Hanna Pazniak

Simon Hurand

Nadia Guignard

Stéphane Celerier

Ulf Wiedwald

Thierry Ouisse

Marie-Laure David

Vincent Mauchamp

Ion Implantation Enhanced Exfoliation Efficiency of V 2 AlC Single Crystal: Implications for Large V 2 CT z Nanosheets Production

Keywords: V2AlC single crystal, ion-implantation, chemical etching, macroscopic V2CTz MXene, TEM-EELS

MXenes are two-dimensional transition metal carbides and nitrides with an attractive combination of physicochemical properties, gaining a notable potential in many 2 applications. Currently MXene synthesis is mainly performed from powder precursors which purity and grain size defines the quality and flake size of 2D sheets, typically not exceeding 2-3 µm. In this work, we successfully synthesized macroscopic nanolayered V2CTz MXenes with lateral dimensions larger than 25 µm from V2AlC single crystal by exploiting a new strategy based on ion implantation. Ne 2+ ion-implantation of the single crystal precursor is applied to introduce defects in the crystal structure of V2AlC which facilitates chemical etching and drastically reduces the etching time down to 8 hours (~ 10 times lower as compared to conventional synthesis from powder precursors). The quality and morphology of exfoliated macroscopic MXene multilayers have been comprehensively studied by performing detailed analysis based on different kinds of microscopies and spectroscopies. The obtained macroscopic flakes are ideal objects to study the intrinsic physical properties of V2CTz MXenes and explore their potential application, in particular as membranes.

INTRODUCTION

MAX phases are nanolayered ternary and quaternary transition metal carbides and nitrides with the chemical formula of Mn+1AXn (n = 1, 2, 3), where M denotes to early transition metal, A is an A-group element and X represents C or N. [START_REF] Barsoum | The MN+1AXN phases: A New Class of Solids: Thermodynamically Stable Nanolaminates[END_REF] This class of materials crystallizes in the hexagonal structure and uniquely combines metal and ceramic properties. In this respect, MAX phases are easily machinable, relatively soft, electrically and thermally conductive, and excellent in their mechanical characteristics and chemical stability. [START_REF] Sokol | On the Chemical Diversity of the MAX Phases[END_REF] To date up to 155 compounds have been experimentally synthesized [START_REF] Sokol | On the Chemical Diversity of the MAX Phases[END_REF] and tested for many possible applications, in particular microelectronics, protective coatings in high-temperature and harsh radiation environments. [START_REF] Gonzalez-Julian | Processing of MAX phases: From Synthesis to Applications[END_REF] Recently MAX phases gained a further boost as precursors of a large class of two-dimensional (2D) materials called MXenes with general formula of Mn+1XnTz (Tz represents surface functional groups, predominantly =O, -OH, -F and -Cl) [START_REF] Naguib | Two-Dimensional Nanocrystals Produced by Exfoliation of Ti3AlC2[END_REF] . As opposed to most 2D materials, produced by easily breaking of weak out-of-plane van der Waals bonds in the corresponding bulk structures, [START_REF] Ajayan | Two-dimensional Van der Waals Materials[END_REF] MXene precursors have quite strong metallic bonds between atomic layers [START_REF] Barsoum | MAX Phases: Properties of Machinable Ternary Carbides and Nitrides[END_REF] and require harsh conditions for conversion into 2D state. In particular, the use of concentrated fluorine-based environment, long etching time (up to 120 h) and temperature (up to 80 o C) defines the degree of removal of the A-element and the efficiency of the synthesis. [START_REF] Naguib | Two-Dimensional Nanocrystals Produced by Exfoliation of Ti3AlC2[END_REF] Recently, several alternative techniques have been developed to produce MXenes in particular using molten salts [START_REF] Li | A General Lewis Acidic Etching Route for Preparing MXenes With Enhanced Electrochemical Performance in Non-Aqueous Electrolyte[END_REF] or surface acoustic waves. [START_REF] Ei Ghazaly | Ultrafast, One-Step, Salt-Solution-Based Acoustic Synthesis of Ti3C2 MXene[END_REF] The use of molten salts prevents the oxidation of MXenes and, more importantly, provides unique halogen functionalization. While the use of surface acoustic waves drastically enhances the productivity.

As a result of chemical etching, the surface of MXenes is naturally functionalized and therefore demonstrates excellent processability by forming organic and inorganic based suspension, [START_REF] Maleski | Dispersion of Two-Dimensional Titanium Carbide MXene in Organic Solvents[END_REF] polymer-based composites, [START_REF] Carey | MXene Polymer Nanocomposites: a Review[END_REF] and viscous inks. [START_REF] Zhang | Additive-Free MXene Inks and Direct Printing of Micro-Supercapacitors[END_REF] Apart from this, MXenes show optical transparency, tuneable electronic properties, and hereby already demonstrated their superiority with respect to other 2D materials in terms of metallic conductivity (11 000 S/cm) [START_REF] Lipatov | High Electrical Conductivity and Breakdown Current Density of Individual Monolayer Ti3C2Tx MXene Flakes[END_REF] and elastic characteristics (386±13 GPa). [START_REF] Lipatov | Electrical and Elastic Properties of Individual Single-Layer Nb4C3Tx MXene Flakes[END_REF] However, the MXene research is mainly focused on application related studies [START_REF] Pang | Application of 2D MXenes in Energy Conversion and Storage Systems[END_REF][START_REF] Pei | Ti3C2Tx MXene for Sensing Application: Recent Progress, Design Principles, and Future Perspectives[END_REF][START_REF] Iqbal | 2D MXenes for Electromagnetic Shielding: A Review[END_REF] while the understanding of their fundamental physical properties is still in early stages and mainly related to theoretical investigations. [START_REF] Champagne | Physical Properties of 2D MXenes: From a Theoretical Perspective[END_REF][START_REF] Khazaei | Electronic Properties and Application of MXenes: a Theoretical Review[END_REF] A problem that hinders the experimental verification of the theoretical predicted properties of MXenes is related to the fact that the commonly measured systems are stacked 2D nanosheets or thin films, which due to the presence of various interfacial/interlayer phenomena hide their intrinsic characteristics. Therefore, single flakes are considered as ideal objects for the exploration of the basic physical properties of MXenes. However, the production of individual flakes is quite critical due to the use of aforementioned harsh etching conditions, which causes many defects on the surface of the synthesized MXenes. [START_REF] Iqbal | Improving Oxidation Stability of 2D MXenes: Synthesis, Storage Media, and Conditions[END_REF] Even so recently proposed mild synthesis conditions [START_REF] Matthews | Guidelines for Synthesis and Processing of Chemically Stable Two-Dimensional V2CTx MXene[END_REF][START_REF] Alhabeb | Guidelines for Synthesis and Processing of 2D Titanium Carbide (Ti3C2Tx)[END_REF] remarkably improve the quality of several MXene compositions, their flake size is non-uniform, relatively small (usually 2-3 µm; the maximum size of 10 µm is reported only for Ti3C2Tz MXenes) and difficult to control. This is quite critical since flake size profoundly impacts the measured properties. For instance, Ti3C2Tz MXenes with small lateral size (200-500 nm) are not suitable for the electrical measurements due to the low environmental stability. [START_REF] Lipatov | Effect of Synthesis on Quality, Electronic Properties and Environmental Stability of Individual Monolayer Ti3C2 MXene Flakes[END_REF] On the opposite, large Ti3C2Tz flakes (with the lateral size of 10 µm) demonstrates a huge value of conductivity up to 11,000 S/cm and field-effect electron mobilities up to 6 cm 2 /V•s. [START_REF] Carey | MXene Polymer Nanocomposites: a Review[END_REF] V2CTz is another interesting MXene structure produced by wet chemical etching in HF or mixture of HF and HCl. [START_REF] Matthews | Guidelines for Synthesis and Processing of Chemically Stable Two-Dimensional V2CTx MXene[END_REF] Transparent V2CTz thin films produced by spin casting have a high figure of merit for optoelectronic properties, demonstrating their high potential in this field. [START_REF] Ying | Conductive Transparent V2CTx (MXene) Films[END_REF] V2CTz freestanding film produced by vacuum-assisted filtration shows a high value of electrical conductivity (1000 S/cm). [START_REF] Matthews | Guidelines for Synthesis and Processing of Chemically Stable Two-Dimensional V2CTx MXene[END_REF] The latter is attributed to the improved chemical stability of delaminated flakes and an increase in their lateral size (up to 2-3 µm). [START_REF] Matthews | Guidelines for Synthesis and Processing of Chemically Stable Two-Dimensional V2CTx MXene[END_REF] The maximum lateral size and quality of MXene nanosheets are defined by the grain size, purity and stoichiometry of its MAX phase precursor. [START_REF] Shuck | Effect of Ti3AlC2 MAX Phase on Structure and Properties of Resultant Ti3C2Tx MXene[END_REF] In this respect, MAX phase single crystals can be considered as an ideal model system to synthesize macroscopic MXene flakes and to explore their properties. So far, there are only three studies reporting on chemical exfoliation of MXenes from MAX phase single crystal precursors, in particular V2AlC [START_REF] Champagne | Electronic and Vibrational Properties of V2C-based MXenes: from Experiments to First-Principles Modelling[END_REF][START_REF] Kim | Elementary processes governing V2AlC chemical etching in HF[END_REF] and V4AlC3. [START_REF] Wang | Achieving Macroscopic V4C3Tx MXene by Selectively Etching Al from V4AlC3 Single Crystals[END_REF] In the case of V2AlC, initially scratched single crystal [START_REF] Champagne | Electronic and Vibrational Properties of V2C-based MXenes: from Experiments to First-Principles Modelling[END_REF] or crystal with designed pillars (from 7 µm to 500 µm lateral size) [START_REF] Kim | Elementary processes governing V2AlC chemical etching in HF[END_REF] are undergoing etching that take from 40 h 26 to 72 h. [START_REF] Champagne | Electronic and Vibrational Properties of V2C-based MXenes: from Experiments to First-Principles Modelling[END_REF] In both cases the etching of V2AlC single crystal is clearly accelerated by the presence of defects and stresses, localized close to the crystal edges, resulting in a maximum exfoliated region of 100 µm. [START_REF] Champagne | Electronic and Vibrational Properties of V2C-based MXenes: from Experiments to First-Principles Modelling[END_REF][START_REF] Kim | Elementary processes governing V2AlC chemical etching in HF[END_REF] While when a defect-free crystal is exposed to the chemical etching, the maximum penetration depth is reduced down to 25 µm. [START_REF] Kim | Elementary processes governing V2AlC chemical etching in HF[END_REF] In the case of V4AlC3 single crystal, the exfoliation for 40 days results in producing of submillimeter flakes. [START_REF] Wang | Achieving Macroscopic V4C3Tx MXene by Selectively Etching Al from V4AlC3 Single Crystals[END_REF] Thus, the presence of defects vastly impacts the exfoliation process.

