La 3+ which results due to the increase of Ce 3+ in the catalytic www.nature.com/scientificreports www.nature.com/scientificreports/ system may also be accountable for the depreciation in the catalytic activity. The specific catalytic activity of the as-designed materials is calculated based on the turnover number and turnover frequency as presented in Table 3. From the values obtained, it is found that the catalyst La 0.95 Ce 0.05 MnO 3 has the highest TON and TOF among all the catalysts prepared. Further studies are determined in order to optimize the reaction temperature for the best catalytic performance, the catalyst La 0.95 Ce 0.05 MnO 3 , is utilized for the oxidation of C 6 H 5 CH 2 OH at various temperatures ranging from 40 °C to reflux temperature, and it was found that the catalyst performance is best at the reflux temperature, while at other temperatures, a slight decrease in catalytic performance was observed, observed results are illustrated in Fig. 10. ## Conclusions We successfully synthesized and characterized the Ce 3+ ion substituted lanthanum magnetite perovskites materials by co-precipitation method and applied for conversion of benzyl alcohol into benzaldehyde. Chemical composition and phase purity of the as-synthesized materials were validated from XRD, EDX, TGA and FTIR analysis. The values of optical energy band gaps were varied because of discrepancy in the grain size of the perovskite materials. The increase in doping quantity of Ce 3+ ions altered the redox (TPR and TPO) behavior of the perovskite oxides. The insertion of co-dopant Ce 3+ ion in perovskite lattice enhanced the quantity of Mn 4+ and chemisorbed oxygen positions on the surface of perovskite lattice to increase the catalytic performance. The XPS spectra of La 3d, Mn 2p, and O 1 s clearly revealed the influence of Ce ion substitution, which confirms the transformation of the Mn oxidation state from 3+ to 4+ due to the substitution of trivalent Ce 3+ ions at the La 3+ site in LaMnO 3 perovskite. The surface Ce 3+ ion in the perovskite matrix simplifies in oxidation and reduction of oxygen species which stimulates the oxy-dehydrogenation of benzyl alcohol to benzaldehyde. The Mn 2p 3/2 core level XPS analysis suggests that due to oxygen vacancies, Mn 2+ ions were generated from the Mn 3+ transformation in perovskites. It is observed that La 0.95 Ce 0.05 MnO 3 catalyst shows the highest TON and TOF among all prepared perovskites. According to our observed results the Ce 3+ ion -doped LaMnO 3 materials could serve as potential heterogeneous catalysts for hydrocarbon conversion. Besides that, trivalent cerium ion doping stimulate the synergistic effect

chemsum

{"title": "Physico-chemical properties and catalytic activity of the sol-gel prepared Ce-ion doped LaMnO3 perovskites", "journal": "Scientific Reports - Nature"}

protein_conjugation_with_triazolinediones:_switching_from_a_general_tyrosine-selective_labeling_meth

## Abstract: Selective labeling of tyrosine residues in peptides and proteins can be achieved via a 'tyrosine-click' reaction with triazolinedione reagents (TAD). We have found that tryptophan residues are in fact often also labeled with this reagent. This off-target labeling is only observed at very low levels in protein bioconjugation but remains under the radar due to the low relative abundance of tryptophan compared to tyrosines in natural proteins, and because of the low availability and accessibility of their nucleophilic positions at the solvent-exposed protein surface. Moreover, because TAD-Trp adducts are known to be readily thermoreversible, it can be challenging to detect these physiologically stable but thermally labile modifications using several MS/MS techniques. We have found that fully solvent-exposed tryptophan side chains are kinetically favored over tyrosines under almost all conditions, and this selectivity can even be further enhanced by modifying the pH of the aqueous buffer to effect selective Trp-labeling. This new site-selective bioconjugation method does not rely on unnatural amino acids and has been demonstrated for peptides and for recombinant proteins. Thus, the TAD-Tyr click reaction can be turned into a highly site-specific labeling method for tryptophans. Site-selective protein modification is of utmost importance for many applications from fundamental biology (fluorescent tagging) to therapeutic development (antibody-drug conjugates). 1,2,3,4 While amino acid selectivity can be achieved by exploiting the nucleophilic functionalities of e.g. lysines and cysteines, 5,6 genuine site selectivity depends on their representation density on the protein surface. In this regard, tryptophan (Trp) is an interesting target for native conjugation strategies, with an abundance of just over 1% in proteins. 7 Despite the indole side chain not being the most chemically tractable target, several groups have reported methodologies for selective modification of tryptophan in peptides and proteins. 8,9,10 ,11 Many of these strategies employ transition metal catalyzed reactions and/or conditions limiting downstream biochemical applications. These reactions are typically alkynylations and C-H arylations of the indole. 12,13,14,15,16 Also, Trp sulfenylation was demonstrated for peptide ligation. 17 While Francis and coworkers showed rhodium carbenoid-based Trp labeling at mild pH, 18 this method is dependent on transition metal catalysis and requires long reaction times. An organoradical Trp conjugation was demonstrated on peptides and proteins 19 and even if the method is devoid of transition metals, it requires acidic conditions and is not compatible with buffers. Very recently, a novel biomimetic approach for the selective conjugation of tryptophan was developed, this method however employs UV irradiation and needs to be performed in absence of oxygen. 20 Scheme 1. Prototype reactions for the TAD-Y click, organoradical tryptophan modification (previous work) and TAD tryptophan labeling (this work). In 2010, Barbas and co-workers reported a click like reaction for the more abundant tyrosine (Tyr, 3.3% abundance 7 ) using triazolinedione chemistry, 21 and several ap-plications for protein conjugation followed. 22,23,24,25,26 Interestingly, when exploring this powerful Tyr click reaction on Trp-containing peptides, we observed a high degree of offtarget labeling on Trp residues, even in aqueous buffers. While the swift reaction of indoles with triazolinediones was reported by Baran, Guerrero and Corey in 2003, 27,28 Barbas and co-workers demonstrated that tyrosine labeling is kinetically favored in buffers. However, we now surmise that this competitive Trp-labeling in protein bioconjugation remained under the radar, likely due to a combination of the low abundance and low solvent accessibility of Trp residues. Moreover, in line with observations of Baran and coworkers, we found that indole-TAD modifications have limited thermal stability and can reverse under MS/MS conditions rendering their detection more tedious. We thus cided to more closely examine the competition between Trp and Tyr labeling by TADs in order to probe the potential of TAD reagents for selective Trp-bio-conjugation (scheme 1). For that purpose, tetrapeptides NWAS 1a and 1b were tested in intermolecular competition experiments with phenyltriazolinedione (PTAD 2a) in PBS-buffer at two different pH values, allowing for head to head comparison between Tyr and Trp side chains embedded in the exact same chemical environment (figure 1). Signals for peptide conjugates 2aa and 2ba overlap on the HPLC UV chromatogram, therefore extracted ion chromatograms (XIC's) were used for the analysis. When analyzing the XIC's of the starting peptide-ions NWAS 1a (green) and NYAS 1b (pink) and conjugated peptide-ions NWAS-PTAD 2aa (orange) and NYAS-PTAD 2ba (blue), a pronounced difference can be observed between the reaction at pH 4 and pH 7. Indeed, at pH 4 Trp conjugate 2aa was detected nearly exclusively while at pH 7 a mixture of conjugates was obtained. This observed pH-dependent reactivity of TADs with Tyr is in accord with previous mechanistic studies of the tyrosine-TAD click reaction, which indicate the phenolate species as the prevalent nucleophile. 29 Lowering the pH will effectively decrease the amount of tyrosine-phenolate form and thus decrease the extent of reaction of Tyr with TAD. This was further confirmed using additional peptides (1a-1h, table 1) and TAD-propanol 2b, PTAD-alkyne 2c and fluorescent DMEQ-TAD 2d (Section S2.2.2). It was also observed that, even without competing Trp-peptide present, lowering of pH causes a significant reduction in Tyr-conjugate formation (Section S2.2.1). These findings at peptide level prompted us to look in more detail to earlier reports on the tyrosine click protein modification. Indeed, off-target Trp-labeling was observed earlier at protein level. In the initial study of Ban et al. modification on tryptophan was observed upon myoglobin labeling albeit in a very low amount. 21,25 Furthermore, careful reinterpretation of the MALDI-TOF MS spectra (kindly provided by the authors) of Vandewalle et al., 23 who labeled BSA with butyl-TAD, showed that Trp-modification was indeed noticeable (Section S3.1). These findings demonstrate that researchers can incorrectly assume that tryptophan will not react with TAD-reagents in protein conjugation reactions, possibly leading to flawed interpretation of data. Table 1. Peptide sequences used in this study, structures of TAD reagents 2b, 2c and 2d. ## Entry Sequence 1a Asn Intermolecular competition between 1a and 1c clearly demonstrates the position-sensitivity of the Trp-TAD reaction: the C-terminal tryptophan in 1c is labeled to a 3 times higher extent, as calculated via HPLC peak integration at 214 nm, compared to its internal tryptophan 1a counterpart. This reactivity difference can be attributed to the more exposed reactive center as well as to the presence of the carboxylic acid which can transiently donate a proton to the TAD moiety rendering it even more electrophilic. A second striking difference resides in the nature of the formed adducts. For the C-terminal tryptophan, two peaks for the labeled product 2cb are observed, indicating the formation of isomers. Indeed, we found this adduct had undergone an additional annulation caused by the reaction of the lone pair on the backbone nitrogen with the indole C2 after reaction of TAD with the indole C3. These findings were confirmed via NMR analysis of Boc-Trp-OH and N-Ac-Trp-OMe adducts with TAD-propanol 2b (Section S4) and are in agreement with the results reported by Baran et al. 27 on non-peptide related TAD-indole reactions. In a subsequent series of experiments, we investigated if the observed intermolecular selectivity, translates into intramolecular Trp versus Tyr selectivity. To this end, competition experiments were performed with peptides containing both tyrosine and tryptophan (1i-1l, table 1). MS/MS analyses were done to determine the modification site. We found that the modification on tryptophan is unstable in all tested MS/MS conditions except for ESI in combination with electron transfer dissociation (ETD). ESI-HCD, ESI-CID as well as MALDI-TOF/TOF all largely lead to the loss of the TAD modification on tryptophan. The TAD modification on tyrosine was found to be stable in all tested conditions. These findings are in agreement with earlier work on the thermoreversibility of indole-TAD reactions. 30 Peptide VWSQKRHFGY 1k was labeled using TAD-propanol In conclusion, we report that competitive tryptophan labeling is liable to have so far been systematically overlooked in the current use of triazolinedione (TAD) chemistry for putative tyrosine-selective protein conjugation, a technique which is growing in popularity. The reversibility of the TADtryptophan in MS/MS analysis, in combination with the low abundance and low accessibility of tryptophan side chains likely caused this off-target effect to have remained under the radar. We have found that an exposed tryptophan is in fact kinetically favored over tyrosine in most conditions. Lowering the buffer pH further enhanced the selectivity resulting in a transition metal free, buffer-compatible amino acid specific labeling method for the least abundant natural amino acid tryptophan. Thus, in addition to a better understanding of the factors that govern the click-like TAD-based protein conjugation, its scope has been expanded, and a very interesting new option for native amino acid selective modification has been revealed. The implementation of Trpsubstitutions at protein surfaces or loops can thus be an interesting rational design strategy for fully site-selective labeling of native proteins.

