Dr Jean-René Hamon

Isabelle M Dixon
email: isabelle.dixon@irsamc.ups-tlse.fr

Sylvain Rat

Alix Sournia-Saquet

Gábor Molnár

Lionel Salmon

Azzedine Bousseksou
email: azzedine.bousseksou@lcc-toulouse.fr

On the spin-state dependence of redox potentials of spin crossover complexes Dedicated to

Keywords: Spin crossover, Redox potential, Density functional theory, Electronic Structure, Cyclic voltammetry

Resistance switching properties of nanoscale junctions of spin crossover molecules have received recently much interest. In many cases, this property has been traced back to the variation of molecular orbital energies upon the spin transition. However, one can also expect a substantial reorganization of the molecular structure due to charge localization, which calls for a better understanding of the relationship between the redox potential and the spin state of the molecule. To investigate this issue we carried out a detailed density functional theory and variable temperature cyclic voltammetry investigation of the benchmark compound [Fe(HB(1,2,4-triazol-1-yl) 3 ) 2 ] in solution. We show that for a correct thermodynamical picture, it is necessary to take into account the charge transfer-induced electronic and structural reorganization as well as spin-equilibria in the oxidized and reduced species.

Spin crossover (SCO) compounds of 3d 4 -3d [START_REF] Ruiz | Charge transport properties of spin crossover systems[END_REF] transition metal complexes display a reversible switching between the low spin (LS) and high spin (HS) electronic states of the central metal ion, which is associated with a remarkable change of the molecular geometry and various physical properties (electrical, optical, magnetic, caloric, mechanical, etc.). [START_REF] Gütlich | Thermal and Optical Switching of Iron(II) Complexes[END_REF][START_REF] Bousseksou | Molecular Spin Crossover Phenomenon: Recent Achievements and Prospects[END_REF] Consequently, the SCO phenomenon provides an appealing scope for the modulation of charge and spin transport in microelectronic circuits, which has been explored recently in various test devices. [START_REF] Demont | Charge Transport and Electrical Properties of Spin Crossover Materials: Towards Nanoelectronic and Spintronic Devices[END_REF][START_REF] Kumar | Emerging trends in spin crossover (SCO) based functional materials and devices[END_REF][START_REF] Rat | Spin Crossover Nanomaterials: From Fundamental Concepts to Devices[END_REF][START_REF] Bellec | Molecular electronics: Scanning tunneling microscopy and single-molecule devices[END_REF][START_REF] Ruiz | Charge transport properties of spin crossover systems[END_REF] At the macroscopic scale, the dominant transport mechanism in SCO materials is charge carrier hopping via localized electronic states near the Fermi level, which corresponds, in essence, to redox events between neighboring molecules. For this reason, the "bulk" conduction is generally associated with low mobility and pronounced thermal activation. [START_REF] Rosseinsky | Temperature Dependence of Dielectric Relaxation and Conductivity in Mixed-valence Potassium Manganate-Permanganate[END_REF] In the opposite size limit, charge transport is governed by direct tunneling from one electrode to the other. This mechanism is limited by the localization of the electron wavefunction to junctions below ca. 5 nm thickness. [START_REF] Mccreery | A critical perspective on molecular electronic junctions: there is plenty of room in the middle[END_REF] This mode of charge transport refers primarily to single molecule SCO junctions, which have been mostly investigated by scanning tunneling microscopy (STM) and density functional theory (DFT). [START_REF] Bellec | Molecular electronics: Scanning tunneling microscopy and single-molecule devices[END_REF][START_REF] Ruiz | Charge transport properties of spin crossover systems[END_REF] In most cases, the HS state appears more conducting, which was ascribed to the sizeable decrease of the HOMO-LUMO gap when the ligand field decreases. [START_REF] Baadji | Giant resistance change across the phase transition in spin-crossover molecules[END_REF][START_REF] Aravena | Coherent transport through spin-crossover single molecules[END_REF] We shall note, however, that SCO in molecular junctions was achieved in general when strong electronic interactions between the electrode(s) and the molecule(s) were prevented. [START_REF] Jasper-Toennies | Robust and Selective Switching of an Fe III Spin-Crossover Compound on Cu 2 N/Cu(100) with Memristance Behavior[END_REF][START_REF] Miyamachi | Robust Spin Crossover and Memristance Across a Single Molecule[END_REF] In this weak coupling limit, a simple orbital-alignment scheme becomes questionable as the junction exhibits Coulomb blockade behavior. [START_REF] Vela | Electron transport through a spin crossover junction. Perspectives from a wavefunction-based approach[END_REF] Besides these two size limits (sic bulk and molecular), there have been several reports on SCO devices operating in the "intermediate" range of charge transport (between ca. 5 and 50 nm), [START_REF] Demont | Charge Transport and Electrical Properties of Spin Crossover Materials: Towards Nanoelectronic and Spintronic Devices[END_REF] wherein multistep tunneling, field emission, directed inelastic hopping, and other mechanisms may occur. Overall, it appears that, apart from the case of coherent tunneling, redox events in SCO junctions represent a fundamental feature. Hence, understanding the relationship between the redox potential and the spin state of the molecule is of primary importance towards the analysis of charge transport properties.

In the past, this relationship has been investigated mostly in the context of electron transfer processes accompanied by a change of the spin-state of the metal ion, [START_REF] Turner | Coupled electron-transfer and spin-exchange reactions[END_REF] which are of particular relevance for a variety of biochemical reactions [START_REF]The Biological Chemistry of Iron[END_REF][START_REF] Sligar | Alteration of Heme Axial Ligands by Site-Directed Mutagenesis: A Cytochrome Becomes a Catalytic Demethylase[END_REF][START_REF] Scheidt | Spin-state/stereochemical relationships in iron porphyrins: implications for the hemoproteins[END_REF] and electrochemical devices. [START_REF] Watanabe | Redox-Driven Spin Transition in a Layered Battery Cathode Material[END_REF][START_REF] Yang | Designing Redox-Stable Cobalt-Polypyridyl Complexes for Redox Flow Batteries: Spin-Crossover Delocalizes Excess Charge[END_REF][START_REF] Emery | Unidimensional unit cell variation and Fe +3 /Fe +4 redox activity of Li 3 FeN 2 in Li-ion batteries[END_REF][START_REF] Mosconi | Cobalt Electrolyte/Dye Interactions in Dye-Sensitized Solar Cells: A Combined Computational and Experimental Study[END_REF] Obviously, one of the most important factors determining mutually the redox potential, HOMO-LUMO levels and the spin state of transition metal complexes is the ligand field and there is an extensive literature dealing with these relationships among different complexes (for a recent example see ref. 23). On the other hand, due primarily to experimental reasons, relatively few reports have been published on the concomitant investigation of redox and spin-crossover properties of the same complex. [START_REF] Sligar | Spin state control of the hepatic cytochrome P450 redox potential[END_REF][START_REF] Shankar | Lightcontrolled switching of the spin state of iron(III)[END_REF][START_REF] Kadish | Spin State Dependent Redox Properties of the [Fe III (X-Sal) 2 trien] + Spin-Equilibrium System in Solution[END_REF][START_REF] Kadish | Spin-State Dependence of Heterogeneous Electron-Transfer Rates for the [Fe III (X-Sal) 2 trien] + Spin-Equilibrium System in Solution[END_REF][START_REF] Kadish | Relationships between Electron-Transfer Rate Constants of Bis(ligated)(octaethylporphinato)iron(III) Perchlorate and the Presence of a Spin Equilibria[END_REF][START_REF] Zhu | Solvent and Structure Effects on the Spin-Crossover and Electron-Transfer Properties of [Fe III (X-Salmeen) 2 ](PF 6 ) and [Fe III (X-Sal) 2 trien](PF 6 ) Complexes[END_REF] Yet, this provides a unique opportunity to investigate the influence of electronic effects on the redox potential, without the additional complexity brought into by ligand substitution. Notably, Kadish et al. [START_REF] Kadish | Spin State Dependent Redox Properties of the [Fe III (X-Sal) 2 trien] + Spin-Equilibrium System in Solution[END_REF][START_REF] Kadish | Spin-State Dependence of Heterogeneous Electron-Transfer Rates for the [Fe III (X-Sal) 2 trien] + Spin-Equilibrium System in Solution[END_REF][START_REF] Kadish | Relationships between Electron-Transfer Rate Constants of Bis(ligated)(octaethylporphinato)iron(III) Perchlorate and the Presence of a Spin Equilibria[END_REF][START_REF] Zhu | Solvent and Structure Effects on the Spin-Crossover and Electron-Transfer Properties of [Fe III (X-Salmeen) 2 ](PF 6 ) and [Fe III (X-Sal) 2 trien](PF 6 ) Complexes[END_REF] reported on a series of cyclic voltammetry (CV) experiments with different ferrous and ferric SCO complexes in solution allowing them to discuss mechanisms relating spin equilibrium and electrochemical reduction and/or oxidation. However, in CV measurements the kinetics of spin-exchange reactions near room temperature is so fast (rate constants range typically between 10 6 -10 9 s -1 ) [START_REF] Brady | Time-Resolved Relaxation Studies of Spin Crossover Systems in Solution[END_REF] that they remain in equilibrium relative to electrochemical events (at typical voltammetric sweep rates). [START_REF] Turner | Coupled electron-transfer and spin-exchange reactions[END_REF] This means that the standard reduction and oxidation potentials cannot be experimentally determined in both spin states. Yet, voltammetry remains a valuable tool to verify the validity of redox potentials calculated by quantum chemistry methods.

