Gerardo Salinas

Serena Arnaboldi

Patrick Garrigue

Giorgia Bonetti

Roberto Cirilli

Tiziana Benincori

Alexander Kuhn

Tiziana Benincoric

Magnetic field-enhanced redox chemistry on-the-fly for enantioselective synthesis

  L'archive ouverte pluridisciplinaire

Introduction

Chemistry on-the-fly is a concept defined as the localized chemical conversion of a substance into a desired product via a specifically functionalized mobile platform.1 In recent years, this approach has gained considerable attention in the field of micro and nano swimmers, since the intrinsic high active surface and continuous motion enables a localized mixing of the reactants.1,2 The efficiency of these self-propelled miniaturized reactors has been extensively exploited for a wide range of physicochemical systems, ranging from organic pollutant degradation3-7 to metal ion removal8-10 and biorecognition.11-13 In this context, the possible enantiodiscrimination, quantification and synthesis of chiral analytes via chemistry-on-the-fly approaches is an interesting challenge. Recently, different enantioselective self-propelled devices have been designed by functionalizing the swimmer surface with different chiral recognition elements, e.g. cyclodextrins, D-or L-amino acid oxidase and also inherently chiral oligomers. [14][15][16] In particular the latter approach presents outstanding enantioselectivity, related to diastereomeric interactions between the chiral oligomer surface and the analyte antipodes in solution, resulting in thermodynamic differences in terms of redox potentials, which allow the preferential conversion of only one of the analyte enantiomers.17,18 This energetic differentiation has been exploited to design unconventional approaches for the electrochemical recognition of chiral probes.19-21 Furthermore, these oligomeric systems were used for the enantioselective conversion of molecules with a prostereogenic carbon-oxygen double bond into the corresponding chiral hydroxyl derivatives via chemistry-on-the-fly. 22 In particular, selfpropelled Zn particles, functionalized with oligomers of 2,2-bis[2-(5,2-bithienyl)]-3,3-bithianaphthene (BT2T4), were employed as mobile microreactors for the enantioselective synthesis of the antipodes of phenyl ethanol and mandelic acid. This approach is based on the coupling of the spontaneous oxidation of Zn in acid media, acting as a source of electrons, and the enantioselective reduction of the prochiral starting compound on the surface of the inherently chiral oligomer. The dynamic behaviour of such Zn/BT2T4 hybrid objects induces a continuous mixing of the solution, allowing a more efficient renewal of the prochiral starting compound at the swimmer interface, overcoming the characteristic mass transport limitations of conventional electroorganic synthesis.23-26 However, the motion is triggered by an asymmetric formation/release of bubbles which partially block the active surface area of the device, and thus might decrease the global yield of the stereoselective conversion.

An interesting concept to enhance the mixing of the solution in a more controlled and efficient way, is to induce a local Lorentz force on the ion flux present around the self-electrophoretic device. In general, the presence of a magnetic field, orthogonal to an electrode surface, generates a Lorentz force which triggers the formation of a magnetohydrodynamic (MHD) flow along the edges of the electrode.27,28 This phenomenon has been extensively explored for improving the overall reaction kinetics e.g. in electrocatalysis and electrodeposition of metals and polymers.29-31 Furthermore, due to the possibility to control the fluid flow around the electrode surface, this concept has been also extended to redox magnetohydrodynamic microfluidics and self-propulsion of active matter. [31][32][33][34] Recently, the synergy between the spontaneous ion flux produced by self-electrophoretic swimmers and an external magnetic field was proposed as an interesting alternative to boost their propulsion speed by up to 2 orders of magnitude.35 These Lorentz force-driven Janus swimmers exhibit a predictable clockwise or anticlockwise rotational motion as a function of the magnetic field orientation. The concept is complementary to already well-studied magnetic field-driven swimmers, where motion is triggered either by a pulling mechanism or rotating/undulating magnetic fields. [36][37][38][39][40][41][42][43][44] In a first order approximation, the above mentioned Zn/BT2T4 swimmers behave as selfelectrophoretic systems, with a flux of cations from the anodic to the cathodic sites of the Janus object (or vice versa for anions), induced by the spontaneous redox reactions. Thus, we propose in the present contribution the use of this ion flux, in combination with an external magnetic field, to design swimmers able to perform redox chemistry on-the-fly for enantioselective synthesis. The synergy between these two main ingredients provides a substantial boost of the dynamic behaviour of the redox swimmers, reflected by an improved efficiency of the stereoselective conversion. Zn wires, modified with a thin Pt layer were obtained by spontaneous deposition of Pt when dipping a zinc wire (GoodFellow, 99.99%, d = 250 µm) in a 20 mM H2PtCl6 solution under constant stirring for 2 minutes. Electrogeneration of the enantiopure oligo-(R)-BT2T4 or oligo-(S)-BT2T4 (Figure 1a) was carried out on these core/shell wires in a vial containing 5 cm3 of a 0.1 M solution of lithium perchlorate (LiClO4; Sigma-Aldrich) in acetonitrile (MeCN; Sigma-Aldrich) and 5 mM of the (R)-or (S)enantiopure monomers. The three-electrode system was composed of the Zn/Pt wire, a Pt wire and a Ag wire, acting as working, counter and pseudo-reference electrodes, respectively. The potentiodynamic synthesis of the oligomers was performed by applying a potential sweep from 0 V to 1.2 V, with a constant scan rate (100 mV s-1) for 36 cycles. All electrochemical experiments were carried out with a PalmSense potentiostat connected to a personal computer.

Characterization.

The morphology and composition of the Zn/Pt/oligo-(R)-BT2T4 or (S)-BT2T4 hybrid device was characterized by scanning electron microscopy and energy-dispersive X-ray spectroscopy, using a Vega3 Tescan 20.0 kV microscope.

Enantioselective synthesis with the redox chemistry-on-the-fly swimmers.

