Ramanjaneyulu Rayala

Alain Giuglio-Tonolo

Julie Broggi Broggi

Thierry F Terme

Patrice Vanelle

Patricia F Theard

Maurice F Médebielle
email: maurice.medebielle@univ-lyon1.fr

Stanislaw F Wnuk
email: wnuk@fiu.edu

Patricevanelle

Studies toward the oxidative and reductive activation of C-S bonds in 2'-S-aryl-2'-thiouridine derivatives

Keywords: Cyclic Voltammetry, Desulfurization-Fluorination, Fluorination, Nucleosides, Organic Electron Donors, Reductive Desulfonylation

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Introduction of fluorine atom(s) into nucleosides dramatically changes their electronic and steric properties,giving them a wide range of biological activity. [1][2][3] Prominent examples of C2' fluorinated nucleosideswith potent biological activities include anticancer drugs gemcitabine, [4][5][6] and clofarabine; 7,8 and hepatitis C virus drug sofosbuvir. 9,10 In the last 40 years, numerous methods for the incorporation of fluorine atoms into organic molecules have been developed, as summarized in excellent reviews. 11- 16 Despite these developments, construction of the tertiary fluorinated stereocenter at the sugar C2' (e.g. sofosbuvir) has been still challenging. 17 Oxidative desulfurization-(di)fluorination is an important fluorination protocol for the preparation of fluoro organic compounds. 16,18 Various reagents or reagent-combinations developed for this approachare known and are based mostly on the combination of an oxidant [e.g., N-halosuccinimides (NBS, NIS) or 1,3-dibromo-5,5-dimethylhydantoin (DBH)] and a potentially hazardous fluoride source [e.g., HFpyridine, [19][20][21] iodine pentafluoride (IF 5 ), [22][23][24] air-and moisture-stable IF 5 -pyridine-HF reagent, 25,26 orBrF 3 -KHF 2 ]. 27 In addition to these chemical approaches, direct and indirect (with the use of a redox mediator) electrochemical approaches have been developed for some oxidative desulfurization-(di)fluorination reactions, using different sources of fluorinating reagents, either in organic solvents or in Ionic Liquids (ILs). [28][29][30][31] Although, chemical and electrochemical-induced reductive desulfonylation reactions have been known for years, [32][33][34][35][36][37][38][39][40] in nucleoside series they have been limitedto reductive dehalogenation or desulfonylation protocols en route to 2',3'-dideoxy-2',3'-didehydro nucleosides. [41][42][43][44][45][46][47] Reductive desulfonylation/functionalization (including (di)fluorination)strategiesin nucleosidesare to the best of our knowledge, unknown processes.Our goal was to investigate alternative methodologies for the modification of nucleosides at C2' position utilizing 2'-S-aryl-2'-thionucleosides as convenient substrates to access well-known fluoro nucleosides (e.g., gemcitabine or PSI 6130, a core of Sofosbuvir).Herein we report studies on the reactivity of 2'-S-aryl-2'-thiouridine substrates (type I, Figure 1)with respect to oxidation processes and 2'-arylsulfonyl-2'-deoxyuridine (type II) with respect to reductive processes. The oxidative fluorination processes are envisioned to proceed via desulfurization-difluorination of the uridine-2'-thioethers (substrate I, X = H) or desulfurization-fluorination of uridine αfluorothioethers(substrate I, X = F) using halonium ion (Br + , I + ) reagents as oxidants and a nucleophilic fluorine source (F -) for quenching the intermediary C2'-carbocation. The reductive fluorination processes are proposed to proceed via cleavage of the sulfonyl moiety (from substrate II, X = H or F) with single electron transfer reagents or electrochemically and quenching the resultant C2'-carbanion with electrophiles such as F + , H + , CH 3 + , etc.

Results and Discussion

Because of the lack of examples for desulfurization-difluorination reactions of aryl-alkyl thioethers with the arylthio group attached to a secondary internal carbon atom, we initially performed model studies with α-arylthio substituted esters (e.g.,2; Scheme 1)that mimic the 2'-postion of the ribosein the nucleoside targets (e.g., I, X = H). Using the methodology developed by Haufe et al. 20,21 conversion to 5a. 48 These results illustrated that 4-chlorophenyl thioethers were better substrates for these difluorination reactions than corresponding phenyl and 4-methoxyphenyl thioethers, as noted also by

Haufe, et al.for the primary alkyl-aryl thioethers. 21 The EDGs on the phenyl ring are believed to stabilize the cationic charge on the resonance-stabilized carbenium-sulfonium ion intermediate and thus promote the first fluorination step; whereas EWGs are assumed to ease the elimination of arylsulfenyl bromide in the last step and therefore promote the critical second fluorination step. 21 The DBH was proven to be more effective than other halogen oxidants (NBS, NIS) in these reactions. 48 Scheme 1. Desulfurization-difluorinations of α-thioesters 2-4.

attempts to extend this protocol to sugars and nucleosides met with only limited success. Thus, treatment of (S)-(+)-2-phenylthio-4-benzyloxymethyl-4-butanolide 49 with DBH (4 equiv.)/Py.9HF (8 equiv.)/CH 2 Cl 2 /35 o C/15 h gave complex reaction mixture. 48 and EDG (MeO) or EWG (Cl) in phenyl ring as well as changing reaction conditions (e.g., halogen source, temperature, reaction time) did not change the outcome. 48 Interestingly, treatment of the 4-methoxyphenyl thioether6 with NIS (2.1 eq.)/Py.9HF (3 eq.) gave the corresponding 5-iodo7 (29%) and the α-fluorothioether8 (12%) products (Scheme 2).Analogous treatment of sulfide 6with NIS/DAST combination 53,54 producedthe mono-α-fluorothioether8 in 44% isolated yield without 5-halogenation. In contrast, treatment of 6 with DBH (3 eq.)/Py.9HF (6 eq.) generated a complex reaction mixture.These results reiterate the mechanistic assumption that ring activating groups (e.g., OMe) on the aryl ring promote the first fluorination step.

Conditions A: NIS (2.1 eq), Py.9HF (3 eq); Conditions B: NIS (2.1 eq), DAST (6 eq). Since the oxidative desulfurization-fluorination approaches were not efficient protocolsfor the utilization of 2'-arylthiouridine derivatives as substrates for the modification of the C2'-position, we turned our attention to the development of a reductivedesulfonylation approach. This strategy is consisted withthe generation of an intermediary carbanion at the C2'-position of uridine derivatives which could be subsequently coupled to an electrophile (e.g., II; Figure 1). We assumed that such anion could be obtained through cleavage of the C2'-S bond in 2'-arylsulfonyl-2'-deoxyuridine substrates. Moreover, such sulfones derivatives could be conveniently synthesized by simple oxidation of the arylthiouridine substrates used for the oxidative approach. 50,51 Reductive removal of sulfones is usually mediated by highly aggressive metal-containing reducing agents, typically alkali metals, not always compatible with the nucleoside chemistry, as they can cause side reactions on the diverse functional groups present in the molecule. 33 Instead, we opted for the use of recently reported organic electron donors (OEDs) [55][56][57] that can selectively cleave C-SO 2 bonds by stepwise transfer of two electrons under mild reaction conditions. 35,58 The bispyridinylideneSEDhas a redox potential of E 1/2 (DMF)= -1.24 Vvs SCE(Figure 2)andefficiently reduces sulfones via the formation ofanion intermediates. 58 Its high tolerance to other functional groups, such as ketones, made it particularly suitable for our 2'-deoxyuridine substrates. Cyclic voltammetry analysis showed that sulfone derivative 10could be reduced in two irreversible reduction steps at potentials of -2.42and -2.64 V vsSCE (Figure S1, Table S1, Supporting

Information),with the first reduction step (E pc1 ) corresponding to the cleavage of the C2'-S bond with the expulsion of the p-methoxybenzenesulfinate. This hypothesis was confirmed by the cyclic voltammetry of an authentic sample 59 of sodium p-methoxybenzenesulfinate(Figure S2). While the reductionpotential is in the array of redox potentials that the effective reducing power of SEDcould reportedly attain, [START_REF]transfer complexes and ion pairing that eases the electron transfer. Additional π-π stacking between SED and nucleoside may help to form intimate complex and facilitate the reduction[END_REF] the redox potential gap between TDAE and 10(E>1.2 V) clearly indicates that reduction of 10 cannot be achieved by TDAE-promoted electron transfer. Since OEDs can act as base or as reducing agent, 61,62 we assumed that TDAE initially acted as a base inducing elimination of AcOH by abstracting H2' to produce 13(Scheme 5).Judging from the first reduction potential of 13 (E pc1 = -2.11 Vvs SCE;Table S1, FigureS3), further reduction of 13 by TDAEto produce 11 would also be rather difficult. One can think that TDAE is only acting as a base and that 13 suffers from base-induced reactions leading in turn to 14

and 11 (base-induced pathway, Scheme 5).The hypothesis of a basic behavior was supported by the fact that reaction of 10 with 4-dimethylaminopyridine (DMAP) led to the quantitative formation of 11.On the other hand, in the case of SED, a mixed base-/electron transfer-inducedmechanism could occur and rapidly lead to11. We assumed that under more forced reducing conditions, 60 13could be reduced in parallel to the base-induced reactions (ET-induced pathway, Scheme 5). Hence, 13 could be reduced by single-electron transfer (SET) leading to glycosidic bond cleavage, followed by trapping of the formed radical by the radical cation of the electron donor (SED •+ ). [START_REF] Fletcher | Trapping of radical species by the radical cation of the SED have already been observed: a)[END_REF] A last base-induced reaction would give 11

and regenerate the SED.

