Publications by authors named "Anne Lesage"

159 Publications

Efficient Dynamic Nuclear Polarization up to 230 K with Hybrid BDPA-Nitroxide Radicals at a High Magnetic Field.

J Phys Chem B 2021 Nov 24. Epub 2021 Nov 24.

Centre de RMN à Très Hauts Champs, Université de Lyon (CNRS/ENS Lyon/UCBL), 69100 Villeurbanne, France.

Pairing the spectral resolution provided by high magnetic fields at ambient temperature with the enhanced sensitivity offered by dynamic nuclear polarization (DNP) is a major goal of modern solid-state NMR spectroscopy, which will allow one to unlock ever-challenging applications. This study demonstrates that, by combining HyTEK2, a hybrid BDPA-nitroxide biradical polarizing agent, with -terphenyl (OTP), a rigid DNP matrix, enhancement factors as high as 65 can be obtained at 230 K, 40 kHz magic angle spinning (MAS), and 18.8 T. The temperature dependence of the DNP enhancement and its behavior around the glass transition temperature () of the matrix is investigated by variable-temperature EPR measurements of the electron relaxation properties and numerical simulations. A correlation is suggested between the decrease in enhancement at the passage of the and the concomitant drop of both transverse electron relaxation times in the biradical.
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http://dx.doi.org/10.1021/acs.jpcb.1c07307DOI Listing
November 2021

Spectroscopic Signature and Structure of the Active Sites in Ziegler-Natta Polymerization Catalysts Revealed by Electron Paramagnetic Resonance.

J Am Chem Soc 2021 Jul 25;143(26):9791-9797. Epub 2021 Jun 25.

Department of Chemistry and Applied Biosciences, ETH Zurich, Wolfgang-Pauli-Strasse 1-5, 8093 Zurich, Switzerland.

Despite decades of extensive studies, the atomic-scale structure of the active sites in heterogeneous Ziegler-Natta (ZN) catalysts, one of the most important processes of the chemical industry, remains elusive and a matter of debate. In the present work, the structure of active sites of ZN catalysts in the absence of ethylene, referred to as dormant active sites, is elucidated from magnetic resonance experiments carried out on samples reacted with increasing amounts of BCl so as to enhance the concentration of active sites and observe clear spectroscopic signatures. Using electron paramagnetic resonance (EPR) and NMR spectroscopies, in particular 2D HYSCORE experiments complemented by density functional theory (DFT) calculations, we show that the activated ZN catalysts contain bimetallic alkyl-Ti(III),Al species whose amount is directly linked to the polymerization activity of MgCl-supported Ziegler-Natta catalysts. This connects those spectroscopic signatures to the active species formed in the presence of ethylene and enables us to propose an ethylene polymerization mechanism on the observed bimetallic alkyl-Ti(III),Al species based on DFT computations.
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http://dx.doi.org/10.1021/jacs.1c02818DOI Listing
July 2021

Structural Analysis of an Antigen Chemically Coupled on Virus-Like Particles in Vaccine Formulation.

Angew Chem Int Ed Engl 2021 06 5;60(23):12847-12851. Epub 2021 May 5.

Centre de RMN à Très Hauts Champs de Lyon-UMR 5082 (CNRS, ENS Lyon, UCB Lyon 1), Université de Lyon, 69100, Villeurbanne, France.

Structure determination of adjuvant-coupled antigens is essential for rational vaccine development but has so far been hampered by the relatively low antigen content in vaccine formulations and by their heterogeneous composition. Here we show that magic-angle spinning (MAS) solid-state NMR can be used to assess the structure of the influenza virus hemagglutinin stalk long alpha helix antigen, both in its free, unformulated form and once chemically coupled to the surface of large virus-like particles (VLPs). The sensitivity boost provided by high-field dynamic nuclear polarization (DNP) and proton detection at fast MAS rates allows to overcome the penalty associated with the antigen dilution. Comparison of the MAS NMR fingerprints between the free and VLP-coupled forms of the antigen provides structural evidence of the conservation of its native fold upon bioconjugation. This work demonstrates that high-sensitivity MAS NMR is ripe to play a major role in vaccine design, formulation studies, and manufacturing process development.
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http://dx.doi.org/10.1002/anie.202013189DOI Listing
June 2021

Two-Photon Absorbing AIEgens: Influence of Stereoconfiguration on Their Crystallinity and Spectroscopic Properties and Applications in Bioimaging.

ACS Appl Mater Interfaces 2020 Dec 20;12(49):55157-55168. Epub 2020 Nov 20.

Univ. Lyon, ENS Lyon, CNRS, Université Lyon 1, Laboratoire de Chimie, UMR 5182, 46 Allée d'Italie, 69364 Lyon, France.

This paper aims at designing chromophores with efficient aggregation-induced emission (AIE) properties for two-photon fluorescence microscopy (2PFM), which is one of the best-suited types of microscopy for the imaging of living organisms or thick biological tissues. Tetraphenylethylene (TPE) derivatives are common building blocks in the design of chromophores with efficient AIE properties. Therefore, in this study, extended TPE AIEgens specifically optimized for two-photon absorption (2PA) are synthesized and the resulting (/) isomers are separated using chromatography on chiral supports. Comparative characterization of the AIE properties is performed on the pure () and () isomers and the mixture, allowing us, in combination with powder X-ray diffraction and solid-state NMR, to document a profound impact of crystallinity on solid-state fluorescence properties. In particular, we show that stereopure AIEgens form aggregates of superior crystallinity, which in turn exhibit a higher fluorescence quantum yield compared to diastereoisomers mixtures. Preparation of stereopure organic nanoparticles affords very bright fluorescent contrast agents, which are then used for cellular and intravital two-photon microscopy on human breast cancer cells and on zebrafish embryos.
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http://dx.doi.org/10.1021/acsami.0c15810DOI Listing
December 2020

The Structure of Molecular and Surface Platinum Sites Determined by DNP-SENS and Fast MAS Pt Solid-State NMR Spectroscopy.

