Thomas G Ribelli

Marco Fantin

Jean-Claude Daran

Kyle F Augustine

Rinaldo Poli

Krzysztof Matyjaszewski

Synthesis and Characterization of the Most Active Copper ATRP Catalyst Based on Tris[(4dimethylaminopyridyl)methyl]amine

The synthesis and characterization of tris [(4-dimethylaminopyridyl)methyl]amine (TPMA NMe2 ) as a ligand for copper catalyzed atom transfer radical polymerization (ATRP) is reported. In solution, the [Cu I (TPMA NMe2 )Br] complex shows fluxionality by variable temperature NMR, indicating rapid ligand exchange. In the solid-state, the [Cu II (TPMA NMe2 )Br][Br] complex exhibits a slightly distorted trigonal bipyramidal geometry (τ = 0.89). The UV-Vis spectrum of [Cu II (TPMA NMe2 )Br] + salts is similar to those of other pyridinebased ATRP catalysts. Electrochemical studies of [Cu(TPMA NMe2 )] 2+ and [Cu(TPMA NMe2 )Br] + showed highly negative redox potentials (E1/2 = -302 mV and -554 mV vs. SCE, respectively), suggesting unprecedented ATRP catalytic activity. Cyclic voltammetry (CV) in the presence of methyl 2-bromopropionate (MBrP; acrylate mimic) was used to determine activation rate constant ka = 1.1 x10 6 M -1 s -1 , confirming the extremely high catalyst reactivity. In the presence of the more active ethyl -bromoisobutyrate (EBiB; methacrylate mimic), total catalysis was observed and an activation rate constant ka = 7.2 x 10 6 M -1 s -1 was calculated with values of KATRP  1. ATRP of methyl acrylate showed a well-controlled polymerization using as little as 10 ppm of catalyst relative to monomer while side reactions such as Cu I catalyzed radical termination (CRT) could be suppressed due to the low concentration of L/Cu I at a steady-state.

INTRODUCTION

Atom transfer radical polymerization (ATRP) has gained widespread use due to its easy setup, tolerance to functional groups, mild conditions and wide range of applications. [START_REF] Matyjaszewski | Atom Transfer Radical Polymerization[END_REF][START_REF] Wang | Controlled/"living" radical polymerization. atom transfer radical polymerization in the presence of transition-metal complexes[END_REF][START_REF] Kato | Polymerization of Methyl Methacrylate with the Carbon Tetrachloride/Dichlorotris-(triphenylphosphine)ruthenium(II)/Methylaluminum Bis(2,6-di-tert-butylphenoxide) Initiating System: Possibility of Living Radical Polymerization[END_REF][START_REF] Matyjaszewski | Atom Transfer Radical Polymerization (ATRP): Current Status and Future Perspectives[END_REF] Since its inception in 1995, when stoichiometric amounts of air-sensitive Cu I relative to alkyl halide initiator were used, [START_REF] Wang | Controlled/"Living" Radical Polymerization. Halogen Atom Transfer Radical Polymerization Promoted by a Cu(I)/Cu(II) Redox Process[END_REF] many advances have been made to improve the efficiency of this polymerization system. [START_REF] Matyjaszewski | Macromolecular Engineering by Atom Transfer Radical Polymerization[END_REF] The development of new operating techniques such as initiators for continuous activator regeneration (ICAR) ATRP [START_REF] Matyjaszewski | Diminishing catalyst concentration in atom transfer radical polymerization with reducing agents[END_REF][START_REF] Konkolewicz | ICAR ATRP with ppm Cu Catalyst in Water[END_REF] , activators regenerated by electron transfer 2 (ARGET) ATRP [START_REF] Chan | ARGET ATRP of Methacrylates and Acrylates with Stoichiometric Ratios of Ligand to Copper[END_REF][START_REF] Jakubowski | Activators Regenerated by Electron Transfer for Atom-Transfer Radical Polymerization of (Meth)acrylates and Related Block Copolymers[END_REF][START_REF] Williams | A Silver Bullet: Elemental Silver as an Efficient Reducing Agent for Atom Transfer Radical Polymerization of Acrylates[END_REF] , supplemental activators and reducing agents (SARA) ATRP [START_REF] Konkolewicz | Reversible-Deactivation Radical Polymerization in the Presence of Metallic Copper. A Critical Assessment of the SARA ATRP and SET-LRP Mechanisms[END_REF] as well as photoATRP [START_REF] Ribelli | How are Radicals (Re)Generated in Photochemical ATRP[END_REF][START_REF] Pan | Photomediated controlled radical polymerization[END_REF][START_REF] Anastasaki | Copper(II)/Tertiary Amine Synergy in Photoinduced Living Radical Polymerization: Accelerated Synthesis of ω-Functional and α,ω-Heterofunctional Poly(acrylates)[END_REF][START_REF] Discekici | Light-Mediated Atom Transfer Radical Polymerization of Semi-Fluorinated (Meth)acrylates: Facile Access to Functional Materials[END_REF][START_REF] Anastasaki | One-Pot Synthesis of ABCDE Multiblock Copolymers with Hydrophobic, Hydrophilic, and Semi-Fluorinated Segments[END_REF] , eATRP [START_REF] Chmielarz | Electrochemically mediated atom transfer radical polymerization (eATRP)[END_REF] and most recently mechanoATRP [START_REF] Wang | Enhancing Mechanically Induced ATRP by Promoting Interfacial Electron Transfer from Piezoelectric Nanoparticles to Cu Catalysts[END_REF][START_REF] Mohapatra | Mechanically controlled radical polymerization initiated by ultrasound[END_REF] have allowed polymerizations to be conducted using ppm levels of catalyst relative to monomer.

As shown in Scheme 1, the control in ATRP is achieved via a reversible redox equilibrium between a L/Cu I/II couple where L signifies a multidentate nitrogen-based ligand. L/Cu I activates a (macro)alkyl halide chain end, resulting in the L/Cu II -X deactivator and a carbon-based radical, [START_REF] Lin | Ab Initio Evaluation of the Thermodynamic and Electrochemical Properties of Alkyl Halides and Radicals and Their Mechanistic Implications for Atom Transfer Radical Polymerization[END_REF] which propagates by adding to monomer before being trapped by the L/Cu II -X deactivator, regenerating the L/Cu I species and the dormant polymer chain. [START_REF] Matyjaszewski | Atom Transfer Radical Polymerization (ATRP): Current Status and Future Perspectives[END_REF] To control the polymerization, [START_REF] Coessens | Functional polymers by atom transfer radical polymerization[END_REF] this equilibrium (KATRP) should lie on the dormant side to diminish the concentration of radicals and retain chain-end functionality (CEF). KATRP can be expressed as the ratio of activation (ka) to deactivation (kd) rate constants and can be tuned over 8-orders of magnitude [START_REF] Tang | Determination of Equilibrium Constants for Atom Transfer Radical Polymerization[END_REF] based on temperature, pressure, solvent, [START_REF] Tsarevsky | The atom transfer radical polymerization equilibrium: structural and medium effects[END_REF][START_REF] Braunecker | Thermodynamic Components of the Atom Transfer Radical Polymerization Equilibrium: Quantifying Solvent Effects[END_REF] polymer chain-end, [START_REF] Tang | Understanding Atom Transfer Radical Polymerization: Effect of Ligand and Initiator Structures on the Equilibrium Constants[END_REF] and choice of catalyst. [START_REF] Tang | Determination of Equilibrium Constants for Atom Transfer Radical Polymerization[END_REF] In order to reach even lower catalyst loadings or to polymerize less active monomers such as vinyl acetate (VAc), [START_REF] Gillies | A DFT Study of R-X Bond Dissociation Enthalpies of Relevance to the Initiation Process of Atom Transfer Radical Polymerization[END_REF] higher values of KATRP must be achieved. One simple way to tune ATRP is by changing the coordination sphere of copper. Over the years, rational ligand design has allowed for the understanding of how the catalyst structure affects reactivity. The activity of the catalyst in ATRP correlates with ligand denticity, nature of the N-donor atom and electron donating ability through the coordinating nitrogen atom(s). [START_REF] Tang | Effect of Ligand Structure on Activation Rate Constants in ATRP[END_REF] Indeed, a linear correlation between the redox potential (E1/2) and ln(KATRP) has been established where a more negative E1/2 results in a larger value of KATRP. [START_REF] Tsarevsky | Competitive Equilibria in Atom Transfer Radical Polymerization[END_REF] The activity of a catalyst can also be further assessed by comparing the stability constants (binding constants), β, of the L/Cu I and L/Cu II complexes since KATRP scales with the β II /β I ratio, as shown in Scheme 1.

While both β II and β I should be large, β II > β I in order to provide a thermodynamic driving force for alkyl halide activation. [START_REF] Tsarevsky | Competitive Equilibria in Atom Transfer Radical Polymerization[END_REF] Indeed, β I values are rather constant but β I values change significantly with the ligand structures. [START_REF] Rorabacher | Electron Transfer by Copper Centers[END_REF] To date, the most active ATRP catalyst has used the ligand tris[((4-methoxy-2,5dimethyl)-2-pyridyl)methyl]amine (TPMA* 3 ) which has three electron donating groups on each pyridine ring. [START_REF] Schroder | Substituted Tris(2-pyridylmethyl)amine Ligands for Highly Active ATRP Catalysts[END_REF][START_REF] Lee | Mechanistic Insights into the Oxidation of Substituted Phenols via Hydrogen Atom Abstraction by a Cupric-Superoxo Complex[END_REF] This led to a catalyst that is 5 million times more active than the seminal catalytic system employing the 2,2'-bipyridine (bpy) ligand and 1000 times more active than the commonly used tris(pyridylmethyl)amine (TPMA) ligand (Scheme 2).

According to Hammett parameters, using the even more electron donating dimethyl amino (-NMe2) group should further increase the catalyst activity as already observed for bpy derivatives. [START_REF] Magenau | Highly Active Bipyridine-Based Ligands for Atom Transfer Radical Polymerization[END_REF] Therefore, we have considered using tris[(4-dimethylamino-2pyridyl)methyl]amine (TPMA NMe2 ) ligand as shown in Scheme S1. [START_REF] Zhang | Copper(I)-Dioxygen Reactivity of [(L)CuI]+ (L = Tris(2-pyridylmethyl)amine): Kinetic/Thermodynamic and Spectroscopic Studies Concerning the Formation of Cu-O2 and Cu2-O2 Adducts as a Function of Solvent Medium and 4-Pyridyl Ligand Substituent Variations[END_REF][START_REF] Comba | Tuning of the Properties of Transition-Metal Bispidine Complexes by Variation of the Basicity of the Aromatic Donor Groups[END_REF][START_REF] Kim | A N3S(thioether)-Ligated CuII-Superoxo with Enhanced Reactivity[END_REF] This ligand was previously reported by Karlin et al where the [Cu I (TPMA NMe2 )] + complex was used as an oxygen activation catalyst to mimic various copper containing enzymes [START_REF] Solomon | Multicopper Oxidases and Oxygenases[END_REF][START_REF] Solomon | Copper Active Sites in Biology[END_REF] such as amine oxdiases, [START_REF] Wilmot | Visualization of Dioxygen Bound to Copper During Enzyme Catalysis[END_REF] multicopper oxidases [START_REF] Solomon | Oxygen Binding, Activation, and Reduction to Water by Copper Proteins[END_REF] (MCOs) and tyrosinases [START_REF] Decker | How Does Tyrosinase Work? Recent Insights from Model Chemistry and Structural Biology[END_REF] as well as to study this complex's interactions with carbon monoxide. [START_REF] Fry | Carbon Monoxide Coordination and Reversible Photodissociation in Copper(I) Pyridylalkylamine Compounds[END_REF] This new Cu-based ATRP catalyst with TPMA NMe2 , in both relevant oxidation states, has been characterized in solution and the solid state and utilized in ATRP systems with low catalyst loadings (down to 10 ppm) and was shown to exhibit unprecedented reactivity with alkyl halides. Scheme 2 Structure of the ligands used in this study.