In this work, we used a DFT approach, which is the most commonly used computational approach in the SCO field, [START_REF] Paulsen | Progress in Electronic Structure Calculations on Spin-Crossover Complexes[END_REF][START_REF] Daku | Modeling Transition Metal Complexes in the Framework of the Spin-Crossover Phenomenon: A DFT Perspective[END_REF][START_REF] Cirera | Benchmarking Density Functional Methods for Calculation of State Energies of First Row Spin-Crossover Molecules[END_REF][START_REF] Kepp | Theoretical Study of Spin Crossover in 30 Iron Complexes[END_REF][START_REF] Reiher | Theoretical Study of the Fe(phen) 2 (NCS) 2 Spin-Crossover Complex with Reparametrized Density Functionals[END_REF][START_REF] Ashley | Ironing out the photochemical and spin-crossover behavior of Fe(II) coordination compounds with computational chemistry[END_REF] to study the redox reactions of the HS and LS states of [Fe(HB(1,2,4-triazol-1-yl) 3 ) 2 ] (compound 1). We have chosen this compound because it exhibits spin-equilibrium in solution near room temperature (allowing thus for CV experiments) [START_REF] Janiak | Effects of Nitrogen Substitution in Poly(pyrazoly1)borato Ligands : From Orbital Energy Levels to C-H … O Hydrogen Bonding[END_REF] as well as for its remarkable resistance switching behavior in nanoscale junctions -recently demonstrated in different test devices. [START_REF] Shalabaeva | Room temperature current modulation in large area electronic junctions of spin crossover thin films[END_REF][START_REF] Poggini | Vertical Tunnel Junction Embedding a Spin Crossover Molecular Film[END_REF]

Results and Discussion

As shown in the Kohn-Sham MO diagrams of the neutral species of 1 (Figure 1), the HOMO-LUMO gap significantly decreases from 1 LS (4.4 eV) to 5 HS (2.8 eV), in agreement with previous experimental and theoretical data on various SCO molecules. [START_REF] Ruiz | Charge transport properties of spin crossover systems[END_REF][START_REF] Baadji | Giant resistance change across the phase transition in spin-crossover molecules[END_REF][START_REF] Aravena | Coherent transport through spin-crossover single molecules[END_REF][START_REF] Jasper-Toennies | Robust and Selective Switching of an Fe III Spin-Crossover Compound on Cu 2 N/Cu(100) with Memristance Behavior[END_REF][START_REF] Miyamachi | Robust Spin Crossover and Memristance Across a Single Molecule[END_REF] The intermediate spin species has an intermediate gap (3 eV, Figure S1). Optimization of neutral low spin ( 1 LS), intermediate spin ( 3 IS) and high spin ( 5 HS) states of 1 was complemented by the optimization of reduced and oxidized species of doublet, quartet and sextet spin multiplicities ( 2 LS ox , 2 LS red , [START_REF] Kumar | Emerging trends in spin crossover (SCO) based functional materials and devices[END_REF] IS ox , [START_REF] Kumar | Emerging trends in spin crossover (SCO) based functional materials and devices[END_REF] IS red , [START_REF] Bellec | Molecular electronics: Scanning tunneling microscopy and single-molecule devices[END_REF] HS ox and 6 HS red ). This latter part of the work is crucial as it brings fundamental insights into the relaxed geometries and electronic structures of these species. (See the Supporting Information, SI, for the computed data, including geometries, energies and orbitals.) Oxidation of the 1 LS species yields a doublet state after removal of one electron from a metallic non-bonding orbital, inducing slight contractions of all Fe-N bonds in the iron(III) species. On the other hand, reduction of 1 LS initially occurs on the ligand-based LUMO (kinetic product) but, following relaxation, yields the 2 LS red species with a formally reduced d 7 iron(I) center (thermodynamic product) resulting from the formal addition of one electron into the LUMO+5 of 1 LS. Following the optimization of two different reduction products starting from the LS state (depending on the optimization convergence criteria), the minimum energy path connecting these two species was computed using the Nudged Elastic Band method. We have previously shown that this method was indeed applicable to molecular open-shell species, provided some caution is taken in order to converge the wavefunction to the desired electronic state. [START_REF] Göttle | Pivotal Role of a Pentacoordinate 3 MC State on the Photocleavage Efficiency of a Thioether Ligand in Ruthenium(II) Complexes: A Theoretical Mechanistic Study[END_REF][START_REF] Dixon | Theoretical illumination of highly original photoreactive 3 MC states and the mechanism of the photochemistry of Ru(II) tris(bidentate) complexes[END_REF] In the starting state, the unpaired electron is located in a ligand-based π* orbital; in the final state, the unpaired electron is located in a metal-based dσ* orbital. Consequently the relaxed geometries are clearly distinguishable, with two elongated Fe-N bonds in the final state (+0.45 Å, Table S2). The internal conversion between the two doublet states corresponds to the transfer of an electron from the ligand to the metal and is accompanied by an increase of one unit in the Mulliken spin population on Fe. This is reminiscent of the 3 MLCT -3 MC internal conversion process occurring for instance in [Ru(bpy) 3 ] 2+ . [START_REF] Soupart | DFT rationalization of the room-temperature luminescence properties of Ru(bpy) 3 2+ and Ru(tpy) 2 2+ : 3 MLCT-3 MC minimum energy path from NEB calculations and emission spectra from VRES calculations[END_REF][START_REF] Soupart | Exploration of Uncharted 3 PES Territory for [Ru(bpy) 3 ] 2+ : A New 3 MC Minimum Prone to Ligand Loss Photochemistry[END_REF] In the current case, an energy barrier as low as 0.06 eV was obtained (Figure 2). Therefore it would seem very difficult, if not impossible, to observe by conventional electrochemistry techniques a reduction product that would differ from the low-lying thermodynamic reduction product involving metal-centered reduction. Let us now examine the redox processes from 5 HS. The least bound electron in [START_REF] Rat | Spin Crossover Nanomaterials: From Fundamental Concepts to Devices[END_REF] HS is a β electron located in a metallic dπ orbital (eigenvalue -5.05 eV). Removal of this electron leads to [START_REF] Bellec | Molecular electronics: Scanning tunneling microscopy and single-molecule devices[END_REF] HS ox with contracted Fe(III)-N bonds. Alternatively, formal removal of the second least bound electron (α electron located in a metallic dσ* orbital, eigenvalue -5.94 eV) leads to [START_REF] Kumar | Emerging trends in spin crossover (SCO) based functional materials and devices[END_REF] IS ox .

Interestingly, these two Fe(III) states are very close in energy after relaxation, [START_REF] Kumar | Emerging trends in spin crossover (SCO) based functional materials and devices[END_REF] IS ox being actually 0.14 eV lower than [START_REF] Bellec | Molecular electronics: Scanning tunneling microscopy and single-molecule devices[END_REF] HS ox (this value lies within the accuracy of the method). We would thus expect [START_REF] Bellec | Molecular electronics: Scanning tunneling microscopy and single-molecule devices[END_REF] HS ox to be the kinetic oxidation product, eventually populating [START_REF] Kumar | Emerging trends in spin crossover (SCO) based functional materials and devices[END_REF] IS ox following spin crossover (Scheme S1). In terms of reduction, this could take place either on the metal (β dπ orbital, eigenvalue -2.25 eV) to yield [START_REF] Kumar | Emerging trends in spin crossover (SCO) based functional materials and devices[END_REF] IS red or on the ligands (α π* orbital, eigenvalue -0.95 eV) to yield [START_REF] Bellec | Molecular electronics: Scanning tunneling microscopy and single-molecule devices[END_REF] HS red . In this case there is a clear energy gap between these two relaxed states (about 1 eV) in favor of [START_REF] Kumar | Emerging trends in spin crossover (SCO) based functional materials and devices[END_REF] IS red , which bears a formal Fe(I) center. Scheme 1 gives an overview of the energetics of the different oxidation and reduction products. It must be noted that these electronic energies were obtained by performing single point energy calculations in acetonitrile solvent, at the vacuum-optimized geometries, in order to be similar to the experimental conditions of the electrochemical studies (vide infra). Overall, the calculations point to metal-based thermodynamic redox products in all instances.

As estimated from the eigenvalue of the least bound electron (HOMO) in the parent neutral species (-5.42 eV in 1 LS; -5.05 eV in 5 HS), oxidation is expected to be slightly easier in the high spin species. In contrast, as estimated from the energy gaps between optimized species ( 2 LS ox -1 LS: 5.08 eV; 6 HS ox -5 HS: 5.36 eV), oxidation is expected to be slightly more difficult for the high-spin species. We expect the latter method, which takes into account the relaxation of the redox species, to be in better agreement with experiment. Following the same line of reasoning based on thermodynamic considerations, the reduction of [START_REF] Rat | Spin Crossover Nanomaterials: From Fundamental Concepts to Devices[END_REF] HS is expected to be easier than the reduction of 1 LS. As indicated in Scheme 1 (see also Scheme S1 in the SI), minimum energy crossing points (MECP) have been optimized in the neutral, cationic and anionic species as their energies and geometries inform us on the ease for the system to undergo spin crossover. It turns out that all MECPs are very close in energy and geometry to one of the neighboring minima (<0.1 eV). As a result, spin crossover processes are expected to be easy whatever the starting spin state and whatever the charge.

In order to assess the validity of our calculations we have conducted a cyclic voltammetry investigation of the redox properties of compound 1 at two different temperatures. Details of the CV experiments and results are given in the SI. Briefly, the electrochemical oxidation of 1 in acetonitrile involves a reversible one-electron transfer that may confidently be ascribed as an Fe(III)/Fe(II) redox process with a half-wave potential of E 1/2 = +1.01 V vs. SHE (standard hydrogen electrode) at 298 K and +1.09 V vs. SHE at 343 K. On the other hand, the reduction of 1 turned out to be electrochemically irreversible and very sensitive to the experimental details.

For this reason, we restrict the following discussion to the oxidation process. In acetonitrile, 1 displays a gradual spin conversion with an equilibrium temperature of ~293 K (as estimated from temperature-dependent UV-vis absorption spectroscopy, Figure S5). In our experimental conditions, the proportion of LS species drops from 50% at room temperature to 10% at high temperature. This means that the HS and LS species are in equilibrium with fast interconversion rates in the whole temperature range of the CV experiments, which prevents the assessment of the redox potential of both species. We can assume that the observed process corresponds to the oxidation of the most oxidizable species, i.e. the LS species according to the DFT results. As discussed in ref. 15, in coupled oxidation and spin-exchange processes, the oxidation potential can be written as:

E°o x  E°L S -(RT/F)ln(n LS ) (1)
where n HS and n LS are the temperature dependent HS and LS fractions, respectively, R is the molar gas constant and F is the Faraday constant (n LS 298K = 0.5, n LS 343K = 0.1). Thus eq. ( 1)

predicts an increase of ca. +50 mV of the oxidation potential when going from 25 to 70°C, which is indeed very close to the experimentally observed value of +80 mV. This discrepancy could be related to solubility issues, which contribute to the temperature dependence of E 1/2 . Then we can estimate the value of E°L S = 1.03 V vs. SHE. Taking into account the literature value of Gibbs free energy change of SHE (G°S HE = -4.28 eV) [START_REF] Kelly | Aqueous sol ation ree energies o ions and ionwater clusters based on an accurate value for the absolute aqueous solvation free energy of the proton[END_REF] and the Gibbs free energy change for the oxidation of the LS species (reoptimized in solvent, G 1 LS/ 2 LSox = 5.09 eV, Table S4) the calculations give E°L S = 0.8 V vs. SHE, in reasonably good agreement with the experiment.

