Dr Lucas Popek

Dr Jorge Juan Cabrera-Trujillo

Dr Vincent Debrauwer

Nicolas Blanchard

Dr Karinne Miqueu

Vincent Bizet
email: vbizet@unistra.fr

Regio-and Stereoselective Hydroelementation of SF 5 -Alkynes and Further Functionalizations

Herein is described a fully regio-and stereoselective hydroelementation reaction of SF5-alkynes with N, O and Snucleophiles and further functionalization of the corresponding Z-(hetero)vinyl-SF5 intermediates, a suitable platform to access α-SF5 ketones and esters, β-SF5 amines and alcohols under mild reaction conditions. Experimental and computational comparative studies between SF5-and CF3-alkynes have been performed to highlight and explain the difference of reactivity and selectivity observed between these two fluorinated motifs.

Introduction

Enamine is a privileged functional group in organic chemistry and it has been worldwide spotlighted with the 2021 Nobel prize in Chemistry about organocatalysis. [1,[START_REF] Mukherjee | For reviews about enamine[END_REF] Enamine chemistry has been widely used in organofluorine chemistry, especially for the stereoselective introduction of fluorine atoms and CF3 group. [START_REF] Bizet | For selective reviews about stereoselective fluorination reactions[END_REF] On the other hand, fluorinated enamines are also of great interest and can be readily prepared by fluoroalkylation, [4] fluorination of ynamides, [5] dehaloamination of haloalkenes, [6] Michael addition, [7] hydroamination of alkynes, [8] and other methods. [9] Nowadays, the pentafluorosulfanyl group (SF5) [10] is growing in interest in many fields such as heterocyclic synthesis, [11] material science, [START_REF] Chan | [END_REF] and medicinal chemistry, [13] and drug development are in progress. [14] However, synthetic routes to SF5 compounds with structural diversity remain highly challenging and rely mainly on two general methods : the direct radical pentafluorosulfanylation of alkenes, alkynes, diazo ketones or [1.1.1]propelane, [15] or the oxidative fluorination of aromatic thiols, disulfide or derivatives. [16] SF5-alkynes are readily accessible substrates which can be used in various transformations, such as cycloadditions, heterocyclic synthesis and hydrofunctionalization. [17] Great discoveries are also under investigation with the closely related R-SF4-alkynes another class of promising SFn subunits. [18] Surprisingly, the hydrofunctionalization of SF5-alkynes has been poorly explored and is mainly limited to hydration and hydrofluorination. [19] Until recently, hydroamination of SF5-alkynes was unknown, [20] but analogous reaction with CF3-alkynes was studied by Trofimov and Nenajdenko (Scheme 1,a). [8] They observed that addition of imidazole derivatives on CF3-alkynes was fully stereoselective, forming exclusively Z-isomers but the regioselectivity of the amination, in α-or β-position with respect to the CF3, is highly dependent on the substitution of the aromatic ring of the CF3-alkynes ranging from 45:55 to 5:95, but without a clear trend. Other syntheses of CF3-enamines are known but rely mainly in addition/elimination strategies (Scheme 1,b-c). [6] Herein is reported a general procedure for the hydroamination of SF5 alkynes 2 with a wide variety of nitrogen-nucleophiles, leading exclusively to a single β,Z regio-and stereoisomer, and this methodology can easily be extended to hydroetherification and hydrothioetherification reactions. Furthermore, it is demonstrated that these vinyl-SF5 scaffolds are suitable platforms to access α-SF5-ketones and esters, β-SF5-amines and alcohols.

Results and Discussion

SF5-alkynes were prepared from β,E-chloro-olefin 1 by dehydrochlorination under basic conditions. [15j, 21] We started the study by the reaction of biphenyl-4-ethynyl pentafluorosulfane 2a with 1.2 equiv. of imidazole at r.t. in THF that delivers the product 3aa with a full conversion and 68% yield (Scheme 2). Compared to the analogous reaction with CF3 alkynes, [8] we were delighted to note that an additional base was not required with SF5-alkynes, and the reaction gave a single regio-and stereoisomer with introduction of the imidazole exclusively in β-position of the SF5 with a Z-configuration, as confirmed by the X-ray diffraction of compound 3ca (CCDC 2221093), 3ae (CCDC 2221162), 3ae' (CCDC 2235645) and 4ab (CCDC 2221641). [START_REF]X-ray diffraction presented using CYLview20[END_REF] Encouraged by this result we investigated the scope and the limitation of hydroamination of SF5-alkynes by screening different amines and other N-containing nucleophiles. Unlike imidazole, we found that using a base achieved complete conversion in all cases. After a short optimization, we found that the combination of NaH in DMSO was compatible with a wide variety of nucleophiles, securing a good solubility of the system, a full conversion and still a perfect regio-and stereoselectivity. Several nitrogen-containing heteraromatic compounds can easily be introduced on SF5alkynes such as indole (3ab), benzotriazole (3ad), tetrazole (3ae), carbazole (3af), 6-or 7-aza-indazoles (3ag-h, 3dh) [START_REF] Brach | [END_REF] with yields ranging from 43 to 73%. In addition, the 2-SF5-indole [21] is also a competent nucleophile in these conditions and provide compound 3ac in 50% yield bearing two SF5 motifs. Natural products such as adenine and theophylline are well tolerated and underwent the reaction smoothly to give 3al and 3aj in good 72 and 56% yield, respectively. Secondary anilines protected with mesyl (3al), acetyl (3am), tosyl (3an) or even tert-butylcarbamate (3ap) are well tolerated with yields ranging from 38 to 68%. Aliphatic secondary amines such as N-Ts allyl amine (3ar) and N-Boc benzylamine (3as) can be introduced with a moderate 42 to 48% yield. Other N-nucleophiles such as phtalimide (3at), oxazolidinones (3au-v), sulfoximine (3aw) or even an imine (3ax) can be introduced easily in yields ranging from 35 to 78%. Interestingly, the addition of hydroxylamine in THF in the presence of KOH gave the oxime 3ay with a decent yield of 45%. Furthermore, when NaN3 was used as nucleophile in DMSO, it resulted in a mixture of the β,Z-N3 addition product 3az in 35% yield along with the corresponding cycloaddition triazole 3az' in 48% yield. In this case, heating of the reaction at 60 °C and/or extended reaction time did not improve the 3az:3az' ratio. Surprisingly, the use of CuI as additive suppressed the formation of 3az' and 3az was isolated in 60% yield as single SF5-containing product. We then capitalized on this reaction and extended the scope of this transformation to sulfur-and oxygen-containing nucleophiles. Aromatic (4aa) and heteroaromatic thiols (4ab-d) were successfully introduced at the sulfur atom with yields ranging from 39 to 85%. Various phenols can also be introduced, with pnitro (5aa), with o-halogens (5ac-d) or even with a bulky 1,1'binapthyl structure (5ae). Noteworthy, substitution of the alkyne is also tolerated as in the case of heteroaromatic groups (5dd) or N-Boc piperidine (5ed) for instance. The reaction can be extended to a CF3-alkyne, where 67% conversion was obtained with the formation of compound 5ad' as single regio-and stereoisomer isolated in 43% yield. Interestingly, the introduction of oxygen nucleophile is not limited to phenols since an oxime (5af) can also be introduced in 60 % yield, and the addition of aliphatic alcohols such as MeOH (5ag) and t-BuOH (5ah) proceeds also well in these conditions. With MeOH, we observed for the first time a mixture of E:Z isomers (50:50) in NMR but the introduction of the MeOH only takes place in β-position of the SF5, while only the β,Z isomer is observed with t-BuOH. In 1964, Hoover and co-workers described a similar nucleophilic addition of methanol in the presence of KOH as base towards SF5-acetylene 2f leading mainly to the Z isomer in 65% yield (Scheme 3, eq. 1). In contrast, nucleophilic addition of MeOH to the β,E-chloro-olefin 1f provided mainly the E isomer in 40% yield suggesting mainly a substitution of the chlorine atom (Scheme 3, eq. 2). [24] As a comparison, we tested these conditions with the SF5-alkyne 2a and corresponding β,E-chloro-olefin 1a (Scheme 3, eq. 3-4). Similar results were obtained in both cases with a Z:E mixture ranging from 50:50 to 40:60, which seems to indicate that a similar reaction pathway takes place by addition of methoxide onto SF5-alkyne 2a (as substrate or generated in-situ from 1a). However, we noticed a clear difference of stability between the Z:E isomers 5ag. Both E:Z isomers can easily be purified by silica gel column chromatography, however Z isomer is stable over time while degradation of the E isomer was observed in the NMR tube (See ESI for details, Figure S11). [25] During the investigation of the hydroamination of SF5-alkynes, we found that some secondary amines such as pyrrolidine and piperidine were effectively transformed into corresponding enamines 6 as a single regio-and stereoisomer (Scheme 4), but they were somehow sensitive to purification and prone to partial hydrolysis over silica gel, delivering a mixture of SF5-enamine 6 and SF5-ketone 7. For a long time, the α-SF5-ketones were known in the literature but remained mostly anecdotal. [26] More recently, specific procedures for the synthesis of α-SF5-ketones have been reported, such as gold catalyzed regioselective hydration of SF5 Scheme 3. Nucleophilic addition of alcoholates, MeOH vs t-BuOH. a E:Z ratio determined by 19 F and 1 H NMR, b Isolated yield into brackets, c Only the Z isomer was isolated after silica gel chromatography, while E isomer degraded overtime.

