Yiran Wang

Masayuki Fukuda

Sergey Nikolaev

Atsushi Miyake

Kent J Griffith

Matthew L Nisbet

Emily Hiralal

|| Romain Gautier

Brandon L Fisher

Masashi Tokunaga

Masaki Azuma

Kenneth R Poeppelmeier

Two Distinct Cu(II)-V(IV) Superexchange Interactions with Similar Bond Angles in a Triangular "CuV 2 " Fragment

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

INTRODUCTION

Anderson's kinetic exchange or superexchange interaction [START_REF] Anderson | Theory of Superexchange Interaction[END_REF][START_REF] Goodenough | Theory of the Role of Covalence in the Perovskite-Type Manganites [La, M(II)]MnO3[END_REF] is ubiquitous in insulating materials and magnetic molecules where two magnetic (M) ions are bridged by one or more non-magnetic (N) ions. Many widely studied low-dimensional spin motifs are found to be mediated by superexchange interactions, including spin dimers in SrCu2(BO3)2, [START_REF] Kageyama | Exact Dimer Ground State and Quantized Magnetization Plateaus in the Two-Dimensional Spin System SrCu2(BO3)2[END_REF] spin ladders in SrCu2O3, [START_REF] Azuma | Observation of a Spin Gap in SrCu2(BO3)2 Comprising Spin-1/2 Quasi-1D Two-Leg Ladders[END_REF] Kagomé lattices in Cs2CuCl4 5 , [NH4]2[C7H14N][V7O6F18] [START_REF] Aidoudi | An Ionothermally Prepared S = 1/2 Vanadium Oxyfluoride Kagome Lattice[END_REF] , and (CH3NH3)2NaTi3F12 [START_REF] Jiang | Synthesis of a D1-Titanium Fluoride Kagome Lattice Antiferromagnet[END_REF] , and many others where an unusual magnetic behavior can be expected from the reduced dimensionality and frustration. [START_REF] Katsumata | Low-Dimensional Magnetic Materials[END_REF][START_REF] Vasiliev | Milestones of Low-D Quantum Magnetism[END_REF][START_REF] Balents | Spin Liquids in Frustrated Magnets[END_REF] With an increasing number of new magnetic systems, it is essential to accurately describe magnetic exchange couplings and understand their microscopic origin. In this regard, the Goodenough-Kanamori-Anderson (GKA) rules have been highly successful in providing a qualitative understanding of the magnetic properties in a wide range of materials. [START_REF] Goodenough | Theory of the Role of Covalence in the Perovskite-Type Manganites [La, M(II)]MnO3[END_REF][START_REF] Kanamori | Crystal Distortion in Magnetic Compounds[END_REF][START_REF] Geertsma | Influence of Side Groups on 90˚ Superexchange: A Modification of the Goodenough-Kanamori-Anderson Rules[END_REF] In practice, however, important details of the orbital structure are discarded when the sign and strength of superexchange interactions are determined based only on the M-N-M bond angles following the GKA rules. As a result, some complications may arise when assigning exchange interactions with bond angles in systems with a non-trivial spatial arrangement of the magnetic orbitals, such as in non-coplanar layouts and distorted geometries, [START_REF] Kanamori | Crystal Distortion in Magnetic Compounds[END_REF][START_REF] Geertsma | Influence of Side Groups on 90˚ Superexchange: A Modification of the Goodenough-Kanamori-Anderson Rules[END_REF][START_REF] Lin | Origin of Insulating Ferromagnetism in Iron Oxychalcogenide Ce2O2FeSe2[END_REF][START_REF] Dabrowski | Transport, and Magnetic Properties of RMnO3 Perovskites[END_REF][START_REF] Blake | Transition between Orbital Orderings in YVO3[END_REF] or in heterometallic materials, where unexpected exchange mechanisms may occur. [START_REF] Azuma | Ferroelectric Bi2NiMnO6[END_REF][START_REF] Blasse | Ferromagnetic Interactions in Non-Metallic Perovskites[END_REF][START_REF] Dass | Oxygen Stoichiometry, Ferromagnetism, and Transport Properties of La2-xNiMnO6+δ[END_REF][START_REF] Kahn | Magnetism of Heterobimetallics: Toward Molecular-Based Magnets[END_REF] Heterometallic Cu(II)-V(IV) compounds hold the potential for realizing various spin-1/2 motifs with low dimensionality and varying magnetic exchange interactions. A Cambridge Structural Database (CSD version 2020.1 from April 2020) search (see the details below) reveals that the magnetic properties of several one-atombridged Cu(II)-V(IV) compounds have been studied experimentally, where strong ferromagnetic (FM) and weak antiferromagnetic (AFM) Cu-V exchange interactions were reported based on magnetic data fitting. A classic example is strong ferromagnetic (FM) coupling in a heterodinuclear copper(II)-vanadyl complex, demonstrated by Khan et al., [START_REF] Kahn | Interaction between Orthogonal Magnetic Orbitals in a Copper(II)-Oxovanadium(II) Heterobinuclear Complex[END_REF][START_REF] Kahn | Crystal Structure and Molecular Conformations, and Magnetic Properties of a Copper-Vanadyl (CuII-VOII) Heterobinuclear Complex: Interaction between Orthogonal Magnetic Orbitals[END_REF] where the microscopic origin can be well rationalized by the GKA rules owing to the orthogonality of the magnetic orbitals. [START_REF] De Loth | Ab Initio Calculation of the Ferromagnetic Interaction in a Copper-Vanadyl Oxide (CuIIVIIO) Heterodinuclear System[END_REF] Nevertheless, strong AFM coupling that is essential for forming low-dimensional spin motifs has not been reported in heterometallic Cu(II)-V(IV) compounds.

In this study, we report on a new Cu(II)-V(IV) compound [Cu(H2O)(dmbpy)]2[V2O2F8] (1) that features molecular tetramers composed of the triangular "CuV2" fragments and displays a pronounced S = 0 spin gapped behavior. By combining electronic and spin models with density functional theory (DFT) calculations, we demonstrate that, despite similar bond angles, Cu-V superexchange interactions carry drastically different coupling strengths along two Cu-F-V pathways in the triangular "CuV2" fragment, owing to the special orientation of the magnetic orbitals stabilized by the local atomic environment. To our knowledge, the dominating AFM Cu-V coupling in the triangular "CuV2" fragment displays the strongest AFM coupling among all the reported Cu(II)-V(IV) compounds. This analysis is further applied to revisit the magnetic properties of the previously reported spin gapped chain compound [enH2]Cu(H2O)2[V2O2F8] (enH2 = ethylene diammonium, compound 2) [START_REF] Gautier | Spin Frustration from Cis -Edge or -Corner Sharing Metal-Centered Octahedra[END_REF] with the same triangular "CuV2" fragments. Based on the database analysis, superexchange interactions in compounds 1 and 2 are compared to other known Cu(II)-V(IV) systems, opening up an avenue for searching and realizing novel low-dimensional spin motifs in Cu(II)-V(IV) and other heterometallic compounds.

RESULTS AND DISCUSSION

Synthesis, Structure and Magnetic Properties of Compound 1. Dark green block crystals of compound 1 with a formula of [Cu(H2O)(dmbpy)]2[V2O2F8] were synthesized through hydrothermal pouch methods. [START_REF] Harrison | Tetrahedral-Atom 3-Ring Groupings in 1-Dimensional Inorganic Chains: Beryllium Arsenate Hydroxide Hydrate (Be2AsO4OH•4H2O) and Sodium Zinc Hydroxide Phosphate Hydrate (Na2ZnPO4OH•7H2O)[END_REF] Powder X-ray diffraction indicates the synthesis is bulk pure (Figure S1). Single-crystal X-ray diffraction reveals that compound 1 crystallizes in the monoclinic space group C2/c and features charge-neutral molecular tetramers where two [Cu(H2O)(dmbpy)] 2+ fragments are bridged by a [V2O2F8] 4-cluster (Figure 1a). The molecular tetramers pack into an extended 3D structure via π-π interactions between the dmbpy ligands and intermolecular hydrogen bonding O2-H2B•••F2 along the c axis (Figure 1b&c). The analysis of the bond valence sum (BVS) calculations [START_REF] Brese | Bond-Valence Parameters for Solids[END_REF] for compound 1 gives a valence of 1.81 and 3.93 for Cu and V (Table S2), respectively, suggesting the presence of Cu(II) and V(IV). The valence state and crystal structure were further supported by FTIR and NMR spectra (details in Supporting Information).

To facilitate the analysis of magnetic properties in compound 1, we examined the coordination environments of V and Cu sites. The [V2O2F8] 4-cluster is composed of two crystallographically equivalent heteroleptic [VOF4] 2-octahedra with an out-of-center distortion and the distortion is stabilized by heteroanionic ligands. [START_REF] Kageyama | Expanding Frontiers in Materials Chemistry and Physics with Multiple Anions[END_REF][START_REF] Harada | Heteroanionic Materials by Design: Progress Toward Targeted Properties[END_REF] The shortest bond V1-O1 (1.6029(9) Å) in [V2O2F8] 4-anions is trans to the longest bond V1-F1 (2.2267(7) Å). The V1-F bond distances on the equatorial positions of [V2O2F8] 4-range from 1.9085(7) to 1.9860(7) Å. Moreover, the O1 atom displays low nucleophilicity from significant π-bonding to the V1 atom, resulting in high nucleophilicity in its trans F1 atom. Thus, the two [VOF4] 2- units are dimerized through F1, with the bond angle of V1-F1-V1 i being 107.06(3)˚. Additionally, the [Cu(H2O)(dmbpy)] 2+ cations are linked to the [V2O2F8] 4-clusters through F3 and F4 atoms, with the angles of Cu1-F3 i -V1 i and V1-F4-Cu1 being 131.67(4) and 136.25(4)˚, respectively. Aside from F3 and F4 i , Cu1 is also coordinated to N1 and N2 from the dmbpy bidentate ligand and O2 from the water ligand. Cu1 is in a slightly distorted square pyramidal coordination environment, indicated by a small τ5 parameter (0.24), given as τ5 = 𝛽𝛽-𝛼𝛼 60° where β and α are the largest and the second largest bond angle in the polyhedron. [START_REF] Addison | Structure, and Spectroscopic Properties of Copper(II) Compounds Containing Nitrogen-Sulphur Donor Ligands; the Crystal and Molecular Structure of Aqua[1,7-Bis(N-Methylbenzimidazol-2′-Yl)-2,6-Dithiaheptane]Copper(II) Perchlorate[END_REF] The bond distances in the copper polyhedron are 1.9858(9), 1.9853(9), 1.9706(8), 2.1487(7) and 1.9358(7) Å for Cu1-N1, Cu1-N2, Cu1-O2, Cu1-F3 i and Cu1-F4, respectively. Notably, the Cu1-F3 i bond is significantly longer than the other Cu1 coordinate bonds owing to the pyramidal coordination of Cu 2+ ions.