chemsum

{"title": "Protein Conjugation with Triazolinediones: Switching from a General Tyrosine-Selective Labeling Method to a Highly Specific Tryptophan Bioconjugation Strategy", "journal": "ChemRxiv"}

diels–alder_reactions_of_myrcene_using_intensified_continuous-flow_reactors

## Abstract: This work describes the Diels-Alder reaction of the naturally occurring substituted butadiene, myrcene, with a range of different naturally occurring and synthetic dienophiles. The synthesis of the Diels-Alder adduct from myrcene and acrylic acid, containing surfactant properties, was scaled-up in a plate-type continuous-flow reactor with a volume of 105 mL to a throughput of 2.79 kg of the final product per day. This continuous-flow approach provides a facile alternative scale-up route to conventional batch processing, and it helps to intensify the synthesis protocol by applying higher reaction temperatures and shorter reaction times. ## Introduction Over the past years, great attention has been devoted to finding alternative, renewable feedstocks to fossil oil for the production of fuel and industrial chemicals. Especially, high value added products from fine chemicals, specialty chemicals or the pharmaceuticals sector allow for a 'drop-in' replacement of existing, fossil resources based synthesis routes with economic alternatives based on renewable sources. Besides chemical platforms based on sugar, lignin or fatty acid containing feedstocks, terpenes present another plant derived feedstock which is of great interest for a variety of industrial applications, first and foremost in the fragrance and flavor industries, but also in the pharmaceutical and chemical industries . Myrcene is a naturally occurring, acyclic monoterpene which is used industrially for the manufacture of flavoring substances and fragrances; in research it is used as a model compound for a series of different reactions and in the synthesis of complex natural products, including several pheromones . Myrcene is a colorless oil and exists as two isomers, the synthetic α-myrcene, containing an isopropenyl group, and the naturally occurring β-myrcene (which will be referred to in the following only as "myrcene" Scheme 1: Diels-Alder reaction of myrcene (1), with various dienophiles 2. (1), see Scheme 1, vide infra). It can be found in significant quantities (up to 39%) in the essential oils of several plants, such as wild thyme , ylang-ylang , bay leaf , juniper berries , lemongrass , or parsley , and in smaller percentages (<5%) in hops , celery , dill , rosemary , tarragon and nutmeg to name but a few. A review by Behr and Johnen describes the manufacture of myrcene from other terpenes, as well as several synthetic routes based on this versatile and reactive starting material to form alcohols, esters, amines, chlorides, dimers, polymers and even complex natural products, amongst others. At present myrcene (1) is manufactured industrially from turpentine; the distillate of pine resin . One of the main components of turpentine is β-pinene, from which myrcene can be synthesized upon thermal isomerization at temperatures between 400 and 600 °C. This was first described by Goldblatt and Palkin in 1947 . Myrcene is a very versatile molecule that can act as the starting material for several valuable compounds. The industrial production of a series of top-selling flavors and fragrances are based on myrcene, such as geraniol, nerol, linalool, menthol, citral, citronellol or citronellal . The terminal diene moiety present in myrcene allows for a reaction with a suitable dienophile following the Diels-Alder reaction mechanism. Dahill et al. describe the synthesis of the Diels-Alder adduct of myrcene and acrylonitrile for the use as an odorant in the perfume industry . A series of Diels-Alder reactions of myrcene (1) and another sesquiterpene, farnesene, with various dienophiles have been reported by Tabor et al. for the use as solvents and surfactants. The emergence of compact continuous-flow reactors has begun to transform the way chemical synthesis is conducted in research laboratories and small manufacturing over the past few years . In several applications, where reaction times are short and heat management is important, intensified continuous processes inside tubular or plate-type flow reactors can successfully replace batch methodologies classically carried out in stirred glass vessels. We have demonstrated the benefits of this superior heat management in previous work looking at exothermic radical polymerizations in continuous flow . Over the past years, Diels-Alder reactions of isoprene using laboratory-scale flow reactors were studied by different research groups . A continuous-flow reactor can offer a range of benefits over batch processing, with the enhanced heat and mass transfer arguable being one of the most important. In many cases increased control over the process and improvements in product quality are the result. Herein, we describe the synthesis of several Diels-Alder adducts made from myrcene (1) and a series of dienophiles, which contain carboxylic acids, esters or acid anhydrides. In particular, the reaction of myrcene (1) with acrylic acid (2b) was investigated in detail, through batch and continuous-flow methods. The intensified flow process presents a more compact and efficient alternative to classic batch manufacture for the production of Diels-Alder adduct surfactants from myrcene. ## Results and Discussion The solution-phase Diels-Alder reactions presented herein follow the general reaction pathway shown in Scheme 1. The 1 for entries 2.1 to 2.6, as in these experiments R was close to 1 (between 0.9 and 1.1). conjugated diene myrcene (1) was reacted with a series of dienophiles 2 to form the Diels-Alder adducts 3. Before investigating this reaction for continuous-flow processing, we first undertook a series of batch experiments to explore the reactivity of the different dienophiles shown in Scheme 1. These experiments were carried out on a batch microwavereactor system (see experimental section) at temperatures between 100 and 140 °C, and the results are presented in Table 1. a Entries 1.1 to 1.3 were reacted with an initial myrcene concentration, c MYR,0 , of 2.8 mol/L; all entries were reacted with a myrcene to dienophile ratio, R, of 0.9; b conversions were calculated based on NMR. Maleic anhydride (2a) proved to be the most reactive of the dienophiles used in this study with reaction completion occurring after a few minutes at 100 °C. Other activated dienophiles such as acrylic acid (2b) and ethyl acrylate (2f) reached high conversions in excess of 90% after 1 to 5 h and the maleates 2d and 2e required up to 10 h reaction time at 140 °C to reach nearcompletion. The slowest reactions were observed using itaconic acid (2c) and the PEG containing acrylate 2g. Acrylic acid (2b) was selected for further study given our interest in products with surfactant properties, and the preferable reaction kinetics of the acrylic acid-myrcene system. Table 2 presents a set of experiments using this system, at different process conditions and in different solvents; samples were analyzed over time in order to establish kinetic profiles of these reactions. Figure 1 shows the kinetic profiles of the reactions presented in Table 2. All reactions followed an expected trend, asymptotically approaching full conversion with increasing reaction time. While both EtOAc and toluene produced similarly fast kinetic data with conversions around 95% after 40 to 60 min toluene was preferred due to its higher boiling point. Figure 1b shows the influence of temperature and the ratio of starting materials. These experiments also showed trends as were expected. Values for the reaction rate constant, k, calculated from these experiments, are presented in Table 2 and are within expected limits when compared to literature values. More details on the derivation of the k values and the literature references can be found in Supporting Information File 1. After the Diels-Alder reaction was optimized in batch on a small scale (typically 2 mL reaction volume) the process was scaled-up first on a Vapourtec R2/R4 tubular flow reactor to a reaction volume of typically 20 mL and then on a Chemtrix Plantrix ® MR260 plate flow reactor to a reaction volume of typically 200 mL (see also experimental section). The results from these continuous-flow experiments are shown in Table 3. The 10-times scale-up in the tubular flow reactor and the 100 times scale-up in the plate flow reactor resulted in similar, if not slightly higher conversions than the batch experiments (see Figure 2). The two continuous reactors produced highquality material at steady state conditions. The reaction profile in the plate flow reactor was quantified by taking samples at the outlet of the reactor over the entire duration of one experiment. These profiles are very uniform with steep fronts and tails and a flat steady state region, suggesting that the residence time distribution inside the reactor is narrow and close to plug flow. One of these profiles is shown in Figure S4 (Supporting Information File 1). The fastest conditions investigated herein were 30 min in the plate reactor at 160 °C giving 99% conversion of 2b and a yield of 94% of a semi-crystalline product (Table 3, entry 3.9). As part of the scale-up investigations, we also performed the Diels-Alder reaction of myrcene (1) and 2b in a 6 mm i.d. stainless steel tubular flow reactor with a reaction volume of 108 mL. A few minutes after start of the reaction, however, we observed a pressure increase in the reactor which was caused by fouling occurring in the reactor entrance section and ultimately led to complete blockage of the tube at this point. This is believed to be caused by a side reaction of 2b and myrcene (1) forming polymeric material, which built up on the metal walls of the reactor, ultimately leading to the complete blockage. The mechanism and circumstances of this side-reaction are unknown; it only occurred in the stainless steel reactor and not in the PFA tubing of the Vapourtec R-series flow reactor or the silicon carbide module of the plate flow reactor. Hence, it was postulated that a metal catalyzed polymerisation on the stainless steel reactor tubes might have occurred, however, this could not be confirmed. Further details on these observations can be found in Supporting Information File 1. Using 13 C NMR an approximate ratio of the two isomers, 3-3 and 3-4 (see Figure 2), was calculated for the continuous-flow reactions performed between 140 and 160 °C (see Table 3). The amount of Diels-Alder adduct with the carboxylic acid located in the 3-substituted position, 3-3, was always larger than the 4-substitituted adduct, 3-4, with an average 3-3/3-4 ratio of 7:3 (3-substituited adduct was between 68 and 71%). For Table 3, entry 3.9, the yield of the semi-crystalline product after solvent removal was 94%. The production capacity (PC) and the space time yield (S.T.Y.) can be calculated based on the amount of isolated product, m P , using Equations 1 and 2. ( Here, is the total volumetric flow rate through the reactor, V SS the combined volume of both stock solutions and V R the volume of the flow reactor. Running the plate reactor at 160 °C (Table 3, entry 3.9), we managed to achieve a production capacity of 116.3 g/h, which equates to an S.T.Y. of 1.11 kg L −1 h −1 . Parallel to the scale-up in the plate flow reactor, we also scaled up the process in batch to a 6 L scale using a jacketed stirred tank reactor. Here, the reaction was run for ~10 h at 100 °C in order to reach completion, compared to only 30 min at 160 °C in continuous flow. Preliminary experiments were carried out looking at the surfactant properties of the Diels-Alder adduct of myrcene (1) and 2b. The results were promising and showed that the product was able to stabilize emulsions for several hours compared to several seconds or minutes in the control experiments without the Diels-Alder adduct. Further details on these surfactant tests are presented in Supporting Information File 1. ## Conclusion We have investigated the Diels-Alder reaction of myrcene (1) with a range of different dienophiles at temperatures between 100 and 160 °C. The Diels-Alder reaction of myrcene (1) with acrylic acid (2b), yielding a carboxylic acid containing surfactant, was scaled-up in a plate-type continuous-flow reactor and a batch stirred tank. The use of continuous-flow processing allows for an efficient synthesis of large quantities of the Diels-Alder adduct and we managed to scale-up the reaction of myrcene (1) with acrylic acid (2b) inside the 105 mL flow reactor to a throughput of 2.79 kg of the final product per day. The small dimensions of the fluidic channels inside the tubular and the plate-type flow reactors ensured that heat and mass transfer were efficient and fast, and that the reaction could be operated under 'quasi isothermal' conditions (i.e., with negligible deviations from the set temperature in the entire bulk reaction volume of the reactor). This resulted in a much more uniform reaction profile than in batch stirred tanks, allowing for a much shorter reaction time than classically applied in batch operations. ## Experimental Materials and analysis The reactants myrcene (1, 90% purity), maleic anhydride (2a), acrylic acid (2b), itaconic acid (2c), dimethyl maleate (2d), ethyl acrylate (2f) and poly(ethylene glycol) methyl ether acrylate (PEGA, 2g) were obtained from Sigma-Aldrich; bis(2ethylhexyl) maleate was provided by TriTech Lubricants. The solvents tetrahydrofuran (THF), ethyl acetate (EtOAc), toluene, dichloromethane (DCM) and isopropanol (iPrOH) were obtained from Merck KGaA. All reagents and solvents were used without further purification. Reaction conversions were calculated from 1 H NMR spectra, which were recorded on a Bruker AC-400 spectrometer in deuterated chloroform (from Cambridge Isotope Laboratories Inc.). Conversion calculations were based on clearly identifiable and non-convoluted peaks of remaining starting material and generated product. The residual solvent peak at δ = 7.26 ppm was used as an internal reference. Product compositions were analyzed by GC-FID and GC-MS; details for both can be found in Supporting Information File 1. The GC-FID results were also used to confirm NMR conversions and to calculate GC-based yields. ## Batch Diels-Alder reaction The following procedure is typical for the preparation of the Diels-Alder adduct of myrcene (1) and a series of different dienophiles. A reactant solution of myrcene (1, 811 mg of myrcene stock solution with a 90% purity, 5.36 mmol of myrcene), 2b (429 mg, 5.95 mmol), in EtOAc (0.49 mL), was premixed and filled into a sealed microwave vial. The reaction was conducted in a laboratory microwave reactor (Biotage Initiator) at 140 °C with a reaction time of 2 h. A transparent, faintly yellow solution was obtained after reaction, from which the conversion was determined by 1 H NMR. The solvent was evaporated under reduced pressure to yield a yellow semi-crystalline paste. Detailed reaction conditions and reagent compositions for each batch experiment can be found in Table 1 and Table 2. For kinetic studies, small samples of the reaction mixture for 1 H NMR were withdrawn through the septum of the microwave reactor glass vial using a syringe. For this the microwave reaction was stopped at various points in time over the course of the reaction, namely at 20, 40, 60 and 120 min. ## Continuous-flow Diels-Alder reaction using a Vapourtec R2/R4 flow reactor The following procedure is typical for the preparation of the Diels-Alder adduct of myrcene (1) and acrylic acid (2b) in a tubular flow reactor. Two reactant solutions were prepared, one containing myrcene (16.22 g of myrcene stock solution with a 90% purity, 107.16 mmol of myrcene) in EtOAc (1.98 mL), and the other containing 2b (8.58 g, 119.06 mmol), in EtOAc (7.75 mL). The two solutions were continuously mixed in a T-piece and then fed into a Vapourtec R2/R4 flow reactor setup , consisting of two 1.0 mm i.d. perfluoroalkoxy alkane (PFA) reactor coil modules in series (10 mL each -total reactor volume: 20 mL). The pump flow rate of the myrcene solution was set to 0.3 mL•min −1 , the pump flow rate of the acrylic acid solution was set to 0.2 mL•min −1 . This resulted in a total flow rate of 0.5 mL•min −1 and a mean hydraulic residence time of 40 min inside the two PFA reactor coils (the mean hydraulic residence time is defined as 'flow rate/reactor volume'). The reaction was conducted at 140 °C. The product, a transparent, faintly yellow solution, was collected at the reactor outlet, after passing through a 75 psi back-pressure regulator. From this solution, the reaction conversion was determined by 1 H NMR. Afterwards, the solvent was evaporated under reduced pressure to yield a yellow semi-crystalline paste. Detailed reaction conditions and reagent compositions for each experiment in the tubular flow reactor can be found in Table 3. ## Continuous-flow Diels-Alder reaction using a Chemtrix MR260 flow reactor The following procedure is typical for the preparation of the Diels-Alder adduct of myrcene (1) and acrylic acid (2b) in a silicon carbide plate-type flow reactor. Two reactant solutions were prepared, one containing myrcene (208.2 g of myrcene stock solution with a 90% purity, 1.375 mol of myrcene) in toluene (21.2 mL), and the other containing 2b (90.1 g, 1.250 mol), in toluene (80.1 mL). The two feed solutions were pumped using two Teledyne Isco D-series dual syringe pumps (100 DX, with Hastelloy™ syringes) and were continuously mixed in a T-piece. After mixing, the combined starting material solution was fed into a Chemtrix Plantrix ® MR260 plate-type flow reactor. This plate flow reactor configuration consisted of a series of 3M™ silicon carbide microstructured plates (see also Figures S2 and S3 in Supporting Information File 1), which was thermally regulated by a Lauda Integral XT 150 heater/chiller unit. The total reactor volume was 105 mL. An SSI Prep 100 dual piston pump with PEEK pump heads was used to flush the reactor before and after the reaction with toluene. The pump flow rate of the myrcene solution was set to 2.21 mL•min −1 , the pump flow rate of the acrylic acid solution was set to 1.30 mL•min −1 . This resulted in a total flow rate of 3.51 mL•min −1 and a reaction time of 30 min inside the plate flow reactor. The reaction was conducted at 160 °C. The product, a transparent, faintly yellow solution, was collected at the reactor outlet, after passing through a stainless steel Swagelok ® R3A series adjustable high pressure valve. This valve was used as a back pressure regulator, in order to set the pressure inside the reactor to between 8 and 10 bar (116 to 145 psi) during operation. From the resulting product solution, the reaction conversion was determined by 1 H NMR. Afterwards, the solvent was evaporated under reduced pressure to yield a yellow semi-crystalline paste. Detailed reaction conditions and reagent compositions for each experiment in the plate-type flow reactor can be found in Table 3.