Additionally, reoptimization of 5 HS, [START_REF] Bellec | Molecular electronics: Scanning tunneling microscopy and single-molecule devices[END_REF] HS ox and 4 IS ox in solvent confirms the degeneracy of the quartet and sextet oxidized species, and confirms that the high spin complex should be more difficult to oxidize (G 5 HS/ 6 HSox = 5.46 eV, G 5 HS/ 4 ISox = 5.43 eV, Table S4) than the low spin complex.

Conclusion

In summary, through a detailed DFT study of the oxidation and reduction processes in the spin crossover complex [Fe(HB(1,2,4-triazol-1-yl) 3 ) 2 ], we have shown that there is no unequivocal connection between the frontier molecular orbital diagram and MO eigenvalues of the neutral molecule and the redox potentials in the two spin states. The effects of electronic repolarization and geometric relaxation in the oxidized/reduced species, as well as spin-state equilibria in the different oxidation states, turned out to be substantial on the localization of the redox events, hence on the electronic structures and final relaxed geometries, explaining why considering solely the HOMO and LUMO of the parent species can be misleading, particularly in spin crossover complexes. As an illustration, during the course of the calculations, we have encountered what can be seen as kinetic oxidation or reduction products as well as a thermodynamic oxidation or reduction products. As such, the computational results obtained here allow to shed light on some aspects that have not received enough attention in the rationalization of combined charge transfer and spin crossover phenomena, which are relevant not only for SCO-based electronic junctions, but also for a variety of biochemical, catalytic and energy storage/conversion processes.

ASSOCIATED CONTENT Supporting Information. The following files are available free of charge. Experimental and computational details. Supplementary CV, UV-VIS and DFT data (PDF).

Table of Contents

Synopsis

In a joint DFT and experimental study, we have explored the interplay between redox and spin crossover processes in [Fe(HB(1,2,4-triazol-1-yl) 3 ) 2 ] in MeCN solution (25 and 70°C). The electronic structure of all spin and redox species is reported. This is required to decipher the variety of processes occurring upon removal or addition of an electron to the complex. This work highlights that a simple picture based on the HOMO-LUMO levels of the neutral HS and LS species cannot provide even a qualitative link between redox potential and spin state of the complex.

Figure 1 .

 1 Figure 1. Kohn-Sham MO diagrams of the neutral 1 LS and 5 HS species showing the calculated HOMO-LUMO gap (single point energy calculation with CPCM-MeCN at the vacuum optimized geometry). Selected orbitals: d block and lowest-lying ligand-based unoccupied orbital or spin-orbital (eigenvalues in eV).

Figure 2 .

 2 Figure 2. Minimum energy path connecting the kinetic and thermodynamic reduction products of the LS state. The x-axis represents the geometric distortion along the reaction coordinate: at x = 0, ligand-based reduction product; at x = 1, metal-based reduction product (the lines are guides to the eye). Singly-occupied molecular orbital of each 2 LS red species is shown.

Scheme 1 .

 1 Scheme 1. Electronic energy gaps (eV) with respect to the LS state (B3LYP* in CPCMacetonitrile). Discs stand for local minima. Arrows indicate the various connections through redox (thick arrows) or spin crossover (thin arrows) processes.

ACKNOWLEDGMENT HPC resources at LCPQ are gratefully acknowledged, as well as discussions with F. Alary and J.-L. Heully.

AUTHOR INFORMATION

Corresponding Authors * isabelle.dixon@irsamc.ups-tlse.fr, azzedine.bousseksou@lcc-toulouse.fr

Notes

The authors declare no competing financial interest.


Ludovic Bellebon

Mauricio Hoyos

Jean - Luc

Acoustic reconcentration or separation of cells

come   L'archive ouverte pluridisciplinaire

Acoustic reconcentration or separation of cells

Ludovic Bellebon 1 , Mauricio Hoyos 1 and Jean-Luc Aider 1

1 Laboratoire Physique et Mécanique des Milieux Hétérogènes (PMMH), UMR7636 CNRS, ESPCI Paris -PSL, Paris Sciences Lettres, Sorbonne Université.

By using an acoustic field in a cavity, we create a standing wave composed of one pressure node. A pressure gradient is created in the cavity, which allows us to manipulate micron-size objects like particles or living cells. Thanks to a force called the Acoustic Radiation Force (ARF) [START_REF] Yosioka | Acoustic radiation pressure on a compressible sphere[END_REF], these objects will move toward the nodal plane at mid-height of the cavity where they will be trapped in acoustic levitation. Each type of cells has mechanic properties (size, density, compressibility), which define their reaction to the acoustic force. Larger, denser, stiffer cells will undergo larger ARF. It is then possible to separate two types of cells in a microchannel using their relative response to the ARF. This non-intrusive method (no contact, no marker) has a lot of potential and can become a useful alternative to classic separation methods like centrifugation or immuno-magnetism.

In this study, we firstly characterize our micro-channel to know the position of the nodal plane depending on the frequency [START_REF] Dron | Varying the agglomeration position of particles in a microchannelusing Acoustic Radiation Force beyond the resonance condition[END_REF]. We show that a small shift of the frequency can change the position of aggregation of cells from the bottom to the top of the channel. We also observed that the medium (plasma or cell culture medium) could react to the acoustic force. A shift in frequency is measured depending on the medium used for cells culture.

The first and easiest application is to increase the concentration of a cell suspension. In this case, we force the cells to reach the nodal plane to be collected in the central outlet.

The second, more challenging application is separation. First, we measure the focalisation velocity toward the nodal plane of cells we want to separate. If two types of cells are mixed, each type will have a focalisation velocity different from the other. Like the position of the nodal plane, this velocity will vary depending the frequency. Knowing these two parameters, we apply the adequate flow rate and acoustic parameters to separate the two populations. Cells with higher acoustic contrast factor reach the nodal plane faster and can be collected in the central outlet while cells with a lower acoustic contrast factor stay on the borders of the channel and be can collected in the lateral outlets. For example, if we use, total blood, Red Blood Cells (RBC) will focus to the central outlet and be separated from platelets which will be collected in the lateral ones.

Different set-ups, using different combinations of transducers, with or without gravity, have been tested. We already achieved reconcentration of HepaRG cells where we increased significantly the concentration rate. We also showed that we can choose in which outlet we want to collect the cells just by moving the nodal plane with the frequency. We also achieved first separation experiments between red blood cells (RBC) and platelets in plasma. We succeeded to double the initial concentration of RBC in one outlet.

Figure 1 .

 1 Figure 1. Micro-channel view from the side. Cells to separate are injected from the lateral inlets. A piezoelectric transducer creates a stationary wave in the channel inducing a nodal plane at midheight. Thanks to the ARF, cells will move to the nodal plane. Big cells will move faster than small cells authorizing a separation. Small cells are collected in the lateral outlets while big cells are collected in the central outlet with a buffer for collection.

Figure 2 .

 2 Figure 2. Concentration of HepaRG cells in the outlet opposed to the transducer, central outlet and the outlet adjacent to the transducer (from left to right). The three top images are observation without acoustic field while the three bottom images are observation after passed the channel under acoustic. Frequency: 2.1MHz, Voltage: 20V, Flow rate: 1.5 mL/min A major part of cells have been collected in the central outlet.


Ludovic Bellebon
email: ludovic.bellebon@espci.fr

Deborah François

Mauricio Hoyos

Jean-Luc Aider

Control of a Bulk Acoustic Wave micro-channel through frequency shifting and its application to cell reconcentration

Introduction

Tuning the acoustic frequency of a Bulk Acoustic Wave (BAW) resonator is the first step before using any acoustofluidics setup, precisely because the Acoustic Radiation Force (ARF) is supposed to be maximum if the resonance condition (ac = 2.h, with h the height of the cavity and ac the acoustic wavelength) is satisfied. If this condition is theoretically simple, it is much more difficult to find the right acoustic frequency when dealing with an actual experimental setup where multiple imperfect boundary conditions have to be dealt with, from the transducer to the reflector and through the transmitter and fluid layer. Many studies have been devoted to this issue, searching for a possible simple method to find the optimal frequency based on electric measurements, admittance or impedance measurements [1][2][3].

In this study we are interested in using the acoustic frequency as a way to control some of the main characteristics of an acoustofluidics cavity or micro-channel. Indeed, it was shown by Dron & Aider [4] that it is possible to move the axial position of the levitation plane zfoc along the entire height of a micro-channel just by shifting the acoustic frequency over a wide range of acoustic frequency centered on the optimal frequency of the transducer (from 1.6 to 2.8 MHz). In this experimental work we go further and show that this phenomenon is robust and can be used to control the position of acoustic focusing as well as the axial acoustic focusing velocity of particles. Finally this approach is applied successfully to various biological cells for cellreconcentration applications.

Height and axial velocity depending the frequency

Using microscopy, we measured the evolution of the axial position of the levitation plane as a function of the acoustic frequency for different types and sizes of particles (10µm and 20µm polystyrene particles and 5µm silica). The channel height is h = 400µm, which corresponds to an optimal resonant frequency Fac = 1.9MHz. As shown on Fig. 1, the axial location of the levitation plane can be moved nearly over the full height of the channel, depending on the type of particles, over a wide range of acoustic frequencies, from 1.4MHz to 2.8MHz. The first observation is that zfoc decreases as the frequency increases. For low frequencies, the levitation plane is close to the transmitter wall and as we increase the frequency, it moves toward the opposite wall of the transducer. It is important to notice that the levitation planes are stable, i.e. the particles can be kept in levitation for each position. To go further, it is important to measure the axial focusing velocity vfoc as a function of the acoustic frequency, in order to assess the yield of the system, as it is directly correlated to the magnitude of the ARF. We measure vfoc using the defocusing technique as presented in [5]. Two peaks of maximal velocities are observed around the resonant frequency (Fig. 1b). This velocity decreases for higher or lower frequencies; nevertheless the velocity is close to its maximum value over a relatively broad range of frequency (0.2MHz). Knowing the frequency dependency of these two parameters it is possible to use it to optimize either separation or reconcentration processes.

