Global NMR Discussion Meetings

2025

  • Role of Quantum Coherence in Chirped DNP

    Mayur Manoj Jhamnani (New York University Abu Dhabi, United Arab Emirates)

    LinkedIn: @Mayur Jhamnani; X: @mayur_jhamnani

    Abstract: DNP is transforming NMR and MRI by significantly enhancing sensitivity through the transfer of polarization from electron spins to nuclear spins via microwave irradiation. However, the use of monochromatic continuous-wave irradiation limits the efficiency of DNP for systems with heterogeneous broad EPR lines. Broad-band techniques such as chirp irradiation offer a potential solution, particularly for Solid Effect (SE) DNP in such cases. Despite its widespread use, the role of quantum coherence generated during chirp irradiation remains unclear, even though it is a key factor in determining the maximum achievable DNP efficiency. In this work, we use density matrix formalism to provide a comprehensive understanding of the quantum coherence generated during non-adiabatic passages through electron-nucleus double-quantum (DQ) and zero-quantum (ZQ) SE transitions and their impact on Integrated Solid Effect DNP under chirp irradiation. Our analysis employs fictitious product-operator bases to trace the evolution of electron-nucleus coherence leading to integrated or differentiated SE. We also explore the role of decoherence in maximizing chirped DNP in microwave power or nutation frequency limited scenario. These findings provide an understanding of the role of coherence generated during pulsed-DNP and MAS-DNP at different temperature ranges. Our results reveal that quantum coherences generated during non-adiabatic passages critically determine whether the chirped DNP process yields Integrated Solid Effect (ISE), or Differential Solid Effect (DSE). By analyzing the evolution of the density matrix in DQ and ZQ subspaces, we show how coherence generation and its decay through decoherence play a decisive role in shaping the net DNP enhancement.

    1. Cory Widdifield Avatar
      Cory Widdifield

      Hello,

      Could you clarify what you mean when you state that adiabatic pulses do not generate coherence, while non-adiabatic pulses generate coherence?
      What would you say was the most surprising finding of your study? Is there a plan to confirm any of your theoretical findings experimentally?

      Reply
      1. Mayur Jhamnani Avatar
        Mayur Jhamnani

        Hello,

        Thanks for your question.

        1. When the chirped MW irradiation is adiabatic (i.e., satisfies the Landau Zener condition for adiabaticity), an initial density matrix that is a polarization, Sz, undergoes complete inversion to -Sz. However, if the chirp is non-adiabatic, an initial density matrix that is a polarization, Sz, does not undergo complete inversion, rather, some coherence is generated.

        2. Most surprising/important finding: We found that when the initial density matrix is a pure coherence (mSx + nSy)- an adiabatic pulse would lead to a generation of only coherence however, a non-adiabatic pulse would give both coherence and +/-polarization (sometimes +ve polarization is generated while other times -ve polarization is generated). This helped us explain the caveat between ISE and DSE in the paper: https://arxiv.org/html/2410.19170v1.

        3. Regarding experiments – our findings are experimentally hard to validate as there are several effects, powder averaging and B1 field inhomogeneity.

        Reply
    2. Arianna Actis Avatar
      Arianna Actis

      Hello Mayur, thank you for the presentation. It is a very interesting study.
      Could you comment more about why a chirp pulse is never adiabatic between ZQ and DQ transitions? Does it depend on the available mw power (omega1) and how?
      Why the decoherence process favours the ISE over the DSE?
      Thank you.

      Reply
    3. Mayur Jhamnani Avatar
      Mayur Jhamnani

      Hello,

      Thanks for your question.

      1. The MW chirp pulse can result in an adiabatic or non-adiabatic transition depending on the Landau-Zener (LZ) condition. The condition is that (pi*p^2) / 2k >> 1 for the chirp pulse to be adiabatic across a transition. Here p is the perturbation and k is the sweep rate.

      For a single quantum transition, perturbation is just MW power (in the rotating frame). As a result, it is much easier to ensure adiabaticity. However, the perturbation for DQ and ZQ transition have the pseudo-secular hyperfine coupling term (B) in the denominator. This means, higher MW power (beyond the available MW power) is required to excite these resonances adiabatically.

      2. The role of quantum coherence was causing the caveat between ISE and DSE. If the coherence is decayed, we can easily look at it from just a polarization standpoint. Since the SQ transition inverts the electron spin polarization from Sz to -Sz, the enhancement from the following ZQ transition will add to that from the DQ transition (leading to ISE). A detailed explanation is provided in https://arxiv.org/html/2410.19170v1.

      Reply
    4. Raj Chaklashiya Avatar
      Raj Chaklashiya

      Hi Mayur, interesting talk! I am curious, what would you expect the results to look like if you assume relaxation and coupling parameters from various known radicals (e.g. Trityl, AMUPOL, P1 centers). Would the resulting DNP mechanism be strongly dependent on the couplings/relaxations expected within such radicals?

      Reply
    5. Arianna Actis Avatar
      Arianna Actis

      Thank you for your reply Mayur.

      Reply

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  • Ions dance, nuclei talk: understanding intermolecular Overhauser transfer in ionic liquids.

    Florin Teleanu (New York University, United States)

    LinkedIn: @Florin Teleanu; X: @teleanuflorin; BlueSky: ‪@teleanuflorin.bsky.social‬

    Abstract: Intermolecular dipolar interactions between nuclear spins residing on different ions is used to map spatial proximities in ionic liquids. This study investigates how temperature impacts the observed polarization transfer among ions in different molecular shells. We provide a detailed explanation of measured intermolecular cross-relaxation rates in two ionic liquids using molecular dynamics simulations.

    1. Jonas Koppe Avatar
      Jonas Koppe

      Thank you for the presentation. Do you use a special experimental setup to run the 1H-19F NMR experiments?