Scheme 5. Proposed "base-versus electron transfer-induced" mechanism for the reaction of 10 with OEDs.

Since the acetyl protection in 10was base labile in the presence of OEDs, and prone to elimination from the intermediate C2'-carbanion, we also studiedbenzylated sulfone substrates. However, treatment of the fully benzylated2'-[(4-methoxyphenyl)sulfonyl]uridine 15 51 (E pc1 = -2.42 V vs SCE; Figure S1, Table S1) with a stoichiometric amount ofSED resulted in a similar rapid glycosidic bond cleavage producing the vinyl sulfone 16 (70%)and3-N-benzyluracil 17(69%; Scheme 6). This result indicated that the basic character of SED was probably predominant over its reducing character with substrates bearing a labile αhydrogen. Treatment of 15with an excess of SED gave two inseparable ribose derivatives: the vinyl sulfone 16 and the furan derivative 18 with possibly the latter being formed from 16 under reducing and/or basic conditions as proposed for 10 in Scheme 5.

Scheme 6.

Reduction studies of benzyl protected sulfone substrate 15with the SED Since the α-hydrogen of 2'-sulfone substrates were too labile under the desired reductive conditions, α-fluorosulfones19 50 and 24 51 were chosen for the further studies. Thus, treatment of α-fluorosulfone19(E pc1 = -2.36 V vs SCE; Figure S4, Table S1) with the SED reagent at room temperature gave the mono 3'-deacetylated product 20 (45% conversion) along with unchanged starting material but no further degradation or glycosidic bond cleavage were observed (Scheme 7). [START_REF]Deacetylation is known to proceed under basic conditions. NH 3 /MeOH and amines are frequently used reagents[END_REF] The reduction of the sulfonyl moiety was not observed at this temperature.However, known fluorovinyl compound21 [START_REF] Martin | [END_REF] (albeit in low amount) were also detected in the crude reaction mixture.These results were in line with the profile of products obtained with anexcess of the SED reagent at 120°C/3h, however it offered an alternative milder approach to prepare 21 by a reductive approach. The results with SED or the electrochemical activation provided evidence that the C2' anion was indeed generated through C2'-S bond cleavage. It is important to note that replacement of SED with other reducing agents such as samarium iodide did not affect the reduction of the sulfonyl moiety. Controlled-potential electrolysis of 24 in DMF at -2.20 V vs SCE, a potential slightly less positive to the first peak potential measured by cyclic voltammetry (see Table S1), gave, after the consumption of 2.1 F/mole of substrate (1 h, r.t), 17 in 74% isolated yield and an inseparable mixture containing 24 and 26 (ratio ~ 2.5:1) with also additional products. The estimated yield of 26 was roughly 18%, a yield slightly higher compared to the reaction using the SED reagent (Scheme 8). Although the electrolysis did not go to complete conversion of starting material, as opposed to the results obtained with the SED reagent,there was no indication of formation of furan 25. The electrochemical reductive cleavage of 24 seems to be more complex than 19 since generation of more products was observed, but formation of 22, 23 and 26under milder electrochemical conditions, is again an attractive starting point for further optimization studies and possible anion trapping.

Conclusion

In conclusion, new methods for the modification of nucleosides at the C2'-position viaoxidative

Experimental Section

Reagent grade chemicals were used and solvents were dried by reflux and distillation from CaH 2 under N 2 unless otherwise specified, and an atmosphere of N 2 was used for reactions. The MBraun glovebox used for some reactions contained dry argon and less than 1 ppm oxygen and water. Reaction progress was monitored by TLC on Merck Kieselgel 60-F 254 sheets with product detection by 254-nm light. Products were purified by column chromatography using Merck Kiselgel 60 (230-400 mesh) or by automated flash chromatography using a CombiFlash system. UV spectra were recorded with a Varian Cary 100 Bio UV-visible spectrophotometer.

C5), 13.9 (CH 3 ), 13.7 (C6); 19 F NMR (CDCl 3 ) δ -105.92 ppm (t, 3 J F-H = 16.8 Hz); GC-MS (t R = 7.5 min) 151 (M + -Et, 1.1), 87 (100).

5b 69 had: 1 H NMR (CDCl 3 ) δ 4.25 (q, 3 J H,H = 7.2 Hz, 2H, CH

, 11H), 0.81 ("t", 3 J H,H = 6.8 Hz, 3H, H6, H6', H6''); 13 (s, 1H, H6), 7.44-7.31 (m, 13H, Ph), 7.12-7.10 (m, 2H, Ph), 6.51 (d, J = 8.9 Hz, 1H, H1'), 6.33-6.30 (m, 2H, Ph), 5.15 ("d", J = 13.4 Hz, 1H, benzylic), 5.02 ("d", J = 13.3 Hz, 1H, benzylic), 4.68-4.52 (m, 4H, benzylic), 4.33-4.25 (m, 2H, H4', H3'), 3.76-3.67 (m, 2H, H2', H5'), 3.66 (s, 3H, OCH 3 ), 3.51 (dd, J = 2.0, 10.5 Hz, 1H, H5''); 13 Volatiles were evaporated in vacuo and the residue was column chromatographed (PE 100%  PE/EtOAc 9/1 EtOAc 100%) to give16(22 mg, 70%) as a white gum and17(9.4 mg, 69%) as a white solid.

16had: 1

Figure 1 .

 1 Figure 1. Proposed pathways for the C2'-functionalization of uridine derivatives

  Also, attempted fluorination of readily available 50 2'-S-aryl-2'-thiouridine analogues of type 6 51 (Scheme 2)or 2'-S-aryl-2'-fluoro-2'thiouridineanaloguesof type 8 51 (Scheme 3)with Py.9HF/DBH failed to give 2',2'-difluoro products yielding instead 5-brominated 52 products as well as the corresponding sulfoxides and/or α-fluoro sulfoxides, among other byproducts. Installing different protection groups on sugar hydroxyls (Ac, Bn)

Scheme 2 .Scheme 3 .

 23 Scheme 2.Attempted fluorination of 2'-S-(4-methoxyphenyl)-2'-thiouridine analogue 6Moreover, treatment of α-fluorothioether8 with DBH/Py.9HF at -78 o C effected selective bromination of the uracil ring at the C5 position 52 yielding the corresponding 5-bromoderivative 9 as a major product (50%), however with no indication of the geminaldifluoro product formation (Scheme 3). Interestingly, the α-fluorothioether moiety in 9remained intact under these oxidative conditions. It was previously noted that oxidation of α-fluorothioethers to the α-fluoro sulfoxides with m-CPBA required higher temperature and longer reaction time than conversion of the unfluorinatedthioethers to the corresponding sulfoxides.50

Figure 2 .Scheme 4 .

 24 Figure 2.Redox potential and equilibria of bispyridinylideneSEDnamed as "Super-electron donor".When the 2'-sulfone 10 50 was treated at r.t.with the organic reductantSED, the reaction cleanly provided the furan product 11in 95% yield after 15 min (Scheme 4). The uracil base 12was identified (but not isolated) by1 H NMR in the aqueous phase along with other impurities. To our surprise, cleavage of the C2'-S bond was not observed and the unexpected formation of 11 could not be explained by a sole electron-transfer mechanism.To rationalize this result, we tried the same reaction with a less powerful organic reductant, the commercially available tetrakis(dimethylamino)ethylene (TDAE) [E 1/2 (DMF) = -0.62 V vs SCE]. Treatment of 2'-sulfone 10with an excess of TDAEgave the 3'-acetoxy elimination product 13 (34%), the enol type (open chain sugar) product 14 (20%) and the same furan derivative 11

Scheme 7 .Scheme 8 .