chemsum

{"title": "Diels\u2013Alder reactions of myrcene using intensified continuous-flow reactors", "journal": "Beilstein"}

organocatalytic_reductive_coupling_of_aldehydes_with_1,1-diarylethylenes_using_an_<i>in_situ</i>_gen

## Abstract: Organocatalytic reductive coupling of aldehydes with 1,1-diarylethylenes using an in situ generated pyridine-boryl radical A pyridine-boryl radical promoted reductive coupling reaction of aldehydes with 1,1-diarylethylenes has been established via a combination of computational and experimental studies. Density functional theory calculations and control experiments suggest that the ketyl radical from the addition of the pyridine-boryl radical to aldehyde is the key intermediate for this C-C bond formation reaction. This metal-free reductive coupling reaction features a broad substrate scope and good functional compatibility. Organocatalytic reductive coupling of aldehydes with 1,1-diarylethylenes using an in situ generated pyridine-boryl radical † Introduction Carbon-carbon bond formation is the most important transformation in organic synthesis. 1 The catalytic reductive coupling of olefns with carbonyl compounds is one of the most economical C-C bond constructing methods, due to the abundant source of olefns and carbonyl compounds. 2 Traditionally, transition metal catalysts have played privileged roles in these transformations, including metal-catalyzed C]O reductive coupling (Scheme 1, top) and redox-triggered C]O coupling via H 2 transfer (Scheme 1, middle). 4 However, sensitive organometallic reagents or transition-metal catalysts are usually required in these reactions. In contrast, organocatalytic reductive coupling of olefns with carbonyl derivatives for C-C bond formation in the presence of sensitive functional groups or congested structural environments is still rare. 5d Boron containing radicals are important reactive intermediates in organic synthesis. In this context, our group recently revealed that the pyridine-ligated boryl radical (Py-Bpinc) could be readily generated from (pinacolato)diboron (B 2 pin 2 ) through a cooperative catalysis involving two 4-cyanopyridine molecules. 11 This kind of pyridine-boryl radical was used for the catalytic reduction of azo-compounds 11 or as a carbon-centered radical for the synthesis of 4-substituted pyridines. 12 Moreover, the pyridine-boryl radical can act as a persistent radical 13 for the synthesis of organoboronate derivatives. 14 Because the precursors (pyridines and B 2 pin 2 ) of these pyridine-boryl radicals are inexpensive and stable, 15 the development of new chemical transformations with these pyridine-boryl radicals is attractive. In this work, we further explored pyridine-boryl radical chemistry in the organocatalytic reductive coupling of aldehydes with 1,1-diarylalkenes (Scheme 1, bottom), which, to the best of our knowledge, has not been reported previously. ## Results and discussion It will be shown that the reductive coupling of aldehydes and olefns can be promoted by an in situ generated pyridine-boryl radical, following the proposed pathway as shown in Scheme 2. The proposed catalytic cycle consists of the following four steps: (1) activation of the B-B bond of B 2 pin 2 by pyridines to form a pyridine-boryl radical (Int1); (2) the addition of the pyridineboryl radical to aldehyde 1a to generate a new ketyl radical (Int3), with the regeneration of the pyridine catalyst; (3) the Scheme 1 Reductive coupling of carbonyl compounds with olefins. a Key Laboratory of Mesoscopic Chemistry of Ministry of Education, Institute of Theoretical and Computational Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210093, P. R. China. E-mail: shuhua@ nju.edu.cn addition of the new ketyl radical to 1,1-diphenylethylene to yield a diaryl-stabilized radical species (Int4); and (4) the hydrogen abstraction of Int4 from an appropriate H-source to yield the fnal reductive coupling product. In addition, one molecule of Int4 may also abstract a hydrogen atom from another molecule of Int4 to give the reductive coupling product and another disproportionation product. To make this catalytic cycle happen, it is necessary to inhibit the possible radical-radical C-C coupling reaction between the pyridine-boryl radical and the ketyl radical, as observed between a,b-unsaturated ketones and 4-cyanopyridine in the presence of B 2 pin 2 . 12 Thus, other pyridines with different substituents may be better catalysts than 4cyanopyridine for the proposed reaction. With a pyridine-boryl radical bearing a suitable substituent, its reactivity might be tuned so that the newly generated ketyl radical could react with 1,1-diphenylethylene to yield a diaryl-stabilized radical species, which then undergoes a hydrogen atom abstraction from an appropriate hydrogen source to produce the reductive coupling product. To fnd suitable pyridines which can react with B 2 pin 2 to form the corresponding pyridine-boryl radical under mild conditions, we frst performed density functional theory (DFT) calculations with the M06-2X 16 functional to screen a series of pyridines. A careful analysis of stationary points revealed that the formation of the pyridine-boryl radical proceed through a -sigmatropic rearrangement/homolytic C-C bond cleavage pathway 17 rather than via the direct homolytic cleavage of the B-B bond 11,18 In order to determine a suitable combination of a pyridine catalyst and a hydrogen source, we conducted an initial investigation on the reaction between isobutyraldehyde 1a and 1,1diphenylethylene 2 (see Tables S1 to S3 † for details). As shown in Table 1, by heating a mixture of isobutyraldehyde 1a (1.0 equiv.), 1,1-diphenylethylene (2.0 equiv.), and B 2 pin 2 (1.0 equiv.) in the presence of 1,3,5-trimethyl-1,4-cyclohexadiene (a hydrogen source, 1.0 equiv.) and 4-cyanopyridine A (0.2 equiv.) in tert-butyl methyl ether (MTBE) at 120 C, the desired reductive coupling product 3a was observed in 28% yield (entry 1), together with a small amount of pyridine-aldehyde adducts (12% yield, see the ESI † for details). When 4-(4-pyridinyl)benzonitrile B was used as the catalyst (entry 2), the NMR yield of 3a improved to 78%, and the yield of a byproduct 3a 0 from the disproportionation of the diaryl radical intermediate (Int4) was 6%. However, when other pyridines (for example C, D, or E, entries 3-5) were adopted, the yield of 3a decreased signifcantly. If Et 3 SiH was chosen as the hydrogen source, the yield of 3a is somewhat lower than that with 1,3,5-trimethyl-1,4-cyclohexadiene as a hydrogen source (entry 6). In the absence of a hydrogen source (entry 7), the ratio of 3a/3a 0 was 52% : 16%, suggesting that the addition of a hydrogen source is important for improving the yield of 3a (see Table S2 Under the optimum conditions (Table 1, entry 2), we explored the generality of this transformation with a series of alkyl and aryl aldehydes. As shown in Table 2, the reductive coupling reactions of several fully aliphatic aldehydes proceeded with good efficiency (1a-1d). It was noteworthy that aldehydes with C]C double bond (1e), methylthio (1f), or furyl (1h) functionalities on the alkyl chain were tolerated, giving the reductive coupling products in moderate to good yields. The abranched aldehydes (1i-1r), in particular, pivaldehyde (1q) and 1-adamantylcarboxaldehyde (1r), also reacted well to afford the desired products in good yields. It should be mentioned that the substrates with a congested structure environment show less reactivity in transition-metal catalyzed reductive coupling of olefns and aldehydes, possibly because the coordination between the metal centre and the corresponding substrates is difficult. 4c However, our method is also suitable for butyl aldehydes (1q and 1r). Beside alkyl aldehydes, aryl aldehydes (1s and 1t) bearing electron-donating groups (CH 3 and CH 3 O) could also serve as the coupling partners, furnishing corresponding products in moderate yields. In addition to aldehydes, alkyl ketones (1u-1w) also reacted smoothly to provide the desired alcohols in 27-42% yield. Diarylalkanes are important pharmacophores in drugs. 19 It would be attractive to apply this metal-free method in the late stage functionalization of medicinally related molecules. As shown in Table 2(C), an abietic acid derivative (1x) and gemfbrozil derivative (1y) reacted smoothly with 1,1-diphenylethylene to form 3x and 3y in acceptable yields, respectively. Next, the scope of 1,1-diarylalkenes (4) was examined (Table 3(a)). Both symmetrical (4a-d) and unsymmetrical (4e-o) 1,1diarylalkenes were converted into the corresponding products 5 in moderate to good yields with modest diastereoselectivities. The reaction tolerated substrates bearing various functional groups on the benzene ring, such as halogen functionalities (4c and 4d), CF 3 (4e), CN (4f and 4g), MeO (4h), CH 3 S (4i), CO 2 Me (4j), and tBu (4k). More importantly, 1,1-diarylalkenes containing heterocyclic structures (4m-o), such as benzofuran (4o) and thioxanthene (4p), also reacted smoothly to give the expected products in reasonable yields. Additionally, we also tested the reactivity of other alkenes with pivaldehyde 1q (Table 3(b)). However, our results show that other alkenes, including ethyl 2phenylacrylate (4q), styrenes (4r and 4s) or aliphatic olefn (4t), generally gave little or no desired product. The reason why 1,1diarylalkenes are suitable coupling partners of ketyl radicals may be due to (1) the radical stabilization effect of two aryl groups, and (2) the less nucleophilicity of present boron-ketyl radicals (compared with typical ketyl radicals). 5b Thus, this protocol provides a metal-free reductive coupling method of 1,1diarylalkenes with aldehydes (via the radical addition mechanism), which traditionally requires transition metal catalysts or organometallic reagents. To understand the mechanism of the reductive coupling of 1,1-diarylalkenes with aldehydes, we have performed DFT calculations with the M06-2X functional to explore the free energy profle of the proposed mechanism for the reaction between isobutyraldehyde (1a) and 1,1-diphenylethylene (2) in the presence of Int1 as a reactive intermediate. Our theoretical studies have shown that the generation of Int1 from B 2 pin 2 and 4-(4-pyridinyl)benzonitrile is exergonic by 13.4 kcal mol 1 (see Fig. S4 †). The calculated free energy profle and transition state structures are displayed in Fig. 1 (the optimized structures of all minimum species are shown in Fig. S12 †). First, the coordination of the oxygen atom of isobutyraldehyde to the boron atom of the pyridine-boryl radical Int1 generates a boron-containing intermediate (Int2) via TS1, with a barrier of 13.3 kcal mol 1 . Then, the breaking of the B-N bond in Int2 yields a ketyl radical (Int3) and regenerates the 4-(4-pyridinyl) benzonitrile catalyst. This process is exothermic by 4.5 kcal mol 1 , with a barrier of 3.2 kcal mol 1 (relative to Int2), suggesting that the formation of the ketyl radical (Int3) from Int2 is possible. Next, the addition of Int3 to the b-position of 1,1diphenylethylene to form a diaryl-stabilized radical (Int4) via TS3 is exothermic by 15.6 kcal mol 1 , with a barrier of 15.5 a Reaction conditions: isobutyraldehyde (0.2 mmol), B 2 (pin) 2 (0.2 mmol), catalyst (0.04 mmol), 1,1-diphenylethylene (0.4 mmol), H-donor (0.2 mmol), 24 hours, 120 C, and MTBE (1 mL). b Yields were determined by 1 H-NMR analysis of the crude mixture using CH 2 Br 2 as the internal standard. c Isolated yield of 3a. TMe-1,4-CHD ¼ 1,3,5-trimethyl-1,4-cyclohexadiene. kcal mol 1 (with respect to the radical Int3). Finally, the fnal product is obtained with a hydrogen atom abstraction from 1,3,5-trimethyl-1,4-cyclohexadiene via TS4 with a barrier of 26.3 kcal mol 1 (relative to the radical Int4). The whole reductive coupling reaction is exergonic by 11.7 kcal mol 1 (with respect to the reactants 1a and Int1). These results suggest that the studied reaction is thermodynamically and kinetically feasible under the experimental conditions. In addition, our calculations suggest that the direct single electron transfer (SET) process between the pyridine-boryl radical and isobutyraldehyde is highly endergonic (see details in Fig. S13 and S14 †). Thus, the SET mechanism for the present reaction can be excluded. Table 2 Substrate scope for the reductive coupling of aldehydes or ketones with 1,1-diphenylethylene a a Reaction conditions: aldehyde (0.2 mmol), B 2 (pin) 2 (0.2 mmol), 4-(4pyridinyl)benzonitrile (0.04 mmol), 1,1-diphenylethylene (0.4 mmol), 1,3,5-trimethyl-1,4-cyclohexadiene (0.2 mmol), MTBE (1.0 mL), 24 h, and 120 C. Isolated yield. The diastereoselectivities (d. r.) were determined by 1 H-NMR analysis of the crude mixture. Boc ¼ tertbutoxycarbonyl. Table 3 Substrate scope for the reductive coupling of pivaldehyde with 1,1-diarylethylenes a a Reaction conditions: pivaldehyde (0. In addition to DFT calculations described above, we also conducted several experiments to verify the proposed pathway. First, the EPR signal was observed for the reaction of 4-(4-pyridinyl)benzonitrile and B 2 (pin) 2 , which supports the formation of the proposed pyridine-boryl radical, as shown in Scheme 3a. Second, the involvement of the ketyl radical was confrmed by a competition experiment (Scheme 3b). It has been reported that thiols are quick hydrogen atom donors that can interfere with the radical reaction. 20 When the hydrogen source 1,3,5-trimethyl-1,4-cyclohexadiene was replaced by 3methylbenzenethiol, the ketyl radical quickly abstracted a hydrogen atom from 3-methylbenzenethiol to yield the reductive product, 3-phenyl-1-propanol, so that its addition to 1,1-diphenylethylene (to form the reductive coupling product) was inhibited (see Page S20 †). This result clearly indicated the involvement of the ketyl radical. Third, the generation of the radical species Int4 (or its analogues) via the addition of the ketyl radical to the b-position of arylethene was confrmed by an intermolecular trapping experiment (Scheme 3c). When 2vinylpyridine and trimethylacetaldehyde were subjected to the standard reaction conditions, species 6 could be detected by HRMS analysis for the crude reaction mixture (see Page S21 †). This result suggests that in this reaction, the radical species Int4-like was further trapped by another 2-vinylpyridine molecule. However, in the presence of 2-vinylpyridine as a substrate, the yield of 6 is quite low and its isolation from the reaction mixture was not successful. Besides, we further conducted analysis of the 11 B-NMR spectrum and HRMS to detect the formation of the proposed O-boron intermediate (Int6, Fig. S17 †). The 11 B-NMR of the crude reaction mixture displays resonances at $21 ppm, which is consistent with the signal of a boron atom bound to three oxygen atoms. 21 In addition, our HRMS analysis (with 4-vinylpyridine as the substrate) also indicates the formation of the O-boron intermediate (Int7), as shown in Fig. S18. † Moreover, we have performed a radical-clock study using cyclopropanecarboxaldehyde as the substrate. The experimental results indicate that some ketyl radicals frst convert into the corresponding carbon radicals (via a ring-opening process) and then add to the alkene to form the ring-opening product (Scheme 3d). The experiments described above provide strong evidence on the involvement of a radical addition step between the ketyl radical and 1,1-diarylethylene in this reaction. , 2018, 9, 3664-3671 This journal is © The Royal Society of Chemistry 2018 ## Conclusions In summary, we have established the organocatalytic reductive coupling of aldehydes with 1,1-diarylalkenes via a combination of computational and experimental studies. This study showed that 4-(4-pyridinyl)benzonitrile is a suitable catalyst for cleaving the B-B bond of B 2 pin 2 , and the ketyl radical from the addition of an in situ generated pyridine-boryl radical to aldehydes is a key intermediate for the C-C bond formation. The reaction is practical and applicable to a broad range of aldehydes and 1,1diarylalkenes with good functional group tolerance. DFT calculations and control experiments were conducted to verify the proposed mechanism. This pyridine-boryl radical promoted radical addition mechanism represents a metal-free reductive coupling reaction of aldehydes with 1,1-diarylalkenes. Further studies will be directed toward the development of new transformations involving readily formed pyridine-boryl radicals with the aid of combined theoretical and experimental studies. ## Conflicts of interest There are no conflicts to declare.