J Am Chem Soc 2020 11 22;142(44):18936-18945. Epub 2020 Oct 22.

Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States.

The molecular level characterization of heterogeneous catalysts is challenging due to the low concentration of surface sites and the lack of techniques that can selectively probe the surface of a heterogeneous material. Here, we report the joint application of room temperature proton-detected NMR spectroscopy under fast magic angle spinning (MAS) and dynamic nuclear polarization surface enhanced NMR spectroscopy (DNP-SENS), to obtain the Pt solid-state NMR spectra of a prototypical example of highly dispersed Pt sites (single site or single atom), here prepared via surface organometallic chemistry, by grafting [(COD)Pt(OSi(OBu))] (, COD = 1,5-cyclooctadiene) on partially dehydroxylated silica (). Compound has a Pt loading of 3.7 wt %, a surface area of 200 m/g, and a surface Pt density of around 0.6 Pt site/nm. Fast MAS H{Pt} dipolar-HMQC and S-REDOR experiments were implemented on both the molecular precursor and on the surface complex , providing access to Pt isotropic shifts and Pt-H distances, respectively. For , the measured isotropic shift and width of the shift distribution constrain fits of the static wide-line DNP-enhanced Pt spectrum, allowing the Pt chemical shift tensor parameters to be determined. Overall the NMR data provide evidence for a well-defined, single-site structure of the isolated Pt sites.
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http://dx.doi.org/10.1021/jacs.0c09101DOI Listing
November 2020

Open and Closed Radicals: Local Geometry around Unpaired Electrons Governs Magic-Angle Spinning Dynamic Nuclear Polarization Performance.

J Am Chem Soc 2020 09 16;142(39):16587-16599. Epub 2020 Sep 16.

Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.

The development of magic-angle spinning dynamic nuclear polarization (MAS DNP) has allowed atomic-level characterization of materials for which conventional solid-state NMR is impractical due to the lack of sensitivity. The rapid progress of MAS DNP has been largely enabled through the understanding of rational design concepts for more efficient polarizing agents (PAs). Here, we identify a new design principle which has so far been overlooked. We find that the local geometry around the unpaired electron can change the DNP enhancement by an order of magnitude for two otherwise identical conformers. We present a set of 13 new stable mono- and dinitroxide PAs for MAS DNP NMR where this principle is demonstrated. The radicals are divided into two groups of isomers, named open (O-) and closed (C-), based on the ring conformations in the vicinity of the N-O bond. In all cases, the open conformers exhibit dramatically improved DNP performance as compared to the closed counterparts. In particular, a new urea-based biradical named HydrOPol and a mononitroxide O-MbPyTol yield enhancements of 330 ± 60 and 119 ± 25, respectively, at 9.4 T and 100 K, which are the highest enhancements reported so far in the aqueous solvents used here. We find that while the conformational changes do not significantly affect electron spin-spin distances, they do affect the distribution of the exchange couplings in these biradicals. Electron spin echo envelope modulation (ESEEM) experiments suggest that the improved performance of the open conformers is correlated with higher solvent accessibility.
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http://dx.doi.org/10.1021/jacs.0c04911DOI Listing
September 2020

Pharmacological Profile of a New Small Molecule Bradykinin B Receptor Antagonist.

Front Pharmacol 2020 19;11:916. Epub 2020 Jun 19.

Pharvaris Netherlands B.V., Leiden, Netherlands.

We here report the discovery and early characterization of Compound 3, a representative of a novel class of small molecule bradykinin (BK) B receptor antagonists, and its superior profile to the prior art B receptor antagonists Compound 1 and Compound 2. Compound 3, Compound 2, and Compound 1 are highly potent antagonists of the human recombinant B receptor (K values 0.24, 0.95, and 1.24 nM, respectively, calcium mobilization assay). Compound 3 is more potent than the prior art compounds and icatibant in this assay (K icatibant 2.81 nM). The compounds also potently inhibit BK-induced contraction of endogenous B receptors in a human isolated umbilical vein bioassay. The potencies of Compound 3, Compound 2, Compound 1, and icatibant are (pA values) 9.67, 9.02, 8.58, and 8.06 (i.e. 0.21, 0.95, 2.63, and 8.71 nM), respectively. Compound 3 and Compound 2 were further characterized. They inhibit BK-induced c-Fos signaling and internalization of recombinant human B receptors in HEK293 cells, and do not antagonize the venous effects mediated by other G protein-coupled receptors in the umbilical vein model, including the bradykinin B receptor. Antagonist potency of Compound 3 at cloned cynomolgus monkey, dog, rat, and mouse B receptors revealed species selectivity, with a high antagonist potency for human and monkey B receptors, but several hundred-fold lower potency for the other B receptors. The off-target profile of Compound 3 demonstrates a high degree of selectivity over a wide range of molecular targets, including the bradykinin B receptor. Compound 3 showed a lower intrinsic clearance in the microsomal stability assay than the prior art compounds. With an efflux ratio of 1.0 in the Caco-2 permeability assay Compound 3 is predicted to be not a substrate of efflux pumps. In conclusion, we discovered a novel chemical class of highly selective and very potent B receptor antagonists, as exemplified by Compound 3. The compound showed excellent absorption in the Caco-2 assay, predictive of good oral bioavailability, and favourable metabolic stability in liver microsomes. Compound 3 has provided a significant stepping stone towards the discovery of the orally bioavailable B antagonist PHA-022121, currently in phase 1 clinical development.
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http://dx.doi.org/10.3389/fphar.2020.00916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316994PMC
June 2020

Silica-Grafted Tris(neopentyl)aluminum: A Monomeric Aluminum Solid Co-catalyst for Efficient Nickel-Catalyzed Ethene Dimerization.