      Reply
      1. Florin Teleanu Avatar
        Florin Teleanu

        Hi, Jonas. Thanks for the question. There’s nothing special about our experimental setup. Just a standard BBO probe to pulse simultaneously on 1H and 19F channels.

        Reply
    2. Blake Wilson Avatar
      Blake Wilson

      Hi Florin, thank you for this interesting presentation! Can this technique be used to measure local solvent dynamics and local viscosity around larger molecules, which may have more complicated interactions with the solvent?

      Reply
      1. Florin Teleanu Avatar
        Florin Teleanu

        Hi, Blake. Great question! Indeed, we expect averaged bulk properties to be different than the ones in the first solvation shell, similar to how water strongly binds to solvated cations. There are two aspects that change across shells: the correlation time and the radial distribution function. The correlation time scales quadratically as you go further away (see slide 5) and RDF has several maxima. However, molecules are constantly changing shells (and rotational tumbling regime) so it seems quite difficult to quantify each shell’s contribution at a given time, though we have been thinking if there’s a way to deconvolute the observed cross-relaxation rates to different shells’ averaged contributions (like a Voronoi tessellation) at different temperatures, which would be quite informative. Alternatively, we can use a simple model for the intermolecular dipolar coupling that doesn’t take strong binding into account and predict the temperature dependency of the cross relaxation rate and see how much it deviates from MD simulations and experiments. Another approach would be to use 11B/10B quadrupolar interactions with the first solvation shells to span local dynamics which we have already done (https://papers.ssrn.com/sol3/papers.cfm?abstract_id=5355636), but with no clear multiple quantum coherences. For now, a simple way would be to have a very reliable force field that predicts many basic (density, bulk viscosity, bulk diffusion) and more complex (auto- and cross-relaxation rates for intra- and intermolecular interactions) and then rely on the FF predictions to get the local descriptors you want. Still, your question is very interesting and I think a clear answer could be provided only if we manage to develop something like a pulse sequence to separate each shell’s contribution to the observed rate.

        Reply

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  • Removing t1-noise in DNP-enhanced NMR at natural isotopic abundance using two-spin order filter

    Quentin Reynard-Feytis (CEA Grenoble, France)

    LinkedIn: @Quentin Reynard-Feytis

    Abstract: Recent developments in MAS-DNP have dramatically enhanced the sensitivity of solid-state NMR, making it possible to perform increasingly complex experiments. Notably, this includes 13C–13C and 13C–15N correlation spectroscopy on powdered samples at natural isotopic abundance (NA), without the need for isotopic enrichment. Working with low-abundance nuclei also reduces dipolar truncation, thereby facilitating the observation of long-range polarization transfers. However, the potential of these techniques is often compromised by strong artefacts such as t₁-noise, which arises from instabilities during indirect evolution. Because t₁-noise is multiplicative, signals from abundant but uncorrelated nuclei can mask weaker cross-peaks, particularly problematic in NA samples where signal overlap is common.

    In this study, we present a new approach to suppress t₁-noise in natural-abundance 13C–13C DQ-SQ correlation spectra. The method involves converting double-quantum (DQ) coherences into longitudinal two-spin order (zz-terms), followed by the application of a “zz-filter” to selectively remove magnetization from uncorrelated 13C spins. We describe the theoretical basis of the technique and demonstrate its application to both J-coupling and dipolar-based DQ-SQ experiments at NA. At 100 K, using a standard Bruker MAS-DNP system, we show that this filtering enables the clear identification of long-range cross-peaks previously obscured by noise. Furthermore, at 30 K on a helium-cooled MAS-DNP setup, where t₁-noise is typically more severe due to higher sensitivity, we observe substantial SNR improvements in the indirect dimension (up to 10×). These advances make it possible to acquire, for the first time, a reliable 13C–13C DQ-SQ spectrum at natural abundance and 30 K.

    1. Amit Bhattacharya Avatar
      Amit Bhattacharya

      Hi Quentin, great work and nice presentation! Could you elaborate how zz-filter distinguish between “correlated” and “uncorrelated” nuclei at the quantum mechanical level? What happens to the overall sensitivity when you apply this filtering – is there a trade-off between noise suppression and signal intensity?

      Reply
      1. Quentin Reynard-Feytis Avatar
        Quentin Reynard-Feytis

        Hi Amit,

        thank you very much !

        before the DQ excitation block, the spins are prepared among the z-axis and from there you apply the DQ-excitation. At this stage, there is two possibilities:

        – correlated spins: you generate DQCs (which are for instance DQy = I1xI2y + I2yI1x)

        – uncorrelated spins: they cannot create DQCs so they stay along the z-axis

        When we apply the zz-filter, we convert these terms such as:

        – correlated spins: the first pulse will create I1zI2z terms from the DQy (cannot be completely converted)

        – uncorrelated spins: the Iz magnetization is put in the x.y plan

        The subsequent delay will diphase uncoupled spins’ Ix.y magnetization, but will preserve the I1zI2z terms that can only be formed from coupled spin pairs.

        The second pulse will convert the I1zI2z terms back into DQCs, and the sequence keeps running 🙂

        Let me know if that was clear or if you have any more questions !

        Reply
        1. Quentin Reynard-Feytis Avatar
          Quentin Reynard-Feytis

          update: I forgot to answer the 2nd part of your question.

          Yes, there is a trade-off. For isotropic DQ-excitation (i.e., all the DQCs generated have the same phase in the DQ subspace), we loose a factor 2 when applying the zz-filter.

          This is problematic, although we obtain a 5 to 12-fold noise reduction with the zz-filter, which leads to SNR improvements of ~2.5 to 6.

          When facing relatively “low” t1-noise, the applicability of the zz-filter isn’t straightforward and there might be other solution more viable. (for instance Fred Perras paper 10.1016/j.jmr.2018.11.008 )

          I hope this was clear !