 78 Scheme 7. Reactivity studies of acetyl protected α-fluorosulfone19 with OED and under electrochemical activation.

  and reductive activation of carbon-sulfurbonds in readily available 2'-thionucleosides were studied. The 10 oxidative desulfurization-difluorination of aryl-alkyl thioethers including 2'-S-aryl-2'-thiouridine substrates, using the protocol of Haufeet al. was studied with mixed results. Althoughsuccessful on 2-(arylthio)alkanoate surrogates,combination of oxidants and fluoride sources was not an efficient fluorination protocol when applied to 2'-thiouridine derivatives, resulting mainly in C5-halogenation of the pyrimidine ringand C2'-monofluorination without desulfurization.Our reductivedesulfonylation approach using Organic Electron Donors (OEDs) was hampered by competitive base-induced mechanismsin the case of substrates bearing a labile α-hydrogen, resulting in the elimination of the uracil moieties. On the other hand, reduction of α-fluorosulfone derivatives with OED or by electrochemical activation provided good evidence that the C2'-anion was indeed generated through C2'-S bond cleavage.The major benefit of the electrochemical activation was the milder conditions of the protocol (r.t., no base, short time) leading to the formation of 2',3'-unsaturated-2'-fluorouridine and 2'-fluorinated products.These results open new horizons for the reductive desulfonylation-functionalization strategies, which, although, are still not fully developed in nucleosides, have the potential to be utilized in the synthesis of highly substituted nucleoside analogues including C2'-difluoro analogues.

  C NMR (CDCl 3 ) δ 164.5 (t, 2 J F,C = 33.0 Hz, C1), 116.4 (t, 1 J F,C = 249.7 Hz, C2), 62.7 (CH 2 ), 34.5 (t, 2 J F,C = 23.2 Hz, C3), 31.4, 28.7, 22.4, 21.4 (t, 3 J F,C = 4.3 Hz, C4), 13.9; 19 F NMR (CDCl 3 ) δ -105.89 ppm (t, 3 J F-H = 17.0 Hz); GC-MS (t R = 7.4 min) 179 (M + -Et, 60.8), 144 (100).3-N-benzyl-3',5'-di-O-benzyl-5-iodo-2'-S-(4-methoxyphenyl)-2'-thiouridine(7)and3-N-benzyl-3',5'-di-O-benzyl-2'-fluoro-2'-S-(4-methoxyphenyl)-2'-thiouridine(8).NIS (95 mg, 0.42 mmol) was added to a stirred solution of 6 (128 mg, 0.2 mmol) and Py.9HF (138 μL, 0.6 mmol) in anhydrous CH 2 Cl 2 (3 mL) at -78 o C in a polypropylene vessel and the resulting brown solution was brought to ~5 o C overnight (16 h). Stirring was continued at ambient temperature for 7 h (total reaction time: 23 h). The reaction was quenched by addition of ice-cold water (10 mL), diluted with CH 2 Cl 2 (5 mL), neutralized with drop-wise addition of conc. NH 4 OH. Organic layer was separated and aqueous layer was back extracted (2 x CH 2 Cl 2 ). Combined organic layer was washed with 1N HCl (10 mL), brine (10 mL), dried (MgSO 4 ), and filtered. Volatiles were evaporated in vacuo and the brown residue was column chromatographed (5%  20% EtOAc in hexanes) to give 7 (44 mg, 29%) as a colorless oil and 8 51 (2'-R/S-S, ~ 1:1; 16 mg, 12%) as a pale-yellow oil.

  hydroxy-2-((4-methoxyphenyl)sulfonyl)-1,3-pentadien-1-yl]uracil(14) and[4-[(4methoxyphenyl)sulfonyl]furan-2-yl]methyl acetate (11

[ 4 -[( 4 -

 44 Methoxyphenyl)sulfonyl]furan-2-yl]methyl acetate(11)and uracil(12). In a glove box, SED (31 mg, 0.1 mmol) was added to a solution of 10(50 mg, 0.1 mmol) in anhydrous DMF (4 mL) and the resulting mixture was stirred at ambient temperature for 15 min. Then the reaction flask was brought out of the glove box and water was added to the crude reaction mixture. The aqueous phase was extracted with CH 2 Cl 2 (3 x), the combined organic phase was dried overanhydrous Na 2 SO 4 and volatiles were evaporated in vacuo to give 11(29.4 mg, 95%) as a colorless oil.Acidification of the aqueous phase (pH ~5-6) followed by extraction (2 x CH 2 Cl 2 )gave a white solid.1 H NMR (MeOD) of the white solid revealed the presence of uracil 12along with other impurities.3,5-di-O-Benzyl-1,2-dideoxy-1,2-didehydro-2-[(4-methoxyphenyl)sulfonyl]ribose (16),2-[(benzyloxy)methyl]-4-[(4-methoxyphenyl)sulfonyl]furan (18) and3-N-benzyluracil (17).In a glove box, SED (22 mg, 7 x 10 -5 mol, 1.05 equiv.) was added to a solution of 15(45 mg, 6.7 x 10 -5 mol) in DMF (4 mL) and the reaction mixture was stirred at ambient temperature for 15 min. Then the reaction flask was brought out of the glove box and water was added to the crude reaction mixture. The aqueous phase was extracted with CH 2 Cl 2 (3 x) and the combined organic phase was dried overanhydrous Na 2 SO 4 .

  In a glove box, SED (68 mg, 0.24 mmol, 3 equiv.) was added to a stirred solution of 19(40 mg, 0.08mmol)in anhydrous DMF (4 mL)and the resulting dark brown solution was stirred at 120 o C for 18 h. Reaction flask was brought out of the glove box, and 10% HCl solution was added to the crude reaction mixture. Aqueous layer was extracted with CH 2 Cl 2 (2 x). Combined organic layer was dried (Na 2 SO 4 ), filtered, and concentrated in vacuo to give a brown solid. Et 2 O was added to the solid and was filtered. Filtrate was concentrated in vacuo to give 21(<10mg,~46%) along with other impurities.1 H NMR of the black solid (DMSO-d 6 ) showed similar peaks to the ones obtained for the oxidized form of the SED (SED 2+ ). 5821 65 had: 1 H NMR (CDCl 3 ) δ 8.47 (br s, 1H, NH), 7.52 (dd, J = 1.0, 8.1 Hz, 1H, H6), 6.90-6.88 (m, 1H, H1'), 5.78 (d, J = 8.1 Hz, 1H, H5), 5.69 (m, 1H, H3'), 5.06-5.02 (m, 1H, H4'), 4.35-4.21 (m, 2H, H5',5"), 2.11 (s, 3H, Ac); 19 F NMR (CDCl 3 ) δ -133.76 (t, J = 4.6 Hz, F2'); MS (EI) m/z 271.09 [M+H] + , calcd for C 11 H 12 FN 2 O 5 + 271.07.3-(Benzyloxy)-2-[(benzyloxy)methyl]-4-[(4-methoxyphenyl)sulfonyl]furan (25).In a glove box, SED (62 mg, 0.22 mmol, 3 equiv.) was added to a solution of 24(50 mg, 7.3 x 10 -5 mol)in anhydrous

  was obtained in 46% yield when 19was treated with 3 eq. of SEDat 120 o C. This result indicated that reductive cleavage of the sulfone took place with excess SED at high temperature. Controlled-potential electrolysis of 19 in DMF at -1.90 V vs SCE, a potential more positive to the first potential peak measured by cyclic voltammetry (see TableS1), gave, after the consumption of 2.0 F/mole of substrate (1 h, r.t), a main fraction that contained 21 and 19 as an inseparable mixture (ratio ~ 8:2), with estimated yield of 21 close to 45%(Scheme 7). Noteworthy to mention that 2'-deoxy-2'-fluoridine 22,the diacetylated23and uracil 12