Considering the beneficial role of defects in facilitating chemical etching, and the results of our previous studies showing the selective damage in Al layers induced by ion implantation in Ti3AlC2 thin films, [START_REF] Bugnet | Contribution of Core-Loss Fine Structures to the Characterization of Ion Irradiation Damages in the Nanolaminated Ceramic Ti3AlC2[END_REF] we employ Ne +2 ion implantation of V2AlC single crystal to introduce defects into the crystal structure. We demonstrate a complete chemical etching of Al layers from V2AlC single crystal within the ion implanted region resulting in production of V2CTz MXene multilayers with a lateral size exceeding 25 µm. We found that defects induced by ion implantation in V-Al layers significantly reduces the etching time by 10 times down to 8 h. The detailed structural analysis (X-Ray diffraction, scanning electron microscopy, transmission electron microscopy) and spectroscopic characterization (electron energy-loss spectroscopy) confirms the production of large scale crystalline V2CTz MXenes. Macroscopic V2CTz will allow performing an in-depth study of its fundamental physical properties. In addition, the large size of multi-layered structure exfoliated from a single crystal would be extremely beneficial for its potential use as capacitor [START_REF] Benchakar | Different MXenes: a Guideline to Understand the Crucial Role of Etching Conditions on Ti3C2Tx Surface Chemistry[END_REF] and membrane. [START_REF] Huang | MXene-Based Membranes for Separation Applications[END_REF] In the latter case, the well-aligned layers resulting from the anisotropic structure of the single crystals can serve as transport channels, providing a better transfer of molecules than films consisting of staked small sheets. Moreover, the vastly enhanced synthesis will greatly accelerate the application of V2CTz MXenes, which already demonstrated their potential as optical transparent coatings, [START_REF] Ying | Conductive Transparent V2CTx (MXene) Films[END_REF] photothermal agent [START_REF] Zada | Algae Extraction Controllable Delamination of Vanadium Carbide Nanosheets with Enhanced Near-Infrared Photothermal Performance[END_REF] and in energy conversion. [START_REF] Vahidmohammadi | Two-Dimensional Vanadium Carbide (MXene) as a High-Capacity Cathode Material for Rechargeable Aluminum Batteries[END_REF]

RESULTS AND DISCUSSION

Phase and microstructural characterization of ion-implanted V2AlC single crystal before and after chemical etching

V2AlC single crystals with typical dimensions of 0.5-2 cm were directly exposed to the ion beam as detailed in the Experimental Section and in Figure 1a. We applied the "Stopping and Range of Ions in Matter" (SRIM) software to simulate Ne 2+ implantation induced damages in V2AlC crystal structure (2.7 × 10 12 ion/cm 2 fluence, 380 keV energy). Figure 1b shows the simulated damage profile which is asymmetric in shape and about 700 nm in depth. Based on the SRIM calculations, the implantation damage within the depth profile gradually increases from 0.04 dpa close to the surface up to a maximum value of 0.15 dpa at 480 nm depth and sharply decreases afterwards.

According to Raman spectroscopy (Figure S1, Supporting Information), Ne 2+ implantation at a fluence of 2.7 × 10 12 ions/cm 2 (corresponding to 0.1 dpa) does not cause structural modification of V2AlC as all Raman modes of the virgin crystal are detected on the implanted one. While an increase in fluence (corresponding to 0.2 dpa) leads to the disappearance of E2g (158 cm -1 ) and E1g (240 cm -1 ) with a slight shift of E2g (258 cm -1 ) and A1g (365 cm -1 ) modes due to structural modifications induced by implantation. This is in complete agreement with results showing a gradual structural modification without amorphization in V2AlC for 1 MeV Au + irradiations corresponding to 0.15 to 0.2 dpa. [START_REF] Wang | Structural Transitions Induced by Ion Irradiation in V2AlC and Cr2AlC[END_REF] Since the most critical step in MXene etching is intercalation of the etchant between M-A layers, we can assume that Ne 2+ implantation can induce some distortions in V-Al bonding, facilitating easier intercalation of etchant ions and reducing the processing time. This assumption is very consistent with the preferential alteration of the Al planes observed in Ti3AlC2 thin films irradiated with 240 keV Ar + ions. 33 After the ion implantation, single crystals were immersed in the concentrated HF solution as described in detail in the Experimental Section and in Figure 1c. The surface of the single crystals before and after chemical etching is shown in Figure 1d, e and 1f, g respectively. During chemical etching the initially shiny grey metallic surface of single crystals (Figure 1d,e) is gradually changed towards black. After 8 h of chemical etching the implanted surface of single crystal is completely black (Figure 1f, g), while the opposite un-implanted surface remains grey. The appearance of black powder on the implanted surface of single crystal is the first indicator of the successful conversion of MAX phase to MXenes. Ab initio molecular dynamics simulation of the etching process of Ti3AlC2 in HF solution [START_REF] Srivastava | Mechanistic Insight into the Chemical Exfoliation and Functionalization of Ti3C2 MXene[END_REF] suggests that exfoliation of Ti3C2 MXene proceeds via HF insertion through edges of MAX phase. After the breaking of M-A bonds, the interlayer gap opens and thereby facilitates further insertion of HF molecules in the structure. The same mechanism was experimentally observed during HF etching of V2AlC single crystal. [START_REF] Kim | Elementary processes governing V2AlC chemical etching in HF[END_REF] The observations were proven by the preferential loss of the Al species at the edges of the crystal as compared to the center with the maximum etched region of 100 μm. Interestingly, in our work the exfoliated region of V2CTz MXenes is largely extended up to mm's area. This finding highlights the crucial role of ion implantation in promoting chemical etching of single crystal. One possible reason is that the dissociated HF molecules react more easily with damaged Al planes and thereby enhance the penetration of F ions into the single crystal from the edges to the center. Moreover, the main benefit for the use of ion implantation manifests in the drastically reduced etching time, down to 8 h, as compared with conventionally used HF etching protocols of V2AlC powder precursor (92 h), [START_REF] Zada | Algae Extraction Controllable Delamination of Vanadium Carbide Nanosheets with Enhanced Near-Infrared Photothermal Performance[END_REF] recently reported milder etching conditions (72 h) [START_REF] Matthews | Guidelines for Synthesis and Processing of Chemically Stable Two-Dimensional V2CTx MXene[END_REF] or equivalent single crystals (72 h). [START_REF] Champagne | Electronic and Vibrational Properties of V2C-based MXenes: from Experiments to First-Principles Modelling[END_REF] To further elucidate the phase composition and microstructure of exfoliated single crystal, we performed detailed structural and morphological investigation presented in Figure 2. The XRD analysis of V2AlC single crystals shows no changes in the phase composition induced by ion implantation (Figure 2a). In both cases (virgin and ion-implanted crystals), the XRD patterns display peaks originating from (000l) planes of V2AlC, and the presence of a single (10-11) peak. After chemical etching, the sharp (000l) peaks are still present in the XRD pattern, indicating the preservation of V2AlC MAX phase structure below the exfoliated surface.

