MD Florence Poizeau

PhD Emmanuel Nowak

MD, PhD Alain Dupuy
email: alain.dupuy@chu-rennes.fr.

Association Between Early Severe Cardiovascular Events and Ustekinumab Treatment?-Reply

appropriateness of the case-crossover design, while our study used a case-time-control design.

The case-crossover design is however an adequate theoretical framework to discuss their objections to our study. Gelfand et al. refer to two concepts related to time that merit clear distinction.

The first concept is the "transience of effect". We are concerned about a misunderstanding on the very question addressed in our study: we addressed the hypothesis of severe cardiovascular events being associated with ustekinumab initiation. If there is an initiationrelated effect, it is, by definition, transient: after some time has passed, the effect possibly related to initiation fades, and a cumulative effect takes over. Distinguishing these two types of effect (transient and cumulative) "can be of great importance, especially in the rare situation that the transient and cumulative effects are in opposite directions", as pointed out by Maclure et al. [START_REF] Maclure | When should case-only designs be used for safety monitoring of medical products?[END_REF] The second concept is the "induction time", i.e. the time necessary for the effect to develop, and this translates into the choice of an exposure window. The time window is derived from the time frame necessary for the exposure-related effect to trigger the outcome. Time windows in case-crossover studies can extend as far as "1 year before the outcome event". [START_REF] Schneeweiss | Why me?" versus 'why now?'--differences between operational hypotheses in case-control versus case-crossover studies[END_REF] Given the hypothesized immunological mechanism (immuno-mediated atherosclerotic plaque destabilization), a "just before" time window (if this means "measured in hours or days") would have been inappropriate. Our 6-month risk period was justified by a hypothesized underlying biological mechanism, and pre-specified in the protocol.

A c c e p t e d M a n u s c r i p t

Beyond these considerations on the case-crossover design, we acknowledge that the observed events are rare and the confidence intervals for the odds-ratios are consequently large. Only large databases can evidence such differences for rare events, and we see this as a strength of our study. The unavailability of clinical and biological ("conventional") cardiovascular risk factors is a limitation of our study. However, the issue was to distinguish high-and lower-risk populations, based on a pre-specified hypothesis of an association between severe cardiovascular events and ustekinumab initiation, anticipated to occur exclusively among patients with high baseline cardiovascular risk.

We would like to stress that our study addresses the general question of "why now", and not "why me", 5 for severe cardiovascular events among patients with high baseline cardiovascular risk at the time of ustekinumab initiation.

Overall, our findings point to the need for clinicians to be aware of the risk of severe cardiovascular events within 6 months after ustekinumab initiation among patients with high baseline cardiovascular risk (while this does not preclude any type of long-term cardiovascular effect). They also point to the need for epidemiologists and immunologists to study similar risks with other biologics targeting the Th17 pathway.

Conflict of Interest Disclosures: None


Alena N Kulakova

Alexey N Bilyachenko

Mikhail M Levitsky

Victor N Khrustalev

Alexander A Korlyukov

Yan V Zubavichus

Pavel V Dorovatovskii

Frédéric Lamaty

Xavier Bantreil

Benoît Villemejeanne

Fredeŕic Lamaty

Jean Martinez

Lidia S Shul'pina

Elena S Shubina

Evgeniy I Gutsul

Igor A Mikhailov

Nikolay S Ikonnikov

S Ul'yana

Tsareva

Georgiy B Shul'pin

Si 10 Cu 6 N 4 Cage Hexacoppersilsesquioxanes Containing N Ligands: Synthesis, Structure, and High Catalytic Activity in Peroxide Oxidations

come   L'archive ouverte pluridisciplinaire

■ INTRODUCTION

In the past decades, metal-containing cagelike compounds (polycyclic 3D structures with well-defined geometry) have attracted enormous attention from scientific groups due to their striking molecular topology 1 as well as their huge potential for practical applications. [START_REF] Koblenz | Reactivity within a confined self-assembled nanospace[END_REF] These latter applications include, for example, intriguing cases of development of polymer science 3 and medicine. 4 A diversity of self-assembly procedures was elaborated for the construction of cagelike compounds, 5 suggesting different ideas on structure control by means of, e.g., an appropriate choice of linkers 5b or ligand shape. 5d Among the variety of metal-containing cage complexes, a family of RSiO 1.5 -based metallacomplexes (cagelike metallasilsesquioxanes, CLMSs) has drawn special attention as attractive molecular architectures 6 exhibiting unusual magnetic (spin glass behavior) effects 7 and opportunities for the creation of inorganic materials 8 or nanoparticles. [START_REF] Davies | Rare Earth Doped Silica Nanoparticles via Thermolysis of a Single Source Metallasilsesquioxane Precursor[END_REF] In turn, great deal of attention has been devoted to the investigation of the catalytic activity of metallasilsesquioxanes. 10 For example, their high activity was reported for such reactions of high demand as olefin 11 or ringopening polymerization, 12 olefin epoxidation, 13 polycarbonate synthesis, 14 and a Meerwein-Ponndorf reaction, [START_REF] Beletskiy | Tetrahedral Snsilsesquioxane: synthesis, characterization and catalysis[END_REF] as well as for hydroformylation. 16 In turn, our team reported on the catalytic activity of cagelike metallasilsesquioxanes in oxidative hydrocarbon functionalization 17 and amidation 18 reactions. Very recently, some of us presented the first example of the successful testing of CLMSs, including additional organic (phosphorusbased [START_REF] Bilyachenko | Ionic Complexes of Tetra-and Nonanuclear Cage Cu(II)phenylsilsesquioxanes: Synthesis and High Activity in Oxidative Catalysis[END_REF] ) ligands in such oxidative reactions. According to this, we were interested in further investigation of "organic ligand assisted" synthesis of metallasilsesquioxanes and the application of potential products of such an approach in catalysis. It should be emphasized that among publications describing synthetic approaches to CLMSs one could find some examples of CLMS formation in the presence of different organic ligands. Mostly, these ligands were used in the reaction of metallasilsesquioxane synthesis as reagents (being a part of a metal complex) and they were inherited in the composition of the product. These cases include the classical work on the very first cubane CLMS [START_REF] Feher | Polyhedral oligometallasilsesquioxanes (POMSS) as models for silica-supported transition-metal catalysts. Synthesis and characterization of (C 5 Me 5 )Zr[(Si 7 O 12 )(c-C 6 H 11 ) 7[END_REF] (complex with Cp*) synthesis as well as numerous types of other complexes: with carborane, [START_REF] Fei | The first tantalasilsesquioxanes[END_REF] acac, [START_REF] Duchateau | Synthesis and characterization of tin containing polyhedral oligometallasilsesquioxanes (POMSS)[END_REF] tricyclohexylphosphine, [START_REF] Baker | Synthesis and Characterization of Iron Silasesquioxane Phosphane Complexes[END_REF] cyclooctenyl, [START_REF] Quadrelli | Molecular insight into the non-innocence of a silica-support: the structure of a platinum-silsesquioxane derivative[END_REF] methyl, [START_REF] Voigt | Organic-Soluble Neutral and Ionic Indium Siloxane Cages: Potential Precursors for Indium-Containing Silicates[END_REF] or silylamide [START_REF] Nehete | Polyhedral Ferrous and Ferric Siloxanes[END_REF] ligands just to mention a few. Several examples of postsynthesis CLMS functionalization by the organic ligands N,N-dimethylhydroxylamine and acacH, [START_REF] Lindemann | Synthesis and Reactivity of Core-Functionalized Polyhedral Titanasiloxanes[END_REF] tris(2-pyridylmethyl)amine [START_REF] Abbati | Towards Stepwise Cluster Assembly: A Decacopper(II) Complex Obtained by Controlled Expansion of a Metallasiloxane Cage[END_REF] and bipy 29 are also worth mentioning. Very recently, our group suggested a quite convenient method of CLMS self-assembly, assisted by the interaction of 2,2′-bipyridine or phenanthroline with the product of the interaction of methylalkoxysilane with NaOH and CuCl 2 . [START_REF] Bilyachenko | Unusual tri-, hexa-and nonanuclear Cu(II) cage methylsilsesquioxanes: Synthesis, Structures and Catalytic Activity in Oxidations with Peroxides[END_REF] It should be mentioned that the nature of the silicon atom substituent could have great influence on the process of cage assembly (compare, for example, penta-7b,d or hexanuclear 18a,31 prismatic CLMSs, characteristic for phenyl-substituted reagent, to octa- [START_REF] Zherlitsyna | ,16octolato)octakis[(dimethyl-formamide)copper(II)] dimethylformamide solvate enclosing a pyrazine molecule[END_REF] or nonanuclear [START_REF] Bilyachenko | Unusual tri-, hexa-and nonanuclear Cu(II) cage methylsilsesquioxanes: Synthesis, Structures and Catalytic Activity in Oxidations with Peroxides[END_REF] methyl-based prisms). This is why we were interested in the investigation of self-assembling reactions involving phenylalkoxysilane and different ligands of the 2,2′-bipy family. These ligands (with a transfer from 2,2′-bipyridine to bathophenanthroline) could give valuable information on the influence of steric factors (due to an increase in N-ligand bulkiness) for the process of cage product assembly. Of course, we were interested in the first study of catalytic properties of potential products of these reactions, CLMSs, bearing N ligands.

We present here an extended series of 17 complexes (with 2,2′-bipy, phenanthroline, or bathophenanthroline ligands) and the determination of their structures by single-crystal X-ray diffraction. A study of the catalytic activity of these complexes in peroxide oxidations of alcohols and alkanes as well as in amidation reactions under mild conditions is also described.

■ EXPERIMENTAL SECTION

Synthesis. PhSi(OMe) 3 , solvents, and N ligands were purchased from Acros Organics and used as received. All manipulations required no inert atmosphere.

Complex 1. A 1 g portion (5.04 mmol) of PhSi(OMe) 3 , 0.20 g (5 mmol) of NaOH, and 20 mL of an ethanol/methanol (1/1) mixture were placed in a three-neck round-bottom flask (equipped with magnetic stirrer and condenser). The resulting solution was heated under reflux for 1.5 h and then was cooled to room temperature, and 0.226 g (1.68 mmol) of CuCl 2 was added at once. The mixture was stirred for 3 h and filtered from NaCl. The filtrate was dried under vacuum, and then 0.131 g (0.839 mmol) of 2,2′-bipyridine in 35 mL of DMSO was placed in the same evaporation flask. The resulting solution was intensely stirred for 2.5 h with a magnetic stirrer and then filtered from the insoluble precipitate. The filtrate was stored in a vial equipped with a septum with a needle to allow the slow evaporation of solvents for crystallization. After 1 week the formation of crystalline material was observed; several single crystals were used for X-ray diffraction analysis (for details of the X-ray diffraction study see below). The rest of the crystalline fraction was separated from the solution, washed with n-heptane, and dried under vacuum. Anal. Calcd for [(PhSiO 1.5 ) 10 (CuO) 6 (HO 0.5 ) 2 (C 10 H 8 N 2 ) 2 ]: Cu, 18.16; N, 2.67; Si, 13.38. Found (for vacuum-dried sample): Cu, 18.07; N, 2.59; Si, 13.29. Yield: 0.36 g (61%).

