Léo Mas

Lilian Schwarz

MD Jean-Baptiste Bachet
email: jean-baptiste.bachet@aphp.fr

Adjuvant chemotherapy in pancreatic cancer: state of the art and future perspectives

Keywords: Pancreatic ductal adenocarcinoma, definition, FOLFIRINOX, biomarker, neoadjuvant

Purpose of the review:

The modalities of management of resectable pancreatic ductal adenocarcinoma (PDAC) have evolved in recent years with new practice guidelines on adjuvant chemotherapy and results of randomized phase III trials. The aim of this review is to describe the state of the art in this setting and to highlight future possible perspectives.

Recent findings:

Resectable PDAC is the tumor without vascular contact or a limited venous contact without vein irregularity. Several pathologic and biologic robust prognostic factors such as an R0 resection defined by a margin ≥ 1 mm have been validated. In phase III trials, the doublet gemcitabine-capecitabine provided a statistically significant, albeit modest overall survival benefit, but failed to show an improvement in relapse-free survival. Similarly, gemcitabine plus nab-paclitaxel did not increase disease-free survival. Modified FOLFIRINOX led to improved disease-free survival, overall survival, and metastasis-free survival, with acceptable toxicity. In the future, prognostic and/or predictive biomarkers could lead the optimization of therapeutic strategies and neoadjuvant treatment could become a standard of care in PDAC.

Summary:

After curative intent resection, modified FOLFIRINOX is the standard of care in adjuvant in fit PDAC patients. Others regimens (monotherapy or gemcitabine-based) are an option in unfit patients.

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is the second most common digestive cancer in

Western countries [START_REF] Ferlay | Cancer incidence and mortality patterns in Europe: Estimates for 40 countries and 25 major cancers in 2018[END_REF][START_REF] Siegel | Cancer statistics 2019[END_REF] with a regularly increasing incidence and is projected to become the second cause of cancer-related death between 2020 and 2030. [START_REF] Rahib | Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States[END_REF] Many of the older studies included patients with both metastatic and locally advanced PDACs in the same cohorts. During the past decade, learned societies recommended carrying out studies dedicated to treatment of these two different group of patients. [START_REF] Philip | Consensus report of the national cancer institute clinical trials planning meeting on pancreas cancer treatment[END_REF][START_REF] Van Laethem | New strategies and designs in pancreatic cancer research: consensus guidelines report from a European expert panel[END_REF] Thereafter, locally advanced PDAC subgroup was divided into « true » locally advanced tumors with a low rate of secondary resection and borderline tumors for which secondary resection is possible after induction treatment (about two third of cases in recent studies).[6,7*] Most of the proposed classifications for borderline tumors are based on the degree of arterial and/or venous contact of the tumor, however an international consensus recently suggested adding an Eastern Cooperative Oncology Group performance status and biological factors aside from anatomical criteria. [START_REF] Callery | Pretreatment assessment of resectable and borderline resectable pancreatic cancer: expert consensus statement[END_REF][START_REF] Abrams | Combined modality treatment of resectable and borderline resectable pancreas cancer: expert consensus statement[END_REF][START_REF] Bockhorn | Borderline resectable pancreatic cancer: a consensus statement by the International Study Group of Pancreatic Surgery (ISGPS)[END_REF][START_REF] Francis | Pancreatic ductal adenocarcinoma radiology reporting template: consensus statement of the Society of Abdominal Radiology and the American Pancreatic Association[END_REF][START_REF] Isaji | International consensus on definition and criteria of borderline resectable pancreatic ductal adenocarcinoma 2017[END_REF] Thus, at diagnosis, only 10%-15% of patients have a resectable PDAC.

To date, resection remains the only potentially curative-intent treatment and upfront surgery remains the standard of care for patients with resectable PDAC. [START_REF] Tempero | Pancreatic Adenocarcinoma, Version 1.2019[END_REF][START_REF] Ducreux | Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up[END_REF] While the benefit of adjuvant chemoradiotherapy (CRT) is a matter of debate, adjuvant chemotherapy has been a standard for over a decade now. [START_REF] Tempero | Pancreatic Adenocarcinoma, Version 1.2019[END_REF][START_REF] Ducreux | Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up[END_REF][START_REF] Neoptolemos | A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer[END_REF][START_REF] Oettle | Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial[END_REF][START_REF] Oettle | Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial[END_REF] Three chemotherapy regimens, gemcitabine plus erlotinib (Roche ® , Bâle, Switzerland), modified FOLFIRINOX (5-fluorouracil, oxaliplatin, and irinotecan), and gemcitabine plus nab-paclitaxel (Celgene ® , Summit, New Jersey, USA) were found to be significantly superior to gemcitabine monotherapy in advanced stage pancreatic cancer, [START_REF] Moore | Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group[END_REF][START_REF] Hoff | Increased survival in pancreatic cancer with nabpaclitaxel plus gemcitabine[END_REF][START_REF] Conroy | FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer[END_REF] and have subsequently been assessed in the adjuvant setting.[21,22**,23**] Several adjuvant randomized phase III trials have been published until now. [START_REF] Neoptolemos | A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer[END_REF][START_REF] Oettle | Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial[END_REF][START_REF] Oettle | Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial[END_REF][START_REF] Sinn | CONKO-005: Adjuvant Chemotherapy With Gemcitabine Plus Erlotinib Versus Gemcitabine Alone in Patients After R0 Resection of Pancreatic Cancer: A Multicenter Randomized Phase III Trial[END_REF][START_REF] Conroy | FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer[END_REF][START_REF] Tempero | APACT: phase III, multicenter, international, openlabel, randomized trial of adjuvant nab-paclitaxel plus gemcitabine (nab-P/G) vs gemcitabine (G) for surgically resected pancreatic adenocarcinoma[END_REF][START_REF] Neoptolemos | Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial[END_REF][START_REF] Neoptolemos | Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial[END_REF] Standard chemotherapy regimens and robust prognostic factors that are used after upfront surgery are now validated and a number of promising biomarkers have been reported. In addition, new therapeutic strategies are currently being evaluated with the development of novel neoadjuvant strategies.

The aim of this review is to describe the state of the art in the adjuvant setting of PDAC and to highlight future possible perspectives.

Text of review

Resectable Tumor

Definition

Many expert consensus groups have proposed definitions of borderline PDAC tumors in order to further improve the criteria for resectability at diagnosis, with the primary objective being a margin-negative resection (R0). Currently, a resectable PDAC is defined by the absence of vascular tumor contact or ≤ 180° contact with the superior mesenteric vein (SMV) or portal vein (PV) without vein contour irregularity (stenosis, deformity). [START_REF] Ducreux | Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up[END_REF][START_REF] Tempero | Pancreatic Adenocarcinoma, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology[END_REF] For the tumors of the body and/or tail of the pancreas, invasion of splenic vessels (artery and/or vein) is not a contraindication to upfront surgery. The presence of peri-pancreatic lymph nodes on the imaging assessment likewise does not a resection. Contrarily, in patients with distant lymph node involvement surgery should not be considered. [START_REF] Agalianos | Positive para-aortic lymph nodes following pancreatectomy for pancreatic cancer. Systematic review and meta-analysis of impact on short term survival and association with clinicopathologic features[END_REF][START_REF] Paiella | The prognostic impact of para-aortic lymph node metastasis in pancreatic cancer: A systematic review and meta-analysis[END_REF][START_REF] Schwarz | Para-aortic lymph node sampling in pancreatic head adenocarcinoma[END_REF] A thoraco-abdomino-pelvien multi-detector computed tomography with intravenous contrast injection and fine sections on pancreatic area is a key diagnostic technique, allowing the assessment of locoregional and distant extensions. [START_REF] Ducreux | Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up[END_REF][START_REF] Tempero | Pancreatic Adenocarcinoma, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology[END_REF] Recently, some studies have highlighted the potential of adding a magnetic resonance imaging (MRI) with diffusionweighted to this exam. Such approach has been suggested to increase the diagnosis of undiscovered infracentimetric liver metastases by 10%-15%. [START_REF] Kim | Adjunctive role of preoperative liver magnetic resonance imaging for potentially resectable pancreatic cancer[END_REF] The recently published French clinical practice guidelines indicate that a liver MRI at diagnosis is an option in patients with localized PDAC. [START_REF] Neuzillet | Pancreatic cancer: French clinical practice guidelines for diagnosis, treatment and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, ACHBT, AFC)[END_REF] Histological proof of PDAC is not usually required before surgery if the medical history, symptoms, and imagery data are concordant with the diagnosis.

However, this confirmation has to be obtained in case of doubt about the diagnosis or when neoadjuvant treatment is planned. [START_REF] Ducreux | Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up[END_REF][START_REF] Tempero | Pancreatic Adenocarcinoma, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology[END_REF][START_REF] Neuzillet | Pancreatic cancer: French clinical practice guidelines for diagnosis, treatment and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, ACHBT, AFC)[END_REF] Data on adjuvant chemotherapy in PDAC discussed below apply to resectable tumors defined along these criteria.

Prognostic factors

Carbohydrate antigen (CA) 19-9, a sialylated Lewis A blood group antigen, is currently the only biomarker validated in PDAC. This factor was found to be useful for monitoring treatment efficacy and follow-up after curative intent surgery, but not for screening. [START_REF] Ducreux | Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up[END_REF][START_REF] Tempero | Pancreatic Adenocarcinoma, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology[END_REF][START_REF] Neuzillet | Pancreatic cancer: French clinical practice guidelines for diagnosis, treatment and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, ACHBT, AFC)[END_REF] While the CA 19-9 can be elevated in case of biliary obstruction or others cancers, it is normal in patients with a Lewis-negative genotype, present in about 5%-10% of the white population. [START_REF] Galli | CA 19-9: handle with care[END_REF] In case of resectable PDAC tumors, the level of pre-operative CA 19-9 is highly prognostic and some authors have proposed various cut-off values to define the resectability (from 100 to 500 U/ml), [START_REF] Isaji | International consensus on definition and criteria of borderline resectable pancreatic ductal adenocarcinoma 2017[END_REF][START_REF] Khorana | Potentially Curable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline[END_REF] in the absence of vascular involvement. Until now, at the exception of the International Association of Pancreatology, there is no preoperative cut-off point recommended by the oncologic societies guidelines. [START_REF] Isaji | International consensus on definition and criteria of borderline resectable pancreatic ductal adenocarcinoma 2017[END_REF][START_REF] Ducreux | Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up[END_REF][START_REF] Tempero | Pancreatic Adenocarcinoma, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology[END_REF][START_REF] Neuzillet | Pancreatic cancer: French clinical practice guidelines for diagnosis, treatment and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, ACHBT, AFC)[END_REF] The level of post-operative CA 19-9 is also highly prognostic. [START_REF] Neoptolemos | Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial[END_REF][START_REF] Neoptolemos | Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial[END_REF] Moreover, it is noteworthy that the latter was added as an inclusion criteria in two recent adjuvant randomized phase III trials (the cut-off of ≤ 180 U/ml in PRODIGE24 and of < 100 U/ml in APACT). [START_REF] Conroy | FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer[END_REF][START_REF] Tempero | APACT: phase III, multicenter, international, openlabel, randomized trial of adjuvant nab-paclitaxel plus gemcitabine (nab-P/G) vs gemcitabine (G) for surgically resected pancreatic adenocarcinoma[END_REF] Patients undergoing SMV or PV resection has been reported to be have worse prognosis. [START_REF] Giovinazzo | Meta-analysis of benefits of portal-superior mesenteric vein resection in pancreatic resection for ductal adenocarcinoma[END_REF] This finding has led to restriction of the resecability definition to the PDAC tumors with limited vein contact (< 180°) and without contour irregularity. [START_REF] Francis | Pancreatic ductal adenocarcinoma radiology reporting template: consensus statement of the Society of Abdominal Radiology and the American Pancreatic Association[END_REF][START_REF] Ducreux | Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up[END_REF][START_REF] Tempero | Pancreatic Adenocarcinoma, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology[END_REF][START_REF] Neuzillet | Pancreatic cancer: French clinical practice guidelines for diagnosis, treatment and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, ACHBT, AFC)[END_REF] Such defined resection was of poor prognosis in the ESPAC4 and PRODIGE24 trials. [START_REF] Conroy | FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer[END_REF][START_REF] Neoptolemos | Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial[END_REF] and venous resections have to be reported in future adjuvant trials.