RESULTS AND DISCUSSION

TPMA NMe2 was prepared by a procedure slightly modified from that used by Karlin et al [START_REF] Zhang | Copper(I)-Dioxygen Reactivity of [(L)CuI]+ (L = Tris(2-pyridylmethyl)amine): Kinetic/Thermodynamic and Spectroscopic Studies Concerning the Formation of Cu-O2 and Cu2-O2 Adducts as a Function of Solvent Medium and 4-Pyridyl Ligand Substituent Variations[END_REF] (Scheme S1). The synthesis of 2-hydroxymethyl-4-dimethylaminopyridine (2; Scheme S1) was conducted as previously published by Comba et al. [START_REF] Comba | Tuning of the Properties of Transition-Metal Bispidine Complexes by Variation of the Basicity of the Aromatic Donor Groups[END_REF] The synthesis of 2-phthalimidomethyl-4chloropyridine (5; Scheme S1) was conducted as previously published by our group. [START_REF] Schroder | Substituted Tris(2-pyridylmethyl)amine Ligands for Highly Active ATRP Catalysts[END_REF] 2-Aminomethyl-4-dimethylpyridine (6; Scheme S1) was synthesized directly from a basic workup of 2-phthalimidomethyl-4-dimethylaminopyridine. It should be noted that it is very important to use chemical resistant O-Ring (ACE glass # 7855-813) for reactions using high pressure tubes.

The ligand has been characterized by 1 H/ [START_REF] Ribelli | How are Radicals (Re)Generated in Photochemical ATRP[END_REF] C NMR and ESI-MS which confirmed the predicted structure.

Variable Temperature NMR of Cu I complexes

It has been previously shown that L/Cu I complexes with multidentate pyridine-based ligands can undergo fast ligand exchange in the presence of excess ligand relative to Cu I . [START_REF] Kaur | Properties and ATRP Activity of Copper Complexes with Substituted Tris(2-pyridylmethyl)amine-Based Ligands[END_REF] The solution prepared by addition of TPMA NMe2 to CuBr was studied by variable temperature NMR, as shown in Figure 1.

Figure 1 Variable temperature 1 H NMR of the aromatic region of the free TPMA NMe2 ligand and its CuBr complex at the molar ratio [CuBr]0:[TPMA NMe2 ]0 = 1:3 in d6-acetone.

Upon reacting equimolar amounts of TPMA NMe2 and CuBr in d6-acetone, the reaction initially turned to a pale-yellow color, common for Cu I complexes coordinated by pyridinic ligands. However, upon stirring, the reaction mixture turned green along with a dark precipitate indicative that the [Cu I (TPMA NMe2 )Br] complex underwent disproportionation to [Cu II (TPMA NMe2 )Br][Br] and Cu 0 + TPMA NMe2 . Typically, unsubstituted TPMA shows little to no disproportionation. The position of the disproportionation equilibrium, KDisp,LCu, depends on the relative stability of LCu II compared LCu I . Since the TPMA NMe2 stabilizes Cu II much more than TPMA, disproportionation is not unexpected. This is especially true in a disproportionating solvent such as acetone which is polar and coordinates weakly to Cu I . [START_REF] Tsarevsky | Competitive Equilibria in Atom Transfer Radical Polymerization[END_REF] To suppress disproportionation and reform the [Cu I (TPMA NMe2 )Br] complex, 2 additional equivalents of TPMA NMe2 were added. [START_REF] Wang | Reversible-Deactivation Radical Polymerization in the Presence of Metallic Copper. Comproportionation-Disproportionation Equilibria and Kinetics[END_REF] Indeed, upon further stirring for 30 minutes, the reaction regained its yellow color and the Cu 0 particles were no longer visible.

The 1 H NMR spectrum shows significant broadening of the aromatic peaks upon complexation, which has been previously been shown for other Cu I complexes. [START_REF] Mason | Patterns of nuclear magnetic shielding of transition-metal nuclei[END_REF][START_REF] Eckenhoff | Highly Efficient Copper-Mediated Atom-Transfer Radical Addition (ATRA) in the Presence of Reducing Agent[END_REF][START_REF] Hsu | Synthesis and Characterization of Copper(I) Complexes Containing Tri(2-Pyridylmethyl)Amine Ligand[END_REF] This broadening indicates a fast exchange between free and coordinated ligand. Upon decreasing the temperature to 240 K, the peaks attributed to coordinated and uncoordinated ligand began to resolve due to the slower rate of exchange. At 180 K, two distinct peaks were observed at 8.05 and 8.5 ppm, attributed to free and coordinated ligand, respectively. [START_REF] Kaur | Properties and ATRP Activity of Copper Complexes with Substituted Tris(2-pyridylmethyl)amine-Based Ligands[END_REF][START_REF] Kitagawa | Binuclear copper(I) complexes which reversibly react with carbon monoxide. 1. Di-.mu.-halogeno-bis(2,2'-bipyridine)dicopper(I) and its derivatives[END_REF][START_REF] Kitagawa | New mixed-ligand copper(I) complexes with 2,2'bipyridine and their NMR spectra[END_REF][START_REF] Munakata | Studies of copper(I) olefin complexes. Formation constants of copper olefin complexes with 2,2'-bipyridine, 1,10phenanthroline, and their derivatives[END_REF][START_REF] Thompson | Copper(I) complexes with unsaturated small molecules. Synthesis and properties of monoolefin and carbonyl complexes[END_REF] The peaks became narrower at lower temperature but were broader than those of previously published TPMA-based Cu I complexes at 180 K. This could be due to the presence of small amounts of paramagnetic Cu II formed from disproportionation and plausible self-exchange between the Cu II and Cu I complexes. This cannot be avoided due to the disproportionating nature of acetone and the highly reactive [Cu I (TPMA NMe2 )] + complex. Although the variable temperature NMR spectra indicate a significant amount of ligand exchange, the total amount of uncoordinated Cu is extremely low due to the large stability constants, β I , as has been previously observed for substituted TPMA ligands. [START_REF] Kaur | Properties and ATRP Activity of Copper Complexes with Substituted Tris(2-pyridylmethyl)amine-Based Ligands[END_REF]

Structural Studies of Cu II Deactivator Complex

The [Cu II (TPMA NMe2 )Br] + complex was synthesized and crystallized as reported in the Supporting Information. The resulting molecular structure is presented in Figure 2 with selected bond distances and angles summarized in Table 1.

Figure 2 Molecular structure of [Cu II (TPMA NMe2 )Br][Br] shown (left) with 50% probability displacement ellipsoids. H atoms, counter Br -anion and solvent molecules have been omitted for clarity.

The [Cu II (TPMA NMe2 )Br] + cation is in a slightly distorted trigonal bipyramidal geometry, indicated by a structural parameter τ = 0.89 (τ = 1.00 for trigonal bipyramidal). Coordination of the tetradentate ligand occurs through three substituted pyridinic nitrogen atoms in the equatorial plane (Neq) and a central anchoring aliphatic nitrogen in the axial plane (Nax). The Nax-Cu-Neq bond angles are all slightly smaller than 90° which is consistent with a previously reported cupric aqua adduct, [START_REF] Kim | A N3S(thioether)-Ligated CuII-Superoxo with Enhanced Reactivity[END_REF] [Cu II (TPMA NMe2 )(H2O)] 2+ . The similar Nax-Cu-Neq angles between the two complexes, although with differently sized axial ligands (Br -vs. H2O), suggests these deviations from 90° are most likely due to the natural bite of the ligand as opposed to steric repulsion from the axial ligand. The previously reported 42 cuprous carbonyl adduct, [Cu I (TPMA NMe2 )(CO)] + , showed a Cu I -Nax bond distance of 2.446 Å which is significantly elongated compared to the Cu II -Nax bond distance of 2.05 Å presented in this study. Although the two complexes cannot be directly compared due to the difference in axial ligand, Cu-Nax bond elongation upon reduction of Cu II to Cu I has been observed in other TPMA-based complexes. [START_REF] Eckenhoff | Structural Comparison of Copper(I) and Copper(II) Complexes with Tris(2-pyridylmethyl)amine Ligand[END_REF] This is attributed to Cu II preferring a 5-coordinate environment while the reduced Cu I ion prefers 4-coordinate geometries. [START_REF] Zerk | Redox-coupled structural changes in copper chemistry: Implications for atom transfer catalysis[END_REF] Thus, the Cu I -Nax bond is elongated to a nonbonding distance forming a distorted tetrahedral geometry. Furthermore, as shown in Figure S5, the crystal structure is stabilized by π-π stacking interactions between substituted pyridine rings as well as weak C-H---Br (2.84 Å) interactions. d This work. e τ parameter is calculated as τ = (φ1 -φ2)/60, where φ1 and φ2 are the largest (N1-Cu-Br1) and second largest (N2-Cu-N3) bond angles, τ = 1 (trigonal bipyramidal geometry), and τ = 0 (square pyramidal geometry).