After depositing the respective oligo-BT2T4 enantiomers, the hybrid wire was cut into short pieces, leading to swimmers where at both cross sections bare Zn is exposed (average length of 1.1 mm ± 0.2 mm; diameter of 250 µm). In order to break the symmetry of the devices, one Zn face was carefully covered with varnish (Scheme S1). For the enantioselective synthesis, six of these Janus swimmers were positioned at the air/water interface of a 0.1 M H2SO4 aqueous solution containing 50 mM of acetophenone (AP) for 1 hour. For the redox synthesis in the presence of a magnetic field, a rectangular FeNdB magnet (B = 200 mT, Area = 98 cm2) was placed below the reaction chamber. After one hour, the products were extracted with heptane and the solution was analyzed on a Jasco HPLC machine (LC-4000) equipped with a photodiode array (PDA) and CD detectors at a wavelength of 210 nm and 260 nm, respectively. HPLC analysis was carried out by using a chiral column Chiralpak IB N-5 (250 × 4.6 mm, 5 µm) and a n-heptane/2-propanol 92:8 (v/v) mixture as mobile phase (flow rate = 0.5 mL min-1). The dynamic behaviour of the swimmers was monitored by using a CCD camera (CANON EOS 70D, Objective Canon Macro Lens 100 mm 1:2.8). Video processing and tracking was performed with ImageJ software.

Results and discussions

The hybrid swimmers were designed by following a two-step approach. First, the macroscopic Zn wire was modified with a thin Pt shell (7 µm ± 1 µm) by the spontaneous reduction of PtCl62-, to guarantee a good electrical contact between the Zn core and the corresponding oligomer. In the second step, the inherently chiral oligomer was generated by the potentiodynamic oligomerization of (R)-BT2T4 and (S)-BT2T4, respectively (Figure 1a). In order to study the composition and evaluate the changes in morphology, scanning electron microscopy (SEM) analysis (Figure 1b andc), coupled with energy dispersive X-ray spectrometry (EDS) (Figure 1d ande), was carried out with a 1 cm long Zn/Pt/oligo-BT2T4 wire. Three different regions have been examined, the pristine Zn wire, a Zn/Pt region and a hybrid Zn/Pt/oligo-BT2T4 section. As can be seen from the SEM images, the hybrid region presents a porous globular morphology in comparison to pristine Zn (Figure 1b andc). The EDX signal for the bare Zn extremity shows the presence of mainly zinc (Zn-Kα), oxygen (O-Kα) and sulphur (S-Kα), probably due to the formation of zinc sulphate during the cleaning of the wire (Figure 1d). The Zn/Pt part of the wire presents characteristic signals of platinum (Pt-Kα) (Figure 1e, black line), which decrease for the hybrid part of the device, accompanied by an increase of the carbon signal (C-Kα) (Figure 1e, orange line), evidencing the presence of the conjugated oligomer on top of the platinum surface.

After this first characterization of the composition of the Zn/Pt/oligo-BT2T4 objects, the propulsion mechanism, driven by the induced Lorentz-force, was examined. Since the use of inherently chiral molecules allows the control of the stereochemical outcome of a reaction, these hybrid materials are an interesting ingredient for asymmetric organic conversions. In this context, we have chosen as a model reaction, the reduction of the ketone moiety of a prochiral precursor, acetophenone, leading to the corresponding enantiomers of 1-phenylethanol (1-PE). Theoretically, in an acidic solution, the oxidation of Zn and the reduction of protons on Pt occur spontaneously with a standard redox potential difference of 0.76 V. Under these conditions, and in the presence of the inherently chiral surface, a certain fraction of the produced electrons can be used to trigger the asymmetric reduction of the prochiral molecule to only one of the enantiomers (Figure 2a). The intrinsic electron flux from the anodic to the cathodic part of the device is accompanied by a movement of ions towards or away from the outer surface at each extremity of the Janus object (Figure 2a, pink arrows). As stated above, in the presence of a magnetic field, orthogonal to the air/water interface, the resulting Lorentz force induces the formation of a MHD flow at each extremity of the device (Figure 2a, green circles). In order to visualize both MHD vortices in the vicinity of the swimmer, a macro-Zn/Pt/oligo-BT2T4 object (l ≈ 1 cm), was immobilized below the air/water interface of a 100 mM H2SO4, 50 mM AP solution. The set-up was placed at the center of a rectangular FeNdB magnet (B ≈ 200 mT, A = 98 cm2) with the north pole facing upwards. A glassy carbon bead (Ø = 500 -1000 µm), acting as a tracer particle, was positioned at the air/water interface in two different regions of the device. Two circular hydrodynamic flow patterns, with a specular clockwise and anticlockwise orientation, are formed above the wire (Figure 2b and Video S1). The circular motion exhibits an oscillating speed, which can be correlated with the relative position of the bead moving above the hybrid wire (Figure S1). Maximum speed values of 0.8 mm/s and 1.5 mm/s (above the Zn cross section and the Pt/oligo-BT2T4 region, respectively), are recorded when the tracer bead is closest to the middle part of the device. The difference in size of the circular hydrodynamic flow patterns and the maximum speed values, depend on the size of the active surface where each reaction is taking place. Thus, since the oxidation of Zn occurs only at the cross section of the wire where the bare metal is exposed, a rather focused MHD vortex is produced. On the contrary, as the reduction of prochiral molecules and consumption of protons takes place everywhere along the Pt/oligo-BT2T4 surface, this causes the formation of stronger MHD flow with a larger vortex diameter. This continuous mixing of the solution, induced by the two cooperating MHD vortices, should increase the mass transport of the prochiral compound towards the catalytic surface, thus improving the overall production rate. In strong contrast to these experiments, only random motion of the tracer particle is observed in the absence of the magnetic field (Figure 2c and Video S1).