Ethyl 2-((4-chlorophenyl)thio)hexanoate (3). Treatment

  1/2 = + 0.05 V in DMF. Controlled-potential electrolyses were run in a cylindrical divided cell (see FigureS5)using a porousreticulouscarbon electrode (S ~ 2.5 cm 2 ) as working electrode, a platinum wire as counter electrode separated from the cathodic compartment with a frit glass (porosity 4) and Ag wire as a pseudo reference. Cyclic voltamograms were recorded before the electrolysis and during the 1H, H4), 1.30-1.21 (m, 3H, H4', H5, H5'), 1.10 (t, J = 7.1 Hz, 3H, CH 3 ), 0.82 (t, J = 7.1 Hz, 3H, CH 3 );13 C NMR (CDCl 3 ) δ 172.2, 160.1, 136.2, 123.4, 114.4, 60.7, 55.2, 51.6, 31.1, 29.3, 22.3, 14.1, 13.8. Cl 2 , and neutralized with drop-wise addition of conc. NH 4 OH. Organic layer was separated and aqueous layer was back extracted (2 x CH 2 Cl 2 ). Combined organic layer was washed with 1N HCl, brine, dried (MgSO 4 ) and concentrated in vacuo to give crude difluorinatedproduct 5b J H,H = 7.1 Hz, 3H, CH 3 ), 0.85 (t, 3 J H,H = 7.2 Hz, 3H, H6, H6', H6''); 13 C NMR (CDCl 3 ) δ 164.4 (t, 2 J F,C = 33.2 Hz, C1), 116.4 (t, 1 J F,C = 249.8 Hz, C2), 63.0 (CH 2 ), 34.5 (t, 2 J F,C = 23.2 Hz, C3), 23.5 (t, 3 J F,C = 4.3 Hz, C4),

	Electrochemical measurements were performed using an EG & G-Princeton Applied Research 263A all-in-one potentiostat, using a standard three-electrode setup with a glassy carbon electrode (working electrode, diameter = 3 mm), platinum wire auxiliary electrode and a non-aqueous Ag/Ag + (0.01M AgNO 3 + 0.1M n-Bu 4 NClO 4 ) system in MeCN as the reference electrode. All solutions under the study were 0.1 M in the supporting electrolyte n-Bu 4 NPF 6 (Fluka, electrochemical grade) with the voltage scan rate of 0.2 V s -1 . Solutions (2.5 mL) were thoroughly bubbled with dry Ar for 15 min to remove electrolysis using a glassy carbon electrode (diameter = 1 mm).The solutions containing the substrate and the supporting electrolyte (n-Et 4 NBF 4 0.1 M) were thoroughly bubbled with dry Ar for 15 min to remove oxygen before any experiment and kept under positive pressure of Ar. Ethyl 2-(phenylthio)octanoate (2). Thiophenol (260 μL, 280 mg, 2.54 mmol) was added to a stirred solution of NaH (60%, dispersion in paraffin liquid; 100.4 mg, 4.18 mmol) in anhydrous DMF (4 mL) at 0 o C. The resulting suspension was stirred at 0 o C for 30 min and at ambient temperature for 30 min, until bubbling (H 2 gas) ceased. The reaction flask was chilled again and ethyl 2-bromooctanoate (540 μL, 630 mg, 2.51 mmol) was added at 0 (CDCl 3 ) δ 7.49-7.46 (m, 2H, Ph), 7.35-7.25 (m, 3H, Ph), 4.16-4.09 (m, 2H, CH 2 ), 3.66 (dd, J = 6.6, 8.4 Hz, 1H, H2), 1.96-1.87 (m, 1H, H3), 1.82-1.73 (m, 1H, H3'), 1.51-1.37 (m, 2H, H4, H4'), 1.36-1.26 (m, 6H, H5, H5', H6, H6', H7, H7'), 1.19 (t, J = 7.1 Hz, 3H, CH 3 ), 0.90 ("t", J = 6.8 Hz, 3H, CH 3 ); 13 C NMR (CDCl 3 ) δ 172.4, 133.8, 132.7, 128.9, 127.7, 61.0, 50.9, 31.7, 31.5, 28.8, 27.2, 22.5, 14.1, 14.0. ofethyl 2-bromohexanoate (500 μL, 610.5 mg, 2.74 mmol) with 4-chlorothiophenol/NaH/DMF, as described for 2, gave 3 67 as a pale yellow oil (763.6 mg, 97%): 1 H NMR (CDCl 3 ) δ 7.41-7.37 (m, 2H, Ph), 7.30-7.26 (m, 2H, Ph), 4.17-4.09 (m, 2H, CH 2 ), 3.61 (dd, J = 6.6, 8.4 Hz, 1H, H2), 1.94-1.84 (m, 1H, H3), 1.81-1.69 (m, 1H, H3'), 1.51-1.27 (m, 4H, H4, H4', H5, H5'), 1.19 (t, J = 7.1 Hz, 3H, CH 3 ), 0.91 ("t", J = 7.1 Hz, 3H, CH 3 ); 13 C NMR (CDCl 3 ) δ 172.1, 134.11, 134.10, 132.1, 129.0, 61.1, 51.0, 31.3, 29.4, 22.2, 14.1, 13.8. Ethyl 2-((4-methoxyphenyl)thio)hexanoate (4). Treatment of ethyl 2-bromohexanoate (500 μL, 610.5 mg, 2.74 mmol) with 4-methoxythiophenol/NaH/DMF, as described for 2, gave 4 68 as a colorless oil added to a stirred solution of esters2or 3or (0.5 mmol) and Py.9HF (3 mmol) in CH 2 Cl 2 (2 mL) in a polypropylene vessel at ambient temperature. The resulting brown solution was stirred at 35 o C for 2 h (2), 1 h (3) or 16h (4). The reaction flask was cooled to room temperature, quenched by addition of ice-cold water, diluted with CH 2 (95% conversion from 2) or 5a(95% conversion from 3; 70% conversion from 4) as a brown oil, with data as reported. 69 5a 69 had: 1 H NMR (CDCl 3 ) δ 4.25 (q, 3 J H,H = 7.2 Hz, 2H, CH 2 ), 2.09-1.88 (m, 2H, H3, H3'), 1.42-1.30 (m, (739.3 mg, 96%): General procedure for the preparation of ethyl difluoroalkanoates (5).DBH (1.5 mmol) was 4H, H4, H4', H5, H5'), 1.28 (t, 3

1

H (400 MHz),

13

C (100.6 MHz), and

19

F (376 MHz) NMR spectrawere recorded at ambient temperature in solutions of CDCl 3 or DMSO-d 6 .MS and HRMS spectra were recorded in ESI+ or ESI-mode, unless otherwise noted. The bispyridinylidene SED was synthesized following reported procedure,

58

stored in a glove boxand used as a well-defined dark purple solid. oxygen before any experiment and kept under positive pressure of Ar. Under these experimental conditions the ferrocene/ferricinium couple, used as internal reference for potential measurements, was located at E o C. The resultant clear, colorless solution was stirred at 0 o C for 20 min and at ambient temperature for 2 h, by which time TLC showed exclusive conversion to a slightly more polar spot. Volatiles were evaporated and co-evaporated with toluene (1 x) (vacuum pump) and the resulting pale gum was partitioned between CHCl 3 (20 mL) and NH 4 Cl/H 2 O (20 mL). The aqueous layer was extracted with CHCl 3 (2 x 5 mL) and the combined organic phase was washed with NaHCO 3 /H 2 O (25 mL), brine (25 mL), and dried (MgSO 4 ). Volatiles were evaporated in vacuo and the residue was column chromatographed (10% EtOAc in hexanes) to give 2

66

(633 mg, 90%) as a pale oil: 1 H NMR 1 H NMR (CDCl 3 ) δ 7.36-7.31 (m, 2H, Ph), 6.78-6.74 (m, 2H, Ph), 4.02 ("q", J = 7.2 Hz, 2H, CH 2 ), 3.41 (dd, J = 6.6, 8.5 Hz, 1H, H2), 1.82-1.75 (m, 1H, H3), 1.68-1.59 (m, 1H, H3'), 1.