          Best,

          Quentin

          Reply
          1. Amit Bhattacharya Avatar
            Amit Bhattacharya

            Thank you Quentin, for your detailed answer.

            Reply
    2. Chloé Gioiosa Avatar
      Chloé Gioiosa

      Dear Quentin,

      Thank you vor the very nice presentation!

      I was wondering if the efficiency of the zz-filter depends on the refocused lifetime of the coherences (T2′) and/or on the spinning frequency ?

      Reply
      1. Quentin Reynard-Feytis Avatar
        Quentin Reynard-Feytis

        Dear Chloé,

        thank you very much for your comment !

        You’re perfectly right, since we want the SQCs associated to uncoupled spins to diphase during the delay of the zz-filter, this needs to be done through various (Zeeman truncated) interactions: CSA, 1H-X couplings, 1H-1H couplings, etc…

        Although all of these interactions are supposely averaged out by MAS, their still quite present in rather slow MAS speed regime (<10kHz). At higher spinning speeds, the time necessary to diphase the SQCs (which create the t1-noise) might be exceedingly high ! The T2' partially transcripts for how present these residual interactions influence the spectrum, so this is definitely linked ! A really long T2' might mean that the residual interactions are not strong enough to quickly diphase the SQCs, which can affect the zz-filter efficiency…

        However:

        – at natural abundance, the zz-terms lifetime is reeeaaaally long since they don't face spin diffusion issues, so in principle there is no limitation to extend the zz-filter delay.

        – It is possible to add a DARR-field on the 1H channel, which reintroduces 1H-13C coupling, to speed up the decay of the SQCs during the zz-filter delay.

        So in conclusion, yes it definitely matters and the stategy needs to be adapted, but one shouldn't face any major limitations….although this still needs to be proved 🙂

        Reply
        1. Chloé Gioiosa Avatar
          Chloé Gioiosa

          Thank you for the detailed answer

          Reply

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  • DNP Semianalytical Calculations and Quantum Mechanical Simulations in MAS and Static Conditions

    Raj Chaklashiya (Northwestern University and University of California, Santa Barbara, United States)

    LinkedIn: @Raj Chaklashiya

    Abstract: Dynamic Nuclear Polarization (DNP) continues to transform NMR spectroscopy by enhancing its signal by several orders of magnitude via polarization transfer from unpaired electron spins to nuclear spins, enabling studies of objects consisting of very few spins such as cells. However, maximizing its potential towards subcellular components consisting of even fewer spins would significantly benefit from optimization of signal enhancement towards its theoretical maximum, which is nontrivial to achieve due to the many different factors that go into signal enhancement. DNP Semianalytical Calculations via simple numerical model assumptions and first principles Quantum Mechanical Simulations via time-evolved Hamiltonian propagators are two distinct methods that can be used to predict DNP performance and assess potential sources of missing enhancement via comparison with experimental DNP frequency profiles. This talk is a tutorial that applies these methods to the analysis of DNP from a highly efficient DNP biradical, TEMTriPol-1, which consists of one part Trityl and another part TEMPO. Inclusion of the effects of microwave saturation and electron spin relaxation in semianalytical calculations and use of the QUEST Northwestern computing cluster in Spinevolution quantum mechanical simulations both provide key improvements to these methods that enable closer matching between experiment and simulation. The results point towards the critical need to understand the J-coupling distribution of DNP radicals to fully understand the underlying DNP mechanism and optimize DNP performance.

    1. Arianna Actis Avatar
      Arianna Actis

      Dear Raj, very interesting study. Could you comment more on the role of the J coupling on the shape of the DNP profile? How would a reduction of J affect the profile? Have you studied other biradicals with different combinations of relaxation times/J couplings?

      Reply
      1. Raj Chaklashiya Avatar
        Raj Chaklashiya

        Dear Arianna, thank you, and thanks for the questions!
        So regarding J coupling and the profile shape, we found that reducing the J coupling narrows the Trityl part of the DNP profile significantly, removing the “bump” in the DNP profile that shows up on the left side of the profile during experiment. It seems that reducing J has the net effect of making the overall DNP profile narrower, leading to clear discrepancies with the broader experimental DNP profile.
        This is the first established biradical that I have done this kind of study on, but I have done simulation studies in the past of multiradicals and coupled monoradicals with varying dipolar, J, and/or relaxation times, and the results can get quite interesting. I’m happy to go more in-depth on this if you’d like! Here are a couple papers where we discuss those cases in detail:
        Multi Electron Spin Cluster Enabled Dynamic Nuclear Polarization with Sulfonated BDPA –in our simulation section we see the impact of J coupling and relaxation times on coupled BDPA and find that there is a combination that matches experimental trends. J coupling matching the nuclear larmor frequency combined with a strong differential in t1e’s can result in an absorptive central feature in the DNP profile lineshape: https://pubs.acs.org/doi/full/10.1021/acs.jpclett.3c02428
        Dynamic Nuclear Polarization Using Electron Spin Cluster – this paper has detailed simulations on Trityl-based multiradicals and the conditions in which dipolar couplings are strong enough to result in strong DNP enhancements, as well as the impact of relaxation time differentials on the DNP profile: https://pubs.acs.org/doi/full/10.1021/acs.jpclett.4c00182

        Reply
    2. Kuntal Mukherjee Avatar
      Kuntal Mukherjee

      Dear Raj, very nice talk! I would like to know that in second method, when you are observing for static case, the dipolar interaction is also present there (which is primarily averaged out in case of MAS), how the role of dipolar interaction and J-coupling can be separately understood?
      Thank you.