After this characterization of the MHD flow at the macroscopic scale, the influence of the orientation of the magnetic field the displacement of miniaturized Janus swimmers has been studied during the redox conversion of AP to 1-PE. Six Janus Zn/Pt/oligo-(R)-BT2T4 swimmers, with an average length of 1.1 mm ± 0.2 mm, were positioned at the air/water interface of a 100 mM H2SO4, 50 mM AP solution, allowing them to move freely for 1 hour. The set-up was placed at the center of a rectangular FeNdB magnet (B ≈ 200 mT, A = 98 cm2) with either the north or south pole facing upwards. The MHD vortices, observed at the macroscopic scale (vide supra), should provide also at these smaller scales a significant driving force to continuously propel the swimmers. However, as these objects are no longer immobilized, like in the previous experiments, an additional Lorentz force, which acts on the ion flux parallel to the main axis of the object, has to be taken into account (Figure 3a, yellow arrow).35 This contributes to the overall displacement of the swimmer, by causing a torque force that translates into a predictable clockwise or anticlockwise motion, as a function of the orientation of the magnetic field.

Consequently, the Janus swimmers present a clockwise motion when the north pole of the magnet is orientated upwards, whereas an anticlockwise rotation is observed by inverting the orientation of the magnetic field (south pole upwards) (Figure 3b, Video S2 for single swimmers and Video S3 for an ensemble of swimmers). After one hour of self-mixing, the products of the stereoselective reaction were extracted with heptane and analyzed by enantioselective HPLC. As mentioned previously, the spontaneous oxidation of Zn is the driving force of the enantioselective reduction of the prochiral compound, since a fraction of the liberated electrons is shuttled to the inherently chiral surface. Thus, by functionalizing the surface of the swimmers with only one enantiomer of oligo-BT2T4, in this case the (R)-oligomer, the enantioselective reduction of AP to R-1-PE is expected. From the analysis of the HPLC chromatograms it was possible to confirm the transformation of AP into R-1-PE with a yield of ≈ 80% ± 4% and an %ee of ≈ 70% ± 1%, independent of the magnetic field orientation (Figure 3c, red curve for north pole up and blue curve for south pole up, respectively). The high stereoselectivity was confirmed by chromatograms with online circular dichroism detection, where the negative and positive signals can be associated to the synthesis of the (R)-and (S)-enantiomer, respectively (Figure S2). Again, the enantioselectivity does not depend on the orientation of the magnetic field, showing that the stereoselective reaction is not influenced by any spin polarization effect. [45][46][47] Using the same experimental conditions, we have evaluated the magnetic field enhancement of the redox conversion by comparing the yield of the reaction in the absence and in the presence of an orthogonal magnetic field. Six Janus Zn/Pt/oligo-(S)-BT2T4 swimmers, (l = 1.1 mm ± 0.2 mm), were positioned at the air/water interface of a 100 mM H2SO4, 50 mM AP solution, allowing them to move freely for 1 hour. The set-up was placed at the center of a rectangular FeNdB magnet (B ≈ 200 mT, A = 98 cm2) with the north pole facing upwards. Under exactly the same conditions, an independent experiment was carried out with six freshly modified oligo-(S)-BT2T4 swimmers without magnet. In the presence of the magnetic field, the self-propelled devices present a clockwise motion with an average speed of 0.7 mm/s ± 0.1 mm/s, which is roughly one order of magnitude faster than the one measured for the random motion in the absence of the magnet (0.1 mm/s ± 0.03 mm/s) (Figure 4a and Video S4). The stereoselectivity of the reaction is preserved, since both redox conversions present a similar %ee value (≈70%), however the enantioselective synthesis in the presence of the magnetic field leads to higher yields (≈80%) in comparison with the low value measured for the experiment without magnet (≈10 %), as illustrated in Figure 4b. This is due to the self-mixing capabilities of the swimmers, based on the magnetic field induced motion.

In a control experiment, the dynamic behaviour and the yield of products generated by the spontaneous motion of six achiral Janus Zn/Pt swimmers, were tested. For comparison, these objects were positioned at the air/water interface of a 100 mM H2SO4, 50 mM AP solution, with the north pole facing upwards for 1 hr. The Janus swimmers present a clockwise motion with an average speed of 0.4 mm/s ± 0.1 mm/s and a very low conversion (≈0.5%) (Figure S3 and Video S5). These results indicate that in this case, the large majority of the electrons liberated by the dissolution of zinc is used for the reduction of protons, as this reaction is thermodynamically and kinetically favoured on platinum, compared to the reduction of the prochiral molecule. There is also a significant difference in speed, in comparison with the swimmers modified with the inherently chiral oligomer, since the continuous production of H2 bubbles everywhere on the Pt shell does not allow an as efficient directional propulsion of the Zn/Pt objects. As expected, in the case of achiral swimmers, the %ee is zero within error bars. Finally, in order to compare the conversion efficiency, the reaction rate of AP was calculated for achiral and chiral swimmers (see supporting information for details). In the presence of the orthogonal magnetic field, values of 0.001 mmol h-1 mm-1 and 0.30 mmol h-1 mm-1 were obtained for the Zn/Pt and the Zn/Pt/oligo-(S)-BT2T4 swimmers, respectively. Once again, this provides evidence that the presence of the inherently chiral oligomer not only induces stereoselectivity, but also greatly promotes the global reactivity by more than two orders of magnitude. Furthermore, the efficiency of the redox chemistry-on-the fly is enhanced in the presence of the magnetic field by up to one order of magnitude, in comparison with the conversion in the absence of the magnet (0.03 mmol h-1 mm-1), due to an improved mixing of the solution caused by the MHD effect.