Complex 2. A 1 g portion (5.04 mmol) of PhSi(OMe) 3 , 0.20 g (5 mmol) of NaOH, and 20 mL of an ethanol/methanol (1/1) mixture were placed in a three-neck round-bottom flask (equipped with a magnetic stirrer and condenser). The resulting solution was heated under reflux for 1.5 h and then was cooled to room temperature, and 0.226 g (1.68 mmol) of CuCl 2 was added at once. The mixture was stirred for 3 h and filtered from NaCl. The filtrate was dried under vacuum, and then 0.131 g (0.839 mmol) of 2,2′-bipyridine in 35 mL of MeCN was placed in the same evaporation flask. The resulting solution was intensely stirred for 2.5 h with a magnetic stirrer and then filtered from the insoluble precipitate. The filtrate was stored in a vial equipped with a septum with a needle to allow the slow evaporation of solvents for crystallization. After 1 week the formation of crystalline material was observed; several single crystals were used for X-ray diffraction analysis (for details of the X-ray diffraction study see below). The rest of the crystalline fraction was separated from the solution, washed with n-heptane, and dried under vacuum. Anal. Calcd for [(PhSiO 1.5 ) 10 (CuO) 6 (HO 0.5 ) 2 (C 10 H 8 N 2 ) 2 ]: Cu, 18.16; N, 2.67; Si, 13.38. Found (for vacuum-dried sample): Cu, 18.05; N, 2.60; Si, 13.27. Yield: 0.24 g (40%).

Complex 3. A 1 g portion (5.04 mmol) of PhSi(OMe) 3 , 0.20 g (5 mmol) of NaOH, and 20 mL of an ethanol/methanol (1/1) mixture were placed in a three-neck round-bottom flask (equipped with magnetic stirrer and condenser). The resulting solution was heated under reflux for 1.5 h and then was cooled to room temperature, and 0.226 g (1.68 mmol) of CuCl 2 was added at once. The mixture was stirred for 3 h and filtered from NaCl. The filtrate was dried under vacuum, and then 0.131 g (0.839 mmol) of 2,2′-bipyridine in 35 mL of a MeCN/PhCN mixture (2/1) was placed in the same evaporation flask. The resulting solution was intensely stirred for 2.5 h with a magnetic stirrer and then filtered from the insoluble precipitate. The filtrate was stored in a vial equipped with a septum with a needle to allow the slow evaporation of solvents for crystallization. After 1 week the formation of crystalline material was observed; several single crystals were used for X-ray diffraction analysis (for details of the X-ray diffraction study see below). The rest of the crystalline fraction was separated from the solution, washed with n-heptane, and dried under vacuum. Anal. Calcd for [(PhSiO 1.5 ) 10 (CuO) 6 (HO 0.5 ) 2 (C 10 H 8 N 2 ) 2 ]: Cu, 18.16; N, 2.67; Si, 13.38. Found (for vacuum-dried sample): Cu, 18.07; N, 2.61; Si, 13.30. Yield: 0.12 g (20%).

Complex 4. A 1 g portion (5.04 mmol) of PhSi(OMe) 3 , 0.20 g (5 mmol) of NaOH, and 20 mL of an ethanol/methanol (1/1) mixture were placed in a three-neck round-bottom flask (equipped with a magnetic stirrer and condenser). The resulting solution was heated under reflux for 1.5 h and then was cooled to room temperature, and 0.226 g (1.68 mmol) of CuCl 2 was added at once. The mixture was stirred for 3 h and filtered from NaCl. The filtrate was dried under vacuum, and then 0.131 g (0.839 mmol) of 2,2′-bipyridine in 35 mL of a MeCN/PhCN mixture (1/2) was placed in the same evaporation flask. The resulting solution was intensely stirred for 2.5 h with a magnetic stirrer and then filtered from the insoluble precipitate. The filtrate was stored in a vial equipped with a septum with a needle to allow the slow evaporation of solvents for crystallization. After 1 week the formation of crystalline material was observed; several single crystals were used for X-ray diffraction analysis (for details of the X-ray diffraction study see below). The rest of the crystalline fraction was separated from the solution, washed with n-heptane, and dried under vacuum. Anal. Calcd for [(PhSiO 1.5 ) 10 (CuO) 6 (HO 0.5 ) 2 (C 10 H 8 N 2 ) 2 ]: Cu, 18.16; N, 2.67; Si, 13.38. Found (for vacuum-dried sample): Cu, 18.09; N, 2.60; Si, 13.29. Yield: 0.06 g (10%).

Complex 5. A 1 g portion (5.04 mmol) of PhSi(OMe) 3 , 0.20 g (5 mmol) of NaOH, and 20 mL of an ethanol/methanol (1/1) mixture were placed in a three-neck round-bottom flask (equipped with a magnetic stirrer and condenser). The resulting solution was heated under reflux for 1.5 h and then was cooled to room temperature, and 0.226 g (1.68 mmol) of CuCl 2 was added at once. The mixture was stirred for 3 h and filtered from NaCl. The filtrate was dried under vacuum, and then 0.131 g (0.839 mmol) of 2,2′-bipyridine in 35 mL of PhCN was placed in the same evaporation flask. The resulting solution was intensely stirred for 2.5 h with a magnetic stirrer and then filtered from the insoluble precipitate. The filtrate was stored in a vial equipped with a septum with a needle to allow the slow evaporation of solvents for crystallization. After 1 week the formation of crystalline material was observed; several single crystals were used for X-ray diffraction analysis (for details of the X-ray diffraction study see below). The rest of the crystalline fraction was separated from the solution, washed with n-heptane, and dried under vacuum. Anal. Calcd for [(PhSiO 1.5 ) 10 (CuO) 6 (HO 0.5 ) 2 (C 10 H 8 N 2 ) 2 ]: Cu, 18.16; N, 2.67; Si, 13.38. Found (for vacuum-dried sample): Cu, 18.07; N, 2.58; Si, 13.26. Yield: 0.08 g (14%).

Complex 6. A 1 g portion (5.04 mmol) of PhSi(OMe) 3 , 0.20 g (5 mmol) of NaOH, and 20 mL of an ethanol/methanol (1/1) mixture were placed in a three-neck round-bottom flask (equipped with magnetic stirrer and condenser). The resulting solution was heated under reflux for 1.5 h and then was cooled to room temperature, and 0.226 g (1.68 mmol) of CuCl 2 was added at once. The mixture was stirred for 3 h and filtered from NaCl. The filtrate was dried under vacuum, and then 0.131 g (0.839 mmol) of 2,2′-bipyridine in 35 mL of THF was placed in the same evaporation flask. The resulting solution was intensely stirred for 2.5 h with a magnetic stirrer and then filtered from the insoluble precipitate. The filtrate was stored in a vial equipped with a septum with a needle to allow the slow evaporation of solvents for crystallization. After 1 week the formation of crystalline material was observed; several single crystals were used for X-ray diffraction analysis (for details of the X-ray diffraction study see below). The rest of the crystalline fraction was separated from the solution, washed with n-heptane, and dried under vacuum. Anal. Calcd for [(PhSiO 1.5 ) 10 (CuO) 6 (HO 0.5 ) 2 (C 10 H 8 N 2 ) 2 ]: Cu, 18.16; N, 2.67; Si, 13.38. Found (for vacuum-dried sample): Cu, 18.10; N, 2.59; Si, 13.29. Yield: 0.28 g (48%).

Complex 7. A 1 g portion (5.04 mmol) of PhSi(OMe) 3 , 0.20 g (5 mmol) of NaOH, and 20 mL of an ethanol/methanol (1/1) mixture were placed in a three-neck round-bottom flask (equipped with magnetic stirrer and condenser). The resulting solution was heated under reflux for 1.5 h and then was cooled to room temperature, and 0.226 g (1.68 mmol) of CuCl 2 was added at once. The mixture was stirred for 3 h and filtered from NaCl. The filtrate was dried under vacuum, and then 0.131 g (0.839 mmol) of 2,2′-bipyridine in 35 mL of a toluene/DMSO mixture (3/1) was placed in the same evaporation flask. The resulting solution was intensely stirred for 2.5 h with a magnetic stirrer and then filtered from the insoluble precipitate. The filtrate was stored in a vial equipped with a septum with a needle to allow the slow evaporation of solvents for crystallization. After 1 week the formation of crystalline material was observed; several single crystals were used for X-ray diffraction analysis (for details of the X-ray diffraction study see below). The rest of the crystalline fraction was separated from the solution, washed with n-heptane, and dried under vacuum. Anal. Calcd for [(PhSiO 1.5 ) 10 (CuO) 6 (HO 0.5 ) 2 (C 10 H 8 N 2 ) 3 ]: Cu, 16.90; N, 3.73; Si, 12.45. Found (for vacuum-dried sample): Cu, 16.81; N, 3.68; Si, 12.37. Yield: 0.08 g (12%).

Complex 8. A 1 g portion (5.04 mmol) of PhSi(OMe) 3 , 0.20 g (5 mmol) of NaOH, and 20 mL of an ethanol/methanol (1/1) mixture were placed in a three-neck round-bottom flask (equipped with magnetic stirrer and condenser). The resulting solution was heated under reflux for 1.5 h and then was cooled to room temperature, and 0.226 g (1.68 mmol) of CuCl 2 was added at once. The mixture was stirred for 3 h and then mixed with 0.131 g (0.839 mmol) of 2,2′-bipyridine (solution in 35 mL of THF). The resulting solution was intensely stirred for 2.5 h with a magnetic stirrer and then filtered from the insoluble precipitate. The filtrate was stored in a vial equipped with a septum with a needle to allow the slow evaporation of solvents for crystallization. After 1 week the formation of crystalline material was observed; several single crystals were used for X-ray diffraction analysis (for details of the X-ray diffraction study see below). The rest of the crystalline fraction was separated from the solution, washed with n-heptane, and dried under vacuum. Anal. Calcd for [(PhSiO 1.5 ) 10 (CuO) 6 (CH 3 O 0.5 ) 2 (C 10 H 8 N 2 ) 2 ]: Cu, 17.92; N, 2.63; Si, 13.20. Found (for vacuum-dried sample): Cu, 18.10; N, 2.59; Si, 13.29. Yield: 0.16 g (27%).

Complex 9. A 1 g portion (5.04 mmol) of PhSi(OMe) 3 , 0.20 g (5 mmol) of NaOH, and 20 mL of an ethanol/methanol (1/1) mixture were placed in a three-neck round-bottom flask (equipped with a magnetic stirrer and condenser). The resulting solution was heated under reflux for 1.5 h and then was cooled to room temperature, and 0.226 g (1.68 mmol) of CuCl 2 was added at once. The mixture was stirred for 3 h and then mixed with 0.131 g (0.839 mmol) of 2,2′-bipyridine (solution in 35 mL of MeCN). The resulting solution was intensely stirred for 2.5 h with a magnetic stirrer and then filtered from the insoluble precipitate. The filtrate was stored in a vial equipped with a septum with a needle to allow the slow evaporation of solvents for crystallization. After 1 week the formation of crystalline material was observed; several single crystals were used for X-ray diffraction analysis (for details of the X-ray diffraction study see below). The rest of the crystalline fraction was separated from the solution, washed with n-heptane, and dried under vacuum. Anal. Calcd for [(PhSiO 1.5 ) 10 (CuO) 6 (CH 3 COO 0.5 ) 2 (C 10 H 8 N 2 ) 2 ]: Cu, 17.46; N, 2.57; Si, 12.86. Found (for vacuum-dried sample): Cu, 17.37; N, 2.49; Si, 12.77. Yield: 0.15 g (25%).