alkynes, [19b] direct pentafluorosulfanylation of α-diazo ketones, [15g] or ozonolysis of allylic SF5 products. [27] The procedure described herein is a complementary approach and had the advantage of using mild reaction conditions and being a metal-free procedure. After some optimization, we found that pyrrolidine (2 equiv.) yielded enamine 6a 1 in 30 min at r.t. in THF, while the kinetic was slower with piperidine (2 equiv., r.t. 5h). Then, we found that acidic treatment either with diluted H2SO4 (10% in water) or HBF4 (50% in water) were efficient conditions to fully hydrolyze the enamines 6a 1 and 6a 2 with good overall yields of 76% (7a) in both cases. In contrast, we observed that the hydrolysis was slower for 6a 1 (6 h) than for 6a 2 (30 min). For the scope of this transformation (Scheme 4), we used the pyrrolidine for 2h at r.t. and then HBF4 50% in water for 6h at r.t. The reaction proceeded smoothly with aromatic, heteroaromatic and alkyl substituted alkynes in moderate to high yields. Surprisingly, substitution with a 2-naphtyl delivers the ketone 7b in 67% yields while the 1-napthyl substitution (2g) stopped at the enamine form without full conversion. It rather looks like a special case because several examples of bulky ortho-substituted aryl ketones (7d, 7h-j) were obtained in yields ranging from 35 to 75%. Nitrogen-heterocycles (7d, 7m) are well tolerated and the reaction is also compatible with alkyl substrates although corresponding ketone 7n and 7o are quite volatile. Unlike the closely related RSF4-alkyne derivatives, [18d] the hydrolysis of SF5-alkynes directly with an acidic aqueous solution is unknown. Following recommendation from referee, we checked that hydrolysis of SF5-alkynes 2a was not possible using H2SO4 (10 mol%) or HBF4 (50% in H2O), thus showing the benefit to pass by the formation of enamine 6. [25] In contrast, much more concentrated solution of H2SO4 proved to be effective to hydrolyze 2a into 7a, and after a short optimization we found that using 80% aq. solution of H2SO4 in THF at r.t. give 94% of 7a after 5 min, isolated in 68 % yield. Since SF5-alkynes 2 are prepared from 1 by a base-mediated dehydrochlorination, we anticipated that the basic conditions we used for the hydroelementation would be suitable for both the dehydrochlorination step and the hydroelementation step, so we could perform this hydroelementation directly from 1 via a telescoped procedure (Scheme 5). So, we tested the hydroetherification from β,E-chloro-olefins 1a and 1d in the presence of LiOH, DMSO and 2-iodophenol as nucleophile and we obtained products 5ad and 5dd in 79 and 74% yield respectively over a two-step sequence. Similarly, hydroamination of 1c with imidazole in the presence of LiHMDS delivered product 3ca in 65% yield. We also confirmed it was possible to make the α-SF5-ketone 7c in 71% yield directly from 1c by reaction with pyrrolidine in the presence of LiHMDS, followed by hydrolysis with aqueous HBF4. In the literature, the SF5 group is often called "super CF3" since many of its physicochemical properties are enhanced compared to CF3. [10] However, the synthesis and reactivity of SF5 compounds differ significantly from the CF3 analogs. During the present study, we wondered why the hydroelementation of SF5 alkynes was perfectly regio-and stereoselective, whereas the hydroamination of CF3 alkynes in similar conditions yielded a mixture of regioisomers. [8] As comparison, Nenajdenko and coworkers described in 2016 the addition of imidazole and derivatives on CF3-alkynes forming exclusively Z-stereoisomers but with α:β regioselectivity ranging from 45:55 to 5:95 without a clear trend about the influence of the alkyne substitution. Since our group also has a strong interest in the synthesis and reactivity of CF3 alkynes, [28] we decided to reinvestigate this transformation experimentally on both CF3-and SF5-alkynes, using reactions conditions X (no base, THF, r.t., 2h) from the present report and conditions Y (20 mol% of KOH, MeCN, r.t., 24h) from Nenajdenko (See ESI, Figure S1). [8] We first observed that in conditions X or Y, the addition of imidazole on the SF5-alkyne 2a leads to a perfect β,Z-selectivity (B1). Surprisingly, with the analogous CF3alkyne 2a' no reaction occurs in conditions X, even after 24h, but the reaction proceeds in conditions Y yielding a 25:75 A1:B1 ratio in favor the β,Z-isomer (B1). Looking for a substrate giving a lower selectivity, we identified the CF3-alkyne 2b' which gave a 40:60 A1:B1 ratio. [8] Scheme 5. Telescoped procedures As expected, no reaction takes place in condition X with 2b', but only conditions Y are suitable to produce a 30:70 A1:B1 ratio which is closely related to what they observed. With the analogous SF5-alkyne 2b, a perfect β,Z selectivity (B1) was observed in conditions X, while a 92:8 B1:B2 mixture of stereoisomers was observed for the first time in conditions Y, and the structure was confirmed by NOE experiments. [25] However, we noticed that the β,E-isomer B2 was poorly stable overtime. For instance, after keeping the mixture of isomers in an NMR tube under sunlight for a couple of days, B1 remains intact whereas B2 evolves to the corresponding ketone 7 and other by-products. In contrast with CF3-alkynes, nucleophilic addition onto SF5alkynes always takes place at the β-position of the SF5 motif, but how to explain this difference of regioselectivity? One could say that SF5 (with an electronegativity of 3.65 vs 3.36 for CF3) polarizes more the alkyne than CF3 making the C≡C bond a better nucleophile acceptor. This is supported by the calculations of the NPA charges of the carbon atoms of the triple bond, C and C, for the fluorinated-alkynes 2a and 2a'. C bears a slightly positive charge (0.09 for 2a and 0.07 for 2a') whereas for C it is negative (-0.30 for 2a and -0.15 for 2a'), leading to a more polarized bond in 2a (q : 0.39 and 0.22 respectively, See ESI, table S3). On the other hand, the larger van der Waals volume of SF5 (55.4 Å 3 vs Figure 1. Energy profiles (G in kcal/mol) computed at PCM(THF)-M06-2X/6-311+G**//M06-2X/def2-SVP level of theory for the hydroamination of SF5/CF3-alkynes (2a/2a') with imidazole, affording A1 (, Z) and B1 (, Z) products. Activation barriers for the formation of all plausible hydroamination products (A1, A2, B1 and B2) are also reported. 34.6 Å 3 for CF3) closer to a tert-butyl group would argue more in favor of steric preferences. To elucidate the origin of the observed selectivity for SF5-alkynes i.e. privileged nucleophilic attack on carbon, as well as the higher reactivity of SF5-alkynes over CF3alkynes in conditions X, we computed the different energy profiles (PCM(THF)/M06-2X/6-311+G**//M06-2X/def2-SVP) for the hydroamination reaction over SF5/CF3-alkyne 2a/2a' with imidazole in absence of base. The more relevant energy profiles associated to the formation of Z-isomers (A1, B1) are depicted in Figure 1 and the whole panorama (Z-and E-isomers) are reported in ESI, Figures S2-3). As displayed in Figure 1, the nucleophilic attack of the imidazole over the fluorinated-alkyne first forms a zwitterionic intermediate (INT), followed by a presumed fast and solvent-mediated proton transfer, leading to the final hydroamination product in a highly exothermic process (G < -19 kcal/mol). This nucleophilic addition is the step governing the regioselectivity. In line with the experimentally observed regioselectivity, DFT calculations have shown that the attack at the -carbon of SF5-alkyne 2a and leading to Z-isomer B1 is kinetically favored over the attack at the -carbon, affording Zisomer A1 (G ǂ = 21.7 vs 24.6 kcal/mol for TS1 and TS2, respectively). Closer inspection of the optimized transition states suggests that TS1 is an earlier TS than TS2, with a C•••N distance of 1.908 Å and 1.765 Å, respectively. It is noteworthy that formation of E-isomers (A2, B2) are less kinetically favorable (G # ~5 kcal/mol compared to TS1).