chemsum

{"title": "Organocatalytic reductive coupling of aldehydes with 1,1-diarylethylenes using an <i>in situ</i> generated pyridine-boryl radical", "journal": "Royal Society of Chemistry (RSC)"}

evaluating_performance_and_cycle_life_improvements_in_the_latest_generations_of_prismatic_lithium-io

## Abstract: The last decade has seen an enormous improvement of energy density for lithium-ion battery cells, particularly for automotive grade cells intended for use in electrified vehicles. This has led to vastly improved range for battery electric vehicles as well as for plug-in hybrids. However, the challenge of uncertain battery lifetime remains. The ageing effect due to fast charging is especially difficult to predict due to its non-linear dependence on charge rate, state-of-charge and temperature. We here present results from fast charging (1C and 3C in a 20 % to 80 % SOC-level) of several energy-optimized, prismatic lithium-ion battery cell generations utilizing NMC/graphite chemistry through comparison of capacity retention, resistance and dQ/dV analysis. Considerable improvements are observed throughout cell generations and the results imply that acceptable cycle life can be expected, even under fast charging, when restricting the usage of the available battery capacity. Even though this approach reduces the useable energy density of a battery system, this trade-off could still be acceptable for vehicle applications where conventional overnight charging is not possible. The tested cell format (the VDA PHEV2-standard) has been used for a decade in different electrified vehicles. The ongoing development and improvement of this cell format by several battery cell manufacturers suggests it will continue to be a good choice for future vehicles. ## Introduction Electrified vehicles such as hybrid electric vehicles (HEV), plug-in hybrid electric vehicles (PHEV), battery electric vehicles (BEV) and fuel cell electric vehicles (FCEV) are now established on the market. The powertrain technology has been proven for both passenger cars and commercial vehicles such as buses and trucks, despite relatively high component costs when compared to conventional vehicles. Despite very rapid development in terms increasing energy density and decreasing cell cost, the battery remains the critical component in EVs when evaluating total cost, service life and performance. Li-ion battery cells experience ageing, i.e. loss of capacity and power, during both storage (calendar ageing) and usage (cycle ageing) due to several ageing mechanisms for which the individual reaction rates depend strongly on operating conditions such as temperature, charge level (state-of-charge, SOC), charge/discharge currents and load cycle characteristics. In addition, many of the ageing mechanisms are inter-dependent. The charge rate can in many cases be regarded as the dominant ageing factor, especially for energy-optimized cells cycled within large state-of-charge (SOC) windows, as are typical for EVs and PHEVs. At the same time, fast-charging capability is widely desired for both passenger cars and commercial vehicles. Subsequently, the vehicle industry needs to develop accurate ageing models to develop robust battery systems and to forecast actual service life for the batteries. The Swedish automotive industry and several universities have, within continuous research collaboration, carried out a number of studies on ageing of automotive grade Li-ion battery cells, through cycling and post-mortem analysis. In the first phase, focused on LFP/Graphite battery cells, it was shown that ageing may be severely non-uniformly distributed within the battery cells, especially for those that have been exposed to high charge rates. This distribution was observed both laterally across the jelly roll surface and throughout the depth of the electrodes . In this cell type, the graphite electrode was particularly affected by severe ageing. . The uneven ageing was argued to be a consequence of inhomogeneous current distribution due to the tab positions, as well as internal variations in temperature, electrolyte wetting and pressure. In the second phase of the research collaboration, the ageing effects of fast charging on NMC111/Graphite cells were studied. From careful post-mortem analysis it could be concluded that different ageing mechanisms dominate, depending on the charging rate . While NMC particle cracking was observed at 1-2C charging rate, lithium plating likely reduced lifetime at 3C charging rate, and gas evolution rapidly killed the cells cycled with 4C charging rate. In a separate study of a similar cell , it was observed by on-line mass spectrometry that the high ageing rate under fast charging was associated with the evolution of large quantities of ethylene gas. Even for NMC111/graphite cells, heterogeneous ageing within the cell was observed. For instance, a difference in direct current internal resistance (DCIR) was observed among samples harvested from the curved and the flat regions of the prismatic cell jelly roll, pointing towards a nonuniform distribution of mechanical pressure affecting the local ageing . The negative electrode is known to be a major bottleneck for practical fast charging rates (i.e. less than 1 hour charging for energy-optimized cells) . This is mainly due to the slow kinetics of lithium insertion into graphite, the typical negative electrode material of choice for energy-optimized cells. If graphite particles are unable to intercalate lithium ions at sufficiently high rate, then lithium deposits onto the particles as tree-like, highly-reactive, metallic dendrites, a process referred to as lithium plating. These dendrites can grow through the separator and hence cause internal short-circuits in the cell or, in less severe cases, cause accelerated electrolyte degradation and subsequent loss of cyclable lithium and increase of cell resistance. In the past, large-format cells have been seldom studied, probably due to the high cost and scarce availability of this type of automotive grade cells. In this work however, we compare performance and ageing for several generations of automotive grade cells. Results are summarized from cycle ageing of three different NMC111/graphite cells performed within this research consortium over the course of several years. The comparisons herein emphasize the progress between the different generations of energy optimized cells. The capacity retention curves after cycling under 1C and 3C charge (which correspond to fully charging the battery in 60 and 20 minutes, respectively) are compared, as well as corresponding DCIR and dQ/dV analyses. Finally, we discuss the progress in performance and durability of this type of cells and include preliminary comparison with a nickel-rich NMC811/graphite cell type cycled within the present third phase of the collaboration. ## Experimental Three different types of prismatic battery cells of the VDA (Verband der Automobilindustrie) PHEV2 format (148 x 26.5 x 91 mm) were cycled at the same temperature and in the same SOC-region. The electrode active material is NMC111/graphite for the three tested cell types. Cycling was done in a 20 % to 80 % SOC window, with constant current charge and discharge currents. The charge and discharge time required to stay in the SOC-window was recalculated every 200 th cycle from periodically performed capacity measurements. In addition to the periodic capacity measurements, DCIR measurements were also performed, followed by constant voltage adjustment to 80 % SOC before the next cycling period. Two cells of each cell type were cycled at 1C/1C (charge/discharge) current and two cells per cell type at 3C/1C. One additional cell type, called D, in the same format but with the electrode active material NMC811/graphite is used as reference but was not included in the original test matrix. This cell type has been cycled under other conditions and detailed results from that work will be published separately. Additional information about all cell types is shown in Table 1. For the cell type C, reference cells were also stored in different temperatures during the testing period in order to measure the calendar ageing separately. The conditions for the cell cycling and reference performance testing of cell types A and B, which were cycled at the same test facility, are described in detail in previous work . The cycling of cell type C was done at another test facility under the following conditions. Cycling and performance testing were done on a Maccor Series 4000 cell tester. All cells were placed in a climate chamber operating at an average temperature of +33 ± 1 °C during testing to obtain an average cell skin temperature of +35 °C (measured individually with surface-mounted thermocouples). Steel plates were attached to all cells during cycling to maintain external cell pressure according to supplier recommendation. The applied test protocol was the same as for cell types A and B. ## Capacity The capacity fade behaviour of cell types A, B and C differs from each other in several ways. A clear difference in ageing characteristics is seen in the appearance of the capacity retention curves. Comparison of different slopes in the capacity retention curves can be done by fitting curves based on coulombic efficiency (CE) calculations. Coulombic efficiency has been used in earlier research as a tool for analysing ageing . If a constant CE is assumed, the capacity retention can be estimated according to following equation: where Q is the capacity retention, ƞ is the coulombic efficiency and Neq is the corresponding number of equivalent full cycles. Using this approach, it is possible to identify three different CEslopes for the capacity retention of cell type A at 1C charge current, as seen in Figure 1a. Also for cell type B, three different CE-slopes for the capacity retention are identified under 1C charging, depicted in Figure 1c. Both cell types experience an increasing coulombic efficiency under 1C charging, hence showing a regressive or decelerating aging behaviour beginning after a couple hundred equivalent full cycles. The capacity retention for cell type A can be fitted with a single CEcurve for the 3C charging case, as seen in Figure 1b. It can be noted that the estimated coulombic efficiency in this case is similar to the estimated CE1 for the 1C cycled cell type A in Figure 1a. A similar behaviour is also seen for cell type B under 3C charge; its fitted CE-curve also has an efficiency corresponding to the first fitted CE-curve for the 1C cycled cells. However, in this case there is also a sudden change in slope at around 80% remaining capacity, where the estimated coulombic efficiency decreases drastically (CE2 in Figure 1d). The capacity retention curves for cell type C are very similar to that of cell type B (Figure 1e and f), i.e. a decelerated ageing rate for the first few hundred cycles, followed by ageing at a constant CE-rate between 90 % and 80 % capacity retention. In addition, there are signs of accelerating ageing towards EOL for the cells cycled with the 3C charge strategy, where the overall lifetime is only about one third of that for the corresponding cells cycled with 1C charging. In summary, the results from the capacity fade analysis show three typical regimes: decelerated, constant and accelerated ageing, i.e. sudden fade close to end-of-life, which is in line with similar published work by Waldmann et al. . Using CE measurements on cells at the beginning of cell life could hence in some cases be helpful to predict battery cell cycle life, but there are cases where this type of extrapolation could either overestimate or underestimate battery lifetime. Regarding the test cases in this study, CE measurements at the beginning of the test could have been useful for predicting ageing of the cells cycled with the 3C charging regime, but they would have underestimated lifetime for cells cycled with the 1C charging regime. The accuracy and relevance of these CE measurements are greatly affected by the temperature and charge rate of each test . Such characterization at BOL would also be very limited in its ability to predict subsequent changes in CE in the different ageing regimes. The effective lifetime of the cells can be discussed as their cyclability, or, the number of cycles to reach 80 % SOH. A general improvement in cyclability was observed through the three subsequent cell candidate generations, with cell type A having the lowest cyclability and cell type C having the highest. However, cell type B seems to have the largest spread between tested cell pairs at 3C charging which could be related to cell manufacturing or slight variations in test conditions. Common for all three cell types is that 3C charging rates result in lower cyclability relative to 1C charging rates. The largest difference can be seen for cell type C that only shows around one third of the cycle life at 3C charging compared to 1C charging. In addition, for cell type C, a time dependent aging mechanism was also measured by means of a calendar aging test at 50 % SOC from which the results are presented in Figure 2. All cycled cells also showed swelling at end of testing, especially cells cycled at high charge C-rates. As expected, calendar ageing of this type of lithium-ion cell has a capacity loss dependency related to the square root of time , with an Arrhenius temperature correction. ## Direct current