Additionally, characteristic high intensity broad peaks downshifted with respect to the MAX phase peaks are clearly seen in the XRD pattern of the V2AlC after chemical etching. This confirms the successful removal of Al layers from V2AlC structure within the implanted depth resulting in expansion of the interlayer distance and thus the increase of c-parameter from 13.1 Å to 17.5 Å.

Further, we studied chemical composition of the surface of the single crystal after chemical exfoliation (black powder) by recording EDX spectra (Figure 2c). We observed the presence of V and C originated from V-C blocks in MAX phase structure and O and F elements appear after replacement of the etched Al layers, while a tiny signal corresponding to Al has been detected over a large area (Table S1, Figure S2 Supporting Information), showing that only a negligible amount of Al remains. This confirms, in addition to the XRD findings, that Al was successfully etched from the ion implanted region of the single crystal. Afterwards, we scrapped part of the exfoliated layer until the grey single crystal surface was bare and recorded EDX spectra on this region (Figure 2d). We detected the signals of V, Al, and C elements, the stoichiometry of which is close to 2:1:1 corresponding to V2AlC MAX phase (Table S1, Supporting Information). This finding further supports the assumption that the chemical conversion of MAX phase to 2D MXene is successful within the damaged region, which is about 700 nm based on SRIM calculation (Figure 1b). We used Monte Carlo simulation of electron trajectory in solids (CASINO v3) while performing EDX analysis, predicting a typical depth of 1 to 2 µm, probed for a V2CTz multilayer at 10 keV energy.

Figure 2 e,f,g presents an AFM image and corresponding height profiles of exfoliated V2CTz multilayer. The investigated part of V2CTz multilayer is quite large with a dimension of at least 20˟30 µm, which is much larger as compared to a typical size of V2CTz produced from the powder precursor (usually less than 3 µm). [START_REF] Matthews | Guidelines for Synthesis and Processing of Chemically Stable Two-Dimensional V2CTx MXene[END_REF] The analyzed region clearly reveals the presence of characteristic wrinkles along the exfoliated surface, a characteristic height profile of which is given in Figure 2g. The presence of such wrinkles is commonly found in large flakes of CVD grown graphene. [START_REF] Surwade | Thermal Oxidation and Unwrinkling of Chemical Vapor Deposition-Grown Graphene[END_REF] The length of wrinkles is quite large varying from 4 to 20 µm, which additionally confirms the production of large exfoliated V2CTz structures, at least of the same lateral size as wrinkles. The measured multilayer thicknesses are between 200 and 300 nm.

TEM and spectroscopic investigation of V2CTz MXenes

Transmission electron microscopy (TEM) and energy-filtered selected area electron diffraction (SAED) were initially used to perform structural investigations of V2CTz MXenes exfoliated from the single crystal. For TEM study, the fragments of black powder were detached by moving the grid over the exfoliated surface of the crystal and subjected to plane-view imaging. We studied fragments of different sizes and thicknesses named as Zone 1 -Zone 3, the structural characterization is presented in Figure 3. Areas where the main TEM images and corresponding EEL spectra were recorded are identified by white circles.

We observed that all investigated fragments are much larger (the lateral size varies from few µm (Zone 1, 2) to 25 µm (Zone 3)) as compared with the typical size of MXenes exfoliated from powder precursor (1-3 µm). [START_REF] Matthews | Guidelines for Synthesis and Processing of Chemically Stable Two-Dimensional V2CTx MXene[END_REF][START_REF] Alhabeb | Guidelines for Synthesis and Processing of 2D Titanium Carbide (Ti3C2Tx)[END_REF][START_REF] Lipatov | Effect of Synthesis on Quality, Electronic Properties and Environmental Stability of Individual Monolayer Ti3C2 MXene Flakes[END_REF][START_REF] Ying | Conductive Transparent V2CTx (MXene) Films[END_REF][START_REF] Shuck | Effect of Ti3AlC2 MAX Phase on Structure and Properties of Resultant Ti3C2Tx MXene[END_REF][START_REF] Champagne | Electronic and Vibrational Properties of V2C-based MXenes: from Experiments to First-Principles Modelling[END_REF][START_REF] Kim | Elementary processes governing V2AlC chemical etching in HF[END_REF][START_REF] Vahidmohammadi | Two-Dimensional Vanadium Carbide (MXene) as a High-Capacity Cathode Material for Rechargeable Aluminum Batteries[END_REF] One can notice that the size of the largest fragment (i.e. Zone 3) is very consistent with that determined from the AFM measurements given in Figure 2e. By focusing on the edges of the exfoliated multilayered fragments we observe the presence of flakelike contrast with clearly visible thin delaminated regions. The fragments are flat comprising of different numbers of layers distinguished by contrast variation increasing from the edges to the center (Zone 1). In addition, there is a pronounced TEM contrast with dark spots on the thin region of the multilayers (Zone 1 and Zone 2), which is a characteristic feature of radiation-induced damages. [START_REF] Seydoux-Guillaume | Microstructure of 24 -1928 Ma Concordant Monazites: Implications for Geochronology and Nuclear Waste Deposits[END_REF][START_REF] Tunes | A Transmission Electron Microscopy Study of the Neutron-Irradiation Response of Ti-based MAX phases at High Temperatures[END_REF][START_REF] David | Effect of Implant Temperature on Defects Created Using High Fluence of Helium in Silicon[END_REF] The insets of Figure 3 show typical SAED patterns of exfoliated thin flakes. We observed that all regions have the characteristic for MXenes hexagonal-like structure originated from the single crystal precursor. The spots in the SAED patterns recorded on the flakes of Zones 2 and 3 are discrete and sharp, while the ones of Zone 1 are diffuse. This suggests a slight distortion of the crystal structure of V2CTz multilayers of Zone 1 caused by Ne 2+ ion-implantation. We note the absence of any extra spots in the recorded SAED patterns, suggesting their environmental stability. As was previously reported [START_REF] Iqbal | Improving Oxidation Stability of 2D MXenes: Synthesis, Storage Media, and Conditions[END_REF][START_REF] Lipatov | Effect of Synthesis on Quality, Electronic Properties and Environmental Stability of Individual Monolayer Ti3C2 MXene Flakes[END_REF] , the large flakes are more oxidation resistant as compared with the flakes of smaller size. Moreover, due to the short etching time of 8 h, V2CTz flakes appear without visible etching induced through-flake holes that also contribute to flakes instability. Based on the SAED patterns we calculate the corresponding inter-reticular distances which are 0.26±0.01 nm for d100 and 0.15±0.01 nm for d110. These values are consistent with that of reference V2AlC. [START_REF] Shi | Synthesis of Single Crystals of V2AlC Phase by High-Temperature Solution Growth and Slow Cooling Technique[END_REF] To further study the chemical composition of the exfoliated MXene multilayers we focused on the fragment of the largest area of 25x10µm² (Zone 3) and performed EDX analysis at different positions within the flake, marked with differently colored dots as indicated in Figure 4. We detected the presence of V and C originated from the core MXene structure, Al remained from MAX phase structure and F attributed to the surface functional groups. The Cu signal comes from the TEM grid. There is almost no Al signal in the EDX spectra recorded at all positions of the studied fragment proving the complete chemical etching within the large crystal area. In addition to point EDS analysis, we performed elemental mapping of the exfoliated fragments with an approximate lateral size of 7 µm (Figure S3, Supporting Information). We observed a uniform distribution of the V, C, and F in the multilayer with a tiny amount of Al (0.3 at.%). This is in line with the conclusion of SEM-EDX results suggesting the successful chemical exfoliation of V2AlC single crystal. We note that the relative intensities between the V-Lα, C-Kα and F-Kα vary depending on the position in the fragment. This could be due to the compositional inhomogeneity within the exfoliated area. To estimate it, we normalized the EDX spectra to the V-Lα signal and compared the V/C ratios obtained along the line taking the third spectrum (i.e. the green one) as a reference; the corresponding values are given in the EDX plots. We find out that V/C ratio is probably smaller at the edges of the exfoliated regions as compared the center part of the studied multilayer. This possibly could be due to the overetching process at the crystal edges, resulting in partial removal of V in addition to Al.