Angew Chem Int Ed Engl 2020 Sep 29;59(37):16167-16172. Epub 2020 Jun 29.

Department of Chemistry and Applied Biosciences, ETH Zürich, Vladimir-Prelog-Weg 1-5, 8093, Zürich, Switzerland.

A silica-supported monomeric alkylaluminum co-catalyst was prepared via surface organometallic chemistry by contacting tris(neopentyl)aluminum and partially dehydroxylated silica. This system, fully characterized by solid-state Al NMR spectroscopy augmented by computational studies, efficiently activates ( Bu P) NiCl towards dimerization of ethene, demonstrating comparable activity to previously reported dimeric diethylaluminum chloride supported on silica. Three types of aluminum surface species have been identified: monografted tetracoordinated Al species as well as two types of bisgrafted Al species-tetra- and pentacoordinated. Of them, only the monografted Al species is proposed to be able to activate the ( Bu P) NiCl complex and generate the active cationic species.
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http://dx.doi.org/10.1002/anie.202006285DOI Listing
September 2020

Atomic-Scale Description of Interfaces between Antigen and Aluminum-Based Adjuvants Used in Vaccines by Dynamic Nuclear Polarization (DNP) Enhanced NMR Spectroscopy.

Chemistry 2020 Jul 8;26(41):8976-8982. Epub 2020 Jul 8.

Centre de résonance magnétique à très hauts champs (CRMN), FRE 2034 CNRS, Université Claude Bernard Lyon-1, ENS-Lyon, 5 rue de la Doua, 69100, Villeurbanne, France.

The addition of aluminum-based adjuvants in vaccines enhances the immune response to antigens. The strength of antigen adsorption on adjuvant gels is known to modulate vaccine efficacy. However, a detailed understanding of the mechanisms of interaction between aluminum gels and antigens is still missing. Herein, a new analytical approach based on dynamic nuclear polarization (DNP) enhanced NMR spectroscopy under magic angle spinning (MAS) is implemented to provide a molecular description of the antigen-adjuvant interface. This approach is demonstrated on hepatitis B surface antigen particles in combination with three aluminum gels obtained from different suppliers. Both noncovalent and covalent interactions between the phospholipids of the antigen particles and the surface of the aluminum gels are identified by using MAS DNP NMR Al and P correlation experiments. Although covalent interactions were detected for only one of the formulations, dipolar recoupling rotational echo adiabatic passage double resonance (REAPDOR) experiments reveal significant differences in the strength of weak interactions.
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http://dx.doi.org/10.1002/chem.202001141DOI Listing
July 2020

TinyPols: a family of water-soluble binitroxides tailored for dynamic nuclear polarization enhanced NMR spectroscopy at 18.8 and 21.1 T.

Chem Sci 2020 Feb 5;11(10):2810-2818. Epub 2020 Feb 5.

Centre de RMN à; Très Hauts Champs, Université; de Lyon (CNRS/ENS Lyon/UCB Lyon 1) 69100 Villeurbanne France

Dynamic Nuclear Polarization (DNP) has recently emerged as a key method to increase the sensitivity of solid-state NMR spectroscopy under Magic Angle Spinning (MAS). While efficient binitroxide polarizing agents such as AMUPol have been developed for MAS DNP NMR at magnetic fields up to 9.4 T, their performance drops rapidly at higher fields due to the unfavorable field dependence of the cross-effect (CE) mechanism and AMUPol-like radicals were so far disregarded in the context of the development of polarizing agents for very high-field DNP. Here, we introduce a new family of water-soluble binitroxides, dubbed TinyPols, which have a three-bond non-conjugated flexible amine linker allowing sizable couplings between the two unpaired electrons. We show that this adjustment of the linker is crucial and leads to unexpectedly high DNP enhancement factors at 18.8 T and 21.1 T: an improvement of about a factor 2 compared to AMUPol is reported for spinning frequencies ranging from 5 to 40 kHz, with of up to 90 at 18.8 T and 38 at 21.1 T for the best radical in this series, which are the highest MAS DNP enhancements measured so far in aqueous solutions at these magnetic fields. This work not only breathes a new momentum into the design of binitroxides tailored towards high magnetic fields, but also is expected to push the application frontiers of high-resolution DNP MAS NMR, as demonstrated here on a hybrid mesostructured silica material.
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http://dx.doi.org/10.1039/c9sc05384kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157490PMC
February 2020

Metal-Metal Synergy in Well-Defined Surface Tantalum-Iridium Heterobimetallic Catalysts for H/D Exchange Reactions.

J Am Chem Soc 2019 Dec 25;141(49):19321-19335. Epub 2019 Nov 25.

Laboratory of Chemistry, Catalysis, Polymers and Processes, C2P2 UMR 5265, Institut de Chimie de Lyon, CNRS, UCB Lyon 1 , Université de Lyon , ESCPE Lyon, 43 Bd du 11 Novembre 1918 , F-69616 Villeurbanne , France.