42- 1.32 (m,

  Py.9HF (62 μL, 0.27 mmol) was added to a chilled solution of DBH (19 mg, 0.066 mmol) in dry CH 2 Cl 2 (1 mL) at -78 o C. The resulting pale solution was stirred at -78 o C for 10 min and a solution of substrate 8 (40 mg, 0.06 mmol) in dry CH 2 Cl 2 (2 mL) was added via syringe. The resultant orange solution was stirred at -78 o C for 2 h and was brought to -30 o C over 45 min. The reaction mixture was diluted with CH 2 Cl 2 (5 mL), washed with NaHCO 3 /H 2 O (5 mL), H 2 O (5 mL), brine (5 mL), dried (MgSO 4 ). Volatiles

	C NMR (CDCl 3 ) δ 159.8, 159.1, 150.8, 142.2 (C6), 137.22, 137.16, 136.2, 135.2,
	130.4, 128.8, 128.6, 128.4, 128.2, 128.1, 128.06, 127.8, 127.7, 123.0, 114.7, 90.2 (C1'), 82.1 (C3'), 80.7
	(C4'), 73.8 (CH 2 ), 72.3 (CH 2 ), 70.5 (C5), 68.9 (C5'), 56.4 (C2'), 55.5 (OCH 3 ), 46.0 (CH 2 ).HRMS (ESI)
	m/z785.1119 [M+Na] + , calcd for C 37 H 35 IN 2 NaO 6 S + 785.1133.
	Analogous treatment of 6 (128 mg, 0.2 mmol) with NIS (95 mg, 0.42 mmol) and DAST (160 μL, 1.2
	mmol) followed by aqueous workup (sat. Na 2 S 2 O 3 , sat. NaHCO 3 , brine, MgSO 4 ) and column
	chromatography gave 8 51 (2'-R/S-S, ~ 1:1; 58 mg, 44%) as a pale-yellow oil.
	3-N-benzyl-3',5'-di-O-benzyl-5-bromo-2'-fluoro-2'-S-(4-methoxyphenyl)-2'-thiouridine(9).
	were evaporated in vacuo and the yellow residue was column chromatographed (15% EtOAc in hexanes)
	to give 9 as mixture of diastereomers (2'-R/S-S, ~ 4:1) (pale-yellow oil, 22 mg, 50%):UV (MeOH) λ max
	253, 280 nm, λ min 239, 271 nm; 1 H NMR (CDCl 3 ) δ 7.84 (s, 1H, H6), 7.81 (d, J = 2.1 Hz, 0.2H, Ph), 7.66
	(d, J = 2.2 Hz, 0.8H, Ph), 7.49-7.23 (m, 17H, Ph), 6.78 (d, J = 8.7 Hz, 0.8H, Ph), 6.75 (d, J = 8.7 Hz,
	0.2H, Ph), 6.44 (d, J = 13.9 Hz, 0.8H, H1'), 6.27 (br s, 0.2H, H1'), 5.09 ("d", J = 13.6 Hz, 1H, benzylic),
	4.92-4.80 (m, 1H, benzylic), 4.73-4.65 (m, 1H, benzylic), 4.62-4.41 (m, 3H, benzylic), 4.18-4.09 (m, 2H,
	H3', H4'), 3.92 (s, 0.6H, CH 3 ), 3.91 (s, 2.4H, CH 3 ), 3.82-3.72 (m, 1H, H5'), 3.61-3.53 (m, 1H, H5''); 19 F
	NMR (CDCl 3 ) δ -133.52 ppm (br s, 0.8F), -131.57 ppm (br s, 0.2F); 13 C NMR (CDCl 3 ) for major isomer:
	δ 158.4, 157.2, 149.4, 138.1, 137.79, 137.76, 137.3, 136.8, 135.9, 134.1, 134.0, 129.3, 128.6, 128.5,
	128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 120.24, 120.23, 112.2, 112.0, 108.7 (d, 1 J C2'-F = 239.1 Hz, C2'),
	96.9, 90.4 (d, 2 J C1'-F = 47.3 Hz, C1'), 80.3 (C4'), 79.7 (d, 2 J C3'-F = 17.7 Hz, C3'), 73.5 (CH 2 ), 73.1 (CH 2 ),
	67.0 (C5'), 56.4 (OCH 3 ), 45.7 (CH 2 ).HRMS (ESI) m/z 755.1182 [M+Na] + , calcd for
	C 37 H 34 79 BrFN 2 NaO 6 S + 755.1197.

  ).TDAE (0.24 mL, 1.04mmol) was added to a stirred solution of 10(100 mg, 0.207 mmol) in anhydrous DMF (2 mL) at -78 o C under argon. The reaction mixture was brought to ambient temperature over 1h 15 min and a 10% HCl solution (2 mL) was then added. The crude was extracted with EtOAC(3 x) and the combined organic phase was dried over anhydrous Na 2 SO 4 . Volatiles were evaporated in vacuo and the residue was column chromatographed (PE OCH 3 ),20.8 (Ac). HRMS (ESI) m/z 423.0856 [M+H] + , calcd for C 18 H 19 N 2 O 8 S + 423.0857.

	100% EtOAc/PE 2/1 EtOAc 100%) to give11 (29.5 mg, 46%), 14 (17.5 mg, 20%), and 13 (30 mg,
	34%), all as colorless oils.
	13 had: 1 H NMR (CDCl 3 ) δ 9.23 (br, 1H, NH), 7.79-7.75 (m, 2H, Ph), 7.24 (d, J = 8.4 Hz, 1H, H6), 7.18
	(t, J = 1.6 Hz, 1H, H3'), 7.03-6.99 (m, 3H, Ph, H1'), 5.55 (dd, J = 2, 8.4 Hz, 1H, H5), 5.12-5.09 (m, 1H,
	H4'), 4.41 (dd, J = 4, 12.4 Hz, 1H, H5'), 4.29 (dd, J = 3.6, 12.4 Hz, 1H, H5''), 3.87 (s, 3H, OCH 3 ), 2.09 (s,
	3H, Ac); 13 C NMR (50 MHZ, CDCl 3 ) δ 170.1 (C=O), 164.9 (C Ph ), 162.9 (C4), 150.3 (C2), 142.1 (C6),
	141.9 (C2'), 139.5 (C3'), 130.8 (CH Ph ), 129.1 (C Ph ), 115.2 (CH Ph ), 103.2 (C5), 87.5 (C1'), 82.8 (C4'), 63.9
	(C5'), 56.1 (14 had: 1 H NMR (CDCl 3 ) δ 9.00 (br s, 1H, NH), 7.76 (d, J = 8.8 Hz, 2H, Ph), 7.58 (s, 1H, H1'), 6.97-6.99
	(m, 3H, Ph, H6), 5.69 (br, 1H, OH), 5.62 (dd, J = 1.2, 8.0 Hz, 1H, H5), 4.93-4.79 (m, 1H, H3'), 4.27 (dd,
	(OCH 3 ), 20.5 (CH 3	Ac ). HRMS (ESI) m/z 423.0864 [M+H] + , calcd for C 18 H 19 N 2 O 8 S + 423.0857; 440.1119
	[M+NH 4 ] + , calcd for C 18 H 22 N 3 O 8 S + 440.1122.
	11had: 1 H NMR (CDCl 3 ) δ 7.93 (d, J = 0.8 Hz, 1H, H1), 7.85-7.89 (m, 2H, Ph), 6.96-7.00 (m, 2H, Ph),
	6.56 (s, 1H, H3), 4.97 (s, 2H, H5, H5'), 3.85 (s, 3H, OCH 3 ), 2.05 (s, 3H, Ac); 13 C NMR (CDCl 3 ) δ 170.3
	(C=O), 163.8 (C Ph ), 152.4 (C4), 145.7 (C1), 132.9 (C2), 131.1 (C Ph ), 129.8 (CH Ph ), 114.7 (CH Ph ), 108.7
	(C3), 57.4 (C5), 55.8 (OCH 3 ), 20.8 (CH 3 Ac ); HRMS (ESI) m/z 328.0852 [M+NH 4 ] + , calcd for
	C 14 H 18 NO 6 S + 328.0849.

J = 4.4, 12.4 Hz, 1H, H5'), 4.21 (dd, J = 4.8, 12.4 Hz, 1H, H5''), 3.86 (s, 3H, OCH 3 ), 1.95 (s, 3H, Ac); 13 C NMR (CDCl 3 ) δ 170.4 (C=O), 164.2 (C Ph ), 162.6 (C4), 160.3 (C1'), 150.3 (C2), 140.2 (broad, C6), 131.5

(C Ph ), 129.9 (CH Ph ), 116.9 (broad, C2'), 114.9 (CH Ph ), 103.7 (C5), 88.7 (broad, C3'), 63.4 (C5'),