Application to cell reconcentration

In order to validate these results in an actual acoustofluidics reconcentration setup, we apply this approach to various cells, illustrated here on Non Parenchymal Cells (NPC). We vary Fac from 1.9MHz to 2.5MHz for a given flow rate of 1.5mL/min and a given voltage of 20V. Samples are collected in three different outlets of the micro-channel: one outlet is close to the transmitter wall, another collect the fluid at the mid-height of the channel while the third collect samples close to the reflector wall (opposite outlet). The result is shown on Fig. 2. We succeed to collect most of the cells in different outlets depending on the frequency. Most of the cells were collected in the adjacent outlet for 1.9MHz, in the central outlet for 2.1MHz and in the opposite outlet for 2.5MHz, in agreement with the frequency evolution shown in Fig. 1.

Conclusion

In this experimental study, we demonstrate that it is possible to control some of the main properties of a broadband bulk acoustic wave micro-channel just through the proper choice of the acoustic frequency. We show that it is possible to control the axial position of the acoustic levitation plane as well as the focusing velocities of particles by tuning the acoustic frequency and we apply it successfully to a reconcentration process of NPC cells.

Figure 1 :

 1 Figure 1: a) Position of 10µm, 20µm polystyrene and 5µm silica particles in micro-channel depending the frequency. Transducer is placed on the upper part of the channel. As we increase the frequency, particles are moving to the opposite wall of the transducer. b) Evolution of the focusing velocity of 5µm silica particles. Two peaks around the resonant frequency are observed while the velocity decreases as we are getting away from it.

Figure 2 :

 2 Figure 2: Pictures of samples of NPC cells in the different outlets after their passage in the BAW micro-channel for a given flow rate (1.5mL/min) and voltage (20V). Depending on the acoustic frequency the concentration of cells is increased in the adjacent outlet (1.9 MHz), central outlet (2.1 MHz) or opposite outlet (2.5 MHz).


Nicolas Dejon
email: nicolas.dejon@orange.com

Chrystel Gaber
email: chrystel.gaber@orange.com

Gilles Grimaud
email: gilles.grimaud@univ-lille.fr

Perspectives on security kernels for IoT

IoT market's growth surge encouraged developers to focus on fast delivery rather than security resulting in several major attacks. Efforts to provide secure-by-design applications or IoT devices rely on trusting physical secure elements or on the lower software layers. Thus, the entire system roots its overall security in the kernel given it is the first software layer above the hardware. However, constrained objects often struggle to combine functionality and security due to inherent low resources and few mechanisms address this problem. In this article, we explore existing approaches and highlight the need for a minimal and formally proven root of trust for constrained objects while presenting the challenges this implies.

I. INTRODUCTION

Today, Internet of Things (IoT) enters a popularization phase and impacts the professional and personal spheres of a growing number of users. IoT is a paradigm that evolved steadily since its apparition in 1999, and according to most forecasting reports, it will become generalized in the years to come [START_REF] Radanliev | New developments in Cyber Physical Systems , the Internet of Things and the Digital Economy -discussion on future developments in the Industrial Internet of Things and Industry 4 . 0[END_REF].

The pace of change and the associated consequences will be pushed by the number of connected devices expecting to explode in the next few years. Indeed, Gartner, which closely follows the trends in IoT, expects a high market adoption by 2023. Gartner calculated that 8.4 billion IoT things were in use in 2017 and forecasts 14.2 billion connected things in 2019 (almost double in two years) and will eventually reach 25 billion by 2021. These devices will conquer homes and industries and the market will mostly be driven by consumer devices [START_REF] Gartner | Top strategic iot trends and technologies through 2023[END_REF].

This substantial twist in the IT market may revolutionise the business environment: costs reduction through the collected data, new business opportunities, and new services. However, IoT products and services are disadvantaged compared to nonconnected devices, because of the concern over cybersecurity risks.

This clearly shows that the ecosystem is at risk and must be protected in order to build a resilient user trusted system. The research community is particularly concerned about the IoT security topic, given the number of devices to be connected and the lack of effective countermeasures preventing the current security issues and attacks. By its very nature, the whole IoT ecosystem could fail from internal (unintentionally?) flawed devices that could lead to business disasters, user threats or even life threats.

The explosion of the IoT devices brings a plethora of IoT device applications. In the recent years, these applications leverage advanced security mechanisms and the scientific community made significant efforts on the static and dynamic security analysis of IoT applications [START_REF] Nguyen | IotSan: Fortifying the safety of IoT systems[END_REF], [START_REF] Celik | Soteria: Automated IoT Safety and Security Analysis[END_REF], [START_REF] Dejon | Automated security analysis of iot software updates[END_REF]. However, they all need to trust the software stack underneath and ultimately the layer in interaction with the hardware (CPU, memory, devices). The latter feature is usually accomplished by the kernel and becomes in such way the first software Trusted Computing Base (TCB) of the firmware. If the kernel is badly designed or compromised, no assumptions can be made about the applications that run above, weakening the security trust in the firmware and potentially compromising the whole IoT ecosystem as a consequence.

This paper explores how to build a minimal kernel for constrained devices with strong security guarantees. We show that IoT devices could benefit from formal methods to reach the expected security level and we identify the current challenges. Section I discusses the requirements for a secured IoT ecosystem built up from trusted devices, which roots in the firmware and its kernel security. Then, section II analyses the state-of-the-art for secure kernels with a specific attention on formally proven kernels. Section III describes the IoT device specificities and the obstacles hindering the use of the methodologies described previously. Section IV identifies future works and perspectives in the design of a formally proven kernel. Finally, section V concludes this paper.

II. STATE-OF-THE-ART A. Kernels

Kernels vary in size and exposed features. Two main categories are frequently opposed: monolithic kernels and microkernels.

Monolithic kernels are usually used by general-purpose operating systems, like Linux for UNIX-like operating systems. They concentrate all the functionalities required to run exclusively the applications and the user interface in user mode. The kernel itself exposes a large API that surfaces an important code base (Linux is composed by more than 36 millions of lines of code [START_REF] Openhub | Website of : Linux statistics[END_REF]). However, customization can reduce drastically the code base (e.g. MuLinux [START_REF] Andreoli | Website of : Linux statistics[END_REF]) and modules can be loaded at runtime which makes it a modular kernel.

Microkernels reject outside the kernel space most of the core features of the monolithic kernels. Thus, they provide only a minimal set of system calls, automatically reducing the attack surface. These system calls are then used by outside servers (programs) that will reproduce the lost features of the monolithic kernels. This way, the kernel code base scales down a lot. However, due to frequent privilege switches between kernel and user spaces, the performances were quite low. The L4 microkernel family [START_REF] Liedtke | Towards real microkernels[END_REF] solved this issue by identifying four major features: virtual memory management, threading, scheduling and inter-process communication.

Many other kernel types exist, such as the experimental pip "protokernel" [START_REF] Jomaa | Formal Development of the Pip Protokernel[END_REF] that restricts even further the exposed features. It only provides virtual memory management and context switching, and leaves all the rest in userland.

B. Design of a secure kernel

Each kernel comes with its own set of strengths and weaknesses and reasons to choose a particular design, but they all share the desire to build a secure kernel.

Security by memory isolation for a kernel can be understood in terms of confidentiality and integrity of the data between the programs and with the kernel. Separation kernels [START_REF] Rushby | Design and verification of secure systems[END_REF] create these isolated environments by simulating a distributed system within a single physical machine.

However, in IoT, common security mechanisms like kernel and process memory isolation are usually not employed. Indeed, many IoT devices have real-time constraints that can't be met by using kernel memory isolation due to frequent privilege switching, or don't possess the required hardware commonly used like the MMU (Memory Management Unit). Yet, recent efforts made it possible to meet all expectations of a real-time system together with the memory isolation capability using the MPU (Memory Protection Unit) [START_REF] Kim | Securing Real-Time Microcontroller Systems through Customized Memory View Switching[END_REF]. MPU has also already been showed important to ensure the integrity and confidentiality of Java Card applets by confining the executable code into sandboxed interpreters [START_REF] Bouffard | Hardening a Java Card Virtual Machine Implementation with the MPU[END_REF].

Programs don't necessarily require hardware mechanisms to be confined. For example, remote updates for low-end devices can be provided in the form of Javascript runtime containers [START_REF] Baccelli | Scripting Over-The-Air: Towards Containers on Low-end Devices in the Internet of Things[END_REF].

C. Design of a formally secure kernel

Despite the trust we can put in all these systems, the bound may still be broken by human mistakes during the design or the use of outdated or insecure components (e.g. top 10 IoT vulnerabilties [START_REF] Owasp | Website of : Owasp[END_REF]), and vulnerabilities are still discovered frequently [START_REF]Website of : Cve, linux kernel vulnerabilties[END_REF].

Therefore, pip has been designed specifically to bring the highest guarantees on memory isolation by providing formal proofs. These proofs mathematically demonstrate the announced security properties and the functional correctness of the features exposed by the kernel, helped and stamped "formally proven" by the Coq proof assistant [START_REF]Website of : Coq[END_REF]. The proofs consist in a set of system invariants that should be present before and after a kernel system call. They are all provided in the form of Hoare triples.

Since the properties that emanate from the kernel are the basis for the exposed security features, they also need to be trusted. These are made simple enough to convince their trustworthiness.

Memory isolation in pip is hardware-enforced by the use of an MMU. Indeed, by controlling the memory pagination, the system could implicitly build an access control mechanism, restricting the use of the memory per running entity (kernel, operating system, programs, threads...). Memory isolation is thus dependent on the correct configuration of the MMU tables, which is the only role assigned to pip as a protokernel.

The sole feature provided by pip creates a very small TCB making the cost of proof to the minimum possible for a kernel.

III. DESIGN OF A FORMALLY SECURE KERNEL FOR CONSTRAINED OBJECTS

IoT devices can be deployed for years and sometimes in difficult reachable areas. Recent works regarding remote accessibility and remote updates like SUIT [START_REF]Website of : Ietf suit draft architecture[END_REF] would benefit from memory isolation guarantees. Indeed, such guarantees would allow the coexistence of modules with different security and update needs. For example, one could design a minimal isolated kernel with little update needs and sandboxed applications with high update needs. Update of the business logic in the sandboxed applications could be more performant since a full update could be avoided. Such devices could also have strong real-time requirements which should cohabit with expected/needed security.