A novel heterobimetallic tantalum/iridium hydrido complex, [{Ta(CHBu)}{IrH(Cp*)}] , featuring a very short metal-metal bond, has been isolated through an original alkane elimination route from Ta(CHBu)(CHBu) and Cp*IrH. This molecular precursor has been used to synthesize well-defined silica-supported low-coordinate heterobimetallic hydrido species [≡SiOTa(CHBu){IrH(Cp*)}], , and [≡SiOTa(CHBu)H{IrH(Cp*)}], , using a surface organometallic chemistry (SOMC) approach. The SOMC methodology prevents undesired dimerization as encountered in solution and leading to a tetranuclear species [{Ta(CHBu)}(Cp*IrH)], . This approach therefore allows access to unique low-coordinate species not attainable in solution. These original supported Ta/Ir species exhibit drastically enhanced catalytic performances in H/D exchange reactions with respect to (i) monometallic analogues as well as (ii) homogeneous systems. In particular, material promotes the H/D exchange between fluorobenzene and CD or D as deuterium sources with excellent productivity (TON up to 1422; TOF up to 23.3 h) under mild conditions (25 °C, sub-atmospheric D pressure) without any additives.
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http://dx.doi.org/10.1021/jacs.9b08311DOI Listing
December 2019

Structural description of surfaces and interfaces in biominerals by DNP SENS.

Solid State Nucl Magn Reson 2019 10 11;102:2-11. Epub 2019 Jun 11.

High Field NMR Center of Lyon, CRNS/ENS Lyon/ UCB Lyon, 5 rue de la Doua, 69100, Villeurbanne, France.

Biological mineralized tissues are hybrid materials with complex hierarchical architecture composed of biominerals often embedded in an organic matrix. The atomic-scale comprehension of surfaces and organo-mineral interfaces of these biominerals is of paramount importance to understand the ultrastructure, the formation mechanisms as well as the biological functions of the related biomineralized tissue. In this communication we demonstrate the capability of DNP SENS to reveal the fine atomic structure of biominerals, and more specifically their surfaces and interfaces. For this purpose, we studied two key examples belonging to the most significant biominerals family in nature: apatite in bone and aragonite in nacreous shell. As a result, we demonstrate that DNP SENS is a powerful approach for the study of intact biomineralized tissues. Signal enhancement factors are found to be up to 40 and 100, for the organic and the inorganic fractions, respectively, as soon as impregnation time with the radical solution is long enough (between 12 and 24 h) to allow an efficient radical penetration into the calcified tissues. Moreover, ions located at the biomineral surface are readily detected and identified through P or C HETCOR DNP SENS experiments. Noticeably, we show that protonated anions are preponderant at the biomineral surfaces in the form of HPO for bone apatite and HCO for nacreous aragonite. Finally, we demonstrate that organo-mineral interactions can be probed at the atomic level with high sensitivity. In particular, reliable C-{P} REDOR experiments are achieved in a few hours, leading to the determination of distances, molar proportion and binding mode of citrate bonded to bone mineral in native compact bone. According to our results, only 80% of the total amount of citrate in bone is directly interacting with bone apatite through two out of three carboxylic groups.
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http://dx.doi.org/10.1016/j.ssnmr.2019.06.001DOI Listing
October 2019

Dynamic Nuclear Polarization Magic-Angle Spinning Nuclear Magnetic Resonance Combined with Molecular Dynamics Simulations Permits Detection of Order and Disorder in Viral Assemblies.

J Phys Chem B 2019 06 11;123(24):5048-5058. Epub 2019 Jun 11.

Department of Chemistry and Biochemistry , University of Delaware , Newark , Delaware 19716 , United States.

We report dynamic nuclear polarization (DNP)-enhanced magic-angle spinning (MAS) NMR spectroscopy in viral capsids from HIV-1 and bacteriophage AP205. Viruses regulate their life cycles and infectivity through modulation of their structures and dynamics. While static structures of capsids from several viruses are now accessible with near-atomic-level resolution, atomic-level understanding of functionally important motions in assembled capsids is lacking. We observed up to 64-fold signal enhancements by DNP, which permitted in-depth analysis of these assemblies. For the HIV-1 CA assemblies, a remarkably high spectral resolution in the 3D and 2D heteronuclear data sets permitted the assignment of a significant fraction of backbone and side-chain resonances. Using an integrated DNP MAS NMR and molecular dynamics (MD) simulation approach, the conformational space sampled by the assembled capsid at cryogenic temperatures was mapped. Qualitatively, a remarkable agreement was observed for the experimental C/N chemical shift distributions and those calculated from substructures along the MD trajectory. Residues that are mobile at physiological temperatures are frozen out in multiple conformers at cryogenic conditions, resulting in broad experimental and calculated chemical shift distributions. Overall, our results suggest that DNP MAS NMR measurements in combination with MD simulations facilitate a thorough understanding of the dynamic signatures of viral capsids.
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http://dx.doi.org/10.1021/acs.jpcb.9b02293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767624PMC
June 2019

F Magic Angle Spinning Dynamic Nuclear Polarization Enhanced NMR Spectroscopy.

Angew Chem Int Ed Engl 2019 05 23;58(22):7249-7253. Epub 2019 Apr 23.

Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015, Lausanne, Switzerland.

The introduction of high-frequency, high-power microwave sources, tailored biradicals, and low-temperature magic angle spinning (MAS) probes has led to a rapid development of hyperpolarization strategies for solids and frozen solutions, leading to large gains in NMR sensitivity. Here, we introduce a protocol for efficient hyperpolarization of F nuclei in MAS DNP enhanced NMR spectroscopy. We identified trifluoroethanol-d as a versatile glassy matrix and show that 12 mm AMUPol (with microcrystalline KBr) provides direct F DNP enhancements of over 100 at 9.4 T. We applied this protocol to obtain DNP-enhanced F and F- C cross-polarization (CP) spectra for an active pharmaceutical ingredient and a fluorinated mesostructured hybrid material, using incipient wetness impregnation, with enhancements of approximately 25 and 10 in the bulk solid, respectively. This strategy is a general and straightforward method for obtaining enhanced F MAS spectra from fluorinated materials.
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http://dx.doi.org/10.1002/anie.201814416DOI Listing
May 2019

One- and Two-Dimensional High-Resolution NMR from Flat Surfaces.