Conclusions

We have demonstrated the possibility to boost the propulsion of Zn/Pt/oligo-BT2T4 hybrid swimmers, using the effect of magnetohydrodynamic convection (MHD effect). The chiral Janus objects are functionalized with the enantiomers of an inherently chiral oligomer. When they are placed in acidic solutions containing a prochiral starting compound, the spontaneous redox reactions that occur on their surfaces trigger the stereospecific conversion of the prochiral molecule into the desired enantiomer. The inherently helical molecular structure of the polymer provides a chiral environment which is the basis for quite important thermodynamic differences when comparing its interactions with the two antipodes of a given chiral molecule. This naturally also affects the outcome of the reduction of a prochiral ketone into a chiral alcohol if it occurs in such a chiral environment. In the transition state the intermediate species is more likely to evolve towards a final enantiomer with the energetically more favorable stereochemistry, as we have already demonstrated in one of our previous studies. 22 The magnetic field enhancement of the redox conversion has been evaluated by comparing the yield of an asymmetric model reaction, the reduction of acetophenone into the enantiomers of phenylethanol, in the absence and in the presence of an orthogonal magnetic field. In the presence of a magnet, the Janus swimmers exhibit well-defined clockwise or anticlockwise motion, with an up to one order of magnitude higher speed. This leads to a significant improvement of the reaction yield and of the conversion rate. Without magnet, the reaction is still stereospecific, but proceeds with a one order of magnitude lower conversion rate.

  Electrosynthesis of enantiopure oligo-(R)-BT2T4 or oligo-(S)-BT2T4.

Fig. 1

 1 Fig. 1 a) Chemical structures of the oligo-(S) and oligo-(R)-2,2-bis[2-(5,2-bithienyl)]-3,3-bithianaphthene (oligo(S)-and oligo-(R)-BT2T4). SEM images of the surface of b) a pristine and c) Pt/oligo-BT2T4 modified Zn surface. Scale bar 5 µm. EDX signals around the emission peaks of carbon, oxygen, zinc, platinum and sulphur of d) a pristine Zn wire and e) a Zn/Pt (black line) and a Zn/Pt/oligo-BT2T4 (orange line) hybrid device.

Fig. 2

 2 Fig. 2 a) Schematic illustration of the formation of the MHD-flow on the surface of a self-propelled swimmer with a representation of the associated chemical reactions, the spontaneous ionic currents, the magnetic field B, the induced Lorentz force FL and the resulting MHD convection. b) Tracking of the trajectory of a tracer particle (glassy carbon bead, Ø = 500 -1000 µm) moving on the air/water interface (0.1 M H2SO4 and 50 mM AP) above a macroscopic Zn/Pt/oligo-BT2T4 device in the presence of a magnetic field (north pole up). c) Same experiment as in (b), but in the absence of the magnetic field. The grey dots indicate the initial position of the tracer particle.

Fig. 3

 3 Fig. 3 a) Schematic illustration of the clockwise motion of a self-propelled Janus swimmer with a representation of the associated chemical reactions, the spontaneous ionic currents, the magnetic field B and the resulting Lorentz force FL. b) Tracking plots of two individual Zn/Pt/oligo-(R)-BT2T4 swimmers moving at the air/water interface of a 0.1 M H2SO4 and 50 mM AP solution, as a function of the magnetic field orientation (indicated in the figure). c) Chromatograms of the product mixtures obtained after 1 hour of asymmetric synthesis carried out by the continuous displacement of 6 Zn/Pt/oligo-(R)-BT2T4 swimmers placed at the air/water interface of a 0.1 M H2SO4 and 50 mM AP solution, as a function of the magnetic field orientation (indicated in the figure).

Fig. 4 a

 4 Fig. 4 a) Tracking plots of two individual Zn/Pt/oligo-(S)-BT2T4 swimmers moving at the air/water interface of a 0.1 M H2SO4 and 50 mM AP solution, in the absence (black line) and in the presence (red line) of an orthogonal magnetic field (north pole upwards). b) Chromatograms of the product mixtures obtained after 1 hour of asymmetric synthesis carried out by 6 Zn/Pt/oligo-(S)-BT2T4 swimmers, placed at the air/water interface of a 0.1 M H2SO4 and 50 mM AP solution, in the absence (black line) and in the presence (red line) of an orthogonal magnetic field (north pole upward).

We can conclude that this better performance is based on the fact that the MHD effect, generated by the presence of a magnet, induces controlled active micro-mixing with a more efficient renewal of the prochiral starting compound at the oligomer surface. In addition, the MHD effect facilitates the detachment of bubbles from the swimmer surface, thus partially liberating active surface area, which otherwise would be blocked by the presence of gas. This leads to a considerable increase in the global yield of the stereoselective conversion. Moreover, in contrast to other concepts of magnetically driven macro-, micro-and nano swimmers described in the literature, where the presence of a ferromagnetic component is mandatory to trigger motion,48 the here presented approach allows to take advantage, in an unconventional way, of the synergy between the local electric and global magnetic field, without the need for ferromagnetic constituents in the swimmer architecture. This offers a higher degree of freedom in the design of motile functional devices, for which the presence of an external magnet will lead to a more efficient propulsion. With respect to future applications, these chiral Janus swimmers might be potentially used for the scale-up of asymmetric reduction processes. Furthermore, the magnetic field enhanced conversion efficiency could be also of interest for other chemistry-on-the fly applications, as long as redox processes are involved in the reaction mechanism.

Acknowledgements

This work has been funded by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement no 741251, ERC Advanced grant ELECTRA) and under the HORIZON-ERC-2021 work program (grant agreement no 101040798, ERC Starting grant CHEIR). References 1 E. Karshalev, B. Esteban-Fernandez de Avila, J. Wang, J. Am. Chem. Soc., 2018, 140, 3810-3820.


F Matteo

R Simola

J Postel-Pellerin

K Coulié

Rousset

Advanced TCAD Simulation of Tunnel Oxide Degradation for EEPROM Applications

In this paper we have simulated dynamic Constant Voltage Stress (CVS) and subsequent degradation of MOS capacitor representative of Non-Volatile Memory (NVM) devices. Oxide degradation was modelled through trap defects generation at SiO2/Si interface and SiO2 bulk. A very good agreement was obtained between simulation and experimental data.