Complex 10. A 1 g portion (5.04 mmol) of PhSi(OMe) 3 , 0.20 g (5 mmol) of NaOH, and 20 mL of an ethanol/methanol (1/1) mixture were placed in a three-neck round-bottom flask (equipped with a magnetic stirrer and condenser). The resulting solution was heated under reflux for 1.5 h and then was cooled to room temperature, and 0.226 g (1.68 mmol) of CuCl 2 was added at once. The mixture was stirred for 3 h and filtered from NaCl. The filtrate was dried under vacuum, and then 0.151 g (0.840 mmol) of 1,10-phenanthroline in 35 mL of DMSO was placed in the same evaporation flask. The resulting solution was intensely stirred for 2.5 h with a magnetic stirrer and then filtered from the insoluble precipitate. The filtrate was stored in a vial equipped with a septum with a needle to allow the slow evaporation of solvents for crystallization. After 1 week the formation of crystalline material was observed; several single crystals were used for X-ray diffraction analysis (for details of the X-ray diffraction study see below). The rest of the crystalline fraction was separated from the solution, washed with n-heptane, and dried under vacuum. Anal. Calcd for [(PhSiO 1.5 ) 10 (CuO) 6 (HO 0.5 ) 2 (C 12 H 8 N 2 ) 2 ]: Cu, 17.75; N, 2.61; Si, 13.08. Found (for vacuum-dried sample): Cu, 17.64; N, 2.53; Si, 12.99. Yield: 0.39 g (65%).

Complex 11. A 1 g portion (5.04 mmol) of PhSi(OMe) 3 , 0.20 g (5 mmol) of NaOH, and 20 mL of an ethanol/methanol (1/1) mixture were placed in a three-neck round-bottom flask (equipped with a magnetic stirrer and condenser). The resulting solution was heated under reflux for 1.5 h and then was cooled to room temperature, and 0.226 g (1.68 mmol) of CuCl 2 was added at once. The mixture was stirred for 3 h and filtered from NaCl. The filtrate was dried under vacuum, and then 0.151 g (0.840 mmol) of 1,10-phenanthroline in 35 mL of toluene was placed in the same evaporation flask. The resulting solution was intensely stirred for 2.5 h with a magnetic stirrer and then filtered from the insoluble precipitate. The filtrate was stored in a vial equipped with a septum with a needle to allow the slow evaporation of solvents for crystallization. After 1 week the formation of crystalline material was observed; several single crystals were used for X-ray diffraction analysis (for details of the X-ray diffraction study see below). The rest of the crystalline fraction was separated from the solution, washed with n-heptane, and dried under vacuum. Anal. Calcd for [(PhSiO 1.5 ) 10 (CuO) 6 (HO 0.5 ) 2 (C 12 H 8 N 2 ) 2 ]: Cu, 17.75; N, 2.61; Si, 13.08. Found (for vacuum-dried sample): Cu, 17.66; N, 2.54; Si, 12.99. Yield: 0.22 g (37%).

Complex 12. A 1 g portion (5.04 mmol) of PhSi(OMe) 3 , 0.20 g (5 mmol) of NaOH, and 20 mL of an ethanol/methanol (1/1) mixture were placed in a three-neck round-bottom flask (equipped with a magnetic stirrer and condenser). The resulting solution was heated under reflux for 1.5 h and then was cooled to room temperature, and 0.226 g (1.68 mmol) of CuCl 2 was added at once. The mixture was stirred for 3 h and filtered from NaCl. The filtrate was dried under vacuum, and then 0.151 g (0.840 mmol) of 1,10-phenanthroline in 35 mL of DMF was placed in the same evaporation flask. The resulting solution was intensely stirred for 2.5 h with a magnetic stirrer and then filtered from the insoluble precipitate. The filtrate was stored in a vial equipped with a septum with a needle to allow the slow evaporation of solvents for crystallization. After 1 week the formation of crystalline material was observed; several single crystals were used for X-ray diffraction analysis (for details of the X-ray diffraction study see below). The rest of the crystalline fraction was separated from the solution, washed with n-heptane, and dried under vacuum. Anal. Calcd for [(PhSiO 1.5 ) 10 (CuO) 6 (HO 0.5 ) 2 (C 12 H 8 N 2 ) 2 ]: Cu, 17.75; N, 2.61; Si, 13.08. Found (for vacuum-dried sample): Cu, 17.68; N, 2.54; Si, 13.00. Yield: 0.28 g (47%).

Complex 13. A 1 g portion (5.04 mmol) of PhSi(OMe) 3 , 0.20 g (5 mmol) of NaOH, and 20 mL of an ethanol/methanol (1/1) mixture were placed in a three-neck round-bottom flask (equipped with a magnetic stirrer and condenser). The resulting solution was heated under reflux for 1.5 h and then was cooled to room temperature ,and 0.226 g (1.68 mmol) of CuCl 2 was added at once. The mixture was stirred for 3 h and then mixed with 0.151 g (0.840 mmol) of 1,10-phenanthroline (solution in 35 mL of pyridine). The resulting solution was intensely stirred for 2.5 h with a magnetic stirrer and then filtered from the insoluble precipitate. The filtrate was stored in a vial equipped with a septum with a needle to allow the slow evaporation of solvents for crystallization. After 1 week the formation of crystalline material was observed; several single crystals were used for X-ray diffraction analysis (for details of the X-ray diffraction study see below). The rest of the crystalline fraction was separated from the solution, washed with n-heptane, and dried under vacuum. Anal. Calcd for [(PhSiO 1.5 ) 10 (CuO) 6 (HO 0.5 ) 2 (C 12 H 8 N 2 ) 2 ]: Cu, 17.75; N, 2.61; Si, 13.08. Found (for vacuum-dried sample): Cu, 17.66; N, 2.52; Si, 12.99. Yield: 0.18 g (31%).

Complex 14. A 1 g portion (5.04 mmol) of PhSi(OMe) 3 , 0.20 g (5 mmol) of NaOH, and 20 mL of an ethanol/methanol (1/1) mixture were placed in a three-neck round-bottom flask (equipped with a magnetic stirrer and condenser). The resulting solution was heated under reflux for 1.5 h and then was cooled to room temperature, and 0.226 g (1.68 mmol) of CuCl 2 was added at once. The mixture was stirred for 3 h and filtered from NaCl. The filtrate was dried under vacuum, and then 0.065 g (0.420 mmol) of 2,2′-bipyridine and 0.076 g (0.420 mmol) of 1,10-phenanthroline (solution in 35 mL of DMF) was placed in the same evaporation flask. The resulting solution was intensely stirred for 2.5 h with a magnetic stirrer and then filtered from the insoluble precipitate. The filtrate was stored in a vial equipped with a septum with a needle to allow the slow evaporation of solvents for crystallization. After 1 week the formation of crystalline material was observed; several single crystals were used for X-ray diffraction analysis (for details of the X-ray diffraction study see below). The rest of the crystalline fraction was separated from the solution, washed with n-heptane, and dried under vacuum. Anal. Calcd for [(PhSiO 1.5 ) 10 (CuO) 6 (CH 3 COO 0.5 ) 2 (C 12 H 8 N 2 )(C 10 H 8 N 2 )]: Cu, 17.27; N, 2.54; Si, 12.72. Found (for vacuum-dried sample): Cu, 17.20; N, 2.47; Si, 12.67. Yield: 0.19 g (31%).

Complex 15. A 1 g portion (5.04 mmol) of PhSi(OMe) 3 , 0.20 g (5 mmol) of NaOH, and 20 mL of an ethanol/methanol (1/1) mixture were placed in a three-neck round-bottom flask (equipped with a magnetic stirrer and condenser). The resulting solution was heated under reflux for 1.5 h and then was cooled to room temperature, and 0.226 g (1.68 mmol) of CuCl 2 was added at once. The mixture was stirred for 3 h and filtered from NaCl. The filtrate was dried under vacuum, and then 0.280 g (0.840 mmol) of bathophenanthroline (solution in 35 mL of MeCN) was placed in the same evaporation flask. The resulting solution was intensely stirred for 2.5 h with a magnetic stirrer and then filtered from the insoluble precipitate. The filtrate was stored in a vial equipped with a septum with a needle to allow the slow evaporation of solvents for crystallization. After 1 week the formation of crystalline material was observed; several single crystals were used for X-ray diffraction analysis (for details of the X-ray diffraction study see below). The rest of the crystalline fraction was separated from the solution, washed with n-heptane, and dried under vacuum. Anal. Calcd for [(PhSiO 1.5 ) 10 (CuO) 6 (HO 0.5 ) 2 (C 24 H 16 N 2 ) 2 ]: Cu, 15.55; N, 2.28; Si, 11.45. Found (for vacuum-dried sample): Cu, 15.48; N, 2.20; Si, 11.36. Yield: 0.28 g (41%).

Complex 16. A 1 g portion (5.04 mmol) of PhSi(OMe) 3 , 0.20 g (5 mmol) of NaOH, and 20 mL of an ethanol/methanol (1/1) mixture were placed in a three-neck round-bottom flask (equipped with a magnetic stirrer and condenser). The resulting solution was heated under reflux for 1.5 h and then was cooled to room temperature, and 0.226 g (1.68 mmol) of CuCl 2 was added at once. The mixture was stirred for 3 h and filtered from NaCl. The filtrate was dried under vacuum, and then 0.280 g (0.840 mmol) of bathophenanthroline (solution in 35 mL of toluene) was placed in the same evaporation flask. The resulting solution was intensely stirred for 2.5 h with a magnetic stirrer and then filtered from the insoluble precipitate. The filtrate was stored in a vial equipped with a septum with a needle to allow the slow evaporation of solvents for crystallization. After 1 week the formation of crystalline material was observed; several single crystals were used for X-ray diffraction analysis (for details of the X-ray diffraction study see below). The rest of the crystalline fraction was separated from the solution, washed with n-heptane, and dried under vacuum. Anal. Calcd for [(PhSiO 1.5 ) 10 (CuO) 6 (HO 0.5 ) 2 (C 24 H 16 N 2 ) 2 ]: Cu, 15.55; N, 2.28; Si, 11.45. Found (for vacuum-dried sample): Cu, 15.47; N, 2.19; Si, 11.36. Yield: 0.21 g (30%).