On the other hand, by comparing the processes involving 2a and 2a', we found that the replacement of the SF5 with CF3 produces a considerable increase of the activation barrier of the nucleophilic attack at -carbon (G ǂ = 21.7 vs 30.1 kcal/mol, respectively). This finding perfectly matches with the fact that the hydroamination reaction of SF5-alkyne 2a with imidazole occurs at r.t. but fails employing the analogous CF3-alkyne 2a'. As revealed by the C•••N distance, the highest activation barrier for TS1' corresponds to a later TS with a C•••N distance of 1.832 Å vs 1.908 Å, for respectively TS1' and TS1.

In order to further understand the origin of the -selectivity observed for the SF5-alkyne 2a, we applied two powerful computational tools to quantitatively analyze the physical factors behind the reactivity trends, namely, the Activation Strain Model of reactivity (ASM) and the Energy Decomposition Analysis (EDA). [25] The Activation Strain Model (ASM) approach was used to assess the relative contributions of the strain (Estrain) and interaction (Eint) terms upon attack of imidazole at -carbon and -carbon of the alkyne. Figure 2 shows the corresponding activation strain diagrams along the entire reaction coordination  (selected as the C•••N bond-forming distance) for the nucleophilic attack of imidazole on alkyne 2a at -carbon (dashed lines) and -carbon (solid lines). As observed in Figure 2, the Estrain term, which quantifies the required energy to distort the reactants, is considerably smaller for the nucleophilic attack at the -carbon compared to the same attack at the -carbon (at a quasi-similar C•••N distance of about 1.9 Å, close to TS1, Estrain : 10.4 for C and 24.6 kcal/mol for C see Table S1). Consequently, this term is not at all responsible for the -selectivity. In sharp contrast, the interaction term (Eint) between the reactants is much more stabilizing for the process involving the -carbon along the whole reaction coordinate, meaning that Eint term is solely responsible for the experimentally observed -selectivity. With the help of the EDA method (M06-2X/TZ2P//M06-2X/def2-SVP), we further analyzed the Eint term by decomposing it into three different chemically meaningful terms: (i) the Pauli repulsion term, Epauli, that quantifies destabilizing interactions between occupied orbitals and is a measure for any steric repulsion, (ii) the Velstat term corresponding to the quasi-classical electrostatic interaction between the reactants and (iii) the Eorb accounting for the stabilizing orbital interactions between occupied orbital of one reactant with unoccupied orbital of the other reactant. Although we computed the EDA terms along the whole reaction coordinate (see ESI, figure S5), for a direct comparison between the attack at -or -carbon, we analyzed the EDA terms at a consistent similar distance C•••N distance of ~1.9 Å, close to TS1. At this point, Eorb and Velstat terms are relatively small (Eorb = 3.7 and Velstat = 2.7 kcal/mol, in favor of C). The largest difference between the two attacks finds its origin in the destabilizing Pauli repulsion term (EPauli = 8.5 kcal, see ESI Table S2), which is much larger for C attack. This result suggests that the origin of the -selectivity observed for 2a is mainly due to a larger steric repulsion upon attack at Cthuspreventing the formation of hydroaminated -isomer.

To understand the higher reactivity of the SF5-alkyne 2a compared to the CF3-alkyne 2a', we applied again the ASM/EDA methodology for the privileged nucleophilic attack at -carbon. We found that the Estrain term for the process involving 2a and the process involving 2a' are nearly identical along the reaction coordinate (Figure 3). However, the Eint term is more stabilizing for the nucleophilic addition of imidazole on SF5-alkyne than CF3alkyne. According to EDA analysis, at a similar distance close to TS1 (C•••N ~ 1.91 Å), the largest difference between the attacks on 2a and 2a' is found in the orbital term (Eorb), which is more stabilizing for 2a [EPauli : 3.2, Velstat= -2.3 and Eorb= -5.8 kcal/mol, see ESI table S4 andFigure S7]. The Natural Orbital for Chemical Valence (NOCV) extension of the EDA method shows that the main orbital interaction Eorb1 comes from the charge flow of the density from the nitrogen lone pair of imidazole to the empty *CC orbital of alkyne (See Figure 4). The highest orbital stabilization for 2a (Eorb1 : -47.5 kcal/mol vs -42.7 kcal/mol in 2a') can be correlated to a more accessible LUMO (*CC/*CC aryl (alkyne)) in SF5-alkyne compared to CF3-alkyne (-1.2 eV in 2a vs -1.0 eV in 2a', see Figure S10). In order to generalize our study, we computed the activation barriers for the attack at the -carbons of SF5-alkyne 2a and affording Z-isomers A1/B1, for two other nucleophiles experimentally reported in Scheme 4 and involving similar experimental conditions (without base) i.e. pyrrolidine and piperidine. DFT calculations (see ESI for details, Table S6) indicate the attack at C is still kinetically favored, in line with the experimental results. The activation barriers for the nucleophilic attack at -carbon were computed lower in energy than for imidazole, at G ǂ = 15.5 and 15.2 kcal/mol, respectively for pyrrolidine and piperidine, suggesting more reactive nucleophiles. In addition, a lower energy difference between the two transition states associated with the attacks in  and  was found for pyrrolidine and piperidine (G # : -1.5 and -1.0 kcal/mol, respectively) compared to imidazole (G # : -2.9 kcal/mol) but did not impact the selectivity. As these DFT studies fully support the experimental selectivities, we then embarked in control experiments to gain further insights into the mechanism (Scheme 6). [8,29] The reaction proceeds smoothly in the presence of 4 equiv. of TEMPO and gave the desired product 5ab without inhibition of the reaction. When DMSO-d6 was used as solvent a mixture of deuterated and not deuterated product was obtained in a 50:50 ratio, showing the crucial role of the solvent in this reaction acting as a H/D-donor. Moreover, the incorporation of deuterium took place only on the olefin in α-position of the SF5. Finally, we studied some downstream functionalizations. Palladium-catalyzed Negishi cross-coupling with diethylzinc delivered 8a in 49% yield. Suzuki-Miyaura cross-coupling with phenyl boronic acid (8b) and Sonogashira cross-coupling with TMS-acetylene (8c) were also performed in 75 and 57% yields, respectively (Scheme 7,a). Intermediate enamine 6a 1 can react with an electrophilic halogen source such as NCS or NBS to form α-chloro or α-bromo α-SF5-ketones (9a, 10a) in presence of water to quench the intermediate iminium (Scheme 7,b). Enamine 6a 1 can also be reduced with BH3.SMe2 to form the corresponding amine 11a in decent 55% yield. Finally, reduction of the α-SF5ketone 7a was performed in high yield (94% 13a) using sodium borohydride in ethanol. Moreover, we succeeded to perform a Baeyer-Villiger oxidation on the ketone 7a leading to the corresponding ester 12a in 71% yield (Scheme 7,c).