While the state-of-the-art proposals provide some suitable solutions for IoT devices, they are usually not formally proven. In the case they are, pip and other formally proven kernels like seL4 [START_REF] Klein | SeL4: Formal verification of an OS kernel[END_REF] from the L4 family strongly rely on the hardware mechanisms of the MMU to conduct their proofs. Due to their constrained resources such as a minimal memory, these IoT devices would most likely include an MPU instead of an MMU, which implies that these formally proven solutions can't be totally usable in the pursued context. To the best of our knowledge, MPU-based proofs are not openly provided to the community (e.g. ProvenCore [START_REF] Lescuyer | ProvenCore : Towards a Verified Isolation Micro-Kernel[END_REF]) but convince us that such solutions are reachable.

IV. CHALLENGES AND PERSPECTIVES

Several scientific challenges and perspectives arise from this point.

Given the presented landscape, there is a possibility to bring native security to IoT devices to replace the trust we have in the kernel with a formal guarantee of security (in the sense of memory isolation).

During this process, new properties required to assure memory isolation in systems could be discovered. The formal verification could follow already employed methods, or explore other techniques like separation logic. Challenges are also to be found in the formulation of the proofs that will need to interface with the real-world, which includes hardware, people and execution environments in the IoT context.

Furthermore, the cost of proof of current solutions is high. IoT devices, even low-end devices with very constrained resources, still are complex systems. Efforts and techniques to bring down this cost of proof are needed to make it suitable even for low-cost devices.

In addition to that, no current formally proven kernels seem to fully cover all existing architectures composed by a different hardware (MMU and MPU together for example). Generalization efforts are needed to cover other hardwareenforced access control mechanisms.

Lastly, the ARMv8-M architecture is currently under a formal verification process [START_REF] Reid | Who guards the guards? formal validation of the Arm v8-m architecture specification[END_REF] and gives the opportunity to explore the proof even beneath the software stack and bridge the proof across the hardware.

V. CONCLUSION

Security in kernels is of uppermost important to make any assumption about the overall security of a system. Being the first fundamental software component which interfaces with the hardware, the kernel is expected to have strong security guarantees. This can be achieved by applying formal methods as current solutions propose, however they are usually hardware dependent, not transferable between different architectures and hardware compositions, and not applicable in the context of IoT and its constrained devices because of limited resources or without compromising with the required performances. Future challenges thus include to identify the minimum set of required features to build-up a secure kernel, to push forward and extend current formal proofs to cover distinct architectures at the same time in a cost of proof effective manner, and to trim down the assumptions by exploring the potentials with on-going hardware verification efforts.

ACKNOWLEDGMENT

The authors would like to address their heartful thanks to Narjes Jomaa.


The Future Arctic Ocean Observing System

Authors: Sagen, Hanne 1); Sandven, Stein1);;Hamre, Torill1);; Sørensen, Mathilde2);; Soltwedel, Thomas3);; Beszczynska-Møller, Agnieszka4);; Blondel, Philippe5);; Sejr, Mikael6);; Houssais, Marie-Noelle7);; Tronstad, Stein8);; Voss, Peter9);; Rønning, Bjørn10);; Worcester, Peter F. 11);; Matthew Dzieciuch11);; The Arctic region is exposed to significant environmental changes including the overall thinning and melting of sea ice, which opens up new areas for resource exploitation and ship traffic. The increased human activities will put more pressure on the Arctic ocean environment including the underwater acoustic environment. While polar orbiting satellites collect large amounts of data from the ocean surface including sea ice (e.g. the Sentinel programme under Copernicus), there are huge gaps in the data coverage under the sea ice. The Arctic Ocean is among the least observed oceans in the world, and there is practically no long-term observing infrastructure for the central Arctic Ocean. Around 70 % of the ocean data collected in the Arctic are funded by time-limited research programs. It is therefore important to establish long-term funding of ocean observing in the Arctic (Ludwigsen et al. 2018).

The United Nations have dedicated the next decade to achieve sustainable development goal number 14 (SDG14): 'Conserve and sustainably use the ocean, seas and marine resources for sustainable development'. Existing ocean research and observing systems must be improved significantly to achieve this. At the OceanObs19 several recommendations were made for the way forward to establish sustainable ocean observing systems globally and regionally. The recommendations include crossdisciplinary engagement and partnership, addressing stakeholder and societal needs as well as improved and shared technology for ocean observing. From the OceanObs19 Arctic Observing Breakout session it was recommended that "by 2029, the Arctic should prominently demonstrate that it has a fully developed, implemented, sustained ocean observing system that meets -at a minimum earth system prediction needs -but also other critical societal needs."

Several European and national infrastructure programs, plan or have already started to build ocean components of Arctic in-situ observing systems, addressing specific thematic areas (e.g. ICOS -Integrated Carbon Observation System, EPOS -The European Plate Observing System, Long-Term Ecological Research [LTER] HAUSGARTEN), platform technologies (e.g. NorArgo, EMSO -European Multidisciplinary Seafloor Observatory, FRAM -FRontiers in Arctic marine Monitoring), or regions (e.g. SIOS Svalbard Integrated Arctic Earth Observing System) in order to serve different application areas or stakeholder groups. This leads to a complex landscape of (national) infrastructures which must be coordinated and developed into a holistic and multidisciplinary ocean observing system to efficiently address societal needs. It will be important to define a backbone observing system with long-term funding and show how research program can complement and improve the observing capacity. To support this, it is crucial to develop roadmaps for building and operating an integrated Arctic Ocean Observing System. The roadmaps should address solutions regarding collaboration and governance; best practice and standards for the different subsystems, how data management should be implemented, and which technologies can and should be used.

To make continuous ocean observation in the Arctic requires autonomous systems capable to operate for sustained periods with minimum human interference. A sparse network of drifting ice-based observatories is currently the only source of year-round near real-time ocean data from central Arctic. Deployment of ice-based observatories are relatively expensive and requires ship time with ice breakers into the central Arctic Ocean. Existing autonomous underwater observing platforms frequently used in open ocean such as Argo floats, and gliders are not yet used operationally in ice-covered regions in the Arctic. This is because sea ice prevents satellite connections necessary for navigation and data transfer, and acoustic networks for navigation and communication are only installed and used for time limited experiments e.g. CANAPE in the Beaufort Sea and ACOBAR in the Fram Strait (e.g. Howe et al. 2019).

To improve the Arctic Ocean Observing capability OceanObs19 recommended 'to pilot a sustained multipurpose acoustic network for positioning, tomography, passive acoustics, and communication in an integrated Arctic Observing System, with eventual transition to global coverage' (Howe et al 2019a[START_REF] Mikhalevsky | Multipurpose acoustic networks in the Integrated Arctic Ocean Observing System[END_REF]. Observing systems based on moorings and seafloor installations are multipurpose, robust, provide year-round observations from fixed positions and can support acoustic networks for geo-positioning of underwater platforms independent of ice cover. We recommend that a Future Arctic Ocean Observing System should be based both on mobile and fixed platforms. It is imperative to perform innovation using subsea technology to bring data from underwater installations in near real time.

Cabled systems and observatories are the most secure way to provide a large amount of multidisciplinary data to the user in real-time and would also provide power supply to the instruments. Several large-scale cabled observatories exist in coastal areas in world oceans, but none in the Arctic Ocean. OceanObs19 recommended to transition SMART subsea cable (combined communication and science) systems from present pilots to trans-ocean implementation, to address climate, ocean circulation, sea level, tsunami and earthquake early warning, ultimately with global coverage. Cabled observatories, either stand alone or branching from a hybrid cable system, could provide power and real time communication to support connected water column moorings and sea floor instrumentation as well as docking mobile platforms. In recent years the concept of sharing communication cables with science has been launched as SMARTcables (e.g. Howe et al., 2019b). Subsea communication cable developers are looking into the possibility to deploy a communication cable across the Arctic Ocean from Europe to Asia, because this offers a much shorter communication route compared to the terrestrial cables. The perspective is that this cable also can facilitate for scientific instrumentation. The road towards the operational Future Arctic Ocean Observing System is complex and expensive and needs careful planning to meet the needs from different users and stakeholders e.g. [START_REF] Lee | A framework for the development, design and implementation of a sustained arctic ocean observing system[END_REF]. It is therefore imperative to perform a detailed analysis of the required infrastructure including both fixed and moving platforms. An international consortium of leading scientists in ocean observing with experience in state-of-the-art technologies on platforms, sensors, subsea cable technology, acoustic communication and data transmission should be established to work together across projects to design, test and implement systems building on experience ongoing and previous Arctic observing system experiments.

1)

  Nansen Environmental and Remote Sensing Center, Bergen Norway 2) University in Bergen, Bergen 3) Alfred-Wegner-Institut Helmholtz-Zentrum fur Polar und Meeresforshung 4) Institute of Oceanology Polish Academy of Science, Sopot, Poland 5) University of Bath, United Kingdom 6) Aarhus University, Aarhus, Denmark 7) Centre National De La Recherche Scientifique -CNRS, Paris, France 8) Norwegian Polar Institute, Tromsø, Norway 9) Geological Survey of Denmark and Greenland 10) Digital Footprint AS, Oslo, Norway 11) Scripps Institution of Oceanography, USA


domain: info shs

text:
Anuragini Shirish
email: anuragini.shirish@imt-bs.eu

Shirish C Srivastava

G Shainesh

Can Technology be leveraged for Bridging the Rural-Urban Divide?

Keywords: Rural-urban divide, Reverse innovation, ICT for development, Business model innovation

Inequalities exist and persist in society in different forms and are often areas of prime concern for governments and policy makers around the globe. One such inequality that plagues societies is the rural-urban divide. Several social entrepreneurs are attempting to leverage technology to bridge this divide. In our research-in-progress paper, we describe the case of an Indian company, which is leveraging technology to create knowledge-based jobs for the rural Indian population. The approach adopted by the company in initiating and sustaining such an effort was an inside-out approach in contrast to the usual approach of focusing only on the internal resources within the company. Specifically, our research aims at abstracting the process mechanisms that enabled such an initiative. The unearthed mechanisms would inform future research on the modalities for orchestrating such an initiative. The findings would also help practitioners, especially social entrepreneurs, to think of innovative business models that would create value not only for the company but also for society as a whole. The delineated learnings would also help enthused social entrepreneurs to transplant such initiatives to other regions of the world.