To probe the magnetic properties of compound 1, variable-temperature magnetic susceptibility data were collected under an external field of 0.1 T (Figure 2). The magnetic susceptibility is found to exhibit Curie-Weiss temperature dependence from 200-400 K:

χ(T) = χ0 + C/(T-θ),
where χ0 is a temperature-independent susceptibility term, C is the Curie constant, and θ is the Weiss temperature. Data fitting gives χ0 = -1.1(5) × 10 -4 emu/mol, C = 1.37(3) emu K/mol, and θ = 0.9( 27) K (Figure 2a). The calculated value of C agrees with a theoretical value of 1.5 emu K/mol that is expected for two Cu(II) and two V(IV) ions. Also, 1/χ is approximately proportional to temperature above 100 K in Figure S4, which supports paramagnetic behavior of compound 1 in the high temperature range.

In the temperature range of 10-50 K, the magnetic susceptibility of compound 1 starts to deviate from the Curie-Weiss law and decreases towards a projected value of χ(0 K) = 0 emu/mol, indicating the formation of non-magnetic spin singlet state. At 10 K, there is another inflection point, below which the magnetic susceptibility increases again, suggesting the presence of free spins. To model the behavior in this complex, the magnetic susceptibility of compound 1 below 100 K was fitted to the following equation:

χtotal = χ0 + χCW + χdimer = χ0 + C1/(T-θ) + 3(C2/T)/(3+e Δ/T ),
where χ0 is the temperature-independent term, χCW is the contribution from the free spins following the Curie-Weiss law with a Curie constant of C1 and a Weiss constant of θ; χdimer is the term associated with spin dimers, where Δ is a spin gap from the singlet ground state to the triplet excited state, and C2 is the corresponding Curie constant. With the parameters varied freely, the fitting gives χ0 = -3.0(3) × 10 -4 emu/mol, C1 = 4.44(4) × 10 -2 emu K/mol, θ = -0.10(2) K, C2 = 2.081(4) emu K/mol, and Δ = 70.24(4) K (Figure 2b). The small C1 value (<5% spin contribution) implies the presence of free spins that likely originate from a small number of defects or a very small amount of another phase, which was undetectable in the XRD experiment. The C2 value is about 1.4 times larger than expected (1.5 emu K/mol); nevertheless, the data can be reproduced well with the model adopted in this study, demonstrating the existence of a spin gap.

To further investigate the spin gap in compound 1, variable field magnetization data were collected under a pulsed high magnetic field up to 58 T (Figure 2c). At 2 K, the magnetization at low magnetic fields remains close to 0 µB, indicating a nonmagnetic singlet ground state, in agreement with the susceptibility data. As the applied magnetic field increases, the sample magnetization shows a sudden increase at around 40 T, revealing a transition from the singlet ground state to the triplet excited state. The magnetization saturates at 3.8 µB at 58 T, close to the value of 4 µB that is expected for a full magnetic moment of the tetramer with two Cu(II) and two V(IV) ions. The magnitude of the spin gap estimated from the crossover field of 45 T is 57.6 K. This is slightly smaller than the obtained value from the susceptibility data fitting at low temperatures (70.24 K). Similar trends have been reported in previous studies on spin singlet compounds. [START_REF] Gautier | Spin Frustration from Cis -Edge or -Corner Sharing Metal-Centered Octahedra[END_REF][START_REF] Azuma | High-Pressure Form of (VO2)P2O7: A Spin-1/2 Antiferromagnetic Alternating-Chain Compound with One Kind of Chain and a Single Spin Gap[END_REF] Considering the presence of the spin gap, we tentatively assumed the formation of AFM spin tetramer in compound 1 as illustrated in Figure 3.

Conflicted Superexchange Assignments from a Previous

Study. The triangular "CuV2" fragments found in compound 1 were previously reported in another crystal [enH2]Cu(H2O)2[V2O2F8], namely compound 2. [START_REF] Gautier | Spin Frustration from Cis -Edge or -Corner Sharing Metal-Centered Octahedra[END_REF] Unlike the molecular-like structure in 1, compound 2 features one-dimensional chain structures as a result of a higher Cu coordination number (Figure 3). In compound 1, Cu atoms are five-coordinated, leading to segregated molecular tetramers, whereas in compound 2, Cu atoms are six-coordinated, allowing "CuV2" fragments to connect into chains through cis-corner-sharing metal-centered octahedra. Although these compounds have different extended structures, their basic building units formed by triangular "CuV2" fragments show highly similar bonding characteristics (Table S3).

Given their structural similarities, comparable magnetic coupling between V-V and Cu-V can be expected to arise in both compounds. According to the previous study, the magnetic behaviour of compound 2 was ascribed to AFM V-V and FM Cu-V exchange interactions, based on the bond angles with adjacent nonmagnetic ions. [START_REF] Gautier | Spin Frustration from Cis -Edge or -Corner Sharing Metal-Centered Octahedra[END_REF] The spin gap behavior in compound 2 was rationalized by assuming the formation of a V-V spin dimer and one free Cu(II) spin, being effectively decoupled due to magnetic frustration (as shown in Figure 3). Consequently, the observed magnetization featuring two plateau states was ascribed to a quick saturation to S = 1/2 by a free spin at a magnetic field below 10 T and then to S = 3/2 at high magnetic fields (> 38 T), when the dimer singlet state is destroyed (right magnetic data in TOC graphic, reproduced with permission from Ref 25. Copyright 2013 American Chemical Society.). Following this analysis, it is reasonable to assume that if a similar magnetic scenario held in compound 1, each tetramer would contain two free Cu spins, resulting in an S = 1 magnetic state at low magnetic fields. This would contradict the observed S = 0 nonmagnetic behavior, thus inefficient to explain their distinct magnetic properties and questioning the previously assigned magnetic scenario. It is evident that magnetic exchange interactions mediated in the isostructural triangular "CuV2" fragments of compounds 1 and 2 should yield comparable spin models and, thus, have to be revisited in order to capture the magnetic behavior of both systems.

Electronic and Spin Models for Compounds 1 and 2.

To provide a microscopic description of the magnetic properties in both compounds 1 and 2, we constructed electronic Hubbard-type models based on first-principles calculations, that take into account all necessary ingredients to specify their magnetic behavior. From the calculated electronic structures (Figure S5), one can see that the states near the Fermi level are primarily formed by the Cu and V 3d states occupying one hole and one electron, respectively. Owing to their large crystal-field splitting, a minimal multi-orbital Hubbard model for both compounds can be formulated on the basis of Wannier functions corresponding to the Cu 3dx2-y2 and V t2g (3dxy, 3dzx, 3dyz) states, as shown in Figure 4b:

ℋ = ℋ CF + � 𝑡𝑡 𝑖𝑖,𝑗𝑗 𝑚𝑚𝑚𝑚′ 〈𝑖𝑖𝑗𝑗〉 𝑚𝑚𝑚𝑚 ′ ,𝜎𝜎 𝑐𝑐 𝑖𝑖𝑚𝑚 †𝜎𝜎 𝑐𝑐 𝑗𝑗𝑚𝑚′ 𝜎𝜎 + ℋ 𝑈𝑈 Cu + ℋ 𝑈𝑈 V ,
where the first term stands for the crystal-field splitting, the second term corresponds to kinetic energy, and the last two terms are the on-site Coulomb interactions. The details on model construction and the resulting model parameters are given in the Supporting Information. It can be seen that both systems fall into a strongly correlated regime with 𝑡𝑡 ≪ 𝑈𝑈, that will open a gap at the Fermi level and lead to an insulating state. Hopping parameters between Cu and V within the "CuV2" fragment are found to be highly asymmetric due to a specific spatial orientation of the half-filled Cu 3dx2-y2 orbital stabilized by the crystal field (as illustrated in Figure 4b). The latter leads to disproportionate orbital overlap along two Cu-F3-V and Cu-F4-V paths, despite their similar bond angles. Importantly, the orientation of the half-filled Cu 3dx2-y2 orbital stabilized by the crystal field is the same in both compounds regardless of their different coordination and chemical environment. On the other hand, hopping parameters along the V-F1-V path prevail predominantly between unoccupied orbitals, that in turn will favor FM coupling according to the GKA rules.