      Reply
      1. Raj Chaklashiya Avatar
        Raj Chaklashiya

        Hi Kuntal,

        Thank you! Good question–so first to clarify, the dipolar coupling definitely plays a role in both the MAS and Static simulations–even though there is averaging of dipolar orientations that would make seeing their effects in the NMR spectra harder, its effects can still be seen in the DNP profile itself, because in both cases the dipolar coupling strength directly determines how coupled the two electron spins are–if they are too weakly coupled, the Cross Effect DNP cannot occur, while if they have strong enough coupling it can occur. So in this sense, it needs to be understood for both static and MAS.

        As to your question–in these simulations I assume a dipolar coupling constant at 12.5 MHz because I don’t expect the distance between the Trityl electron and the TEMPO electron of TEMTriPol-1 to change. However, J-Coupling is a different story, as it is already known based on liquid state EPR experiments that there is a broad distribution of J couplings.

        However, if we assume both the dipolar and J couplings can change, what happens, and how do the effects differentiate from one another? I think in this case, the key difference lies in how they impact the EPR spin populations:
        – Dipolar coupling acts as a means to broaden electron spin populations. Stronger dipolar coupling results in broader EPR lines, while weaker dipolar coupling results in narrower EPR lines
        – J coupling acts as a means of splitting electron spin populations. Stronger +J coupling results in a wider split in the EPR line, while weaker +J coupling results in a narrower split in the EPR line. And crucially, negative J coupling when strong vs weak can flip this dependence (which results in the better fit with -J as opposed to +J)

        From this, one can see how dipolar coupling alone would result in different a different input EPR line, and therefore a different DNP profile–while it can broaden the already existing electron spin populations, it cannot necessarily create new populations further away. This means it would be harder for a small “bump” to suddenly appear due to dipolar broadening as opposed to J couplings–that bump however could easily be created if a population were shifted due to J couplings.

        The beauty of these simulations, however, is that it can be easy to test these hypotheses! We could input a range of dipolar coupling values and compare that with what happens if we input a range of J coupling values, and vice-versa, all while keeping the other coupling fixed.

        Let me know if you have any more questions!

        Reply
        1. Kuntal Mukherjee Avatar
          Kuntal Mukherjee

          Ok, that clears the query, thank you!

          Reply
          1. Raj Chaklashiya Avatar
            Raj Chaklashiya

            No problem!

            Reply

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  • Effects of Membrane Composition on Kindlin-2 Binding to Phosphatidyl Inositol Phosphates in Lipid Bilayers

    Zainab Mustapha (Rutgers University, United States)

    Abstract: Kindlin-2, K2, is a peripheral membrane protein and co-activator of integrin signaling in the cell, which is implicated in cell migration, adhesion, and cancer. K2 contains a pleckstrin homology (PH) domain, which, like many PH domains, binds to the phosphoinositide components of the cell membrane, specifically phosphatidylinositol-3,4,5-trisphosphate (PIP3), to enhance integrin activation. However, the mechanism of PIP3 recognition and binding is not fully understood, as no structural studies to date use full-length PIP3 in lipid bilayers, focusing instead on the soluble inositol headgroup.
    In this study, we use a combination of solid-state and solution NMR to investigate the structure and dynamics of PIP3-bound K2-PH in a model membrane containing PIP3, phosphatidylcholine, phosphatidylserine, and cholesterol. We study changes in the bound state with respect to the model membrane and the unbound protein. Using proton detection and very fast MAS, ssNMR results show chemical shift perturbations in the backbone of the bound protein compared to the unbound form. These perturbations confirm interactions in areas predicted to interact with the membrane (in our MD simulations). We also describe how additional membrane components, such as cholesterol, can stabilize the binding of the protein.
    Together, these results suggest that PIP3 binding induces structural changes in membrane-interacting regions of K2-PH, and that additional membrane components may help stabilize this interaction. Our findings help explain the mechanism of K2-PH binding to PIP3s in the context of a full-length lipid bilayer, which has broad implications for the PIP-based regulation of numerous important cellular processes.

    1. Nicolas Bolik-Coulon Avatar
      Nicolas Bolik-Coulon

      Nice presentation!

      I have a few questions:
      1) Are the bilayers preserving their structural integrity upon spinning in MAS?
      2) T398 seem to split into two. Would you have an explanation for this?
      3) Can you quantify the fraction of PH bound to the bilayers?

      cheers

      Reply
    2. Zainab Mustapha Avatar
      Zainab Mustapha

      Thank you! Very good questions and observation
      1) Usually, we spin the rotors containing liposomes only at 15 kHz, because they preserve their structural integrity and give good linewidth at this MAS rate. However, the 31P 1D data of the bound sample was spun at 40 kHz and the 31P static spectra taken before and after shows that the bilayer structure is preserved. So yes, the bilayers preserve their structural integrity

      2) Very nice observation, I am still trying to make sense of all the changes we see.

      3) Yes, so we start out with solution NMR titration, which of course renders the membrane-associated protein invisible as the titration progresses. When we pellet the complex, we collect the supernatant and take 15N-HSQC to estimate how much of it is left in solution. We use this as a measure of what is bound to the bilayer.

      I hope this answers your question. Please let me know if you have any suggestions or input. I’ll be happy to take them. Thank you again.

      Reply
    3. KSHAMA SHARMA Avatar
      KSHAMA SHARMA

      Dear Zainab,
      Thank you for your presentation.

      1. I was wondering if you were able to determine the binding constants from your titration studies. If so, could you share the binding affinity you observed between the PH domain and PIP3?
      2. Looking at your static 31P spectra, I noticed slight differences between the bound and unbound forms. Could you please elaborate on what might be causing these differences?

      Thank you!

      Reply
    4. Zainab Mustapha Avatar
      Zainab Mustapha

      Hi KSHAMA,

      Very good questions.

      1. We didn’t determine binding affinity from our solution NMR titrations. However, in a pioneering work with the soluble headgroup of PIP3, the Kd was measured to be about 2.12 uM. It’s worth thinking about if the presence of the tails would give a different measurement.