Conclusion

In summary, we have developed an efficient and general hydroelementation reaction on SF5-alkynes. The reaction tolerates a wide range of N-, O-, and S-nucleophiles and gives the corresponding adducts in good yields and in all the cases as a single regio-and stereoisomer. A complementary synthesis of α-SF5-ketones was performed under mild condition and without any use of metals. Moreover, it was shown that these transformations can also be performed directly from the corresponding β,E-chloroolefins which shorten the synthesis by one step. A selection of downstream functionalizations was demonstrated, including C-C cross coupling, halogenation, reduction and Baeyer-Villiger oxidation. DFT calculations were also performed to better understand the impact on reactivity of the SF5 compared to the CF3 group, which nuance the comparison of SF5 as a super CF3, but seems to indicate that they have very distinct properties and reactivities. DFT calculations combined with ASM/EDA analyses were performed to have better insight on the -selectivity for SF5alkyne and the impact of the fluorinated group (SF5 vs CF3) for the hydroamination reaction with imidazole. The origin of the selectivity for the SF5-alkyne is related to a lower steric repulsion (EPauli) upon attack at C. Compared to CF3-alkyne, the Cnucleophilic attack of imidazole on SF5-alkyne occurs in the absence of base thanks to better orbital interaction between the nitrogen lone pair of imidazole and the empty *CC (alkyne), which is more accessible in energy than in CF3-alkyne.

Scheme 1 .

 1 Scheme 1. State of the art and proposed strategy for the hydroelementation of SF5-alkynes.

Scheme 2 .

 2 Scheme 2. Scope and limitation for the N, O and S-nucleophilic addition. The reaction was performed from SF5-alkyne 2 unless otherwise noted. a THF was used instead of DMSO with 2 equiv. of nucleophile without base, b Obtained from the reaction with NaN3 as nucleophile, c KOH was used instead of NaH, d Same yield on 0.03, 0.3 and 0.6 mmol scale, e Reaction performed from the corresponding β,E-chloro-olefin 1, f Only the Z-isomer was recovered after silica gel chromatography.

  Scheme 4. Scope and limitation for the formation of α-SF5-ketones. a H2SO4 10% was used instead of HBF4, b Enamine 6g was partially obtained but not isolated.

Figure 2 .

 2 Figure 2. Activation strain diagrams computed along the IRC for the paths to TS1 (attack at C, dashed lines) and TS2 (attack at C, solid lines) of the hydroamination reaction of SF5-alkyne 2a with imidazole. Energy level: M06-2X/def2-SVP.

Figure 3 .

 3 Figure 3. Activation strain diagrams computed along the IRC for the privileged path through TS1 (attack at C for 2a, dashed lines) and TS1' (attack at C for 2a', solid lines) of the hydroamination reaction of the fluorinated alkynes with imidazole. Energy level: M06-2X/def2-SVP.

Figure 4 .

 4 Figure 4. Plot of the evolution of the orbital interaction energy contribution (ΔEorb,1 in kcal/mol) of the main pairwise orbital interaction between the fluorinated-alkynes and imidazole all along the process for the attack at C.TS1 is in solid line and TS1' in dashed line. Plot of the contours of deformation density contribution (Δρorb,1) of the main pairwise orbital interaction and associated orbital interaction energy contribution (ΔEorb1 in kcal/mol).

  Scheme 6. Control experiments and proposed mechanism

Acknowledgements

This work is supported by ANR DEFIS project (grant ANR-PRC-17-CE07-0008) and ANR SULFIVE project (grant ANR-PRC-21-CE07-0042) of the French National Research Agency (ANR). The authors thank Dr. Didier Le Nouen responsible for the analytical platforms and facilities of LIMA (UMR7042 CNRS-Unistra-UHA). The "Direction du Numérique" of the Université de Pau et des Pays de l'Adour and Mésocentre de Calcul Intensif Aquitain (MCIA) are acknowledged for computational facilities. This work was also performed using HPC resources from GENCI-IDRIS (Grant 2023-[project AD010800045R1]). We also would like to thank referees for their valuable suggestion and comments. Keywords: pentafluorosulfanyl • enamine • hydroelementation • regioselective • stereoselective ORCID Lucas Popek, orcid.org/0000-0002-8894-1467 Jorge-Juan Cabrera-Trujillo, orcid.org/0000-0002-1158-5409 Vincent Debrauwer, orcid.org/0000-0002-2399-6053 Nicolas Blanchard, orcid.org/0000-0002-3097-0548 Karinne Miqueu, orcid.org/0000-0002-5960-1877 Vincent Bizet, orcid.org/0000-0002-0870-1747

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Herein, fully regio-and stereoselective hydroamination, hydroetherification and hydrothioetherification reactions of SF5-alkynes and further functionalizations of the corresponding Z-(hetero)vinyl-SF5 intermediates towards α-SF5-ketones, α-SF5-ester and β-SF5-amine are described. Experimental and computational comparative studies with CF3-alkynes are also discussed.

Institute and/or researcher Twitter usernames: @BizetVincent, @LIMA_UMR7042


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Adrien Loncle

Caroline Piau

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Marie Gousseff

Vincent Cattoir

Emmanuel Allory

Aurélien Lorléac'

Mathieu Dupont

Agathe Goubard

Pierre Tattevin
email: pierre.tattevin@chu-rennes.fr

Current profile and management of gonococcal infections: a populationbased study in Western France Profil et prise en charge des gonococcies: une étude à base populationnelle dans l'Ouest de la France

Keywords: Neisseria gonorrhea, general practitioner, population-based study

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

Since the late 1990s, the incidence of sexually transmitted infections (STI) has been gradually increasing [START_REF] Ruche | Current epidemiology of bacterial STIs in France][END_REF]. A recent study in France estimated that between 2014 and 2016, the number of gonorrhea cases had increased by 127% in men who have sex with men, by 21% in heterosexual women, and by 40% in heterosexual men [START_REF] Ngangro | Bacterial sexually transmitted infections in France: recent trends and patients' characteristics in 2016[END_REF]. In parallel, the advent of nucleic acid amplification tests (NAATs), including PCR, has dramatically improved the diagnosis of various STIs. While the diagnosis of gonococcal infections in men used to require painful urethral sampling and immediate processing in a microbiology lab, it is currently easily obtained through NAATs on urinary samples [3][4][5] [START_REF] Gerhardt | Male urethritis][END_REF]. Hence, a growing proportion of cases are currently diagnosed outside of referral centers and STI clinics [START_REF] Falchi | A survey of primary care physician practices in antibiotic prescribing for the treatment of uncomplicated male gonoccocal urethritis[END_REF] [START_REF] Rossignol | Estimate of male urethritis incidences in France between 2007 and 2017 with a specific focus on Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis infections[END_REF].