Several studies have reported variety of robust pathologic prognostic factors including grade of tumoral differentiation, N and T stage (maximal tumor diameter), and the resection margin status of which. [START_REF] Neoptolemos | A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer[END_REF][START_REF] Oettle | Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial[END_REF][START_REF] Oettle | Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial[END_REF][START_REF] Conroy | FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer[END_REF][START_REF] Neoptolemos | Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial[END_REF][START_REF] Neoptolemos | Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial[END_REF] Most of these factors have subsequently been validated. The definitions of T and N categories have been modified in the 8 th version of American Joint Committee on Cancer (AJCC) TNM classification, [START_REF] Kamarajah | Validation of the American Joint Commission on Cancer (AJCC) 8th Edition Staging System for Patients with Pancreatic Adenocarcinoma: A Surveillance, Epidemiology and End Results (SEER) Analysis[END_REF] that recommends to look at least 15 lymph nodes to distinguish the N stage. [START_REF] Tol | Definition of a standard lymphadenectomy in surgery for pancreatic ductal adenocarcinoma: a consensus statement by the International Study Group on Pancreatic Surgery (ISGPS)[END_REF] Historically among patients with PDAC, no consensual precise definition of the R0 resection margin and the modalities of its assessment were defined. Therefore, the R1-resection rate differs between adjuvant randomized phase III trials, ranging from 16% reported in the ESPAC1 trial to 61% in the ESPAC4 study. [START_REF] Neoptolemos | A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer[END_REF][START_REF] Oettle | Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial[END_REF][START_REF] Oettle | Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial[END_REF][START_REF] Conroy | FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer[END_REF][START_REF] Tempero | APACT: phase III, multicenter, international, openlabel, randomized trial of adjuvant nab-paclitaxel plus gemcitabine (nab-P/G) vs gemcitabine (G) for surgically resected pancreatic adenocarcinoma[END_REF][START_REF] Neoptolemos | Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial[END_REF][START_REF] Neoptolemos | Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial[END_REF] According to the British College of Pathologists guidelines that have been validated by the International Study Group of Pancreatic Surgery, a positive-R1 resection margin is currently defined as < 1 mm. [START_REF] Bockhorn | Borderline resectable pancreatic cancer: a consensus statement by the International Study Group of Pancreatic Surgery (ISGPS)[END_REF][START_REF] Ducreux | Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up[END_REF][START_REF] Neuzillet | Pancreatic cancer: French clinical practice guidelines for diagnosis, treatment and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, ACHBT, AFC)[END_REF] Different surgical margins (anterior, posterior, medial, or SMV groove, superior mesenteric artery, pancreatic transection, bile duct, and enteric) have to be clearly identify by surgeon, at best by inking them with different colors. [START_REF] Bockhorn | Borderline resectable pancreatic cancer: a consensus statement by the International Study Group of Pancreatic Surgery (ISGPS)[END_REF][START_REF] Delpero | Prognostic Value of Resection Margin Involvement After Pancreaticoduodenectomy for Ductal Adenocarcinoma: Updates From a French Prospective Multicenter Study[END_REF] In most studies on adjuvant chemotherapy for PDAC, the efficacy of this treatment on survival was reported in all subgroups defined by the grade of differentiation, N stage, T stage and the resection margin status. [START_REF] Neoptolemos | A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer[END_REF][START_REF] Oettle | Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial[END_REF][START_REF] Oettle | Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial[END_REF][START_REF] Conroy | FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer[END_REF][START_REF] Tempero | APACT: phase III, multicenter, international, openlabel, randomized trial of adjuvant nab-paclitaxel plus gemcitabine (nab-P/G) vs gemcitabine (G) for surgically resected pancreatic adenocarcinoma[END_REF][START_REF] Neoptolemos | Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial[END_REF][START_REF] Neoptolemos | Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial[END_REF] Although, adjuvant chemotherapy is indicated in all patients who undergo curative intent resection of PDAC, a recent retrospective analysis from the US National Cancer database has suggested that patients with infra-centimetric PDAC (T1aN0 or T1bN0) may not necessary require this treatment.[38*] Indication of adjuvant chemotherapy in PDAC patients with infra-centimetric tumor should be discussed during multidisciplinary team meeting.

Adjuvant treatment

Adjuvant chemoradiotherapy

Adjuvant CRT was not associated with a clinical benefit in the ESPAC-1 trial and the results of this study actually suggested that it might even be harmful. [START_REF] Neoptolemos | A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer[END_REF] This trial had however some limitations as neither the protocol of CRT used was optimal according to current standards and nor quality control for CRT was planned in this trial. In fact, the interest of adjuvant CRT is discussed and debated in the published literature with several studies reporting discordant results. [START_REF] Delpero | Prognostic Value of Resection Margin Involvement After Pancreaticoduodenectomy for Ductal Adenocarcinoma: Updates From a French Prospective Multicenter Study[END_REF][START_REF] Shaib | Role of adjuvant therapy in resected stage IA subcentimeter (T1a/T1b) pancreatic cancer[END_REF] The meta-analysis of pooling patient data from five adjuvant randomized trials has suggested that patient with R1 resection could benefit from adjuvant CRT. [START_REF] Stocken | Meta-analysis of randomised adjuvant therapy trials for pancreatic cancer[END_REF] However, the R1 rate ranging from 17% to 82% across studies highlighted high heterogeneity in evaluation of the resection margin preventing any clear conclusions.

Adjuvant CRT is not recommended by all oncologic guidelines. [START_REF] Ducreux | Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up[END_REF][START_REF] Tempero | Pancreatic Adenocarcinoma, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology[END_REF][START_REF] Neuzillet | Pancreatic cancer: French clinical practice guidelines for diagnosis, treatment and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, ACHBT, AFC)[END_REF] The RTOG 0848 trial assessing the role of CRT after adjuvant gemcitabine (ClinicalTrials.gov identifier: NCT01013649) is ongoing and results are expected shortly. Patients without evidence of relapse after 5 cycles of gemcitabine are randomized between one more cycle of chemotherapy alone or one more cycle of chemotherapy followed by CRT.

Adjuvant monochemotherapy

The benefit of adjuvant chemotherapy has been demonstrated in the ESPAC-1 trial (5fluorouracil [5FU] bolus; Mayo clinical FUFOL regimen for 6 months) and in the CONKO-001 trial (gemcitabine for 6 months). [START_REF] Neoptolemos | A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer[END_REF][START_REF] Oettle | Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial[END_REF][START_REF] Oettle | Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial[END_REF] These two regimens have been directly compared in the ESPAC-3 trial. [START_REF] Neoptolemos | Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial[END_REF] The oncological results obtained were strictly identical, but the safety profile was better with gemcitabine, positioning 5FU as an alternative treatment option. It should be noted that unlike for colorectal cancers, the LV5FU2 protocol (bolus 5FU then continuous 5FU over 46h) or capecitabine monotherapy were not evaluated as adjuvant treatment after resection of PDAC. Summary of results from major phase III trials of adjuvant chemotherapy after curative resection of pancreatic ductal adenocarcinoma are presented in Table 1. Adjuvant gemcitabine monotherapy has been the standard of care for more than a decade.

Adjuvant gemcitabine-based chemotherapy

Several randomized clinical trials have evaluated the value of adding an additional drug to gemcitabine in the adjuvant setting following encouraging results from studies in metastatic PDAC. [START_REF] Moore | Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group[END_REF][START_REF] Hoff | Increased survival in pancreatic cancer with nabpaclitaxel plus gemcitabine[END_REF][START_REF] Conroy | FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer[END_REF] The erlotinib plus gemcitabine regimen was associated with increased overall survival (OS; HR=0.82, 95% CI 0.69-0.99; p=0.038) in comparison to gemcitabine alone in patients with advanced PDAC. [START_REF] Moore | Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group[END_REF] Although statistically significant, the OS benefit was not clinically relevant with an only 14-day median difference. Therefore, this protocol was not considered as a standard, but more as an option. Adding erlotinib to gemcitabine did not increase diseasefree survival (DFS) or OS in the adjuvant CONKO-005 trial (Table 1) [START_REF] Sinn | CONKO-005: Adjuvant Chemotherapy With Gemcitabine Plus Erlotinib Versus Gemcitabine Alone in Patients After R0 Resection of Pancreatic Cancer: A Multicenter Randomized Phase III Trial[END_REF] and showed no benefit in the LAP07 trial of patients with locally advanced PDAC. [START_REF] Hammel | Effect of Chemoradiotherapy vs Chemotherapy on Survival in Patients With Locally Advanced Pancreatic Cancer Controlled After 4 Months of Gemcitabine With or Without Erlotinib: The LAP07 Randomized Clinical Trial[END_REF] Two randomized phase III trials reported an increase in progression-free survival (PFS), but not in OS by the addition of capecitabine to gemcitabine in patients with advanced PDAC. [START_REF] Herrmann | Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group[END_REF]44] Following these findings, the ESPAC-4 trial compared the gemcitabine plus capecitabine (GEMCAP) combination to gemcitabine monotherapy in the adjuvant setting. [START_REF] Neoptolemos | Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial[END_REF] This trial was positive for its main objective with a significant but modest increase in OS with the 5-year survival rate of 28.8% (vs 16.3%; Table 1). Nevertheless, these results have been criticized, in particular because of the absence of a significant relapse-free survival (RFS) difference between the two arms despite a trend in favor of the GEMCAP arm (the 3 and 5-year survival rate of 23.8% and 18.6% with GEMCAP and 20.9% and 11.9% with monotherapy, respectively). The GEMCAP protocol was also associated with a poorer safety profile (Table 2).