internal resistance Direct current internal resistance (DCIR) was also measured on all cells throughout the testing. These measurements were done at a constant current pulse for short duration which captures information about electronic and ionic resistance of the cells. Cell type A has a steadily increasing DCIR throughout cycling, both for 1C and 3C charging, while cell types B and C reach an DCIR minimum after some hundred equivalent full cycles. This decrease in DCIR during early cycles is seldom reported in literature and could be related to several possible causes, of which one could be how the formation process differ between cell candidates . Certain electrolyte additives or protective layers may also be used to stabilize the cell for storage before sale and use. The decrease may be related to the consumption of these sacrificial additives or some other activation behaviour inside the cell (e.g. porosity increase). As this minimum was not observed for the oldest cell type A, this likely reflects recent advances in cell materials, design, and production. For cell type A it hence seems possible to correlate capacity loss to DCIR rise with a linear fit under the conditions applied. However, it is seen from Figure 3 that despite this correlation, the spread between corresponding cells of cell type A is large. This makes estimation of remaining battery capacity from DCIR data challenging in a real-life vehicle application. The relationship between DCIR and capacity retention is not linear for cell types B and C. However, after the point where the cell DCIR reached the minimum, it could be possible to find a correlation between DCIR and capacity retention. This behaviour makes it considerably more complicated to apply a model for battery capacity estimation from DCIR measurements alone in a real-life vehicle application. ## Qualitative capacity loss analysis Incremental capacity analysis, i.e. analysing the inverse derivative (dQ/dV) of charge and discharge voltage curves versus voltage, has been demonstrated as a valuable tool to analyse ageing of the negative and positive electrode respectively . This method was applied to all test cases and is presented for beginning of life and end of life in Figure 4. Peaks dQ/dV curves relate to phase equilibrium of active electrode material (voltage plateaus in voltage versus capacity plots) . For the cell type NMC111/graphite, two peaks are dominant, one at around 3.5 V mostly related to the negative active electrode material graphite and one at around 3.65 V mostly related to the positive active electrode material NMC111. For the 1C cycled type A cells depicted in Figure 4a, the low-voltage peak has moved to higher cell voltage at EOL, indicating loss of cyclable lithium However, the behaviour of the peak at 3.65 V is quite complicated, and could be linked to several different ageing phenomena. The loss of peak area could be related to a loss of NMC active material, though cursory analysis of the corresponding dV/dQ curves shows no strong evidence for this. The decrease and shift in this 3.65 V peak is likely due primarily to the loss of cyclable lithium. (a) (b) ## dQ/dV-plots for a) cell type A at 1C charge, b) cell type A at 3C charge, c) cell type B at 1C charge, d) cell type B at 3C charge, e) cell type C at 1C charge and f) cell type C at 3C charge and calendar aged (red curves) On the other hand, for the 3C cycled type A cells depicted in Figure 4b, both main peak features have more or less disappeared at EOL. This could again indicate several different ageing phenomena or a combination thereof. Capacity attributed to the solid solution behaviour of NMC111 at cell voltages above 3.7 V appears to be retained . This capacity is observed as a constant, non-zero dQ/dV value at high voltage. This implies that while much of the positive electrode material remains intact, it may be incompletely lithiated on discharge due to limitations of the negative electrode, lithium inventory, or other factors. The marked decrease in the lowvoltage peak further suggests that loss of graphite active material at the negative electrode may be responsible, alongside loss of cyclable lithium. The behaviour of cell type B is depicted in Figure 4c and d. In this case, it is seen that both 1C and 3C cycled cells experience loss of area under both main peaks at EOL. Many of the peak features are better preserved under 3C cycling, indicating better rate capability compared to cell type A. Again, there appeared only slight losses at high voltage, indicating that loss of NMC performance may not be caused by loss of active material. Peak shifts indicating loss of cyclable lithium are observed, alongside a broadening of several peaks, particularly for the negative electrode. The sharp, well-defined peaks at BOL represent the electrochemical reactions in relatively homogenous electrodes. The broadening and smudging of these peaks at EOL indicate the occurrence of these reactions over wider windows of cell voltage. In this way, peak broadening indicates increasing heterogeneity and local gradients of both SOC and overpotential within the cell. Broadening without loss of integrated peak area does not entail loss of capacity. Lastly, cell type C is depicted in Figure 4e and f. As with cell type B, features are not eliminated under 3C cycling, indicating acceptable rate capability. Broadening indicative of electrode heterogeneity is seen, but it is difficult to assess the relative impacts of loss of active material at each electrode. Both 1C and 3C cycled cases continue to show shift of the peaks indicating loss of cyclable lithium. ## Discussion and summary The energy density of prismatic lithium-ion battery cells of the PHEV2 VDA-format has increased significantly from the market introduction until the present. Our results on cell aging for NMC111/graphite PHEV2-size cells show that the evolution towards higher energy density is accompanied by an increased slow charging (1C) cyclability, while the fast (3C) charging cyclability has a much lower increase throughout cell generations (in a 20 % to 80 % SOC-window, Fig. 5). Regarding DCIR, the linear relationship between capacity retention and DCIR rise seen for the early version of this cell size has evolved to a more complex non-monotonic relationship. This may be a consequence of additives used to enhance shelf stability or cell performance. In any case, the increased complexity of DCIR data reveals an increasingly complex field of electrochemical phenomena within the cell and increases the difficulty of meaningful cell monitoring. Both early and more recent versions of the PHEV2-format cells show tendencies of swelling towards EOL, especially at higher (3C) charging currents. Such swelling can be due to expansion of the solid-phase electrode materials as well as gas generation from breakdown of the liquid electrolyte. Cell type A shows more severe aging of the NMC111 material compared to graphite when cycled at slower charging currents. However, the graphite seems to be more affected by cycling at higher charging currents. When compared to cell types B and C, which in turn show no severe loss of active material, it appears that optimizations have been implemented to improve the performance and longevity of the NMC and graphite electrodes. All three cell types also show loss of cyclable lithium upon cycling, both at slow and fast charging currents. One possible explanation of the different aging behaviours between cell types could be that different rates of loss of cyclable lithium affect the final outcome of electrode active material loss at EOL . In some cases, loss of cyclable lithium by formation of a solid-electrolyte interphase could help to passivate certain mechanisms and hold particles together. However, after a certain amount lost, local overpotentials could increase to the point that lithium plating or other catastrophic mechanisms are induced. One such mechanism could be electrode dry out due to long-term electrolyte degradation . In this way, the internal electrochemical environment is dynamic and changing with age of the cell. These changing mechanisms of passivation and aging could contribute to fitted changes in coulombic efficiency during the life of a cell. For each cell type, the initial coulombic efficiency appears to be similar for both slow charging and fast charging. When cycling with high charging currents, a constant coulombic efficiency is seen until EOL; in some cases there is a shift to sudden fade (decreased coulombic efficiency) close to EOL. When cycling with low charging currents, the initial low coulombic efficiency improves after a few hundred equivalent full cycles, sometimes in several steps. This decelerated ageing behaviour is well known for lithium-ion batteries but still hard to predict in models, especially if it is followed by a sudden fade. Overall, our results indicate that this type of cell could be suitable for applications such as PHEV distribution trucks, where there are demands for zero tail pipe emissions and silent driving during night delivery. However, to obtain a reasonable lifetime from a corresponding battery pack, the charging rate should be limited to around 1C. For example, a PHEV distribution truck that cycles the battery between 20 % and 80 % SOC two times per day for 250 days per year should, in the best case, be able to achieve a battery service life of around 10 years (until 80 % capacity retention), as estimated from the data obtained for cell type C. With a 3C charging regime this figure would instead be less than 4 years, which could be challenging for the customer. For heavyduty BEV applications where all traction and auxiliary energy needs to come from the battery, a traction battery with very high energy density is needed. In applications where charging can be done during longer periods (< 1C), a pure energy-optimized cell type should be a suitable choice. Today, more energy-optimized cells in the PHEV2-size are also available. For example, it has from around 2019 been possible to obtain PHEV2-size cells with around 50 Ah from selected cell suppliers . These cells seem to utilize a nickel-rich NMC positive active electrode material, sometimes also in combination with a silicon-containing graphite negative active electrode to reach high capacity. Looking into the future, from a simple model based on current cell designs, we project that a high-nickel-content cathode combined with a solid-state electrolyte could push future PHEV2 battery cell capacities towards 100 Ah, corresponding to a very high energy density as well as specific energy (>350 Wh/kg, >1000 Wh/L). Since the trend in automotive electrification increasingly points towards pure BEVs, many battery suppliers are focusing on developing more energy-dense battery cells. This development over the course of cell types A (2012), B (2014), C (2016), and beyond is shown in Figure 5. In addition to the improvement in energy density throughout cell generations, there is also an improvement in specific energy, though this is less pronounced. This means that for each generation of cells in this format, more capacity can be fit into the same cell housing, but at a greater weight. This effective densification of the cells has interesting implications for the automotive industry. A battery pack built with a certain size specification in 2018 may deliver about 90 % more energy than a visually-identical pack built in 2012, but will also be around 30 % heavier, assuming a gravimetric cell-to-pack ratio of 60 %. Hence, the same weight of batteries would in 2018 have given a 38 % increase in capacity compared to 2012. The impact of this tradeoff between pack energy and pack weight can be far-reaching for mobile applications. Trucks designed with heavier battery packs would in some cases have to sacrifice payload in favour of range. However, alongside these increases in energy density and specific energy, it can also be noted from Figure 5 that the cyclability using the 1C-charge strategy is vastly improved throughout the generations while cyclability using 3C-charge has had a slower rate of improvement. ## Conclusions We have compared three different lithium-ion battery cell generations of the prismatic VDAstandard PHEV2 regarding lifetime, with focus on the usage in electrified heavy-duty vehicles. The energy density has increased by almost 50 % over a four-year period and three cell generations, while the specific energy has increased by a more moderate 18 %. The equivalent full cycle throughput, under 1C/1C charge/discharge in a 20 % to 80 % SOC-window and at +35 °C, is also much improved through cell generations while a more moderate increase in cyclability at 3C/1C is seen. The DCIR behaviour changes throughout the cell generations from a linear relationship with capacity retention to a non-monotonic one. Present versions of the VDA PHEV2 cell format offer almost 50 Ah capacity, which means an impressively doubled capacity in 8 years. Altogether, the results from this study point out that the VDA PHEV2 cell format is still a viable choice for electrified heavy-duty vehicles such as inner-city distribution PHEV trucks or even BEVs.

chemsum

{"title": "Evaluating performance and cycle life improvements in the latest generations of prismatic lithium-ion batteries", "journal": "ChemRxiv"}

the_potential_of_jak/stat_pathway_inhibition_as_a_new_treatment_strategy_to_control_cytokine_release