In the absence of mandatory notification in France, the surveillance of gonococcal infections is currently based on two sentinel networks: RésIST (clinician network for STI surveillance), and Rénago (laboratory network for surveillance of gonococcal infections) [START_REF] Ngangro | Bacterial sexually transmitted infections in France: recent trends and patients' characteristics in 2016[END_REF][9] [START_REF]Dépistage et prise en charge de l'infection à Neisseria gonorrhoeae : état des lieux et propositions[END_REF]. However, contemporary data on the characteristics and management of gonococcal infections are scarce [10][4]. We performed a three-year retrospective population-based study of all gonococcal infections having been documented in two departments in Western France.

Materials and Methods

Setting and design

Morbihan and Ille-et-Vilaine are two predominantly rural departments in Western France, with 747,548 and 1,052,779 inhabitants respectively during the study period (source: https://www.insee.fr/fr/information/4172214).

Inclusion criteria

We enrolled all cases of gonococcal infections documented by PCR from January 2014 to December 2016. Cases were identified through i) laboratory databases of the 4 major hospitals in the two departments (Rennes, Vannes, Lorient, St Malo/Dinan); ii) the Rénago database for cases diagnosed outside of hospitals. To avoid duplicates, only one gonococcal infection per patient per year was included.

Data collection

For patients managed in hospitals (inpatients and outpatients), clinical and microbiological data as well as those on management were collected from medical files by one investigator (AL), using a standardized questionnaire. For patients enrolled through the Rénago network, baseline data were extracted from the Rénago database. Antibiotic susceptibility testing was performed in accordance with CA-SFM guidelines (www.sfmmicrobiologie.org) and MICs were determined using ETEST strips (bioMérieux) according to manufacturer's recommendations. As regards patients enrolled through the Rénago database, no information on treatment and outcome was available.

Ethics

RésIST and Rénago networks were approved by the French Personal Data Protection Authority (Comité National Informatique et Libertés, CNIL, authorization numbers 10362 and 999298). Patients' informed consent was required before any data collection. The number of people having opted out of this surveillance system by not providing their consent remains unknown. For patients enrolled through a hospital database, the study was approved by the Rennes University Hospital review board. Informed consent was waived.

Statistics

Continuous variables were reported as median with interquartile range [IQR].

Qualitative variables were expressed as number and proportion and compared using chisquare, or Fisher exact test, as appropriate. The mean yearly incidence rate of gonococcal infections during the study period was estimated by dividing the number of documented cases by the number of inhabitants living in the two departments (2016 census), and then by the study duration in years.

Results

During the study period (2014-2016), 245 cases of gonococcal infections were documented by PCR in the two departments, identified from the Rénago (n=132) or the hospital (n=113) databases. The incidence of documented gonococcal infections was estimated at 4.54 per 100,000 inhabitants-year. There were 149 males (60.8%), and 96 females (39.2%). Median age was 25 years [21-33], with extremes of 10 days and 64 years.

Median age was 23 years in women [19-29], and 27 years [22-33] in males.

Most cases were diagnosed by a general practitioner (n=122, 49.8%) or a gynecologist (n=45, 18.4%). Other places of diagnosis were hospital emergency department (n=17, 6.9%), family planning (n=15, 6.1%), and proctology consultation (n=11, 4.5%). Clinical manifestations, available for only 134 cases, included urethritis (n=59, 44.0%), pelvic inflammatory disease (n=40, 29.9%), cervicitis (n=12, 9.0%) and anorectitis (n=11, 8.2%). The main coinfections were Chlamydia trachomatis (n=40, ?? %), and HIV (n=8, ??%). C. trachomatis coinfection was more common in females (30/96, 31.2%), than in males (10/149, 6.7%), P<0.001. Ceftriaxone MIC was <0.12 mg/L in 146/147 patients with positive culture.

The medical files of the 113 patients diagnosed in the participating hospitals were consulted. Partner(s) screening was reported in 56 cases (49.6%), and details on antibacterial treatment were available for 74 cases (65.5%). Most patients (63/74, 85.1%) received a combination of antibacterial treatments, which included ceftriaxone (54/74, 73.0%), metronidazole (29/74, 39.2%), doxycycline (24/74, 32.4%), ofloxacin (22/74, 29.7%) and azithromycin (8/74, 10.8%). While the treatment regimen was in agreement with national guidelines for gonococcal infections in 52 patients overall (70.2%), the rate of agreement varied according to site of gonococcal infection, ranging from 47.4% (18/38) in patients with pelvic inflammatory diseases, to 100% (14/14) in those with urethritis, P<0.001.

Discussion

The main findings of this population-based study on 245 gonococcal infections from 2014 to 2016 in Western France during years 2014-2016 are the following: i) almost half of the cases were managed by general practitioners; ii) the main clinical manifestations were urethritis and pelvic inflammatory disease; iii) >99% of isolates were susceptible to ceftriaxone; iv) partner screening was mentioned in only 50% of medical files; v) antibacterial treatment was in line with current recommendations for 70% of patients, to a much greater extent in urethritis (100%) than in pelvic inflammatory diseases (50%); vi) the incidence of documented gonococcal infections was estimated at 4.54 per 100,000 inhabitants-year in two rural departments of Western France.

To the best of our knowledge, no previous study has documented the predominant role of general practitioners in the management of gonococcal infections in France. Although this observation is a reflection of health system organization in France, where general practitioners are at the front line for primary care, STIs have long been considered as diseases for specialists. This may have been related to the need for comprehensive STI testing (not readily available in primary care settings until recently), along with the reluctance, among some patients and some general practitioners, to disclose sexual practices; moreover, general practitioners are traditionally considered as 'family doctors'. Of note, these hypotheses have not been substantiated by rigorous studies. Our documentation of the fact that in France, general practitioners are of paramount importance in the management of gonococcal infections, is consequential: GPs henceforth need to be integrally involved in numerous areas having to do with STIs, including medical education, guidelines, and operational research.

The second major finding of our study is the rate of agreement between guidelines and practices, which ranges from very good for urethritis (100% concordance), to suboptimal for antibiotic treatment of pelvic inflammatory diseases and for partner notification (around 50% of concordance for both). A 2008 study in France was much less encouraging, as only 20% of general practitioners prescribed the recommended treatment for urethritis [START_REF] Falchi | A survey of primary care physician practices in antibiotic prescribing for the treatment of uncomplicated male gonoccocal urethritis[END_REF], but it was conducted only two years after guidelines had first recommended ceftriaxone as first-line treatment for gonococcal urethritis [START_REF]Agence française de sécurité sanitaire des produits de santé (Afssaps). [Antibiotherapy applied to uncomplicated urethritis and cervicitis. French Agency for Health Product Safety][END_REF], and was based on clinical vignettes sent by electronic questionnaire, with a response rate of only 35% [START_REF] Falchi | A survey of primary care physician practices in antibiotic prescribing for the treatment of uncomplicated male gonoccocal urethritis[END_REF]. Being population-based, with systematic collection of data from all documented cases, our study is more likely to reflect real-life contemporary practices. Another study, by the French network of general practitioners, showed that the proportion of males with urethritis having received a combination of third-generation cephalosporin with macrolide or tetracycline had increased from 17.5% in 2009 (27/154), to 32.4% in 2017 (47/145, P=0.0327) [START_REF] Rossignol | Estimate of male urethritis incidences in France between 2007 and 2017 with a specific focus on Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis infections[END_REF].

The low rate of partner notification in medical files is probably an underestimate, as it is not the main information to be collected. As regards management of pelvic inflammatory diseases, our study was carried out at a time when significant discrepancies were observed between the guidelines of different medical societies. Fortunately, a consensus document recently published by the main societies of gynecology, obstetrics, and infectious diseases in France [START_REF] Verdon | Treatment of uncomplicated pelvic inflammatory disease: CNGOF and SPILF Pelvic Inflammatory Diseases Guidelines[END_REF] should improve the rate of agreement between guidelines and practices regarding a puzzling disease.