Solution Studies of Cu II Complexes

The UV-Vis-NIR spectra were obtained using CuBr2 to form [Cu II (TPMA NMe2 )Br] + and also Cu(OTf)2 to form [Cu II (TPMA NMe2 )(MeCN)] 2+ , since the OTf -anion coordinates very weakly to the Cu II center in solution. As shown in Figure 3A, two dd transitions are observed in the NIR and visible region at 1038 and 776 nm for the [Cu II (TPMA NMe2 )Br] + and 980 and 725 nm for the [Cu II (TPMA NMe2 )(MeCN)] 2+ complex, respectively. These two transitions are typical of d [START_REF] Chan | ARGET ATRP of Methacrylates and Acrylates with Stoichiometric Ratios of Ligand to Copper[END_REF] Cu II possessing trigonal bipyramidal geometry and are attributed to dxz ≈ dyz  dz2 and to dx2-y2 ≈ dxy  dz2. [START_REF] Hiskey | Synthesis, spectroscopy, electrochemistry, and photochemistry of a series of M(bpym)2Cl2 (M=Mn(II), Co(II), Ni(II), and Cu(II)) complexes. Precursor complexes in the preparation of polymetallic systems[END_REF][START_REF] Mclachlan | Synthesis, Structure and Properties of Five-Coordinate Copper(II) Complexes of Pentadentate Ligands with Pyridyl Pendant Arms[END_REF] A ligand to metal charge transfer (LMCT) band is apparent in both complexes, centered around 425 and 395 nm for [Cu II (TPMA NMe2 )Br] + and [Cu II (TPMA NMe2 )(MeCN)] 2+ , respectively. The absorption spectra of these two complexes are consistent with previously published results for many ATRP deactivator complexes presenting trigonal bipyramidal geometry. [START_REF] Kaur | Properties and ATRP Activity of Copper Complexes with Substituted Tris(2-pyridylmethyl)amine-Based Ligands[END_REF][START_REF] Pintauer | Synthesis, Characterization, and Bromine Substitution by 4,4'-Di(5-nonyl)-2,2'-bipyridine in CuII(4,4'-di(5-nonyl)-2,2'bipyridine)Br2[END_REF] A sample of [Cu II (TPMA NMe2 )Br][Br] crystals was also investigated, after dissolution into a dichloromethane/toluene mixture, by EPR spectroscopy at 120 K (Figure 3B), revealing a pattern and g/A parameters rather close to those of the related [Cu II (TPMA)Br] + complex. A rather uninformative cubit tensor at g = 2.123 and a linewidth of ca. 110 G, without observable copper hyperfine coupling was observed, on the other hand, under the same conditions in a MeCN/toluene mixture, as well as in pure MeCN or pure dichloromethane (see Supporting Information Figure S4). Thermodynamic Parameters As noted above, one method to determine catalyst activity in ATRP is by measuring the stability constants, β I and β II , for the L/Cu I and L/Cu II complexes. [START_REF] Kaur | Properties and ATRP Activity of Copper Complexes with Substituted Tris(2-pyridylmethyl)amine-Based Ligands[END_REF] The redox potential of the [Cu(L)] 2+ complex gives the β II /β I ratio as shown in Eq 1, where 𝐸 Cu 2+ /Cu + ° and 𝐸 LCu II /LCu I ° represent the standard redox potential of solvated Cu and the ligated Cu species, respectively. [START_REF] Bortolamei | Thermodynamic Properties of Copper Complexes Used as Catalysts in Atom Transfer Radical Polymerization[END_REF] Furthermore, according to Eq 2, it is also possible to obtain the ratio β X,app II /β X,app I electrochemically, where β X,app II and β X,app I are the apparent equilibrium constants of halide association to ligated copper, L/Cu II -X or L/Cu I -X, respectively. [START_REF] Kaur | Properties and ATRP Activity of Copper Complexes with Substituted Tris(2-pyridylmethyl)amine-Based Ligands[END_REF] ligand is able to sufficiently stabilize the electrochemically generated Cu I , and indicates that these complexes have small rearrangement energies between the Cu I/II oxidation states. Using Eq 1, the β II /β I ratio was calculated as 1.1 x 10 23 which is 1500 times larger than the previously reported value for the tris(2-dimethylaminoethyl)amine (Me6TREN) complex in MeCN. [START_REF] Bortolamei | Thermodynamic Properties of Copper Complexes Used as Catalysts in Atom Transfer Radical Polymerization[END_REF] This large increase may be either due to a more stabilized Cu II or a destabilized Cu I . However, it was previously shown [START_REF] Kaur | Properties and ATRP Activity of Copper Complexes with Substituted Tris(2-pyridylmethyl)amine-Based Ligands[END_REF] that stability constants for Cu I were similar using variously substituted pyridine-based ligands in DMF. [START_REF] Rorabacher | Electron Transfer by Copper Centers[END_REF] Upon introduction of coordinating bromide anions, the complex [Cu(TPMA NMe2 )Br] + is formed, and the redox potential shifts by -252 mV to give E1/2 = -554 mV vs. SCE. KATRP increases roughly one order of magnitude for every 59 mV shift of redox potential, indicating KATRP should be approximately 140,000 times greater relative to the unsubstituted TPMA-based catalyst, which has E1/2 = -240 mV vs. SCE, [START_REF] Eckenhoff | Highly Efficient Copper-Mediated Atom-Transfer Radical Addition (ATRA) in the Presence of Reducing Agent[END_REF] and >10 9 times greater than the original bpy catalyst, which has E1/2 = +30 mV vs. SCE. [START_REF] Qiu | Cyclic voltammetric studies of copper complexes catalyzing atom transfer radical polymerization[END_REF] Furthermore, using Eq. 2, the β X,app II /β X,app

𝐾 disp,LCu = [LCu II ] eq [L] eq [LCu I ] eq 2 (Eq. 3) Cu disp, LCu disp, 2 I II ) β ( β K K  (Eq. 4)
Since cyclic voltammetry can only provide the β II /β I ratio, further analysis was carried out to estimate the individual β values. We previously reported [START_REF] Kaur | Properties and ATRP Activity of Copper Complexes with Substituted Tris(2-pyridylmethyl)amine-Based Ligands[END_REF] on the disproportionation equilibrium allowing for the calculation of β II /(β I ) 2 , as shown in Eq's 3 & 4, where Kdisp,LCu and Kdisp,Cu are the equilibrium constants of disproportionation for ligated and solvated copper, respectively. [START_REF] Kaur | Properties and ATRP Activity of Copper Complexes with Substituted Tris(2-pyridylmethyl)amine-Based Ligands[END_REF] The determination of the disproportionation equilibrium, when coupled with electrochemical measurements, allows for the calculation of individual stability constants.

Analysis of Kdisp,LCu is difficult in MeCN due to the highly comproportionating nature of this solvent, i.e. very small values of Kdisp,. In fact, values of Kdisp,Cu for the solvated Cu I complex in acetonitrile have previously been estimated on the order of 10 -21 . [START_REF] Ahrland | Thermodynamics of the Copper(I) Halide and Thiocyanate Complex Formation in Acetonitrile[END_REF] Therefore, it was only possible to estimate a limit of Kdisp,LCu < 1.0 x 10 -4 . Nonetheless, using this value the lower limits of β II and β I as 3.5 x 10 29 and 1.9 x 10 6 were estimated, respectively. These values, although likely underestimated due to uncertainty of Kdisp,LCu, are in good agreement with previously reported values for other ATRP catalysts. [START_REF] Kaur | Properties and ATRP Activity of Copper Complexes with Substituted Tris(2-pyridylmethyl)amine-Based Ligands[END_REF][START_REF] Bortolamei | Thermodynamic Properties of Copper Complexes Used as Catalysts in Atom Transfer Radical Polymerization[END_REF] All thermodynamic parameters obtained in this study, as well as for TPMA and TPMA* 3 -based complexes, are summarized in

Assessment of ATRP Activity

The ability of L/Cu I complexes to activate (macro)alkyl halide bonds is paramount to the success of an ATRP system. The bond dissociation free energy (BDFE) of a C-X (X = Cl or Br) has been correlated to values of KATRP via DFT. [START_REF] Lin | Ab Initio Evaluation of the Thermodynamic and Electrochemical Properties of Alkyl Halides and Radicals and Their Mechanistic Implications for Atom Transfer Radical Polymerization[END_REF][START_REF] Gillies | A DFT Study of R-X Bond Dissociation Enthalpies of Relevance to the Initiation Process of Atom Transfer Radical Polymerization[END_REF] Generally, the activation reaction is faster (larger values of ka) if the resulting radical is more stabilized either through steric or resonance effects.

Electrochemistry is a useful tool in determining kinetic parameters in ATRP. The use of a rotating disk electrode allowed for measurement of ka and KATRP for systems with moderately high activity (ka < 10 4 ). For more active processes such as in aqueous media [START_REF] Fantin | ATRP in Water: Kinetic Analysis of Active and Super-Active Catalysts for Enhanced Polymerization Control[END_REF] and systems involving highly active catalysts [START_REF] Bell | A Rapid Electrochemical Method for Determining Rate Coefficients for Copper-Catalyzed Polymerizations[END_REF] , cyclic voltammetry of copper complexes under catalytic conditions (in the presence of RX) coupled with digital simulations can be used to obtain ka. to prevent the deactivation reaction. The dramatic increase in the cathodic current, as the scan rate decreased, is consistent with previous reports. [START_REF] Fantin | Understanding the Fundamentals of Aqueous ATRP and Defining Conditions for Better Control[END_REF] The absence of an oxidation peak indicates that the electrochemically generated Cu I was completely consumed in the activation of MBrP, showing the high activity of this catalyst in the activation of acrylates. As shown in Figure S7, simulations of the cyclic voltammetry under catalytic conditions gave a rate coefficient of activation, ka, of 1.1 x 10 6 M -1 s -1 , which is the largest value reported for this initiator with copper-based ATRP catalysts. As will be shown later, values of kd were calculated to be 5 x 10 7 M -1 s -1 . Thus, KATRP was estimated on the order of 10 -1 . This value is consistent with that estimated from the redox potential (Table 2, KATRP = 1.0 x 10 -1 ). This also indicates that deactivation for so active and reducing complexes is still very efficient. These preliminary studies further indicate that this new complex is the most active copper-based ATRP catalyst to date. This particular phenomenon is attributed to "total catalysis", which is usually found for extremely efficient catalysts with rate constants for bimolecular reactions > 10 6 M -1 s -1 . Indeed, in this case, only an infinitesimal amount of L/Cu I is required for the complete reduction of RBr, giving a first irreversible peak at E > E1/2,LCuBr due to the very fast catalytic reduction of EBiB. On the other hand, the electrochemical reduction of [Cu(TPMA NMe2 )Br] + is still reversible since the majority of the catalyst is not involved in the electrocatalytic process. Overall, these results

show the extreme reactivity of [Cu(TPMA NMe2 )Br] + , which can be used in ATRP with unprecedentedly low ppm concentrations.