## Abstract: COVID-19, a pandemic affecting virus, which is caused by the current SARS-CoV2 coronavirus. The present research is performed on anti virus and immune-modulating therapies. Cytokine storms are the toxic drivers and mortality caused by various human viral infections. In addition, the intensity was linked to an elevated risk of acute respiratory failure, myocardial injury, and mortality in SARS-CoV-2-infected patients. The Janus kinase (JAK) therapeutic inhibitor class showed significant clinical benefits in anti-inflammatory and anti-viral effects. Among them, filgotinib has been approved as an active JAK inhibitor by decreasing biomarkers with main immune reaction functions and markers supporting matrix-degradation, angiogenesis, leukocyte adhesion, and recruitment in both research trials. In this study, we tried to get an insight into the choice of this drug in controlling the jack, to treat Covid 19 using drug design methods will be discussed. ## Introduction: A new coronavirus disease with high mortality, emerging as pandemic disease, is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite many public health initiatives, pharmacological therapies remain desperately required to treat patients affected, to decrease mortality, and to limit virus shedding and eventual transmission optimally. The infection with SARS-CoV-2 pushes the host to a deep cytokine response, which involves a sequence of mediators aimed at Immune-mediated inflammatory diseases (IMIDs). No specific therapy for COVID-19 is available up to now, cause many of the current treatments are symptomatic. (1) , (2) Efficient prevention and care products are an immediate imperative, in particular in difficult, life-threatening situations. Pathogen infection with coronavirus (e.g., SARS, SARS-CoV-2) also contributes to the development of acute respiratory distress syndrome (ARDS) through severe cytokine and chemokine activity. Anti-viral cytokine signaling develops like a secondary haemophagocytic lymphohistiocytosis in some patients with moderate to severe COVID-19, hyper inflammatory status triggered by viral infections. Maintains the unacceptable levels of acute lung injury, chronic interferon activation, and deteriorate resistance to T cells and antibodies, perhaps for inadequate viral clearance. While the inflammation must mount most cytokines induced by SARS-CoV-2 infection and those attacked in some \IMIDs, they do not regulate the virus clearance. The role of immunosuppressive drugs widely used in immunemediated diseases in the susceptibility and natural history of COVID-19 can be appropriately taken and concern expressed. (3)(4)(5) The cytokine excess associated with the SARS-CoV-2 reaction may also affect both viral clearance and defensive immune responses. Patients with autoimmune disorders have a high risk of infection as a result of endogenous and external factors such as immunosuppressants (dysfunctional immune system). One of the primary deficiencies of COVID-19 infection is the control of the cytokine storm. ( 6) , (7) As described above, current COVID-19 management is mostly positive, and medically validated therapies are not available. ARDS and cytokine storms are the leading causes of death. In addition, 50% of cytokine storm syndrome patients suffer from ARDS. Considering the exceptionally rapid progression of systemic and pulmonary inflammation in a subset of COVID-19 patients, it is highly necessary to recognize and control the immune reactions that are disrupted at an early stage. However, this must be checked, and other biomarkers that are more sensitive and more precise can be identified. ( 8) , ( 9) Several explosive cytokines that include automatic diseases associated with their receptors have activated a JAK based phosphorylation cascade, which constitutes signals of gene transcription. Thus, medications block signals of cytokine that impede the action of JAK. These antagonists target medical treatment to HIV, RA, Psoriasis, Psoriatics, and inflammatory bowel diseases. (10) Signal transduction plays a significant role in having and blocking the cytokine releases of the JAK family of enzymes and JAK inhibitors. Inhibitors of JAK can handle a cytokine storm by the induction of many inflammatory cytokines. Most inhibitors for JAK 1, JAK 2, less JAK 3, and the Tyrosine kinase 2 (TYK 2) are immensely successful for inhibition of Interleukin 6 (IL-6) and interferon, but also inhibit the signal cascade of both Interleukin 2 (IL-2) and Interferon alfa or beta (IFN-α / β). JAK inhibitors have been efficient in inhibition. (11) Inhibitions of small molecules in JAK are quite a recent concept for systemic autoimmune/inflammatory conditions. JAK Inhibitors are biological inhibitors that interact with the Adenosine triphosphate (ATP) binding domain by inhibition of type I / II cytokine receptors. Jak inhibitors have provided targeted synthetic immunosuppressant products that interfere with JAK Signal transducer and activator of transcription (JAK-STAT) signaling by inhibiting one or more members of the JAK family (JAK1, JAK2, JAK3, TYK2). These molecules mediate the transcription factors of the STAT family, which contribute to pro-inflammatory cytokine release. Thus, cytokine expression can be decreased by them and help regulate cytokine storms. Additional inhibition of JAK by small modules can also be detrimental as they further restrict the isolation and clearance of the pathogen and can cause unexpected complications. ( 12) On the other hand, these compounds are provided as medications orally, with highly trained pharmacodynamics and pharmacokinetics. They can provide a more practical approach to calm down the cytokine storm transiently to avoid ARDS and fulminating myocarditis. In addition to blocking IL-6, JAK1 inhibitors not only block inflammatory pathways in a cytokine storm. ( 13) The aims of JAK1 and JAK3 affect some cytokines involved in anti-viral reactions such as interferons, IL-2, IL-15, IL-21, and IFNβ. Thus, potentially, JAK1 inhibitors can inhibit SARS-CoV-2 clearance. Inhibition of the SARS-CoV-2 or the IL-17-induced cytokine inhibits viral induction. In particular, it seems to be very promising to apply interleukin 6 (IL-6) and GM-CSF blockers to manage the massive cytokine storm that is linked to the development of lung damage typically and resulting ARDS in the most attacking patterns of SAR S-CoV disease. Both of whom rely on SARS-CoV-2 signaling in part or entirely (Figure 1). ( 14) Therefore, clinical trials have been JAK1 inhibitors are also suggested as a safe treatment in hospitalized patients with COVID-19. Based on recent analyzes of the COVID-19 inflammatory markers and previous knowledge of inflammatory responses in other mortal lung infections, the potential strategy for anti-ARDS, brilliant myocarditis, organ failure, and mortality at an advanced stage of the condition has been assessed . (15) One of the significant challenges in this regard is the replacement of more effective drugs. It has been indicated to be given to patients with COVID-19 in the late inflammatory process by baricitinib or other JAK inhibitors. Also, using different anti-viral medications, as a result of a growing understanding of infection pathophysiology, other drugs widely used in RA diagnosis have been proposed as alternative therapies for COVID-19. Baricitinib were tested for their anticytokine and anti-inflammatory function. Baricitinib induces cytokines with a lower IC50 value, which indicates that cytokine-induced JAK1 / STAT signalling becomes more impaired in the dosing period. It implies a more potent overall inhibition of cytokine-induced JAK1 / STAT signalling during dosing. But finding a drug with better therapeutic properties can help in the treatment of this disease. ( 16) Finding new drugs is a challenging, expensive, and time-consuming task because there is no structured way to immediately discover a drug even though the drug activity's disorder, targets, and molecular mechanisms are well understood. There are millions of candidate molecules, and because of prohibitive costs, both in terms of time and energy, individual tests cannot be performed on any candidate. Reasonable drug design strategies have been introduced in recent months, particularly for In silico-based solutions, and this strategy has been backed by a recent study as a promising substitute or complementary method for efficient screening of potential drugs. Here, we used a bioinformatics approach to repurpose medication to classify the active antagonists of SARS-CoV2 Key Jak1-inhibitors. ( 17) , ( 18) EXPERIMENTAL : In this study, the three-dimensional structures of ligand and proteins were obtained from PubChem and PDB database, respectively. Density functional theory at B3LYP/631+G (d, p) level implemented was used for 3D and geometry optimizations with energy minimization of each molecule. The protein-ligand interaction calculations were done by Autodock 4.2 and 2D ligand-protein interaction was calculated by Ligplot software. DRAGON software was used for molecular descriptors calculation. Genetic Algorithm and Partial least squares regression were used for feature selection. The evaluation of the active site, surface, and volume of protein was done by Computed Atlas for Surface Topography of Proteins (CASTp). Swiss ADME and target prediction were used to determine the pharmacokinetics properties and target analysis of molecules. GROMACS-2019 version using OPLS force field during was used for Molecular dynamic simulations during 20 ns by selecting periodic boundary conditions and the TIP3P water model for solvating complexes, followed by addition of ions to neutralize. Energy minimization was Tolerance for energy minimization was 1000 kJ/mol/nm. (19)(20)(21) ## Results and discussion The interaction of the JAK1 inhibitor drugs (clinical and pre-clinical) using Autodock software was studied, and the results are given in Table 1. The binding force of molecular docking demonstrates the affinity of a specific ligand and energy, by which a compound interacts and binds to the pocket of a target protein. As a potential drug choice, a compound with fewer binding energy is favoured. The results showed that the drug Filgotinib is more stable with Jack1. ## Name Filgotinib (GLPG0634 / GS-6034) is an active and selective inhibitor of JAK1 that under investigation in the treatment of RAs and inflammatory bowel disease. Filgotinib has demonstrated promising efficacy and is well tolerated for the treatment of rheumatoid arthritis. It is an orally delivered, potent, and selective seed inhibitor of JAK1. The pharmacokinetics and active metabolite of filgotinib in safe volunteers and the usage and analysis of pharmacokineticpharmaceutical models to help the design of the dosage for Phase IIB for patients with rheumatoid arthritis were addressed here. Two-phase II tests of another treatment for JAK1filgotinib in 2018 showed effectiveness in both patients with psoriatic arthritis1 and ankylosing spondylitis in patients2. Compared to Upadacitinib 3,4, Filgotinib therapy provided a mean positive improvement in hemoglobin and platelet counts. A study of the interaction of 33 derivatives of this drug using Autodock software showed that compared to the drugs studied in the previous section, ΔG shifted to more stable values (Table 2) (Figure -2). QSAR calculations performed using algorithm-PLS genetics showed that the number of benzene ring and polarity is an essential factor in molecule-JAK1 interaction (Figure -2). Also, compared to filgotinib, only entry five has created a more stable complex. Pharmacophore analysis showed that the behaviour of this substance is similar to that of filgotinib, and changes in volume and area are similar (Table -3) (Figure 4) . But the results of 2d interaction result showed more hydrophobic interaction with amino acids (Table-4) (Figure -6). Target prediction results show that the A 93% composition targets the LAK, while the B 73.3% composition interacts (Figure -7). ADME studies also showed similar behavioural similarities to filgotinib (Table -5). As a result of these two compounds can be the alternative of Barticinib drug. Still, need supports a more in-depth study on JAK-1 inhibits as the mechanism for therapeutic prevention of a cytokine storm and the downstream organ failure under this situation. ## Compliance with ethical guidelines Conflict of interest: The Autors have no financial or non-financial conflict of interest to declare. For this article, no studies with human participants or animals were performed by any of the authors. All studies conducted were in accordance with the ethical standards indicated in each case.

chemsum

{"title": "The potential of JAK/STAT pathway inhibition as a New Treatment Strategy to Control Cytokine Release Syndrome in COVID-19", "journal": "ChemRxiv"}

enantioselective_phase-transfer_catalyzed_alkylation_of_1-methyl-7-methoxy-2-tetralone:_an_effective