Our study has limitations. First, it was retrospective, relied on passive surveillance, and only included documented cases. In addition, it was performed in two rural departments, whereas most STI hot spots have been reported in large cities. Hence, our estimates of yearly incidence most likely represent a sizable underestimation. It bears mentioning that the incidence of gonococcal infections in France has been estimated at 39 per 100,000 people aged 15-59 years [START_REF] Ruche | Incidence of gonococcal and chlamydial infections and coverage of two laboratory surveillance networks, France[END_REF]. Second, data available from the Rénago sentinel included no information on treatment and outcome, and they were retrospectively collected, with missing data, and limited sample size. However, our study has strengths, including its population-based design, which enabled enrollment of the whole spectrum of gonococcal infections diagnosed during the study period, from asymptomatic to complicated cases; referral bias was thereby prevented. contributes to the robustness of our findings.

In France, gonococcal infections are managed primarily by general practitioners.

While the antibiotics they prescribe are in line with national recommendations for the most common manifestation (urethritis), they have remained sub-optimal for pelvic inflammatory diseases.

Funding: None

Potential conflict of interests: None for any of the authors

Fig. 1 .

 1 Fig. 1. Flow chart

Table 1 .

 1 Patient characteristics data available for only 113 cases, i.e. patients managed in participating hospitals £ data available for only 74 cases & metronidazole (n=29), doxycycline (n=24), ofloxacin (n=22), azithromycin (n=8)

	Characteristics				Number (%) or median [interquartile range]
	Age (years)				25 [21-33]
	Sex				96 females (39.2%), 149 males (60.8%)
	Clinical manifestations #
	Urethritis				59/134 (44.0%)
	Pelvic inflammatory diseases		40/134 (29.9%)
	Cervicitis				12/134 (9.0%)
	Anorectitis				11/134 (8.2%)
	Miscellaneous *				15/134 (11.2%)
	Coinfections
	Chlamydia trachomatis			40/245 (16.3%)
	-Females				30/96 (31.2%)
	-Males				10/149 (6.7%)
	HIV				8/245 (3.3%)
	Partner notification $			56/113 (49.6%)
	Antibacterial treatment £
	Ceftriaxone				54/74 (73.0%)
	Combination &				63/74 (85.1%)
	Treatment	in	line	with	52/74 (70.2%)
	recommendation			18/38 (47.4%)
	-Pelvic inflammatory disease		14/14 (100%)
	-Urethritis
	# data available for only 124 cases
	* arthritis (n=4), asymptomatic (n=3), orchitis (n=2), endocarditis, conjunctivitis,
	pyelonephritis (one patient each)

$

Acknowledgements:

We are indebted to all the health care workers who cared for of the patients, and to the participants from the Rénago network.


Yannick Vanhove
email: yannick.vanhove@univ-artois.fr

Chafika Djelal
email: chafika.dantec@univ-artois.fr

Influence of the formwork removal by polarization on the facing aesthetics in reinforced concrete

Keywords: Concrete, Electro-osmosis, Formwork, Facing quality, Demoulding

Formwork removal by means of polarization offers an alternative solution to compensate for some of the disadvantages and risks of using mineral-based oil due to its petrochemical origin. This technique consists of applying an electrical current between the steel reinforcing bars and the metal formwork wall in order to obtain a thin water film at the concrete/formwork interface and allow for formwork removal. This paper focuses on the facing quality of the reinforced concrete and formwork surface at various temperatures for both conventional and self-compacting concretes. A series of experimental tests have been conducted in the laboratory to determine the optimal polarization parameters (voltage value, time and duration of its application). On-site tests were then performed to observe the scaling effect. Results indicate that the proposed polarization technique can indeed provide an effective means to separate the concrete from its formwork without requiring demoulding oil.

Concrete mixtures implemented both in the laboratory and on-site display high-quality facing without the presence of any attachment points. A chromatographic analysis of the concrete pore solution and water transported by electro-osmosis shows that ion concentrations remain unaffected. This polarization approach can thus be used as an alternative to avoid the use of oils of a chemical or petrochemical origin.

Introduction

To protect formwork from corrosion and facilitate the concrete demoulding process, the application of a release agent appears to be an essential step. Such an agent is intended to prevent adhesion between the concrete and formwork walls. In France and Europe, 2 approximately 10,000 tons and 80,000 tons of mold release oil are respectively consumed annually. The market is currently dominated by oils of petrochemical origin, called mineral oil; they are entrained into the ground via formwork cleaning and rainwater leaching, thus contaminating the water and soil with highly non-degradable and toxic compounds. In addition, operator exposure to mineral oil through skin contact or inhalation of vaporized droplets generates occupational diseases that have been recorded by public health agencies [START_REF] Caro | Influence of the nature of the demoulding agent on the properties of the formwork[END_REF][2][START_REF] Courtois | Produits de démoulage des bétons compositions, dangers, mesure[END_REF].

Vegetable oils are extremely attractive substitutes for petroleum-based oils by virtue of being environmentally friendly, renewable, less toxic and readily biodegradable, hence lessening the risks associated with these products [START_REF] Shashidhara | Vegetable oils as a potential cutting fluid -An evolution[END_REF]. The use of vegetable oils would make it possible to considerably reduce the impact of such products on the surrounding natural environment.

From a sanitary standpoint, the use of vegetable formulations would likely improve working conditions. However, their low oxidation and thermal stability, accompanied by poor lowtemperature properties and a narrow range of available viscosities, serve to limit potential applications as an industrial lubricant [START_REF] Fox | Vegetable oil-based lubricant -A review of oxidation[END_REF].

For this reason, operators have sought to forgo oils altogether through implementing new easy-to-use techniques like polarization [START_REF] Goudjil | Electro-osmosis applied for formwork removal of concrete[END_REF][START_REF] Bian | Influence of electro-osmosis to concrete demoulding on its properties[END_REF], creating new liners featuring self-lubricating surfaces [START_REF] Spitz | On functional signatures of bare and coated formwork skin surfaces[END_REF] or introducing a controlled permeable formwork (CPF) [START_REF] Kothandaraman | The effect of controlled permeable formwork (CPF) liner on the surface quality of concretes[END_REF]. This liner allows the air and water trapped inside to drain or seep out from the concrete surface while retaining small particles and cement.

The polarization technique consists of applying an electrical current between the reinforcement (anode) and the metal formwork wall (cathode). Based on the widely accepted Gouy-Chapman-Stern's theory [START_REF] Camberfort | Electro-osmose et consolidation électro-chimique des argiles[END_REF][START_REF]Designing and perfecting a tribometer for the study of friction of a concentrated clay-water mixture against a metallic surface[END_REF], the cement grain surface carries electrical charges that are in electro-neutrality with ions in the pore solution (i.e. an electrical double layer). Under the action of an external electric field, this double layer moves along the wall in a direction that depends on the sign of the surface charge. The water is then transported in the double layer motion (i.e. anode to cathode). The displaced water creates a film capable of forming a separator screen between concrete and formwork, thus facilitating formwork removal. A number of chromatography tests have been performed to ensure the absence of any risk of transporting dissolved ions, since such transport could disrupt the polarization-related hydration reactions.