ACS Cent Sci 2019 Mar 11;5(3):515-523. Epub 2019 Feb 11.

Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.

Determining atomic-level characteristics of molecules on two-dimensional surfaces is one of the fundamental challenges in chemistry. High-resolution nuclear magnetic resonance (NMR) could deliver rich structural information, but its application to two-dimensional materials has been prevented by intrinsically low sensitivity. Here we obtain high-resolution one- and two-dimensional P NMR spectra from as little as 160 picomoles of oligonucleotide functionalities deposited onto silicate glass and sapphire wafers. This is enabled by a factor >10 improvement in sensitivity compared to typical NMR approaches from combining dynamic nuclear polarization methods, multiple-echo acquisition, and optimized sample formulation. We demonstrate that, with this ultrahigh NMR sensitivity, P NMR can be used to observe DNA bound to miRNA, to sense conformational changes due to ion binding, and to follow photochemical degradation reactions.
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http://dx.doi.org/10.1021/acscentsci.8b00916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439530PMC
March 2019

Preferential Siting of Aluminum Heteroatoms in the Zeolite Catalyst Al-SSZ-70.

Angew Chem Int Ed Engl 2019 May 26;58(19):6255-6259. Epub 2019 Mar 26.

Department of Chemical Engineering, University of California, Santa Barbara, CA, 93106, USA.

The adsorption and reaction properties of heterogeneous zeolite catalysts (e.g. for catalytic cracking of petroleum, partial oxidation of natural gas) depend strongly on the types and distributions of Al heteroatoms in the aluminosilicate frameworks. The origins of these properties have been challenging to discern, owing in part to the structural complexity of aluminosilicate zeolites. Herein, combined solid-state NMR and synchrotron X-ray powder diffraction analyses show the Al atoms locate preferentially in certain framework sites in the zeolite catalyst Al-SSZ-70. Through-covalent-bond 2D Al{ Si} J-correlation NMR spectra allow distinct framework Al sites to be identified and their relative occupancies quantified. The analyses show that 94 % of the Al atoms are located at the surfaces of the large-pore interlayer channels of Al-SSZ-70, while only 6 % are in the sub-nm intralayer channels. The selective siting of Al atoms accounts for the reaction properties of catalysts derived from SSZ-70.
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http://dx.doi.org/10.1002/anie.201813533DOI Listing
May 2019

Supported Ru olefin metathesis catalysts via a thiolate tether.

Dalton Trans 2019 Feb;48(9):2886-2890

University of Lyon, Institute of Chemistry of Lyon, Laboratory C2P2 UMR 5265-CNRS-University Lyon 1-CPE Lyon, 43 Bd du 11 Novembre 1918, 69616 Villeurbanne, France.

Thiolate-coordinated ruthenium alkylidene complexes can give high Z-selectivity and stereoretentivity in olefin metathesis. To investigate their applicability as heterogeneous catalysts, we have successfully developed a methodology to easily immobilize prototype ruthenium alkylidenes onto hybrid mesostructured silica via a thiolate tether. In contrast, the preparation of the corresponding molecular complexes appeared very challenging in solution. These prototype supported complexes contain small thiolates but still, they are slightly more Z-selective than their molecular analogues. These results open the door to more active and selective heterogeneous catalysts by supporting more advanced thiolate Ru-complexes.
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http://dx.doi.org/10.1039/c8dt04592eDOI Listing
February 2019

DNP NMR of biomolecular assemblies.

J Struct Biol 2019 04 29;206(1):90-98. Epub 2018 Sep 29.

Centre de RMN à Très Hauts Champs, Institut des Sciences Analytiques (UMR 5280 - CNRS, ENS Lyon, UCB Lyon 1), Université de Lyon, 5 rue de la Doua, 69100 Villeurbanne, France.

Dynamic Nuclear Polarization (DNP) is an effective approach to alleviate the inherently low sensitivity of solid-state NMR (ssNMR) under magic angle spinning (MAS) towards large-sized multi-domain complexes and assemblies. DNP relies on a polarization transfer at cryogenic temperatures from unpaired electrons to adjacent nuclei upon continuous microwave irradiation. This is usually made possible via the addition in the sample of a polarizing agent. The first pioneering experiments on biomolecular assemblies were reported in the early 2000s on bacteriophages and membrane proteins. Since then, DNP has experienced tremendous advances, with the development of extremely efficient polarizing agents or with the introduction of new microwaves sources, suitable for NMR experiments at very high magnetic fields (currently up to 900 MHz). After a brief introduction, several experimental aspects of DNP enhanced NMR spectroscopy applied to biomolecular assemblies are discussed. Recent demonstration experiments of the method on viral capsids, the type III and IV bacterial secretion systems, ribosome and membrane proteins are then described.
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http://dx.doi.org/10.1016/j.jsb.2018.09.011DOI Listing
April 2019

BDPA-Nitroxide Biradicals Tailored for Efficient Dynamic Nuclear Polarization Enhanced Solid-State NMR at Magnetic Fields up to 21.1 T.

J Am Chem Soc 2018 Oct 5;140(41):13340-13349. Epub 2018 Oct 5.

AixMarseille Univ, CNRS, ICR , 13013 Marseille , France.