EDS line 0,0 0,5 1,0 1,5 C K α L α Cu 0,0 0,5 1,0 1,5 C K α V L α F K α Cu L α Al K α C K α V L α F K α Cu L α Al K α C K α V L α F K α Cu L α Al K 0,0 0,5 1,0 1,5 C K α V L α F K α Cu L α K α 1.
To further explore the elemental composition of the synthesized V2CTz MXenes and identify the chemical environment at the nanoscale, we performed electron energy-loss spectroscopy (EELS) of exfoliated multilayers. Figure 5 displays the characteristic core-loss low-loss spectra recorded on different zones of the exfoliated crystal marked in Figure 3. MXenes, in particular for Ti3C2Tz and Ti2CTz. [START_REF] Bylik | Electronic Structure Sensitivity to Surface Disorder and Nanometer-Scale Impurity of 2D Titanium Carbide MXene Sheets as Revealed by Electron Energy-Loss Spectroscopy[END_REF] Interestingly, in Zones 1 and 2, the peak located at 295 eV (labelled B) is quite broad as compared to that in Zone 3 where the shoulder labelled C can clearly be identified. As was theoretically and experimentally established in our previous works, the C-K edge is quite sensitive to the structural disorder resulting in a broadening of the fine structure at higher energy (i.e., peaks C the case), the first peak A being mainly affected by surface disorder in Ti-based MXenes. [START_REF] Bylik | Electronic Structure Sensitivity to Surface Disorder and Nanometer-Scale Impurity of 2D Titanium Carbide MXene Sheets as Revealed by Electron Energy-Loss Spectroscopy[END_REF][START_REF] Pazniak | Ion Implantation as an Approach for Structural Modification and Functionalization of Ti3C2Tx MXenes[END_REF] We suggest that the exfoliated multilayers are more damaged due to the implantation in Zones 1 and 2 than in Zone 3. That the structural disorder induced by implantation is not homogeneously distributed in different zones along the implantation profile is consistent with the damage profile given in Figure 1b and shows that there is room for reduction of radiation-induced damages in the MXene multilayers by adjusting the implantation conditions or by selecting only MXene flakes close to the surface of the crystal. Finally, comparison between the C-K edge in the MXene and in the corresponding MAX phase precursor clearly show a significant modification in the electronic structure after exfoliation with a strong decrease of the intensity of peak A; this is expected from the replacement of the Al layers by terminal groups. This modification is confirmed at the V-L2,3 edge (Figure 5b) which also evidence major changes between the MXene and V2AlC with a strong change in the L2/L3 ratio characteristic of a modification in the V-3d bands.

The characteristic V-L2,3 edges at 518 eV are also reproducible for different zones and exhibit well-defined fine structure with sharp peaks. By recording EEL spectra at the V-L2,3 edges we clearly observe the presence of the O-K edge at 532 eV. This attributed to the terminal groups on the surface of the exfoliated layers confirming successful etching. The F-K edge (see Figure S4, Supporting Information) was also clearly identified, further confirming the replacement of the Al layers in the MAX phase by the usually observed terminal groups of MXenes.

The experimental low-loss EEL spectra recorded on exfoliated fragments of the different zones are compared to the low-loss EEL spectra recorded on the V2AlC MAX phase powders (Figure 5c). It should be noted that the main differences between the aforementioned spectra is the position of the bulk plasmon peak. This peak appears at around 20 eV in the V2AlC MAX phase structure, while it is about 5 eV higher in the structure of exfoliated V2CTz multilayers. This shift is the characteristic feature of the exfoliation as demonstrated by Magné et al. in Ti3C2Tx, [START_REF] Magne | Spectroscopic Evidence in the Visible-Ultraviolet Energy Range of Surface Functionalization Sites in the Multilayer Ti3C2 MXene[END_REF] and a strong proof of the successful conversion of MAX phases to MXenes. In addition, we performed the quantification of elements by EELS on the fragments of Zone 1 and calculated the V/C ratio correspondingly (Figure 5d). We choose three regions: at the edges of the exfoliated flakes (Zone III), in the centre (Zone I), and between them (Zone II). The precise elemental quantification by EELS is difficult due to the fact that O-K edge is superimposed to the V-L2,3 edge. However, the calculated V/C ratio is close to the value in the initial MAX phase with 10% uncertainty. We observed that the quantification results are heterogeneous and depends on the region although the V/C ratio increases from the edge to the center (orange arrow, Figure 5d). This finding is consistent with a possible V overetching on the edges of the single crystal as we already observed by EDX analysis and previously reported by Kim et al. [START_REF] Kim | Elementary processes governing V2AlC chemical etching in HF[END_REF]

CONCLUSION

EXPERIMENTAL SECTION

Growth and ion-implantation of V2AlC single crystal. The V2AlC single crystal precursors are grown via a flux growth method. [START_REF] Shi | Synthesis of Single Crystals of V2AlC Phase by High-Temperature Solution Growth and Slow Cooling Technique[END_REF] Growth takes place in alumina crucibles by using melted pellets of vanadium and aluminum. The C incorporation is controlled by dipping a predetermined height of a rotating graphite rod in the solution at the maximum temperature for 2 h. After the high-temperature step, aimed at dissolving all elements, the temperature is slowly decreased (over days) to enhance Ostwald ripening and decrease the number of small crystals in the solution. equipped with an energy dispersive X-ray (EDX) spectrometer from Oxford Instruments (UK).

Raman spectroscopy of the single crystals before and after ion-implantation was carried out using a HORIBA Jobin Yvon LabRAM HR800 confocal Raman microscope with a CCD detector.

Spectra were acquired at room temperature using an excitation wavelength of 632.8 nm, supplied by an internal He-Ne laser. The power delivered at the sample is 3 mW. An 1800 grooves.mm -1 grating is used resulting a spectral resolution of 0.5 cm -1 . The spectrometer is calibrated by a silicon wafer. The samples for transmission electron microscopy (TEM) were prepared by lightly scratching the chemically etched surface of ion-implanted V2AlC single crystals with Cu grid covered with a lacey carbon film so as to deposit MXene flakes on it. The electron energy loss (EEL) spectra were recorded in image mode in a JEOL 2200 FS microscope equipped with an incolumn omega filter and operated at 200 kV. The energy resolution determined from the zero-loss peak full width at half-maximum was about 1.0 eV. The core edges (i.e., the C-K, V-L2,3 and F-K edges) were extracted from the background signal using a power law and were deconvolved from multiple scattering using the Fourier-ratio method. The EDX analysis were performed using a Bruker XFLASH 6T/60 SDD spectrometer. The topography of the samples was characterized by Atomic Force Microscopy (AFM) in tapping mode using a Dimension 3100 microscope from Bruker.

Figure 1 .

 1 Figure 1. Schematic illustration of the fabrication process of V2CTz MXenes using ion implantation approach. a The implantation process of V2AlC single crystal using a Ne 2+ ions at

Figure 2 .

 2 Figure 2. Structural and morphological characterization of V2AlC single crystal before and after

Figure 3 .

 3 Figure 3. Structural characterization of V2CTz MXenes multilayers. TEM images of the studied

Figure 4 .

 4 Figure 4. Chemical composition of the exfoliated V2CTz MXene multilayers. e TEM image of the

1 Figure 5 .

 15 Figure 5. EEL spectra of exfoliated V2CTz multilayers. a C-K and b V-L2,3 and O-K edges (grey

  This work demonstrates a new approach to produce macroscopic V2CTz multilayer MXenes from V2AlC single crystal precursor by exploiting an ion-implantation strategy. It is based on the selective damaging of the Al layers with Ne 2+ ion-implantation which drastically facilitate chemical etching of Al layers within the implanted region and reduce the exfoliation time by a factor of ~10 as compared to V2AlC powder exfoliation or previously reported V2AlC single crystal exfoliation. The complete conversion of implanted MAX phases to MXenes and formation of macroscopic 2D V2CTz flakes was comprehensively proven by XRD, SEM, EDX and TEM measurements. The lateral size of exfoliated fragments is much larger as compared with MXenes produced from powder precursors. By combining TEM and EELS results we found that the exfoliated nanosheets are quite stable with a slight distortion in the structure induced by ionimplantation. The macroscopic size of exfoliated flakes suggests they could be ideal objects to explore the fundamental physical properties of MXenes. In addition, the large size of the exfoliated V2CTz MXenes has potential in membrane applications due to the well-aligned layers resulting from the anisotropic structure of the single crystal precursor. Finally, we assume that using ionimplantation, an industrial compatible technique, could open new perspectives in MXene synthesis by largely enhancing the efficiency of the chemical etching of MAX phases.