## Abstract: In order to prepare asymmetrically (R)-(+)-1-(5-bromopentyl)-1-methyl-7-methoxy-2-tetralone (3a), a key intermediate of dezocine, 17 cinchona alkaloid-derived catalysts were prepared and screened for the enantioselective alkylation of 1-methyl-7methoxy-2-tetralone with 1,5-dibromopentane, and the best catalyst (C7) was identified. In addition, optimizations of the alkylation were carried out so that the process became practical and effective. ## Introduction The preparation of enantiomerically pure compounds has become a stringent requirement for pharmaceutical synthesis . In this context, asymmetric catalysis is probably one of the most attractive procedures for the synthesis of active pharmaceutical ingredients (APIs) due to environmental, operational, and economic benefits. Dezocine, (5R,11S,13S)-13-amino-5-methyl-5,6,7,8,9,10,11,12octahydro-5-methyl-5,11-methanobenzocyclodecen-3-ol (1, Scheme 1), a typical opioid analgesic developed by AstraZeneca, was extensively used in China recently. Because of its effectiveness and safety , it would have a very good marketing prospect. However, the cost of dezocine was very high since the commercial synthesis process involved the tradi-tional resolution : alkylation of 1-methyl-7-methoxy-2tetralone (2) with 1,5-dibromopentane gave the designed (R)-(+)-1-(5-bromopentyl)-1-methyl-7-methoxy-2-tetralone (3a) and an equal amount of the S-isomer 3b, both 3a and 3b underwent the following cyclization, oximation and reduction, and then, (5R,11S,13S)-3-methoxy-5-methyl-5,6,7,8,9,10,11,12octahydro-5,11-methanobenzocyclodecen-13-amine (6a) and (5S,11R,13R)-3-methoxy-5-methyl-5,6,7,8,9,10,11,12octahydro-5,11-methanobenzocyclodecen-13-amine (6b) were separated by two times of resolution with L-tartaric acid and D-tartaric acid (Scheme 1). the topics in stereoselective synthesis in both industry and academia . It was reported that the alkylation of 2 in the catalysis of N-(p-trifluoromethylbenzyl)cinchonidinium bromide in a two-phase system gave the enantioselective product 3a, although the ee value of the product was 60%, determined by 1 H NMR. And so far, no further report on the stereoselective alkylation of 2a was found. (Some reports on the nonstereoselective alkylation of 2 were given in references ). In this paper, several cinchona-derived phase-transfer catalysts were screened for this reaction, and the structure-activity relationship for the catalysis was studied. In addition, optimizations had been made to make the process efficient. ## Results and Discussion A series of the quaternary ammonium bromides from cinchonidine or quinine as phase-transfer catalysts was prepared (Scheme 2). Cinchonidine was reacted with the benzyl bromides (R 1 Br) in THF to obtain catalysts C1-C11 . And then C7 reacted with allyl or propargyl bromide to obtain C12 and C13. In another way, cinchonidine was reduced by H 2 /Pd/C to yield dihydrocinchonidine, and then reacted with 4-trifluoromethylbenzyl bromide to obtained C14. C15 was prepared from cinchonidine via bromination, debromination and condensation with 4-trifluoromethylbenzyl bromide . Quinine was reacted with 4-trifluoromethylbenzyl bromide or 3,5-bis(trifluoromethyl)benzyl bromide to obtain C16 or C17. In the beginning, the alkylation of 2 in the catalysis of C1 in the two-phase system (toluene and 50% NaOH aqueous solution) was tested, although the yield was moderate (60.1%, entry 1 in Table 1), the enantiomeric ratio (3a:3b) was only 55:45. When the benzyl in C1 was replaced by the bulky groups, such as methylnaphthalene or methylanthracene, neither the enantiomeric ratio was improved (Table 1, entry 2) nor the reaction took place (Table 1, entry 3). Subsequently, when the groups substituted at the para-position on the benzyl group were investigated, the structure-activity relationship showed that catalyst C4 (with methyl substituent) did not work for the reaction (Table 1, entry 4) and those with Cl or F (C5 and C6) worked well with an improvement in enantiocontrol (Table 1, entries 5 and 6). Fortunately, the p-CF 3 derivative (C7) promoted the reaction to give a enantiomeric ratio of 83:17 (Table 1, entry 7). These findings suggested that the presence of electron-withdrawing groups on the benzyl group was favourable for the enantioselective reaction except the case of a nitro group (Table 1, entry 8). And then, the catalysts with a di-substituted benzyl group were examined. C9 with 3.4-dichlorobenzyl resulted in a slightly higher enantiomeric ratio (68:32) than C5 (Table 1, entry 9). But, neither C10 nor C11 (Table 1, entries 10 and 11) were as good as the mono-substituted counterparts (C6 and C7). The derivatives (C12-C15) of C7, the best one so far, were further studied. When the hydroxy group in C7 was protected by an allyl or a propargyl group, racemic product was obtained a The reaction was performed with 0.045 mol/L of 2 in toluene (24 mL), 3.0 equiv of 1.5-dibromopentane and 50% aq NaOH (2.4 mL) in the presence of 10 mol % of catalyst at 15-25 °C for 48 h under N 2 . b Isolated yield including 3a and 3b. c The enantiomeric ratio was determined by HPLC using a chiral column (Daicel chiral AY-H) with hexane/isopropyl alcohol 90:10 as the eluent, detected at 280 nm. (Table 1, entries 12 and 13). This suggested that the free hydroxy group in C7 was crucial to guarantee the stereoselectivity. Meanwhile, the good catalysis was maintained with both dihydrocinchonidine-derived C14 and dehydro compound C15. Finally, the quaternary ammonium group from quinine was examined (Table 1, entries 16 and 17), and C16 and C17 gave the result inferior to the cinchonidine derivatives (C7 and C11). After a suitable catalyst (C7) was identified, further reaction optimization was performed (Table 2). In general, dichloromethane (DCM) was the common solvent for the two-phase reaction, but to our surprise, when the reaction was run in DCM (entry 2 in Table 2), it resulted in the racemic product. When other solvents, such as benzene, bromobenzene and fluorobenwere used, neither the enantiomeric ratio nor the yield was compared with toluene as the solvent (Table 2, entries 1, 3-5). But, the reaction in chlorobenzene gave a slightly improved yield at a substrate concentration of 0.045 mol/L (Table 2, entry 1 and 6). Surprisingly, when the concentration increased to 0.07 mol/L, the improvement became more significant (Table 2, entries 7 and 8). However, further increasing the substrate concentration (Table 2, entry 9) decreased the stereoselectivity. For the screening of the base, the reduction of volume or concentration of 50% aq NaOH resulted in a decreased yield (Table 2, entries 11 and 12). If NaOH was replaced by K 2 CO 3 , no reaction took place (Table 2, entry 13). As far as the reaction temperature was concerned (Table 2, entry 7, 14 and 15), it was found that the reaction at 15-25 °C gave the best result. Finally, the reaction was scaled up (90 g of 2) according to the conditions in entry 7, a similar outcome was obtained (Table 2, entry 16). On the base of the above experimental results, a catalytic mechanism was proposed (Scheme 3). Compound 2 is deprotonated by sodium hydroxide into an anion in the organic layer. The anion goes to the interface between chlorobenzene and water, where it interacts with the quaternary ammonium group of catalyst C7. The distance between two molecules is getting close by the attraction between charges, then two additional interaction forces in the complex are produced on the same plane, including: 1) the carbonyl of 2 makes a hydrogen bond with the hydroxy group of C7; 2) the phenyl group of 2 forms a face-to- The volume ratio of aqueous solution and organic solvent was 1:10. c Isolated yield including 3a and 3b. d The enantiomeric ratio was determined by HPLC using a chiral column (Daicel chiral AY-H) with hexane/isopropyl alcohol 90:10 as the eluent, detected at 280 nm. e The volume of 50% aq NaOH decreased to 5% of volume of PhCl. f 90 g of 2 was added. ## Scheme 3: The proposed catalytic mechanism of stereoselective alkylation. face π-stacking interaction with the benzyl moiety of C7. The complex of 2 with C7 goes to the organic phase. Due to the sterical hindrance from the benzyl group, the alkylation by 1,5dibromopentane takes place at the opposite side of the benzyl group of C7 to afford 3a. ## Conclusion In summary, an enantioselective synthesis of (R)-(+)-1-(5bromopentyl)-1-methyl-7-methoxy-2-tetralone (3a), a key intermediate of dezocine, in the catalysis of the quaternary ammonium benzyl bromides from cinchonidine was investigated and the best catalyst (C7) was identified. In addition, the preparation of 3a with the optimized conditions was performed and the product was isolated in 77.8% yield with an enantiomeric ratio of 79:21. This method can be easily performed in large scale. In addition, the structure-activity relationships for the cinchona alkaloids catalysts were elucidated. ## Experimental All solvents and reagents were of commercial sources and used without further purification. Melting points were determined on a Büchi Melting Point M-565 apparatus and are uncorrected. 1 H and 13 C NMR spectra were recorded using a Bruker 400 MHz spectrometer with TMS as an internal standard. Mass spectra were recorded with a Q-TOF mass spectrometer using electrospray positive ionization (ESI + ). The enantiomeric ratio was determined by HPLC using a chiral column (Daicel chiral AY-H) with (hexane/isopropyl alcohol 90:10) as eluents, detected at 280 nm. Specific rotations were determined on a Rudolph Research Analytical automatic polarimeter IV. All reactions were monitored by TLC, which were carried out on silica gel GF254. Column chromatography was carried out on silica gel (200-300 mesh) purchased from Qindao Ocean Chemical Company of China. General procedure for the preparation of (R)-(+)-1-(5-bromopentyl)-1-methyl-7-methoxy-2tetralone (3a) To a stirred mixture of 2 (90.0 g, 0.47 mol), C7 (25.2 g, 0.047 mol) and 1,5-dibromopentane (326.3 g, 1.4 mol) in chlorobenzene (6750 mL) was added 50% aq NaOH solution (675 mL) at 0 °C. The mixture was allowed to warm up slowly to 15-25 °C and stirred for 48 h under N 2 , and then aqueous layer was separated and extracted with chlorobenzene (700 mL). The combined organic layers were washed with 1 M HCl aqueous solution (2 L) and water (2 L), then the solvent and excess of 1,5-dibromopentane were recovered, respectively, under reduced pressure and then in vacuo. The above-obtained product underwent subsequent cyclization, oximation and reduction according to the literature (without resolution) to get compound 6a, and then 6a was trans-formed to dezocine with 23.0% overall yield and 100% purity. The mp, optical rotation value, MS and 1 H NMR of the product were consistent with those in the literature . ## Supporting Information Supporting Information File 1 Synthesis of catalysts C1-C17, synthesis of dezocine, 1 H NMR and MS spectra of catalysts C1-C17 and chiral HPLC diagrams of 3. 1 H NMR, 13 C NMR, MS spectra of 3. 1 H NMR, MS spectra HPLC diagrams of dezocine. [https://www.beilstein-journals.org/bjoc/content/ supplementary/1860-5397-14-119-S1.pdf] ## ORCID ® iDs Ruipeng Li -https://orcid.org/0000-0001-9520-0635

chemsum

{"title": "Enantioselective phase-transfer catalyzed alkylation of 1-methyl-7-methoxy-2-tetralone: an effective route to dezocine", "journal": "Beilstein"}

efficient_luminescence_control_in_a_dithienylethene_functionalized_cyclen_macrocyclic_complex