Low ppm ATRP of Acrylates

To assess the efficiency of the [Cu(TPMA NMe2 )Br] + catalyst, various forms of ATRP with activator regeneration were conducted. First, ICAR ATRP was conducted at catalyst loadings ranging from 10 to 100 ppm relative to monomer with 2,2′-azobis(2-isobutyronitrile) (AIBN) as radical initiator. [START_REF] D'hooge | Kinetic Modeling of ICAR ATRP[END_REF] As shown in Figure 7, linear semi-logarithmic plots vs. time were observed at all catalyst loadings. This is consistent with previously established ICAR kinetics with bimolecular termination for which the amount of catalyst does not change the rate of polymerization as shown in Eq 5, where f is initiator efficiency of AIBN, kazo is the decomposition rate coefficient and kt is the rate coefficient of radical-radical termination. 69-70

t azo AIBN] [ ] [R k k f   (Eq. 5) ] Cu [ AIBN] [ ] [R I app CRT azo k k f   (Eq. 6)
After 4 hours, >90% conversion was achieved for all reactions with a linear increase of molecular weights with conversion, typical of a well-controlled polymerization. While the rate of polymerization was unaffected by the initial amount of catalyst, molecular weight distributions gradually broadened upon decreasing catalyst concentration (Figure S9). This is attributed to decreased rate of deactivation relative to propagation. Although the initial amount of catalyst does not affect the rate of polymerization, at lower catalyst loadings there is less deactivator complex to reversibly trap radicals. This causes more monomer additions per activation cycle and thus a broadening of the molecular weight distribution. (cf. Eq. 7) An interesting point to note is that, according to the kinetic plots presented in Figure 7A and PREDICI simulations provided in the SI, bimolecular radical termination (RT) should dominate catalytic radical termination (CRT), contrary to previous studies with other ATRP catalysts. [START_REF] Ribelli | How are Radicals (Re)Generated in Photochemical ATRP[END_REF] If CRT would significantly contribute to overall termination, the polymerization kinetics would depend on catalyst concentration (Eq. 6), where app CRT k is the apparent CRT rate coefficient. 71 This is because, as shown in Scheme 3, CRT requires the coordination of a propagating radical ( • Pn) to the L/Cu I complex to form a L/Cu II -Pn organometallic species. 71 Since the L/Cu I concentration in ICAR ATRP is governed by the dynamic ATRP equilibrium [START_REF] Krys | Relation between Overall Rate of ATRP and Rates of Activation of Dormant Species[END_REF] (Scheme 1), and considering the very high values of KATRP ≈ 10 -1 for this system, the amount of TPMA NMe2 /Cu I present in solution is calculated to be 9.6 x 10 -10 at equilibrium (See Supporting Information for calculation). [START_REF] Krys | Relation between Overall Rate of ATRP and Rates of Activation of Dormant Species[END_REF] In other words, a radical will kinetically terminate with a second radical faster than with the trace amounts of TPMA NMe2 /Cu I . This should still happen, even if addition of a radical to TPMA NMe2 /Cu I occurs at diffusion controlled rates (kadd = 10 8 M -1 s -1 ). This is not the case of less active catalysts such as TPMA-based systems (KATRP ≈ 10 -5 ) [START_REF] Ribelli | Disproportionation or Combination? The Termination of Acrylate Radicals in ATRP[END_REF] where CRT dominates because of a relatively higher concentration of TPMA/Cu I of 1.8 x 10 -6 M. As shown in Figure S10, these findings are supported by PREDICI simulations: the much more active TPMA NMe2 -based system kinetically suppressed CRT because only a small fraction of TPMA NMe2 /Cu I is present in solution, resulting in a relatively larger fraction of living chains compared to less active systems.

Then, Ag 0 ATRP, a form of ARGET ATRP, was conducted to further test the scope of the newly synthesized catalyst. Ag 0 ATRP employs silver wire to heterogeneously reduce L/Cu II to L/Cu I , with oxidation of Ag 0 to Ag I Br. [START_REF] Williams | A Silver Bullet: Elemental Silver as an Efficient Reducing Agent for Atom Transfer Radical Polymerization of Acrylates[END_REF] As shown in Figure 8, the TPMA NMe2 catalyst successfully polymerized MA via Ag 0 ARGET ATRP using as little as 10 ppm of catalyst relative to monomer. However, at 5 ppm, the polymerization was no longer living as confirmed by the molecular weights decreasing with conversion and high Ð values (>1.5). Since the rate of Ag 0 ARGET ATRP depends on the rate of Cu I generation, the linear semi-logarithmic kinetic plots showed that Cu II was still reduced but unable to efficiently deactivate radicals. This is because, at such low catalyst concentrations, the rate of propagation and termination are competing with the rate of deactivation. Thus, it is likely that 10 ppm is around the lowest possible limits to achieve a wellcontrolled polymerization in copper catalyzed ATRP of acrylates. Nevertheless, unprecedented control was achieved using as little as 10 ppm of catalyst for the polymerization of acrylates.

The nearly colorless nature of the polymerization solution at 10 ppm can be seen in Figure 8C. Using the results from the two polymerization systems shown in Figures 6 &7, one can estimate the rate coefficient of deactivation, kd, according to Eq 7 where DP is the degree of polymerization, kp is the propagation rate constant, [START_REF] Barner-Kowollik | Critically evaluated rate coefficients in radical polymerization -7. Secondary-radical propagation rate coefficients for methyl acrylate in the bulk[END_REF] and p is monomer conversion.

4                      1 2 ] X LCu [ ] RX [ DP 1 1 / II d p n w p k k M M (Eq. 7)
Due to the negligible amount of termination, it has been assumed that [RX] = [RX]0.

Furthermore, since the KATRP is so large, it can be assumed that essentially all copper is in the form of L/Cu II -X and therefore [L/Cu II -X] = [L/Cu II -X]0. Using the final dispersity data of the polymerizations in Figures 6 &8, kd = 5.4 (± 1.7) x 10 7 M -1 s -1 was obtained which gives an estimated value of KATRP = 2.2 x 10 -2 for acrylate systems. This indicates that the degree of substitution and redox potential of pyridinic-based catalysts have very little effect on kd.

Instead, only the total amount of Cu II -X deactivator, which is regulated by [Cu II ]0 and KATRP, will define the level of control in a particular ATRP system with activator regeneration.

Comparison of TPMA NMe2 to Other Ligands in ATRP

As shown in Figure 8, the redox potential scales linearly with log(KATRP) for EBiB in MeCN at room temperature for a variety of ligands (Figure S11 for structures of ligands). Based on E1/2 values, the newly synthesized TPMA NMe2 -based catalyst (E1/2 = -554 mV) is almost 10 billion times more active than seminal bpy-based catalyst (E1/2 = +30 mV). Even looking at catalysts which are widely used for low ppm ATRP, the TPMA NMe2 -based system is ≈300,000 and 30,000 times more active than the TPMA (E1/2 = -240 mV) and Me6TREN (E1/2 = -300 mV) based catalysts, respectively. Unfortunately, with such a highly active catalyst as [Cu(TPMA NMe2 )] + , activation of alkyl halides approaches diffusion controlled limits (ka >10 6 M -1 s -1 ), and with already diffusion controlled deactivation rates (kd = >10 7 M -1 s -1 ), values of KATRP begin to approach unity. This would mean that for commonly used monomers such as acrylates and methacrylates, this catalytic system may be the upper limit of activity since the only way to further increase KATRP would be to decrease kd. This is not best since the control achieved in ATRP is due to fast rates of deactivation. Encouragingly, the high ATRP activity provided by the

Conclusions

The synthesis of a new ATRP catalyst employing the p-dimethylamino substituted TPMA ligand, tris[(4-dimethylaminiopyridyl)methyl]amine (TPMA NMe2 ), is reported. Variable temperature NMR showed a fluxional Cu I complex with rapid ligand exchange. In the solid state, the [Cu II (TPMA NMe2 )Br] + complex exhibited nearly perfect trigonal bipyramidal geometry.

UV-Vis and EPR confirmed that this geometry was retained in solution. Electrochemical measurements showed a quasi-reversible TPMA NMe2 Cu I/II couple indicating small geometric rearrangement throughout the redox cycle. Stability constants for Cu I and Cu II were comparable to other copper ATRP catalysts in MeCN. Electrochemistry was also utilized to assess the activation of methyl 2-bromopropionate (MBrP; acrylate mimic) and ethyl αbromoisobutyrate, for which a rate coefficient of activation was measured as ka = 1.1 x 10 6 M -1 s - 1 and 7.2 x 10 6 M -1 s -1 , respectively. This leads to an estimation of KATRP = 2.2 x10 -2 and 7.2 x10 -1 , respectively which indicated this is the most active ATRP catalyst to date. A large value of kd > 10 7 M -1 s -1 was calculated and indicated that the catalyst is also a good deactivator. Both ICAR and Ag 0 ATRP of acrylates were well-controlled using as little as 10 ppm of catalyst relative to

Scheme 1

 1 Scheme 1 Mechanism of ATRP (boxed) and equilibria involving association of ligand (β m ) and halide (β m x) to either the Cu I (m = I) or Cu II (m = II) ion.

×Figure 3

 3 Figure 3 A: Absorption spectra of the [Cu II (TPMA NMe2 )Br] + deactivator complex (red) and [Cu II (TPMA NMe2 )(MeCN)] 2+ complex (blue) in MeCN. [CuX2]0 = 1 mM (X = Br -or OTf -). Add MeCN to complex name B: Experimental (blue) and simulated (red) EPR spectrum of the [Cu II (TPMA NMe2 )Br] + deactivator complex in a 1:1 CH2Cl2/toluene mixture at 120K (g1 = 2.198, A1 = 336.5 MHz; g2 = 2.173, A2 = 255.3 MHz; g3 = 260.1, A3 = 260.1 MHz).

I 43 -Figure 4

 434 Figure 4 Cyclic voltammograms of (A) 1 mM [Cu(TPMA NMe2 )(MeCN)] 2+ and (B) 1 mM [Cu(TPMA NMe2 )Br] 2+ + 20 mM Et4NBr in dry MeCN at different scan rates using Et4NBF4 as a supporting electrolyte and glassy carbon working electrode; [L/Cu II ]0 = 1 mM.

Figure 5

 5 Figure 5 Cyclic voltammograms of [Cu(TPMA NMe2 )Br] + in the presence of methyl 2bromopropionate (MBrP; acrylate mimic) at (A) varying scan rates and (B) different [MBrP]0 in MeCN at scan rate 0.2 V s -1 at room temperature. In (A) current was normalized by dividing by square root of the scan rate. [MBrP]0:[TPMA NMe2 ]0:[CuBr2]0:[TEMPO]0 = 0-10:1:1:10; [CuBr2]0 = 1 mM.

Figure

  Figure6Ashows cyclic voltammetry of [Cu(TPMANMe2 )Br] + in the presence of more active ethyl α-bromoisobutyrate (EBiB; methacrylate mimic). With [EBiB]0 >> [Cu II (TPMA NMe2 )Br]0 a large increase of the cathodic current and complete disappearance of the anodic peak was observed, similar to the voltammograms in the presence of the less active MBrP. Simulation of the experimental voltammograms gave ka = 7.2 x 10 6 M -1 s -1 indicating that KATRP approaches unity. However, at a ratio of [Cu II (TPMA NMe2 )Br]0:[EBiB]0 = 1, an interesting cyclic voltammogram was observed where the cathodic wave splits into two peaks (Figure6B).

Figure 6 .

 6 Figure 6. Cyclic voltammograms of 1 mM [Cu(TPMA NMe2 )Br] + in the presence of ethyl αbromoisobutyrate (EBiB; methacrylate mimic) at (A) 5 mM (B) 1 mM concentration in MeCN at at room temperature. In (A) current was normalized by dividing by square root of the scan rate. [EBiB]0:[TPMA NMe2 ]0:[CuBr2]0:[TEMPO]0 = 1-5:1:1:10. Fix x axis

5 PDIFigure 7

 57 Figure 7 A) Semi-logarithmic plots and B) Mn and Ð vs. conversion for the ICAR ATRP of n-butyl acrylate (BA) at different [Cu II (TPMA NMe2 )Br][Br] loadings under the initial conditions [BA]0:[EBiB]0:[L/CuBr2]0:[TPMA NMe2 ]0:[AIBN]0 = 160:1:0.016-0.0016:0.2 in anisole at 60 °C; catalyst loadings in ppm vs. monomer; [BA]0 = 4.5 M.