Complex 17. A 1 g portion (5.04 mmol) of PhSi(OMe) 3 , 0.20 g (5 mmol) of NaOH, and 20 mL of an ethanol/methanol (1/1) mixture were placed in a three-neck round-bottom flask (equipped with a magnetic stirrer and condenser). The resulting solution was heated under reflux for 1.5 h and then was cooled to room temperature, and 0.226 g (1.68 mmol) of CuCl 2 was added at once. The mixture was stirred for 3 h and then mixed with 0.280 g (0.840 mmol) of bathophenanthroline (solution in 35 mL of benzene). The resulting solution was intensely stirred for 2.5 h with a magnetic stirrer and then filtered from the insoluble precipitate. The filtrate was stored in a vial equipped with a septum with a needle to allow the slow evaporation of solvents for crystallization. After 1 week the formation of crystalline material was observed; several single crystals were used for X-ray diffraction analysis (for details of the X-ray diffraction study see below). The rest of the crystalline fraction was separated from the solution, washed with n-heptane, and dried under vacuum. Anal. Calcd for [(PhSiO 1.5 ) 10 (CuO) 6 (HO 0.5 ) 2 (C 24 H 16 N 2 ) 2 ]: Cu, 15.55; N, 2.28; Si, 11.45. Found (for vacuum-dried sample): Cu, 15.48; N, 2.18; Si, 11.34. Yield: 0.15 g (22%).

IR spectra were recorded on a Shimadzu IR Prestige21 FTIR spectrometer in KBr pellets. UV-vis absorption spectra were recorded on a Varian Cary 50 spectrophotometer in a cell with 10 mm optical path length.

X-ray Crystal Structure Determination. X-ray diffraction data for 1, 4, 6-9, 11, 12, 14, 16, and 17 were collected on the "Belok" beamline of the National Research Center "Kurchatov Institute" (Moscow, Russian Federation) using a Rayonix SX165 CCD detector. A total of 720 images were collected using an oscillation range of 1.0°and φ scan mode and corrected for absorption using the Scala program. 33a The data were indexed, integrated, and scaled using the utility iMOSFLM in the CCP4 program. 33b X-ray diffraction data for 2, 3, 5, 10, 13, and 15 were collected on a three-circle Bruker APEX-II CCD diffractometer (graphite monochromator, φ and ω scan mode) and corrected for absorption using the SADABS program. 33c The data were indexed and integrated using the SAINT program. 33d For details, see Table S1 in the Supporting Information. The structures were determined by direct methods and refined by full-matrix least-squares techniques on F 2 with anisotropic displacement parameters for non-hydrogen atoms. In the case of 7, 8, 10, 11, 16, and 17, all attempts to model and refine positions of the solvate molecules were unsuccessful. Therefore, their contribution to the total scattering pattern was removed by use of the utility SQUEEZE in PLATON06 33e or the Solvent mask procedure in the Olex2 program. The hydrogen atoms of the OH groups as well as the water and acetonitrile solvate molecules were localized in the difference Fourier map and included in the refinement within the riding model with fixed isotropic displacement parameters. The other hydrogen atoms were placed in calculated positions and refined within the riding model with fixed isotropic displacement parameters (U iso (H) = 1.5U eq (C) for the CH 3 groups and 1.2U eq (C) for the other groups). All calculations were carried out using the SHELXTL 33f and Olex2 33g programs. Crystallographic data for 1-17 have been deposited with the Cambridge Crystallographic Data Center as files CCDC 1565028-1565032, 1565113-1565124.

Oxidation of Alcohols to Amides. All reagents were purchased from Aldrich Chemical Co., Fluka, and Alfa Aesar and used without further purification. Analyses were performed at the "Plateforme Technologique Laboratoire de Mesures Physiques" (IBMM, Universited e Montpellier). 1 H NMR spectra were recorded on a Bruker Avance DPX 400 MHz spectrometer. Chemical shifts are reported in ppm and referenced to the solvent peak (CDCl 3 at 7.26 ppm). Data are reported as follows: s = singlet, d = doublet, t = triplet, q = quadruplet, qt = quintuplet, sept = septuplet, m = multiplet; coupling constant in Hz; integration. 13 C NMR spectra were recorded on a Bruker Avance AM 100 MHz spectrometer. Chemical shifts are reported in ppm and referenced to the solvent peak (CDCl 3 at 77.16 ppm).

General Procedure for the Formation of Amides. In a sealed tube were added successively amine hydrochloride (0.5 mmol), CaCO 3 (50.1 mg, 0.5 mmol), CH 3 CN (1 mL), 1 (20 μL of a solution of 1.8 mg of 1 in 2 mL of CH 2 Cl 2 ) or 10 (40 μL of a solution of 1.7 mg of 10 in 4 mL of CHCl 3 ), benzylic alcohol (105 μL, 1.0 mmol), and TBHP (5.5 M in nonane, 225 μL, 1.25 mmol). The mixture was stirred at 80 °C for 2 h, and TBHP (5.5 M in nonane, 225 μL, 1.25 mmol) was again added to the mixture. After 16-22 h at 80 °C, the mixture was cooled to room temperature and 1 N HCl and EtOAc were added. The mixture was extracted twice with EtOAc, and the combined organic phases were washed with a saturated solution of NaHCO 3 and brine and concentrated under reduced pressure. To remove the excess of benzylic alcohol, 80 mL of H 2 O was added and evaporated under reduced pressure. The crude product was then purified using silica gel chromatography with gradients of cyclohexane/EtOAc to yield the pure compounds.

Oxidation of Alcohols to Ketones. The substrate was added to the reaction solution, and the process was started when the oxidant was introduced in one portion. The reactions of alcohols were carried out in air in thermostated Pyrex cylindrical vessels with vigorous stirring and using MeCN as solvent. Concentrations of products obtained in the oxidation of 1-phenylethanol after certain time intervals were measured using 1 H NMR methods (solutions in acetone-d 6 ; Bruker AMX-400 instrument, 400 MHz). In the oxidation of cyclohexanol, concentrations of the substrate and products were measured by GC.

Oxidation of Alkanes. Catalysts 1, 10, and 15 were introduced into the reaction mixture in the form of solid powder. The alkane was then added, and the reaction was started when hydrogen peroxide was introduced in one portion. (Caution! The combination of air or molecular oxygen and H 2 O 2 with organic compounds at elevated temperatures may be explosive!). The reactions after addition of nitromethane as a standard compound were analyzed by GC. As we had done previously, the samples obtained in the alkane oxidation were typically analyzed twice (before and after their treatment with PPh 3 ) by GC (Model 3700 chromatograph; fused silica capillary column FFAP/ OV-101 20/80 w/w, 30 m × 0.2 μm × 0.3 μm; argon as a carrier gas). This method (the comparison of chromatograms of the same sample obtained before and after addition of PPh 3 ) which was proposed by Shul'pin earlier [START_REF] Shul'pin | Hydroperoxidation of alkanes by atmospheric oxygen in the presence of hydroquinone or quinone catalyzed by copper(II) acetate under visible light irradiation[END_REF] allows us to estimate the real concentration of alkyl hydroperoxide, ketone (aldehyde) and alcohol present in the reaction solution. Attribution of peaks was made by comparison with chromatograms of authentic samples and by GC-MS. In our kinetic studies described below, we measured concentrations of cyclohexanone and cyclohexanol only after reduction of the reaction mixture with PPh 3 because in this case we measured the precise concentration of a sum of the oxygenates. Blank experiments with cyclohexane showed that in the absence of a catalyst products were formed in negligible concentrations.

■ RESULTS AND DISCUSSION

Synthesis and Structures of the Complexes. A two-stage scheme of synthesis of complexes of Cu(II) phenylsilsesquioxanes with bidentate N ligands was applied. In the first step of the reaction an interaction of the phenyltrialkoxysilane PhSi(OMe) 3 with sodium hydroxide (NaOH) in alcohol solution occurs. According to previous results, 6a,f this reaction leads to the formation of highly reactive sodium siloxanolate species. No doubt, an investigation of such alkali-metal-based species is an interesting scientific topic by itself. 35 Nevertheless, in the context of cage metallasilsesquioxane assembly, an elucidation of the sodium siloxanolate structure in this work seemed for us to be not very essential. In several works by us 35a,m and others 35i,k,l,n,p,r it has been established that such siloxanolates tend to form tri-or tetrameric cyclic structures in the crystal phase. In turn, the corresponding trimeric silsesquioxane cycles were never observed in the composition of arised CLMSs, while tetrameric cycles remain an extremely rare type of CLMS ligand. 6g Thus, we focus on the second stage of the synthetic schemethe in situ interaction of presumably formed sodium siloxanolate [(PhSiO 1.5 )(NaO 0.5 )] n with CuCl 2 in the presence of 2,2′-bipyridine in different solvent media. It was found that, despite changes in the reaction regime, the synthesis gives rise to a family of only hexacopper complexes 1-9 (Figure 1). These products are characterized by the presence of analogous central frameworks, with two cisoid silsesquioxane rings [(PhSiO 1.5 ) 5 ] forming a skewed sandwich cage.

Symptomatically, each of the complexes 1-9 contains six Cu 2+ ions, giving 12 positive charges. Two pentameric silsesquioxane ligands donate 10 negative charges. Two extra negative charge carriers are hydroxide, methoxide, and acetate anions (for 1-7, 8, and 9, respectively). The formation of some of these anions deserves to be discussed. The appearance of methoxy groups in 8 could be easily explained by the methanol-containing media of synthesis. The formation of acetate groups in 9 is not so evident. Similarly to copper methylsilsesquioxanes from ref 30, we could suggest the possible mechanism of homogeneous oxidation of ethanol (in the presence of copper ions), giving rise to the acetate groups (Figure 2). This transformation could be compared to the process mentioned earlier by Rudakov and co-workers 36a as well as Sakharov and Skibida: 36b namely, the oxidations of primary alcohols directly to the corresponding carboxylic acids in aqueous alkaline solutions catalyzed by copper phenanthroline complexes.

Another attractive feature of complex 9 in comparison to compounds 1-8 is "a flipping" of charged (HO -, CH 3 COO -, CH 3 O -) and neutral (DMSO, MeCN, THF, PhCN, H 2 O) ligands. Namely, in the case of compounds 1-8 the "charge balancing" groups (HO -or CH 3 O -) directly coordinate Cu(II) ions (forming tight ion pairs). In case of compound 3 the positions next to Cu(II) are occupied by neutral acetonitrile molecules (Figure 3a). Anionic CH 3 COO -fragments are located in the outer sphere of the complex, forming solventseparated ion pairs (Figure 3b). We may suggest as an explanation of this fact the coordinative strength of acetonitrile (ligation factor) acting along with the bulkiness of phenyl and acetate groups (steric factor). For the methyl-based hexacopper complexes from ref 30 such "flipping" was not detected.

In turn, we would like to mention several features of products 5, 7, and 8 in the context of their solvate surroundings. The presence of benzonitrile ligands in the composition of 5 allows us to observe a specific "triple π-π aromatic connection" including a phenyl group (at the silicon atom)-bipy-benzonitrile (Figure 4). It is of note that another benzonitrile-containing compound (benzonitrile/water complex 4) does not reveal such a stacking.