      2. The presence of the protein may be inducing some sort of membrane curvature on the bound sample compared to the unbound. It can be that some of phosphates in the bilayer now have a different orientation as a result of protein binding. Overall, even though there are subtle differences between the two spectra, we think the bilayer may not be completely destroyed because at a different protein:lipid ratio (data not shown), the static spectra completely shows a different powder pattern.

      Thanks for engaging with my research and I hope this answers your questions. Happy to take any suggestions or further questions.

      Reply

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  • Slow Water in Engineered Nanochannels Revealed by Color-Center-Enabled Sensing

    Rohma Khan (CUNY City College of New York, CUNY Graduate Center, United States)

    Bluesky: @gbalavoi.bsky.social‬

    Abstract: Characterization of nanoscale confinement of liquids via quantum sensing can overcome the sensitivity, spatial, and temporal limitations of other measurement techniques, allowing deeper understanding of dynamics central to areas spanning geophysics, tribology, catalysis, polymer science, and biology. Using shallow nitrogen vacancy (NV) centers as our quantum sensors we probe the molecular dynamics of water molecules confined within engineered ~5-nm-tall channels formed by a hexagonal boron nitride (hBN) structure on the diamond surface. Our resultant NV-enabled nuclear magnetic resonance spectra of confined water protons reveal a reduced H2O self-diffusivity, orders of magnitude lower than that in bulk water. Correlation measurements show us long lasting nuclear spin coherences, indicative of molecular dynamics intermediate between bulk water and ice. Molecular dynamics modeling indicate cluster formations may arise from accumulation of surface charge and carrier injection into the fluid under laser illumination. Our next step is the extension of these experiments to variable temperatures with preliminary findings showing narrowing of our NV NMR Spectra as we approach freezing point.

    1. Yunfan Qiu Avatar
      Yunfan Qiu

      Hi Rohma,
      Excellent presentation. From the perspective of an organic chemist, I am curious if you could use the same system to detect protons in other solvents, such as organic solvents instead of water. Would you expect to observe different proton frequencies depending on the chemical structure of the solvents, and achieve NV-enabled H NMR? Thanks!

      Reply
    2. Rohma Khan Avatar
      Rohma Khan

      Hello Yunfan Qiu,

      Thank you for your question!

      We can use the same system to detect protons in other solvents, in my colleague’s case he is able to detect protons in fluorinated oil. We have also tried this with PEG. In our system we would not be able to observe different proton frequencies depending on the chemical structure of the solvents, but others have with a slightly modified setup. Here is the citation for them Glenn, D., Bucher, D., Lee, J. et al. High-resolution magnetic resonance spectroscopy using a solid-state spin sensor. Nature 555, 351–354 (2018). https://doi.org/10.1038/nature25781

      One of the key points in our system is that we work with statistical polarization but to see the chemical shifts we need thermally polarized nuclear spins. Please let me know if you have any further questions, thanks!

      Rohma

      Reply
    3. Raj Chaklashiya Avatar
      Raj Chaklashiya

      Hi Rohma, interesting presentation! I am wondering if there are good ways to optimize this technique without substantially changing the result. I am thinking of two ways:
      1) Optimizing the diamond properties (e.g. number of NV centers, closeness of NV centers to the surface, size of the diamond, etc.)
      2) Implementing Dynamic Nuclear Polarization via organic radicals being placed in the solvent and microwaves being shined onto the water to enhance the NV-NMR signal
      I am curious about your thoughts on these two and whether you already know ways the diamond could be optimized or how compatible DNP could be with your methodology (would the radicals interfere too much with the end result?)
      Thank you!

      Reply

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  • Solid State Characterization of Co-amorphous, Co-crystal and Eutectic systems with Solid-state NMR

    Shovik Ray (Indian Institute of Science, India)

    LinkedIn: @Shovik Ray; X: @ray_shovik

    Abstract: Solid-state nuclear magnetic resonance (SSNMR) spectroscopy is an indispensable tool in pharmaceutical research that provides detailed structural and dynamic insights. This non-invasive technique is particularly critical for identification and quantification of polymorphs forms and tracking of local dynamics. Thus, SSNMR plays a key role at various stages of drug development from preformulation to manufacturing.
    In this presentation, I will show the applications of SSNMR in characterization of co-amorphous systems, developed to enhance the solubility and dissolution rates of active pharmaceutical ingredients (APIs). In particular, the molecular interactions leading the co-amorphization of Dasatinib, a tyrosine kinase inhibitor used in chronic myeloid leukaemia therapy, with various co-amorphous systems will be discussed in detail. I will show the use of 1H, 13C and 1H-1H double quantum – single quantum correlation experiments to confirm presence or absence of inter- and intra-molecular hydrogen bonding, which is a key factor in determining formation of co-formers.
    I will also discuss recent results on Venetocloax, which is a medication used to treat adults with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL) or acute myeloid leukemia (AML). Our studies highlight the capabilities of SSNMR in combination with other characterization techniques to gain pivotal information and optimize pharmaceutical formulations.

    1. Amit Bhattacharya Avatar
      Amit Bhattacharya

      Hi Shovik, nice work! Could you briefly explain how you concluded that intramolecular interactions predominate in the DAS:MAL system based on the DQ-SQ data?

      Reply
      1. Shovik Ray Avatar
        Shovik Ray

        Hi, Amit, thanks!

        We have executed the DQ-SQ with a DQ excitation time such that, it corresponds to the distance of 1.8-2.3 Å (calculating corresponding H-H dipolar coupling), which is the conventional hydrogen bonding distance. We did get strong intermolecular interactions. But, for DAS-MAL case for the same mixing time I did not get inter-molecular peaks but intra-molecular peaks are present. Therefore, we concluded intra-molecular interaction is predominate in DAS:MAL system, whereas in DAS:SU the inter-molecular interaction is present.