Finally, the gemcitabine plus nab-paclitaxel (GEMNAB) combination has been evaluated in adjuvant randomized phase III APACT trial. [19,23**] The study did not meet its main objective, the DFS in centralized reviewing (GEMNAB 19.4 months vs gemcitabine 18.8 months [HR=0.88; p=0.182]). In per-investigator analysis, GEMNAB conferred a significant but modest benefit in DFS, (Table 1) and a significant increase in OS. The toxicity profiles corresponded to those expected with significantly more toxicities in the GEMNAB arm (Table 2).

Adjuvant modified FOLFIRINOX

In metastatic PDAC, the FOLFIRINOX protocol has demonstrated its superiority compared to gemcitabine. [START_REF] Conroy | FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer[END_REF] This protocol was further evaluated in the PRODIGE24 trial in the adjuvant setting. [22**] To improve the tolerability, 5FU bolus was removed. The dose of irinotecan had to be reduced from 180 mg/m² to 150 mg/m² (modified FOLFIRINOX

[mFOLFIRINOX]) due to a grade 3-4 diarrhea rate greater than 20% at the first planned interim analysis. The mFOLFIRINOX regimen was associated with a significant increase in DFS (the 3-year rate 39.7% vs 21.4%), OS (the 3-year rate 63.4% vs 48,6%), and metastasisfree survival (Table 1). The benefit of mFOLFIRINOX chemotherapy was found in all of the predefined subgroups with a statistically significant survival improvement in patients older than 65 years (n=201, 41%) and a trend in patients older than 70 years (n=101, 20%). There was no difference in neutropenia rates between the two arms, but 62% of patients in the mFOLFIRINOX arm had received granulocyte-colony stimulating factor. mFOLFIRINOX was associated with more mucositis, diarrhea, fatigue, vomiting, and neuropathy (Table 2), but these toxicities were manageable and no toxic deaths were reported. Diarrhea was most frequent in patients with a higher number of lymph nodes (≥20 vs <20; adjusted odds ratio, 2.4; 95% CI 1.3-4.4; p<0.001), which was expected given that extensive lymphadenectomy can be associated with more diarrhea in post-operative treatment but not with better oncologic outcomes. [START_REF] Tol | Definition of a standard lymphadenectomy in surgery for pancreatic ductal adenocarcinoma: a consensus statement by the International Study Group on Pancreatic Surgery (ISGPS)[END_REF] Gemcitabine chemotherapy resulted in more thrombocytopenia and flu-like illness. Overall, 66% of patients from the mFOLFIRINOX arm and 79% from the gemcitabine arm received all of the scheduled cycles.

Summary of adjuvant chemotherapy phase III trials

Considering the remarkable results of the PRODIGE24 trial, mFOLFIRINOX is now the standard adjuvant chemotherapy regimen in fit PDAC patients, while GEMCAP or monochemotherapies with gemcitabine or 5FU are validated treatment options in unfit patients.

Gemcitabine monotherapy should be preferred over 5FU based on the better safety profile, while no consensus exists to favor GEMCAP over gemcitabine monotherapy. These regimens are proposed as equivalent updated options in the latest ASCO guidelines. [45] Although the APACT trial was negative for its primary objective, future indications of the GEMNAB regimen will need to be clarified in clinical guidelines given the positive per-investigator DFS and OS results.

Perspectives

Promising biomarkers

At least two major lines of research are currently underway to improve oncological results using biomarkers.

The first line of research has been undertaken in order to better define the optimal chemotherapy to use in the adjuvant setting for PDAC according to intra-tumoral expression of predictive biomarkers. Among these, the levels of intra-tumoral expression of human equilibrative nucleoside transporter 1 (hENT1) and deoxycytidine kinase (dCK) have proven to be the most promising potential biomarkers of the gemcitabine efficacy. [START_REF] Farrell | Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer[END_REF][START_REF] Maréchal | Levels of gemcitabine transport and metabolism proteins predict survival times of patients treated with gemcitabine for pancreatic adenocarcinoma[END_REF][START_REF] Greenhalf | Pancreatic cancer hENT1 expression and survival from gemcitabine in patients from the ESPAC-3 trial[END_REF][START_REF] Sinn | Human equilibrative nucleoside transporter 1 expression analysed by the clone SP 120 rabbit antibody is not predictive in patients with pancreatic cancer treated with adjuvant gemcitabine -Results from the CONKO-001 trial[END_REF][START_REF] Wei | A meta-analysis of gemcitabine biomarkers in patients with pancreaticobiliary cancers[END_REF][START_REF] Elander | Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer[END_REF] Nevertheless, discordant results have been reported due to the use of antibodies not equivalent in activity. [46-53*] The level of dihydropyrimidine dehydrogenase (DPD) expression could also be predictive of the 5FU efficacy.[51*] Similarly, the recent molecular signatures (based on mRNA expression profiles) could also be predictive of chemotherapy efficacy, but there are no data in the adjuvant setting. [54*] The second line of research has been undertaken to better define the patients with a resectable PDAC who will benefit the most from an upfront surgery. In fact, the risk of relapse remains very high after curative intent surgery, superior to 60%, [START_REF] Conroy | FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer[END_REF] and PDAC is commonly considered as a systemic disease. The detection of circulating prognostic biomarkers could help to identify the patients who have the highest risk of early relapse after surgery and to propose them alternative therapeutic strategies (e.g. neoadjuvant chemotherapy). For instance, patients with detectable circulating tumor DNA before surgery do not seem benefit from upfront surgery. [55,56*] Others circulating biomarkers such as circulating tumor cells or exosomes are promising and could also be used as reliable markers of treatment efficacy. [START_REF] Poruk | Circulating Tumor Cell Phenotype Predicts Recurrence and Survival in Pancreatic Adenocarcinoma[END_REF][START_REF] Allenson | High prevalence of mutant KRAS in circulating exosome-derived DNA from early-stage pancreatic cancer patients[END_REF] However, robust and reproducible methodologies to assess these biomarkers have to be developed and prospectively validated before any used in routine practice.

Neoadjuvant strategies

Like for gastric or rectal cancers, development of neoadjuvant strategies could allow to improve oncologic outcomes of patients with resectable PDAC. After pancreatic resection, about one third of patients cannot receive an adjuvant treatment because of postoperative morbidity and mortality. [START_REF] Deoliveira | Assessment of complications after pancreatic surgery: A novel grading system applied to 633 patients undergoing pancreaticoduodenectomy[END_REF][START_REF] Cameron | One thousand consecutive pancreaticoduodenectomies[END_REF] Moreover, the rate of relapse remains superior to 60% in adjuvant phase III trials in which only fit patients have been included. [START_REF] Conroy | FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer[END_REF][START_REF] Tempero | APACT: phase III, multicenter, international, openlabel, randomized trial of adjuvant nab-paclitaxel plus gemcitabine (nab-P/G) vs gemcitabine (G) for surgically resected pancreatic adenocarcinoma[END_REF][START_REF] Neoptolemos | Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial[END_REF][START_REF] Neoptolemos | Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial[END_REF] Data from the recent studies of patients with borderline PDAC have shown that neoadjuvant/induction strategies (most often, chemotherapy follow or not by CRT) were well tolerated and did not impair the morbidity and mortality after secondary pancreatic resection, and even reduced the rate of pancreatic fistula.[6,7*,59-61] Moreover, and like in others digestive cancers, the pathologic response is a prognostic factor after neoadjuvant/induction treatment. [START_REF] Pietrasz | Pathologic Major Response After FOLFIRINOX is Prognostic for Patients Secondary Resected for Borderline or Locally Advanced Pancreatic Adenocarcinoma: An AGEO-FRENCH, Prospective, Multicentric Cohort[END_REF] Promising preliminary results of the PREOPANC-1 trial assessing a neoadjuvant/induction strategy coupling gemcitabine and CRT in patients with resectable and borderline PDAC have been presented, [START_REF] Ettrich | Neoadjuvant plus adjuvant or only adjuvant nab-paclitaxel plus gemcitabine for resectable pancreatic cancer -the NEONAX trial (AIO-PAK-0313), a prospective, randomized, controlled, phase II study of the AIO pancreatic cancer group[END_REF] and several randomized neoadjuvant phase II and III trials are currently ongoing. [START_REF] Motoi | Randomized phase II/III trial of neoadjuvant chemotherapy with gemcitabine and S-1 versus upfront surgery for resectable pancreatic cancer (Prep-02/JSAP05)[END_REF][START_REF] Schwarz | Resectable pancreatic adenocarcinoma neoadjuvant FOLF(IRIN)OX-based chemotherapy -a multicenter, non-comparative, randomized, phase II trial (PANACHE01-PRODIGE48 study)[END_REF][START_REF] Labori | Neoadjuvant chemotherapy versus surgery first for resectable pancreatic cancer (Norwegian Pancreatic Cancer Trial -1 (NorPACT-1)) -study protocol for a national multicentre randomized controlled trial[END_REF][START_REF] Ettrich | Neoadjuvant plus adjuvant or only adjuvant nab-paclitaxel plus gemcitabine for resectable pancreatic cancer -the NEONAX trial (AIO-PAK-0313), a prospective, randomized, controlled, phase II study of the AIO pancreatic cancer group[END_REF]

Conclusions

The definition of resectable PDAC has evolved in recent years, but upfront surgical resection remains the standard of care in this disease setting. The mFOLFIRINOX regimen is now the adjuvant standard in fit patients. Modified FOLFIRINOX, gemcitabine-based regimens (GEMNAB, GEMCAP), monotherapy with gemcitabine or with 5-fluorouracil are the alternative options in unfit PDAC patients. Several promising predictive or prognostic biomarkers have been proposed, but they still need prospective validation. Neoadjuvant treatment will likely shape the future in this setting and several randomized trials are currently ongoing.

Key points

•

Resectable PDAC is defined as the tumor without vascular contact or ≤ 180° contact with the superior mesenteric vein (SMV), or portal vein (PV) without vein contour irregularity.

•

Upfront surgery remains the standard of care for resectable PDAC and robust and validated biological and pathological factors coupled with the sound international guidelines are in place.

•

In fit patients, the modified FOLFIRINOX regimen is now the standard treatment after curative intent surgery of PDAC, while the gemcitabine-base regimens (GEMCAP or GEMNAB) or monotherapies are an option in unfit patients.

•

Prospective validation of methodologies used to assess promising predictive and/or prognostic biomarkers and of steps that lead to interest in a specific therapeutic strategy with their use are necessary before these are applied in routine clinical practice.

•

Neoadjuvant treatment strategies are probably the future and several randomized trials are ongoing.

Acknowledgements

Acknowledgements: The authors thank Magdalena Benetkiewicz for editorial assistance.