I. INTRODUCTION

Charge Storage Floating Gate-based Non-Volatile Memory Electrically Erasable Programmable Read Only Memory (EEPROM) and Flash-EEPROM (or, more simply, Flash), are among the most successful devices ever introduced in the semiconductor market [START_REF] Capelletti | Non Volatile Memory Evolution and Revolution[END_REF]. Either stand-alone in Storage Charge Memory (SCM) or embedded in Microcontroller Units (MCUs), they are at the very core of every modern digital equipment, from digital cameras to smartphones, tablets and personal computers, to mention a few. Their operating principle relies in charge transfer from/to a polysilicon layer (called floating gate) through a thin silicon dioxide layer (called tunnel oxide) when appropriate voltage biases are applied to control gate and silicon substrate (Fig. 1a, for EEPROM). The basic element for both EEPROM and Flash is therefore a simple PolySi/SiO2/Si stack planar capacitor, commonly called MOS capacitor (Fig. 1b). The oxide integrity is what ultimately determines the devices' reliability, and consequently, it has been extensively studied in the past three decades [START_REF] Papadas | Model for Programming Window Degradation in FLOTOX EEPROM cells[END_REF][START_REF] Aritome | Reliability issues of Flash memory cells[END_REF][START_REF] Pananakakis | Generalized trapping kinetic model for the oxide degradation after Fowler-Nordheim uniform gate stress[END_REF][START_REF] Schroder | Negative bias temperature instability: Road to cross in deep submicron silicon semiconductor manufacturing[END_REF].

II. TCAD Simulation Framework

This study was carried out using Sentaurus™ Suite by SYNOPSYS®, for both process and electrical simulations [7]. Process simulation was based on a 110 nm embedded NVM CMOS technology. All the relevant front-end process flow steps were included up to metal contacts. The obtained TCAD nMOS structure is shown in Fig. 2a and corresponds to a large plate capacitor device with an area of 1×10 5 µm² (in this 2D simulation total surface was taken into account by a scaling area factor). Tunnel oxide thickness is around 8 nm, as measured in TEM cross section (Fig. 2b).

A. Charge transport across tunnel oxide

For typical EEPROM operating voltages (> 10 V) and tunnel oxide thickness (7 ~ 10 nm), charge transport across the silicon dioxide is driven by quantum mechanical tunneling through a trapezoidal potential barrier. This phenomenon was first described by Fowler and Nordheim (FN), with a simple closed-form expression for the current density J !" that is given by [START_REF]Sentaurus™ Device User Guide Version Q[END_REF][START_REF] Lezlinger | Fowler-Nordheim tunneling into thermally grown SiO2[END_REF]:

𝐽 #$ = 𝐴𝐹 % 𝑒𝑥𝑝)-𝐵 𝐹 , - (1)
where F is the electric field at the Si/SiO2 interface and A, B are physical related parameters. Despite its utility in modeling high field tunneling current thanks to its reliability and simplicity, this model doesn't cover direct tunneling for ultra-thin oxide and trap assisted tunneling of degraded oxide. Consequently, a more general model [START_REF] Ieong | Comparison of Raised and Schottky Source/Drain MOSFETs Using a Novel Tunneling Contact Model[END_REF] is used in this paper, that considers band edge profile along the entire path across the SiO2 between the two points connected by tunneling, also called Non-Local Tunneling (NLT) [START_REF]Sentaurus™ Device User Guide Version Q[END_REF]. The key parameter in NLT is the electron effective tunneling mass, which has been set equal to 0.48 times the electron mass. Moreover, coupled with trap capture and emission models described in [START_REF]Sentaurus™ Device User Guide Version Q[END_REF][11] [START_REF] Palma | Quantum two-dimensional calculation of time constants of random telegraph signals in metal-oxide-semiconductor structures[END_REF], the simulation accounts for traps assisted tunneling (TAT) thus covering a wide spectrum of tunneling phenomena.

B. Degradation model

Several models for oxide degradation under high voltage stress can be found in the literature. According to anode hole injection (AHI) mechanism, some of the tunneling electrons reaching the anode with high-enough energy will generate electron-hole pairs in the oxide, and some of the generated holes will be trapped in the oxide [START_REF] Chen | Hole trapping and breakdown in thin SiO2[END_REF][START_REF] Schuegraf | Hole injection SiO2 breakdown model for very low voltage lifetime extrapolation[END_REF][START_REF] Schuegraf | Effects of temperature and defects on breakdown lifetime of thin SiO2 at very low voltage[END_REF]. This mechanism was initially heralded as the origin of dielectric breakdown, a claim that was first disputed [START_REF] Dimaria | Hole trapping, substrate currents, and breakdown in thin silicon dioxide films[END_REF] and later disproven [START_REF] Vogel | Reliability of ultrathin silicon dioxide under combined substrate hot-electron and constant voltage tunneling stress[END_REF]. According to another model, hot electrons release hydrogen (HR) near the anode which drift or diffuse through SiO2 consequently generating defects [START_REF] Dimaria | Impact ionization, trap creation, degradation, and breakdown in silicon dioxide films on silicon[END_REF][START_REF] Dimaria | Interface states induced by the presence of trapped holes near the silicon silicon-dioxide interface[END_REF][START_REF] Sune | A new quantitative hydrogen-based model for ultra-thin oxide breakdown[END_REF]. In this paper, defects generation is modeled by stress-induced breaking of Si-H bonds (depassivation). From first-order kinetics [START_REF]Sentaurus™ Device User Guide Version Q[END_REF][21] Si-H concentration 𝑁 &' is given by:

𝑑𝑁 &' 𝑑𝑡 = -𝑣 * 𝑁 &' ( 2
)
where 𝑣 is a reaction constant that can be described approximately by an Arrhenius law [START_REF] Penzin | MOSFET Degradation Kinetics and Its Simulation[END_REF]:

𝑣 = 𝑣 ( exp : -𝜀 ) 𝑘𝑇 ? 𝑘 *+, ( 3
)
where 𝑣 ( is the reaction depassivation constant, k is the Boltzmann constant, T is the absolute temperature, and 𝑘 *+, = 1 + 𝛿 *+, (𝐼 * 𝐼 ( ⁄ ) -!"# is an enhancement factor due to tunneling current 𝐼 * . The activation energy 𝜀 ) (not constant) is given by:

𝜀 ) = 𝜀 ) ( -𝛿 . |𝐹| -$ + 𝑘𝑇(1 + 𝛽𝐹) 𝑙𝑛 I 𝑁 -𝑁 &' 𝑁 -𝑁 &' ( J (4)
where 𝜀 ) ( is the activation energy constant, 𝑁 &' ( is the initial Si-H concentration and 𝛽 , 𝛿 . , 𝜌 . are field-enhanced parameters. 𝑁 is the trap concentration saturation value and varies as a function of energy within the bandgap, 𝑁 -𝑁 &' is the concentration of hydrogen released (i.e concentration of traps) and 𝑁 -𝑁 &'

( corresponds to the initial concentration of traps which we have set to 1×10 cm -2 . Although this model was first developed to describe Si-H breaking mechanism occurring at Si/SiO2 interface, we have extended it to the bulk oxide where we have set 𝑁 -𝑁 &' ( equal to 1×10 12 cm -3 . The complete parameter set used for simulations is reported on Table 1 below 0.33

C. Traps distribution

Distribution of the trap concentration parameter 𝑁 in bulk oxide and at Si/SiO2 interface are reported in Fig. 3 and Fig . 4, respectively. For bulk oxide traps, following [START_REF] Scott | Properties of High-Voltage Stress Generated Traps in Thin Silicon Oxide[END_REF] we have assumed that for each acceptor trap there is a corresponding donor trap. Thus, traps in SiO2 are generated in the whole bandgap (but only acceptors levels are represented in Fig. 3). Since we neglected impact ionization during electron injection into polysilicon gate, donor traps stay mostly neutral because no hole are available for trapping. Deep acceptor traps (A), which extend 2 eV from mid-gap (MG), are mostly filled with electrons and have low probability for electron release. This negative trapped charge is responsible for Fowler-Nordheim efficiency reduction. Shallow traps (B) located within the range 2 eV to 3.5 eV from MG, have high capture and emission rates and trigger TAT mechanism. Finally, we assumed that very shallow traps located above 3.5 eV from MG are neutral with a too low capture probability to have any significant effect. We have therefore neglected them.

At Si/SiO2 interface traps spread over the entire silicon bandgap (Fig. 4), both acceptor and donor states are therefore included in this model. Acceptor states, however, have higher concentrations. The concentration peak located at 0.8 eV from the valence band edge is the typical signature of Pb0 center [START_REF] Li | First-principles study of defects in amorphous-SiO2/Si interfaces[END_REF] and was reported by the authors in [START_REF] Chiquet | Investigation of the effects of constant voltage stress on thin SiO2 layers using dynamic measurement protocols[END_REF], who performed similar stress to ours. The spatial location of traps is schematically represented in Fig. 5. At the interface, we set a uniform spatial distribution along the entire interface. Furthermore, shallow traps (B) were distributed mainly at the center of the oxide (when they are positioned close to interface, it induces nonrealistic simulated tunneling current value), whereas deep traps (A) evenly distributed inside SiO2.

III. Results & Discussion

A. Constant Voltage Stress (CVS)

In Fig. 6, the measured and simulated CVS curves are represented. Since deep traps located near MG (A traps in Fig. 3) have highest electron capture section, they will charge negatively, leading to the observed gate current decrease during CVS. This mechanism is well captured in our simulations, leading to the excellent agreement with experimental data.

B. Capacitance vs Voltage (C-V)

The measured and simulated C-V curves before and after stress are shown in Fig. 7, where we can appreciate a very good agreement between the two. The reason is briefly explained in the following considerations Si/SiO2 interface traps are very sensitivity to the electrostatic field, since small change in the applied voltage (few volts) drastically modify their occupancy state. They therefore strongly influence the C-V shape after oxide degradation. A detailed analysis of C-V after laser induced degradation on MOS [START_REF] Llido | Effects of 1064 nm laser on MOS capacitor[END_REF] showed that donor interface traps (i.e traps with an energy level between the valence band and the mid gap) are the first to release their holes becoming neutral from positively charged, then acceptor interface traps (i.e traps with an energy level between de mid gap and the conduction band) capture electrons and become negatively charged. Assuming this to be also valid after CVS induced oxide degradation, from -4.5 V to -3 V the capacitance degradation is ruled by donor traps, then from -3 V to -1.5 V by acceptor traps and, finally, above -1.5 V there is the cumulate influence of filled interface traps and bulk oxide traps. The small C-V mismatch in the strong inversion regime (above 2V), where poly-depletion effects are known to take place, are likely due to poor TCAD electrical modelling of PolySi.

C. Gate Tunneling Current

In Fig. 8, the measured and simulated I-V curves are represented before and after CVS. For an oxide of approximatively 8 nm thick and at low electric field, gate current is mostly due to TAT. At high field, gate current main contributor is Fowler-Nordheim tunneling mechanism.

Concerning the unstressed nMOS capacitor, gate current follows, as expected, a pure Fowler-Nordheim injection curve from 5.5 V to 10 V. On stressed nMOS capacitor, from 5 V to 6 V, TAT is the main contributor to gate current. A combination of TAT and Fowler-Nordheim is observed between 6V to 7V and above, Fowler-Nordheim mechanism becomes preponderant.

Vertical cuts (TCAD simulated structure) of volumetric trap concentration after stress and electrostatic field at Vg=10V are shown in Fig. 9. Due to higher electrostatic field close to the gate, traps concentration increase. However, the impact of electric field is probably overestimated here since we have neglected traps generation due to high kinetic energy injected electrons.