Introduction

Global wealth has risen to a new high of 361 trillion US Dollars in 2019 but unfortunately, only a very small group at the top has captured most of the increase. The top 1 percent of the world's population accounts for nearly 45 percent of the total wealth, while the bottom 50 percent owns only 1 percent of the total wealth [START_REF]Global Wealth Report[END_REF]. Such stark inequalities exist and persist in the society in different forms (e.g. regional, racial and gender) and are often areas of prime concern for governments and policy makers around the globe. For example, the recent yellow vests protests (Gilets Jaunes) in France or the farmer protests in India are attributable to the growing discontentment due to the ruralurban divide [START_REF] Bera | Farmers' protests brings urban rural divide to the fore[END_REF][START_REF] Bruneau | Rural France in Revolt[END_REF]. Although the thorny issue of spanning these societal inequalities are primarily viewed as governmental tasks, several grassroots social entrepreneurs, especially in developing countries are implementing innovative local solutions to bridge these gaps [START_REF] Mair | Institutional Voids as Spaces of Opportunity[END_REF]. Such innovative bridging solutions often involve extensive use of Information and Communication Technologies (ICTs) [START_REF] Sen | Development as Capability Expansion[END_REF]. However, the modalities and mechanisms through which these solutions are orchestrated are highly contextualized and need to be examined [START_REF] Johns | The Essential Impact of Context on Organizational Behavior[END_REF][START_REF] Bamberger | Beyond Contextualization: Using Context Theories to Narrow the Macro-Micro Gap in Management Research[END_REF]. Deep theoretical abstractions emerging from an understanding of these inequality-bridging mechanisms can greatly benefit other inequality-ridden contexts and regions through the process of reverse innovation [START_REF] Govindarajan | Reverse Innovation, Emerging Markets, and Global Strategy[END_REF].

Grounding our work in social resource-based view (SRBV) and the literature on reverse innovation and information systems, we examine an impactful social entrepreneurship initiative in a developing country context, with a view to transplant the learnings to the required pockets in other developing and developed economies [START_REF] Govindarajan | Reverse Innovation: Create Far From Home, Win Everywhere[END_REF][START_REF] Govindarajan | Reverse Innovation, Emerging Markets, and Global Strategy[END_REF][START_REF] Sen | Development as Capability Expansion[END_REF][START_REF] Srivastava | Bridging the Service Divide Through Digitally Enabled Service Innovations: Evidence from Indian Healthcare Service Providers[END_REF]. We believe that such an effort will be useful in developing impactful theories for reducing the inequalities within countries. In our study, we focus on bridging the urbanrural divide, as it is one of the areas that the governments of most countries around the world are concerned. In specific, we focus on a grassroots social entrepreneurship initiative (rather than focusing on government-sponsored initiatives) aimed at reducing the rural-urban inequalities. Our study is set in the Indian context, which serves as a fertile ground for many social entrepreneurship initiatives. As aforementioned, our focus will be on how the learnings/theoretical abstractions from this initiative could be translated to benefit other parts of the world.

The two research questions that we intend to examine in our study are:-1. How are social entrepreneurship initiatives in developing countries conceptualized and executed to bridge the rural-urban divide? 2. What are the key enablers that facilitate delivery of such ICT-enabled bridging solutions in the context of developing countries?

Research Context

To better appreciate the research setting and the problem proposed to be examined in our study, it would be necessary to understand the rural-urban divide in the Indian context. According to the 2011 Census Report, 83.3% of India's population lives in rural areas. However, most economic and service benefits are accrued by the urban centers. For example, in the health care sector nearly 75% of medical dispensaries, 60 % of the hospitals and 80% of doctors are located in urban areas. Similarly, there are limited regular employment opportunities in rural areas leading to a large-scale migration to the urban centers creating undue pressure on the limited resources in Indian cities. According to the 2017 National Economic Survey, 8 to 9 million people migrate for work opportunities within India annually, which is severely affecting the quality of life in urban centers. Some studies have projected that by 2050, more than half of India will be living in urban areas, which will further accentuate the issues related to the quality of life in urban centers.

Background Literature

We ground our research in the social resource-based view (SRBV). So far literature has mainly used the resource based view (RBV) or natural resource based view (NRBV) approach to understand how companies can achieve economic performance or environmental performance as a competitive advantage by using their own internal resources and by deploying internal capabilities [START_REF] Hart | A natural-resource-based view of the firm: Fifteen years after[END_REF]. Recent work by Tate and Bals [START_REF] Tate | Achieving Shared Triple Bottom Line (TBL) Value Creation: Toward a Social Resource-Based View (SRBV) of the Firm[END_REF] uses social entrepreneurship literature and extends the RBV and NRBV logic, which is primarily based on instrumental parameters of economic performance, to that of social performance. In summary, SRBV integrates social capabilities with Triple Bottom Line (TBL) sustainability outcomes related to social, economic and environmental impacts.

Tate and Bals [START_REF] Tate | Achieving Shared Triple Bottom Line (TBL) Value Creation: Toward a Social Resource-Based View (SRBV) of the Firm[END_REF], through inductive case studies, conceptualized several social strategic capabilities, social driving forces and key resources that contribute to shared TBL value creation. An SRBV allows us to study social capabilities, allows us to examine complex stakeholders embedded in different domains such as those with economic, environmental, and/or social stakes. The theory also offers the possibility to link link social capabilities and shared TBL value creation. Thus, SRBV allows us to study the social capabilities of grassroot social entrepreneurs acting as the micro-foundations for bringing about societal change. However, the propositions of SRBV have not yet been tested empirically, and the process view on how the resource and capabilities integration takes place, needs further examination. Because embedded innovation and social innovations are influenced by ambiguities and uncertainties in the external environment, exploring TBL value creation by social entrepreneurs is highly complex. Research that demonstrates how social capabilities are orchestrated by hybrid organizations such as grassroots social entrepreneurs using SRBV for alleviating social issues at the Bottom of the Pyramid (BoP) will be a valuable contribution to academic literature as well as practice [START_REF] Hart | A natural-resource-based view of the firm: Fifteen years after[END_REF][START_REF] Tate | Achieving Shared Triple Bottom Line (TBL) Value Creation: Toward a Social Resource-Based View (SRBV) of the Firm[END_REF].

We believe that actions taken at various stages of an entrepreneurship project in general and a resource-constrained social entrepreneurship project in particular are based on the ability of the entrepreneur to leverage the internal resources within the company and garner resources from outside the company (based on the emergent need) as shown by SRBV. This resource orchestration exercise is a dynamic one that continuously evolves as the project unfolds. Our aim is to understand this evolutionary process with a view to perhaps replicate it in other contexts.

Method

This research aims at theory building by adopting a social resource-based view (SBRV) perspective. We intend to use a qualitative case-based methodology and a process view to analyze data from an Indian company (VillageTechServ 1 ) (VTS) to understand the social resource-based actions that the company undertook to fulfil their objective of creating jobs for the rural Indian population. We will also examine how these patterns evolve over time [see [START_REF] Chakraborty | An Exploration into the Process Requirements Elicitation: A Grounded Approach[END_REF][START_REF] Sarker | Exploring Value Cocreation in Relationships between an ERP Vendor and its Partners: A Revelatory Case Study[END_REF][START_REF] Silva | Fighting Against Windmills: Strategic Information Systems and Organizational Deep Structures[END_REF]. Consistent with the case study approach, we will provide an overview of some of the streams of research that will contribute to our theory building, namely, literature on social resource-based view and the role of ICT for bridging societal inequalities. Finally, we intend to situate each of our findings within the literature to contextualize the emergent theoretical concepts before arriving at our theoretical and practical implications.

Our study utilizes a mix of primary and secondary data to analyze the research problem. We have already conducted 42 interviews and have attended several presentations given by the senior management team of the VTS. Many of the key respondents were interviewed multiple times to clarify new facts as they emerged during the data collection process. We took detailed notes during all interviews. We also had email exchanges with officials for an in-depth understanding of the underlying processes, mechanisms, and interactions associated with their implementation process.

We also visited the VTS work centers at different locations in India and took detailed observational notes during the site visits, which will form part of the data for our analysis. For secondary data, we went through the organizations' activity reports, websites, published articles, internal reports, and video clips. We are using a process view to analyze the data, aimed at unearthing the patterns of their resource-based actions to understand how their implementation unfolded [START_REF] Chakraborty | An Exploration into the Process Requirements Elicitation: A Grounded Approach[END_REF][START_REF] Lyytinen | Explaining Information System Change: A Punctuated Socio-Technical Change Model[END_REF].

Preliminary Findings and Expected Implications

India, traditionally has been one of the world's major IT-services provider hub. However, these IT service centers are primarily located in big cities such as Bangalore, New Delhi, Hyderabad and Chennai. VTS was initiated in 2008 on the premise of creating knowledge-based jobs for rural Indian population. The founder of VTS had the idea of sourcing some of the knowledge work from the villages with a view to provide the rural population with steady incomes through meaningful employment. The mission of VTS is a social oneto enskill, employ, empower and engage the rural youth. Their objective is to provide sustainable employment to 100,000 rural youth by opening business process outsourcing (BPO) centers in each of the 500 rural districts of India. They particularly want to create shared value in TBL, i.e. on the economic front, the social front and the environmental front. They are a hybrid organization that focuses on integrating their resources and capabilities for creating shared values through impact souring, training, rural employment, family saving, social engagement and conserving environmental ecosystems of the local rural districts. As of 2019, they have 16 Business Process Outsourcing (BPO) rural centers in north, south, east, west and central India. 65 percent of their clients are from the telecom sector and the remainder 35 percent comprise di-verse sectors related to logistics and retail. VTS is perhaps the world's largest and relatively oldest (10 years) rural IT services company offering sustainable direct and indirect social value to its stakeholders since its inception.