Financial support and sponsorship: none

Conflict of interest: LM: none; LS received fees from Bayer, Servier, Sanofi, Mayoly Spindler, Intuitive, Roche; JBB serves as a board member and/or received fees from Amgen, AstraZeneca, Bayer, Celgene, Merck Serono, Mundipharma, Pierre Fabre, Roche, Sanofi, Shire, Servier. -5FU bolus: leucovorin 20 mg/m 2 bolus follow by 5-fluorouracil 425 mg/m 2 /day bolus for 5 consecutive days, every 28 days, for a total of 6 cycles.

-Gem: gemcitabine 1000 mg/m 2 in 30 minutes intravenous (IV) at days 1, 8, and 15, one cycle every 28 days, for a total of 6 cycles.

-Gem + Erlo: gemcitabine 1000 mg/m 2 in 30 minutes IV at days 1, 8, and 15, plus erlotinib 100 mg/day from day 1 to day 28, one cycle every 28 days, for a total of 6 cycles.

-Gem + Cap: gemcitabine 1000 mg/m 2 in 30 minutes IV at days 1, 8, and 15, plus capecitabine 1660 mg/m 2 /day from day 1 to day 21, one cycle every 28 days, for a total of 6 cycles.

-FOLFIRINOX: oxaliplatin 85 mg/m 2 , leucovorin 400 mg/m 2 , irinotecan 150 mg/m 2 at day 1 follow by 5-fluorouracil 2400 mg/m 2 in 46h continuous infusion, one cycle every 14 days, for a total of 12 cycles.

-Gem + Nab: nab-paclitaxel 125 mg/m 2 in 30-40 minutes IV follow by gemcitabine 1000 mg/m 2 in 30 minutes IV at days 1, 8 and, 15, one cycle every 28 days, for a total of 6 cycles.


Marine Cognet

Thibaut Gutel
email: thibaut.gutel@cea.fr

Romain Gautier

Xavier F Le Goff

Adel Mesbah

Nicolas Dacheux

Michaël Carboni
email: michael.carboni@cea.fr

Daniel Meyer

Pillared Sulfonate-Based Metal-Organic Framework As Negative Electrode For Li-Ion Batteries

Keywords: Metal-Organic Framework, Li-Ion Battery, Negative electrodes, Sulfonate based MOF, Pillared strategy

The syntheses of sulfonate-based metal-organic frameworks (MOFs) following or not a pillared strategy using a linear N-donor ligand have been successfully developed. These MOFs based on Co, Ni or Mn present a layered structure separated by a solvent molecule of DMF or by a bridging ligand (4,4'-BiPyridine -bpy). Due to the presence of transition metals on the coordination nodes bridged by ligands (bpy), these materials have been tested as negative electrodes materials in a coin cell. It reveals that materials have capacities up to 350 mAh.g -1 and good electrochemical stability over 50 charge/discharge cycles. This strategy may shed light on designing new MOF-based electrode materials with the use of organic ligands structured in a hybrid material.

Introduction

Increased attention is focused on the design of efficient and clean energy storage devices. The development of Lithium ion Batteries (LiBs), first formulated by Armand [START_REF] Armand | Intercalation Electrodes[END_REF] and later commercialized in large scale by Sony Corporation (1991), has grown exponentially due to their high energy density and relatively low self-discharge. [START_REF] Tarascon | Issues and challenges facing rechargeable lithium batteries[END_REF] Research in this field has continued to display some remarkable progresses in terms of capacity, energy and cost reduction. [START_REF] Blomgren | The Development and Future of Lithium Ion Batteries[END_REF] The future capabilities of this technology are correlated to the development of new electrode materials (anodes and cathodes).

Anodes are mainly composed of graphite or carbonaceous materials. [START_REF] Sun | Graphene based new energy materials[END_REF] However, some important improvements have been recently made such as the Ti-based compounds [START_REF] Zhu | Ti-based compounds as anode materials for Li-ion batteries[END_REF] or the silicon nanowires materials [START_REF] Peng | Silicon nanowires for rechargeable lithium-ion battery anodes[END_REF] which exhibit a good safety and cycling stability for a low cost.

Metal Organic Frameworks (MOFs) have proven to be very versatile materials due to the great number of metallic clusters or organic ligands that can be used in the construction of these materials. [START_REF] Kitagawa | Functional Porous Coordination Polymers[END_REF] Thanks to these characteristics, they have been tested for gas storage, [START_REF] Li | Selective gas adsorption and separation in metal-organic frameworks[END_REF] heterogeneous catalysis, [START_REF] Manna | Salicylaldimine-Based Metal-Organic Framework Enabling Highly Active Olefin Hydrogenation with Iron and Cobalt Catalysts[END_REF] metals extraction [START_REF] Carboni | Highly porous and stable metal-organic frameworks for uranium extraction[END_REF] or artificial photosynthesis. [START_REF] Amador | Photosensitive titanium and zirconium Metal Organic Frameworks: Current research and future possibilities[END_REF] MOFs have also been recently proposed as new electrode materials for battery [START_REF] Li | Metal-organic frameworks as platforms for clean energy[END_REF] as positive electrode materials [START_REF] Proietti | Iron-based cathode catalyst with enhanced power density in polymer electrolyte membrane fuel cells[END_REF] or as anode materials [START_REF] Zheng | High lithium anodic performance of highly nitrogen-doped porous carbon prepared from a metal-organic framework[END_REF]. Due to the possibility to control different morphologies [START_REF] Tang | MOF morphologies in control: Carbon materials[END_REF] it has been possible to prepare nanoscale carbon materials that have revealed to enhance ions intercalation performance. [START_REF] Zhang | Hollow carbon nanobubbles: monocrystalline MOF nanobubbles and their pyrolysis[END_REF] This thermal conversion, under air [START_REF] Salunkhe | A highperformance supercapacitor cell based on ZIF-8-derived nanoporous carbon using an organic electrolyte[END_REF] or N 2 atmosphere [START_REF] Song | Hollow metal organic frameworksderived porous ZnO/C nanocages as anode materials for lithium-ion batteries[END_REF], to carbon/metal oxide materials [START_REF] Chaikittisilp | Synthesis of Nanoporous Carbon-Cobalt-Oxide Hybrid Electrocatalysts by Thermal Conversion of Metal-Organic Frameworks[END_REF] can retain the stable porous architecture of the original MOF and give some interesting properties for electrochemical application. Some other strategies as the loading of metal nanoparticles [START_REF] Fu | Co3O4 nanoparticles@MOF-5derived porous carbon composites as anode materials with superior lithium storage performance[END_REF] or carbon nanotubes [START_REF] Wu | Zn-Fe-ZIF-derived porous ZnFe 2 O 4 /C@NCNT nanocomposites as anodes for lithium-ion batteries[END_REF] with MOF have been successfully demonstrated.

Carboxylate anions ligands [START_REF] Eddaoudi | Modular Chemistry: Secondary Building Units as a Basis for the Design of Highly Porous and Robust Metal-Organic Carboxylate Frameworks[END_REF] and neutral nitrogen heterocycles [START_REF] Park | Exceptional chemical and thermal stability of zeolitic imidazolate frameworks[END_REF] are often used as linkers in MOFs because they are usually commercially available or they can be obtained quite easily by organic synthesis. Other functionalities such as sulfonate or phosphonate motifs have been considerably less studied. [START_REF] Shimizu | Phosphonate and sulfonate metal organic frameworks[END_REF] However, we have recently shown that phosphonate based MOF have a great potential as electrode material in LiBs [START_REF] Cognet | Iron(II)-Benzene Phosphonate Coordination Polymers as an Efficient Active Material for Negative Electrode of Lithium-Ion Batteries[END_REF] and leads us to use of sulfonic acid linkers. Indeed, compared to the carboxylate analogues, [START_REF] Panasyuk | Copper terephthalate and its thermal decomposition products[END_REF] these ligands can easily stabilize high coordination number complexes due to the three oxygen donor atoms per sulfonate group and consequently corresponding MOFs exhibit a better thermal stability when coordinated to transition-metals. [START_REF] Mietrach | Sulfonic Acid Analogs of Terephthalic and Trimesic Acid as Linkers in Metal-Organic Frameworks -Synthesis of Thermally Robust MOFs[END_REF] But the lower structural predictability related to the versatile coordination modes of sulfonate to the metal is the main issue to obtain well-defined crystalline porous materials. [START_REF] Cote | The supramolecular chemistry of the sulfonate group in extended solids[END_REF] To increase rigidity and to favor 3D-network of such materials, the use of a mixed-ligand strategy can be efficient. [START_REF] Lian | A series of metal-organic frameworks constructed with arenesulfonates and 4,4'-bipy ligands[END_REF][START_REF] Zhang | A Robust Sulfonate-Based Metal-Organic Framework with Permanent Porosity for Efficient CO 2 Capture and Conversion[END_REF][START_REF] Maity | Sulfonic Group Functionalized Mixed Ligand Coordination Polymers: Synthesis, Characterization, Water Sorption, and Proton Conduction Studies[END_REF] By using linear N-donor ligands during the MOFs synthesis, the possibility was shown to include these ligands in a layered structure and these MOF-based electrodes lead to high capacities and good cycling stability as shown by PANI-ZIF-67CC [START_REF] Wang | Flexible Solid-State Supercapacitor Based on a Metal-Organic Framework Interwoven by Electrochemically-Deposited PANI[END_REF] or [Ni(bpy)(tfbdc)(H 2 O) 2 ][33]. In the last example, the use of the 4,4'-bipyridine (bpy) as spacer could be an original way to include a solid state organic molecule that has already shown great interest as electroactive moieties in polyviologen for organic batteries. [START_REF] Striepe | Viologens and Their Application as Functional Materials[END_REF] Inspired by these results, we propose in this study the use of a Mn(II), Co(II) and Ni (II) systems based on BenzeneDiSulfonic Acid (BDS) that are stabilized with bpy ligands as potential electrode materials for LiBs. The crystal structures of these materials (Mn(BDS)(DMF) and M(BDS)(bpy)(DMF) 2 , M = Ni, Mn or Co)) have been solved from single crystal X-ray diffraction data. Moreover, electrochemical studies in coin cell have revealed a capacity around 350 mAh.g -1 (0.1-3.5 V vs Li + /Li) at low rate and a good stability over charge/discharge cycles.