55.6

  H NMR (CDCl 3 ) δ 7.83-7.79 (m, 2H, Ph), 7.42 (s, 1H, H1), 7.37-7.31 (m, 3H, Ph), 7.26-7.24 (m, 5H, Ph), 7.09-7.07 (m, 2H, Ph), 6.86-6.84 (m, 2H, Ph), 4.86 (d, J = 3.2 Hz, 1H, H3), 4.77 (td, J = 3.2, 5.6 Hz, 1H, H4), 4.49 (d, J = 2.4 Hz, 2H, CH 2 ), 4.40 (s, 2H, CH 2 ), 3.81 (s, 3H, OCH 3 ), 3.48 (dd, J = 5.6, 10.4 Hz, 1H, H5), 3.40 (dd, J = 5.6, 10.4 Hz, 1H, H5); 13 C NMR (CDCl 3 ) δ 163.3 (C Ph ), 159.7 (C1), 137.4 (C Ph ), 137.3 (C Ph ), 133.6 (C Ph ), 129.8 (2 CH Ph ), 128.7 (2 CH Ph ), 128.4 (2 CH Ph ), 128.1 (3 CH Ph ), 128.0 (CH Ph ), 127.9 (2 CH Ph ), 119.7 (C2), 114.2 (2 CH Ph ), 90.3 (C3), 80.7 (C4), 73.7 (CH 2 ), 70.8 (CH 2 ), 68.9 (C5), 55.7 (OCH 3 ); HRMS (ESI) m/z 484.1789 [M+NH 4 ] + , calcd for C 26 H 30 NO 6 S + 484.1788. Analogous treatment of 15(50 mg, 7.5 x 10 -5 mol) with SED (64 mg, 2.2 x 10 -4 mol, 3 equiv.) in DMF : 1 H NMR (200MHz, CDCl 3 ) δ 7.93 (s, 1H, H1), 7.91-7.84 (m, 2H, Ph), 7.36-7.30 (m, 5H, Ph), 7.01-6.96 (m, 2H, Ph), 6.49 (s, 1H, H3), 4.53 (s, 2H, CH 2 ), 4.42 (s, 2H, H5), 3.86 (s, 3H, OCH 3 ); MS (ESI) m/z 376.17 [M+NH 4 ] + , calcd for C 19 H 22 NO 5 S + 376.12.

(4 mL) for 30 min at room temperature gave 18as a mixture with 16(colorless oil; 7.4 mg;ratio of 16:18is 33/67) and 17(13 mg, 86%) as a white solid.

18had

Acknowledgements

This investigation was supported by SC1CA138176 (NIH/NCI; SFW) award, Centre National de la RechercheScientifique (CNRS) through "Action CNRS-USA n° 4020", and Aix-Marseille and Claude Bernard Lyon 1 Universities. We also thank FIU Graduate School for the Dissertation Year Fellowship (RR), and NIH MARC U*STAR (GM083688-02) scholarship program(PT) as well as Romain Simon, Christian Duchet and Nathalie Enriques from the Centre Commun de Spectrométrie de Masse (CCSM) of Claude Bernard Lyon 1 Université, for the assistance and access to the mass spectrometry facility.JB,AGT, TT and PV express their thanks to Vincent Remusat and the Spectropole(Fédération des Sciences Chimiques de Marseille) for NMR and HRMS analyses.

glove box, and water was added to the crude reaction mixture.The aqueous phase was extracted with CH 2 Cl 2 (3 x) and the combined organic phase was dried with Na 2 SO 4 . Volatiles were evaporated in vacuo and the residue was column chromatographed (PE/EtOAc 9/1 EtOAc 100%)to give 25(19.6 mg, 58%) as a white gumand 3-N-benzyluracil (17; 12.4 mg, 84%) as white solid.

Analogous treatment, in a glove box, of 24 (58.3 mg, 8.5 x 10 -5 mol)with SED(72 mg, 0.25 mmol, 3 equiv.) at ambient temperature for 4 h showed only trace amounts of 25and 17on TLC. Addition of degassed water (0.5 mL, 500 mg, 27.75 mmol) followed by heating at 80 o C for 30 min gave,after workup and silica gel chromatography,25 (31.7 General procedure for the electrolysis of 19 and 24. Under argon was introduced in the cathodic compartment, 10 mL of an anhydrous DMF solution containing n-Et 4 NBF 4 0.1M and 2.5 mL of the same solution in the anodic compartment (see Figure S6 for the cell). The cathodic solution was deoxygenated with argon bubbling for 15 min and then were introduced 19or 24. Solution was stirred and deoxygenated further for 10 min. A cyclic voltamogram was then recorded using a glassy carbon electrode in order to determine the reduction potential of starting material.A constant potential of -2.21 V for 19 or -2.51 V for 24was then applied at room temperature, with an itinital current close to 12-18 mA. The progress of the electrolysis was followed by cyclic voltammetry. After 2.0-2.1F/mole of starting material (1 h), the electrolysis was stopped and quenched with an aqeous NH 4 Cl solution and extracted with EtOAc (3 x), the combined organic phase were washed with H 2 O (3 x), dried over Na 2 SO 4 and filtered. Concentration under vacuo left a residue that was purified by silica gel chromatography. From 0.09g (0.131 mmol) of 24, 89.6 mg of a viscous yellow oil was obtained as crude product.

Column chromatography (5% MeOH in CHCl 3 ) gave a fraction (50 mg) that containedan inseparable mixture of 24and26 and (ratio ~ 2.5:1) with estimated yields of 24 (43%) and 26 (18%)from 1 H-and 19 F-


Teddy Lisle

Marie-Laetitia Pastor

Christophe Bouvet
email: christophe.bouvet@isae.fr

Philippe Margueres

Damage of woven composite under translaminar cracking tests using infrared thermography

Keywords: infrared thermography (IRT), fiber failure, fracture toughness, composite fracture

The aim of this work is to increase the study of the notch translaminar propagation of the woven structures, using the InfraRed Thermography (IRT). A test of notch propagation under quasi-static traction was developed and used to study the failure phenomena on two different draping sequences. For each study, a local estimation of dissipated energies, associated with different damages, is carried out using the measurement of the surface temperature field. The study of heat source fields combined with micrographic observations allowed to define the matrix microcracking as the predominant damage phenomenon in crack tip. The critical energy release rate, obtained using IRT, corresponds to critical energy release rate reported in the literature for translaminar rupture of laminates. Furthermore, when brittle cracking develops in a thermosetting matrix laminate, the majority of irreversible mechanical energy (>90%) is dissipated as heat. In the case of brittle cracking, the developed method proves to be an efficient alternative technique for the local measure of energy release rate, even in cases where the variations in stiffness due to cracking phenomena remain low.

Introduction

Woven composites are advanced materials that are commonly used in aerospace applications. Their use is interesting owing to their excellent drapability oven complex geometries, their effective manufacturing cost and their good damage tolerance properties. For example, the skin of helicopter blades is often made of a few woven plies. Nevertheless, in these thin structures parts, a through-the-thickness crack might appear in service. In fact, composites are subjected to a lot of failure processes due to the inhomogeneous and complex microstructure.

For the past decades, several authors have investigated the damage scenario of different woven composite laminates under quasi-static tensile loading [START_REF] Herszberg | Longitudinal and transverse damage taxonomy in woven composite components[END_REF][START_REF] Osada | Initial fracture behavior of satin woven fabric composites[END_REF][START_REF] Daggumati | Local damage in a 5-harness satin weave composite under static tension: part I-experimental analysis[END_REF][START_REF] Vieille | Influence of matrix toughness and ductility on the compression after impact behavior of woven-ply thermoplastic and thermosetting composites: a comparative study[END_REF]. For woven glass-fibrereinforced composites, transverse yarn cracking is the first readily observable type of damage occurring during tensile loading. As the strain increases, damage develops on the meso-scale by intra-yarn cracking and delamination, and on the micro-scale by local debonding at the fibrematrix interface [START_REF] Herszberg | Longitudinal and transverse damage taxonomy in woven composite components[END_REF]. The final macro-fracture is characterized by dense cracking, intersection of several small cracks and fiber rupture.

A failure which causes the structure breaking is the ply translaminar failure. So a lot of works have dealt with study of translaminar propagation in order to characterize it [START_REF] Jumahat | Fracture mechanisms and failure analysis of carbon fibre/toughened epoxy composites subjected to compressive loading[END_REF][START_REF] Laffan | Translaminar fracture toughness testing of composites : A review[END_REF][START_REF] Kumar | Intralaminar fracture toughness of a cross-ply laminate and its constituent sub-laminates[END_REF][START_REF] Gutkin | On the transition from shear-driven fibre compressive failure to fibre kinking in notched CFRP laminates under longitudinal compression[END_REF][START_REF] Catalanotti | Measurement of resistance curves in the longitudinal failure of composites using digital image correlation[END_REF].

Nevertheless, the traditional experimental methods have gaps. The ECT test is only standardized for the translaminar failure tests [START_REF]Standard test method for translaminar fracture toughness of laminated polymer matrix composite materials[END_REF]. The standard only deals with the characterization of the rupture initiation from a method for the isotropic materials [START_REF]Standard test method for linearelastic plane strain fracture toughness KIc of metallic materials[END_REF]. The experimental difficulties are  To estimate the energy release rate due to the failure initiation. The definition of the initiation beginning and the associated damage characterization are still badly established. The use of the acoustic emission enabled to improve detection of the damage beginning and the associated events at the propagation beginning [START_REF] Laffan | Translaminar fracture toughness testing of composites : A review[END_REF][START_REF] Gutkin | On the transition from shear-driven fibre compressive failure to fibre kinking in notched CFRP laminates under longitudinal compression[END_REF].