The derived Hubbard models can further be mapped onto the isotropic spin Heisenberg models by using the theory of superexchange starting from the single occupied Cu dx2-y2 and V t2g orbitals (details in Supporting Information). The calculated isotropic exchange parameters are JFM ≡ JV-F1-V = -0.16 and -0.39 meV, JAFM1 ≡ JCu-F4-V = 7.39 and 6.84 meV, JAFM2 ≡ JCu-F3-V = 0.29 and 0.25 meV for compounds 1 and 2, respectively. The Cu-Cu exchange interactions for both compounds as well as intercluster exchange parameters for compound 1 are weakly AFM owing to the small magnitude of the hopping parameters and can be discarded from the analysis. Our results demonstrate that the magnetic behavior of both compounds is governed by strong AFM Cu-F4-V coupling that significantly outweighs adjacent AFM Cu-F3-V and FM V-F1-V interactions in the "CuV2" fragment. In the previous study, all exchange interactions were erroneously found to have the opposite sign. [START_REF] Gautier | Spin Frustration from Cis -Edge or -Corner Sharing Metal-Centered Octahedra[END_REF] The calculated magnetization as a function of magnetic field and temperature is shown in Figure S7, whose qualitative behavior is in excellent agreement with the experiment for both systems. The calculated spin gap for compound 2 is found to be ~120 K, which is larger than the previously reported value of 60 K but can further be reduced by extending the electronic model and including other exchange interactions. The calculated value of the saturation magnetic field of ~ 65 T (assuming g = 2) for compound 1 is in good agreement with the experimental value of 58 T. Thus, one can see that the magnetic properties of compound 1 directly follow those of a simple spin dimer, while the quasi-one-dimensional chains in compound 2 can be regarded as a chain of weakly coupled linear spin-1/2 trimers 𝐽𝐽 AFM1 𝑺𝑺 1 • 𝑺𝑺 2 + 𝐽𝐽 AFM1 𝑺𝑺 2 • 𝑺𝑺 3 , where only two pairs of neighboring spins are antiferromagnetically coupled (as schematically shown in Figure 5c). Other examples of spin trimers were reported in compounds A3Cu3(PO4)4 (A = Ca, Sr, Pb), [START_REF] Matsuda | Magnetic Excitations from the Linear Heisenberg Antiferromagnetic Spin Trimer System A3Cu3(PO4)4 (A=Ca, Sr, and Pb)[END_REF] (C5H11NO2)2•3CuCl2•2H2O, [START_REF] Hasegawa | Magnetic Excitation in Interacting Spin Trimer Systems Investigated by Extended Spin-Wave Theory[END_REF] and Cu3(P2O6OH)2. [START_REF] Hase | 1∕3 Magnetization Plateau Observed in the Spin-1∕2 Trimer Chain Compound Cu3(P2O6OH)2[END_REF] From the energy diagram in Figure S8, it follows that in the absence of a magnetic field the ground state of the spin-1/2 trimer is double degenerate and given as a superposition of two S = 0 states It is worth noting that the revisited spin model for compound 2 fits well and explains the temperature dependence of the reported magnetic susceptibility and spin gap behavior (see Supporting Information).

Varied Cu(II)-V(IV) Superexchange Mechanisms from Different Spatial Arrangements of the Magnetic Orbitals. As demonstrated by our calculations, both the previously reported magnetic assignment for compounds 2 and tentative magnetic assignment for compound 1 are found to be inadequate for the triangular "CuV2" fragment. Namely, the two Cu(II)-V(IV) superexchange pathways in the fragment that were considered to be equivalent in the previous study turn out to be drastically different, with substantially disproportionate coupling strengths. This result is essentially not intuitive considering the similar bond angles in the Cu-F3-V and Cu-F4-V pathways of the triangular "CuV2" fragment (see Figure S9).

Apart from the two systems considered in this work, there are several other heterometallic Cu(II)-V(IV) compounds with reported strong FM and weak AFM interactions. In the search in Cambridge Structural Database (CSD version 2020.1 from April 2020), we found 522 compounds containing both Cu and V (see Figure S10 and spreadsheet in Supporting Information). Among these systems, 164 compounds contain at least one Cu(II) and one V(IV) atoms, with 99 of them having Cu and V connected through a one-atom bridge, which can potentially mediate superexchange interactions (transition metals in some compounds were reported to have ambiguous or mixed valence states). Nevertheless, among these 99 oneatom-bridged compounds, only 8 compounds (CSD REFCODE: BIGFAY [START_REF] Kahn | Crystal Structure and Molecular Conformations, and Magnetic Properties of a Copper-Vanadyl (CuII-VOII) Heterobinuclear Complex: Interaction between Orthogonal Magnetic Orbitals[END_REF] ; DAKROW [START_REF] Bencini | EPR Spectra of and Exchange Interactions in Trinuclear Complexes. 3. Synthesis, Crystal Structure and Magnetic Properties of the Oxovanadium(IV) Adduct of a Tetradentate Schiff Base Copper(II) Complex[END_REF] ; PUSJOC 36 ; SEJPON 37 ; RAXTOB [START_REF] Baggio | Magneto-Structural Study and Synthesis Optimization of a Phosphovanadate Copper Complex[END_REF] ; UXOZEO02 39 ; RAGCAE01 40 ; XAKXUD [START_REF] Yucesan | Solid State Coordination Chemistry: Temperature Dependence of the Crystal Chemistry of the Oxovanadium-Phenylphosphonate-Copper(II)-2,2′-Bipyridine System. Crystal Structures of the One-Dimensional [{Cu(Bpy)}VO[END_REF] ) have been reported experimentally with available magnetic data fitted into spin models (see Table S4, including the study of compound 2). [START_REF] Kahn | Crystal Structure and Molecular Conformations, and Magnetic Properties of a Copper-Vanadyl (CuII-VOII) Heterobinuclear Complex: Interaction between Orthogonal Magnetic Orbitals[END_REF][START_REF] Gautier | Spin Frustration from Cis -Edge or -Corner Sharing Metal-Centered Octahedra[END_REF][START_REF] Bencini | EPR Spectra of and Exchange Interactions in Trinuclear Complexes. 3. Synthesis, Crystal Structure and Magnetic Properties of the Oxovanadium(IV) Adduct of a Tetradentate Schiff Base Copper(II) Complex[END_REF][START_REF] Mohanta | Spin Exchange Coupling in Heterobimetallic MIIVIVO (M = Cu, Ni, Co, Fe, Mn) Macrocyclic Complexes. Synthesis, Structure, and Properties[END_REF][START_REF] Glaser | Ferromagnetic Coupling by Orthogonal Magnetic Orbitals in a Heterodinuclear CuIIVIVO Complex and in a Homodinuclear CuIICuII Complex[END_REF][START_REF] Baggio | Magneto-Structural Study and Synthesis Optimization of a Phosphovanadate Copper Complex[END_REF][START_REF] Manson | Bimetallic MOFs (H3O)x[Cu(MF6)(Pyrazine)2]•(4-x)H2O(M=V 4+ , x =0; M=Ga 3+ , x =1): Co-Existence of Ordered and Disordered Quantum Spins in the V 4+ System[END_REF][START_REF] Yucesan | Secondary Metal-Ligand Cationic Subunits {ML} n+ as Structural Determinants in the Oxovanadium/Phenylphosphonate/{ML} n+ System, Where {ML} Is a Cu 2+ /Organonitrogen Moiety[END_REF][START_REF] Yucesan | Solid State Coordination Chemistry: Temperature Dependence of the Crystal Chemistry of the Oxovanadium-Phenylphosphonate-Copper(II)-2,2′-Bipyridine System. Crystal Structures of the One-Dimensional [{Cu(Bpy)}VO[END_REF] Besides the two compounds from the present study, only one compound is found to be bridged by an F atom, while the other seven compounds are bridged by an O atom.

Among the 8 studied compounds, 4 compounds (BIGFAY 23 ; DAKROW [START_REF] Bencini | EPR Spectra of and Exchange Interactions in Trinuclear Complexes. 3. Synthesis, Crystal Structure and Magnetic Properties of the Oxovanadium(IV) Adduct of a Tetradentate Schiff Base Copper(II) Complex[END_REF] ; PUSJOC 36 ; SEJPON [START_REF] Glaser | Ferromagnetic Coupling by Orthogonal Magnetic Orbitals in a Heterodinuclear CuIIVIVO Complex and in a Homodinuclear CuIICuII Complex[END_REF] ) were reported to exhibit strong FM Cu(II)-V(IV) coupling and contain Cu-V clusters in which Cu is double-bridged to V through O atoms, all residing in the same plane (Figure 5a). Kahn et al. have attributed strong FM superexchange interactions to the orthogonality of the magnetic Cu dx2-y2 and V dxy orbitals. [START_REF] Kahn | Crystal Structure and Molecular Conformations, and Magnetic Properties of a Copper-Vanadyl (CuII-VOII) Heterobinuclear Complex: Interaction between Orthogonal Magnetic Orbitals[END_REF][START_REF] Glaser | Ferromagnetic Coupling by Orthogonal Magnetic Orbitals in a Heterodinuclear CuIIVIVO Complex and in a Homodinuclear CuIICuII Complex[END_REF] Having different symmetries with respect to the mirror plane of the complex, their overlap cancels out, suppressing the AFM contribution and stabilizing strong FM coupling between Cu(II) and V(IV). In the remaining 4 compounds, RAXTOB [START_REF] Baggio | Magneto-Structural Study and Synthesis Optimization of a Phosphovanadate Copper Complex[END_REF] also contains Cu and V double bridged by O atoms, which are not coplanar, with the dihedral angle of the planes containing Cu dx2-y2 and V dxy orbitals being 135.4˚ (Figure 5b). In this case, data fitting gives a weak Cu-V AFM coupling, which was ascribed to the non-coplanarity of the magnetic orbitals, allowing for their small overlap.