Experimental

Synthesis and characterizations

Reagents were purchased from Sigma-Aldrich and were used as received without further purification. The ligand BDS was synthesized according to a previous reported protocol [START_REF] Mietrach | Sulfonic Acid Analogs of Terephthalic and Trimesic Acid as Linkers in Metal-Organic Frameworks : Synthesis of Thermally Robust MOFs[END_REF] and was obtained by using hydrogen peroxide in a mixture of water and methanol containing the dithioterephthalic acid. M(BDS)(DMF) and M(BDS)(bpy)(DMF) 2 were obtained by mixing 1 equivalent of ligand (50 mg, 0.2 mmol) with 1 equivalent (68 mg for Mn and 57 mg for Co and Ni salts, 0.2 mmol) of Mn(NO 3 ) 2 (H 2 O) 9 , Co(NO 3 ) 2 (H 2 O) 6 or Ni(NO 3 ) 2 (H 2 O) 6 and 1 equivalent of bpy (31 mg, 0.2 mmol) in the case of the pillared MOF in 5 ml of dry DMF. The reaction was then performed in a solvothermal conditions at 120 °C for 2 days in an oven. Then the mixture was centrifuged and single crystals of each materials were isolated and solved by single crystal diffraction.

Single crystal diffraction

The crystal structures of the compounds M(BDS)(bpy)(DMF) 2 (M= Ni, Mn, Co) were solved from data collected on the single-crystal X-ray Bruker-Nonius Kappa CCD diffractometer with monochromated MoKα ( λ= 0.71073 Å) at 100 (2) K. The crystal to detector distance was 60 mm. Data collection strategy and data reduction were done with the use of SUPERGUI software. While the data related to Mn(BDS)(DMF) were collected with a bruker APEX II diffractometer at 150 (2) K, the absorption corrections were carried out with SADABS. [START_REF] Zhang | A Robust Sulfonate-Based Metal-Organic Framework with Permanent Porosity for Efficient CO 2 Capture and Conversion[END_REF] The determination of the structure and the final refinement was carried out with the use of the SHELXL 2016 package. [START_REF] Maity | Sulfonic Group Functionalized Mixed Ligand Coordination Polymers: Synthesis, Characterization, Water Sorption, and Proton Conduction Studies[END_REF] Crystal data and data collection details for each compound are reported in Table S1.

Electrochemical characterizations

Coin cell assembly was carried out in an argon-filled MBraun glove box using metallic lithium foil as counter and reference electrode and Celgard® 2400 and Viledon® (Freudenberg) as separator, the latter soaked with a 1M solution of LiPF 6 in a 1:1 volume mixture of ethylene carbonate (EC) and dimethyl carbonate (DMC) (UBE), serving as electrolyte. Galvanostatic cycling were performed using a multichannel Arbin BT-2000. Composite electrodes for the electrochemical characterization were prepared by mixing M(BDS)(bpy)(DMF), Super P® (SP; Imerys) and poly(vinylidene difluoride) (PVdF, SOLEF® 5130; Solvay), in N-methyl-2-pyrrolidone (NMP; Sigma-Aldrich). The overall weight ratio was 40/40/20 M(BDS)(bpy)(DMF)/SP/PVdF. The slurry were coated on copper foil, serving as current collector, and after pre-drying disk-shaped electrodes were punched, having an average active material mass loading of about 1 mg.cm -2 for M(BDS)(bpy)(DMF)/SP/PVdF. The electrodes were subsequently pressed at 10 tons for 10 s prior all the electrodes were dried at 80 °C for 48 h under vacuum. Since lithium foil served as counter and reference electrode, all potential values given herein refer to the Li + /Li 0 redox couple.

Results and discussion

Structure analyses

The crystal structures of the three isostructural compounds M(BDS)(bpy)(DMF) 2 with M = Mn, Co and Ni were solved in the orthorhombic system in the Pbca space group. There are four formula units per unit cell with a = 10.6241 ( 8 S1. Each M has an octahedral coordination formed by four oxygen atoms, two provided by the DMF molecules and two other supplied by the sulfonate groups of the BDS molecule. The coordination sphere is completed by two nitrogen atoms coming from the bi-pyridine molecules. S4). It is worth noting that the crystal structure of Mn(BDS)(DMF) 2 was already reported in the literature, however, from our refinement, we found that the most suitable solution consisted in doubling the volume caused in our opinion by the configuration of the DMF molecules. The electrochemical performances of the three materials were evaluated in half coin cells. For all the materials, a first lithiation was observed with capacities up to 1200 mAh.g -1 . Most of the capacity is observed between 1.2 V and 0.1 V with a large hysteresis. After 5 charge/discharge cycles, the specific capacity of the materials remain constant up to 50 cycles. The large irreversible capacity during the first cycles is typical of a conversion mechanism and the MOF structure is probably not maintained. However, in such material metal clusters are separated by organic ligands that lead to very small and isolated metallic particles at the end of this conversion process and avoid any particles recombination that will decrease the electrochemical performances. [START_REF] Lee | Coordination Polymers for High-Capacity Li-Ion Batteries: Metal-Dependent Solid-State Reversibility[END_REF] Composite electrodes based on Ni(BDS)(bpy) and Mn(BDS)(bpy) have revealed the lowest capacities of the three materials with capacities of around 250 mAh.g -1 and 260 mAh.g -1 , respectively. These capacities could be mainly attributed to the contribution of Super P® carbon used to form the electrodes (Figure S1). Only the Co(BDS)(bpy) material has revealed a significant electro-activity with a capacity value of 350 mAh.g - 1 (with a contribution of 2/5 due to Super P® carbon in this condition). These results indicate that, even if the MOF structure is probably lost, the pre-organization of the metallic clusters is important for the overall stability during the cycling. This result is in accordance with what was observed (406 mAh.g -1 ) with the pillared ([Ni(4,4′-bpy)(tfbdc)(H 2 O) 2 ] previously reported. 26 Finally, this last material presents an interesting stability after couple of charge/discharge cycles and a low operating voltage.

Conclusions

In summary, three new pillared hybrid materials based on sulfonate ligands have been synthesized and tested as potential electrode materials. Even if the variations in ligating mode of the sulfonate can generate multiple polymorphs in such materials, it has been possible to crystallize these compounds and to solve their structures from single-crystal XRD data. The use of a bridging ligand during the MOF synthesis, i.e. the bpy, allowed to increase the distance between the MOF layers and to immobilize a molecule inside a porous network. From the different electrochemical tests, Co(BDS)(bpy) has revealed the most interesting capacity of 350 mAh.g -1 and a good retention up to 50 cycles. These results show that the development of new electrode materials is essential to increase cell capacities and that the design of new materials can be supplied by hybrid materials.

  ) Å, b = 11.6242(16) Å, c = 19.7900(20) Å (Mn), a = 10.8881 (12) Å, b = 11.3927 (14) Å, c = 19.2902(15) Å (Co), a = 10.9666 (12) Å, b = 11.2905 (12) Å, c = 19.1256 (8) Å (Ni). Crystal data and refinement parameters are reported in Table

Figure 1 -

 1 left presents a general view of the structure along the a axis. The MO 4 N 2 octahedra are connected to the bi-pyridine molecules to form infinite chains along the b axis. These chains are separated from each other down the b axis by the DMF molecules to form what could be described as organic-inorganic pseudo-layers (Figure 1-middle). The overall structure consists in BDS molecules separating these latter described pseudo-layers by the share of one oxygen atom as viewed in Figure 1-right. The interatomic distances are reported in Table S2. The M-O and M-N distances with M = Mn, Co and Ni evolve in agreement with the crystal radii reported in the Shannon tables.

Figure 1 :

 1 Figure 1 : left -Projection of the M(BDS)(bpy)(DMF) 2 crystal structure down the a axis, middlecrystal structure down the b axis, right -Arrangement of the isolated MO 4 N 2 octahedra viewed perpendicular to the [001] direction. The materials without the bpy have also been obtained under the form of single crystal with the Manganese. Mn(BDS)(DMF) 2 crystallizes in the triclinic system with the P-1 space group. There are two formula units per cell with a = 9.858(1) Å, b = 9.931(1) Å, c = 10.310(1), α = 69.224(1)°, β = 68.214(1)°, γ = 87.106(1)°, V = 872.47(15) Å 3 . Crystal data and refinement parameters are reported in Table S3. In the present structure, there are two different Mn atoms, each one is octahedrally coordinated to six oxygen atoms. Four provided by the sulfonate group and two others belong to the DMF molecules. The difference between the two sites reside in the orientation of the DMF molecules positioned in trans configurations down the b axis and have different orientations. The overall structure consists of isolated MnO 6 octahedra bridged by the sulfonate groups down the c axis and separated also by the BDS molecules down the b axis.Figure 2 represents a view of the crystal

Figure 2

 2 represents a view of the crystal structure of the Mn(BDS)(DMF) 2 compound down the c and b axis, respectively. The Mn-O distances are typical which are comprised between 2.1467(11) -2.1831(10) Å for Mn1 and 2.1704(11) -2.1868(11) Å (Table

Figure 2 :

 2 Figure 2 : (left) Projection of the Mn(BDS)(DMF) 2 crystal structure down the c axis. (right) View of the Mn(BDS)(DMF) structure down the b axis

Figure 3 :

 3 Figure 3: (left) Charge-Discharge profiles (right) and cycling performance (reduction) at 300 mA.g -1


Julien Hervochon

Vincent Dorcet

Kathrin Junge

Matthias Beller

Cedric Fischmeister

Convenient synthesis of cobalt nanoparticles for the hydrogenation of quinolines in water