Scheme 3

 3 Scheme 3 Interplay between conventional bimolecular radical termination (RT) and catalytic radical termination via the reactive L/Cu II -Pn intermediate in ATRP of acrylates.

5 PDIFigure 8

 58 Figure 8 A) Semi-logarithmic plots and B) Mn and Ð vs. conversion for the Ag 0 ATRP of methyl acrylate (MA) at different loadings of [Cu II (TPMA NMe2 )Br][Br] under the initial conditions [MA]0:[EBiB]0:[Cu II (TPMA NMe2 )Br][Br]0 = 200:1:0.02-0.002 with 10 cm Ag 0 wire (SA/V) = 0.53 cm -1 in DMF at 50 °C; catalyst loadings in ppm vs. monomer; [MA]0 = 5.75M and C) pictures of polymerization solution at decreasing catalyst loadings of [Cu II (TPMA NMe2 )Br][Br].

TPMAFigure 9

 9 Figure 9 Redox potential (E1/2) vs. log(KATRP) for various ATRP catalysts complexed by multidentate nitrogen-based ligands. Values for E1/2 have previously been determined experimentally vs. an SCE electrode in MeCN at room temperature. Values of KATRP are for ethyl -bromoisobutyrate (EBiB; methacrylate mimic) in MeCN at room temperature. Structures of all ligands are shown in Figure S11.

Table 1 Selected Bond Distances and Angles of Relevance for L/Cu II -Br Deactivator Species a [Cu II (TPMA)Br][Br] b [Cu II (TPMA* 3 )Br][Br] c [Cu II (TPMA NMe2 )Br][Br] d

 1 Bond lengths are given in angstroms (Å) and angles in degrees (°). b From Ref 51. c From Ref 42.

	Cu-N1ax	2.040(3)	2.028(3)	2.047(3)
	Cu-N2eq	2.073(15)	2.059(3)	2.051(2)
	Cu-N3eq	2.073(15)	2.149(3)	2.108(3)
	Cu-N4eq	2.073(15)	2.044(3)	2.046(3)
	Cu-Br1	2.384(6)	2.3740(5)	2.3898(6)
	N1-Cu-N2	80.86(5)	81.07(12)	80.59(10)
	N1-Cu-N3	80.86(5)	82.81(12)	80.60(10)

a

  Figure 4, both the [Cu(TPMA NMe2 )(MeCN)] 2+ and [Cu(TPMA NMe2 )Br] +complexes exhibit a reversible redox wave at E1/2 = -302 mV and -554 mV vs. SCE, respectively, representing the most reducing ATRP catalysts to date. Separation between the anodic and cathodic peaks is ca. 60 mV at a scan rate of 0.2 V s -1 , indicating good reversibility. Increasing the scan rate results in the expected increase in current; peak separation also increases, revealing a quasi-reversible nature of the electron transfer. This shows that the TPMA NMe2

				As shown in
																			sim.
																			exp.
																			2600	3100	3600 Field (G)
																			For
	efficient deactivation, β X II values must be high. Values of β X I should be low, since the [Cu I (L)Br] is
	an inefficient activator in ATRP. 58
	ln	II I β β		RT F	 E Cu o	2		/Cu			o LCu E	II	/LCu	I		(Eq. 1)
	ln	β β	I X II X		RT F	 E LCu o	II	/LCu I		o LCu E	II		X/LCu	I		X		(Eq. 2)

Table 2 .

 2 It should be noted that values of β I are significantly limited by unattainable values of Kdisp,LCu in MeCN. Redox potentials in V vs. SCE; ka in M -1 s -1 . a Taken from literature 61 . b Taken from Ref 43 , c Taken from Ref 46 using the conversion factor E o (Fc + /Fc) = 0.390 V vs. SCE. d From Ref 60 e Experimental limiting value of KDisp,LCu. f Estimated for acrylates based on values of E1/2,LCuBr based on trend of E1/2 vs. KATRP 43 g From Ref 62

	Table 2 Thermodynamic Properties of the [Cu(L)(MeCN)] 2+ and [Cu(L)Br] + Complexes in MeCN
	(L = TPMA, TPMA* 3 , TPMA NMe2 )
		TPMA	TPMA *3	TPMA NMe2
	a E1/2,Cu	1.06	1.06	1.06
	E1/2,LCu	-0.030 c	-0.177 b	-0.302
	E1/2,LCuBr	-0.240	-0.420	-0.554
	E1/2,Cu-E1/2,LCu	1.090	1.237	1.362

h From Ref 31 .

ACKNOWLEDGEMENTS

Support from the NSF (CHE 1707490) is acknowledged. We thank the Centre National de la Recherche Scientifique (CNRS) for support through the PICS06782 grant and through the Laboratoire International Associé (LIA) "Laboratory of Coordination Chemistry for Controlled Radical Polymerization". We are also grateful to the French Embassy in Washington D.C. for a Chateaubriand Fellowship to T.R. We would like to acknowledge Mateusz Olszewski for designing the graphical abstract for this manuscript.

monomer. Encouragingly, due to the high values of KATRP and low [TPMA NMe2 /Cu I ], unwanted side reactions involving Cu I such as catalytic radical termination (CRT) are suppressed leading to higher chain-end functionality. Furthermore, this catalyst can potentially allow for the successful ATRP of less active monomers. Investigations in this direction are currently ongoing in our laboratories.

AUTHOR INFORMATION

Corresponding Author: *(K.M.) Email: km3b@andrew.cmu.edu ◊ T.R. and M.F. contributed equally.

Notes

The authors declare no competing financial interest.


Dr Sanjib Banerjee

Dr Vincent Ladmiral

Antoine Debuigne

Dr Christophe Detrembleur

Rinaldo Poli
email: rinaldo.poli@lcc-toulouse.fr

Bruno Améduri
email: bruno.ameduri@enscm.fr

Dr B Ameduri

Dr A Debuigne

Prof R Poli

Organometallic Mediated Radical Polymerization of Vinylidene Fluoride

Keywords: alkyl cobalt species, block copolymer, organometallic mediated radical polymerization, one pot synthesis, vinylidene fluoride

An unprecedented level of control for the radical polymerization of vinylidene fluoride (VDF), yielding well-defined PVDF (up to 14,500 g/mol) with low dispersity (≤1.32), was achieved using organometallic mediated radical polymerization (OMRP) with an organocobalt compound as initiator. The high chain-end fidelity was demonstrated by the synthesis of PVDF-and PVAc-containing di-and tri-block copolymers. DFT calculations rationalize the efficient reactivation of both head and tail chain end dormant species.

Poly(vinylidene fluoride), PVDF, is the second largest commercially available fluoropolymer after polytetrafluoroethylene (PTFE). It exhibits remarkable properties such as hydrophobic and oleophobic properties, chemical resistance to acids and solvents, low dielectric constants and excellent weathering. [1] Hence, it finds uses in many high-tech applications in aerospace and aeronautical engineering, coatings, [1d] piezo/ferroelectric devices, [START_REF] Yang | [END_REF] backsheets for photovoltaic devices and functional membranes for water treatment. [3] VDF has a reactivity close to those of TFE [1b] and chlorotrifuoroethylene, [4] but it is not explosive and much less toxic. [1c] Reversible deactivation radical polymerization (RDRP) of VDF has only been achieved using two techniques: (i) iodine transfer polymerization (ITP), [1c, 5] and (ii) reversible addition fragmentation chain transfer (RAFT) polymerization. [6] Both techniques require the use of a radical initiator and a suitable chain transfer agent (CTA), which ensures the reversible degenerative transfer (DT) at the heart of ITP and RAFT. Both were shown to produce relatively well-defined diblock [1c, 5b, 5c, 6c, 7] and triblock [1c, 5b] copolymers. However, the chain defects resulting from head-to-head (HH, -CH2CF2-CF2CH2-) and tail-totail (TT, -CF2CH2-CH2CF2-) monomer additions impose limits on the molar masses (Mn) and dispersities (Đ) attainable with these techniques, as demonstrated in both ITP [5c] and RAFT [6c] polymerization. Upon transfer to the CTA, the HH additions generate less reactive species that lead to a slowdown of the degenerative chain transfer, a broadening of the molar mass distribution and a degradation of the control. [6c, 6d, 8] Ideally, a RDRP technique should reactivate both PVDF chain ends at the same rate. Asandei et al. [9] were able to reactivate the -CF2CH2-I terminated PVDF chains and to synthesize block copolymers using Mn2(CO)10 and a photoirradiation process in ITP. However, this was only possible using conventional radical polymerization. Liepins et al. [10] reported the synthesis of PVDF with a low content of HH chain defects using a modified Ziegler-Natta Catalyst, while Chung's group [11] used a trialkylborane/oxygen mixture as the initiating system, resulting in significant chain defects. However, the controlled nature of these polymerizations was not addressed. In terms of the coordination-insertion strategy for fluorinated alkenes, Jordan et al. [12] described the copolymerization of vinyl fluoride and ethylene using (phosphine-arenesulfonate)Pd(Me)(py) and phosphinebis (arenesulfonate)PdMe(py) catalysts, while Rieger and coworkers reported the copolymerization of 3,3,3-trifluoropropene with ethylene using (phosphine-sulfonate)Pd(Me)(DMSO) as catalyst. [13] However, these catalysts did not provide a very good control and, in addition, were not applied to the VDF homopolymerization or VDF-olefin copolymerization Among other RDRP techniques, organometallic-mediated radical polymerization (OMRP), in which a transition-metal complex reversibly traps the propagating polymer radicals, [14] has been successfully employed for the radical (co)polymerization of less reactive monomers, including vinyl acetate (VAc) [14a-c] and VAc-ethylene, [15] with Co II (acac)2 (acac = acetylacetonate) as controlling agent. However, there is no report of the application of this technique to homopolymerize fluorinated alkenes. We report here the first OMRP of a fluorinated monomer (VDF) under mild experimental conditions, leading to unprecedented control over the homopolymerization of this monomer (Scheme 1). Furthermore, macromolecular engineering was achieved using the in situ generated PVDF-Co(acac)2 macroinitiator to prepare well-defined PVAc and PVDF-containing diblock-and triblock copolymers (Scheme S1).

VDF homopolymerizations were carried out in dimethyl carbonate (DMC, a solvent with a low aptitude to transfer H atoms to PVDF radicals and which swells PVDF [1c] ) in a Hastelloy (HC 276) autoclave at 40 °C using [R0(VAc)~4Co III -(acac)2 as initiator (R0 = primary radical generated by V-70)], [16] abbreviated as R-Co III , at three [VDF]0/[R-Co III ]0 initial molar ratios (100, 200 and 300). Notably, no polymerization was observed when V-70/Co II (acac)2 was used at 40 °C or even at 50 o C. This shows that azo initiators are not able to initiate the polymerization of VDF [13] and justifies the choice of R-Co as initiating species. The selected temperature was the mildest one, allowing to attain a reasonable control. These polymerizations produced PVDFs with higher targeted molar masses (Mn = 5,900 to 14,500 g/mol) and lower dispersities (Đ ≤ 1.32) (P1-P3, Table S1 and Figure S1), than those achieved by ITP or RAFT under the same conditions.

