SYNTHESIS, MOLECULAR MODELING AND CHARACTERIZATION OF NEW POLYPHENOLIC DENDRONIZED POLYMERS VIA ROMP Florent Allais, 1 Alexandre Lancelot, 1 Florian Pion, 1 Karim Mazeau, 2 Stéphane Méry 3 and Paul-Henri Ducrot 1 1 INRA Centre de Versailles-Grignon, UMR1318 Institut Jean-Pierre Bourgin F-78026 Versailles Cedex France 2 CERMAV, F-Grenoble France 3 IPCMS, F- Strasbourg France Introduction The quest for larger well-defined molecular objects drove chemists to work on new extensions of the dendrimer concept, 1 one of which is the use of a polymer as a polyfunctional, polydisperse core. In the ideal case, the focal points of the dendrons are connected to the pending functional groups at every repeating unit along the polymer backbone. The result is a special case of a graft copolymer 2,3 or, in the case of complete coverage, a comb polymer, 2,3 with the particular feature that all of the side chains are dendrons. Polymers with this architecture are referred to as ‘dendronized polymers’. 4 Dendronized polymers were first introduced in 1987 by Tomalia. 5-7 Research on dendronized polymers has meanwhile developed into a whole new and growing field at the interfaces of organic chemistry, polymer synthesis, and materials science. 4,8-11 ROMP of norbornenyl bearing dendrons is an attractive method for the synthesis of dendronized polymers bearing sterically hindered dendrons, since the relief of ring strain in norbornenyl group results in a strong thermodynamic driving force for the polymerization. 12,13 The absence of chain-transfer and termination reactions in such polymerizations allows the production of homopolymers and block copolymers of low molecular dispersity, along with the control of terminal group in the initiation site and in the termination site. Another advantage of ROMP over classical living polymerization is that this reaction uses milder and less drastic conditions due to the tolerance of Grubbs’ catalyst to a large number of functional groups and impurities. In addition, the pendant dendrons on a poly(norbornene) dendronized polymer are placed further apart along the backbone compared to a homopolymer of vinyl functional dendrons, resulting in a less sterically demanding environment. 14 The focus of this paper is the synthesis, molecular modelling and characterization of new polyphenolate-dendronized polymers from diastereopure endo norbornene-based macromonomers using ROMP in the presence of Grubbs’ 1 st and 2 d generation catalysts. Experimental Materials. All reagents were purchased from the Aldrich Chemical Co and used without further purification. Dichloromethane (DCM) and tetrahydrofuran (THF) were distilled over calcium hydride and benzophenone/sodium respectively prior use. Instrumentation. Gel permeation chromatography (GPC) was used to determine molecular weights of polymer samples with respect to polystyrene standards. 1 H and 13 C spectra were obtained on a Varian Gemini. Molecular modelling has been realized using Cerius 2 and Material Studio from Accelrys with Universal Force Field methods. Steglich coupling general procedure To a solution of carboxylic acid (1 equiv) and alcohol (1 equiv) in DCM (C = 0.2 M) at r.t. was added DIC (1 equiv) and DMAP (0.5 equiv). The mixture was stirred at r.t. until completion (TLC). The crude mixture was filtered on Celite®. The filtrate was concentrated in vacuo and the crude solid was purified by flash chromatography (cyclohexane–AcOEt) to yield the pure ester. Synthesis of 3,5-bis(benzyloxy)benzoic acid (G1-2) 3,5-bis(hydroxy)benzoic acid (10.0 g, 64.9 mmol, 1 eq) was dissolved in DMF (65 mL) in presence of K 2 CO 3 (49.4 g, 357 mmol, 5.5 eq). BnBr (31 mL, 260 mmol, 4 eq) was then added dropwise and the mixture was kept at 40 °C for 3 hours. The reaction mixture was then filtered, and diluted with water (150 mL). The aqueous layer was extracted with Et 2 O (3 x 150 mL). The organic layers were combined, dried over anhydrous MgSO 4 , filtered and the solvent was removed in vacuo. The crude product was then dissolved in H 2 O/EtOH (50/50, 400 mL) along with NaOH (80.0 g, 2 mol, 31 eq) and refluxed for 2 hours. After cooling to room temperature, the solution was acidified