come

Introduction

Reduction reactions and more particularly hydrogenati ons are ubiquitous in organic synthesis and play a major role as part of industrial processes in bulk and fine chemical synthesis. This situation will likely persist owing to the growing concerns and demands for sustainable supply of chemicals arising from biomass 1 as well as new energy carriers based on chemi ca l hydrogen storage. 2 N-Heterocycles are important building blocks in natural and synthetic bioactive molecules among which 1,2,3,4tetrahydroqui noli ne is specifically valuable with numero us applications in drugs and agrochemi cals. 3 Recently, such molecules have also been envisioned as hydrogen reservoi rs . 4 As usually observed with aromatic compounds, the catalyti c hydrogena ti on of quinoline derivatives is a challenging reacti on because of potential catalyst deactivation due to coordina ti o n of quinoline reagents and tetrahydroqui noli ne derivati ves . Various homogeneous catalysts [START_REF] Sanchez-Del Ga D O | For hydrogenation reactions[END_REF] have been reported for the hydrogena ti on of quinolines while iridium-based catalys ts exhibited best performa nces and chemoselecti vities. Howeve r, the cost of these catalysts, the sometimes necessary presence of additives and the non-recycla bility of homogeneous catalys ts encouraged the development of less expensive catalysts bas ed on iron, 6 manganese, 7 and cobalt. 8 Despite their economi c interest, these catalysts still need to be improved as they displ a y in general lower efficiency than noble metal-based catalysts and they often require expensive ligands such as pincer ligands. In the past decades, numerous heterogeneous catalysts based on noble metals have also been reported for the hydrogenati on of quinoline derivatives. 9 Although they usually display hi gh reactivity, these catalysts suffer from low chemoselecti vi t y hence hampering the scope of accessible product. Rare examples of chemoselecti ve hydrogenati on of quinoline ma ke use of supported Rh, 9i Au 9v and Ru 9q nanoparticl es. As for homogeneous catalysts, the search for lower cos t heterogeneous catalysts is a topic of high importance in catalysis (Figure 1). In 2015, some of us reported the selective hydrogena tion of heteroarenes using cobalt oxide/cobal t nanoparticles modif i ed by nitrogen doped graphene layers on alumina. 10 Thes e catalysts efficiently hydrogenated a number of quinol i ne derivatives in 60-72 h, in toluene at 120 °C and 20-30 bar of hydrogen pressure. One year later, Wang disclosed coba l t encapsulated in N-doped graphene layers for the hydrogena ti on of quinolines in 3-15 h, in methanol at 120 °C under 30 bar of hydrogen pressure. 11 More recently, Corma reported nanolayered cobalt-mol ybdenum sulphides for the selective hydrogenati on of quinolines. 12 This catalyst opera ti ng at 120 °C and 12 bar of hydrogen pressure displayed impres s i ve chemoselecti vity as it did not hydrogenate olefins, ketone, nitrile, ester and amide functions of quinoline derivati ves . However, this catalyst was moderatel y recyclable as convers i o n and yields dropped by 50% in a third run. Very recently in 2019, Balaraman reported a Co-Phen@C catalyst for the reduction of quinolines working at 120 °C and 50 bar of hydrogen pressure. 13 Apart from cobalt, one example of heterogeneous iron catalys t was reported in 2018. 14 Here, an N-doped carbon modified ironbased catalyst performed the hydrogena ti on of a number of quinoline derivatives at 130-150 °C under 40-50 bar of hydroge n pressure in a MeOH/H2O solvent mixture. Nitrile, ester and amide moieties were not hydrogenated by this catalyst, whi ch was recycled 6 times without loss of catalytic efficiency. Whatever the nature of the metal (noble/non-noble), most of the known heterogeneous catalysts for this transforma ti o n require multistep synthesis or their scale up is difficult. Thus , the preparation of general and selective catalysts in a straightforwa rd manner is stimulating for academic and industrial researchers. In this respect, metal nanoparti cl es attracted specific interest in recent years. For instance, naked iridium oxide nanoparticles, easily prepared from iridi um trichloride and sodium hydroxide, were shown to be efficient catalysts for the hydrogena tion of several quinoline derivati ves at mild conditions (room temperature, 1 bar (H2 balloon) to 60 bar). 15 Similarly, Jacobi von Wangelin reported "quasi-na ked " cobalt nanoparticles stabilized by olefinic substrates whi ch were efficient for C=C, C=O and C=N bond hydrogena ti ons in THF. 16 To prepare cobalt nanoparticles in an easy and conveni e nt manner in aqueous reaction media, the reduction of coba l t salts with sodium borohydri de caught our attenti on. Interestingl y, the activation of sodium borohydri de is catalysed by numerous transition metals of which coba l t attracted most attention due to its lower cost. In fact, it is well established that hydrolysis of NaBH4 in the presence of Co(II) salt leads to various cobalt species 17 includi ng nanoparticles . 18 Inspired by these results, we developed a novel cobalt-catalysed hydrogena tion of quinoline and quinoline derivatives in aqueous media. Here, we report the synthesis and application of the optimal catalyst system, which is conveniently prepared from inexpens i ve precursors without any additives or stabilising species.

Results and discussion

Catalytic experiments

We started our investigations with the reduction of quinoline 1 using in situ generated cobalt(0) nanoparticl es. More specifically, a high-press ure reactor was successively loaded with CoCl2 (5 mol%), NaBH4 (10 mol%), H2O (1 mL) and quinol i ne 1, charged with dihydrogen and heated to temperat ur es between 115 °C and 130 °C. As depicted in Table 1, only mi nor amounts of catalytic hydrogenati on of 1 to 2 occurred at 20 ba r of hydrogen (Table 1, entry 1). Even increasing the tempera tur e to 130°C resulted in no repeatable results (Table 1, entry 2). However, stable and quantitative reactions were achieved at 130 °C and 30 bar of hydrogen pressure (Table 1, entry 3). Applying a reduced catalyst loading (2.5 mol%) still resulted in 72% conversion and excellent selectivity (Table 1, entry 4). Following these preliminary results, several other experimen ta l parameters were varied. Literature reports on the hydrolysis of NaBH4 catalysed by Co(II) salts clearly established that the Co(II)/Na BH4 ratio is a key parameter determining the nature of the generated cobalt species. 16 Hence, the hydrogenati on of quinoline was studied in the presence of different amounts of NaBH4 showing an interesting influence on the reacti on selectivity. The reaction could be performed with only 5% of NaBH4 but again the repeatability of the reaction was not full y satisfactory leading to 80% to full conversions (Table 1, entry 6). Notably, increasing the amount of sodium borohydri de to 20 mol% and to 50 mol%, respectively resulted in a different reduction pathway leading to product 3 arising from the hydrogena ti on of the carbon-ring (Table 1, entries 7-8). Apparently, different kinds of active cobalt nanoparticl es are formed depending on the amount of sodium borohydri de. This selectivity issue has already been mentioned with severa l heterogeneous catalysts with sometimes trace amounts of full y hydrogena ted product. 19 Notably, the reaction was successful l y scaled-up to 2 g of quinoline using best experimental conditi ons (Table 1, entry 9). The activation period correspondi ng to the amount of time between the addition of water to CoCl2/Na BH4 and quinol i ne was also considered and studied as a key parameter. As the reduction of cobalt salts by NaBH4 is a fast reaction, a study wa s conducted with short activation periods. The initial assumpti o n was verified as an increase in conversion was observed upon increasing the activation period to 6 minutes. Further extens i on 2). The involvement of quinoline and/or tetrahydroqui noli ne in the stabilisation of cobalt species shoul d also not be ruled out.

Next, we examined the influence of various cobalt(II) precursors. Apart from cobalt(II) acetylacetonate which was less suitable for this reaction, it is worth noting that the less toxi c (NH4)2Co(SO4)2 . 6H2O was found as effective as CoCl2 (Table 3, entry 3) and was used in some examples of the substrate scope study (vide infra). After a first run performed under the previousl y optimi s ed conditions, the reaction mixture was extracted with ethyl acetate and the aqueous phase containing the cobalt catalys t was reloaded with sodium borohydri de, quinoline and stirred at 130 °C for 17 h under 30 bar of dihydrogen. Following this procedure, it was possible to perform three runs with excell ent conversion and selectivity after which a quick drop in conversion was observed without deterioration of selectivi ty (Figure 3). This result is attributed to the deactivation of the catalyst as a black layer accumulated with time over the vial walls. This assumption was confirmed by analysing the reacti on mixture arising from a recycling test in which the vial walls were coated by a black solid. Indeed, cobalt could not be detected by TEM/EDS analyses of this reaction mixture that all the cobalt was coated onto the vial walls and was catalytica l l y inactive. To understand this catalyst deactivation, another recycling experiment was performed in which the aqueous reaction mixture was separated from the insoluble materi a l after the first run. The generated black solid was washed with water and a second run was started under standard conditions giving a lower conversion of only 50%. This observation is most likel y explained by the removal of soluble catalytic cobalt species. 18 Next, the scope and limitations of the present catalyst wa s investigated by the hydrogenati on of a broad range of substrates diversely substituted on the phenyl-or pyridyl-ri n g (Table 4). The substitution of the pyridyl-ring by alkyl or aryl groups led to the desired products in good yields with the exception of 3-methylqui noli ne where a mixture of the correspondi ng tetrahydroqui noline along with 3-methyl -5,6,7,8-tetra hydroqui noli ne was formed (Table 4, entry 2). On the contrary, quinolines substituted at the pyridyl-ri ng by bromine and chloride atoms were unreactive even at higher temperature (150 °C; Table 4, entries 4-5). However, to the bes t of our knowledge, such reactions have not been reported in the literature and it should be mentioned that no dehalogena ti o n was observed with the brominated reagents as reported for Pdnanoparticules . 20 In case of the chloro-substi tuted deriva ti ve dechlorinati on occurred to a small extent (~5 %). Neverthel es s , these failures provide some hints on the reaction mecha ni s m indicating that N-coordinati on of quinolone to the catalyst is necessary. Interestingl y, the catalyst was found much less sensitive to the substitution pattern on the phenyl ring. Indeed, alkyl-, alkoxy-and halo-substituted products were obtained in good to high yields (Table 4, entries 6-12). The chemoselecti vi t y of the catalyst was investigated using either functional i z e d reagents or mixtures of reagents. Indeed, the selecti ve hydrogena ti on of quinoline derivatives in the presence of an ester group or internal carbon-carbon double bonds wa s demonstra ted (Table 4, entries 14 and 17). However, as exemplified in entry 14, the catalyst also selectivel y hydrogena ted a terminal carbon-carbon double bond. The selective reduction of quinolines bearing carbonylfunctionalities was investigated, as only very few catalysts for such transformati ons have been reported. As evidenced in entries 15-17, the formyl-and keto-group were readi l y hydrogena ted while the ester group was not reduced vide supra. The scope of the reaction was further extended to other N-heterocyclic compounds that were all converted with hi gh conversion leading to the desired products in good to excell ent yields except for isoquinoline and 1H-benzoi mi daz ole (Table 5, entries 18-24). As explained earlier, the less toxi c (NH4)2Co(SO4)2.6H2O precursor was employed in some examples and found to be a suitable cobalt precursor , too (Table 4, entries 3, 14, 21).

Characterisation of the catalyst

With these results in hands, we turned our attention to the nature of the catalyst. As mentioned in the introducti on, the hydrolysis of NaBH4 in the presence of CoCl2 is a very compl ex process likely to generate several cobalt species. Severa l parameters such as the ratio CoCl2/Na BH4 or the rate of hydrolysis influence this process. In general, we applied for the catalytic experiments a catalyst prepared by hydrolysis of NaBH4 in the presence of CoCl2 in a 2/1 ratio. The resulting da rk suspension in water was analysed by Transmission Electron Microscopy and Energy Dispersive Spectrometry. As shown in Figure 4, the analysed material consisted essentially of nanosheet structures (Fig 4, a, b & c) containing cobalt, as demonstra ted by EDS analyses (See SI). Interestingl y and despite the absence of any stabilizers, it was also possible to identify cobalt nanoparticles by HRTEM (Fig 4, d). We were also interested in the stabilty of the formed nano-sheet structures during catalysis. For this reason, a reaction mixture arising from the hydrogena ti on of quinoline under standard conditions wa s also analysed by TEM. As displayed in Figure 5, this reacti on mixture yet consisted in amorphous particles but of bigger size and it was no longer possible to identify crystalline particles . Consequentl y, the contribution of cobalt nanoparticles to the overall catalytic activity cannot be discarded in the first run, but other "true" heterogeneous cobalt species are also involved as evidenced by the recycling test. However, it is worth noting tha t cobalt nanoparticl es prepared from organometalli c coba l t complexes and sodium borohydride in isopropanol were inactive for the hydrogena tion of quinoline. 21

Conclusions

In conclusion, we have prepared catalytically active coba l t nanoparticles by hydrolysis of NaBH4 in the presence of Co(II) salts. The catalyst consists initially of a mixture of coba l t nanoparticles and cobalt-containi ng nanosheets and evolves to bigger Co particles upon reuse. The activity and chemoselecti vity of this catalyst are comparabl e to other welldefined heterogeneous catalyst made of cobalt only. 22 Nota bl y, this catalyst is easily prepared from inexpensive coba l t precursors and readily accessible to synthetic chemis ts . Furthermore, the catalyst preparation does not need any additives and to the contrary of many heterogeneous catalysts , it is prepared and used in water hence making the overa l l process convenient and more environmentall y friendly.