        Reply
        1. Amit Bhattacharya Avatar
          Amit Bhattacharya

          Thanks Shovik.

          Reply
    2. Riley Hooper Avatar
      Riley Hooper

      Hi Shovik, nice study. How were the samples prepared – is there any impact of solvent on whether the co-amorphous or co-crystal systems will form? And did you try any other co-former with Ven?

      Reply
      1. Shovik Ray Avatar
        Shovik Ray

        Hi Riley,

        extremely sorry for the delayed response.

        The samples were prepared by liquid assisted grinding method. Methanol was used as a solvent to co-grind them and to form the co-amorphous system. the impact of solvent we did not check explicitly but yes, if we see the “screening of the co-formers” section in. the poster, with nicotinic acid and phenanthrene, Dasatinib did not form a co-amorphous system, rather a co-crystal. Therefore, I think there is impact of solvent directing co-amorphization/crystallization process. For details please check out (https://doi.org/10.1039/D5CE00064E). We can have more discussions.

        For Ven yes we are studying more co-formers also, and the study is in progress.

        Reply
    3. Raj Chaklashiya Avatar
      Raj Chaklashiya

      Hi Shovik, interesting study! One question I have is with regards to your deconvolution. I see many different populations in your deconvolution, each with different heights, and was curious about how you performed your fitting procedure (I may have to do something similar for an EPR line in the near future so I could use a few pointers haha!)

      Reply
      1. Shovik Ray Avatar
        Shovik Ray

        Hi Raj,

        thank you for the question. Let me answer you genuinely.

        The peaks were really broad even after echo-filtering. Therefore, we performed solution NMR to get the chemical shift assignments. Then based on that information and the nature of peaks we performed the deconvolution. The deconvolution was done on topspin (software provided by bruker) with a gaussian/lorentzian model. After initial guesses are given (based on the solution NMR data and their chemical nature), it fitted the spectra. We tried with multiple different initial guesses also, it turned out to be similar end point. So, that’s how we got the deconvolution. If unambiguity of deconvoluted peaks is a question, then to prove that we need the experiments to be done in high sample spinning.

        Reply
        1. Raj Chaklashiya Avatar
          Raj Chaklashiya

          Gotcha! Thank you for describing how you did that in detail! That is very helpful to know. 🙂

          Reply
    4. Shovik Ray Avatar
      Shovik Ray

      Hi Raj,

      thank you for the question. Let me answer you genuinely.

      The peaks were really broad even after echo-filtering. Therefore, we performed solution NMR to get the chemical shift assignments. Then based on that information and the nature of peaks we performed the deconvolution. The deconvolution was done on topspin (software provided by bruker) with a gaussian/lorentzian model. After initial guesses are given (based on the solution NMR data and their chemical nature), it fitted the spectra. We tried with multiple different initial guesses also, it turned out to be similar end point. So, that’s how we got the deconvolution. If unambiguity of deconvoluted peaks is a question, then to prove that we need the experiments to be done in high sample spinning.

      Reply

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  • An NICS study on Modulation of Aromaticity of Nitroaniline Isomers in Binary Solvent Mixtures

    Prince Sebastian (St.Berchmans College, Changanacherry, India)

    LinkedIn: @Prince Sebastian

    Abstract: The stability and chemical reactivity of substituted benzene derivatives are largely determined by their aromatic nature. Using the Nucleus-Independent Chemical Shift at 1 Å above the ring center [NICS(1)] as an aromaticity probe, we examine how binary solvent mixtures affect the modulation of aromaticity in ortho, meta, and para-nitroaniline isomers. To simulate different solvation environments, binary mixtures comprising water, chloroform, dimethyl sulfoxide, acetonitrile, trifluroethanol, N,N-Dimethylformamide, dioxane, and tetrahydrofuran were employed. Less negative NICS(1) values in solvent combinations indicate that solvation reduces aromaticity for all three nitroaniline isomers, according to our computational analysis. Solvent-induced polarisation and hydrogen bonding effects, which affect electron delocalisation within the aromatic ring, are responsible for this decrease in aromaticity. Interestingly, the type of isomer and solvent composition affect the amount of aromaticity loss, with para-nitroaniline exhibiting the highest sensitivity to solvation effects. The reactivity and mechanism of chemical transformations involving nitroaniline derivatives may be influenced by solvent-dependent aromaticity, according to these findings, which also emphasise the critical role of solvent environment in modulating electronic properties.

    1. Blake Wilson Avatar
      Blake Wilson

      Hi Prince, great presentation. I have two questions.

      1) From your data it seems like NICS(0) values in binary mixtures are often lower than the NICS(0) values for each solvent making up the mixture. Can you comment on this?
      2) How are your calculated NICS values validated? Or is that the next step?

      Reply
    2. PRINCE SEBASTIAN Avatar
      PRINCE SEBASTIAN

      Hi Blake,

      1)Yes, our observations indicate that the NICS(0) values for binary mixtures are generally lower than those of the individual pure solvents. This suggests a decrease in aromaticity when two solvents are mixed. The possible reason for this decrease is the presence of specific intermolecular interactions, such as hydrogen bonding or other non-covalent interactions, that alter the electronic environment of the aromatic ring.

      In particular, inter-hydrogen bonding appears to play a crucial role in modulating aromaticity within the mixtures. These interactions can lead to redistribution of electron density, thereby reducing the magnetic shielding experienced in the aromatic system, which manifests as a lower NICS(0) value. To further support this interpretation, we carried out AIM (Atoms in Molecules) analysis, which confirmed the presence and nature of these intermolecular interactions in the mixtures.