1 H, 19 F and 13 C NMR enabled the structural analysis of the synthesized PVDFs, including the chain ends (see details in SI).

The recovered polymers, isolated after quenching with TEMPO (see SI, Figures S2-S4, P2, Table S1), showed the expected features (normal Head-to-Tail and reversed Head-to-Head and Tail-to-Tail monomer additions) of radically polymerized VDF, the -CF2H and -CH3 end-groups originating from transfer reactions to solvent, the characteristic signals of the oligo(VAc) group from the R-Co initiator ( 1 H NMR, Figure S2), and the TEMPO chain end ( 19 F NMR, Figure 2B and Figure S3). Notably, only the R0-(VAc)~4-CH2CF2-and not the R0-(VAc)~4-CF2CH2-αchain end could be identified, whereas both -CF2CH2-CH2CF2-TEMPO and -CH2CF2-CH2CF2-TEMPO ω-chain ends were visible at -66.5 and -61.5 ppm, respectively. The SI offers a more detailed discussion of these assignments.

Scheme 1. Mechanism of OMRP of vinylidene fluoride (VDF).

A polymerization kinetic study was carried out through a series of single point experiments (ranging from 0.5 to 24 h, entries 1-7, Table S2), with TEMPO quenching to eliminate the cobalt complex from the polymer chain-end. [17] The VDF conversion was determined gravimetrically, while the Mn and Đ values were assessed by SEC calibrated with poly(methyl methacrylate) standards (Table S2). The slope of the "linear" first order kinetic plot (Figure S5B) yields kp(app) = 9.6 x 10 -6 s -1 . This "point by point" kinetic study with seven independent runs demonstrates the reproducibility of the system. The SEC traces (Figure S6) remained narrow and monomodal throughout the polymerization. The Mn vs conversion plot (Figure 1) exhibits a monotonous linear increase, maintaining low Đ values (1.14-1.29), consistent with the features of RDRP. [5c] The evolutions of the -CF2CH2-TEMPO and -CH2CF2-TEMPO end groups as a function of VDF conversion, monitored by 19 F-NMR spectroscopy (Figures S7-S8) are very different from those observed in RAFT [6c] and ITP [18] . The -CH2CF2-TEMPO chain end proportion initially decreases, but subsequently stabilizes at 77% after 20% conversion.

Meanwhile, the proportions of intrachain TT and HH reverse additions (equations S4-S5), which remain close to each other as expected [6c] , increase gradually with VDF conversion (Figure S9), reaching a plateau at ca. 4%. The polymerization pursual at approximately the same rate after stagnation of the terminal HH and TT inversions demonstrates that both types of dormant chains, PVDF-CH2CF2-Co III (acac)2 and PVDF-CF2CH2-Co III (acac)2, are reactivated. Based on this result, we propose that the polymerization proceeds by a typical reversible termination mechanism with Co II (acac)2 as the radical trapping species (Scheme 1). S2).

[VDF]0/[R-Co]0 = 200.
The aptitude of both dormant species to reactivate may be evaluated from the results of a recent DFT study of the Co-C homolytic bond dissociation enthalpies (BDEs) in various (C2H5-nFn)Co(acac)2 molecules, with all possible F substitutions at the α and β positions. [19] The CH3CF2-Co III (acac)2 and CHF2CH2-Co III (acac)2 compounds, which may be considered as models of the head and tail dormant chains, yield BDEH = 27.4 kcal/mol and BDET = 26.0 kcal/mol, respectively, [19] for a BDE difference of 1.4 kcal/mol, which is very small. Even more strikingly, the tail chain-end yields a weaker bond than the head chain-end, predicting an easier reactivation of the tail dormant species. In the case of the CH3CF2-X and CHF2CH2-X models of the 'head' and 'tail' dormant species in ITP (X = I) and RAFT {X = SC(S)OMe}, on the other hand, the BDE is greater for the latter [ΔBDE = BDET -BDEH = 4.2 kcal/mol for I or 6.2 kcal/mol for SC(S)OMe]. [8,19] In order to further improve the model, the chain simplification was implemented only at the level of the δ C atom. Thus, PVDF-CF2CH2-Co III (acac)2 was modeled by CHF2CF2CH2-Co III (acac)2, for which the calculated BDE is 25.2 kcal/mol, and PVDF-CH2CF2-Co III (acac)2 was modeled by CHF2CH2CF2-Co III (acac)2 (product of a regular HT addition, BDE = 27.9 kcal/mol) and CH3CH2CF2-Co III (acac)2 (product of a TT addition, BDE = 27.4 kcal/mol). The computational details are given in the SI. Qualitatively, the bond strengths remain in the order PVDFT-Co III (acac)2 < PVDFH-Co III (acac)2, predicting no accumulation of the PVDFT-Co III (acac)2 in the medium (contrary to RAFT and ITP). In reality, the observation of a greater proportion of PVDFT-Co III (acac)2 dormant chains (Figure S8) relative to the in-chain errors means that the experimental bond strengths must be in the opposite order (PVDFT-Co III (acac)2 > PVDFH-Co III (acac)2), but the difference must be much smaller than in the corresponding ITP and RAFT dormant species. In addition to improved control in VDF homopolymerization, the labile carbon-metal bond in PVDF-Co III (acac)2 allowed reactivation for chain extension with VAc, leading to PVDF-b-PVAc diblock copolymers and increasing the scope of available PVDF-containing block copolymers. [6d, 20] The SEC chromatograms (Figure 2A) show a shift of the PVDF-Co III (acac)2 distribution (trace a, Mn = 4,100 g/mol, Đ = 1.27) toward higher molar masses upon chain extension to form the PVDF-b-PVAc diblock, while maintaining low Đ values (trace b, Mn = 10,300 g/mol, Đ = 1.28). As expected, the RI-SEC chromatograms of the PVDFs were negative (fluoropolymers have low refractive index). [1b, 6b, 21] 1 H and 19 F NMR spectra (Figures S10 and 2B,respectively) show the characteristic PVAc -CH(OAc)signal at 4.8 ppm and the VDF-VAc dyad -CF2signal at -93.3 ppm, confirming the product structure. [6d] Co III (acac)2-terminated polymers prepared by OMRP are known to undergo rapid chain-chain coupling upon addition of a conjugated diene, affording double-molecular weight terminated products [22] and allowing the facile synthesis of symmetric ABA triblock copolymers when starting from Co III (acac)2-terminated AB diblock copolymers. [22] Application of this technique to PVDFb-PVAc-Co III (acac)2 using isoprene as coupling agent yielded a symmetrical PVDF-b-PVAc-b-PVDF triblock copolymer (Scheme S1). The SEC chromatograms revealed that the Mn of the coupled product approximately doubled (19,900 g/mol vs 10,300 g/mol) while the dispersity remained low (Table S3).

As expected, the thermal stability of the produced PVDFs increases with increasing Mn (P1-P3, Table S1), as shown by the thermogravimetric analyses (TGA) (Figure S11). The melting points (Tm) of these samples, determined by differential scanning calorimetry, were similar (ca. 163 °C) (Figure S12). Expectedly, the degree of crystallinity increased from 34 to 54% (calculated using equation S3) with increasing Mn.

The thermal stabilities (TGA, Figure S13) of the PVAccontaining di-/tri-block copolymers were close to those of the PVDF homopolymers as evidenced by their Td,10% decomposition temperatures (Table S3). However, the di-and triblock copolymer displayed a Tg characteristic of the PVAc block (at ca. 35 °C) [23] and a reduced degree of crystallinity (≤8%) relative to neat PVDF (Table S3, Figures S15-S16).

In conclusion, this communication reports the first example of an organometallic-mediated radical polymerization (OMRP) of VDF and demonstrates an unprecedented level of control for this monomer, including the first synthesis of a block copolymer with successful transition to a second RDRP process. This was possible thanks to the facile reactivation of the dormant species formed after an inverted monomer addition, PVDFT-X, when X = Co III (acac)2, whereas the reactivation of these chains is inefficient in ITP (X = I) and RAFT (X = xanthate). Due to the remarkable properties of the fluorinated groups (low dielectric constant and interesting thermal, electroactive and surface properties), the resulting copolymers might find applications in high value added materials (e.g., coatings, binders for lithium ion batteries, piezoelectric devices, and membranes).

Figure 1 .

 1 Figure 1. Plots of Mn and Đ vs conversion for the OMRP of VDF initiated by R0(VAc)~4Co(acac)2 at 40 °C in DMC (TableS2).[VDF]0/[R-Co]0 = 200.

Figure 2 .

 2 Figure 2. A) SEC traces of the PVDF prepared by Co(acac)2-mediated OMRP (trace a, after 24 h), of the PVDF-b-PVAc diblock copolymer (trace b, after 24+24 h) obtained by chain extension with VAc, and of the PVDF-b-PVAc-b-PVDF triblock copolymer (trace c, after 24+24+16 h) prepared by chain coupling of the previous diblock copolymer using isoprene. B) 19 F NMR spectra of PVDF (bottom), of the PVDF-b-PVAc diblock copolymer (middle), and of the PVDF-b-PVAc-b-PVDF triblock copolymer (top).

Acknowledgements

Financial support from the French national agency (ANR grant FLUPOL) is greatly appreciated. C.D. and A.D. are Research Director and Research Associate by FNRS, respectively, and thank FNRS for financial support. This work was granted access to the HPC resources of CINES and IDRIS under the allocation (2006-2017)-086343 made by GENCI (Grand Equipement National de Calcul Intensif) and to the resources of the CICT (Centre Interuniversitaire de Calcul de Toulouse, project CALMIP).

Entry for the Table of Contents

COMMUNICATION

Towards new possibilities: An unprecedented organometallic mediated radical polymerization (OMRP) of VDF yielded well-defined PVDF (at least up to 14,500 g/mol) with low dispersity (≤1.32). The experimental findings show that both head and chain ends exhibits reactivation and these experimental findings are supported by DFT calculations.


Background: Obesity in children is considered the main childhood health problem. Objective: To assess the impact of 7-year community-based interventions on the trend prevalence of overweight and obesity in French preschool children and primary school children between 2008 and 2015. Methods: Two cross-sectional studies were performed in last grade of every pre-school and primary schools of 6 cities in 2008 and 2015. In 2008 and 2015, 3387 children and 3415 children (aged 5 and 11 years old) participated in the 2 surveys. Interventions consisted to promote physical activity, healthy dietary, sleep habits and well-being. Prevalence of overweight and obesity were defined according to age-and sex-specific BMI cut-off points.

Priority education area of the schools was also recorded.

Results: Prevalence of overweight and obesity decreased significantly between 2008 and 2015 in children from pre-schools (18.1% vs 13.0%) and primary schools (20.9% vs 16.9%) (P < 0.05). No effects of priority education area and sex were found related to the decrease of prevalence in overweight and obesity.