Although setting a village IT service center may appear to be a straightforward process, it is not a simple exercise. Many of the taken for granted resources in the urban centers are unavailable in rural areas. The two primary contextual constraints, which made this venture extremely difficult, were (1) the rural areas did not have efficient Internet connectivity and regular power supply, and (2) there was an absence of sufficiently trained employable workers for knowledge based IT service jobs in rural areas. To tackle these challenges, VTS took upon itself to arrange for the required infrastructure as well as to develop the required manpower skills for making the IT-enabled service centers operational. Apart from socially driven motivations, the founders of VTS were confident that the trained employees would be permanent assets for the company because the jobs (or rather opportunities) had moved to their villages so there would be less attrition. Job turnover or attrition is one of the major challenges faced by the IT services sector in India (with attrition rates in some cities touching a high of 25%). In addition to having near zero attrition rates, the cost of wages are also much lesser in rural centers simply because the living costs in rural areas are significantly lesser than in cities. Some measurable social value impacts created by VTS include, providing direct employment for 5280 rural youth (in 2018). Out of these 90 percent were internally trained after employment. 40 percent of employment was provided for the female youth. 5 percent of these beneficiary are persons with disabilities. The average family income increased by 65 percent from the current income level due to jobs at VTS. At the societal level the rate of migration from rural area to cities in search of jobs have reduced to 55 percent in the villages where the initiative has been undertaken. A positive spinoff that the research team discovered in its initial interviews is that some of the villages that were initially selected by VTS for starting IT service centers now have permanent schools and the income levels in these villages have risen, leading to better quality of life for many people living in those villages. The journey of VTS has been one of trial and error. In fact, following the philosophy of reverse innovation, VTS has recently started its centers in some of the rural areas in California in the US to serve the underprivileged rural population there.

Thus far, we see empirical evidence for propositions of the emergent theory on SRBV. VTS is an example of how TBL values are generated by grassroots social entrepreneurs who know how to use their social capabilities such as social innovative model, mission driven approach and stakeholder management for bridging opportunity divide in the society. Social values that are generated by this initiative include providing access to food, access to decent livelihood, access to education, access to secure income, access to meaningful employment, access to equality and access to involve in community engagement. In our research, we seek to unravel these theoretical mecha-nisms which can perhaps be replicated by other aspiring social entrepreneurs. This allows us to understand how social entrepreneurship initiatives in developing countries can be conceptualized and executed to bridge the rural-urban divide. Our study hopes to unearth specific key enablers for facilitating the delivery of ICT-enabled bridging solutions in the context of developing countries.

Name camouflaged -VillageTechServ (VTS for short)


Alexey N Butkevich

Lieven Meerpoel

Ian Stansfield

Patrick Angibaud

Andrei Corbu

Janine Cossy
email: janine.cossy@espci.fr

Tandem Suzuki-Miyaura Coupling/Acid-Catalyzed Cyclization between Vinyl Ether Boronates and Vinyl Halides: A Concise Approach to Polysubstituted Furans

Polysubstituted 2-(ω-hydroxyalkyl)furans were prepared by tandem Suzuki-Miyaura coupling/acid-catalyzed cyclization starting from appropriately substituted 3-haloallylic alcohols and dihydrofuran-, dihydropyran-or glycal-derived pinacol boronates.

The furan ring is a ubiquitous structural motif in many classes of natural products such as pheromones, 1 terpenes 2 and alkaloids (e.g., selaginoidine 3a , nakadomarin A 3b ), as well as in numerous synthetic compounds. In a recent compilation of pharmacologically active furans, 4 it has been demonstrated that a variety of furans, fused furans and furanones exhibit antimicrobial, 5 anti-inflammatory, antiarrhythmic or antihypertensive activities. Two among the most potent hallucinogenic compounds, salvinorin A 6 (neoclerodane diterpenoid and κ-opioid receptor agonist from Salvia divinorum) and bromo-DragonFLY 7 (synthetic 5-HT 2 serotonin receptor agonist), contain a furan ring. Furanosteroid viridin, 8 the naturally occurring fragrance rosefuran, 9 the phytotoxin perilla ketone 10 and unsaturated ketones rehmanones AÀC, 11 all of which are diversely substituted furans, demonstrate the great variety of furan-derived natural products.

Several recent reports illustrated the synthetic utility of 2-(ω-hydroxyalkyl)furan building blocks. 12À14 These

B

Org. Lett., Vol. XX, No. XX, XXXX compounds have served as starting materials for the preparation of spiroacetal natural products, 12 cis-fused bicyclic ethers 13 by a tandem Achmatowicz reaction/ spiroacetalization approach, and spirocyclic ethers by Piancatelli rearrangement. 14 2-(ω-Hydroxyalkyl)furans are generally prepared by alkylation 15 or acylation 16 of 2-lithiofurans or by addition of organolithium reagents to furfural. 17 In addition, furans with a polyhydroxylated side chain can be conveniently synthesized using the Garcı´a Gonz alez reaction. 18 Allylation of dienol carbonates followed by a Cope rearrangement/reduction/dehydration sequence, recently proposed by our group, leads to a variety of polysubstituted furans. 19 A number of metalcatalyzed furan syntheses have been developed using Au-, Hg-, Ir-, Rh-, Ru-, Pd-and Cu-catalyzed transformations of suitably substituted alkynes, allenes and cyclopropenes. 20 Strong base-catalyzed 21 and oxidative 22 cyclizations of 2-penten-4-yn-1-ols can also lead to polysubstituted furans, and acidic treatment of γ-hydroxy-R,β-unsaturated ketones has been reported to induce furan ring closure under mild conditions. 23 Recently, we have reported a rapid and high-yielding preparation of spiroacetals based on a tandem Suzuki-Miyaura/acid-catalyzed spiroacetalization. 24 Herein, we disclose the outcome of a process involving (Z)-3-haloallylic alcohols instead of 2-halobenzylic alcohols. Upon in situ acidic treatement of the Suzuki-Miyaura coupling products, substituted furans were formed instead of the expected spiroacetals (Scheme 1).

Employing the conditions optimized for the crosscoupling of aryl bromides and aryl iodides [Pd(dppf)Cl 2 (2 mol %), NaOH (2 equiv), dioxane/H 2 O (4:1), microwave irradiation (MW), 100 °C, 10 min followed by pTsOH (2.2 equiv), rt, 10 min] to a panel of subsituted 3-bromoor 3-iodoallylic alcohols, a series of polysubstituted 2-(ωhydroxyalkyl)furans were successfully prepared in moderate to excellent yields (Table 1). 23 The halogenated allylic alcohols were prepared according to literature procedures. 25 From a reactivity standpoint, there was no difference between bromo-and iodoalkenes under the Suzuki-Miyaura coupling conditions, so the substrates were chosen according to their ease of access. The alcohols 3À12 were treated with boronate 1 or 2 under the previously described conditions. 24 The coupling with dihydrofuranyl boronate 1 (Table 1, entry 1) suffered from significantly lower yield because of the sensitivity of the starting boronate and the cross-coupling intermediate. The yields with boronate 2 were generally good to excellent for both 3-bromo-and 3-iodoallylic alcohols. 2,3-, 2,4-, 2,5-disubstitued furans (Table 1, entries 1À4), 2,3,4-and 2,3,5-trisubstituted ( a Yield increased to 34% when the cross-coupling was performed under anhydrous conditions (MeCN, 2 equiv Cs 2 CO 3 ); 3 equiv of TsOH was used for cyclization.

entries 5À7) and fused furans (Table 1, entries 8À11) have been prepared by this one-pot procedure.

The Suzuki-Miyaura coupling intermediates containing 1-aryl-or 1-alkynyl-2-propen-1-ol fragments proved particularly acid sensitive and required the use of the weaker trifluoroacetic acid 26 instead of pTsOH to increase the yield of furans (Table 2). Under these conditions, several 2,5-disubstituted and 2,3,5-trisubstituted furans were prepared.

The reaction is regioselective as only the disubstituted furan 35 was obtained from allylic diol 28 and diol 29 was converted to the trisubstituted furan 36 (Table 2, entries 6 and 7), suggesting that only (Z)-allylic alcohols cyclize to the corresponding furans. Indeed, the (E)-allylic alcohol 30 produced the corresponding R,β-unsaturated ketone 37 as the only major product in 43% yield (Table 2, entry 8). This result indicates that the cyclization of (Z)-allylic alcohols to furans proceeds much faster than the possible acid-catalyzed E/Z-isomerization of the double bond. 27 The preparation of furans possessing a polysubstituted side chain was next investigated. The starting glycal boronates were prepared by Ir-catalyzed CÀH borylation of glycals 38À40 described by Miyaura et al. {B 2 pin 2 (1.2 equiv), [Ir(cod)(OMe)] 2 (1.5 mol %), dtbpy (3 mol %) in hexane}. 28 The reaction was regioselective for glucose derivatives but required prolonged heating (8À16 h in hexane at 80 °C). However, under microwave irradiation, in the presence of an inert microwave absorber (graphite powder) the reaction temperature was increased to 120 °C and the borylation was complete within 15 min, attaining 80À90% conversion of the starting glycal to the corresponding C6-boronate (GC control). The crude boronates thus obtained were used directly in the cross-coupling/ cyclization sequence upon filtration through a short pad of silica and concentration of the filtrate.

The dihydropyranyl pinacol boronates, prepared from tri-O-methyl-D-glucal 38 and tri-O-methyl-D-galactal 39 were involved in the cross-coupling/cyclization process to form furans 41À43 with polysubstituted side chains in 40À91% yields (Table 3, entries 1À3). As benzyl protecting groups were found incompatible with the borylation conditions (due to competing borylation of the aromatic ring), the transformation was instead performed on glycal ether 40 protected as a tris-3,5-dimethylbenzyl (DMB) ether. 29 The corresponding trisubstituted furan 44 was obtained in 91% yield (Table 3, entry 4).

The proposed overall reaction mechanism of the described preparation of furans is presented in Scheme 2.

Once the cross-coupling intermediate B is protonated, the resulting carbocation C has three possible pathways (aÀc) dictated by its structural constraints. Path a leads, by a kinetically favored 5-endo-trig spiroacetalization followed by a protonation/aromatization cascade, to the target polysubstituted furans E. To prove that the formation of furans proceeds through a spiroacetal intermediate D, 1,1-disubstituted 3-iodoallylic alcohol 45 was prepared and subjected to the same cross-coupling/ cyclization sequence. The expected 2,5-dihydrofuran spiroacetal 46 30 was isolated as a minor product along with the diastereomeric products of the double bond hydration (47a,b). This result can be explained if an alternative Path b is followed when the aromatization step is not possible. Finally, if the starting allylic alcohol possesses an (E)-configuration, the ringopening at the C6ÀO bond with the formation of an R,β-unsaturated ketone G is thermodynamically preferred (Path c).

In summary, we have developed a microwave-assisted synthesis of polysubstituted furans with a 2-(ω-hydroxyalkyl) side chain by a tandem one-pot Suzuki-Miyaura coupling/ acid-catalyzed cyclization sequence. The scope and limitations of the process have been evaluated. The proposed method provides rapid access to a variety of alkyl-and aryl-substituted furans and may be applied to the synthesis of complex molecules, such as pharmaceuticals and natural products.