Dynamic nuclear polarization (DNP) solid-state nuclear magnetic resonance (NMR) has developed into an invaluable tool for the investigation of a wide range of materials. However, the sensitivity gain achieved with many polarizing agents suffers from an unfavorable field and magic angle spinning (MAS) frequency dependence. We present a series of new hybrid biradicals, soluble in organic solvents, that consist of an isotropic narrow electron paramagnetic resonance line radical, α,γ-bisdiphenylene-β-phenylallyl (BDPA), tethered to a broad line nitroxide. By tuning the distance between the two electrons and the substituents at the nitroxide moiety, correlations between the electron-electron interactions and the electron spin relaxation times on one hand and the DNP enhancement factors on the other hand are established. The best radical in this series has a short methylene linker and bears bulky phenyl spirocyclohexyl ligands. In a 1.3 mm prototype DNP probe, it yields enhancements of up to 185 at 18.8 T (800 MHz H resonance frequency) and 40 kHz MAS. We show that this radical gives enhancement factors of over 60 in 3.2 mm sapphire rotors at both 18.8 and 21.1 T (900 MHz H resonance frequency), the highest magnetic field available today for DNP. The effect of the rotor size and of the microwave irradiation inside the MAS rotor is discussed. Finally, we demonstrate the potential of this new series of polarizing agents by recording high field Al and Si DNP surface enhanced NMR spectra of amorphous aluminosilicates and O NMR on silica nanoparticles.
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http://dx.doi.org/10.1021/jacs.8b08081DOI Listing
October 2018

Determinants of high-grade anal intraepithelial lesions in HIV-positive MSM.

AIDS 2018 10;32(16):2363-2371

Service de Proctologie Médico-Interventionnelle, Groupe Hospitalier Diaconesses Croix-Saint-Simon.

Objective: To assess determinants for histologically proven high-grade anal intraepithelial lesions (hHSIL) in HIV-positive men who have sex with men (MSM), a population at high-risk of HPV-related anal cancer.

Design: APACHES is a prospective study of anal HPV and related-lesions in 513 HIV-positive MSM aged at least 35 years in six centres across France.

Methods: At baseline, participants underwent high-resolution anoscopy (HRA) with biopsy of suspicious lesions, preceded by anal swabs for liquid-based cytology, p16/Ki67 immunostaining, and HPV DNA. hHSIL diagnosis was established by histopathological review panel consensus, and determinants assessed by logistic regression.

Results: Baseline hHSIL prevalence was 10.4% and did not differ significantly by age, sexual behaviour or HIV/immunodeficiency markers. hHSIL prevalence was significantly elevated in participants who smoked (ORadj = 2.6, 95% CI 1.3-5.5) or who, in concurrent anal swabs, had ASCUS/LSIL (3.6, 95% CI 1.4-9.3) or ASC-H/HSIL (22.2, 95% CI 6.8-72.6) cytologic abnormalities, p16/Ki67 dual positivity (3.4, 95% CI 1.5-7.5), or non-HPV16 HR (13.0, 95% CI 1.7-102), but most notably, HPV16 (46.3, 95% CI 6.1-355) infection. Previous diagnosis of low-grade (2.3, 95% CI 1.0-5.4) or high-grade (3.8, 95% CI 1.5-9.9) anal lesion also conveyed higher hHSIL risk. After controlling for patient-specific determinants, there remained significant centre-specific effects, most clearly in higher risk groups (HPV16-positive participants: 31.3% hHSIL in centres A-D versus 5.1% in centres E and F, P < 0.01).

Conclusion: Anal cytology and HPV16 infection are potentially useful determinants of hHSIL risk in HIV-positive MSM, but HIV/immunodeficiency-related variables appear not to be. Controlling for patient-specific hHSIL determinants highlights variability in HRA practice across diverse clinical settings and the need for better standardization of this difficult procedure.
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http://dx.doi.org/10.1097/QAD.0000000000001947DOI Listing
October 2018

Predicting the DNP-SENS efficiency in reactive heterogeneous catalysts from hydrophilicity.

Chem Sci 2018 Jun 30;9(21):4866-4872. Epub 2018 Apr 30.

King Abdullah University of Science and Technology (KAUST) , KAUST Catalysis Center (KCC) , Thuwal , 23955-6900 , Saudi Arabia . Email:

Identification of surfaces at the molecular level has benefited from progress in dynamic nuclear polarization surface enhanced NMR spectroscopy (DNP SENS). However, the technique is limited when using highly sensitive heterogeneous catalysts due to secondary reaction of surface organometallic fragments (SOMFs) with stable radical polarization agents. Here, we observe that in non-porous silica nanoparticles (NPs) ( = 15 nm) some DNP enhanced NMR or SENS characterizations are possible, depending on the metal-loading of the SOMF and the type of SOMF substituents (methyl, isobutyl, neopentyl). This unexpected observation suggests that aggregation of the nanoparticles occurs in non-polar solvents (such as -dichlorobenzene) leading to (partial) protection of the SOMF inside the interparticle space, thereby preventing reaction with bulky polarization agents. We discover that the DNP SENS efficiency is correlated with the hydrophilicity of the SOMF/support, which depends on the carbon and SOMF concentration. Nitrogen sorption measurements to determine the BET constant () were performed. This constant allows us to predict the aggregation of silica nanoparticles and consequently the efficiency of DNP SENS. Under optimal conditions, > 60, we found signal enhancement factors of up to 30.
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http://dx.doi.org/10.1039/c8sc00532jDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5982197PMC
June 2018

Refocused linewidths less than 10 Hz in H solid-state NMR.

J Magn Reson 2018 08 2;293:41-46. Epub 2018 Jun 2.

Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland. Electronic address:

Coherence lifetimes in homonuclear dipolar decoupled H solid-state NMR experiments are usually on the order of a few ms. We discover an oscillation that limits the lifetime of the coherences by recording spin-echo dephasing curves. We find that this oscillation can be removed by the application of a double spin-echo experiment, leading to coherence lifetimes of more than 45 ms in adamantane and more that 22 ms in β-AspAla, corresponding to refocused linewidths of less than 7 and 14 Hz respectively.
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http://dx.doi.org/10.1016/j.jmr.2018.06.001DOI Listing
August 2018

Dynamic Nuclear Polarization-Enhanced Biomolecular NMR Spectroscopy at High Magnetic Field with Fast Magic-Angle Spinning.