Conclusions:

Our results show that over 7 years period, the community-based intervention have a positive impact on the overweight and obesity prevalence in childhood. These results are promising and encouraging in addressing obesity and related issues in French young boys and girls.

INTRODUCTION

Obesity in children is considered the main childhood health problem in European countries. Indeed, the prevalence of obesity has tripled in European countries in the last 30 years, especially in young people. [START_REF]NCD-RisC). Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128•9 million children, adolescents, and adults[END_REF] In a recent systematic review and meta-analysis, it was shown that the prevalence of overweight and obesity in children and adolescents was very high, although trends have stabilized in most European countries, especially in France. [START_REF] Garrido-Miguel | Prevalence and Trends of Overweight and Obesity in European Children From 1999 to 2016: A Systematic Review and Meta-analysis[END_REF] Many studies have demonstrated that paediatric obesity has a number of health consequences for physical, social and psychological parameters in children and adolescents. [START_REF] Hruby | Determinants and Consequences of Obesity[END_REF] Equally alarming is that 40-70% of obese children will remain obese in adulthood. In addition, this persistence of paediatric obesity into adulthood can lead to developing important risk factors for type 2 diabetes, coronory heart diseases, some types of cancers and increased early mortality. [START_REF] Llewellyn | Childhood obesity as a predictor of morbidity in adulthood: a systematic review and meta-analysis[END_REF] All these consequences lead to a considerable long-term health and economic burden. [START_REF] Wang | Health and economic burden of the projected obesity trends in the USA and the UK[END_REF] Studies have elucidated the role of dietary and lifestyle factors in obesity, especially sugarsweetened beverages, poor diet quality, physical inactivity, prolonged screen time, short sleep duration or shift work and built environment characteristics. [START_REF] Hruby | Determinants and Consequences of Obesity[END_REF][START_REF] Karalexi | Nonnutritive sweeteners and metabolic health outcomes in children: a systematic review and meta-analysis[END_REF][START_REF] Thompson | Food purchased away from home as a predictor of change in BMI z-score among girls[END_REF][START_REF] Ludwig | Relation between consumption of sugarsweetened drinks and childhood obesity: a prospective, observational analysis[END_REF][START_REF] Saunders | Screen time and health indicators among children and youth: current evidence, limitations and future directions[END_REF][START_REF] Fatima | Sleep quality and obesity in young subjects: a metaanalysis[END_REF][START_REF] Arble | Impact of Sleep and Circadian Disruption on Energy Balance and Diabetes: A Summary of Workshop Discussions[END_REF] Many intervention studies taking into account these variables for the treatment of overweight and obesity in children and adolescents have been performed, although with limited success. [START_REF] Mead | Diet, physical activity and behavioural interventions for the treatment of overweight or obese children from the age of 6 to 11 years[END_REF] Because the prevalence of childhood overweight and obesity remains high, and intervention effectiveness has shown low success in the short and long term, prevention is now widely pinpointed as crucially important in the treatment of obesity. For some years, an original strategy has been emerging, based on multilevel, community-based approaches to addressing childhood obesity prevention [START_REF] Khambalia | A synthesis of existing systematic reviews and meta-analyses of school-based behavioural interventions for controlling and preventing obesity[END_REF][START_REF] Hollar | Effective multi-level, multi-sector, schoolbased obesity prevention programming improves weight, blood pressure, and aca-demic performance, especially among low-income, minority children[END_REF][START_REF] Vinck | Downward trends in the prevalence of childhood overweight in two pilot towns taking part in the VIASANO community-based programme in Belgium: data from a national school health monitoring system[END_REF][START_REF] Romon | Downward trends in the prevalence of childhood overweight in the setting of 12-year school-and community-based programmes[END_REF][START_REF] Wolfenden | A systematic review and meta-analysis of whole of community interventions to prevent excessive population weight gain[END_REF] , which is considered to be more effective. [START_REF] Bemelmans | Overview of 71 European community-based initiatives against childhood obesity starting between 2005 and 2011: general characteristics and reported effects[END_REF] However, data about this type of intervention are still scarce. [START_REF] Bleich | Systematic review of community-based childhood obesity prevention studies[END_REF] Moreover, available data in France are old; for example, Romon et al reported a substantial and significant decrease in the prevalence of overweight in children between 1992 and 2000 in two towns in northern France. [START_REF] Romon | Downward trends in the prevalence of childhood overweight in the setting of 12-year school-and community-based programmes[END_REF] With children spending an increasing time in sedentary activities in the last two decades, and a prevalence of obesity that is stable but high, there is a real need to pursue the development of prevention programmes throughout France and to assess the current effectiveness of these interventions. Therefore, the aim of this study was to assess the changes in prevalence of overweight and obesity in French preschool children and primary school children between 2008 and 2015.

METHODS

Study design and participants

This study used data from the VIF (Vivons en Forme, "live healthy") Programme. The VIF organization is a continuation of the obesity prevention scheme previously called EPODE (Ensemble Prévenons l'Obésité des Enfants), a community-based prevention programme aimed at promoting healthier lifestyles among children and their families, involving municipal services in charge of child education and care. [START_REF] Borys | EPODE approach for childhood obesity prevention: methods, progress and international development[END_REF] Actions included in the VIF intervention scheme aim at improving eating and physical activity habits among children. In addition, the VIF Programme includes also an approach based on a social marketing framework to improve our targeted behavioural intervention programmes. [START_REF] Raffin | Can social marketing improve health programs' efficiency ?[END_REF][START_REF] Gurviez | Social Marketing Campaigns for Healthier Eating Habits in France[END_REF] The community-based intervention based on VIF methodology leads to the mobilization of four complementary levels of implementation: central and local organizations, the local setting and the child lifestyle level.

The VIF Programme has been described in detail elsewhere. [START_REF] Borys | EPODE approach for childhood obesity prevention: methods, progress and international development[END_REF][START_REF] Henley | Preventing childhood obesity: evidence policy and practice. Social marketing to prevent childhood obesity[END_REF][START_REF] Pettigrew | Process evaluation outcomes from a global child obesity prevention intervention[END_REF] Mobilizing these local stakeholders within a co-creation process, the intervention is organized around pluri-annual themes of focus, such as considering the food portion size [START_REF] Gurviez | Social Marketing Campaigns for Healthier Eating Habits in France[END_REF] , indulging product management or enhancing water consumption, or how to be more physically active via extra-curricular activities and at home. Each theme is built up according to a full social marketing methodology. [START_REF] Carins | Eating for the Better: A Social Marketing Review (2000-2012)[END_REF] Hence, the approach is designed to empower in a sustainable manner the local relays thanks to comprehensive training programmes carried out by the VIF teams. The final objective is to train the instructors to host practical workshops involving children and families, thereby benefiting from the dedicated tool-kits based on the identified constraints and motivation levers linked to each behaviour change. For this methodology, a personal from the VIF association formed local project managers designed in each community by the mayor.

The role of the local project manager is to mobilize a wide diversity of local stakeholders, especially in schools, pre-schools, extracurricular organizations and any social network of associations, which are key settings to implement activities with children and families. Topics addressed during this health prevention program were dietary intake and physical activity in order to promote the health lifestyle. Severals thematics were discussed with children: (i) breakfast, (ii) morning snack, (iii) snacking, (iv) importance of hydration, (v) food groups, (vi) fruits, (vii) daily physical activity. In addition, workshops have been set up on several occasions with children, but also with parents.

All cities in France were invited to participate to the program, with each mayor deciding whether to participate or not. If the invitation was accepted, the VIF methodology was implemented in the town, as previously described. For the present analysis, two crosssectional surveys in French preschool children and primary school children were conducted in 2008 and 2015 in six towns (Beauvais, Meyzieu, Royan, Douchy-les-Mines, Saint-Quentin and Vitré). Five of these same towns (except Vitré) were included in the last grade of preschool, and all six towns for the last grades in primary school. All schools were enrolled in the VIF Programme. For this present analysis, all school children aged 5-6 years (i.e., the last grade of preschool) and 10-11 years (i.e., the last grade of primary school) who were living in the towns that participated in 2008 and 2015 were included. A total of 7264 children took part in the two surveys, among whom there were 6802 children with complete data for height, body weight, age and sex and were thus included in the present analysis. In 2008 and 2015, 3387 children (1756 boys, 1631 girls) and 3415 children (1750 boys, 1665 girls) participated, respectively. Sample characteristics are shown in Table 1.

All data obtained from this program were anonymized, and declared and approved by the Commission Nationale de l'Informatique et des Libertes (National Commission on Informatics and Liberty). The program were explained to both children and their parents living in the participating town, after which the children or their parents could accept or decline record anonymously their information technology data. Data were recorded by the responsible of the town and to communicate to the VIF association by an electronic data system. An audit of the complete dataset was performed, and aberrant data were excluded.

Measurements

Physical measurements including weight, height and body mass index (BMI) were performed by school physicians and/or school nurses. Body weight was measured to the nearest 0.1 kg using an electronic scale with the participant wearing light clothes and without shoes. Height was measured without shoes to the nearest 0.1 cm using a standard physician's scale. BMI was calculated as weight/height squared (kg/m 2 ). Obesity and overweight prevalence were calculated according to International Obesity Task Force (IOTF) cut-offs. [START_REF] Cole | Extended international (IOTF) body mass index cut-offs for thinness, overweight and obesity[END_REF]

Statistical analysis

Results are expressed as means, standard deviations for continuous variables, and frequencies and percentages for categorical variables. Children's main characteristics were described according to the survey year (2008 vs. 2015). The magnitude of the between-survey differences was assessed by calculating the absolute standardized differences; an absolute standardized difference >20% was interpreted as meaningful. Comparisons in combined and individual prevalences of overweight and obesity between the two surveys (2008 vs. 2015) were carried out using a mixed logistic regression model by including towns as random effect to account for the clustering effect. Odds ratios (ORs) were derived from models as effect size. Analyses were performed in preschool and primary school grades separately and key subgroup analyses on priority education area (i.e socio-economic environment: low or high) and sex were conducted. Heterogeneity in between-period difference across subgroups was tested by including the corresponding interaction term into the mixed logistic regression model. All statistical tests were two-sided and performed at the 0.05 level. Data were analysed with SAS version 9.4 (SAS Institute, Cary, NC, USA).

RESULTS

Table 1 shows the characteristics of the population studied in 2008 and 2015 for both school grades (preschool and primary school). Excepted for age and body mass in last grade preschool group (ASD > 20%), there is no meaningful differences in main study population characteristics. In last grade of preschool, the study population in 2008 have a higher age (~0.1 years on average) and body mass (~0.7 kg) compared to 2015. Comparisons of the prevalence in overweight and obesity between 2008 and 2015 for both school grades are presented in Table 2. By applying recommended international standards, it can be seen that the combined prevalence of overweight and obesity decreased significantly between 2008 and 2015 in preschool children (18.1% vs. 13.0%; OR, 0.67; 95% CI, 0.57 to 0.79). This decrease was observed in children in priority education areas (OR, 0.64; 95% CI, 0.50 to 0.82) as well as in children not in priority education areas (OR, 0.69; 95% CI, 0.55 to 0.86; p for heterogeneity = 0.70). Similarly, there is no evidence of a difference in decrease from 2008 to 2015 according to sex (Table 2; p for heterogeneity = 0.87). When overweight and obesity were differentiated, a decrease in prevalence was observed for both overweight (12.6% vs. 9.2%, OR, 0.70; 95% CI, 0.58 to 0.84) and obesity (5.5% to 3.8%; OR, 0.67; 95% CI, 0.50 to 0.89). Similar results were found for primary school children (Table 2) with a combined prevalence of overweight and obesity of 20.9% in 2008 and 16.9% in 2015 (OR, 0.78; 95% CI, 0.63 to 0.96). The specific prevalence of overweight was 16.6% in 2008 compared with 13.0% in 2015 (OR, 0.77; 95% CI, 0.61 to 0.97) and the specific prevalence of obesity was 4.3% in 2008 vs. 3.8% in 2015 (OR, 0.88; 95% CI, 0.58 to 1.33).