      2)The calculated NICS values were validated by comparison with literature data, ensuring that the observed trends match previously reported results, and by verifying consistency across computational methods, confirming that variations in the computational approach did not significantly affect the trends.

      Reply

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  • 13C hyperpolarized NMR by Dissolution-DNP enables snapshot detection of degradation products in lithium-ion battery electrolytes

    Chloé Gioiosa (CRMN Lyon, France)

    LinkedIn: @Chloé Gioiosa

    Abstract: Dissolution Dynamic Nuclear Polarization (dDNP) is a powerful hyperpolarization technique enabling tremendous sensitivity gains in solution nuclear magnetic resonance (NMR). Over the last decades, researchers’ efforts have led to an extension of dDNP applications in numerous research fields. Lithium-ion batteries are among the most widespread rechargeable batteries, and a proper understanding of the physicochemical reactions at stake inside them is paramount to make them safer, more efficient, and sustainable. One of the key challenges lies in better understanding and limiting the degradation of the battery electrolyte, which can significantly impact the battery’s performance. While NMR has been used in attempts to understand these mechanisms, notably by investigating the degradation products, the intrinsic lack of sensitivity of this technique, combined with the limited accessible volume of such compounds, makes its application often challenging. This work combines several state-of-the-art dDNP methodologies, including using recently introduced hyperpolarizing polymers (HYPOP) to acquire hyperpolarized 13C NMR spectra of degraded battery electrolytes. We show that we can successfully detect 13C signals on formulated battery electrolyte solutions in different degradation stages, on a 600 MHz spectrometer, with sensitivity gains of up to 3 orders of magnitude. This work paves the way for studying lithium-ion battery electrolyte degradation under usage conditions (cycling, thermal aging, air exposure…) with a 13C detection limit below the micromolar range. This methodology has the potential to provide new insights into degradation mechanisms and the role and effectiveness of additives to mitigate electrolyte degradation.

    1. KSHAMA SHARMA Avatar
      KSHAMA SHARMA

      Dear Chloe, I have 2 questions:
      1. Considering the transient nature of hyperpolarized states, what is the practical time window available for spectral acquisition? To what extent does this limit your ability to resolve and differentiate between various chemical species?
      2. In achieving the observed sensitivity enhancements, did you encounter any trade-offs in spectral resolution, such as line broadening, arising either from polarization transfer mechanisms or sample handling procedures?

      Reply
      1. Chloé Gioiosa Avatar
        Chloé Gioiosa

        Dear Kshama,

        1. If we consider the shortest T1 measured on the methyl moieties of the carbonates, which is of approximately 5 seconds, you have around 10 seconds to dissolve and acquire your 90° pulse while ensuring that you see most of the carbon signals, although there is a possibility that some signals might be missing if the T1 is very short. It has already happened that some fast relaxing nuclei were missing from the spectrum. However, the fast injection system still allows us to see signals with T1 in the order of the second, but with diminished enhancements (hence why we report enhancements ranging from 100 to 1000). We also control the magnetic field during the transfer with solenoids to avoid any polarization losses due to a sudden change in the magnetic field strength.

        2. We did. We had to trade off some sensitivity enhancements to achieve a satisfying resolution by adding a “resting time” to the sequence, allowing the solution to stabilize inside the tube prior to the start of acquisition. Here, the fwhm was measured to be 3.5 Hz, and our best reported value was 1.3 Hz. We also had to deal with a lack of repeatability in the injected volume due to the significant pressure drop caused by the addition of the filter, resulting in additional losses of resolution. We are currently working on finding the best compromise to acquire a resolved spectrum with maximzed enhancement, in a repeatable manner.

        Reply
        1. KSHAMA SHARMA Avatar
          KSHAMA SHARMA

          Thanks!

          Reply
    2. Raj Chaklashiya Avatar
      Raj Chaklashiya

      Nice Talk! One question I have is, how do polymers like HYPOP “preserve” the polarization within them for use in DNP? I find these materials to be very interesting and am wondering how they work and whether they are compatible with other radicals (e.g. metal-based radicals like Gd-DOTA).

      Reply
      1. Chloé Gioiosa Avatar
        Chloé Gioiosa

        Hello! Thank you for your question.

        In our case, the polymer is synthesized in a manner that allows the radicals (amino-TEMPO) to be grafted and incorporated within the polymer network. The polymer is therefore filled with radicals. Another important aspect is that it is a high-porosity polymer (up to 80%), which enables us to impregnate the polymer with the solution to hyperpolarize. Then, by shining microwaves on the impregnated powder, you can perform DNP in the same fashion as with a DNP juice.

        They can be synthesized with any radicals that :
        1. Contains a primary or secondary amine group
        2. Can survive at 100°C for 24h (curing process)

        If you want more details on the synthesis, you can go check this paper in which it is described : https://www.nature.com/articles/s41467-021-24279-2

        Reply
        1. Raj Chaklashiya Avatar
          Raj Chaklashiya

          Awesome, thanks!

          Reply

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  • What happens when a 1H of a methyl group is substituted by a 19F?

    Gottfried Otting (The Australian National University, Australia)

    Abstract: Fluorine is bigger than hydrogen and the C-F bond is longer than a C-H bond, but not by much. CF groups prefer hydrophobic environments (think of Teflon). 19F-spins provide site-specific probes easy to detect by 1D 19F-NMR. Using cell-free protein synthesis, we replaced all valine residues in the protein GB1 by fluorinated analogues with a 19F spin in either the CG1 methyl group, the CG2 methyl group or both. The 19F NMR signals were distributed over a large chemical shift range. The protein structure remains unchanged. While CH3 groups rotate rapidly, the CH2F groups preferentially populate different staggered rotamers. Transient contacts between different fluorinated valine residues are manifested by through-space 19F-19F couplings that are observed more easily than 19F-19F NOEs.