However this technique allows, neither to locate these damages, nor to determine their sizes [START_REF] Laffan | Translaminar fracture toughness testing of composites : A review[END_REF][START_REF] Catalanotti | Measurement of resistance curves in the longitudinal failure of composites using digital image correlation[END_REF].

In order to study the complex damage scenario of woven composite, traditional techniques such as X-ray, ultrasound C-scan imaging, acoustic emission, or digital image correlation may be insufficient and thermography can provide interesting additional information. From the past 20 years, IRT has been widely used to study the dissipative phenomena in materials, such as plasticity in metals [START_REF] Chrysochoos | An infrared image processing to analyse the calorific effects accompanying strain localisation[END_REF][START_REF] Dumoulin | Heat sources, energy storage and dissipation in high-strength steels: experiments and modeling[END_REF] or damage in polymers [START_REF] Wattrisse | Thermomechanical effects accompanying the localized necking of semi-crystalline polymers[END_REF]. Using the framework of irreversible thermodynamics, Chrysochoos et al. [START_REF] Chrysochoos | Analyse thermomécanique des lois de comportement par thermographie infrarouge[END_REF] have presented a methodology to estimate the internal heat sources associated with the dissipative phenomenon from temperature measurement on the sample surface. They show that an estimation of the heat sources makes it possible to locate the damage in time and space and to evaluate the energy-related information that can be used to characterize the irreversible energy dissipated [START_REF] Soumahoro | Etude du couplage thermomécanique dans la propagation dynamique de fissure[END_REF][START_REF] Lisle | Damage analysis and fracture toughness evaluation in a thin woven composite laminate under static tension using IRT[END_REF][START_REF] Lisle | Measure of fracture toughness of compressive fiber failure in composite structures using infrared thermography[END_REF][START_REF] Freund | High strain-rate crack-growth in rate-dependent plastic solids[END_REF].

Nevertheless in order to evaluate this dissipated energy quantitatively, the ratio of energy dissipated as heat to irreversible energy, i.e. the Taylor-Quinney coefficient [START_REF] Taylor | The latent energy remaining in a metal after cold working[END_REF], is needed, and it can be difficult to evaluate this coefficient [START_REF] Rittel | On the conversion of plastic work to heat during high strain rate deformation of glassy polymers[END_REF][START_REF] Zh | Strain rate effects on the thermomechanical behavior of polymers[END_REF].

The aim of this work is thus to increase the study of the notch translaminar propagation of the woven structures, using the IRT. A test of notch propagation under quasi-static traction was developed and used to study the failure phenomena on two different draping sequences. For each study, a local estimation of dissipated energies, associated with different damages, is carried out using the measurement of the surface temperature field. From these temperature fields, an experimental technique, based on a 2D or 3D-thermal approach, is carried out for the local measurement of the energy release rate associated with different cases of cracks.

I. Experimental set-up and material

The crack propagation is studied in glass/epoxy woven composite. These laminates are made of 8-harness satin balanced woven fabric (8-HS) pre-pegs plies with a fibre volume fraction of 50% (see Figure 1). The yarn size is 0.5 mm-width and 0.1 mm-thickness. The elastic moduli are 21.5 and 20.5 GPa, the limit strength 385 and 280 MPa, respectively in the warp and weft directions, the shear modulus is 3.5 GPa and the shear strength 65 MPa. The samples are always manufactured with the warp woven face on the top of the thickness, so the top face is a warp side and the underside face a weft one. The samples are made of 2 glass/epoxy woven plies surrounded with 2 unidirectional carbon plies (see Figure 2) [START_REF] Bizeul | Contribution à l'étude de la propagation de coupure en fatigue dans les revêtements composites tissés minces[END_REF][START_REF] Bizeul | Fatigue crack growth in thin notched woven glass composites under tensile loading. part I : Experimental[END_REF]. The carbon plies allow increasing the specimen stiffness. A finite element study has been performed in order to determine the limit conditions and the crack length in order to obtain propagation stabilization (dG/da < 0). So the specimen geometry is given in Figure 2. The crack length is equal to 20 mm and is carried out with a diamond wire saw.  thermal resolution: 0.025 K (for relative temperature measurement);

 spatial resolution (pixel size): 0.17 mm;

 observed zone: 54*43 mm² with a resolution of 3 pixels by woven width.

The temperature variations are raised on a zone located at the specimen centre in order to avoid the thermal disturbances observed close to the clamps.

Heat sources were estimated as described in [START_REF] Bizeul | Contribution à l'étude de la propagation de coupure en fatigue dans les revêtements composites tissés minces[END_REF][START_REF] Bizeul | Fatigue crack growth in thin notched woven glass composites under tensile loading. part I : Experimental[END_REF]. In fact, the experimental temperature variations are approximated on a moved window by a 2D-polynomial function ( app ). The smoothing of the temperature field at a time t is thus carried out by moving in each measure point the centre of the smoothing window. Then the obtained temperature field is approximated within the meaning of least squares on a moved smoothing window of 5*5 pixels². The heat sources in each pixel p ' ch are estimated with the centre of the smoothing window for each image (Eq.1).

𝑝 𝑐ℎ ′ ⃗⃗⃗⃗⃗⃗ (𝑖, 𝑗, 𝑘) = 𝜌𝐶 ( 𝜃 𝑎𝑝𝑝 (0,0,𝑘+1)-𝜃 𝑎𝑝𝑝 (0,0,𝑘-1)

2∆𝑡

+ 𝜃 𝑎𝑝𝑝 (0,0,𝑘)

𝜏 𝑡ℎ 2𝐷 ) -(𝑘 𝑥𝑥 𝑐 2,0 ∆𝑥 2 + 2𝑘 𝑥𝑦 𝑐 1,1 ∆𝑥∆𝑦 + 𝑘 𝑦𝑦 𝑐 0,2 ∆𝑦 2 ) Eq. 1
And the time constant 𝜏 𝑡ℎ 2𝐷 is given by experiments.

The material parameters employed for the calculation of the heat sources are given in the Table 1.

Longitudinal and transverse thermal conductivity, k xx =k yy 0.55 W.m -1 .K -1

Thermal conductivity in the thickness direction,

k zz 0.35 W.m -1 .K -1 Specific heat capacity, C 882 J.kg -1 . K -1 Density,  1730 kg.m -3
Coefficient of heat exchange by convection, h /air 8.15 W.m -2 .K -1

Table 1: Material parameters considered for the glass/epoxy woven plies [START_REF] Bigaud | A globallocal non-linear modelling of effective thermal conductivity tensor of textile-reinforced composites[END_REF][START_REF] Emery | A generalised approach to the calibration of orthotropic materials for thermoelastic stress analysis[END_REF] The damage maps are then obtained by temporal sum of the positive heat sources in each pixel (w d , Eq.2).

𝑤 𝑑 = ∑ 𝑝 𝑐ℎ ′ ̅̅̅̅ + (𝑖, 𝑗, 𝑘)∆𝑡 𝑁 𝑘=1
Eq. 2 𝑝 𝑐ℎ ′ ̅̅̅̅ + represents the heat sources positive and higher than the detection threshold estimated at 0.8x10 6 W.m -2 .

N indicates the image number at the considered time.

II. Notch propagation tests on [0°] specimens

A lot of studies [START_REF] Bizeul | Contribution à l'étude de la propagation de coupure en fatigue dans les revêtements composites tissés minces[END_REF][START_REF] Bizeul | Fatigue crack growth in thin notched woven glass composites under tensile loading. part I : Experimental[END_REF][START_REF] Shindo | Characterization of mode i fatigue crack growth in GFRP woven laminates at low temperatures[END_REF] have shown that the crack propagates in the notch axis following the weaving points. In our study, the notch tip damage corresponds to intralaminar failure of the weft woven but also propagation of vertical cracks in the warp woven (see Figure 3).