In turn, features of CLMSs 8 and 9 are as follows. It is known that CLMSs often form solvates with different organic solvents. Surprisingly, compound 8 contains no solvate molecules at all, while water molecules are the only solvating ligands in compound 7. This is also a quite rare feature among known CLMSs; we could cite only the Cu 2 Na 2 CLMS reported very recently. [START_REF] Bilyachenko | Bi-and Tri-metallic Cage Silsesquioxanes: Features of Supramolecular Assembling and Magnetic Properties[END_REF] Note that compound 7 contains (in addition to two 2,2′-bipyridines at copper ions) one extra uncoordinated 2,2′-bipyridine.

At the second stage of the synthetic work similar self-assembly reactions but in the presence of phenanthroline have been studied. These yielded (Figure 5) the four hexacopper complexes 10-13 with a molecular architecture similar to that of the aforementioned compounds 1-9.

For all compounds 10-13 the charge compensation is achieved by the presence of HO -groups exclusively (unlike the "anion diversity" mentioned for products 1-9). In addition, products 10-13 could be easily distinguished from compounds 1-9 by their tendency toward π-π stacking interactions of aromatic systems of the phenanthroline ligands. While 2,2′-bipyridinebased compounds 1-9 show no affinity for the "ligand to ligand" packing, products 10 (solvated by DMSO) and 11 (containing no solvates) pack in the crystal to form a ladderlike motif (Figure 6). In turn, compounds 12 and 13 (DMF and pyridine solvates, correspondingly) crystallize in an islandlike structure. This points to a possible important role of solvate molecules for the formation/cleavage of the packing. We will try to shed some light on this intriguing situation in our future reports. Corresponding investigations on CLMS structure formation assisted by ligands of other types (not just of bipy family) are currently in progress iby our team.

It is interesting that our efforts in similar self-assembly reactions with both 2,2′-bipyridine and phenanthroline simultaneously present in the reaction mixture resulted in the formation of complex 14 (Figure 7a). One could expect the formation of a product with alternating 2,2′-bipyridine-and phenanthrolinecontaining CLMSs in the crystal. In reality, 14 includes both types of ligands statistically disordered over the same structural position. Both ligands coordinate the copper ion in the same fashion as was described for compounds 1-13. It is worth noting that we succeeded in the isolation of single crystals of 14 only from a nitromethane solution. To the best of our knowledge, product 14 is the first example of a CLMS complex with nitromethane. Along with products 10 and 11, compound 14 demonstrates the ability to pack into an infinite ladder structure (Figure 7b). It is important to emphasize the presence of two "charge compensating" CH 3 COO -moieties in the composition of this complex. Unlike the case for compound 9, these groups in 14 form tight ion pairs with the copper ions. We suggest that this difference could be explained by the similarity in molecular geometries of nitromethane and acetate anion (∠ONO 125.9°, ∠OCO = 129.2°). Thus, the ionic interactions could play the principal role and, indeed, acetate anions coordinate copper centers.

The self-assembly reaction approach was efficiently applied yet another time by adding bathophenanthroline to the reaction mixture. The three complexes 15-17 with the same type of molecular topology as described for compounds 1-14 were obtained (with OH -groups as charge balancers, Figure 8). To the best of our knowledge, complexes 15-17 are the first CLMSs containing bathophenanthroline ligands. Compounds 15-17 show no tendency to form supramolecular aggregates through packing.

As a short conclusion to the synthetic part of this work, it could be also stated that formation of one and the same type of central cage core (of Si 10 Cu 6 composition) for 17 products no doubt witnesses to the high stability of such a structural unit under conditions of the CLMS synthesis assisted by bidentate chelating ligands of the 2,2′-bipy family. An opportunity of isolation of another core, Me 8 Si 8 Cu 3 , in the case of using a methyl-substituted silane for the synthesis of the bipy derivative of Cu(II)-CLMS (ref 30) indicates the complicated character of such a type of selfassembly reaction. To some extent, such a difference could be due to steric and solubility differences for phenyl-and methylbased silsesquioxane matrixes. Further investigations of this intriguing synthetic scheme deserve significant attention and are being studied now by our team.

Catalyzed Oxidation of Alcohols to Ketones and Benzene to Phenol. Alcohols are efficiently oxidized to the corresponding ketones with TBHP in MeCN when complex 1 or 10 is used as a catalyst (Figure 9). The oxidation of 1-phenylethanol with TBHP at 50 °C catalyzed by 10 gave acetophenone in 94% yield (TON = 600) after 14 h. Figure S1 in the Supporting Information shows that aliphatic cyclohexanol is oxidized to cyclohexanone. Complex 10 exhibited moderate activity in benzene oxidation with H 2 O 2 . Thus, the reaction of benzene (0.3 M) with H 2 O 2 (50%, 3 M) in the presence of 10 (5 × 10 -4 M) and HNO 3 (0.05 M) at 60 °C afforded phenol after 2 h in 15% yield. The efficiency of complex 1 turned out to be the same: the reaction at 60 °C gave after 2 h 0.41 M (14%) of phenol and 0.008 M of p-quinone.

Catalyzed Oxidation of Alkanes with H 2 O 2 to the Corresponding Alkyl Hydroperoxides. It is noteworthy that alkanes can be oxidized [38][39][40] in acetonitrile solution to the corresponding alkyl hydroperoxides by hydrogen peroxide in air in the presence of catalytic amounts of complex 1, 10, 15 and nitric acid. The alkyl hydroperoxide is relatively stable in solution and can be easily reduced by PPh 3 to the corresponding alcohol. The chromatogram obtained after reduction with PPh 3 is distinguished from the chromatogram obtained for an unreduced sample (compare graphs A and B in Figure 10), which indicates that cyclohexyl hydroperoxide is formed in the process. [START_REF] Shul'pin | Hydroperoxidation of alkanes by atmospheric oxygen in the presence of hydroquinone or quinone catalyzed by copper(II) acetate under visible light irradiation[END_REF] The reaction proceeds not only at 60 °C (Figure 10) but also at 20 °C (Figure S2 in the Supporting Information). Regioselectivity parameters in the oxidation of n-heptane catalyzed by complex 1 are collected in Table 1. The oxidation of cis-1,2-dimethylcyclohexane with H 2 O 2 occurs without retention of configuration (the trans/cis ratio was in the Supporting Information. All of these peculiarities indicate that the oxidation with H 2 O 2 occurs with the participation of free hydroxyl radicals. [START_REF] Voigt | Organic-Soluble Neutral and Ionic Indium Siloxane Cages: Potential Precursors for Indium-Containing Silicates[END_REF] Catalyzed Oxidation of Alcohols to Amides. Complexes 1 and 10 were also evaluated in the oxidative amidation of alcohols (Table 2). This reaction, initially developed using copper, [START_REF] Bantreil | Copper-Catalyzed Direct Synthesis of Benzamides from Alcohols and Amines[END_REF] iron, 42 and zinc salts, [START_REF] Wu | The First ZnII-Catalyzed Oxidative Amidation of Benzyl Alcohols with Amines under Solvent-Free Conditions[END_REF] proved to be highly efficient when copper silsesquioxanes were used, with catalyst loadings down to 100 ppm of copper. 18a,19 This represents a good alternative to methodologies using expensive ruthenium [START_REF] Gunanathan | Direct synthesis of amides from alcohols and amines with liberation of H2[END_REF] and rhodium catalysts. 45 Thus, benzyl alcohol was reacted with several amines, protected as their ammonium salts, in the presence of catalytic quantities of 1 or 10 and TBHP as oxidant. Calcium carbonate, with a high purity of 99.995% to avoid any metallic contamination, was also added to slowly deprotonate the ammonium. As demonstrated in Figure 11, oxidation of benzylic alcohol in the presence of α-methylbenzylamine and catalyst 1 produced, in addition to the expected benzamide 19, benzaldehyde and benzoic acid as side products:

Interestingly, the proportion of benzaldehyde reached a maximum after 2 h and then slowly decreased as the quantity of benzamide and benzoic acid increased. After 24 h of reaction, benzylic alcohol was converted at 60% into benzamide, 24% into acid, and 6% into benzaldehyde. This kinetic plot also shows that it is necessary to use an excess of alcohol in this reaction, since the formation of benzoic acid is difficult to avoid under the reaction conditions.

Even though compounds 1 and 10 have a unique structure, their catalytic activities in the oxidative amidation were found to be similar, giving secondary and tertiary amides 19-24 in 59-86% yields (Table 2). As observed previously with other cagelike compounds, it was found possible to work with as low as 100 ppm of copper in this reaction without affecting the yields. Moreover, turnover number (TON) and frequency (TOF) values up to 8600 and 478 h -1 could be obtained, respectively, which is significantly better than the 44 and 11 h -1 values obtained in the initial report with CuO as catalyst. [START_REF] Nehete | Polyhedral Ferrous and Ferric Siloxanes[END_REF] Discussion on Precatalyst Transformations. In order to study the possible structural transformation of the catalyst under catalytic act conditions, we were interested in additional studies. To simulate the catalytic act of C-H compound oxidation, we performed the following experiments. Successive measurements of UV-vis spectra (for example of compound 1) were made for (i) 1′ acetonitrile solution, (ii) this solution with nitric acid additive, and finally (iii) the solution with hydrogen peroxide additive. These activities provoked no significant changes in spectra (see the Supporting Information), which is not surprising, bearing in mind the results of UV-vis experiments presented recently by some of us for Fe(III) silsesquioxane. 18b Thus, we may conclude that compound 1 could undergo some structural modification during the catalytic reaction but total decomposition of cage structure did not occur.

■ CONCLUSION

An extended series of 17 new complexes were found to be easily available through the self-assembly reaction of in situ generated sodium phenylsiloxanolate and copper(II) chloride in the presence of four types of nitrogen-based ligands: 2,2′-bipyridine (compounds 1-9), 1,10-phenanthroline (compounds 10-13), 1,10-phenanthroline/2,2′-bipyridine (compound 14), and bathophenanthroline (compounds 15-17). As was established by single-crystal X-ray diffraction, compounds 1-17 all belong to the same type of molecular topology despite the difference in the N-ligand chemical nature. That no doubt points at the high stability of such "major" type (Si 10 Cu 6 ) of cluster under conditions of copper(II) phenylsilsesquioxane synthesis, assisted by ligands of the bipy family. This fascinating molecular cage can be described as a metal oxide (CuO) 6 layer sandwiched by two pentagonal phenylsiloxanolate [PhSiO 1.5 ] 5 ligands. Two opposite copper ions are additionally coordinated by the nitrogen atoms of the corresponding ligand and oxygen atom of hydroxy (compounds 1-7, 10-13, 15-17), methoxy (compound 8), or acetoxy groups (compounds 9 and 14). The formation of acetoxy fragments most likely may be explained by homogeneous oxidation of ethanol (reaction medium) in the presence of copper centers.

Complexes 1, 10, and 15 efficiently catalyze oxidation of alcohols to ketones with TBHP and of alkanes to alkyl hydroperoxides with H 2 O 2 in acetonitrile. The oxidation of alcohols apparently involves the generation of hydroxyl radicals. Complexes 1 and 10 catalyzed the amidation of benzyl alcohols with low catalyst loading and high turnover.