In order to avoid possible concrete stripping or fouling of the formwork walls, the quantity of water required to produce this film must be in appropriate supply. Studies conducted by Goudjil et al. have shown that the quality of facings depends on: the quantity of water transported to the concrete/wall interface [START_REF] Goudjil | Electro-osmosis applied for formwork removal of concrete[END_REF], the ambient temperature [START_REF] Goudjil | Impact of temperature on the demoulding of concrete elements with a polarization process[END_REF], and the electrical conductivity of the concrete, which is an intrinsic characteristic of the material. As a complement to previous studies, the present article focuses on this conductivity, which varies as a function of the concrete mix design. This paper proposes studying the water flow from polarized self-compacting concretes (SCC) and conventional concretes by using an experimental device specially designed for such tests, so as to optimize both the demoulding conditions and facing quality. The popularity of SCC is in fact likely to be enhanced thanks to the improved facing quality. The parameters influencing facing quality, demoulding and facing optimization have been assessed using molds sized 300×300×200 mm at various temperatures. This process was then applied on molds sized 1×1×0.2 m before to transport it in situ onto a 2.8-m high formwork. The scoring criteria for concrete facings and the mold wall selected for purposes of this study are: dusting, fouling, and attachment points [START_REF]Surface et parements de béton -Eléments d'identification[END_REF]. For the concrete facings, appearance, dusting and micro-bubbles have all been evaluated. Our work has served to prove that this demoulding process offers the possibility to forgo use of oil products.

Material and methods

Mixtures proportioning

Three mix designs commonly used for concrete wall elements, with consistencies of S3, S4 (plastic concrete) and SF2 (self-compacting concrete), are listed in Table 1. Concrete NC1, which relies on a CEM III-based design, is only used during hot weather periods given its low heat of hydration. During the remainder of the year, concrete designs are typically based on CEMI. The setting initiation times of CEMI and CEMIII are respectively 140 and 230 minutes.

A CEMI 52.5 N for the SCC concretes and a CEMIII/A 42.5 N for the NC1 and NC2 mixtures were selected with a Blaine fineness of 410 m²/kg and 420 m²/kg, respectively. The chemical and physical characteristics of the cements are given in Table 2. A limestone powder was introduced to replace a portion of the Portland cement clinker for the SCC mixture. For the NC mixture, pulverized fly ash was added to the mix, in consideration of the effect of its round shape on improving workability. For both concretes, riverbed siliceous sand with a fineness modulus of 2.50, a water absorption rate of 0.7% and a specific gravity of 2.59 was used. Two siliceous-based coarse aggregates 4/12.5 and 11.2/22.4 were employed, with a specific gravity of 2.54 and water absorption rates of 2.54% and 0.7%, respectively.

A lignosulphonate polymer, characterized by a specific gravity of 1.21 and a 40% solid content, was introduced as a water-reducing agent into the NC1 mixture. A high-range, waterreducing admixture (HRWRA), specially adapted for SCC workability, was also selected. This particular HRWRA is a polycarboxylate-ether based superplasticizer with a specific gravity of 1.05 and a 22% solid content. A chlorine-free setting and hardening accelerator was added to both mixtures in order to offset the effects of lower temperature, i.e. between 6° and 9°C at the study site, by increasing the rate of cement hydration.

Preliminary tests were performed in the laboratory on molds of dimensions 300×300×200 mm to optimize the electrical current at low temperature. All mixtures were prepared in batches of 45 liters using a DIEM DZ 120V type mixer with a 100-liter capacity. The absorption of water necessary for cement hydration by the aggregates could potentially cause a modification in the rheological characteristics of the concrete. To avoid such an alteration, a 10-min wait time (for prewetting) was required after the initial mixing phase (applied to gravel and dry sand with a quarter of the mixing water quantity). The mixing sequence employed is presented in Fig. 1.

At the end of the mixing sequence, the concretes were sampled to determine slump consistency, unit weight and temperature. The ambient temperature was maintained during mixing and sampling at 20±2°C. Both the plastic viscosity and dynamic yield stress were determined with the ICAR rheometer [START_REF] Koehler | Development of a portable rheometer for Portland cement concrete[END_REF]. These results are provided in Table 3.

For concrete hydration reactions to undergo as little disturbance as possible, polarization must be initiated before the end of the latent period, which means before cement setting has begun.

For this purpose, tests were conducted to characterize the hydration kinetics.

Concrete setting time

The starting time of chemical setting was determined using an isothermal calorimeter coupled with a CDM210 type conductometer/resistance meter (Fig. 2) [START_REF] Goudjil | Impact of temperature on the demoulding of concrete elements with a polarization process[END_REF]. This set-up consisted of a sample holder composed of two regulated exchangers that, once assembled, accommodated an isothermal cylinder able to hold a 110×220 mm cardboard specimen covered on the inner surface with a plastic film [START_REF] Broda | Conception of an isothermal calorimeter for concrete -Determination of the apparent activation energy[END_REF]. The temperatures are measured by T-type thermocouples incorporated in the flux sensors and by a thermocouple placed in the core of the concrete. In this way, it is possible to check the quality, of the isothermal conditions. Two pumps connected to a thermostat-controlled bath maintain the liquid (water) at a constant temperature.

The NC1 and NC2 concretes (whose temperatures varied from 18° to 21°C for tests carried out at 20°C and between 6° and 9°C for those conducted at 8°C) were introduced into the cardboard specimen in two layers. To ensure proper consolidation of these two concretes, each layer was compacted 25 times [START_REF]Bétons -Exécution des structures en béton -Règles spécifiques pour les BFUP[END_REF].

Conductivity was monitored by a probe inserted into the middle of the specimen, with a 5minute recording interval set. The results obtained are displayed in Fig. 3. Two periods characterize each of the three concretes tested:

-The first, during which conductivity was observed to increase due to the dissolution of cement anhydrates in the concrete pore solution, corresponds to the latent period.

-The second, during which conductivity was decreasing, lies beyond the end of the latent period, i.e. corresponding to the time when setting begins: the quantity of calcium ions was sufficient for precipitation to occur, hydration reactions were accelerating rapidly, and ions were thus being consumed to form hydrates, lowering conductivity in the process.

The values of both conductivity and setting initiation time for the three mix designs are presented in Table 4. At 8°C, like at 20°C, all three concretes exhibited different conductivities as well as different setting initiation times, with deviations less pronounced between NC2 and SCC mixtures. These results are widely demonstrated in the literature. The conductivity of NC1 mixture was in fact lower than that of NC2 and SCC mixtures, and its setting initiation time was longer. This difference is correlated with the mix design, in noting that the NC1 mixture was based on CEMIII (45% clinker) and the other two on CEMI (90% clinker). The proportion of clinker, whose main component C3S (an element fundamental to hydration reactions) was higher in NC2 and SCC mixtures, would have been responsible for advancing their setting initiation and increasing their conductivity value.

Let's note that regardless of the mix design, the conductivity of any given concrete was greater at 20°C than at 8°C. This phenomenon is due to the decrease in both ion concentration and mobility upon the occurrence of hydration reactions, resulting from the temperature drop [START_REF] Heikal | Effect of treatment temperature on the early hydration characteristics of superplasticized silica fume blended cement pastes[END_REF][START_REF] Morsy | Effect of temperature on electrical conductivity of blended cement pastes[END_REF]. More specifically, lower temperature triggers a deceleration in the hydration reactions [START_REF] Vanhove | Effect of temperature on the thixotropic behaviour of self-consolidating concrete[END_REF] and, consequently, reduces the conductivity value.

For all concretes studied and at each temperature setting, the current is applied during the latent period, i.e. 1 hour after the initial water/cement contact.

Test protocol and measurement

The formwork removal tests were preceded by a study of water flow in fresh concrete subjected to the polarization effect, based on mix designs at two ambient temperatures (20°C and 8°C). For this purpose, the test setup (Fig. 4) featured an insulated cylindrical mold made of PVC (120×160 mm) intended to receive the concrete, along with an electric generator, a data acquisition chain and a scale. The mold contained two covers, one made of wood the other in stainless steel and equipped with a water outlet orifice. A perforated disc (80-μm mesh), fitted with a paper filter, was placed in the stainless-steel cover in order to filter the transported water. To verify the repeatability of results, three identical molds were used simultaneously under the exact same conditions (Fig. 4).