III. Notch propagation tests on [±45°] specimens

For propagation tests on [±45°] composites the direction of the cut is still governed by the position of weaving points (Figure 8). However, depending on the ply which controls the propagation (+45° or -45° ply), the notch path may be variable. Figure 8a shows the preferred alignments of weaving points to several directions of the woven ply. For plies oriented at +45° the weaving points have preferred orientations: ±27° and 90° relative to the horizontal. For -45° plies the characteristic angles are 0° and ±63°. Figure 8b shows the fracture surfaces obtained for two different tests. The observed disparity reflects the poor reproducibility of the cut paths. Indeed, in the first case the notch is initially propagates horizontally then bifurcates at an angle of about 33° relative to the horizontal, which suggests that the -45° ply and the +45° ply control successively the propagation (see warp face, Figure 8a). For the second specimen (weft face, Figure 8b), the propagation is totally controlled by the + 45° ply since the cut has an orientation at an angle of 27° relative to the horizontal. The damage observed on a microscopic scale is essentially characterized by shear microcracks in transverse and longitudinal strands (Figure 9). These microcracks initially parallel to the fibre direction propagate almost horizontally between two successive strands. The absence of "cups" on these cracks leads us to believe that the spread of intralaminar shear cracks is due to resin breakage.

IV. Evaluation of critical energy release rate

The energy release rate (G) is calculated from the integral heat source fields:

𝐺 = 𝑒 ∫ [∫ 𝑝′ ̅̅̅ 𝑐ℎ 𝑑𝑆 𝐼𝑅 𝑆 𝐼𝑅 ] 𝑑𝑡 𝑡 𝐴+𝑑𝐴 𝑡 𝐴 𝛽 𝑑𝐴 Eq. 3
where dA, the increase in the fractured surface, is estimated by assuming that the crack propagates rectilinearly in thickness. dA = e × a , where e is the thickness and a the notch spread determined from the cumulative heat source fields. S IR is the integration area and β ratio is the proportion of energy converted into heat during notch propagation. specimen. a (Figure 13c) is measured using profile A defined in Figure 13a. The damage length (Figure 13d) is measured using profile A defined in Figure 12a. Hence the size of the damaged area is known and sets the minimum size of the integration area S IR (Figure 13a andb). For [±45°] 2 specimens the cut path is not horizontal. Crack length is estimated as the norm of the vector defined by a 0 and a 1 (Figure 13b). G is here measured with a modified S IR in order not to take into account the displacements of the crack edges (Figure 13b). β is estimated as the ratio of the rate of heat energy release Gir and the energy release rate G (irreversible mechanical energy release rate). For [±45°] 2 specimens obtained results highlight low values for initiation. It is consistent with the smaller damaged areas observed previously. However, the initiation value obtained with the areas method is abnormally high (68.5 kJ.m -2 ). This comes from outliers obtained for initiation on weft face (Figure 14d) linked to the fact that it is difficult to get an accurate measurement of G from the variations of the load/displacement curve at the beginning of the test. If we consider only the initiation value on warp face, Ginit is equal to 26.8 kJ.m -2 which is consistent with the average value obtained for the initiation on [0°] 2 specimens.

[0°] 2 ). The proposed method (using the source fields) allows to define more accurately the initiating propagation which may explain the lower obtained values. As materials and failure modes are different, the authors assume that the energy release rates are comparable to those obtained in the literature for the translaminar cracking in mode I. Furthermore, whatever the configuration, obtained source fields on both faces are quantitatively equivalent. Therefore, we will assume that they are representative of the average dissipative sources field.

For both configurations, the heat energy release rates Gir and mechanical G, with associated R-curves (IR fit. and Mec. Fit), are compared in Figure 15. R-curves obtained by measuring heat energy remains below those obtained from the estimation of the mechanical energy. For each configuration, an average value of β is then estimated as the ratio between the calorific and the mechanical R-curves. R-curves are approximated using power laws: G = m.a n , where n is respectively set to n 0 = 0.24 and n 45 = 0.35 for [0°] 2 and [±45°] 2 configurations. β is thus the ratio of m coefficients. This set value of n requires that the irreversible mechanical proportion of energy converted to heat remains constant during initiation and propagation of the cut for each configuration. If the spread is stable, notch-tip damages are supposed qualitatively and quantitatively identical and β remains constant. However, define an identical β for propagation and initiation is more debatable. However, areas method is too imprecise to obtain quantitative data when the stiffness variations are small as at the initiation of cracking. β therefore could not be accurately assessed for initiation. The obtained average values are β 0 = 0.92 and β 45 = 0.95. This indicates that the majority of irreversible mechanical energy is dissipated as heat. As seen previously crack tip damage occurs mainly by multiple microcracks, fibre fractures and interface debonding. With such a high β it can be concluded that the proportion of pseudo-plasticity (shear in the resin) remains low and is mainly localized at the crack tip. It is therefore likely that the damage at the crack tip spreads mainly in the form of longitudinal and transverse microcracks in the yarns, thus relaxing the shear stresses in the resin-rich areas before that they reach their pseudo-hardening threshold.

In addition, the intensity of the measured dissipation field during translaminar propagation test (p' ch ~ 107 W.m -3 ) is 10 times greater than that obtained from the disoriented tensile tests (p' ch ~ 106 W.m -3 ) and 100 times greater than that observed for the rail shear test (p' ch ~ 105 W.m -3 ). So even if a pseudo-plastic phenomenon manifested in notch tip, its contribution would be negligible compared to that generated by purely dissipative micro-cracking. In conclusion, for the studied laminates, the propagation of a macroscopic cut can be characterized as a highly dissipative cracking phenomenon, spending between 90 and 100% of irreversible mechanical energy into heat (0.9 < β < 1.0).

Conclusion

In this study notch propagation tests were conducted on [0°] 2 and [±45°] 2 glass/epoxy woven composites and were monitored using IRT. This allowed to establish damage maps as well as quantitative data in the form of energy release rate (Gir) for both studied configurations ([0°] 2 and [±45°] 2 ). The study of heat source fields combined with micrographic observations allowed to define the matrix micro-cracking as the predominant damage phenomenon in crack tip. The obtained results also highlight that the source fields obtained on warp and weft sides are quantitatively representative of the volumetric heat capacity, although heterogeneity inherent in the material certainly remains, even for thin laminates. The obtained energy release rate Gir corresponded to GIc reported in the literature for translaminar rupture of laminates. Furthermore, when brittle cracking develops in a thermosetting matrix laminate, the majority of irreversible mechanical energy (>90%) is dissipated as heat. The assumption was made that β remained constant during the crack propagation and was measured for both configurations: β = 0.92 and β 45 = 0.95. In the case of brittle cracking, the developed method proves to be an efficient alternative technique for the local measure of energy release rate, even in cases where the variations in stiffness due to cracking phenomena remain low.



  To propagate a steady crack without other damaging modes disrupting measurements or the failure scenario. The stability of the propagation is an important point because the size of the damaged zone in notch tip and thus the Gc values depend on it.  To evaluate the cracked length.  To calculate the contact stress and the dissipated energy by friction when the crack edges remain in contact during the propagation. The effects to the measure of the energy release rate are still badly defined by the literature studies [Blackman et al., 2005].

Figure 1 Figure 2 :

 12 Figure 1: Weave pattern

Figure 3 :

 3 Figure 3: Micrographic views of the warp face (a) in notch tip, (b) after specimen failure and (c) transverse view in notch tip

Figure 4 :Figure 5 :

 45 Figure 4: Micrographic views in notch tip obtained under SEM[START_REF] Garcia | Behaviour of 8-harness satin weave composite under static tensile loads: Failure analysis of woven composites[END_REF]

Figure 6 : Zone 1 : Zone 2 :

 612 Figure 6: (a) strain/displacement curve; (b) warp face pattern; (c) temperature variation field ; (d) heat source field p' ch and (e) cumulated heat source field w d on warp face

Figure 7 : Zone 3 :

 73 Figure 7: Comparison of the damaged zones size (a) weft face and (b) warp face before the crack propagation

Figure 8 :

 8 Figure 8: (a) Warp face of the weave pattern oriented in the directions 0°, 90°, + 45° and -45°. (b) Photographs of the ±45° specimens after spread of the notch

Figure 9 :

 9 Figure 9: Micrographs after breakage of the warp face of a ±45° specimen

Figure 10 :Figure 11 :Figure 12 :

 101112 Figure 10: Micrographs after breakage of the warp face of a ±45° specimen

Figure

  Figure 13a shows an example of cumulative heat source fields at crack tip on a [0°] 2

Figure 13 :Figure 14 :

 1314 Figure 13: Cumulative source fields Δw d during a notch propagation: (a) [0] 2 weft side and (b) [±45] 2 weft side. Changes in Δw d along profile: (c) A and (d) B defined in (a)

Figure 15 :

 15 Figure 15: Comparison of energy release rates G and Gir for configurations (a) [0°] 2 and (b) [±45°] 2

Table 2 :

 2 Average values and relative standard deviations of energy release rate calculated for

	[± 45°]2