Angew Chem Int Ed Engl 2018 06 27;57(25):7458-7462. Epub 2018 Apr 27.

Univ Lyon, CNRS, Université Claude Bernard Lyon 1, Ens Lyon, Institut des Sciences Analytiques, UMR 5280, 5 rue de la Doua, F-69100, VILLEURBANNE, France.

Dynamic nuclear polarization (DNP) is a powerful way to overcome the sensitivity limitation of magic-angle-spinning (MAS) NMR experiments. However, the resolution of the DNP NMR spectra of proteins is compromised by severe line broadening associated with the necessity to perform experiments at cryogenic temperatures and in the presence of paramagnetic radicals. High-quality DNP-enhanced NMR spectra of the Acinetobacter phage 205 (AP205) nucleocapsid can be obtained by combining high magnetic field (800 MHz) and fast MAS (40 kHz). These conditions yield enhanced resolution and long coherence lifetimes allowing the acquisition of resolved 2D correlation spectra and of previously unfeasible scalar-based experiments. This enables the assignment of aromatic resonances of the AP205 coat protein and its packaged RNA, as well as the detection of long-range contacts, which are not observed at room temperature, opening new possibilities for structure determination.
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http://dx.doi.org/10.1002/anie.201801016DOI Listing
June 2018

Expanding the horizons for structural analysis of fully protonated protein assemblies by NMR spectroscopy at MAS frequencies above 100 kHz.

Solid State Nucl Magn Reson 2017 10 3;87:117-125. Epub 2017 Jul 3.

Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, United States; Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States. Electronic address:

The recent breakthroughs in NMR probe technologies resulted in the development of MAS NMR probes with rotation frequencies exceeding 100 kHz. Herein, we explore dramatic increases in sensitivity and resolution observed at MAS frequencies of 110-111 kHz in a novel 0.7 mm HCND probe that enable structural analysis of fully protonated biological systems. Proton- detected 2D and 3D correlation spectroscopy under such conditions requires only 0.1-0.5 mg of sample and a fraction of time compared to conventional C-detected experiments. We discuss the performance of several proton- and heteronuclear- (C-,N-) based correlation experiments in terms of sensitivity and resolution, using a model microcrystalline fMLF tripeptide. We demonstrate the applications of ultrafast MAS to a large, fully protonated protein assembly of the 231-residue HIV-1 CA capsid protein. Resonance assignments of protons and heteronuclei, as well as H-N dipolar and H CSA tensors are readily obtained from the high sensitivity and resolution proton-detected 3D experiments. The approach demonstrated here is expected to enable the determination of atomic-resolution structures of large protein assemblies, inaccessible by current methodologies.
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http://dx.doi.org/10.1016/j.ssnmr.2017.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824719PMC
October 2017

Dynamic Nuclear Polarization Efficiency Increased by Very Fast Magic Angle Spinning.

J Am Chem Soc 2017 08 27;139(31):10609-10612. Epub 2017 Jul 27.

Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne , CH-1015 Lausanne, Switzerland.

Dynamic nuclear polarization (DNP) has recently emerged as a tool to enhance the sensitivity of solid-state NMR experiments. However, so far high enhancements (>100) are limited to relatively low magnetic fields, and DNP at fields higher than 9.4 T significantly drops in efficiency. Here we report solid-state Overhauser effect DNP enhancements of over 100 at 18.8 T. This is achieved through the unexpected discovery that enhancements increase rapidly with increasing magic angle spinning (MAS) rates. The measurements are made using 1,3-bisdiphenylene-2-phenylallyl dissolved in o-terphenyl at 40 kHz MAS. We introduce a source-sink diffusion model for polarization transfer which is capable of explaining the experimental observations. The advantage of this approach is demonstrated on mesoporous alumina with the acquisition of well-resolved DNP surface-enhanced Al cross-polarization spectra.
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http://dx.doi.org/10.1021/jacs.7b05194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5719465PMC
August 2017

Local Structures and Heterogeneity of Silica-Supported M(III) Sites Evidenced by EPR, IR, NMR, and Luminescence Spectroscopies.

J Am Chem Soc 2017 07 21;139(26):8855-8867. Epub 2017 Jun 21.

Department of Chemistry and Applied Biosciences, ETH Zürich , Vladimir-Prelog-Weg 1-5, CH-8093 Zürich, Switzerland.

Grafting molecular precursors on partially dehydroxylated silica followed by a thermal treatment yields silica-supported M(III) sites for a broad range of metals. They display unique properties such as high activity in olefin polymerization and alkane dehydrogenation (M = Cr) or efficient luminescence properties (M = Yb and Eu) essential for bioimaging. Here, we interrogate the local structure of the M(III) surface sites obtained from two molecular precursors, amides M(N(SiMe)) vs siloxides (M(OSi(OBu))·L with L = (THF) or HOSi(OBu) for M = Cr, Yb, Eu, and Y, by a combination of advanced spectroscopic techniques (EPR, IR, XAS, UV-vis, NMR, luminescence spectroscopies). For paramagnetic Cr(III), EPR (HYSCORE) spectroscopy shows hyperfine coupling to nitrogen only when the amide precursor is used, consistent with the presence of nitrogen neighbors. This changes their specific reactivity compared to Cr(III) sites in oxygen environments obtained from siloxide precursors: no coordination of CO and oligomer formation during the polymerization of ethylene due to the presence of a N-donor ligand. The presence of the N-ligand also affects the photophysical properties of Yb and Eu by decreasing their lifetime, probably due to nonradiative deactivation of excited states by N-H bonds. Both types of precursors lead to a distribution of surface sites according to reactivity for Cr, luminescence spectroscopy for Yb and Eu, and dynamic nuclear polarization surface-enhanced Y NMR spectroscopy (DNP SENS). In particular, DNP SENS provides molecular-level information about the structure of surface sites by evidencing the presence of tri-, tetra-, and pentacoordinated Y-surface sites. This study provides unprecedented evidence and tools to assess the local structure of metal surface sites in relation to their chemical and physical properties.
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http://dx.doi.org/10.1021/jacs.7b02179DOI Listing
July 2017

Frozen Acrylamide Gels as Dynamic Nuclear Polarization Matrices.