  Crystals are extracted from the flux by hydrochloric acid etching. The high-temperature solution growth parameters and the choice of the appropriate liquid composition as well as structural characterization of crystals are thoroughly described in Ref.39. To perform ion-implantation, V2AlC single crystals are mounted on a sample holder having an implantation surface of about 10 cm 2 and directly exposed to the ion beam in EATON ion implanter. Ne 2+ ions were accelerated at 190 kV (resulting in a 380 keV energy) with probe currents of 2.5 μA and a chamber pressure of 5 × 10 -7 mbar at room temperature. The chosen fluence is of 2.7 × 10 12 ion/cm 2 . The projectile trajectory of implanted ions was perpendicular to the surface of the single crystals. The damage profile of V2AlC single crystal (density of 4.85 g/cm 3 ) are simulated using the Stopping and Range of Ions in Matter (SRIM) code.[START_REF] Ziegler | SRIM -The Stopping and Range of Ions in Matter[END_REF] The used displacement energies are Ed = 25 eV for V, Ed = 25 eV for Al, and Ed = 28 eV for C.Chemical exfoliation of V2AlC single crystal. Ion-implanted V2AlC single crystals are directly exposed to the chemical etching. With this aim, 20 ml 48% HF (Sigma Aldrich, ≥99.99%) is added in a Teflon vial and placed on the magnetic steering. Ion-implanted single crystals are placed in a plastic vial with small holes in the bottom and partially immersed in the acid solution (Figure1c).The chemical etching is carried out for 8 h at room temperature under continuous magnetic stirring with the rate of the stir-bar of 500 rpm. After chemical etching the exfoliated crystals are carefully removed from the acid solution and washed multiple times by immersing into deionized water.After washing, the exfoliated crystals were dried and stored inside an argon-filled glovebox.Structural characterization of V2AlC single crystal and V2CTzMXenes. The X-ray diffraction (XRD) patterns of the V2AlC single crystals after ion-implantation and chemical etching are collected using a D8 diffractometer (Bruker Ltd. Germany) in Bragg-Brentano geometry, equipped with Cu Kα radiation (1.5406 Å) with a continuous θ-2θ scan with 0.017° 2θ/s (U = 40 kV, I = 40 mA). Chemical composition of the chemically etched single crystal was studied using JSM-7001F TTLS field emission gun scanning electron microscope (SEM) (Jeol Ltd., Japan)

ACKNOWLEDGEMENT This work was supported by the French government program "Investissements d'Avenir" (EUR INTREE, reference ANR-18-EURE-0010). This work was partially funded by the "Région Nouvelle-Aquitaine" and the European Regional Development Fund (ERDF 2014-2021) within the NanoTrans project No. PC-2016-2916910 and by ANR project ANR-18-CE09-0041. The authors thank Marc Marteau for the assistance with ion implantation. REFERENCES

ASSOCIATED CONTENT Supporting Information. The Supporting Information is available free of charge on the ACS Publications website. Additional information contains Raman spectra of V2AlC single crystal before and after Ne +2 ion-implantation, chemical composition of V2AlC single crystal after chemical etching, and F-K edge EEL spectra of exfoliated V2CTz flakes.

AUTHOR INFORMATION

Corresponding Authors

*Emails: hanna.pazniak@univ-poitiers.fr (H.P.); marie-laure.david@univ-poitiers.fr (M.-L.D.); vincent.mauchamp@univ-poitiers.fr (V.M.)

Notes

The authors declare no competing financial interest.


Marc Camats

Isabelle Favier

Sonia Mallet-Ladeira

Daniel Pla

Montserrat Gómez

Understanding Cu( ii )-based systems

Keywords: Cu(II) complexes, aldimines, C(sp 3 )-H bond functionalization, imidazo[1,5-a]pyridines, catalysis

come

Introduction

In contrast to 4d and 5d transition metal catalysts (e.g. Pd, Pt, Ru, Rh), [START_REF]Catalytic C-H/C-X Bond Functionalization[END_REF] first row transition metals have received less attention in direct functionalization methodologies of unactivated C-H bonds. 2 Among them, copper occupies a preferential place due to its abundance, low toxicity and versatility in terms of reactivity as evidenced by the many reports on C(sp 2 )-H activation reactions, 2g, 3 in particular those using bidentate ligands. 4 Since Fujiwara's early reports on the C(sp 3 )-H aminomethylation of alkanes catalyzed by Cu(II) salts, 5 the advent of direct functionalization methodologies for the selective transformation of unactivated C(sp 3 )-H bonds has enabled novel synthetic routes by means of C-C crossdehydrogenative reactions, 6 carbonylative 7 and decarboxylative couplings, 6e, 8 aminations, 3b, 9 amidations, 10 alkoxylations, 11 acetoxylations 12 and phosphorothiolations, 13 among the most relevant transformations. 3a, 6f, 14 The use of bidentate ligands to direct functionalization of C(sp 3 )-H bonds in a regioselective fashion has afforded promising results for the functionalization of such recalcitrant bonds. 3a, 4a, 4c, 15 From a mechanistic point of view, organometallic C-H bond activation, ligand-assisted functionalization and single electron-transfer pathways have been postulated in the process (Figure 2). 16 In particular, the C(sp 3 )-H activation in α position to a nitrogen atom has been described to undergo via the formation of an iminium group arising from a radical cation. This reactivity has thus far been applied in Cu-catalyzed annulation of N-heteroaryl aldehydes 17 or ketones 9c, 18 with alkylamines and aminoacids via C(sp 3 )-H amination. The affinity of heterocyclic aldimines for electrophilic Cu(II)-based catalysts represents a straightforward and atom economical manner to accomplish remote C(sp 3 )-H bond activation. Thus, we envisioned that the imidazo [1,5a]pyridine scaffold could be formed via C(sp 3 )-H bond functionalization of aldimines bearing pendant saturated hydrocarbon chains. In this work, we report the direct synthesis of 3-substituted imidazo [1,5-a]pyridines via a Cu-mediated C(sp 3 )-H activation/cyclization in excellent yield and regioselectivity, thus providing novel methods which are complementary to established strategies. S1-S5, Figures S1-S5, Schemes S1-S4, synthesis and characterization of compounds type-1, type-2, 4 and 6a, NMR spectra of type-1, type-2, 4 and 6a compounds, and single-crystal X-ray diffraction data for CuA, Cu4B, 4 and 6a (Tables S6-S9) (PDF). • X-ray crystallographic files in CIF format for CuA, Cu4B, 4 and 6a.

• CCDC-2077016 (CuA), CCDC-2077017 (Cu4B), CCDC-2077019 (4), and CCDC-2077018 (6a), contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. See DOI: 10.1039/x0xx00000x Diversity-oriented synthesis 19 strategies to explore the chemical space around privileged leads such as purine, 20 imidazo [1,2a]pyridine, 3f pyrazolo [1,5-a]pyrimidine, 21 pyrazolo[1,5a]pyridine 22 and pyrrolo [2,1-f][1,2,4]triazine, 23 found in numerous natural products and drug scaffolds (Figure 1) prompted us to explore novel synthetic methodologies for the synthesis of isosteric scaffolds. 24 In particular, imidazopyridine derivatives are garnering increased attention in recent years as tryptophan-2,3-dioxygenase and indoleamine 2,3-dioxygenase inhibitors. [START_REF] Cowley | Novel substituted imidazopyridine compounds as inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan-2,3-dioxygenase[END_REF] Thus, medicinal chemistry approaches to access variations on such fundamental building blocks in a rapid and efficient manner could provide important breakthroughs in translational science. In this regard, the functionalization of recalcitrant C-H bonds represents a powerful and sustainable transformation in organic synthesis, affording new entries to such valuable motifs of potential biological interest. 26 In this work, we focus on the use of Cu-promoted C-H bond functionalization strategies towards the preparation of new compounds with untapped potential.

Results and Discussion

We prepared original aldimines by condensation of 3-fluoro-2pyridinecarboxaldehyde and the corresponding primary amine in 2-methyltetrahydrofuran and in the presence of sodium sulfate, affording the expected products 1a-1k in high yields (>89%, Scheme 1), together with an ease of analysis by 19 F-NMR.

Scheme 1. Synthesis of aldimines 1a-1k.

Our attempts towards the functionalization of pyridinylaldimine substrate 1a began with the use of superstoichiometric amounts of CuBr2 (1.5 equiv.) in CHCl3 or CH3CN at 100 °C under microwave irradiation, resulting in the formation of Cu(II) coordination complexes (no C-H bond activation was observed). Thus, the bimetallic CuA was isolated and further crystallized by reaction of CuBr2 with 1a in CH2Cl2 at room temperature. Similar results were obtained with 1b and 1c (Scheme 2). Scheme 2. Synthesis of complexes CuA, CuB and CuC from aldimines 1a, 1b and 1d, respectively.