Figure 1

 1 Figure 1 Overview of Co-catalyzed hydrogenation of quinoline

  of this activation period led to lower performances indica ti ng the evolution of the catalytic species into non-or less reacti ve species (Table

a

  Conditions: Quinoline (0.100 g, 0.78 mmol), NaBH4 (10 mol%), H2O (1 mL), H2 (30 bar), 130 °C, 17 h. b Conversion determined by 1 H NMR. c Average of 3 reactions (79%, 85%, 89%). All reactions were done two or three times.The recycling of the Co-Nps was evaluated by means of consecutive quinoline hydrogenati on runs taking advantage of the magnetic properties of the in situ formed Co-Nps allowi ng for a facile separation of the heterogeneous catalyst (Figure2).

Figure 2

 2 Figure 2 Separation of magnetic cobalt particles

Figure 3

 3 Figure 3 Catalytic hydrogenations of quinoline: Recycling of cobalt catalyst

Figure 4 :Figure 5

 45 Figure 4: a, b, c: TEM images of catalytic material; d: HRTEM image of crystalline particl e with corresponding Fast Fourier Transform

  Puylaert, A. Dell'Acqua, F. El Ouahabi, A. Spannenberg, T. Roisnel, L. Lefort, S. Hinze, S. Tin and J. G. de Vries, Catal. Sci. Technol., 2019, 9, 61. 22 The selectivity is not as good as that reported by Corma with a cobalt-molybdenum catalyst, ref 12.

Table 1

 1 Catalytic hydrogenation of quinoline in the presence of cobalt nanoparticles a Conversion determined by 1 H NMR. d CoCl2 (2.5 mol%). All experiments were done twice. e 2 g scale of quinolone.

	Entry	NaBH4	P (H2)	T	Conv.	2 (%) c	3 (%) c
		(mol%)	(bar)	(°C) b	(%) c
	1	10	20	115	10	10	0
	2	10	20	130	84-99	84-99	0
	3	10	30	130	100	100	0
	4 d	10	30	130	72	72	0
	5	2.5	30	130	36	36	0
	6	5	30	130	79-≥ 99	79-≥ 99	0
	7	20	30	130	≥ 99	82	8
	8	50	30	130	>99	78	22
	9 e	10	30	130	100	100	0
	a Conditions: Quinoline (0.100 g; 0.78 mmol), CoCl2 (0.038 mmol; 5 mol%), NaBH4
	(2.95 mg, 10 mol%), H2O (1 mL), 17 h.

b

Oil bath temperature. c

Table 3

 3 Catalytic hydrogenations of quinoline: Evaluation of Co(II) precursors a

Table 2

 2 Co-nanoparticles catalyzed hydrogenations of quinoline: Influence of the activation period a

	Entry	t (min)	Conv. (%) b	2 (%) b
	1	0	15	15
	2	3	19	19
	3	6	23	23
	4	8	16	16
	5	10	14	14
	a Conditions: Quinoline (0.100 g; 0.78 mmol), CoCl2 (0.038 mmol; 1 mol%);
	NaBH4 (2 mol%), H2O (1 mL), H2 (30 bar), 130 °C, 17 h. b Conversion and yield
	determined by 1 H NMR.

Table 4

 4 Scope and limitations a

	Entry	Substrate	T	Product	Con./Yield
			[°C]		[%] b,c
	1		130		>99 (83)
	2		130		77/39 (23/4)
	3 d		130		85 (57)
	4		150		0
	5		150		0
	6		130		>99 (70)
	7		130		>99 (81)

Acknowledgements

The authors acknowledge the Région Bretagne (ARED) for a grant to JH.

Conflicts of interest

"There are no conflicts to declare".


Quang-Anh Phan

Olivier Chadebec

Gerard Meunier

Jean-Michel Guichon

Bertrand Bannwarth

3D BEM Formulations for Eddy Current Problems with Multiply Connected Domains and Circuit Coupling

Quasi-static linear problems can be solved efficiently with Boundary Element Method (BEM). This method is based on surface integral equations dealing with equivalent magnetic and electric surface current densities. Many works have shown the potentiality of BEM especially for the modeling of non-destructive testing devices. In this paper, after selecting formulations enabling the modeling of multiply-connected regions, an original coupling is proposed in order to take into account external electric circuit in the problem.

Index Terms-Boundary Element Method, eddy currents, quasi-static, circuit coupling.

T HIS study is motivated by the need of efficient quasi- static electromagnetic formulations associated to nonsimply connected domains and which can be coupled with circuit equations. For this kind of problems, methods based on coupling between BEM and Finite Element Method (FEM) have already shown very good results. However, the accuracy of these methods is strongly influenced by the volume mesh of the conductive region which has to be adapted to the skindepth in the FEM context. The pure BEM method does not suffer from this disadvantage because it is only based on surface discretizations and is more insensitive to frequency increase keeping the same mesh.

Many BEM formulations have already been proposed to solve Eddy Current (EC) problems and two options are possible. The first one consists in solving the full Maxwell equations including capacitive effects and to use an Helmholtz-Hodge decomposition to remove low-frequency numerical noise like proposed in [1]. The second option is to solve directly Maxwell equations under the quasi-static assumption (i.e the EC problem) as proposed in [3], [4] or [5]. In this work, the preference is given to the last approach.

In classical EC problems (like eddy current testing problems for instance), the active region can be multiply connected, meaning that it can have through-holes. It is fundamental to develop formulations which can solve accurately such a problem. An another key point is the ability of the formulation to be coupled with external electric circuits which create the external inductor field. This is what we aim to do in this paper. After selecting efficient BEM formulations for EC problems, an original circuit coupling is proposed. All the formulations are validated on numerous examples by a comparison with FEM.

I. SURFACE INTEGRAL FORMULATIONS

A. Integral Equations

Let us consider a linear, isotropic and homogeneous conducting material region Ω characterized by the conductivity σ 1 and the permeability µ 1 and embedded in the free space Ω 0 . Γ is the border of the region Ω with the outward unit normal n. Surface integral equations of E and H at an arbitrary target point P in Ω 0 are :

hH = H s + Γ ((n • H 0 ) ∇G 0 + J s × ∇G 0 )dΓ (1)
hE = E s + Γ ((n • E 0 ) ∇G 0 -M s × ∇G 0 )dΓ -jωµ 0 Γ J s G 0 dΓ (2)
and for a target point in Ω are :

hH = - Γ µ 0 µ 1 (n • H 0 ) ∇G 1 -σ 1 M s G 1 dΓ - Γ J s × ∇G 1 dΓ (3)
hE = Γ (M s × ∇G 1 + jωµ 1 J s G 1 )dΓ (4)
where h = 0.5 if P is a regular point of the border Γ, h = 1 if P belongs to Ω or Ω 0 . The Green kernels expressions are G 0 = 1 r and G 1 = 1 4πr e -(1+j)kr with k = ωµ1σ1 2 , H 0 and E 0 are the magnetic and electric fields in the air region respectively, H s and E s denote the electric and magnetic vectors of the incident field respectively, expressed by the current density of source j s as:

H s = Ω s j s × ∇G 0 dΩ E s = -jω Ω s j s G 0 dΩ (5)
where Ω s is source current region, J s and M s are equivalent magnetic and electrical surface currents such as :

J s = n × H M s = -n × E
For the sake of clarity, we use some definitions as follows:

A (U) = p.v. Γ UG dΓ B (U) = p.v. Γ U × ∇G dΓ C (u) = -p.v. Γ u∇G dΓ A × (U) = A (U) × n, B × (U) = B (U) × n, C × (u) = C (u) × n, A n (U) = A (U) • n, B n (U) = B (U) • n, C n (u) = C (u)
• n, where p.v. denote Cauchy principal value, index ∈ {0, 1}.

From the four equations ( 1)-( 4) and by considering their normal and tangential projections on Γ, we get eight integral boundary equations. On the outer side:

E s × = 1 2 M s + iωµ 0 A 0 × (J s ) + B 0 × (M s ) + C 0 × (E 0n ) (6)
H s × = - 1 2 J s -B 0 × (J s ) + C 0 × (H 0n ) (7)
E s n = 1 2 E 0n + jωµ 0 A 0 n (J s ) + B 0 n (M s ) + C 0 n (E 0n ) (8) H s n = 1 2 H 0n -B 0 n (J s ) + C 0 n (H 0n ) (9)
On the inner side:

0 = - 1 2 M s + jωµ 1 A 1 × (J s ) + B 1 × (M s ) (10) 0 = 1 2 J s -B 1 × (J s ) + σ 1 A 1 × (M s ) + C 1 × (H 1n ) (11) 0 = jωµ 1 A 1 n (J s ) + B 1 n (M s ) (12) 0 = - 1 2 H 1n -B 1 n (J s ) + σ 1 A 1 n (M s ) + C 1 n (H 1n ) (13
) Combining these integral equations by multiplying ( 6)-( 13) respectively by the weighting factors α , β , a , b and summing contributions of Ω 0 and Ω, we obtain the system of six formulations given by Tab. I.

The obtained formulations called from EC1 to EC6. EC1 and EC2 have already been presented in [3]. EC4, EC5 with a combination such as the PMCWHT formulation was presented in [1], [5]. EC5 was proposed in [4], the idea of combination comes from formulation of Muller [7]. The EC6 formulation has been added to complete the set of combinations.

B. Choice of BEM formulation

Formulations in Tab. I are now examined in the context of a low frequency eddy current problem. A conductive ring (r int = 4mm, r ext = 10mm, h = 2mm) is considered. An excitation coil is placed 1mm above (r int = 6.75mm, r ext = 7.25mm, h = 0.5mm, I = 10A, 1 turn). The surface of the ring is discretized by 1792 quadrangle elements. The current density M s , J s are interpolated by the facet shape function (2-form Whitney elements) and the 0-form Whitney elements for E 0n .