In contrast to the systems above, UXOZEO02 [START_REF] Manson | Bimetallic MOFs (H3O)x[Cu(MF6)(Pyrazine)2]•(4-x)H2O(M=V 4+ , x =0; M=Ga 3+ , x =1): Co-Existence of Ordered and Disordered Quantum Spins in the V 4+ System[END_REF] has an entirely different connectivity, in which Cu is connected to V through a single F bridge, and the Cu-F-V path forms a linear 180 ° bond (Figure 5c). However, lateral overlap of the Cu dx2-y2 and V dxy orbitals is rather small, leading to a nearly zero AFM superexchange coupling with a fitting value of J = 0.04 meV. As for the last 2 compounds RAGCAE01 [START_REF] Yucesan | Secondary Metal-Ligand Cationic Subunits {ML} n+ as Structural Determinants in the Oxovanadium/Phenylphosphonate/{ML} n+ System, Where {ML} Is a Cu 2+ /Organonitrogen Moiety[END_REF] and XAKXUD [START_REF] Yucesan | Solid State Coordination Chemistry: Temperature Dependence of the Crystal Chemistry of the Oxovanadium-Phenylphosphonate-Copper(II)-2,2′-Bipyridine System. Crystal Structures of the One-Dimensional [{Cu(Bpy)}VO[END_REF] , the magnetic data were fitted into a Heisenberg mixed-dimer model with weak AFM couplings, but no further discussion was provided on their mechanism. Apart from the aforementioned scenarios, a recent study on the magnetic properties of CuVOF4(H2O)6•H2O affords another unusual situation (Figure 5d). [START_REF] Donakowski | The Role of Polar, Lamdba (Λ)-Shaped Building Units in Noncentrosymmetric Inorganic Structures[END_REF][START_REF] Curley | Anomalous Magnetic Exchange in a Dimerized Quantum Magnet Composed of Unlike Spin Species[END_REF] In this compound, Cu is connected to V through a O bridge with a bond angle of 142.88° and the Cu(II)-V(IV) coupling is fitted into a dimer model with the fitted value of 1.81 meV. First-principles calculations reveal that the magnetic orbitals reside in the Jahn-Teller plane and a significant spin density at the bridging O atom leads to a quantum disordered state at low magnetic fields.

As a new example, superexchange interactions in compounds 1 and 2 are mediated by another strikingly different scenario. The crystal field of Cu(II) ions fixes the lobes of the half-filled Cu dx2-y2 orbital to align along the Cu-F4 direction and be perpendicular to the Cu-F3 bond (Figure 5e), which is similar in both compounds despite their different coordination and chemical environments. As a result, the Cu-F4 σ bonding is found to be much stronger, owing to direct orbital overlap, than the one along the Cu-F3, despite their similar bond connectivity in the triangular "CuV2" fragment. Moreover, unlike the scenario in Figure 5a and 5b, the bond angle and the dihedral angle of the planes containing Cu dx2-y2 and V dxy orbitals in the Cu-F4-V pathway avoid the special symmetry to suppress the AFM contribution. Thus, the magnetic coupling via the Cu-F4-V pathway displays the strongest AFM coupling strength among all the reported Cu(II)-V(IV) compounds. Summing up, the versatile magnetic orbital arrangements in heterometallic Cu(II)-V(IV) coupling offer 6 different magnetic mechanisms within 11 compounds and the diverse magnetic interactions between Cu(II)-V(IV) ions can be manipulated by coordination geometries and ligands choice. In addition, the microscopic scenario realized in the triangular "CuV2" fragment offers an approach to maximize AFM interactions, providing opportunities to realize emergent AFM spin motifs with Cu(II)-V(IV) compounds.

CONCLUSIONS:

Through the unique triangular "CuV2" fragment, this study has demonstrated that distinct superexchange interactions can exist in a single spin motif in the presence of similar bond angles, thus emphasizing the importance of orbital structure in the case of a non-trivial arrangement of magnetic ions. Based on DFT calculations and electronic models, a microscopic description of the observed spin gap behavior in the newly synthesized compound 1 and previously reported compound 2 has been provided. Two essentially distinct AFM Cu-V couplings in the "CuV2" fragment are found to originate from a specific orientation of the magnetic orbitals stabilized by the crystal field. This work offers another perspective on searching for new low-dimensional magnetic systems and shows that heterometallic materials can be regarded as a promising platform for realizing various spin motifs.

Figure 1 .

 1 Figure 1. (a) Molecular and crystal structure of compound 1 along the (b) c axis and (c) a axis. Selected atoms are labeled. Blue, green, grey, red, orange, brown, and white spheres represent Cu, V, F, O, N, C and H atoms, respectively. Blue and green octahedra represent copper-centered cations and vanadium-centered anions, respectively. The dashed line represents the hydrogen bond. [Symmetry code: (i) 1-x, 1-y, 1-z.]

Figure 2 .

 2 Figure 2. Magnetic data for compound 1. Variable-temperature magnetic susceptibility data under an external field of 0.1 T in the (a) high temperature region and (b) low temperature region. The results of fittings are plotted with solid lines and the experimental data are shown as open circles. (c) Magnetization curves as a function of magnetic field at various temperatures.

Figure 3 .

 3 Figure 3. Structure comparison between compounds 1 and 2, and the illustration of triangular "CuV2" fragments. Green and blue polyhedra represent V-centered anions and Cu-centered cations, respectively. The red dashed line indicates the tentative superexchange pathways and spin models. The conflicted magnetic assignmentss between this work for compound 1 (upper) and the previous study for compound 2 (lower) are labeled.

Figure 4 .

 4 Figure 4. (a) Crystal field splitting of the 3d electrons at Cu (blue levels) and V (green levels) sites for compounds 1 (left) and 2 (right). Electronic states used for constructing the minimal electronic model are shown with figure brackets. (b) Wannier functions corresponding to the Cu dx2-y2 and V t2g states (arbitrarily named as dxy, dzx, dyz) as constructed for compound 2. The same set of Wannier functions is employed for compound 1. (c) Schematics of the spin models in compounds 1 (left) and 2 (right). Thick black (JAFM1), hollow (JAFM2), and thick dashed (JFM) lines denote the strong and weak AFM JCu-V and the weak FM JV-V interactions, respectively. Thin dotted lines in compound 1 represent weak AFM couplings between neighboring tetramers.

1 √6( 1 √6( 1 √6(

 111 |↑↑↓⟩ -2|↑↓↑⟩ + |↓↑↑⟩) and |↑↓↓⟩ -2|↓↑↓⟩ + |↓↓↑⟩) . Upon applying a magnetic field, the degeneracy is lifted, and at a critical field h = |↑↑↓⟩ -2|↑↓↑⟩ + |↓↑↑⟩) further changes to the fully polarized state |↑↑↑⟩ with S = 3/2.

Figure 5 .

 5 Figure 5. Magnetic mechanisms in (a) BIGFAY, DAKROW, PUSJOC, SEJPON, (b) RAXTOB (the grey lines indicate the non-coplanar fact), (c) UXOZEO02, (d) CuVOF4(H2O)6•H2O, (e) Cu-F3-V and Cu-F4-V pathways of the triangular "CuV2" fragments (this work).

ACKNOWLEDGMENT

This work was supported by funding from the National Science Foundation (DMR-1904701). Y.W. acknowledge funding from the MRSEC program of the National Science Foundation (DMR-1720139) at the Materials Research Center of Northwestern University. K.J.G. acknowledges funding from the Joint Center for Energy Storage Research (JCESR), an Energy Innovation Hub funded by the US Department of Energy, Office of Science, Basic Energy Sciences. Single-crystal and powder X-ray diffraction data, FTIR spectra and solid-state NMR spectra were acquired at IMSERC at Northwestern University, which has received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-1542205), the State of Illinois, the International Institute for Nanotechnology (IIN), and the National Science Foundation (DMR-0521267). Use of the Center for Nanoscale Materials, a DOE Office of Science User Facility, was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357. The authors thank Dr. J. C. Hancock, Mr. I. L. Peczak and Mr. A. D. Sample for helpful discussions and Ms. C. Stern for experimental assistance.

ASSOCIATED CONTENT

Supporting Information. The Supporting Information is available free of charge on the ACS Publications website.

Additional experimental details, characterization data, and CSD search (PDF)

Crystallographic data for compound 1 (CIF)

Accession Codes

CCDC 2159103 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

AUTHOR INFORMATION Corresponding Author

* krp@northwestern.edu ORCID Author Contributions § Y.W., M.F., and S.N. contributed equally to this work.

Notes

The authors declare no competing financial interest.

For Table of Contents Only:

Synopsis: Two drastically different Cu(II)-V(IV) interactions with similar bond angles in the triangular "CuV2" fragment originates from the specific orientation of the Cu dx 2 -y 2 orbital stabilized by the crystal field. As a result, the spin gap behavior in the tetramer and chain compounds can be rationalized with the spin dimer and spin trimer models, respectively.


Romain Gautier

Michael Paris

Florian Massuyeau

Templating Effect of Trans-2,5-dimethylpiperazine (TDMP) on the Structure Dimensionality of Hybrid Metal Halides

 2-. Despite different crystal structures (space-groups, inorganic frameworks,…), the dimensionalities (from 0D to 2D) of the inorganic networks of these 13 hybrid materials could be rationalized according to only two parameters: the oxidation states (+1 or +2) and the coordination sphere (tetrahedron or octahedron) of the metal ions. The luminescence properties of the new hybrid silver bromide have been analyzed and discussed by comparing the luminescence mechanisms of the other previously reported trans-2,5dimethylpiperazine-1,4-diium metal halides.

Introduction

The templating effect of N-based compounds has been of great importance in modern chemistry for the directed synthesis of zeolites, metal phosphates, polyoxometalates or Metal Organic Frameworks with diverse physical and chemical properties. [1][2][3][4][5][6] This approach, firstly developed in the 1960s with organic groups encapsulated in zeolite structures, was then generalized to other microporous crystalline solid phases with diverse dimmensionalities. 4 The organic species, which are supposed to be chemically and thermally stable in the medium, usually contribute to the stability of the inorganic framework through van der Walls interactions or H-bonding and play the role of charge compensator of the negatively charged inorganic network. Thus, the size, shape and charge of the organic cations are key parameters influencing the templated assemblies.