CuA X-ray crystal structure shows the formation of a centrosymmetric bimetallic complex with two bromide anions bridging both metals, in agreement with other related structures containing N,N-bidentated ligands: pyridylbenzimidazole, 27 pyridyl-oxime, 28 and pyridyl-pyrazole. 29 The asymmetric unit consists of a five-membered metallocycle featuring a bidentate N,N-coordination of the 1-(3fluoropyridin-2-yl)-N-propylmethanimine ligand (bite angle N1Cu1N2 = 80.11(8)°) and two bromide anions in a slightly distorted square planar arrangement around the metal center (the distance between the N1N2Br1Br2 plane and Cu is 0.21 Å). Each Cu(II) center is pentacoordinated exhibiting a distorted square pyramidal arrangement constituted of a N1N2Br1Br2

Please do not adjust margins Please do not adjust margins plane and an apical bromide anion (Cu-Br(apical) distance = 2.781(1) Å); no metal-metal interaction is observed (Cu-Cu distance = 3.601(1) Å) (Figure 3 and Figure S1 in the ESI). 6); N2-Cu1-Br2 = 94.48 (6).

Reactivity studies of CuA in the absence of base were carried out in CHCl3 and CH3CN, but no conversion was detected, pointing that this complex is not involved in the C-H bond activation, probably due to the formation of unsaturated reactive copper species (see Table S1 Table 1, entries 1 and2) arising from deleterious hydrolytic pathways. The formation of 3 can be justified by imine transimination with ammonia followed by condensation with a second aldehyde in the absence of copper(II) species as described in the literature (Table 1, entry 2). 30 This secondary reaction was also favored in glycerol (69% conversion, Table 1, entry 3). Concerning the formation of 4, a rational is proposed in the mechanistic discussion (see below). Transformation of the dimer CuA into the heterocycle 2a occurred in CH3CN the presence of NH4OAc, albeit in low yield (23%, Table 1, entry 4), whereas only traces of the product could be detected in CHCl3 (4% Table 1,entry 5).

Table 1. Reactivity of CuA in different solvents and bases under microwave irradiation. [a] Entry Solvent Base Conversion (%) [b] Yield (%) [b] 2a 3 4 1 AcOH:CHCl3 (1:4) NH4OAc 76 <1 49 15 2 [c] AcOH:CHCl3 (1:4)

NH4OAc 90 [d] 0 34 0 3 Glycerol NH4OAc 69 [e] [f] n.d. [f] 7 CH3CN KOPiv 87 84 n.d. [f] n.d. [f] [a] Reaction conditions: CuA (0.15 mmol, 117.0 mg), 0.45 mmol of base, 4 mL of the corresponding solvent, at 100 °C for 10 min under microwave irradiation (max. 200 W). [b] Conversions and yields were determined by 19 F NMR with 4fluorotoluene as standard. [c] 1a was used as starting material instead of CuA. [d] Complex mixture of degradation by-products. [e] Complex mixture composed of acetals and by-products.

[f] n.d. for not detected.

In CH3CN, other bases were tested (Table 1, entries 6-7 and Table S2 in the ESI). Notably, NBu4OAc furnished up to 72% conversion and good selectivity towards 2a (64% yield, Table 1, entry 6) and KOPiv, 87% conversion (84% yield, Table 1, entry 7). CsOAc or KOAc showed low conversions (8 and 26%, respectively, Table S2 in the ESI) albeit in excellent selectivity for the latter. Other salts were tested as bases, namely, KOH and KO t Bu; KOH did not trigger any transformation and more basic KO t Bu directed a nucleophilic attack to the imine moieties of the binuclear complex (see Table S2 in the ESI). These results point to a plausible anion exchange on the complex (bromide by carboxylate; encompassing an instantaneous color change from deep red to green) that enables the C-H bond functionalization.

Once the reactivity of the binuclear copper complex was optimized, we studied the in-situ reaction of imines type-1 with CuBr2 (1.5 equiv.) in the presence of NBu4OAc (1.5 equiv.). Gratifyingly, under these conditions, the C(sp 3 )-H amination and cyclization furnished the desired imidazo [1,5-a]pyridine product (2a) in comparable yield and selectivity to the reaction carried out from the preformed complex CuA (52% vs 64% yield, Table S3, entry 1 vs Table 1, entry 6, respectively). [START_REF]One-pot reaction attempts aiming at in-situ condensation of 1-propylamine and 3-fluoro-2-pyridinecarboxaldehyde preclude C-H bond functionalization probably due to the strong coordination of copper with primary amines (see Table S3[END_REF] This result prompted us to examine the use of Cu(OAc)2 towards the C-H functionalization of the aldimine 1a (reaction conditions: 100 °C under microwave irradiation for 10 min in different solvents: EtOH, glycerol, AcOH, CF3COOH, CHCl3, EtOAc, CH3CN; see Table S4 in the ESI). Full decomposition was observed with superstoichiometric amounts of Cu(OAc)2 in both CF3COOH and EtOAc as solvents; moreover, major substrate hydrolysis to propylamine and 6-fluoropyridine-2carboxaldehyde precursors was obtained for many of the tested conditions using protic solvents. When CH3CN and CHCl3 were Please do not adjust margins Please do not adjust margins used as solvents, 2a was obtained in low to moderate yields (48 and 17%, respectively, see Table S4 in the ESI, entries 6-7). Interestingly, a cubane tetranuclear copper(II) complex (Cu4B) with the composition [Cu4OCl6(2b)4] was obtained by crystallization of the crude reaction mixture in CHCl3. Its singlecrystal X-ray analysis showed a central oxygen atom coordinated to four copper atoms in a tetrahedral geometry (Cu-O-Cu angles are 110.57(5)° and 108.92(2)°), each of which connected to the three other Cu atoms via bridging chlorine atoms (placed at the tetrahedron edges), analogously to related structures already reported in the literature. [START_REF] Löw | [END_REF] Each copper center shows a distorted trigonal bipyramid geometry with chlorine atoms occupying the three equatorial positions and the central oxygen atom and imine nitrogen of the heterocycle 2b in axial positions (Figure 4). The isolation of this copper cluster encouraged us to assess its role in the reaction. Thus, its plausible precursor [Cu4OCl6(CH3CN)4] ( 5) was prepared. 33 However, the reaction of 5 with aldimine 1b, aiming at the in situ generation of Cu4B via the displacement of the CH3CN ligands by 1b, did not furnish any traces of the desired product 2b under our reaction conditions, suggesting that the copper cluster 5 is inactive towards C(sp 3 )-H activation (see Scheme S1 in the ESI). With the aim of obtaining Cu(II) carboxylate complexes, we carried out a number of attempts to prepare the corresponding 1a and 1b aldimine complexes with Cu(OPiv)2 (due to its better reactivity; see below); unfortunately, no suitable monocrystals for XRD analyses were obtained. However, MS analyses revealed the complexation of 1a affording bis-pivalate [Cu(OPiv)2(1a)] species ([M+H], m/z 432.1), together with the presence of the mono-pivalate peak, [Cu(OPiv)(1a)] + (m/z 330.1; see Figure S2 in the ESI). To assess the determinant role of copper carboxylates in facilitating the C-H amination, several copper salts (namely formate, acetate, benzoate and pivalate) were tested (see Table S3 in the ESI, entries 3-5). Despite the poor results obtained for both copper formate and copper benzoate (2a obtained in 55 and 14% yields, respectively), these results point to the key assistance of carboxylate groups in the C-H activation event. Among the copper(II) carboxylates used, Cu(OPiv)2 exhibited the best conversion and selectivity (95% conversion and 83% yield; Scheme 3 and see Table S3 in the ESI, entry 5). Scheme 3. Optimized reaction conditions for the synthesis of imidazo [1,5-a]pyridines type-2 with stoichiometric Cu(OPiv)2. 16), 94.50 (15) and 97.99 (18); Cl-Cu-O 84.03 (6), 84.36 (5) and 85.75(5); N1-Cu-O = 177.36 (17).