■ ASSOCIATED CONTENT * S Supporting Information

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.7b02320.

Details of X-ray experiments and catalytic oxidations (PDF)

Figure 1 .

 1 Figure 1. General scheme of synthesis of hexacoppersilsesquioxanes 1-9 containing 2,2′-bipyridine ligands. Color code: Si, yellow; O, red; C, black; H, gray; Cu, green; N, blue.

Figure 2 .

 2 Figure 2. Presumable scheme of oxidation of a primary alcohol directly to the corresponding carboxylic acid.

Figure 3 .

 3 Figure 3. "Acetonitrile to copper" coordination in complex 9: (a) van der Waals radii given to show the steric limitations; (b) molecular structure of complex 9. Color code: Si, yellow; O, red; C, dark gray; H, light gray; Cu, green; N, blue.

Figure 4 .

 4 Figure 4. Triple π-π aromatic stacking (phenyl group-bipy-benzonitrile) interactions in complex 5. Color code: Si, yellow; O, red; C, gray; Cu, green; N, blue.

Figure 5 .

 5 Figure 5. General scheme of synthesis of hexacoppersilsesquioxanes 10-13 containing 1,10-phenanthroline ligands. Color code: Si, yellow; O, red; H, white; Cu, green; N, blue.

Figure 6 .

 6 Figure 6. π-π aromatic stacking ("phenanthroline to phenanthroline") in complex 11. Color code: Si, yellow; O, red; Cu, green; N, blue.

Figure 7 .

 7 Figure 7. (a) General scheme of synthesis of hexacoppersilsesquioxane containing 1,10-phenanthroline and 2,2′-bipyridine ligands 14. (b) π-π aromatic stacking ("phenanthroline to bipyridine") in complex 14. Color code: Si, yellow; O, red; C, black; Cu, green; N, blue.

Figure 8 .

 8 Figure 8. General scheme of synthesis of hexacoppersilsesquioxanes 15-17 containing bathophenanthroline ligands. Color code: Si, yellow; O, red; C, black; Cu, green; N, blue.

Figure 9 .

 9 Figure9. Accumulation of acetophenone with time in the oxidation of 1-phenylethanol (initial concentration was 0.33 M) with TBHP (70% aqueous; initial concentration 1.2 M) catalyzed by compounds 10 (5 × 10 -4 M, curve 1) and 1 (5 × 10 -4 M, curve 2; curve 2a, in the presence of 0.05 M of HNO 3 ). The solvent was acetonitrile (total volume of the reaction solution was 5 mL), and the temperature was 50 °C.

Figure 10 .

 10 Figure 10. Oxidation of cyclohexane (0.46 M) with H 2 O 2 (50%, 3 M) catalyzed by complex 10 (5 × 10 -4 M) in the presence of HNO 3 (0.05 M) at 60 °C. Concentrations of cyclohexanol (curves 1) and cyclohexanone (curves 2) were measured both before and after reduction with PPh 3 .

a

  The selectivity parameter in the n-heptane oxidation C(1):C(2): C(3):C(4) denotes reactivities of the H atoms at carbons 1-4 (relative to the reactivity of hydrogens at carbon 1) of the n-heptane chain, which are normalized by taking into account the number of hydrogen atoms at each carbon.

aa

  Reaction conditions: amine•HCl (0.5 mmol), benzyl alcohol (1.0 mmol), CaCO 3 (99.995% pure; 0.5 mmol), TBHP (5.5 M in nonane, 2.5 mmol), 1 or 10 (100 ppm of Cu), CH 3 CN (1 mL), 80 °C, 24 h. Isolated yields are given. b TON = (mmol of product)/(mmol of Cu). c TOF = TON/(reaction time); given in h -1 . 0.7 for 1 and 10 and 0.8 for 15, where trans/cis is the ratio of isomers of tert-alcohols with mutual trans and cis orientation of the methyl groups). The experiments on the methylcyclohexane oxidations are described in FiguresS3 and S4 and Tables S1-S4

Figure 11 .

 11 Figure 11. Conversion of benzylic alcohol in the oxidative amidation reaction.

Table 1 .

 1 Regioselectivity Parameters in the n-Heptane (0.46 M) Oxidation with H 2 O 2 (0.5 M) Catalyzed by Complex 10 at 60 °Ca

Table 2 .

 2 Oxidative Amidation at Low Catalyst Loading

  Accession CodesCCDC 1565028-1565032 and 1565113-1565124 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/ data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

	■ AUTHOR INFORMATION Corresponding Authors
	ORCID
	Alexey N. Bilyachenko: 0000-0003-3136-3675
	Victor N. Khrustalev: 0000-0001-8806-2975
	Xavier Bantreil: 0000-0002-2676-6851
	Elena S. Shubina: 0000-0001-8057-3703
	Notes

*E-mail for A.N.B.: bilyachenko@ineos.ac.ru. *E-mail for F.L.: frederic.lamaty@umontpellier.fr. *E-mail for G.B.S.: shulpin@chph.ras.ru.

DOI: 10.1021/acs.inorgchem.7b02320 Inorg.Chem. 2017, 56, 15026-15040

The authors declare no competing financial interest.

■ ACKNOWLEDGMENTS

The publication was prepared with the support of the "RUDN University Program 5-100", the Russian Foundation for Basic Research (Grants 16-03-00254, 17-03-00993, 16-29-05180), RFBR-CNRS project No. 16-53-150008, the CNRS (Programme de Recherche Conjoint), and the University of Montpellier. Synchrotron single-crystal diffraction measurements were performed at the unique scientific facility Kurchatov Synchrotron Radiation Source supported by the Ministry of Education and Science of the Russian Federation (project code RFME-FI61917X0007).


Christian Cilas
email: christian.cilas@cirad.fr

Philippe Bastide
email: bastide.philippe@gmail.com

Challenges to Cocoa Production in the Face of Climate Change and the Spread of Pests and Diseases

Keywords: pest and disease management, climate change, cropping system, breeding for resistance 1. Historical Trajectory of Cocoa Production

The evolution of cocoa farming was quickly confronted with the development of pests and diseases. These sanitary constraints have shaped the geographical distribution of production over the centuries. Current climate change adds an additional constraint to the plant health constraints, making the future of cocoa farming more uncertain. Climate change is not only affecting the areas where cocoa is grown for physiological reasons, particularly in relation to changes in water regimes, but also affects the distribution of pests and diseases affecting this crop. These different points are discussed in the light of the trajectories observed in the different cocoa-growing areas. The breeding programs of cocoa trees for sustainable resistance to plant health constraints and climate change are therefore particularly important challenges for cocoa farming, with the other management practices of plantations.

When the Spaniards discovered Central America and Mexico (1504-1525), cocoa had already been produced, traded and consumed there for several centuries [START_REF] Touzard | L'économie coloniale du Cacao en Amérique Centrale[END_REF]. The cocoa tree was cultivated by the Aztecs and Mayas at that time, and archaeological studies have indicated its cultivation in the region called Soconusco (southern Mexico, northern Guatemala) long before that time [START_REF] Powis | Cacao use and the San Lorenzo Olmec[END_REF]. Indeed, the first domestication of the cocoa tree would have been made by the Olmecs from 1000 BC. The Olmec civilization is considered the "mother civilization" of Mesoamerica [START_REF] Soustelle | La Plus Ancienne Civilisation du Mexique[END_REF]. Even more recent research indicates that the use of cocoa beans already existed in the upper Amazon (currently Ecuador and Peru) in 5000 BC [START_REF] Zarrillo | The use and domestication of Theobroma cacao during the mid-Holocene in the upper Amazon[END_REF]. However, the first organized plantations seem to have been carried out in the Soconusco region, sometimes with drainage and irrigation systems when rainfall was insufficient. The choice to plant cocoa trees in marginal rainfall conditions may be due to the identification of these areas as less prone to fungal diseases, such as pod rot due to various species of phytophthora. Indeed, traces of plantations date back to the centuries before the arrival of the Spanish; for example, cocoa tree fragments and drainage structures have been found at the archaeological site of Izapa in the state of Chiapas in Mexico [START_REF] Muhs | Soils and the location of cacao orchards at a Maya site in western Belize[END_REF]. Intensive plantations, with more than 1000 trees per hectare, are mentioned at the time of the conquistadors and the cocoa tree was often associated with Gliricidia sepium [START_REF] Ponce | Relacion breve y verdadera del padre Fray Alonso Ponce[END_REF].

After the discovery of this plant and the use of cocoa by Europeans, the extension of its cultivation has continued to grow. A first extension of plantations took place throughout Central America in the 16th century. Then plantations developed in South America, particularly in Colombia, Ecuador, and Venezuela towards the end of the 16th century and the 17th century; a few plantations were also established in Southeast Asia at this time. From the 19th century onwards, the cocoa tree was massively exported to other continents, mainly Asia and Africa (Figure 1). Cocoa is now cultivated in most humid tropical countries. The production cycles of the different producing countries have been described in numerous works [START_REF] Ruf | Booms et Crises du Cacao: Les Vertiges de l'or Brun; Economie et développement[END_REF][START_REF] Ruf | Libéralisation, cycles politiques et cycles du cacao: Le décalage historique Côte-d'Ivoire-Ghana[END_REF], with stages of population migration, accompanied by deforestation, plantation establishment, then more or less rapid declines caused by socio-economic reasons, but also, as we will see, by the emergence of sanitary problems.

Ecuador, and Venezuela towards the end of the 16th century and the 17th century; a few plantations were also established in Southeast Asia at this time. From the 19th century onwards, the cocoa tree was massively exported to other continents, mainly Asia and Africa (Figure 1). Cocoa is now cultivated in most humid tropical countries. The production cycles of the different producing countries have been described in numerous works [START_REF] Ruf | Booms et Crises du Cacao: Les Vertiges de l'or Brun; Economie et développement[END_REF][START_REF] Ruf | Libéralisation, cycles politiques et cycles du cacao: Le décalage historique Côte-d'Ivoire-Ghana[END_REF], with stages of population migration, accompanied by deforestation, plantation establishment, then more or less rapid declines caused by socio-economic reasons, but also, as we will see, by the emergence of sanitary problems.

Sanitary Constraints and Geographic Distribution of Main Cocoa Pests and Diseases

Difficulties in cocoa tree cultivation were reported by the first Spaniards including, in particular, black pod rot (due to Phytophthora genus) when there is too much shade [START_REF] De Pineda | Descripcion de la provincia de Guatemala[END_REF]. The health situation of cocoa trees has always been a major problem facing producers. Some pathogenic organisms, originating from the American continent, have co-evolved with the cocoa tree, while others originating from other producing continents have adapted to the cocoa tree after a host jump has occurred. A host jump means that an existing disease in a given species affects a new species that had not previously faced the disease in question.