## Abstract: We report the synthesis of an original ligand scaffold based on a dimethyl-cyclen platform Medo2pa with two dithienylethene units attached to each picolinate arms and the corresponding yttrium(III), europium(III) and ytterbium(III) complexes. All three complexes show reversible photochromism with high photo-conversions. Photoluminescence experiments demonstrate that this design is versatile and adapted for both europium and ytterbium emission switching when measured in frozen organic glasses at 77 K. The OFF/ON luminescence ratio are excellent in the case of europium (4 to 8 %) and still quite good in the case of ytterbium (around 13 %). ## Introduction Responsive materials in which a key property can be modulated by an external stimulus in a controlled way are a great achievement in the field of molecular materials. Among them "alloptical" systems, that are triggered by light to change their optical (absorption, emission) properties, combine fast response, remote control and a low level of technical requirements for their implementation in real life applications. Applications could be as diverse as labels for cell imaging, 3 super resolution imaging, 4 anti-counterfeiting dyes, optical data-storage 7 and many others. In this context, several research groups have explored the photo-modulation of lanthanide-based luminescent systems, 5, mainly focusing on the association of photochromic compounds with the red-emitting europium(III) ion. 5, The ubiquitous diarylethene (DAE) photochromic units, 17 on top of their excellent photo-physical properties, fatigue resistance and thermal stability of both open and closed isomers, is perfectly suited. Indeed, DAE scaffolds can be easily designed so that the closed isomers show strong absorptions around 610 nm, matching the narrow emission lines of europium(III) and then favoring emission quenching typically via an energy transfer. However, according to this strategy, a complete quenching of europium luminescence in the closed form has not been realized yet. The only total quenching of europium luminescence by a photochromic unit reported to date consist of a tris(dipicolinate)europium core decorated with three N^C chelate four coordinate organoboron T type (reversible upon heating) photoswitches. 15 Therefore, it is highly desirable to achieve a complete optical control of ON/OFF switching of europium luminescence with the P (thermally stable) photochromic DAE. Recently, some of us reported an example of partial photo-modulation in a dithienylethene (DTE) appended dipicolinic amide europium complex (Chart 1), 18 and we hypothesize that a partial lability of the complex could be a factor contributing to the moderate efficiency of the quenching in the closed form. At the same time, surprisingly, this previous paper showed that DTE photochromic units could actually be more versatile modulators of lanthanide luminescence than initially thought since ytterbium(III) NIR emission could be sensitized by the 580 nm absorption of the closed isomer. Based on this, two important goals remain to be achieved in this field: i) the improvement of the efficiency of europium(III) emission quenching by closed DTE system in order to reach real ON/OFF switching, and ii) the generalization and optimization of photo-modulation of ytterbium(III) ion by DTE units. These two goals thus require a better understanding of the underlying photo-physical mechanisms and the exploration of new systems combining DTE and lanthanide ions. between the open and closed state (TTA is 2-thenoyltrifluoroacetonate). 18 (middle) Medo2pa provides water soluble and stable lanthanide complexes and M-Medo2pa-2P chlorine salts enable cell imaging in the NIR range in the case of the ytterbium(III) complex. (bottom) Target complexes. In parallel, macrocyclic lanthanide complexes have been widely studied as imaging bioprobes in general, 3, and as luminescent systems in particular. Among them, the cyclen based Medo2pa platform (Chart 1) has provided complexes of various lanthanide ions displaying high stability constants, 25 that are typically stable in water solutions. 26 This cyclen platform Nfunctionalized by two picolinate pendants and two methyl groups, when modified with two photon active conjugated antennas, provides bright luminescent complexes of europium(III) and ytterbium(III) that are spontaneously internalized into live cells, the latter remaining highly luminescent in biological media (Chart 1). 20 Based on these convincing results, and complementary to another strategy on based DTE modified acetyl acetonate ligands that we are developing in parallel, 27 we thought that the association of the Medo2pa platform with appropriate DTE units could lead to "all optical" switches with improved stability and, therefore, better switching ratio between the open and closed state, as well as to provide a new efficient ytterbium based switch in the NIR range through the closed DTE unit sensitization. We therefore targeted the synthesis of a new Medo2pa platform bearing two DTE units (on each picolinate arms) as shown in Chart 1. First motivated by the ease of synthesis, the presence of two photochromic units within the same scaffold could also be anticipated as an advantage to improve i) quenching efficiency in the case of the europium(III) complex, and ii) sensitization through the closed DTE unit in the case of the ytterbium(III) complex. In this paper, we report on the synthesis of this new ligand and of the corresponding europium(III), ytterbium(III) and yttrium(III) complexes. We study in detail the photo-switching of these three complexes by absorption and ( 1 H, 19 F) NMR spectroscopies to illustrate that a reversible and complete isomerization occurs, the two DTE units behaving independently. Our strategy is proved effective in improving the quenching efficiency of europium luminescence as shown by a residual intensity of 4-8 % of the initial one for the closed form as compared to the open one when measured at 77 K. We also show that the ytterbium complex luminescence can be modulated at 77 K although it does not exhibit any sensitization through the closed DTE. ## Results and Discussion Complex synthesis. Synthesis of the target complexes [MLoo]Cl (M = Y, Eu, Yb) is described in scheme 1. The DTE-photochromic-picolinate arm 1 was obtained by Sonogashira coupling from the alkyne terminated DTE and methyl 6-(hydroxymethyl)-4-iodopicolinate 28 (see SI). Mesylation of the latter was performed under usual conditions and trans-dialkylation of the dimethyl-cyclen macrocycle with two equivalents of compound 2 in the presence of K2CO3 led to the desired diester 3 with an excellent yield of 95%. Saponification of compound 3 in the presence of KOH in THF led to the ligand Loo as a potassium salt which was purified, thanks to a precipitation in an EtOAc/hexane mixture. The synthesis of the complexes was further performed in MeOH at pH around 7. Washings with water and precipitations in CH2Cl2/hexane gave the desired [MLoo]Cl complexes with yields comprised between 61% and 90%. These new compounds were fully characterized (see experimental section and SI). As characteristic features in its 1 H NMR spectrum, the diamagnetic complex [YLoo]Cl exhibit shielded pyridine protons chemical shifts, similarly to other yttrium(III) dimethyl cyclen complexes, 29 while the signals from the cyclen moiety become significantly broadened upon coordination (Figure S12). In the case of the [EuLoo]Cl complex, additional paramagnetic shifts (pseudo contact shifts) are observed. Typically, the photochromic moiety shows small paramagnetic shifts, of around -0.1/-0.2 ppm as compared with the yttrium(III) complex, while the pyridine protons are observed at  = 38.4 and 25.8 ppm and the cyclen protons give broad signals down to -16 ppm as expected (Figure S21). 19 For [YbLoo]Cl complex, in line with the greater magnetic anisotropy tensor of ytterbium(III) compared with europium(III), 30 shifts of the same sign but of greater magnitude are observed, the pyridine protons being observed at  = 83.8 and 55.5 ppm and the cyclen ones down to  = -40.5 ppm (Figure S18). The paramagnetic shifts observed for the photochromic moiety are also larger with, for instance, the thiophene protons shielded to  = 6.97 and 6.37 ppm instead of  = 7.47 and 7.28 ppm in [YLoo]Cl. ## Electronic absorption spectra and photochromism of 3oo and [MLoo]Cl complexes. The absorption spectrum of 3oo in DCM shows several intense bands in the UV range (Figure 1) that can be assigned to local -* transition of the picolyl unit (275 nm) overlapping with one of the DTE open form (315 nm). Upon irradiation at 330 nm, a decrease of absorption is observed at max =272 nm while two new bands appear at max = 382 and 607 nm (Figure 1). The initial spectrum can be recovered by 580 nm irradiation. This is in line with the usual photochromic behavior of DTE units 18 and consistent with the above mentioned assignment of the bands. Photo-cyclisation is evidenced by the characteristic lower energy band (max = 607 nm) ascribed to an intra-ligand (IL) transition centered on the closed DTE moiety. 17 In this system with two DTE units, isomerization proceeds through the intermediate 3oc compound with one closed ring. However, at intermediate photo-conversions, no shifting of the lower energy transition was observed, suggesting that the two DTE units are electronically decoupled and behave independently in that case (Figure S24). 31 The isomerization was also studied by 1 H NMR that proved that a high photoisomerization conversion (up to 94 % of 3cc and 6 % of 3oc) can be reached in the photo-stationary state (PSS) (Figure S29). Typically, the thienyl protons chemical shifts change from  = 7.25 and 7.31 ppm in 3oo to 6.72 and 6.43 ppm in 3cc. In the NMR conditions ([c] = 1.2×10 -3 M), the cycloreversion process is almost quantitative with the recovery of 3oo in 94 % yield accompanied by unknown species, probably coming from partial degradation upon prolonged exposure to light. This behavior is in contrast to the more diluted UV-vis experiment that displays quantitative recovering. Scheme 2. Synthetic pathway yielding the target complexes. 300 400 500 600 700 800 0,0 2,0x10 4 4,0x10 4 6,0x10 4 e (M -1 cm -1 ) 1 and Figures S27 and S28). The initial spectra were recovered after bleaching at 580 nm. Once the cyclen group is coordinated, clean photochromic behavior, exempt of photo-degradation was observed as evidenced by the presence of isobestic points. The absorption spectra of the three complexes are very similar with two main transitions at max = 269 nm and 350-360 nm and Figure 1 shows the representative behavior of the europium complex (the cases of Y and Yb complexes are depicted in figures S27 and S28 respectively). Both bands are strongly modified upon UV irradiations and subsequent ring closure, and new transitions appear with max values of 330 and 627 nm. The lower energy transition is slightly red shifted upon coordination as compared with 3cc. Under visible light irradiation (max = 580 nm), the cycloreversion process is triggered as attested by the quantitative recovery of the initial spectra. Further 1 H NMR monitoring of the process unambiguously shows that the photochromic process upon UV irradiation is almost complete with the reaching of a photo-stationary state composed of ca. 95 % of closed DTE units and a recovery of the initial spectra upon 580 nm irradiation, in contrast to the organic precursor. Details of the changes in the NMR spectra are highlighted in Figures 2 and S31 Photoluminescence of [MLoo]Cl complexes. We further studied the photoluminescence of all three complexes (M = Y, Eu, Yb). The yttrium complex serves as a reference to understand the photo-physics of the ligand since no metal-based emission is expected for this compound. Thus, upon excitation at ex = 350 nm of [YLoo]Cl in an ethanol:methanol glass (77 K), a ligand-based fluorescence centered at em = 395 nm was observed (Figure S32) with the presence of additional peaks in its tail. A time-gated measurement performed with a 1 ms delay allows us to assign unambiguously these features to a simultaneous structured phosphorescence with maximum at em = 517 nm and a corresponding lifetime of 14 ms at 77K (Figure S33). This phosphorescence process corresponds to a ligand-centered triplet at around 19 000 cm -1 . Upon continuous irradiation at 350 nm and closing of the DTE units, both fluorescence and phosphorescence progressively disappeared, and at the PSS the closed yttrium(III) complex was almost non-emissive (Figure S32). Concerning the spectroscopy of the europium complex, [EuLoo]Cl was studied at room temperature and at 77 K. At room temperature, excitation at 350 nm induces both emission and competitive closing of the DTE units. The spectrum is actually dominated by an intense ligandcentered emission at em = 395 nm accompanied by a weak europium emission at 616 nm (Figure S34). In contrast, at 77 K in a methanol/ethanol organic glass, ligand centered emission is drastically decreased as compared with the sharp f-f transitions. The difference in the response of the system with temperature could be ascribed to the occurrence of thermally activated back energy transfer that is hampered at 77 K. We also observed a drastic slowing down of the closing reaction by this lowering of temperature and immobilization in an organic glass that allows to measure the emission spectrum of pure [EuLoo]Cl with an excellent resolution. Therefore, the characteristic europium(III) emission profile assigned to the 5 D0  7 FJ (J = 0-4) transitions were detected at em = 580 (J = 0), 588, 593, 595 (J = 1), 610, 613, 622, 627 (J = 2), 646, 650 , 652, 658, 673 (J = 3), and 694, 704, 711 nm (J = 4) (Figure 4) and overall, the spectrum and particularly the crystal field splitting, is very similar to the one of a previously published europium complexes with a similar Medo2pa ligand for which a C2 symmetry was calculated by DFT. 19 The same measurement at 77 K was performed on [EuLcc]Cl (PSS state) and showed that an impressive quenching of europium luminescence occurs after closing of the DTE since only very weak emission (about 8 % of the original intensity determined by integration of the open state more intense band (J = 2), see Figure 3) was detected. It is also possible to follow the emission quenching in the glass at 77K upon successive scans, highlighting the progressive closing of the DTE during each luminescence measurement (Figure S35). An attempt to reach the PSS was performed upon irradiation of the glass during 1000 s. A 90% quenching was achieved after only 40 s but the complete closing was not reached at the end of the experiment where less than 4% of the initial emission was still observed. A perfect reproducibility of the behavior was observed after several re-opening performed with white light irradiation (Figure 4). 4,0x10 5 6,0x10 5 8,0x10 5 1,0x10 6 1,2x10 6 1,4x10 6 1,6x10 4,0x10 5 6,0x10 5 8,0x10 5 1,0x10 6 1,2x10 6 1,4x10 For complex [YbLoo]Cl, no ytterbium emission was detected upon 350 nm excitation at room temperature. In contrast, in an ethanol/methanol organic glass at 77 K, the typical emission of ytterbium(III) was detected in the NIR. In order to avoid distortion of the signal due to concomitant closing, the emission was detected with a CCD camera. First, a resolved spectrum can be obtained, clearly showing the different lines expected for the 2 F5/2 → 2 F7/2 transition and again very similar to previously reported complexes with C2 symmetry, 20 with the main crystal field splitting lines at 971, 996, 1025 and 1040 nm (Figure 5). In order to follow the effect of photo-isomerization on ytterbium emission, fast-acquired successive spectra were obtained, clearly showing a 10 fold quenching of luminescence due to the closing reaction (Figure S36). Note that the quenching ratio is not rendered by figure 5 because the initial intensity actually corresponds to a system already undergoing a significant amount of closing. Rather, the ratio between the initial and final states can be obtained from integration of the fast acquired data (Figure 6), giving a 13 % ratio. Finally, we have addressed the possibility of sensitization by excitation at 600 nm, and unlike complex Yb-DTEc (Scheme 1) no ytterbium emission was detected in such case. 18 For both europium and ytterbium complexes, it is unclear whether the remaining emission after closing arises from the closed species or whether a PSS composition different from the one in DCM solutions at room temperature (95 % of closed units, no remaining oo isomer) is reached due to immobilization in a frozen organic glass. Discussion. Altogether, and in light with the objectives mentioned in the introduction, the results of the photoluminescence experiments deserve a few comments. First, temperature/medium dependence of the response is very spectacular for both systems and in both cases, no lanthanide based emission can be detected at room temperature. In the case of europium, this is probably because of thermally activated back-transfer, hence causing ligand-centered emission as suggested by the presence of the open form ligand triplet state at 19000 cm -1 . In the case of ytterbium, it is more likely that luminescence is inherently weak due to efficient non-radiative processes and therefore difficult to detect without causing the closing of the DTE. At 77 K in an organic glass, the non-radiative processes are drastically slowed down as well as the closing reaction and both factors favor the observation of ytterbium emission. Second, when measured in appropriate conditions, the contrast between the responses of the two states for our europium complex is much higher than in previous photoswitchable systems based on europium and diarylethene combinations (Table 2) and only one example relying on N^C chelate four coordinate organoboron photoswitches of T type previously showed better quenching ratio. 15 Provided that back transfer and non-radiative processes are reduced by further chemical engineering, our design with a macrocycle bearing two DTE units could lead to very efficient RT europium luminescence switches. Nonetheless, this design leads to the second example of efficient ytterbium luminescence photo-control reported so far. In that case, the mechanism for emission quenching does not rely on spectral overlap between the closed DTE and the lanthanide emission lines and we are currently investigating the possibility of a low lying triplet state quenching the emission in the closed state. We also postulate that the position of this state is not favorable to sensitization of ytterbium emission through the visible transition of the closed DTE unit unlike in Yb-DTEc. This leaves room for improvement of ligand design in order to obtain optimized positioning of this state depending on the targeted behavior ie UV sensitization with quenching by a low lying state or controllable visible light sensitization. ## Conclusion. With this work, we report the synthesis of an original ligand scaffold with two DTE units attached to a cyclen based macrocycle designed for luminescence switching and the corresponding complexes of yttrium(III), europium(III) and ytterbium(III). All three complexes show reversible photochromism with high photo-conversions. Our design proved to be versatile and adapted for both europium and ytterbium emission switching, when measured in frozen organic glasses. The OFF/ON luminescence ratio are excellent in the case of europium compared to all previously published compounds and still quite good in the case of ytterbium, that represents the second example of such behavior. More important, our study, combined with on-going in depth photophysical studies, will contribute to the understanding of important factors for the design of further improved molecular switches with custom switching, excitation and emission wavelengths. Complex [YLoo]Cl. To a solution of compound Loo (60 mg, 41 µmol) in MeOH (HPLC grad, 10 mL) was added YCl3.6H2O (37 mg, 122 µmol, 3 eq). The pH was controlled at 7 and the reaction mixture was stirred at room temperature for 3.5 days. Solvents were evaporated to dryness and water was added to the residue. Water was then filtered on cotton and the solid kept on the cotton was dissolved with CH3CN (HPLC grad). CH3CN was evaporated to dryness and the residue was dissolved in the minimum of CH2Cl2. A large amount of hexane was added and the precipitated was filtered, washed with hexane and dried under vacuum to yield [YLoo]Cl (38 mg, 25 µmol, 61%) as a pale yellow solid.

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{"title": "Efficient Luminescence Control in a Dithienylethene Functionalized Cyclen Macrocyclic Complex", "journal": "ChemRxiv"}