In order to translate the stoichiometric reaction into its catalytic version, several oxidizing reagents were studied under microwave irradiation (10-20 mol% catalyst loadings of Cu(OPiv)2 in CH3CN at 100 °C; see Table 2 andTable S5 in the ESI). Among the oxidizing agents tested, only stoichiometric amounts (related to copper salt) of the desired product were obtained in the presence of pivalic anhydride (1.5 equiv.), benzoquinone (1.5 equiv.) and a mixture of K3[Fe(CN)6] (1.5 equiv.) and dibenzo-18-crown-6 (for further details, see Table S5 in the ESI). It is noteworthy to mention that a new 8fluoroimidazo [1,5-a]pyridine-1-carbonitrile product (6a) was obtained when 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) was used (Table 2, entry 1; see the ESI for single-crystal XRD of 6a). Taking into account literature reports on the role of CH3CN as a cyanating reagent with copper catalysts, 34 we reasoned that the nitrile group could come from the solvent. However, this hypothesis was discarded as the reaction in CpOMe did also provide 6a together with by-products (Table 2, entry 2), whereas the reaction in the absence of DDQ did not Please do not adjust margins Please do not adjust margins provide any traces of 6a (Table 2, entry 3). These results indicate that DDQ acts as cyanating agent, in agreement with coppercatalyzed cyanation of arylboronic acids described by Cheng and co-workers. 35 Optimization of the reaction was carried out (Table 2, entries 4-6), finding the following optimal conditions: Cu(OPiv)2 (20 mol%), DDQ (1 equiv.) in CH3CN at 100 °C for 10 min under microwave irradiation (Table 2,entry 4). This new copper-mediated C-H cyanation reaction brings a new entry to non-hazardous cyanide sources. 36 [d] 6 0 1 CH3CN 100 0 [b] [a] Conversions and yields were determined by 19 F NMR with 4-fluorotoluene as standard. [b] Complex mixture of 6-fluoropyridine-2-carboxaldehyde and byproducts. [c] 2a was obtained in the absence of DDQ. [d] Two non-identified byproducts were obtained (in 15% each), m/z 218 and 230.

With the optimized reaction conditions both in stoichiometric and catalytic versions in hand, we next investigated the substrate scope. A variety of aldimines gave the corresponding 3-substituted 8-fluoroimidazo [1,5-a]pyridines and 8fluoroimidazo [1,5-a]pyridine-1-carbonitrile derivatives in good to excellent yields (Scheme 4). Substrates 1a and 1b including linear alkyl chains (Cn, n = 3, 12; Scheme 4) showed excellent regioselectivity for the geminal C(sp 3 )-H functionalization α' to the aldimine, providing 2a-b and 6a-b in good yields. To test the feasibility of remote functionalization in β' or γ' positions, α'branched substrates (isopropyl 1c, neopentyl 1d and tert-butyl 1e) were tested without success. Gratifyingly, when an aldimine substrate bearing a benzyl group was employed, the desired heterocycles arylated in position 3 were obtained (2h in 52%, and 6h 92% yield) in high regioselectivity, precluding C(sp 2 )-H activation on the aryl ring. The ester group is a well-tolerated functionality and gives the desired products 2i and 6i in 76 and 55% yields, respectively. In the search of applying this methodology to other substrates incorporating heterocyclic units, we found that the placement of a tetrahydrofurfuryl moiety provides the C-H cyclization products 2j and 6j in good yields (70% and 62%, respectively, Scheme 4), despite the fact that free alcohol functional groups were not compatible with these reaction conditions (only decomposition by-products were obtained from 1k).

The generality of both methods has been assessed with a nonfluorinated substrate 1a', exhibiting good selectivities towards 2a' (38% conv., 36% yield) and 6a' (quant. conv., 68% yield), respectively (Scheme 4). Notably, the bidentate N,N'coordination of the substrate poises 1a' to selectively undergo C(sp 3 )-H activation and cyclization (no C(sp 2 )-H functionalization by-products on the pyridine ring were detected). Scheme 4. TOP: Reaction scope for the synthesis of imidazo [1,5-a]pyridines type-2 and type-6 in both stoichiometric and catalytic versions. BOTTOM: Reactivity of 1a' towards 2a' and 6a'. [a] Conversions and yields were determined by 19 F NMR with 4-fluorotoluene as internal standard.

With the aim of studying a plausible surface reactivity, preformed zero-valent copper nanoparticles (CuNPs) were used as catalyst for the synthesis of 2a and 6a; the reactivity observed was similar to that using Cu(OPiv)2 (see Figures S3 and S4 in the ESI). Considering that only copper agglomerates were detected after reaction (TEM analysis), it can be assumed that the C-H functionalization is merely promoted by molecular species, due to copper leaching from CuNPs. [START_REF]ICP analyses of the organic extracts coming from the reactions under stoichiometric and catalytic conditions revealed 0.3 mg and 0.8 mg of Cu, respectively[END_REF] Taking into account that imidazo [1,5-a]pyridines are only formed in the presence of copper(II) carboxylates together with the coordination ability of aldimines to give five-coordinated Cu(II) complexes ([I], Figure 5), a concerted metalation-deprotonation mechanism can be proposed for the α'-C(sp 3 )-H activation via the formation of a six-membered cupracycle [II], analogously to what has been proposed for Pd-promoted C-H activation. 3839 A reductive elimination then delivers 2a and Cu(0), both observed for the stoichiometric reaction [Cu(0) evidenced by powder Xray diffraction; see Figure S5 Reaction manifolds involving single electron transfer processes and Cu(I) species could be ruled out (see Scheme S3 in the ESI). Thus, the presence of the radical scavenger 2,6-di-tert-butyl-4methylphenol (1 equiv.) did not inhibit the catalytic transformation (53% yield of 2a). The reaction of 1a with CuI (1.5 equiv.) and potassium pivalate (1.5 equiv.) only resulted in traces of 2a (9% yield). [START_REF]A partial oxidation of copper(I) salts by air can be feasible as microwave reactions are carried out under aerobic conditions. 41. The instability of 2a and 2b upon purification precluded their isolation in pure form (see Figure S7 in the ESI for 2b)[END_REF] These experiments evidence the crucial role of both electrophilic Cu(II) species and carboxylates to promote aldimine α'-C(sp 3 )-H functionalization. Furthermore, the isolation of an acrylonitrile derivative (4) under harsher reaction conditions, indicates that successive C-H deprotonation events may be feasible (see Scheme S4 in the ESI).

Conclusion

This work focuses on the study of N,N'-bidentate substrates that act as directing groups towards multiple C-H bond functionalization reactions via coordination to Cu(II) carboxylate salts. We have developed a Cu(II)-mediated C(sp 3 )-H amination/cyclization of 1-(2-pyridinyl)methanimines to afford imidazo [1,5-a]pyridine heterocycles via a Cu(II)/Cu(0) mechanism, under microwave irradiation. In addition, a telescoped Cu-catalyzed C(sp 3 )-H amination/cyclization followed by C(sp 2 )-H cyanation process could be optimized towards the synthesis of imidazo [1,5-a]pyridine-1-carbonitrile derivatives through a Cu(II)/Cu(0) mechanism. Notably, the N,N'-bidentate coordination renders this process selective towards C(sp 3 )-H functionalization, precluding side C(sp 2 )-H activation reactions on the pyridine ring. This synthetic platform offers great potential for the straightforward syntheses of bioisosteres of purine alkaloids and analogues thereof, providing novel means to explore the vast chemical space of non-natural alkaloids. Transition-metal promoted C-H functionalization strategies confer powerful and versatile tools towards late stage molecular edition via the installation of functional groups in a selective manner. Thus, orthogonal methods for the synthesis of imidazo [1,5-a]pyridine and imidazo [1,5-a]pyridine-1-carbonitrile derivatives were successfully achieved. These methods highlight the emerging value of unactivated C(sp 3 )-H bonds as functional groups in organic synthesis. A fine tuning of the carboxylate basicity resulted a determinant factor, suggesting a concerted metalation-deprotonation mechanism. Moreover, this contribution enables the development of sustainable processes based on simple copper salts.

Experimental Section

1. General procedure for the synthesis of aldimines 1a-1l. Amine al (8.00 mmol) was added to a suspension of 3-fluoro-2pyridinecarboxaldehyde (1.00 g, 8.00 mmol) and sodium sulfate (6.81 g, 47.99 mmol, 6 equiv.) in 2-methyltetrahydrofuran (40 mL), and the resulting mixture was stirred at r.t. for 16 h. The solid was then filtered out and the filtrate was evaporated under reduced pressure to furnish aldimine 1a-1l (yields 89 to 99%, see the ESI for characterization details). 2. General procedure for the preparation of CuBr2-aldimine complexes CuA, CuB and CuC.

CuBr2 (402 mg, 1.80 mmol) was added in one solid portion to a solution of aldimine 1a (200 mg, 1.20 mmol) in CH2Cl2 (10 mL). The initial green solution was stirred for 90 min at rt, turning rapidly to a dark red color. The reaction mixture was then filtered through a 0.2 µm PTFE filter and the solvent was removed under reduced pressure, furnishing the desired complex CuA (459 mg, 99%) as a dark solid that was used without further purification. Suitable monocrystals for XRD analysis of CuA were obtained by vapor diffusion crystallization of pentane in a CH2Cl2 solution. In an analogous manner and starting from 1b (351 mg, 1.20 mmol) or 1d (233. (3 × 15 mL, 0.4 M solution, pH 10-11). The combined organic extracts were dried with anhydrous Na2SO4, filtered and solvents evaporated under reduced pressure. The residue was then purified by column chromatography on neutral alumina to give compound 2a-2b, 41 2j (yields 69-87%).