DISCUSSION

The study assessed the effects of a 7-year community-based intervention on the trend in prevalence of overweight and obesity in French children. Findings from our study are important because studies have shown that childhood overweight and obesity are associated with a number of social, psychological and physical health problems. [START_REF] Reilly | Long-term impact of overweight and obesity in childhood and adolescence on morbidity and premature mortality in adulthood: systematic review[END_REF] Short-and long-term health outcomes associated with overweight and obesity in children and adolescents are important issues influencing public health policy. There is now a growing body of data on the intervention and prevention of childhood obesity in many countries worldwide. Indeed, in recent decades, the number of studies aiming to reduce the prevalence of obesity and overweight in youth that target their intervention towards daily physical activity and sedentary and dietary behaviours has increased significantly. [START_REF] Mead | Diet, physical activity and behavioural interventions for the treatment of overweight or obese children from the age of 6 to 11 years[END_REF] That said, most of these studies have shown limited effectiveness of interventions, which may be explained by the large variation in study design, intervention duration and study quality (methodological bias). [START_REF] Mead | Diet, physical activity and behavioural interventions for the treatment of overweight or obese children from the age of 6 to 11 years[END_REF] A potential major bias concerns follow-up times, which vary considerably from one study to another. Indeed, in most cases, the length of time for which interventions were conducted was too short to obtain a positive result on obesity or weight status, and without follow-up in subsequent years. Some studies have shown encouraging results but with a specific approach towards the prevention of childhood obesity and overweight. [START_REF] Khambalia | A synthesis of existing systematic reviews and meta-analyses of school-based behavioural interventions for controlling and preventing obesity[END_REF][START_REF] Hollar | Effective multi-level, multi-sector, schoolbased obesity prevention programming improves weight, blood pressure, and aca-demic performance, especially among low-income, minority children[END_REF][START_REF] Vinck | Downward trends in the prevalence of childhood overweight in two pilot towns taking part in the VIASANO community-based programme in Belgium: data from a national school health monitoring system[END_REF][START_REF] Romon | Downward trends in the prevalence of childhood overweight in the setting of 12-year school-and community-based programmes[END_REF][START_REF] Wolfenden | A systematic review and meta-analysis of whole of community interventions to prevent excessive population weight gain[END_REF] It has been noted by some health professionals and researchers that successfully addressing childhoodonset obesity requires multilevel (individual, community and governmental) and multi-agency collaboration. [START_REF] Bemelmans | Overview of 71 European community-based initiatives against childhood obesity starting between 2005 and 2011: general characteristics and reported effects[END_REF] As central institutions for the socialization of children and as a hub of community-wide activities, schools are ideal locales for organizing obesity-prevention programmes. The VIASANO community-based programme aimed to reduce the prevalence of overweight in two pilot towns in Belgium among children aged 3-4 and 5-6 years. [START_REF] Vinck | Downward trends in the prevalence of childhood overweight in two pilot towns taking part in the VIASANO community-based programme in Belgium: data from a national school health monitoring system[END_REF] The preliminary results of the 3-year follow-up (2007-2010) showed a decrease in the prevalence of overweight (-2.1%) and obesity including overweight (-2.4%). [START_REF] Vinck | Downward trends in the prevalence of childhood overweight in two pilot towns taking part in the VIASANO community-based programme in Belgium: data from a national school health monitoring system[END_REF] An earlier study in France, with a 12-year follow-up (1992-2004) included two towns with an intervention following a community-based approach and two other towns with no intervention. [START_REF] Romon | Downward trends in the prevalence of childhood overweight in the setting of 12-year school-and community-based programmes[END_REF] After 12 years, it was shown that the prevalence of overweight was significantly lower (8.8%) in the two towns receiving the intervention compared with those with no intervention (17.8%). Thus, the results from the present study concord with previous findings. [START_REF] Khambalia | A synthesis of existing systematic reviews and meta-analyses of school-based behavioural interventions for controlling and preventing obesity[END_REF][START_REF] Hollar | Effective multi-level, multi-sector, schoolbased obesity prevention programming improves weight, blood pressure, and aca-demic performance, especially among low-income, minority children[END_REF][START_REF] Vinck | Downward trends in the prevalence of childhood overweight in two pilot towns taking part in the VIASANO community-based programme in Belgium: data from a national school health monitoring system[END_REF][START_REF] Romon | Downward trends in the prevalence of childhood overweight in the setting of 12-year school-and community-based programmes[END_REF][START_REF] Wolfenden | A systematic review and meta-analysis of whole of community interventions to prevent excessive population weight gain[END_REF] In our study, with its multilevel, community-based approach to childhood obesity prevention over 7 years, the combined prevalence of overweight and obesity in youth decreased significantly between 2008 and 2015 in preschool children (18.1% vs. 13.0%) and primary school children (20.9% vs. 16.9%). Our results also indicated a decrease in prevalence rates separately of overweight and obesity for each age range (i.e., preschool and primary school). Compared with national data on the prevalence of childhood overweight and obesity during the same period, the towns included in the prevention programme had prevalence rates that were lower than in other towns without such programmes. [START_REF] Vanhelst | Prevalence of overweight, obesity, underweight and normal weight in French youth from 2009 to 2013[END_REF] Thus, our study updates findings and information from previous work. [START_REF] Vinck | Downward trends in the prevalence of childhood overweight in two pilot towns taking part in the VIASANO community-based programme in Belgium: data from a national school health monitoring system[END_REF][START_REF] Romon | Downward trends in the prevalence of childhood overweight in the setting of 12-year school-and community-based programmes[END_REF] Indeed, our results show homogeneity in the effectiveness of the prevention programme in the two age groups, with a decrease in both boys and girls, as well as in children in priority education areas and not in priority education areas. These results are encouraging and suggest that the VIF Programme may be a good strategy for reducing the rates of prevalence of childhood overweight and obesity over an extended period of time.

However, findings from this study need further assessment including on longer-term impacts on health. Indeed, a major limitation of the intervention and prevention programmes to treat overweight and obesity concerns the follow-up assessment over a period of time. In addition, in our study, the final point of measurement was when children were 10 years old, that is, before puberty and adolescence. This issue is important because adolescence is a crucial period in life that includes multiple physiological and psychological changes that have a considerable effect on physical activity and dietary habits, and consequently on weight status. [START_REF] Lake | Long-itudinal change in food habits between adolescence (11-12 years) and adulthood (32-33 years): the ASH30 Study[END_REF][START_REF] Corder | Change in physical activity from adolescence to early adulthood: a systematic review and meta-analysis of longitudinal cohort studies[END_REF] Low habitual physical activity in adolescents and children-characteristic of modern sedentary living-may be the dominant factor in increasing obesity. [START_REF] Prentice | Obesity in Britain: gluttony or sloth?[END_REF] Therefore, it would be valuable to continue the programme in participating towns into adolescence and adulthood to gain a complete picture of the impact of these school and community-based interventions. It has been suggested that long-term results may be achieved through ongoing support from society as a whole, including parents, schools and government agencies, but this notion needs to be examined. [START_REF] Ockene | Integrating evidence-based clinical and community strategies to improve health[END_REF] Finally, by applying recommended international standards, it can bee seen that the prevalence of combined childhood overweight and obesity was higher in girls compared with boys (in preschool and/or primary school) (21.5% vs. 17.7% for girls and boys, respectively). Our data thus reflect previous investigations carried out in France and other countries that reported prevalence rates of overweight and obesity that were significantly higher in girls compared with boys. [START_REF] Garrido-Miguel | Prevalence and Trends of Overweight and Obesity in European Children From 1999 to 2016: A Systematic Review and Meta-analysis[END_REF][START_REF] Vanhelst | Prevalence of overweight, obesity, underweight and normal weight in French youth from 2009 to 2013[END_REF][START_REF] Ncd-Risc | Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19$2 million participants[END_REF][START_REF] Rokholm | The levelling off of the obesity epidemic since the year 1999--a review of evidence and perspectives[END_REF] The current study has both strengths and limitations. The main strength is the model and implementation scheme of the intervention programme. Our study was developed as a crosscutting community-based prevention programme involving municipal services in charge of child education and care (i.e., schools, preschools, local sports and parents' associations, catering structures, health professionals, elected representatives, and local stakeholders from the public and private sectors). Another strength involves the study's large, diverse sample of children from across France with sex-specific information, and the harmonization and standardization of assessment of anthropometric measurements. However, although the present data derive from a large country-wide sample, this study did not use a stratified sample design. Therefore, it is not possible to assume that the studied cohort is fully representative of the populations of French children and adolescents. We did not also excluded the confusion bias between the two study periods regarding the study population characteristics. Another limitation concerns the absence of a control group. Because there was no randomized control group (school or town control), our results should be interpreted with caution. Indeed, we cannot attribute all of the reductions to obesity to the intervention against background trends of reductions in obesity in routine surveys. We must consider that the findings are preliminary, although encouraging.

In summary, the results of a 7-year community-based intervention are promising for addressing obesity and related issues in French youngsters, regardless of sex or socioeconomic environment. Thus, the VIF Programme may potentially play a role in the prevention of childhood overweight and obesity.

Competing of interests statement

The authors do not have any competing interests. This study is made possible by contributions of participating cities to the VIF programme, and by private financial supports established within a rigorous ethical framework of the "Ferrero, Assurance prevention, Fondation Nestlé France and Fondation Roquette". The content of this paper reflects only the authors' views, and "Ferrero, Assurance prevention and Fondation Roquette" are not liable for any use that may be made of the information contained therein.

Table 1 .

 1 Characteristics of the population studied (3296 girls and 3506 boys)Values are mean ± standard deviation unless otherwise as indicated. ASD indicates absolute standard difference.

	2008	2015	ASD, %
	(n=2253)	(n=2242)

Acknowledgements

The authors thank all participating, cities, school physicians and nurse, youths, directors and teachers of the schools for their collaboration in the study.

Each author of this article significantly contributed to the study, especially: JV, GB, SR, AD and MR designed research; JV, GB, SR and MR conducted research; VD and AD analyzed data; JV, GB, SR, and MR wrote the paper; VD analyzed data and performed statistical analysis ; MR had primary responsibility for final content. All authors read and approved the final manuscript.