With the expansion of cocoa cultivation to other continents, diseases that co-evolved with cocoa, such as frosty pod rot (Moniliophthora roreri) or witches' broom (Moniliophthora perniciosa), have so far spared the new producing continents. On the other hand, new diseases to which the cocoa tree had not previously been subjected have appeared (host jump), including cacao swollen shoot virus, Phytophthora megakaria in Africa, and vascular streak dieback in Asia. These diseases that have adapted to cocoa reveal the particular susceptibility of this plant species. Comparatively, the rubber tree (Hevea brasiliensis), which comes from the same area of origin, is less attacked by new diseases, although caution should be exercised in making predictions, particularly due to the influence of climate change, which influences epidemic risks [START_REF] Pautasso | Impacts of climate change on plant diseases-Opinions and trends[END_REF].

Many pests, particularly insects, have also disrupted cocoa production in many geographical areas. Some insects exist in the areas where the cocoa tree originates, such as Carmenta theobromae, which is a pod borer [START_REF] Morillo | Pupal development, longevity and behavior of Carmenta theobromae (Lepidoptera: Sesiidae)[END_REF]. Other insects have adapted to the cocoa tree, such as the cocoa tree mirids in Africa (Salhbergella singularis and Distentiella theobroma) or cocoa pod borer (Conopomorpha cramerella) in Southeast Asia. Diseases and pests have often been brakes that have limited the expansion of cocoa production in many parts of the world. The cocoa pod borer (CPB) has particularly hampered the development of cocoa production in most Asian countries. Malaysia,

Sanitary Constraints and Geographic Distribution of Main Cocoa Pests and Diseases

Difficulties in cocoa tree cultivation were reported by the first Spaniards including, in particular, black pod rot (due to Phytophthora genus) when there is too much shade [START_REF] De Pineda | Descripcion de la provincia de Guatemala[END_REF]. The health situation of cocoa trees has always been a major problem facing producers. Some pathogenic organisms, originating from the American continent, have co-evolved with the cocoa tree, while others originating from other producing continents have adapted to the cocoa tree after a host jump has occurred. A host jump means that an existing disease in a given species affects a new species that had not previously faced the disease in question.

With the expansion of cocoa cultivation to other continents, diseases that co-evolved with cocoa, such as frosty pod rot (Moniliophthora roreri) or witches' broom (Moniliophthora perniciosa), have so far spared the new producing continents. On the other hand, new diseases to which the cocoa tree had not previously been subjected have appeared (host jump), including cacao swollen shoot virus, Phytophthora megakaria in Africa, and vascular streak dieback in Asia. These diseases that have adapted to cocoa reveal the particular susceptibility of this plant species. Comparatively, the rubber tree (Hevea brasiliensis), which comes from the same area of origin, is less attacked by new diseases, although caution should be exercised in making predictions, particularly due to the influence of climate change, which influences epidemic risks [START_REF] Pautasso | Impacts of climate change on plant diseases-Opinions and trends[END_REF].

Many pests, particularly insects, have also disrupted cocoa production in many geographical areas. Some insects exist in the areas where the cocoa tree originates, such as Carmenta theobromae, which is a pod borer [START_REF] Morillo | Pupal development, longevity and behavior of Carmenta theobromae (Lepidoptera: Sesiidae)[END_REF]. Other insects have adapted to the cocoa tree, such as the cocoa tree mirids in Africa (Salhbergella singularis and Distentiella theobroma) or cocoa pod borer (Conopomorpha cramerella) in Southeast Asia. Diseases and pests have often been brakes that have limited the expansion of cocoa production in many parts of the world. The cocoa pod borer (CPB) has particularly hampered the development of cocoa production in most Asian countries. Malaysia, which produced up to 247,000 t in 1990, produces barely 1000 t today, mainly because of this pest [START_REF] Arshad | Modelling boom and bust of cocoa production systems in Malaysia[END_REF]13]. Of course, CPB may not be the only reason for this decline, but it was nonetheless a decisive constraint. Another example is how moniliasis drastically reduced cocoa production in Costa Rica from around 10,000 t in 1978 to around 600 t now [START_REF] Phillips-Mora | Fifty years of frosty pod rot in Central America: Chronology of its spread and impact from Panama to Mexico[END_REF]. Moniliasis is now in all the countries of Central America. In Mexico, cocoa production was around 50,000 t in 2003, just before the advent of moniliasis, and has decreased to under 30,000 t since 2007 [START_REF] Díaz-José | Current state of and perspectives on cocoa production in Mexico[END_REF]. For the moment, moniliasis has not moved to Brazil and Guyana, but the disease is in all the other producing countries of Latin America. In the Caribbean, just Jamaica is affected by moniliasis. Another example is production in the state of Bahia (Brazil), which decreased from 242,000 t in 1990 to 69,000 t in 1995, mainly due to the arrival of witches' broom in the state. The arrival of witches' broom would have been intentional in this case [START_REF] Evans | Globalisation and the threat to biosecurity[END_REF].

In Africa, Ghana became the world's largest cocoa producer in 1911, but ceded its position as the largest producer to Côte d'Ivoire in 1978, mainly due to the cocoa swollen shoot virus (CSSV) epidemic in Ghana [START_REF] Danquah | Sustaining a West African cocoa economy: Agricultural science and the swollen shoot contagion in Ghana, 1936-1965[END_REF]. The evolution of cocoa production areas is therefore clearly linked to the evolution of health pressures on the different production areas.

Until now, diseases originating in the areas of cocoa origin (moniliasis, witches' broom) have not spread to the other producing continents. Similarly, diseases that have adapted to cocoa in other continents, such as CSSV in Africa or vascular streak dieback (VSD) in Asia, have not left their continents of origin. However, extreme caution is needed to avoid the spread of diseases and pests between different production areas. The use of the quarantine facility at the University of Reading plays a key role in preventing the spread of diseases [START_REF] Turnbull | The role of the international cocoa germplasm database and the international cocoa quarantine centre in information management and distribution of cocoa genetic resources[END_REF]. It is indeed strongly recommended that all transfers of plant material should go through this quarantine, even transfers within the same continent.

It is indeed important to prevent the spread of pests and diseases. For other crops, such as coffee, the lack of international quarantine has surely been a handicap to the prevention of the spread of pests and diseases. The coffee berry borer (Hyptothenemus hampei), which originated in Africa, is now present in almost all production areas [START_REF] Dufour | Effect of coffee tree pruning on berry production and coffee berry borer infestation in the Toba Highlands (North Sumatra)[END_REF].

The Effects of Climate Change

Global warming has been detected in most parts of the world and is expected to worsen in the future; its impact on agriculture has been studied for many years and models are being proposed for different crops [START_REF] Sultan | Evidence of crop production losses in West Africa due to historical global warming in two crop models[END_REF]. Climate change can be characterized through different components; considering trees and climate change interactions, the main components influencing tree behavior are: (i) increasing atmospheric CO 2 , (ii) warming, and (iii) changes in rainfall and drought patterns and duration [START_REF] Masson-Delmotte | Global Warming of 1.5 • C; An IPCC Special Report on the Impacts of Global Warming of 1.5 • C Above Pre-Industrial Levels and Related Global Greenhouse Gas Emission Pathways, in the Context of Strengthening the Global Response to the Threat of Climate Change, Sustainable Development, and Efforts to Eradicate Poverty[END_REF]. Climate change is also changing climate events around the world. For example, the evolution of the El Niño-Southern Oscillation (ENSO) phenomenon, which has been studied for many years [START_REF] Rosenzweig | Climate Change and Extreme Weather Events-Implications for Food Production, Plant Diseases, and Pests[END_REF], shows more difficult transitions between rainy and dry seasons with extreme climatic events and consequences for crops and soils [START_REF] Pan | Forecasts of ENSO evolution using spatial-Temporal projection model[END_REF]. It was showed that the ENSO would probably cause decreased cocoa yields in the coming decades in cocoa agroforest of Bahia, Brazil [START_REF] Gateau-Rey | Climate Change could threaten cocoa production: Effects of 2015-2016 El Niño-related drought on cocoa agroforests in Bahia, Brazil[END_REF].

Climate change will modify cultivation area characteristics and conditions for many crops and Theobroma cacao requirements, such as daily water needs [START_REF] Carr | The water relations and irrigation requirements of cocoa (Theobroma cacao L.): A review[END_REF], a high level of relative humidity, and the absence of wind [START_REF] Almeida | Ecophysiology of the cacao tree[END_REF][START_REF] Lahive | The physiological responses of cacao to the environment and the implications for climate change resilience. A review[END_REF], may not be met in several currently cultivated regions, such as West Africa [START_REF] Läderach | Predicting the future climatic suitability for cocoa farming of the world's leading producer countries, Ghana and Côte d'Ivoire[END_REF]. Climate change, especially through water availability, CO 2 elevation, and highest elevation temperature, will induce important changes in terms of tree functioning and consequently phenology [START_REF] Restrepo | Phenology of Cocoa Tree in a Tropical Moist Forest[END_REF] and physiological traits such as water use efficiency, gaseous exchange, carbohydrate metabolism, and the translocation of assimilates and nutrients [START_REF] Acheampong | Improving Field Establishment of Cacao (Theobroma Cacao) through Mulching, Irrigation and Shading[END_REF]. Several recent studies reviewed by [START_REF] Lahive | The physiological responses of cacao to the environment and the implications for climate change resilience. A review[END_REF] [START_REF] Lahive | The physiological responses of cacao to the environment and the implications for climate change resilience. A review[END_REF] show evidence of changes and interactions in cocoa tree behavior, linking genotypes, physiological traits, and climatic parameters.

According to Schroth et al. (2016) [START_REF] Schroth | Vulnerability to climate change of cocoa in West Africa: Patterns, opportunities and limits to adaptation[END_REF], climate change could induce a significant decrease in areas suitable for cocoa cultivation in West Africa (65% of current world production) due to drying, rather than increasing temperature (by about 2 • C by 2050), to which the cocoa tree seems less sensitive. Climatic drying would thus result in an increase in evapotranspiration resulting from an increase in temperature not compensated by annual rainfall, which is slightly decreasing, thus increasing water deficit. This drying up would lead to reduced suitable land for cocoa, particularly due to the difficulties in setting up new fields, with significant mortality of young trees [START_REF] Garcia Lozano | Respuestas fisiológicas de Theobroma cacao L. en etapa de vivero a la disponibilidad de agua en el suelo[END_REF]. In such conditions, a lot of recent studies have aimed to promote smart agriculture to limit climate change impacts and have promoted agroforestry systems (AFSs) as a way to buffer those impacts and to reduce deforestation [START_REF] Luedeling | Agroforestry systems in a changing climate-Challenges in projecting future performance[END_REF][START_REF] Kroeger | Forest-and Climate-Smart Cocoa in Côte d'Ivoire and Ghana, Aligning Stakeholders to Support Smallholders in Deforestation-Free Cocoa[END_REF], even if an AFS cannot be an absolute response [START_REF] Abdulai | Cocoa agroforestry is less resilient to sub-optimal and extreme climate than cocoa in full sun[END_REF]. Climate change also has impacts on pollination and pollinators [START_REF] Toledo-Hernández | Neglected pollinators: Can enhanced pollination services improve cocoa yields? A review[END_REF], and it would be useful to understand all the production components affected, from flowering to mature pods [START_REF] Doare | Genetic and environmental links between traits of cocoa beans and pods clarify the phenotyping processes to be implemented[END_REF].