3.2. General procedure with CuA. A base (0.45 mmol) was added to a solution of the CuBr2-aldimine complex CuA (0.15 mmol, 117.0 mg) in the specified solvent (4 mL). The reaction mixture was heated to 100 °C for 10 min under microwave irradiation (max. 200 W). Work-up A: Na2S (50.0 mg, 0.65 mmol) was then added and the crude reaction mixture was stirred for 20 min with intermittent ultrasonic irradiation. The crude was then filtered through a 0.45 µm PTFE filter and solids were rinsed with 2-methyltetrahydrofuran (5 × 5 mL) and the solvent was removed under reduced pressure. Work-up B: The reaction crude was diluted with 2-methyltetrahydrofuran (15 mL) and washed with tetrasodium ethylenediaminetetraacetate (3 × 15 mL, 0.4 M solution, pH 10-11). The combined organic extracts were dried with anhydrous Na2SO4, filtered and solvents evaporated under reduced pressure. Conversion and yields were determined by 19 F NMR with 4-fluorotoluene as standard. 4. General procedure for the catalytic C-H bond functionalization reaction: synthesis of 6a-k. 2,3-Dichloro-5,6dicyano-1,4-benzoquinone (DDQ) (0.30 mmol, 68.1 mg) was added in one solid portion to a solution of aldimine 1a-k (0.30 mmol) and of Cu(OPiv)2 (16 mg, 0.06 mmol, 20 mol%) in CH3CN (4 mL). The reaction mixture was heated to 100 °C for 10 min under microwave irradiation (max. 200 W). Na2S (14 mg, 0.18 mmol) was then added and the crude reaction mixture was stirred for 20 min under ultrasonic irradiation. The crude was then filtered through a 0.20 µm PTFE filter and solids were rinsed with 2-methyltetrahydrofuran (5 × 5 mL) and the solvent was removed under reduced pressure. The reaction residue was then purified by column chromatography on silica gel to give the title compound 6a-k (yields 55-81%).

Figure 2 .

 2 Figure 2. C(sp 3 )-H bond activation pathways of aldimines.

Figure 1 .

 1 Figure 1. Purine nucleobases and drugs of interest featuring structurally related heterocyclic scaffolds.

Figure 3 .

 3 Figure 3. Molecular view of CuA. Hydrogen atoms have been omitted for clarity purposes (ellipsoids representing 50% probability). Selected distances (Å) and angles (°) [symmetry code (i): 1-x, 2-y, 1-z]: Cu1-Br1 ' = 2.781(1), Cu1-Br1 = 2.425(1), Cu1-Br2 = 2.386(1), Cu1-N1 = 2.065(2), Cu1-N2 = 2.039(2); N1-Cu1-N2 = 80.11(8); Br1-Cu1-Br2 = 91.24(1); N1-Cu1-Br1 = 92.33(6); N2-Cu1-Br2 = 94.48(6).

  in the ESI). When Ac2O was used as solvent, only by-products coming from imine hydrolysis were observed. Even though the use of a solvent mixture of AcOH:CHCl3 (1:4) rendered a very low conversion (5%), a new 3-alkyl-8-fluoroimidazo[1,5-a]pyridine product (2a) was identified albeit in low yield. Finding the right balance in terms of stability and reactivity of the Cu-based intermediates seems crucial to enable a selective transformation overriding hydrolysis pathways. To facilitate the C(sp 3 )-H amination, NH4OAc (1.5 equiv.) was used to perform the transformation under buffered conditions in a solvent mixture of AcOH:CHCl3 (1:4), but only 8-fluoro-3-(3-fluoropyridin-2-yl)imidazo[1,5a]pyridine (3) and (2Z)-3-(3-fluoropyridin-2-yl)-2-methylprop-2enenitrile (4; see the ESI for single-crystal XRD structure) byproducts were obtained (

Figure 4 .

 4 Figure 4. TOP: Molecular view of a cubane tetranuclear copper(II) complex Cu4B with the composition Cu4OCl6(2b)4 (ellipsoids representing 50% probability) where hydrogen atoms have been omitted for clarity purposes and only the major position of the disordered alkyl chain is shown (for atom labelling see bottom view). BOTTOM: Cu4B molecular view where hydrogen and carbon atoms of the alkyl chains have been omitted for clarity purposes. Selected (Å) and angles (°): Cu-N1 = 1.967(6); Cu-Cl = 2.374(2), 2.407(3) and 2.424(2); Cu-O = 1.909(1); Cl-Cu-Cl = 114.04(6), 119.85(4) and 123.60(6); Cl-Cu-N1 = 93.26(16), 94.50(15) and 97.99(18); Cl-Cu-O 84.03(6), 84.36(5) and 85.75(5); N1-Cu-O = 177.36(17).

  in the ESI]. To gain an insight on the metal intermediates, monitoring studies by cyclic voltammetry of the stoichiometric reaction [Cu(OPiv)2 and 1a in CH3CN] revealed the exclusive presence of Cu(II) species in solution, together with a peak intensity decrease over time, due to the formation of insoluble Cu(0) (see Figure S6 in the ESI). Under catalytic conditions, DDQ acts both as oxidant and cyanating agent, taking advantage of the fairly acidic proton in Please do not adjust margins Please do not adjust margins the imidazole ring and leading to the formation of 6a through a plausible intermediate [III]. According to control experiments, Copper(II) cyanide species were detected by FTIR when DDQ was reacted with Cu(0) in the presence of potassium pivalate (C≡N stretching bands at ca. 2160 cm -1 ; see Figure S7 in the ESI). The cyanation step was demonstrated by the addition of DDQ (1 equiv.) to 2a, furnishing 6a (62% yield; see Scheme S2 in the ESI).

Figure 5 .

 5 Figure5. A plausible reaction mechanism for the synthesis of imidazo[1,5-a]pyridines via Cu(II) C-H bond functionalization reactions. For simplicity purposes, 1a was used as substrate.

Table 2 .

 2 Optimization of the reaction conditions for the Cu(II)-catalyzed synthesis of 6a under microwave irradiation.

	Entry	Catalyst loading (mol%)	DDQ (equiv.)	Solvent	Conversion (%) [a]	6a (%) [a]
	1	20	1.5	CH3CN	100	87
	2	20	1.5	CpOMe	100	25 [b]
	3	20	0	CH3CN	18	0 [c]
	4	20	1	CH3CN	100	89
	5	10	1	CH3CN	100	68

bond functionalization reactions 3.1. General procedure with Cu(OPiv)2

  1 mg, 1.20 mmol), CuB and CuC complexes . A solution of aldimine 1 (0.30 mmol) and Cu(OPiv)2 (119.6 mg, 0.45 mmol) in CH3CN (4 mL) was heated to 100 °C for 10 min under microwave irradiation (max. 200 W). The reaction crude was diluted with 2methyltetrahydrofuran (15 mL) and washed with tetrasodium ethylenediaminetetraacetate

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	were obtained [548 mg, 89% (CuB), and 401 mg, 80% (CuC)],
	respectively (see the ESI for characterization details).
	3. Stoichiometric C-H
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(s)

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| Org. Biomol. Chem. © 2021 The Author(s). Published by the Royal Society of Chemistry

Acknowledgements

The Centre National de la Recherche Scientifique (CNRS) and the Université Toulouse 3 -Paul Sabatier are gratefully acknowledged for their financial support. M. C. thanks the Ministère de l'Enseignement Supérieur et de la Recherche of the French government for a PhD scholarship. Dr. Gyorgy Szaloki is acknowledged for his valuable help in the cyclic voltammetry studies. The authors thank Dr. Nathalie Saffon-Merceron of the X-ray diffraction service of the Institut de Chimie de Toulouse ICT-UAR 2599 (www.ict.ups-tlse.fr) for her valuable help in single crystal analysis.

Author Contributions

M. C. prepared the substrates, optimized the C-H bond functionalization reactions, studied the scope and mechanistic studies. I. F. carried out the cyclic voltammetry experiments and proofread the experimental part and main article. S. M-L. carried out the X-ray crystallographic studies and the refinement of the structures. D. P. identified the heterocycle via C-H bond functionalization, revised the experimental part, designed a research plan and co-wrote the manuscript. M. G. supervised the work, cowrote the manuscript and coordinated the overall project.

Conflicts of interest

There are no conflicts to declare.