to pH 2 using concentrated HCl. After cooling to 0 °C, the white precipitate was filtered and recrystallized from MeOH. Pure G1-2 was then obtained as white fluffy crystals (78 %). Synthesis of tert-butyl 3,5-dihydroxybenzoate (3) DCI (30 mL, 193.7 mmol, 1 eq.) was mixed with t-BuOH (21.4 mL, 223.8 mmol, 1.15 eq.) in the presence of CuCl (278.6 mg, 2.81 mmol, 0.01 eq.). The reaction mixture was stirred at room temperature for 21 days. Then, it was diluted with hexane and filtered on Celite © . Solvents were evaporated in vacuo to get tert-butyl N,N'-diisopropylcarbamimidate as a green liquid (27,16 g, 70%). G1-2 (3.71 g, 11.19 mmol, 1 eq.) was mixed with tert-butyl N,N'- diisopropylcarbamimidate (9.375 g, 46.78 mmol, 4.2 eq.) into DCM (78 mL). The reaction mixture was stirred at room temperature for 17 hrs, and the solvent removed in vacuo. Crude tert-butyl 3,5-bis(benzyloxy)benzoate was purified on silica gel (cyclohexane:AcOEt 9:1) to give a white powder (3.25 g, 75 %). tert-butyl 3,5-bis(benzyloxy)benzoate (3.26 g, 8.26 mmol, 1 eq.) was dissolved into EtOH (41.8 mL) and was stirred under argon for 15 min. Then, Pd/C (10%) was added and the reaction mixture was placed under H 2 flow. The reaction mixture was stirred at room temperature until completion. Finally, after filtration on Celite © and removal of the solvents in vacuo, 3 was obtained as a white solid (1.70g, 98 %). Debenzylation through catalytic hydrogenation Benzylated compound was dissolved into AcOEt and/or EtOH (C = 0.02 M) and stirred under argon flow before adding Pd/C (10% w). The reaction was stirred at room temperature under H 2 flow until completion, then filtered on Celite®. Solvent was evaporated and the crude product purified on silica gel. Selective t-Butyl ester saponification via TFA treatment t-Butyl ester (1 eq) was dissolved in DCM (C = 0.05 M) before adding TFA (10 eq). The mixture was stirred at room temperature until completion. Toluene was then added and solvents were evaporated under vacuum to get pure carboxylic acid. ROMP general procedure G1-2 (401 mg, 0.91 mmol, 1 eq.) was dissolved into dried and degassed DCM (1.5 mL) and was stirred under argon during 15 min. Grubbs’ second generation catalyst (17.7 μmol.mL -1 in DCM) was added. The reaction mixture was stirred under argon for 1-3 days. Ethyl vinyl ether (0.5 mL) was added and the reaction mixture was stirred at room temperature for 2 hours. The mixture was then filtered on alumina. Solvent was evaporated in vacuo. Crude product was dissolved into a tiny amount of DCM and was precipitated in MeOH. The precipitate was then filtered to give G1-3. The polymer was dried in vacuo for 48 h. Results and Discussion Synthesis of macromonomers. The dendronized macromonomers used in this study were synthesized according to Scheme 1 starting from the readily available diastereopure 5- norbornene-2-methanol endo 1 15 and the corresponding dendrons G1-2, G2-2 and G3-2. The 5-norbornene-2-methanol was chosen for two main reasons: this compound has a large ring strain and can be polymerized by ROMP using Grubbs’ first and second generation catalysts at room temperature. Second, preformed dendrons can be efficiently esterified to the free alcohol using Steglich carbodiimide-mediated esterification. Finally, the use of diastereopure norbornene derivatives warrants the obtention of a highly stereospecific organization of the polymer backbone, thus allowing a close-to- perfection coil-like spatial distribution of the dendrons along the poly(norbornene) chain. As depicted in scheme 2, the synthesis of the dendrons is based on orthogonal protection/deprotection chemistry and carbodiimide esterifications. The t-butyl and benzyl groups were selected because of their near quantitative cleavages (using TFA or H 2 on Pd/C, respectively) and relative ease of introduction at multigram scale. The crude dendrons were efficiently purified by flash liquid chromatography eluted with a gradient of ethyl acetate and cyclohexane. O O O O OBn BnO OBn OBn O OH HO O Ot-Bu CO2H OBn BnO Ot-Bu DIC, DMAP DCM, rt 1) H2, Pd/C, rt 2) G1-2, DIC, DMAP DCM, rt 3) TFA, DCM, rt G2-2 G3-2 TFA DCM rt G1-2 3 Polymer Preprints 2011, 52(2), 379