V. Conclusion

In this paper, we have performed advanced TCAD simulation of NVM device tunnel oxide degradation during Constant Voltage Stress. We showed that Si/SiO2 interface traps modify MOS electrostatic behavior throughout capacitance versus voltage measure, whereas SiO2 bulk acceptor-type traps lead to Fowler-Nordheim tunneling current decrease and to TAT at lower electric field. A very good agreement with experiments was obtained for C-V and I-V pre and post stress. The model used in these simulations could be further improved using dedicated degradation kinetics for bulk and interface traps. Finally, this approach can be easily implemented for endurance and retention simulation of industrial NVM devices.

Figure 1 :

 1 Figure 1: a) EEPROM 2T device, consisting of a Sense Transistor (for data storage) and Select Transistor (for data accessing). b) Basic storage element of Sense device is a planar capacitor.

Figure 2 :

 2 Figure 2: Planar MOS Capacitor. a) TCAD process simulation. b) TEM cross section

Figure 3 :

 3 Figure 3: Distribution of traps parameter 𝑵 in bulk SiO2. Only the upper part of the band gap is shown (energy levels relative to the mid-gap).

Figure 4 :

 4 Figure 4: Distribution of traps parameter 𝑵 at Si/SiO2 interface. Both acceptors and donors states are included in the simulation.

Figure 5 :

 5 Figure 5: Traps spatial distribution. Deep traps (A) are uniformly distributed in the oxide. Shallow traps (B) are mainly located at the SiO2 center.

Figure 6 :

 6 Figure 6: Gate current during Constant Voltage Stress (CVS).

Figure 7 :

 7 Figure 7: Capacitance vs voltage before and after stress.

Figure 8 :

 8 Figure 8: Capacitance vs voltage before and after stress

Figure 9 :

 9 Figure 9: a) Vertical cut of volumetric trap concentration and b) Vertical cut of electrostatic field

  In this paper, we have performed Technology Computer Aided Design (TCAD) simulations of MOS oxide degradation due to Constant Voltage Stress (CVS). The applied voltage stress is representative of the operating conditions of a 110 nm-CMOS technology node-based 4Mbit EEPROM manufactured by STMicroelectronics and recently introduced in the semiconductor market [6].

Table 1 :

 1 . Degradation model parameters set

	Parameter	Value	Unit
	𝑣 (	2.1×10 -12	s -1
	𝜀 ) (	0	eV
	𝑇	300	K
	𝛽	1.0×10 -7
	𝛿 *+,	8.9×10 5
	𝜌 *+,	0.9
	𝛿 .	1e-3
	𝜌 .


Scholarone, 375 Greenbrier Drive, Charlottesville, VA, 22901

Transactions on Device and Materials Reliability P)^Q! E%' 9:B758Z' BH' 5@%L' o0BDB8HGL' 95\@H' E?MB@:I;L' 5IM' -BGH' 0BAB@?N>BIH' 9F5>BC?FZ' D?F' ..KEGLp' IS% =8+,3S% 5+@(*/0S% ?/89:'S% 672'S' <aL' YL' KFH:8@B'X)'L')&))%' ' H. AZIZA received his B.S. and M.S. degrees in Electrical Engineering, both from University of Marseille, France. He received his Ph.D. degree in 2002 from the University of Marseille, France.

Hassen Aziza is currently associate professor at Aix-Marseille University-IM2NP laboratory (Institute of materials, microelectronics and nanosciences of Provence). His research fields cover design, test and reliability of conventional non-volatile memories (Flash & EEPROM) as well as emerging memories (Resistive RAM). He is (co)author of more than 120 papers in international conferences and journals and is (co)inventor of 5 patents. Hassen AZIZA was involved the French National Research Agency project DIPMEM dedicated to hybrid circuit design (CMOS-ReRAM). Since 2017, Hassen AZIZA is the IM2NP's "Memory Team" leader. IM2NP's "Memory Team" is composed of 12 permanents. Research thematics conducted by the group are fully dedicated to Resistive RAM technology, Design and Test. (all the cells are connected in parallel), is presented and processed in Section II.B. This is 16x16 array of cells connected in parallel. Text added in Section II.B: "Note that the 16x16 STATE test structure differs from a classical memory array (such as the 8x8 1T1R elementary array used to characterize the variability of the technology in Section II.A) as all the cells are connected in parallel."

5. In section III-A it is mentioned that slow IV ramp is preferred instead of pulses. Since the RRAM properties LRS, RHRS, endurance and retention depend on the FRM/SET/RESET condition (voltage, time), can the authors comment (ideally in the manuscript) on how the results are applicable to real products which most likely use pulses in the few us range? Thanks for this valuable feedback. Indeed, real products use pulses for programming operation (FRM/SET/RESET), which is different from the programming signals used in the proposed methodology.

However, the proposed methodology is dedicated to test chips, not to real products. As mentioned in the text (Section II.B), "during the early phase of development, it is often difficult to obtain sufficient reliable data on RRAM memories. The process itself is not stabilized and fully functional devices are not yet available. At this stage, test structures can play an important diagnostic role in climbing the yield learning curve and in providing valuable reliability data."

This methodology is intended to become a standard for high-speed endurance tests for a given technology. Each technology/process optimization trial would provide a test chip for endurance evaluation. Different technologies/recipe can be benchmarked regarding endurance based on the proposed test chip.

6. In section III-C the authors compare their endurance results to [5]. Are you both using the same RRAM process and hardware? If not, couldn't the difference in endurance just be due to different stack properties?

In fact, different stacks are benchmarked in [5]. Among these stacks, two are considered for comparison (same technology as the one proposed in this paper: TiN/Hf/HfO2/TiN stack):

-Chen, Y. Y.; Goux, L.; Clima, S.