In addition to the size of voids in porous materials, the organic structure-directing agents have also an influence on the dimensionality of the inorganic frameworks and the resulting physical properties. However, the role of the templates on this dimensionality has been little discussed up to now. Thus, the hydrogen bonding has been reported to influence the variable modes of condensation of metal centered polyhedra in hybrid compounds such as organoammonium-molybdenum oxide phases. 2 By bridging preferentially to the terminal or to oxo groups through H-bonding, the template molecules can influence the propagation of the connectivity in different directions. However, a complete understanding of the structural role of the organic cations is still not available because a large diversity of dimensionalities can be observed when the same quartenary amine is used for different inorganic components.

In this context, we decided to investigate the role of one single template on the dimensionalities of different inorganic frameworks. The trans-2,5-dimethylpiperazine was used as structure directing agent for different metal halides. This amine was recently used in combination of different metal halide anions to reach high quantum yield and record color rendering of white light emissions.

Structure determination

Structure determinations of compounds 4 (CCDC 1424480), 5 (CCDC 1424481), 11 (CCDC 1424485), 12 (CCDC 1424486), and 13 (CCDC 1424487) were carried out from single-crystal X-ray diffraction with a Bruker-Nonius Kappa CCD diffractometer with monochromated Mo K radiation. Absorption corrections were carried out with SADABS. 14 Direct methods were used to determine the crystal structures and were completed by Fourier difference syntheses with SIR2004. 15 The refinement of the crystal structures with anisotropic displacement parameters was carried out using SHELXL-2013. 16 The CIFs were compiled with Olex2.12. 17 Additional symmetry elements were checked with the program PLATON. 18 Crystallographic data for these compounds are summarized in Table 1.

Photoluminescence properties

Photoluminescence spectra were collected using a Fluorolog-3 spectrofluorometer from Horiba. 450W Xe light was used as excitation source.

Results and discussion

Structure description. Please do not adjust margins

Zero dimensional crystal structures with tetrahedral

Please do not adjust margins 13)) isolated between cationic TDMP (Figure 3). The ratio of organic cation: inorganic anion is Owing to the recent interest in the photoluminescence properties of hybrid metal halides compounds based on TDMP, [7][8][9][10]12,13 the solid-state photoluminescence properties of silver bromide compound 13 have been investigated. [19][20][21] The compound 13 exhibits an emission at 550 nm under excitation at 254 nm (Figure 4). Since the free amine shows no photoemission, this emission can be assigned to the inorganic layers. Interestingly, this yellow emission is similar to the one of the previously reported zinc bromide (compound 2). 10 In the latter compound, the photoemission was associated with the formation of V k centers. Such V k centers could also be created within the dimeric edge-sharing metal halide units without significant deformation of the layers (Figure 4).

Influence of the metal halide building units on the dimensionality

The hybrid compounds 1-13 are built of metal halide complexes in tetrahedral or octahedral environments, and This journal is © The Royal Society of Chemistry 20xx

Please do not adjust margins Please do not adjust margins TDMP. During the hydrothermal synthesis, the condensation of metal halide polyhedral anions can occur and leads to 0D (compounds 1-5), 1D (compounds 6-10) or 2D (compounds 11-13) inorganic frameworks. In these materials, theTDMP cation plays the role of organic structure-directing agent. As previously reported for other templates, this cation influences the inorganic assembly by its size, shape and charge. However, the dimensionality is also related to the charge of the inorganic anions. Thus, the oxidation states of the metal ions and their coordinations are two important parameters influencing the dimensionality in this chemical system: (i) M 2+ ions in tetrahedral MX 4 units crystallize in 0D compounds, (ii) M 2+ ions in octahedral MX 6 units crystallize in 1D compounds and (iii) M + ions in tetrahedral MX 4 units lead to layered compounds (Table 2 and Figure 5). For example, copper halides crystallize, with the same organic template, in a 0D crystal structure (compound 4) when Cu ions are in the oxidation state +2 in CuBr 4 tetrahedral units, a 1D crystal structure (compound 9) when Cu ions are in the oxidation state +2 in CuCl 6 octahedral units, or a 2D crystal structure (compound 11) if Cu ions are in the oxidation state +1 in CuBr 4 tetrahedral units. It is worth noting that the two copper bromide materials can be identified in the same sample and can also be synthesized within the same conditions. The charges are relatively uniform in the anionic MX n units and cationic TDMP units (i.e. no polarity). In addition, the volumes of both MX n and TDMP units are similar. For these reasons and in order to satisfy electrostatic interactions, the volumes occupied by anions and cations in the crystal structure can be expected to be similar. As the oxidation state of the metal ions differ, the anionic MX n units have different charges. In the crystal structure, this charge must be balanced with the fixed charge of the cationic templates. To balance the charges and the different volumes occupied by cations and anions, the condensation of inorganic anions can occur. This condensation also modifies the dimensionality of the inorganic network. For tetrahedral anions with M 2+ , the [MX 4 ] 2-units have a charge equal and opposite to the ones of the organic cations. As cations and anions occupy similar spaces and have opposite charges, they can crystallize in the ratio 1:1 and be isolated in an hydrogen bond network (i.e 0D structure). For octahedral anions with M 2+ , the charge of [MX 6 ] 4-units is twice the ones of the organic cations. Previously, the influence of the templating agents on the dimensionality of the crystal structures has been discussed by comparing the effect of different amines on the polyhedral connectivity. [22][23][24] From our results, one can conclude that the synergy between the organic templates and the inorganic frameworks is also important to consider. Thus, significant differences in the dimensionality can be observed for the same organic template and similar inorganic constituents.

Please do not adjust margins

Please do not adjust margins

Conclusions

The templating effect of the trans-2,5-dimethylpiperazine on hybrid compounds built with different metal halides has been investigated. Thirteen compounds based on different metals (Zn, Co, Cu, Cd, Ag, Pb, and Sn) and different halogens (Cl, Br) lead to very different structures but the dimensionalities of the inorganic network of all thirteen materials were shown to be dependent on only two key parameters: the oxidation states and the coordination sphere of the metal ions. Thus, the tetrahedral M 2+ X 4 , the octahedral M 2+ X 6 , and the tetrahedral M + X 4 lead, respectively, to 0D, 1D and 2D crystal structures.

We believe this analysis of thirteen compounds illustrates well the tendency of metal halide building units to condensate into high dimension inorganic networks in order to balance both the size and charges of organic cations vs. inorganic anions. Thus, this work shows that, in the future, a better understanding of the synergy between inorganic components and organic templates would enable a better design of materials with specific properties.

  MX 4 building units (Compounds (1-5)). The crystal structures of compounds 1-5 are built of anionic [MX 4 5)), and TDMP. The ratio of organic cation: inorganic anion is 1:1 for all compounds. Compounds 1-3 crystallize in the space-group C2/c (Figure 1(a)). The bond lengths in the tetrahedral anionic units are 2.2546(12) Å < d Zn-Cl < 2.2837(11) Å for 1, 2.3965(6) Å < d Zn-Br < 2.4248(6) Å for 2, and 2.2605(9) Å < d Co-Cl < 2.2854(8) Å for 3. Compound 4 crystallizes in the space-group P-1 (Figure 1(b)). The bond lengths in the tetrahedral [CuBr 4 ] 2-anionic units are 2.3667(7) Å < d Cu-Br < 2.3890(7) Å. Compound 5 crystallizes in the spacegroup Pnma (Figure 1(c)). The bond lengths in the tetrahedral [CdBr 4 ] 2-anionic units are 2.5325(11) Å < d Cd-Br < 2.6167(7) Å.

Figure 1 .

 1 Figure 1. Representation of the 0D crystal structures for (a) compounds 1-3, (b) compound 4, and (c) compound 5.

Figure 2 .

 2 Figure 2. Representation of the 1D crystal structures of (a) compounds 6-8 (Due to structural disorder, the amines cannot be localized by X-ray diffraction -the chains of [MX 4 ] 2-units are ordered for clarity), and (b) compounds 9-10.

Figure 3 .

 3 Figure 3. Representation of the 2D crystal structures for compounds 11-13. Photoluminescence

Figure 4 .

 4 Figure 4. Photoluminescence properties of compound 13 ( exc = 254 nm) and mechanism with the formation of Vk centers.

Figure 5 .

 5 Figure 5. Classification of the dimensionalities of the inorganic network of the hybrid metal halides according to the oxidation states and the coordination polyhedron of the metal ion.

Table 1 .

 1 Crystallographic data for compounds 4-5 and 11-13

		4	5	11	12	13
	Space group	P-1	Pnma	P21/c	P21/c	P21/c
	a/Å	7.20781(14)	13.7873(5)	8.0150(4)	7.8025(3)	7.9147(16)
	b/Å	7.23746(13)	14.7844(10)	7.8040(2)	7.7952(4)	8.0914(16)
	c/Å	13.4221(2)	6.9901(3)	12.2864(2)	12.6471(6)	12.985(4)
	α/°	92.2638(15)	90	90	90	90
	β/°	97.7120(17)	90	117.617(2)	119.124(4)	118.58(2)
	γ/°	90.2231(16)	90	90	90	90
	V (Å 3 )	693.28(2)	1424.84(13)	680.94(4)	671.97(6)	730.2(4)
	Z	2	4	4	4	4
	Radiation	Mo Kα	Mo Kα	Mo Kα	Mo Kα	Mo Kα
	2Θ range for data collection/°	12.82 to 56.18	12.84 to 61	12.86 to 66.6	12.82 to 56.96	13 to 55.2
	Reflections collected	22934	25708	25270	13666	12933
	Data/restraints/parameters	3354/0/118	2219/0/63	2602/0/64	1681/0/63	1669/0/64
	Goodness-of-fit on F 2	1.044	1.039	1.060	1.029	1.036
	Final R indexes [I>=2σ (I)]	R1 = 0.0318 wR2 = 0.0778	R1 = 0.0425 wR2 = 0.0815	R1 = 0.0361 wR2 = 0.0866	R1 = 0.0382 wR2 = 0.0993	R1 = 0.0314 wR2 = 0.0741
	Largest diff. peak/hole / e Å -3	0.85/-0.76	1.77/-1.63	1.87/-1.84	1.15/-1.15	1.35/-1.49

Table 2 .