Angew Chem Int Ed Engl 2017 07 19;56(30):8726-8730. Epub 2017 Jun 19.

Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015, Lausanne, Switzerland.

Aqueous acrylamide gels can be used to provide dynamic nuclear polarization (DNP) NMR signal enhancements of around 200 at 9.4 T and 100 K. The enhancements are shown to increase with crosslinker concentration and low concentrations of the AMUPol biradical. This DNP matrix can be used in situations where conventional incipient wetness methods fail, such as to obtain DNP surface enhanced NMR spectra from inorganic nanoparticles. In particular, we obtain Cd spectra from CdTe-COOH NPs in minutes. The spectra clearly indicate a highly disordered cadmium-rich surface.
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http://dx.doi.org/10.1002/anie.201703758DOI Listing
July 2017

Donor-acceptor stacking arrangements in bulk and thin-film high-mobility conjugated polymers characterized using molecular modelling and MAS and surface-enhanced solid-state NMR spectroscopy.

Chem Sci 2017 Apr 14;8(4):3126-3136. Epub 2017 Feb 14.

Department of Chemistry , University of Cambridge , Lensfield Road , Cambridge CB2 1EW , UK.

Conjugated polymers show promising properties as cheap, sustainable and solution-processable semiconductors. A key challenge in the development of these materials is to determine the polymer chain structure, conformation and packing in both the bulk polymer and in thin films typically used in devices. However, many characterisation techniques are unable to provide atomic-level structural information owing to the presence of disorder. Here, we use molecular modelling, magic-angle spinning (MAS) and dynamic nuclear polarisation surface-enhanced NMR spectroscopy (DNP SENS) to characterise the polymer backbone group conformations and packing arrangement in the high-mobility donor-acceptor copolymer diketopyrrolo-pyrrole-dithienylthieno[3,2-]thiophene (DPP-DTT). Using conventional H and C solid-state MAS NMR coupled with density functional theory calculations and molecular dynamics simulations, we find that the bulk polymer adopts a highly planar backbone conformation with a laterally-shifted donor-on-acceptor stacking arrangement. DNP SENS enables acquisition of C NMR data for polymer films, where sensitivity is limiting owing to small sample volumes. The DNP signal enhancement enables a two-dimensional H-C HETCOR spectrum to be recorded for a drop-cast polymer film, and a C CPMAS NMR spectrum to be recorded for a spin-coated thin-film with a thickness of only 400 nm. The results show that the same planar backbone structure and intermolecular stacking arrangement is preserved in the films following solution processing and annealing, thereby rationalizing the favourable device properties of DPP-DTT, and providing a protocol for the study of other thin film materials.
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http://dx.doi.org/10.1039/c7sc00053gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413886PMC
April 2017

Dendritic polarizing agents for DNP SENS.

Chem Sci 2017 Jan 22;8(1):416-422. Epub 2016 Aug 22.

Department of Chemistry and Applied Biosciences , ETH Zürich , Vladimir-Prelog-Weg 1-5 , 8093 Zürich , Switzerland . Email:

Dynamic Nuclear Polarization Surface Enhanced NMR Spectroscopy (DNP SENS) is an effective method to significantly improve solid-state NMR investigation of solid surfaces. The presence of unpaired electrons (polarizing agents) is crucial for DNP, but it has drawbacks such as leading to faster nuclear spin relaxation, or even reaction with the substrate under investigation. The latter can be a particular problem for heterogeneous catalysts. Here, we present a series of carbosilane-based dendritic polarizing agents, in which the bulky dendrimer can reduce the interaction between the solid surface and the free radical. We thereby preserve long nuclear ' of the surface species, and even successfully enhance a reactive heterogeneous metathesis catalyst.
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http://dx.doi.org/10.1039/c6sc03139kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5365053PMC
January 2017

Reactive surface organometallic complexes observed using dynamic nuclear polarization surface enhanced NMR spectroscopy.

Chem Sci 2017 Jan 15;8(1):284-290. Epub 2016 Aug 15.

King Abdullah University of Science and Technology (KAUST) , KAUST Catalysis Center (KCC) , Thuwal , 23955-6900 , Saudi Arabia . Email: ; Email:

Dynamic Nuclear Polarization Surface Enhanced NMR Spectroscopy (DNP SENS) is an emerging technique that allows access to high-sensitivity NMR spectra from surfaces. However, DNP SENS usually requires the use of radicals as an exogenous source of polarization, which has so far limited applications for organometallic surface species to those that do not react with the radicals. Here we show that reactive surface species can be studied if they are immobilized inside porous materials with suitably small windows, and if bulky nitroxide bi-radicals (here TEKPol) are used as the polarization source and which cannot enter the pores. The method is demonstrated by obtaining significant DNP enhancements from highly reactive complelxes [( 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 Si-O-)W(Me)] supported on MCM-41, and effects of pore size (6.0, 3.0 and 2.5 nm) on the performance are discussed.
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http://dx.doi.org/10.1039/c6sc02379gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5365068PMC
January 2017
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