M s = n M i=1 w i M si , J s = n J i=1 w i J si , E 0n = n E i=1 α i E 0ni .
where n M , n J , n E are numbers of degree of freedom corresponding to M s , J s and E 0n . Using the Galerkin approach, we perform calculations with frequencies ranging from 10Hz to 100kHz for each formulation. The reference result is computed by axisymmetric finite element method. Figure 1 shows the relative loss in three cases respectively: σ = 5.5E7, µ r = 1 (case 1), σ = 5.5E6, µ r = 10 (case 2), σ = 5.5E5, µ r = 100 (case 3). The skin depth varies from 21.46mm to 0.21mm in these cases. The tests carried out show that the EC1 formulation does not work in this case multiply-connected regions, the distribution obtained being wrong. That's why we don't show results of EC1 formulations. For the circuit coupling problem, it is necessary to have the magnetic potential A outside the conductor (see next section) which depends on E 0n . In EC4, this quantity is not computed. That's why we didn't test this formulation. The number of candidate formulations for circuit coupling is then reduced to EC2, EC3, EC5 and EC6, which are compatible with multiply connected problems and enable the computation of the magnetic vector potential outside. In the case of non-magnetic conductivity, the results obtained with EC2, EC5 and EC6 lead to a better accuracy than EC3 up to a few kHz. However, with a higher frequency, EC3 becomes more accurate. In the case of conductive and magnetic material, when relative permeability is high at 100, all three formulations give poor results, especially for EC3, EC6 at a frequency below 10kHz and for EC2, EC5 at a frequency above 1kHz. With a lower magnetic permeability µ r = 10, EC2 gives better results than the others in the frequency range considered.Let us notice that if an iterative solver like GMRES is used, EC6 presents the best convergence rate.

II. CIRCUIT COUPLING

A. Electrical circuit equations

In this part, the construction of the equation dealing with imposed voltage electrical circuit is according like proposed in which makes the assumption that the current density is uniform in the section of the conductor. Note j s 0 (x, y, z) the space function of the corresponding current density which is obtained by the electrokinetic resolution of the problem with the total current is 1A [6]. In the case where the total current

α 1 = 1, α 0 = β 1 = 0, β 0 = 1 a 1 = a 0 = 0, b 1 = 0, b 0 = 1 Js, Ms, H 0n EC2 α 1 = 0, α 0 = β 1 = 1, β 0 = 0 a 1 = 0, a 0 = b 1 = 1, b 0 = 0 Js, Ms, H 0n , E 0n EC3 α 1 = α 0 = β 1 = β 0 = 1 a 1 = 0, a 0 = 1, b 1 = b 0 = 0 Js, Ms, E 0n EC4 α 1 = α 0 = β 1 = β 0 = 1 a 1 = 0, a 0 = 1, b 1 = b 0 = 0 Js, Ms EC5 α 1 = -1, α 0 = 1, β 1 = -µ 1 , β 0 = µ 0 a 1 = -1, a 0 = 1, b 1 = b 0 = 0 Js, Ms, E 0n EC6 α 1 = -1, α 0 = 1, β 1 = -1, β 0 = 1 a 1 = -1, a 0 = 1, b 1 = b 0 = 0 Js, Ms, E 0n
is equal to I with a voltage imposed U on the conductor U = V a -V b with V a , V b respectively the uniform potential on borders Γ a , Γ b , thanks to Stock's theorem the following relationship can be written:

Ω s j s 0 • ∇V dΩ = V a Γa j s 0 • ndΓ + V b Γ b j s 0 • ndΓ = -U (14)
The electric field E in the conductor is written as:

E = -jωA -∇V (15)
In combination with the above equation and ( 14), we get:

U = Ω s j s 0 • EdΩ + jω Ω s j s 0 • AdΩ (16)
The term of j s 0 • E can be written as:

Ωc j s 0 • EdΩ = - Ωc j s • ∇V 0 dΩ = U 0 I = RI ( 17
)
where R is static resistance and R = ρ Ωc (j s 0 ) 2 dΩ.

Equations ( 16) and (17) to the following electrical circuit equation :

U = Ω s ρI (j s 0 ) 2 dΩ + jω Ω s j s 0 • AdΩ (18)
The total magnetic potential A in (18) is created by both current flowing in the electric circuit and by eddy currents.

B. Coupling model

The circuit coupling is implemented with the assumption that the excitation circuits are wound conductors where the wire size is small enough to not need to take into account the skin effect in each strand. In the context of circuit coupling, the conducting region Ω is excited by a set of n electrical circuits in which the k th electrical circuit Ω s k is connected to voltage sources U k . The governing equation is (18). Let us consider (2). By setting the coefficient h to 1, we get the electrical total field outside the considered conductor Ω:

E = -jωµ 0 n i=1 I i Ω s i j s 0i G 0 dΩ -jωµ 0 Γ J s G 0 dΓ - Γ M s × ∇G 0 dΓ + Γ E n0 ∇G 0 dΓ (19)
Thanks to the relation E = -jωA, the equation governing the k th electric circuit becomes:

U k = I k   ρ Ω s k (j s 0k ) 2 dΩ + jωµ 0 Ω s k j s 0k • Ω s k j s 0k G 0 dΩdΩ    Term 1 +jωµ 0 Ω s k j s 0k n i =k I i Ω s i j s 0i G 0 dΩdΩ Term 2 - Ω s k j s 0k   -jωµ 0 Γ J s G 0 dΓ - Γ M s × ∇G 0 dΓ + Γ E n0 ∇G 0 dΓ   dΩ Term 3
Term 1 presents the proper impedance of the k th electrical circuit. Term 3 and Term 2 express the reaction of eddy currents and the influences of others electrical circuits on the k th electrical circuit respectively.

C. Resolution

Both eddy current BEM formulations and their coupling with electric circuits are solved simultaneously. According to (5), the electric and magnetic source fields in BEM formulations can be represented by integral depending on I k which are additional unknowns. The final matrix system to solve is presented in Fig. 2.

k k M 11 M 12 = 0 M s J s E n0 M 21 M 22 {I } {U } Fig. 2.
Matrix system for solving the coupling problem.

In the system, M s(n M ×1) , J s(n J ×1) , E n0(n E ×1) are vectors of the degrees of freedom corresponding to M s , J s and E n0 . The matrix M 11 is constructed as the one used to solve the single eddy current problem by BEM formulation. The M 11 matrix is built like the one used to solve the eddy current problem by BEM formulation. Let's establish the matrices M 12 , M 21 and M 22 . The current density j s 0k is interpolated also by the facet shape function:

j s 0k = n k i=1 w ki j ki
where j ki can be determinded thanks to the pre-computation of the electrokinetic current density j 0k discussed in the section III.B. Suppose that the M 21 matrix is composed of three parts N 1 , N 2 , N 3 corresponding to three sets of unknown M s , J s , E n0 respectively. The k th row of these matrices corresponds to the Term 3 of equation of the k th electrical circuit.

N 1 kj = jωµ 0 n k i=1   jki Ω s k w ki Γ w j G 0 dΓdΩ    N 2 kj = n k i=1   jki Ω s k w ki Γ w j × ∇G 0 dΓdΩ    N 3 kj = - n k i=1   jki Ω s k w ki Γ α j ∇G 0 dΓdΩ   
The matrix M 22 is constructed according to Term 1 and Term 2. Its k th row takes the following form:

M 22 kk = ρ n k i=1 j ki n k j=1 j kj Ω s k w ki w kj dΩ (20)
M 22 kt = jωµ 0 n k i=1 j ki nt j=1 j tj Ω s k w ki Ω s t w tj G 0 dΩdΩ (21)
M 12 is established in the same way as M 22 , follows the source formula (5).

D. Validation

The circuit coupling has been tested with EC6 formulation. A conductive square section ring is taken into account. The system is excited by an external circuit, which is concentric and coaxial with the ring. The geometric and property descriptions are shown in Tab. II and Fig. 3. In BEM, the geometry is meshed with about 2464 quadrangle elements. The reference is calculated by the FEM method with a 2D axisymmetric model and a circuit coupling in which a mesh of 43500 triangles is used. The total currents flowing in the electrical circuit are compared in Tab. III. The magnetic flux density is calculated on line segment A(28.5, 0, 5) -B(28.5, 0, 30) at frequency f = 10Hz and shown in Fig. 4. The component B y = 0 is not displayed in the figure. The eddy current distribution in this case is shown in Fig 3. The BEM circuit coupling leads to results very close to those calculated by FEM method with a axisymetric model. Differences can be explained by the difference of the mesh

N 1 kj = jωµ 0 n k i=1   jki Ω s k w ki Γ w j G 0 dΓdΩ    N 2 kj = n k i=1   jki Ω s k w ki Γ w j × ∇G 0 dΓdΩ    N 3 kj = - n k i=1   jki Ω s k w ki Γ α j ∇G 0 dΓdΩ   
The matrix M 22 is constructed according to Term 1 and Term 2. Its k th row takes the following form:

M 22 kk = ρ n k i=1 j ki n k j=1 j kj Ω s k w ki w kj dΩ (20)
M 22 kt = jωµ 0 n k i=1 j ki n t j=1 j tj Ω s k w ki Ω s t w tj G 0 dΩdΩ (21)
M 12 is established in the same way as M 22 , follows the source formula (5).

D. Validation

The circuit coupling has been tested with EC6 formulation. A conductive square section ring is taken into account. The system is excited by an external circuit, which is concentric and coaxial with the ring. The geometric and property descriptions are shown in Tab. II and Fig. 3. In BEM, the geometry is meshed with about 2464 quadrangle elements. The reference is calculated by the FEM method with a 2D axisymmetric model and a circuit coupling in which a mesh of 43500 triangles is used. The total currents flowing in the electrical circuit are compared in Tab. III. The magnetic flux density is calculated on line segment A(28.5, 0, 5) -B(28.5, 0, 30) at frequency f = 10Hz and shown in Fig. 4. The component B y = 0 is not displayed in the figure. The eddy current distribution in this case is shown in Fig 3. The BEM circuit coupling leads to results very close to those calculated by FEM method with a axisymetric model. Differences can be explained by the difference of the mesh size and by the order of the shape functions ( first order for BEM functions and second order for FEM) but results remains very goods. IV. CONCLUSION In this article, different formulations for the eddy current problem have been recalled and compared at low frequency. These formulations generally work well with low relative permeability. A coupling model that simultaneously solves the eddy current and electrical circuit equations has also been proposed. size and by the order of the shape functions ( first order for BEM functions and second order for FEM) but results remains very goods.

III. CONCLUSION

In this article, different formulations for the eddy current problem have been recalled and compared at low frequency. These formulations generally work well with low relative permeability. A coupling model that simultaneously solves the eddy current and electrical circuit equations has also been proposed.

Fig. 1 .

 1 Fig. 1. on Joule losses. Comparison of different BEM formulations with axisymetric FEM problem.

Fig. 3 .Fig. 4 .

 34 Fig. 3. Eddy current distribution J(A • m -2) on the surface of the ring at f = 10Hz

Fig. 3 .Fig. 4 .

 34 Fig. 3. Eddy current distribution J(A • m 2) the surface of the ring at f = 10Hz