  Preparation of Polysubstituted Furans by Tandem Borylation/Cross-coupling/Cyclization of Glycals a The intermediate vinyl dihydropyran cross-coupling product could be isolated in 65% yield, see Supporting Information for details. DMB = 3,5-dimethylbenzyl. (25) See Supporting Information. (26) Guthrie, J. P. Can. J. Chem. 1977, 2342-2354. (27) (a) Nokami, J.; Nishimura, A.; Sunami, M.; Wakabayashi, S. Tetrahedron Lett. 1987, 28, 649-650. (b) Boto, A.; Hern andez, D.; Hern andez, R. Org. Lett. 2007, 9, 1721-1724. D Org. Lett., Vol. XX, No. XX, XXXX

Table 1 ,

 1 Scheme 1. Tandem Suzuki-Miyaura Coupling/Acid-catalyzed Cyclization

Table 1 .

 1 Preparation of Furans 13À23

Table 2 .

 2 Preparation of Furans 15 and 31À37

Table 3 .

 3

Acknowledgment. Janssen Pharmaceutica is gratefully acknowledged for financial support.

Supporting Information Available. Full experimental details and characterization data ( 1 H NMR, 13 C NMR, IR and HRMS) for all new compounds. This material is available free of charge via the Internet at http://pubs.acs. org.


Alexey N Butkevich

Andrei Corbu

Lieven Meerpoel

Ian Stansfield

Patrick Angibaud

Pascal Bonnet

Janine Cossy
email: janine.cossy@espci.fr

Two-Step One-Pot Synthesis of Benzoannulated Spiroacetals by SuzukiÀMiyaura Coupling/Acid-Catalyzed Spiroacetalization

Substituted benzoannulated spiroacetals were prepared from (2-haloaryl)alkyl alcohols and dihydropyranyl or dihydrofuranyl pinacol boronates using a SuzukiÀMiyaura coupling followed by an acid-catalyzed spirocyclization. Application of the reaction to a glycal boronate provides an approach to annulated spiroacetals in enantiopure form.

The spiroacetal ring system, in particular 1,6-dioxaspiro- [4.4]nonanes, 1,6-dioxaspiro [4.5]decanes, and 1,7-dioxaspiro- [5.5]undecanes, is present in a variety of natural products of different origins. 1 Several benzoannulated spiroacetals, such as rubromycins, heliquinomycin, papulacandin, paecilospirone, and berkelic acid, have demonstrated potent biological activity 2 and therefore remain attractive synthetic targets.

Spiroacetals have been prepared by acid-catalyzed cyclization of ω,ω 0 -dihydroxyketones, 3 1,3-dipolar cycloaddition, 4 oxidative enolate coupling, 5 addition of 2-lithiofurans to phenylacetaldehydes followed by cyclization, 6 or an aromatic Pummerer-type reaction. 7 Metal-catalyzed (Ir, Rh, and Au) double hydroalkoxylation of disubstituted alkynes provides benzoannulated spiroacetals; however these reactions are rarely regioselective. 8 Several syntheses of B Org. Lett., Vol. XX, No. XX, XXXX benzoannulated spiroacetals have relied on a Pd-catalyzed cross-coupling between aryl halides and stannylated dihydropyrans or dihydropyranyl silanols leading to 6-aryl-3,4dihydro-2H-pyrans. These pyrans underwent spirocyclization with a side chain at the C-2 position of the aryl group when reacted with an electrophilic epoxidation reagent, such as DMDO or m-CPBA. [START_REF] Denmark | [END_REF] Recently, the treatment of 6-(ω-hydroxyalkyl)-3,4-dihydro-2H-pyrans and related dihydrofurans and tetrahydrooxepins with binaphtholphosphoric acids 10a or binaphthol-derived iminodiphosphoric acids 10b has been reported to lead to optically active spiroacetals.

Due to the known toxicity and persistence of organostannanes, and as the preparation of silanols has to be realized in several steps, we have planned to access benzoannulated spiroacetals A in an efficient convergent manner from the corresponding (2-haloaryl)alkyl alcohols B and pinacol boronates C, employing a one-pot SuzukiÀMiyaura coupling/acid-catalyzed spiroacetalization approach (Scheme 1).

In a test reaction, the starting boronate 2b 11 was reacted with 2-bromobenzyl alcohol 1a followed by an acidic treatment of the obtained intermediate 3a. At first, different palladium catalysts and bases were tested in order to optimize the conditions of the SuzukiÀMiyaura coupling. The reaction was carried out in 1,4-dioxane/H 2 O (3:1) at 100 °C under microwave irradiation. Among the palladium catalysts and bases tested, Pd(dppf)Cl 2 (5 mol %) in the presence of Na 2 CO 3 or NaOH (2 equiv) led to the highest yield of the coupling product 3a (82%). The desired spiroacetal 4a was also obtained in 6% yield, likely due to Lewis acid properties of the Pd catalyst (Table 1, entry 3). To achieve the complete transformation of 3a into 4a, p-TsOH (3 equiv) was added to the reaction mixture, leading directly to spiroacetal 4a in 86% yield (Table 1, entry 4). The palladium catalyst loading could be successfully decreased to 2 mol %; however using smaller amounts of catalyst (0.5 mol %) resulted in a significantly lower yield of 4a (Table 1, entry 5). Spiroacetals of type A were prepared from various (2-haloaryl)alkyl alcohols B, such as iodide 1b, chloride 1c, and tosylate 1d, by using the conditions reported in Table 2.

2-Iodobenzyl alcohol 1b was converted to 4a in 92% yield under conditions A (Table 2, entry 2), while 2-chlorobenzyl alcohol 1c was not reactive and required a more active catalytic system, Pd(MeCN) 2 Cl 2 (3 mol %)/XPhos (6 mol %), to produce 4a in 84% yield after acid-catalyzed cyclization (conditions B, difficult to achieve and required an even more active catalyst (Pd(0)/BrettPhos) 12 (conditions C, Table 2, entry 6). Importantly, under conditions A, chloride and tosylate substituents present on the aromatic ring are tolerated and not involved in cross-coupling reactions.

The results are summarized in Table 3. Substituted 2-halobenzyl alcohols 1eÀ1n were transformed into the corresponding spiroacetals 4eÀ4n in moderate to excellent yields (38À90%). As can be concluded from the results, electron-withdrawing groups were generally well tolerated (Table 3, entries 1 and4), while very electron-rich substrates suffered from diminished yields due to side reactions during the cyclization step. Alternative reaction conditions (conditions B) had to be employed to attain practical yields (Table 3, entry 8).

Benzoannulated [5,5]-, [5,6]-, [5,7]-and [6,6]-spiroacetals were successfully prepared under conditions A depending on the length of the hydroxyalkyl side chain of the aryl halide as well as on the ring size of the boronates 2a,b (Table 4, entries 1À4). A diastereomeric ratio of 60:40 was observed when secondary benzyl alcohols 1s and 1t were used; however, the diastereomeric spiroacetals were found to interconvert rapidly in the presence of a catalytic amount of acid (Table 4, entries 5 and 6).

To demonstrate the applicability of our method to the synthesis of chiral spiroacetals, boronate ester 6, prepared from trimethyl-D-glucal 5, 13 was reacted with either 1a or 1c in the presence of a Pd catalyst and Na 2 CO 3 as a base in anhydrous 1,4-dioxane or MeCN (use of NaOH in a 1,4-dioxane/water mixture resulted in complete protodeboronation of 6 to the starting glycal 5). The product of this reaction was spiroacetal 7 as the anomerically stabilized diastereoisomer, isolated in 55À63% yield (Scheme 2).

In summary, we have developed a rapid convergent microwave-assisted synthesis of benzoannulated spiroacetals using a one-pot SuzukiÀMiyaura coupling reaction/ spiroacetalization. This versatile and chemoselective process is potentially applicable to the synthesis of complex biologically active natural products.

Table 2

 2

, entry 4). The crosscoupling with 2-(hydroxymethyl)phenyl tosylate 1d was Scheme 1. Retrosynthetic Approach

Table 1 .

 1 Optimization of the Reaction Conditions

		Pd cat.		yield	yield
	entry	(mol %)	base	3a	4a
	1	Pd(PPh 3 ) 4 (5)	Na 2 CO 3	67%	À
	2	Pd(MeCN) 2 Cl 2 (5) PCy 3 (10)	Na 2 CO 3	64%	3%
	3	Pd(dppf)Cl 2 (5)	Na 2 CO 3	82%	6%
	4 a	Pd(dppf)Cl 2 (2)	NaOH	À	86% b
	5 a	Pd(dppf)Cl 2 (0.5)	NaOH	À	58% b

a Reaction time 10 min. b Yield of 4a after cyclization with TsOH (3 equiv) for 10 min at rt.

Table 2 .

 2 Scope of the Leaving Group a

	entry	X, 1	cond	yield 4a
	1	B r , 1a	A	86%
	2	I , 1b	A	92%
	3	Cl, 1c	A	0 %
	4	Cl, 1c	B	84%
	5	O T s , 1d	A or B	0%
	6	O T s , 1d	C	21%

D

Org. Lett., Vol. XX, No. XX, XXXX

† ESPCI ParisTech. ‡ Janssen Research & Development, Janssen Pharmaceutica N.V. § Janssen Research & Development, Oncology and Medicinal Chemistry, Campus de Maigremont.

Acknowledgment. Janssen Pharmaceutica is gratefully acknowledged for financial support.

Supporting Information Available. Full experimental details and characterization data ( 1 H NMR, 13 C NMR, IR, and HRMS) for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. (12) (a) Bhayana, B.; Fors, B. P.; Buchwald, S. L. Org. Lett. 2009, 11, 3954-3957. (b) Pd/XPhos-catalyzed SuzukiÀMiyaura coupling of aryl tosylates has also been reported but was not successful in our case; see: Nguyen, H. N.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 11818-11819. (13) (a) Kikuchi, T.; Takagi, J.; Ishiyama, T.; Miyaura, N. Chem. Lett. 2008, 37, 664-665. (b) Kikuchi, T.; Takagi, J.; Isou, H.; Ishiyama, T.; Miyaura, N. Chem. ÀAsian J. 2008, 3, 2082-2090. The authors declare no competing financial interest.