 2 Comparison of dimensionalities and oxidation states of metal ions in compounds 1-13.

	Compound	Anion	Coordination polyhedron	Oxidation state of the metal ion	Dimensionality	Space-group	Reference
	1 2 3 4 5 6 7 8 9 10 11 12 13	2-2-[ZnBr 4 ] [ZnCl 4 ] 2-[CoCl 4 ] 2-[CuBr 4 ] 2-[CdBr 4 ] [PbCl 4 ] 2-[PbBr 4 ] 2-[SnBr 4 ] 2-2-[CuCl 4 ] 2-[CdCl 4 ] [CuBr 2 ] -[AgCl 2 ] -[AgBr 2 ] -	Tetrahedron Tetrahedron Tetrahedron Tetrahedron Tetrahedron Octahedron Octahedron Octahedron Octahedron Octahedron Tetrahedron Tetrahedron Tetrahedron	+2 +2 +2 +2 +2 +2 +2 +2 +2 +2 +1 +1 +1	0D 0D 0D 0D 0D 1D 1D 1D 1D 1D 2D 2D 2D	C2/c C2/c C2/c P-1 Pnma P-42 1 m P-42 1 m P-42 1 m C2/c C2/c P2 1 /c P2 1 /c P2 1 /c	10 10 11 This work This work 12 7 8 13 13 This work This work This work

This journal is © The Royal Society of Chemistry 20xx J. Name., 2013, 00, 1-3 | 3

This journal is © The Royal Society of Chemistry 20xx J. Name., 2013, 00, 1-3 | 5

Acknowledgements

The work was supported by the CNRS, the National Agency for Research (ANR-16-CE08-0003-01 and ANR-21-ERCC-0009-01), the Region Pays de la Loire (Etoiles montantes en Pays de la Loire 2017, project "Découverte de pérovskites hybrides assistée par ordinateur").


MD, MPH, MBA Javed Butler
email: jbutler4@umc.edu

) ; Muhammad

MD Shariq Usman

PhD Kevin J Anstrom

MD Robert O Blaustein

MD, MPH Marc P Bonaca

MBBCh, MSc Justin A Ezekowitz

Cecilia Freitas

MBBS Carolyn Sp Lam

F Eldrin

MD Lewis

MD, FHSA Joann Lindenfeld

J Ciaran

MD Mcmullan

MD Robert J Mentz

MD ) Christopher O'connor

MD Giuseppe Mc Rosano

Inés Clara

Saldarriaga

MD Michele Senni

MD James Udelson

MD Adriaan A Voors

MD Faiez Zannad

Soluble Guanylate Cyclase Stimulators in Patients with Heart Failure with Reduced Ejection Fraction Across the Risk Spectrum

Patients with heart failure with reduced ejection fraction (HFrEF) have a high residual risk of adverse outcomes, even when treated with optimal guideline-directed medical therapy and in a clinically stable state. Sodium guanylate cyclase (sGC) stimulators have the potential to lower this risk by modifying the nitric oxide-sGC-cyclic guanosine monophosphate cascade -a pathophysiological pathway that has been targeted with limited success in HFrEF previously.

Vericiguat, an sGC stimulator, was shown to improve outcomes in patients with HFrEF in the VICTORIA (A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction) trial. However, this trial included patients with recently worsening disease. In this brief review, we discuss the rationale of evaluating sGC stimulators in lower-risk HFrEF patients.

First, all key HFrEF medications have been evaluated in both higher and lower-risk populations, and the treatment effect is not always consistent across the risk spectrum. Second, preclinical studies and post-hoc studies of the VICTORIA trial have suggested that sGC stimulators may have cardioprotective effects -these effects may be more apparent when the medication is initiated earlier in the disease process. Third, the effect of vericiguat on cardiovascular mortality remains uncertain and a trial with a longer follow-up in a lower-risk population may allow better assessment of its effect on cardiovascular mortality. Therefore, there is a pertinent need to investigate the effects of vericiguat in optimally-treated, low-risk HFrEF patients (i.e., those without recent worsening heart failure).

Patients with heart failure with reduced ejection fraction (HFrEF) have a substantially increased risk of mortality and hospitalization [START_REF] Greene | Risk Profiles in Heart Failure[END_REF]. Early initiation of guideline-directed medical therapy (GDMT) decreases this risk [START_REF] Greene | Titration of Medical Therapy for Heart Failure With Reduced Ejection Fraction[END_REF]. For patients with HFrEF, quadruple therapy with angiotensin receptor-neprilysin inhibitor (ARNI), beta-blockers, mineralocorticoid receptor antagonists (MRAs) and sodium glucose cotransporter 2 (SGLT2) inhibitors is now recommended as the standard of care [START_REF] Bassi | Association of Optimal Implementation of Sodium-Glucose Cotransporter 2 Inhibitor Therapy With Outcome for Patients With Heart Failure[END_REF]. However, patients with optimal medical therapy continue to have a substantial residual risk of adverse outcomes (4). In the EMPEROR-Reduced (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction) trial, of the 3730 patients randomized, 1863 (50%) were in the empagliflozin arm and were receiving excellent background medical therapy with renin-angiotensin modulators (89%), beta-blockers (95%) and MRAs (70%) [START_REF] Packer | Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure[END_REF]. Despite widespread quadruple therapy in the SGLT2 treatment arm, the residual two-year risk of all-cause mortality and heart failure hospitalization was ~20% and ~19%, respectively [START_REF] Mcmurray | Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction[END_REF]. This residual risk is much higher than other chronic cardiovascular diseases (Figure 1) [START_REF] Greene | Contextualizing Risk Among Patients With Heart Failure[END_REF]. According to the 2021 European Society of Cardiology guidelines, 50-69-year-olds should be considered at 'high-risk' if their cumulative 10-year risk of atherosclerotic cardiovascular disease (ASCVD) events exceeds 7.5% [START_REF] Visseren | ESC Guidelines on cardiovascular disease prevention in clinical practice[END_REF]. In contrast, the annualized mortality rate is 8-9% even in the lowest-risk stratum of HFrEF, i.e., well-treated and clinically stable individuals with no prior history of heart failure hospitalization [START_REF] Solomon | Efficacy of Sacubitril/Valsartan Relative to a Prior Decompensation: The PARADIGM-HF Trial[END_REF]. Many such patients experience sudden cardiac death without a preceding hospitalization. Contextualizing the residual risk associated with HFrEF against other common cardiovascular conditions highlights the need to develop therapies with novel mechanisms of action to further improve outcomes in this population [START_REF] Greene | Contextualizing Risk Among Patients With Heart Failure[END_REF].

Physiology of the Nitric Oxide Pathway, and it's Impairment in Heart Failure

The NO generated by the endothelium has important biologic effects [START_REF] Lim | Cardiac endotheliummyocyte interaction: clinical opportunities for new heart failure therapies regardless of ejection fraction[END_REF][START_REF] Hassan | The endothelium and endothelin: beyond vascular reactivity[END_REF]. NO readily diffuses across cell membranes into the vascular smooth muscle cells and binds to hemecontaining (active) sGC, which catalyzes the conversion of guanosine triphosphate to cGMP. Downstream, this counteracts vasoconstriction and helps maintain perfusion to vital organs [START_REF] Ahmad | Role of Nitric Oxide in the Cardiovascular and Renal Systems[END_REF].

Expression of sGC is highest in the myocardial cells, and the sGC-generated cGMP causes ventricular relaxation, decreased contractility, and has anti-hypertrophic and anti-fibrotic effects [START_REF] Massion | Nitric Oxide and Cardiac Function[END_REF]. The myocardial effects of the NO-sGC-cGMP pathway may be due to regulation of titin, a major determinant of myocardial stiffness (Figure 2).

In HFrEF, the NO-sGC-cGMP pathway is impaired [START_REF] Breitenstein | Novel sGC Stimulators and sGC Activators for the Treatment of Heart Failure[END_REF]. HFrEF is characterized by neurohormonal activation and systemic vasoconstriction, which overpowers NO-sGC-cGMP mediated vasodilation. HFrEF is also associated with endothelial dysfunction due to oxidative stress, which results in reduced endothelial NOS activity and an absolute insufficiency of NO.

The functionality of the NO-sGC-cGMP pathway is dependent on the redox status of the body.

Previous Attempts to Counter Nitric Oxide Signaling Abnormalities

The use of nitrates has been tested as a method to upregulate cGMP levels in HFrEF. However, this approach is limited due to the development of tolerance and the potential for increased rather than decreased oxidative stress [START_REF] Sandner | Hydralazine and nitrates in the treatment of heart failure with reduced ejection fraction[END_REF]. Nitrates appear to be most effective in Black patients in combination with hydralazine [START_REF] Sandner | Hydralazine and nitrates in the treatment of heart failure with reduced ejection fraction[END_REF]. Intracellular cGMP levels may be increased by inhibiting phosphodiesterase, the enzyme responsible for cGMP degradation; however, this relies on sufficient endogenous NO and cGMP production, which is impaired in HFrEF. Clinical trials have not yielded encouraging findings with phosphodiesterase inhibitors in HFrEF and have, in fact, suggested increased morbidity and mortality [START_REF] Cuffe | for the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure I. Short-term Intravenous Milrinone for Acute Exacerbation of Chronic Heart FailureA Randomized Controlled Trial[END_REF][START_REF] Packer | Effect of Oral Milrinone on Mortality in Severe Chronic Heart Failure[END_REF].