    1. Marco Schiavina Avatar
      Marco Schiavina

      Hello! An amazing work! Thanks for sharing.

      I have a couple of questions.
      1) this might be a bit naif but I was wondering: I can clearly appreciate 3 distinct peaks for the 19F-G1 spectrum as well as 4 peaks in the 19F-G2 spectrum. Thus I was expecting 8 peaks in the G1-G2 spectrum. Could you comment on the minor forms and on the relative intensities of the major form of this latter spectrum?
      2) You mentioned you were decoupling 1H during 19F acquisitions thus I am assuming you are using a QCI-19F probe (or something similar). If this is the case, did you try any 19F-1H correlation experiment?
      3) In the abstract you mention that the protein structure is unchanged upon incorporation of the 19F moiety. How did you prove it? Do you think this would be true even for a putative CF3 group?

      Thanks again!

      Reply
    2. Gottfried Otting Avatar
      Gottfried Otting

      good questions!
      1) Difluorovaline is not as easily accepted by the E. coli valyl-tRNA synthetase as monofluorovaline. Therefore, the tiny amounts of canonical valine present in the cell-free reaction mixture get used preferentially and some of the protein ends up with 3 difluorovalines and 1 valine. This species produces different 19F chemical shifts. Statistically, ~20% of each site contains valine instead of difluorovaline.
      2) We use a 400, where 19F is on the X-channel like all other non-1H nuclei. Indeed, to assign the 19F-NMR spectrum, we used 1H-19F correlation spectra.
      3) We assigned the 1H NMR spectra. The 1H chemical shifts and NOEs are conserved. Circular dichroism indicates that the melting temperature dropped by ~10 degrees. A CF3 group would perturb the structure more. More critically, it could be quite a challenge for the valyl-tRNA synthetase.

      Reply
    3. Nicolas Bolik-Coulon Avatar
      Nicolas Bolik-Coulon

      Hello,
      Very interesting and very nice presentation!
      Just a few questions:
      1) the g1,g2 1D spectrum looks quite different from a ‘visual sum’ of the g1 and g2 1D spectra. Are the CSPs arising from the presence of more 19F in the g1,g2 sample?
      2) Did you measure some proton relaxation rates? Relaxation in CH3 (and even more in CF3) methyl groups is quite tricky to analyze, but maybe just the magnitude of the decay would be quite informative on the increased rigidity of the CF3.

      Cheers

      Reply
    4. Gottfried Otting Avatar
      Gottfried Otting

      1) Indeed, the 19F chemical shifts depend very much on whether there is another fluorine nearby, either in the same amino acid residue or simply in another residue nearby! Based on 1H-1H NOEs and the appearance of Halpha-Hbeta COSY-cross-peaks (reflecting large or small 3J(Alpha,Hbeta) coupling constants), the fluorovaline side chains feature the same Chi1 angles as the valine residues in the wild-type protein. Using a 1H,19F-HOESY spectrum, we obtained stereospecific resonance assignments of the 19F spins in the difluorovaline residues. In 3 of the 4 difluorovaline residues, the relative 19F-chemical shifts (high-field or low-field) proved to be conserved between the samples made with singly fluorinated valines and the sample made with difluorovaline. (Subscripts in the FF-TOCSY spectrum indicate the stereospecific resonance assignments.)

      2) Interesting idea! No, we haven’t measured the 1H relaxation of the CH2F groups. (We worked only with CH2F groups, not with CF3 groups, in order to minimise structural perturbations.) Obviously, the 1H relaxation of CH2 groups is difficult to compare with the 1H relaxation of CH3 groups. In an attempt to find evidence for minor rotamer species of the CH2F groups that may be in slow exchange with other rotamers, we performed 19F-CPMG experiments. In the protein made with difluorovaline, only the gamma2-fluorine of residue 54 showed significantly slower relaxation (36 s-1) when we applied 180 degree pulses rapidly as opposed to applying a single refocusing 180 degree pulse (26 s-1). The CH2F group associated with this fluorine atom is right in the hydrophobic core of the protein and more solidly immobilized than the other CH2F groups, which is also demonstrated by a large 3J(1H,19F) coupling. None of the other 19F spins relaxed as quickly.

      Reply
    5. Gottfried Otting Avatar
      Gottfried Otting

      Oops, correction: 26 s-1 with CPMG, 36 s-1 with a single 180(19F) refocussing pulse.

      Reply
    6. Zainab Amin Avatar
      Zainab Amin

      Very nice presentation and really fascinating work. I have a somewhat naive question!
      Since the CH₂F groups preferentially populate distinct staggered rotamers and exhibit through-space ¹⁹F–¹⁹F couplings, have you explored whether these interactions might also reflect transient conformational states of the protein backbone, rather than being driven purely by side-chain rotamer preferences? And do you think this strategy could be extended to detect low-population backbone conformers that are often invisible to other NMR probes?

      Reply
    7. Gottfried Otting Avatar
      Gottfried Otting

      Good thought!
      GB1 is a very stable protein and the backbone atoms would not easily deviate far from their average conformations. Nonetheless, in previous work, we found that a through-space scalar 19F-19F coupling can be detected between the CF3 groups of two residues of N6-trifluoroacetyl-L-lysine (TFAK) installed 33 residues apart (one of the TFAK residues being at the C-terminus of a solvent-exposed, flexible polypeptide segment). This observation is interesting because, in this case, the fluorine-fluorine contacts would certainly be transient and infrequent: https://doi.org/10.1021/jacs.1c10104
      The big question is, whether a scheme can be designed that uses this effect to detect non-random conformational changes of backbone conformations? I fear that the chemistry may become prohibitive. For example, the alpha-hydrogen would be difficult to replace by fluorine. Furthermore, there would be no detectable scalar coupling, unless the fluorine atoms definitely (and repeatedly) make a contact with some orbital overlap.

      Reply

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