Climate Change, Global Change, and Plant Health Risks

Climate change may also alter plant health risks, depending on the diseases and pests present in different ecological zones [START_REF] Anderson | Emerging infectious diseases of plants: Pathogen pollution, climate change and agrotechnology drivers[END_REF][START_REF] Cilas | Tropical crop pests and diseases in a climate change setting-A few examples[END_REF]. The arrival of new pests and diseases is often due to human movement; the movement of goods and people is often blamed for the emergence of new health problems [START_REF] Bandyopadhyay | Contemporary global movement of emerging plant diseases[END_REF][START_REF] Wilson | Travel and the emergence of infectious diseases[END_REF]. However, in Central America, the increase in the number of hurricanes, more frequent with climate change, and the associated strong winds were suspected in the rapid spread of moniliasis from Costa Rica to Mexico in the 2000s. The expansion of CSSV in Côte d'Ivoire seems to be linked to changes in the population dynamics of the vectors, which include several species of mealybugs. This change in population dynamics seems to be linked to climate change, or more generally global change, including ecological modifications linked to deforestation and its related impact on the protective buffer effect of tree strata [START_REF] Oro | Spatiotemporal pattern analysis of Cacao swollen shoot virus in experimental plots in Togo[END_REF][START_REF] Schroth | Pests and Diseases in Agroforestry Systems of the Humid Tropics[END_REF]. In the future, some emergences and/or developments of pests and diseases could be due to climate change. Indeed, the distribution pattern of pests and diseases could change with changes in rainfall and temperature patterns and this aspect would indeed merit further study.

In view of these elements and based on the current, sometimes fragmentary, knowledge on the effects of climate change, rapid effects can be expected both in terms of the development and the intensity of health problems in cocoa plantations. Several breeding programs therefore have, as the main objective, the improvement of disease resistance. The aim is to build sustainable resistances in order to control certain plant health constraints as sustainably as possible.

Management in the Context of the Geographical Spread of Pests and Diseases and Climate Change

Several disease and pest control systems have been developed in line with the knowledge acquired, particularly in the fields of biology and chemistry. Biological control was certainly the first method used in agriculture to control plant health problems [START_REF] Heimpel | Biological Control[END_REF]. During the 20th century, advances in chemistry led to the development of pesticides to control various pests and diseases. The use of these pesticides then led to resistances, making these products less and less effective and requiring higher and higher doses. Moreover, the massive use of pesticides has led to human health problems, polluted environments, and most of the current research to control pests and diseases is aimed at getting rid of pesticides. Today, biological control is a subject of research to control several cocoa pests and diseases [START_REF] Deberdt | Impact of environmental factors, chemical fungicide and biological control on cacao pod production dynamics and black pod disease (Phytophthora megakarya) in Cameroon[END_REF][START_REF] Rosmana | Dynamic of Vascular Streak Dieback Disease Incidence on Susceptible Cacao Treated with Composted Plant Residues and Trichoderma asperellum in Field[END_REF][START_REF] Mbarga Manga | Field testing an oil-based Trichoderma asperellum formulation for the biological control of cacao black pod disease, caused by Phytophthora megakarya[END_REF]. The development of more resilient cropping systems, including shade management, is also a promising research avenue to reduce biotic pressures in cocoa production [START_REF] Andres | Agroforestry systems can mitigate the severity of cocoa swollen shoot virus disease[END_REF][START_REF] Babin | Impact of shade on the spatial distribution of Sahlbergella singularis in traditional cocoa agroforests[END_REF][START_REF] Gidoin | Tree spatial structure, host composition and resource availability influence mirid density or Black pod prevalence in cacao agroforests in Cameroon[END_REF]. Finally, the genetic improvement of cocoa trees for their resistance to pests and diseases is an essential lever to better manage cocoa sanitary problems [START_REF] Nyassé | Integrated management of Phytophthora diseases on cocoa (Theobroma cacao L.): Impact of plant breeding on pod rot incidence[END_REF][START_REF] Phillips-Mora | Evaluation of cacao (Theobroma cacao) clones against seven Colombian isolates of Moniliophthora roreri from four pathogen genetic groups[END_REF][START_REF] Teh | Variation of the response of clonal cocoa to attack by cocoa pod borer Conopomorpha cramerella (Lepidoptera: Gracillariidae) in Sabah[END_REF]. However, pest and disease resistance are not the only selection criteria to be taken into account in genetic improvement processes. Productivity, quality, and adaptation to growing conditions, particularly important in the context of climate change, must also be improved. Multi-criteria selection is therefore necessary to develop varieties that meet the various objectives of the production chain. Selection indexes can be constructed for this purpose in order to jointly improve several characteristics [START_REF] Ndoumbé | Multi-trait selection in a diallel crossing scheme of cocoa[END_REF][START_REF] Jaimez | A disease and production index (DPI) for selection of cacao (Theobroma cacao) clones highly productive and tolerant to pod rot diseases[END_REF], and molecular markers could be also developed in order to reduce breeding/selection cycles.

Adaptation to climate change is a more complicated concept because it requires determining the changes in climate that actually affect crops. Drying out or temperature elevation are a priori the two main factors for which an evolution in agricultural management is possible. On the other hand, extreme climatic events (e.g., hurricanes or typhoons) are more complicated to take into account. Concerning the drying out of cropping areas or temperature increases, an adaptation of cropping systems is a possible response with the adaptation of adequate agroforestry systems [START_REF] Abdulai | Cocoa agroforestry is less resilient to sub-optimal and extreme climate than cocoa in full sun[END_REF]. The subject of research remains very open, as the choice of species to be associated with cocoa trees, as well as the distribution of species in production fields, still requires a great deal of research. In addition, certain sanitary constraints must be taken into account in the choice of tree species and plantation designs; for example, in Côte d'Ivoire and Ghana, where CSSV is prevalent, it is important to choose tree species that are not host to the virus, and it is important to surround plots with tree species that limit the spread of the virus [START_REF] Oro | Spatiotemporal pattern analysis of Cacao swollen shoot virus in experimental plots in Togo[END_REF][START_REF] Domfeh | Use of immune crops as barrier in the management of cacao swollen shoot virus disease (CSSVD)-Long-term assessment[END_REF]. Regarding the climate drying out, irrigation devices are sometimes used [START_REF] Carr | The water relations and irrigation requirements of cocoa (Theobroma cacao L.): A review[END_REF], and it should be remembered that irrigation was used for cocoa by the Aztecs and Mayas in pre-Columbian times [START_REF] Touzard | L'économie coloniale du Cacao en Amérique Centrale[END_REF]. Temperature elevation does not seem to pose significant problems for cocoa; however, a shift of cultivation areas to higher altitudes could be envisaged, particularly in Latin American countries that benefit from a wide variation in altitude. Genetic improvement is also an option, especially to adapt plant material to areas that are becoming drier, such as parts of Côte d'Ivoire or Ghana, the two largest cocoa producers.

Conclusions

Native from Latin America, the cocoa tree has been established in most intertropical areas, sometimes successfully, as in Côte d'Ivoire or Ghana, sometimes with failures due to pests that were particularly difficult to control, such as cocoa pod borer in Malaysia. The evolution of cocoa production has adapted to biotic and abiotic constraints that have changed over time under the influence of climate change and the emergence and development of pests and diseases (Figure 2). This history of cocoa farming should encourage us to anticipate risks, for example, through preventive breeding or the development of more resilient cropping systems. Research to establish new cocoa plantations in cultivation areas should also allow us to move away from the old model of "pioneer fronts", in which new plantations were established in cleared forest areas and their medium-term soil fertility was used. It is indeed important to preserve areas of tropical forest that have escaped deforestation and to propose new innovative agroforestry systems with adapted plant material for all component parts.

Agronomy 2020, 10, x FOR PEER REVIEW 5 of 8 main factors for which an evolution in agricultural management is possible. On the other hand, extreme climatic events (e.g., hurricanes or typhoons) are more complicated to take into account.

Concerning the drying out of cropping areas or temperature increases, an adaptation of cropping systems is a possible response with the adaptation of adequate agroforestry systems [START_REF] Abdulai | Cocoa agroforestry is less resilient to sub-optimal and extreme climate than cocoa in full sun[END_REF]. The subject of research remains very open, as the choice of species to be associated with cocoa trees, as well as the distribution of species in production fields, still requires a great deal of research. In addition, certain sanitary constraints must be taken into account in the choice of tree species and plantation designs; for example, in Côte d'Ivoire and Ghana, where CSSV is prevalent, it is important to choose tree species that are not host to the virus, and it is important to surround plots with tree species that limit the spread of the virus [START_REF] Oro | Spatiotemporal pattern analysis of Cacao swollen shoot virus in experimental plots in Togo[END_REF][START_REF] Domfeh | Use of immune crops as barrier in the management of cacao swollen shoot virus disease (CSSVD)-Long-term assessment[END_REF]. Regarding the climate drying out, irrigation devices are sometimes used [START_REF] Carr | The water relations and irrigation requirements of cocoa (Theobroma cacao L.): A review[END_REF], and it should be remembered that irrigation was used for cocoa by the Aztecs and Mayas in pre-Columbian times [START_REF] Touzard | L'économie coloniale du Cacao en Amérique Centrale[END_REF]. Temperature elevation does not seem to pose significant problems for cocoa; however, a shift of cultivation areas to higher altitudes could be envisaged, particularly in Latin American countries that benefit from a wide variation in altitude. Genetic improvement is also an option, especially to adapt plant material to areas that are becoming drier, such as parts of Côte d'Ivoire or Ghana, the two largest cocoa producers.

Conclusions

Native from Latin America, the cocoa tree has been established in most intertropical areas, sometimes successfully, as in Côte d'Ivoire or Ghana, sometimes with failures due to pests that were particularly difficult to control, such as cocoa pod borer in Malaysia. The evolution of cocoa production has adapted to biotic and abiotic constraints that have changed over time under the influence of climate change and the emergence and development of pests and diseases (Figure 2). This history of cocoa farming should encourage us to anticipate risks, for example, through preventive breeding or the development of more resilient cropping systems. Research to establish new cocoa plantations in cultivation areas should also allow us to move away from the old model of "pioneer fronts", in which new plantations were established in cleared forest areas and their mediumterm soil fertility was used. It is indeed important to preserve areas of tropical forest that have escaped deforestation and to propose new innovative agroforestry systems with adapted plant material for all component parts.

Figure 1 .

 1 Figure 1. Expansion of cocoa cultivation from its area of origin, the American continent.

Figure 1 .

 1 Figure 1. Expansion of cocoa cultivation from its area of origin, the American continent.

Figure 2 .

 2 Figure 2. Evolution of cocoa cultivation, facing changing constraints.

Figure 2 .

 2 Figure 2. Evolution of cocoa cultivation, facing changing constraints.

Agronomy 2020, 10, x FOR PEER REVIEW

Funding: This research was funded by Cirad grant (DGDRS).

Acknowledgments:

The authors hereby acknowledge Alain Rival for the invitation to write the paper for the Special Issue "Sustainable Production and Breeding Research for Tropical Plantation Crops".