Soluble Guanylate Cyclase as a Therapeutic Target

Direct sGC stimulators provide an alternative pharmacological modulation of the NO-sGC-cGMP pathway. sGC stimulators bind to the heme-containing (active) form of sGC and stimulate cGMP formation. Also, they act in synergy with NO, increasing the sensitivity of sGC to the NO that is bioavailable. Preclinical studies suggested that direct activation of sGC may address several of the pathophysiologic mechanisms in HFrEF, without the adverse effects seen with nitrates and phosphodiesterase inhibitors. In the blood vessels, sGC stimulators may increase compliance and decrease remodeling (Figure 3). Increased renal perfusion can subsequently decrease neurohormonal activation and progression to kidney disease. In the myocardium, sGC stimulators may slow or reverse left ventricular hypertrophy and fibrosis. Evidence suggests that these anti-remodeling effects of sGC stimulators are independent of its effect on vascular tone Failure) trial evaluated the safety and efficacy of the sGC stimulator vericiguat (tested in 4 doses ranging from 1.25 mg to 10 mg daily) in patients with worsening chronic HFrEF. An exploratory secondary analysis of the trial showed a dose-response relationship, with higher vericiguat doses being associated with greater reductions in NT-proBNP compared to placebo [START_REF] Gheorghiade | Effect of Vericiguat, a Soluble Guanylate Cyclase Stimulator, on Natriuretic Peptide Levels in Patients With Worsening Chronic Heart Failure and Reduced Ejection Fraction: The SOCRATES-REDUCED Randomized Trial[END_REF].

Subsequently the VICTORIA trial evaluated the safety and efficacy of vericiguat in 5050 patients with worsening HFrEF with either a recent hospitalization within 6 months or outpatient intravenous diuretic treatment within 3 months [START_REF] Armstrong | Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction[END_REF]. Vericiguat demonstrated a significant reduction in the primary composite outcome of CVD/HHF (hazard ratio 0.90; 95% confidence interval: 0.82 to 0.98; p=0.02). The absolute risk reduction in the primary outcome was 4.2 events per 100 patient-years, translating to a number needed to treat of 24 to prevent one CVD/HHF event over a year.

Generalizability of VICTORIA Trial Results

The VICTORIA trial enrolled a subset of patients with worsening HFrEF [START_REF] Armstrong | Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction[END_REF]. The absolute risks of CVD/HHF and all-cause mortality in the trial population were 17 and 38 per 100-patient years, respectively, which is considerably higher than in trials that enrolled stable outpatient population of patients. In the VICTORIA trial, vericiguat led to greater improvement in patients in the lower three quartiles of natriuretic peptide levels at baseline. Another analysis demonstrated a trend towards greater benefit in patients who had a longer duration since their most recent HF [START_REF] Lam | Clinical Outcomes and Response to Vericiguat According to Index Heart Failure Event: Insights From the VICTORIA Trial[END_REF]. Thus, amongst patients enrolled in the VICTORIA trial, vericiguat appeared to be more effective in patients who were relatively stable. Thus, SGc stimulators may provide greater benefit in lower-risk patients who were not enrolled in the VICTORIA trial, and this merits evaluation

The Uncertain Effect of Soluble Guanylate Cyclase Inhibitors on Cardiovascular Mortality

The effect of sGC stimulators on cardiovascular mortality in patients with HFrEF remains unclear. In the VICTORIA trial, cardiovascular deaths were numerically lower in the vericiguat arm and contributed to the statistical significance of the composite endpoint; however, cardiovascular mortality did not reach statistical significance by itself. One plausible explanation for this is that the follow-up time of VICTORIA (median 10.8 months) was not enough to detect a reduction in mortality. Indeed, a separation of the Kaplan-Meier curve was noted late in the VICTORIA trial (after ~22 months of follow-up), which supports this hypothesis [START_REF]The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial[END_REF]. Evaluating sGC stimulators in a trial with a longer follow-up in patients without worsening HF may better elucidate its effects on mortality. Moreover, the potential anti-remodeling effects of sGC stimulators may reduce the incidence of fatal arrhythmias and prevent sudden cardiac death in HF. The existence of this effect can be better tested in a lower-risk HFrEF population, which has a higher ratio of sudden cardiac death to pump failure death [START_REF] Greene | Contextualizing Risk Among Patients With Heart Failure[END_REF].

Need for Developing Evidence across the Spectrum of Risk

For all key HFrEF pharmacotherapies, randomized trials have generally been conducted in both the higher-and lower-risk populations. The specific criteria used to determine risk has varied, with trials of some agents evaluating risk based on NYHA class (e.g., EMPHASIS-HF vs RALES), while others have utilized time since last HFH (e.g., DAPA-HF vs SOLOIST-WHF).

Regardless of the axis of risk used, most agents have been evaluated in populations with low as well as high absolute risk of clinical events (Figure 4). This is important since difference in risk 18790844, ja, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2720 by Chu De Nancy Dse, Wiley Online Library on [25/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License may modify the treatment effects of a drug. On the one hand, high-risk patients may have more 'opportunity' for improvement. On the other hand, these patients may be too sick to realize benefit from a novel agent. While MRA and ACEi trials were first conducted in higher risk patients, beta-blocker, angiotensin receptor neprilysin inhibitors (ARNI), and SGLT2i trials, first targeted a lower risk population. The efficacy of beta-blockers and SGLT2 inhibitors was consistent in both low-to-intermediate risk, as well as high-risk HFrEF populations [START_REF] Packer | Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure[END_REF][START_REF] Mcmurray | Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction[END_REF][START_REF] Bhatt | Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease[END_REF][START_REF]Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF)[END_REF][START_REF]The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial[END_REF][START_REF] Eichhorn | The Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial[END_REF].

Although by and large GDMT has been beneficial in HFrEF, the degree of benefit has not always been consistent across the risk spectrum, e.g., ACEis demonstrated a 27% relative risk reduction in mortality in the higher-risk population in the CONSENSUS (Cooperative North Scandinavian Enalapril Survival Study) trial, but a 16% relative risk reduction in a lower-risk population enrolled in the SOLVD-T (Studies of Left Ventricular Dysfunction-Treatment) trial.

Conversely, ARNI improved outcomes in a moderate-risk population, but this was not replicated in the very high-risk HFrEF patients [START_REF] Solomon | Efficacy of Sacubitril/Valsartan Relative to a Prior Decompensation: The PARADIGM-HF Trial[END_REF][START_REF] Mann | Effect of Treatment With Sacubitril/Valsartan in Patients With Advanced Heart Failure and Reduced Ejection Fraction: A[END_REF].

Need to Assess Soluble Guanylate Cyclase Modulation in Lower-Risk Patients

Given the above background, there are reasons to evaluate the efficacy of vericiguat in lowerrisk patients with HFrEF who have not experienced a recent worsening event (graphical abstract). First, not all therapies have shown consistent presence and extent of benefit across the spectrum of risk in HFrEF. Second, post-hoc analyses suggested that the effect of vericiguat was modified by risk within the VICTORIA trial population with an indication of greater benefit in patients at lower risk. Third, mechanism of action as well as benefits of sGC stimulators seen in preclinical studies are preventive in nature, such as anti-hypertrophic and anti-fibrotic effects in the heart and anti-remodeling effects in blood vessels. This suggests that the drug may also be useful in preventing the progress of HFrEF if initiated in the low-risk phase. Fourth, a trial of vericiguat with a longer follow-up and a lower-risk population may allow better assessment of its effect on cardiovascular mortality. Fifth, the VICTORIA trial enrolled patients with a recent worsening HFrEF event and was conducted when ARNI therapy was just being introduced into practice, and prior to the demonstration of benefit of SGLT2i in HFrEF. Incremental benefit of sGC stimulators on modern standard of care therefore needs to be evaluated.

While it may seem logical that sGC stimulators can further reduce the high residual risk seen even in lower risk HFrEF, this nevertheless requires testing in a contemporary trial of patients optimally treated with currently accepted guideline-directed medical therapy. This is important especially in an era of increasing costs and polypharmacy.

The VICTOR trial

The VICTOR trial, page 11: "VICTOR is a phase 3, randomized, double-blind, placebocontrolled clinical trial, which will evaluate the safety and efficacy of vericiguat in a lower-risk HFrEF population, compared with the VICTORIA trial. The VICTOR trial is expected to enroll an estimated 6000 patients. Patients will be eligible for inclusion if they have (i) a history of chronic HF (New York Heart Association Class II to IV); (ii) a left ventricular ejection fraction <40%; (iii) elevated NT-proBNP levels; and (iv) no HHF or outpatient IV diuretic therapy in the 3 months before randomization. Participants will be randomized to either vericiguat (started at 2.5mg and titrated to 5mg and 10mg) or matching placebo. The primary outcome of interest is first HHF/CV death. Other outcomes that will be evaluated include first HHF, CV death, total HHF, all-cause mortality and composite of all all-cause mortality or HHF. In the higher-risk population of the VICTORIA trial, CV death events comprised of a relatively smaller component of the primary outcome (ratio of HHF:CV deaths >3) due to the short average follow-up in this cohort with high risk for hospitalization. In contrast, in trials with more stable HFrEF populations, the HHF:CV death ratio is ~1. Thus, although the VICTOR trial may not be powered to study CV death and the overall CV death event rate may be lower due to advances in background therapy, this outcome is likely to play a more prominent role in the primary endpoint in this particular patient population and will better illustrate the effect of vericiguat on it. Like VICTORIA, VICTOR is an

  The original focus of treatment for HFrEF has been modulating the neurohormonal pathways, but recently alternate mechanisms, e.g., SGLT2 inhibition, have been explored. The VICTORIA (A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction) trial, evaluated the efficacy of vericiguat, a soluble guanylate cyclase (sGC) stimulator, 18790844, ja, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2720 by Chu De Nancy Dse, Wiley Online Library on [25/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License in 5050 patients with recently worsening HFrEF (10). Vericiguat, compared with placebo, demonstrated a significant reduction in the primary composite outcome of cardiovascular death or hospitalization for HF (CVD/HHF). However, the results from this trial cannot be extrapolated to a lower-risk HFrEF population without recently worsening disease. The ongoing VICTOR (A Study of Vericiguat (MK-1242) in Participants With Chronic Heart Failure With Reduced Ejection Fraction) trial (NCT05093933) will enroll patients with chronic HFrEF with neither a heart failure hospitalization nor outpatient intravenous diuretic use in the past 6 months. In this brief review, we discuss the importance of evaluating sGC stimulators across the risk spectrum in HFrEF, considering its mechanism of action, findings from previous trials, and historical drug development patterns in HFrEF.