M

  . J. Postel-Pellerin was born in 1982. He received M.S. and Ph.D. degrees from Aix-Marseille University, Marseille, France, in 2005 and 2008, respectively. He joined the Memory Team of the Institut Matériaux Microélectronique Nanosciences de Provence (IM2NP), Marseille, France, in 2009 and became an Associate Professor with Aix-Marseille University. His current research interests include the electrical characterization, the modeling and the TCAD simulation of Flash memories, especially for reliability and security studies. He is also working on the development of innovative floating-gate NVM architectures for low-energy applications. M. Moreau received the Master of Science and Ph.D. degrees in micro and nanoelectronics from Aix-Marseille University, France, respectively in 2007 and 2010. His doctoral research at the Institute of Materials Microelectronics and Nanosciences of Provence (IM2NP) covered numerical simulation and compact modeling of advanced nano-devices, like FinFET, based on new materials (high-k and III-V semiconductors). From 2010 to 2011, he was teaching assistant at polytech'Marseille and work on compact modeling of organic thin film transistors (OTFT). Since 2012, he is associate professor at Aix-Marseille University and conducts his research at IM2NP in the field of hybrid circuit design based on emerging non-volatile memories (ReRAM, MRAM, …). He is recipient of the Newcas 2013 Best Paper Award and the 2017 IEEE Transactions on Circuits and Systems Guillemin-Cauer Best Paper Award. Drive, Charlottesville, VA, 22901 Transactions on Device and Materials Reliability Scholarone, 375 Greenbrier Drive, Charlottesville, VA, 22901 Transactions on Device and Materials Reliability -The STATE test structure, which architecture is different from a classical memory array

7 .

 7 The authors misspelled their names in the cover page (Hassan instead of Hassen) and in the bio section (M. Postel-Pellerin instead of J. Postel-Pellerin). Fixed

  ; Govoreanu, B.; Degraeve, R.; Kar, G. S.; Fantini, A.; Groeseneken, G.; Wouters, D. J.; Jurczak, M. Endurance/Retention Trade-Off on HfO2/Metal Cap 1T1R Bipolar RRAM. IEEE Trans. Electron Devices 2013, 60, 1114-1121. -Chen, Y. Y.; Govoreanu, B.; Goux, L.; Degraeve, R.; Fantini, A.; Kar, G. S.; Wouters, D. J.; Groeseneken, G.; Kittl, J. A.; Jurczak, M.; et al. Balancing SET/RESET Pulse for 1010 Endurance in HfO2/ Hf 1T1R Bipolar RRAM. IEEE Trans. Electron Devices 2012, 59, 3243-3249.

Scholarone, 375 Greenbrier Drive, Charlottesville, VA, 22901

Transactions on Device and Materials Reliability P)^Q! E%' 9:B758Z' BH' 5@%L' o0BDB8HGL' 95\@H' E?MB@:I;L' 5IM' -BGH' 0BAB@?N>BIH' 9F5>BC?FZ' D?F' ..KEGLp' IS% =8+,3S% 5+@(*/0S% ?/89:'S% 672'S' <aL' YL' KFH:8@B'X)'L')&))%' ' H. AZIZA received his B.S. and M.S. degrees in Electrical Engineering, both from University of Marseille, France. He received his Ph.D. degree in 2002 from the University of Marseille, France.

Hassen Aziza is currently associate professor at Aix-Marseille University-IM2NP laboratory (Institute of materials, microelectronics and nanosciences of Provence). His research fields cover design, test and reliability of conventional non-volatile memories (Flash & EEPROM) as well as emerging memories (Resistive RAM). He is (co)author of more than 120 papers in international conferences and journals and is (co)inventor of 5 patents. Hassen AZIZA was involved the French National Research Agency project DIPMEM dedicated to hybrid circuit design (CMOS-ReRAM). Since 2017, Hassen AZIZA is the IM2NP's "Memory Team" leader. IM2NP's "Memory Team" is composed of 12 permanents. Research thematics conducted by the group are fully dedicated to Resistive RAM technology, Design and Test. It is defined in the third paragraph of the first section: "In this work, a lightweight test structure, presented for the first time in [9], and referred to as STATE (A Test Structure for Rapid Prediction of Resistive RAM Electrical Parameter Variability)".

The sentence has been rephrased to better highlight the meaning of the acronym: "In this work, a lightweight test structure, presented for the first time in [9], and referred to as STATE (StrucTure for rApid predicTion of RRAM Electrical parameter variability)" 2. In the 1st paragraph of the introduction, endurance is defined as the max number of SET & RESET cycles. But in the 2nd paragraph of the introduction, you write that "...claimed high endurance (>10^6)...few cycles (in many cases even <50) [5][6]". I don't understand that statement. Are you saying that some authors are measuring <50 cycles and claim 10^6? At least in [6] Fig. 5 it seems that endurance was tested for >1.5x10^5 cycles. Please clarify and update the manuscript. Thanks for the feedback. Indeed, the sentence creates confusion. What I mean is that some authors are only plotting electrical parameters for less than 50 cycles in the endurance plots, while the endurance test lasts 10^6 cycles (i.e., electrical parameter extraction is performed once in a while during the endurance test). Thus, some potential electrical parameter drifts are missed during the test. To accurately monitor RRAM parameter evolution, electrical parameters have to be extracted 10^6 times (i.e., after each cycle). The sentence has been rephrased: "First, most of the publications that claimed high endurance (>10 6 ) are based on endurance plots considering very few cycles (in many cases even <50) [5]. Which means that RRAM electrical parameter extraction is performed considering less than 50 cycles out of 10 6 cycles". Indeed, in [6], endurance was tested for >1.5x10^5 cycles, but it is not clear if resistances have been extracted for each cycle. Anyway, to be compliant with Ref [6] findings, Ref [6] has been moved here: Secondly, most studies only consider one single device, masking the intrinsic variability of the technology [6][7].

3. For most figures the symbols, axis titles and labels are too small (especially Fig. 2,4,5,6,8,9). For better readability, especially after printing, please improve. 4. You mention 8x8 cells, 16x16 cells and an array of 500x64 cells. From the text it is not clear why different cells were used and which test was done on which cell. Please add that info.

-To characterize the variability of the technology and assess the impact of variability on the HRS/LRS resistance ratio, a 8x8 1T-1R classical array is used (64 cells). Measurement results are presented in section II.A. As this elementary array is cycled 500 times, 500x60 measurements points are plotted in Fig. 2