  Increased oxidative stress in HFrEF disrupts the signaling cascade by varying levels of 18790844, ja, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2720 by Chu De Nancy Dse, Wiley Online Library on [25/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons Licenseinactivation of NO, sGC and cGMP (15). The downstream effects include increased vascular tone, stiffness, afterload, and left ventricular pressures. Coronary microcirculation is impaired, predisposing myocardial cells to ischemic injury. Impairment of the NO-sGC-cGMP pathway leaves the myocardium vulnerable to hypertrophy and myocardial fibrosis.

( 19 )

 19 . These beneficial mechanisms of sGC stimulators are unique from neurohormonal blockers and may result in additive or synergistic effects when used simultaneously. Clinical Trials with Soluble Guanylate Cyclase Stimulators in Heart Failure Following the positive findings in preclinical studies, the phase-II SOCRATES-Reduced (Phase IIb Safety and Efficacy Study of Four Dose Regimens of BAY1021189 (vericiguat) in Patients with Heart Failure with Reduced Ejection Fraction Suffering From Worsening Chronic Heart

Figure 1 :Figure 2 :

 12 Figure 1: The risk associated with heart failure with reduced ejection fraction versus atherosclerotic cardiovascular disease Reproduced with permission from: Greene SJ, Butler J, Fonarow GC. Contextualizing risk among patients with heart failure. JAMA. Published online November 15, 2021. doi:10.1001/jama.2021.20739

Figure 3 :

 3 Figure 3: Potential clinical benefits of sGC stimulators in patients with HFrEF. Abbreviations: sGC: Sodium guanylate cyclase; NO: Nitric oxide; GTP: Guanosine triphosphate; cGMP: Cyclic guanosine monophosphate; HFrEF: Heart failure with preserved ejection fraction

Figure 4 :

 4 Figure 4: The absolute risk of populations enrolled in pivotal HFrEF clinical trials with different drug classes Absolute risks are presented for the entire trial population. Absolute risks are as estimated by Spall et al, EJHF, May 2021 and Skali et al, Circulation, Nov 2006. Abbreviations: N/A: Not available; N/P: Not powered for clinical outcomes; AR: Absolute risk; RRR: Relative risk reduction; HFH/CVM: Composite of first heart failure hospitalization or cardiovascular mortality; ACE: Angiotensin converting enzyme; MR:

  18790844, ja, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2720 by Chu De Nancy Dse, Wiley Online Library on [25/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

  18790844, ja, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2720 by Chu De Nancy Dse, Wiley Online Library on [25/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

	hospitalization

  18790844, ja, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2720 by Chu De Nancy Dse, Wiley Online Library on [25/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

18790844, ja, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2720 by Chu De Nancy Dse, Wiley Online Library on [25/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

Ingelheim/Eli Lilly, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Medtronic, Merck, Novartis, Relypsa, Respicardia, Roche, Sanofi, Vifor, Windtree Therapeutics, and Zoll. MS has received personal fees from Novartis during the conduct of the study and personal fees from Bayer, Abbott, Merck, AstraZeneca, Vifor Pharma and Boehringer outside the submitted work. JEU reported receiving grants from Heartflow, Lantheus Medical Imaging, Abbott Laboratories, and the National Heart, Lung, and Blood Institute and participating in clinical trial committee work for Pfizer/GlaxoSmithKline and HeartFlow outside the submitted work. AAV AAV received honoraria and/or research support from Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Bayer, Cytokinetics, Merck, Novartis, Novo Nordisk, Roche Diagnostics. FZ reports personal fees from Janssen, Novartis, Boehringer Ingelheim, Boston Scientific, Amgen, CVRx, AstraZeneca, Vifor Fresenius, Cardior, Cereno pharmacuetical, Applied Therapeutics, Merck, Bayer, and Cellprothera; and other support from CVCT and Cardiorenal. The remaining authors have no conflicts of interest to declare.

18790844, ja, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2720 by Chu De Nancy Dse, Wiley Online Library on [25/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License event-driven trial; however, the events will likely take longer to accumulate in the relatively stable population of VICTOR, and thus follow-up times will be longer. The trial is expected to conclude mid-2025." 18790844, ja, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2720 by Chu De Nancy Dse, Wiley Online Library on [25/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

Disclosures: JB is a consultant to Abbott, Adrenomed, Amgen, Applied Therapeutics, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Cardior, CVRx, G3 Pharma, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Roche, Sanofi, Sequana Medical, and Vifor. KJA reports grants from NIH, Merck, grants from Bayer, grants from PCORI, outside the submitted work. ROB is a full-time employee of Merck. MPB was supported by the American Heart Association Strategically Focused Research Network in Vascular Disease under award numbers 18SFRN3390085 (BWH-DH SFRN Center) and 18SFRN33960262 (BWH-DH Clinical Project). JAE reports study funding from Novartis and Servier as well as grants from Merck, Bayer, Trevena, and Amgen. CF is a full-time employee of Bayer AG. CSPL is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, and Vifor Pharma; has served as consultant or on the advisory board, steering committee, or executive committee for Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, Vifor Pharma, Novartis, Amgen, Merck, Janssen Research & Development, Menarini, Boehringer Ingelheim, Novo Nordisk, Abbott Diagnostics, Corvia, Stealth BioTherapeutics, JanaCare, Biofourmis, Darma, Applied Therapeutics, MyoKardia, Cytokinetics, WebMD Global, Radcliffe Group, and Corpus; and is co-founder and non-executive director of Us2.ai. JL has received research support from AstraZeneca, Sensible Medical, and Volumetrix; and has received consulting fees from Abbott, AstraZeneca, Boehringer Ingelheim, Boston Scientific, CVRx, Cytokinetics, Edwards Lifesciences, Impulse Dynamics, V-Wave, and Vifor. CJM is a full-time employee of Merck. EFL reports research grant support from Novartis; consulting fees from Amgen, Dal-Cor, and Merck. Dr Granger reports consultan-cy fees and/or research support from Novartis, AstraZeneca, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Correvio, Daiichi Sankyo Co., Janssen Global Services, and Pfizer Inc. RJM has received research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer 18790844, ja, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2720 by Chu De Nancy Dse, Wiley Online Library on [25/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License


Kevin Bouaziz

Vittoria Aragno

Mehdi Batras

Christophe Baudouin

Antoine Labbé
email: dr.antoinelabbe@gmail.com

Antoine Pr

Labbé

Radius-Maumenee syndrome: A rare cause of glaucoma

Keywords: Syndrome de Radius Maumenee, Glaucome secondaire, hyperpression épisclérale Radius-Maumenee syndrome, secondary glaucoma, elevated episcleral venous pressure

diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Cas clinique

Nous rapportons le cas d'une patiente de 59 ans ayant consulté dans notre service pour avis sur un glaucome unilatéral de l'oeil gauche. L'histoire de la maladie commence à l'âge de 16 ans, avec l'apparition d'une rougeur de l'oeil gauche. L'examen clinique retrouvait une hypervascularisation épisclérale avec un aspect en tête de méduse sans autre anomalie oculaire associée. Cet aspect étant évocateur d'une anomalie vasculaire, de multiples imageries par IRM et angio-TDM ont été effectuées mais aucune n'a retrouvé d'anomalie pouvant expliquer l'aspect clinique. A l'âge de 32 ans, une hypertonie oculaire (HTO) à 30 mmHg a été détectée à l'oeil gauche. Un traitement par travoprost a été débuté, puis une association dorzolamide -timolol a été ajoutée. Malgré cette trithérapie, les valeurs de PIO ont toujours été comprises entre 25 et 30 mmHg pour des pachymétries mesurées à 575 µm à droite et 577 µm à gauche.

Lors de la consultation dans notre service, l'examen ophtalmologique retrouvait une acuité visuelle à 10/10 ème P2 aux deux yeux. La PIO mesurée à l'applanation était à 17 mmHg à droite et 28 mmHg à gauche sans traitement. L'examen à la lampe à fente était sans particularité à droite. À gauche, on retrouvait une dilatation des vaisseaux épiscléraux (Figure 1). La cornée était transparente, le cristallin clair et l'iris sans anomalie. En gonioscopie, on retrouvait aux deux yeux un angle ouvert à 3 selon la classification de Shaffer, pigmenté à 1+ selon la classification de Scheie. Le fond d'oeil retrouvait à droite un nerf optique de taille normale avec un C/D à 0.2. A gauche, le nerf optique était aussi de taille normale avec un amincissement diffus de l'anneau neuro-rétinien et un C/D à 0.8, associé à un aspect de boucle prépapillaire (Figure 2).

LFigure 1 :

 1 Figure 1 : Aspect de vascularisation épisclérale en « tête de méduse ».

Figure 2 :

 2 Figure 2 : Nerfs optiques en rétinophotographies. La papille de l'oeil gauche montre une

Figure 3 :

 3 Figure 3 : OCT RNFL péri-papillaire retrouvant une atteinte unilatérale avec une excavation

Figure 4 et 5 :

 5 Figure 4 et 5: Champs visuels.