NC1 and NC2 mixtures were poured into the molds in three successive layers. Each layer (NC1 and NC2) was punctured 25 times in accordance with Standard NF P 18-451 to obtain optimal compaction. After placement of the first layer, a steel rod 60 mm long and 6 mm in diameter was set into the concrete at 100 mm from the perforated disc. The remainder of the concrete was then introduced into the mold in two layers. The steel rod was connected to the generator's positive pole (anode) and the disc to its negative pole (cathode). Voltage values above 8 V caused a modification in the concrete microstructure [START_REF] Goudjil | Electro-osmosis applied for formwork removal of concrete[END_REF]. Moreover, at a relative high voltage, e.g. from 5 to 10 V, porosity was even greater than in the absence of an electric field [START_REF] Bian | Influence of electro-osmosis to concrete demoulding on its properties[END_REF]. Voltages of 1, 2.5, 3.5 and 5 V were thus selected for this study. During each test, the voltage was applied simultaneously to all molds. Recording of the displaced water mass, which lasted 10 min (the optimal polarization period, as determined by N. Goudjil et al. [START_REF] Goudjil | Impact of temperature on the demoulding of concrete elements with a polarization process[END_REF], began after placing the concrete into the molds, i.e. 10 min after the initial water/cement contact.

The water recovered in each mold represented on each occasion the sum of the quantity of water transported by electro-osmosis plus that conveyed by gravity. This latter component, determined ahead of time (without any voltage being applied), was deducted from the total mass to determine the mass of water transported by means of electro-osmosis. The water flow rate could thus be determined.

To study the impact of mix design on both formwork removal and facing quality, stainless steel molds sized 300×300×200 mm were used to avoid any formwork wall corrosion (Fig. 5).

Each formwork removal test required a concrete batch whose temperature varied between 7° and 9°C for tests conducted at 8°C and between 18° and 22°C for those at 20°C. The concretes were placed according to Standard NF 18-451 in two successive layers [START_REF]Bétons -Exécution des structures en béton -Règles spécifiques pour les BFUP[END_REF]. Except for the SCC mixture, each layer was vibrated for 5 s. The electrical current was then applied between the H-shaped rebar of 6 mm-diameter (positioned 100 mm from each of the two walls) and the two opposite walls of the mold.

As a result, the water migrated toward the concrete/formwork interface and formed a film capable of ensuring effective formwork removal (Fig. 5). To improve the concrete facing quality and formwork demoulding, Goudjil et al. [START_REF] Goudjil | Impact of temperature on the demoulding of concrete elements with a polarization process[END_REF] recommended using a voltage value of 3 V at 8°C when electrical conductivity was weak (2.66 mS/cm). A voltage value of 1 V offers good surface quality without fouling or dusting when the conductivity value lies around 6.6 mS/cm.

For the NC2 and SCC mixtures, the electrical conductivities equaled 6.8 and 6.69 mS/cm, respectively, at a temperature of 8°C. These values lie close to that of the NC1 concrete at 20°C (6.6 mS/cm), which is why a 1-V voltage was selected for both these concretes at temperatures of 20°C and 8°C for 10 minutes, 1 hour after the initial water/cement contact. A 3-V voltage was selected for the NC1 mixture at 8°C due to its electrical conductivity, recorded at 3.83 mS/cm (Table 4).

After demoulding, two hours were necessary to dry the concrete facing and remove all traces of moisture. The following parameters were assessed as a means of characterizing the quality of formwork release (Table 5). It should be noted that the grading criteria adopted to evaluate facing quality were based on Standard P18-503 [START_REF]Surface et parements de béton -Eléments d'identification[END_REF] and have been listed in Table 6.

Results and discussion

Optimization of applied voltage

During the first phase, pore water migration was studied on the NC1 and NC2 mixtures at 8° and 20°C as a function of applied voltage. The electrical conductivity of the SCC mixture was of the same order of magnitude as that of the NC2 mixture at 8°C and above the value recorded at 20°C (Table 4). For both temperatures tested, independently of the two mix designs, the increase in applied voltage produced a rise in water flow rate (Fig. 6). The higher number of displaced ions wound up inducing an increase in the quantity of transported water.

For a given voltage, again regardless of mix design, the water flow rate at 8°C was lower than that obtained at 20°C. The conductivity of all concretes was less at 8°C than at 20°C (Table 4). The decrease in conductivity induced a smaller number of displaced ions, thus lowering the water flow rate. Let's note that the temperature influencing conductivity also exerted an effect on concrete viscosity and, therefore, on the electro-osmotic flux. For temperatures below 20°C, the concrete viscosity actually increased as temperature dropped, bringing the electro-osmotic flux down as well [START_REF] Vanhove | Effect of temperature on the thixotropic behaviour of self-consolidating concrete[END_REF][START_REF] Escalante | Effect of temperature on the hydration of the main clinker phases in Portland cements: part II, blended cements[END_REF][START_REF] Paumier | Nanoscale actuation of electrokinetic flows on thermoreversible surfaces[END_REF].

At 20°C, like at 8°C, the electro-osmotic flow rate of water with the NC1 mixture was greater than that of NC2 mixture. Given its weak conductivity (Fig. 3), NC1 mixture should (compared to NC2) enable less water to be transported. Yet in reality the opposite phenomenon was observed; this situation was most likely due to the presence of a large number of fine components in the NC1 mixture (Table 1), thus promoting electro-osmosis.

Such an effect was present as well in the SCC mixture. The electrical potential, or zeta potential, might also have been responsible for the higher electro-osmotic flux with the NC1 mixture. In light of the differences observed in hydration speed, the CEMIII cement used to produce the NC1 mixture did display a more highly negative zeta potential than that of the CEMI cement introduced into the NC2 mix design [START_REF] Amiri | Influence of cement, aggregates and chlorides on zeta potential of cement-based materials[END_REF]. Moreover, this difference could explain the rise in electro-osmotic flux of the NC1 mixture relative to NC2 mixture.

Preliminary tests were thus conducted on the NC2 mixture at 8°C using the initially selected 1-V voltage, along with a slightly higher voltage (1.5 V) (Fig. 7). The voltage was applied for 10 minutes once an hour had elapsed following the initial water/cement contact. For the 1-V voltage (Fig. 7a), concrete stripping was observed subsequent to formwork removal. The electro-osmotic flux was too weak to obtain sufficient water thickness at the concrete/formwork interface. Application of the 1.5 V voltage upgraded the formwork removal without concrete stripping and produced a high-quality concrete surface (Fig. 7b).

Let's point out however a fouling of the mold surface, which proved detrimental to the formwork, though could easily be cleaned.

During the remainder of the testing campaign, a 1.5 V voltage was selected for the NC2 and SCC mixtures at 8°C. A 3 V voltage was adopted for the NC1 mixture at 8°C given its weak electrical conductivity.

These tests served to demonstrate that regardless of the applied voltage, the electro-osmotic flux and hence the quantity of transported water varied with respect to both temperature and concrete mix design. Formwork removal testing made it possible to determine whether these selected voltages exerted an influence on the quality of formwork removal and facings.

Facing wall aesthetics at a temperature of 20°C

The photographs of facings taken after formwork removal are shown in Fig. 8, while Table 7 summarizes the notations used for all three mix designs studied herein.

The formwork removal step was straightforward and exposed facings with an attractive appearance. The high yield stress of the NC2 mixture would have caused the occurrence of air bubbles present on the concrete walls. The mold walls, on the other hand, exhibited not a single trace of stripping or fouling across all concretes tested. Dusting had also been detected on the SCC mixture, as evidenced by whitish streaks (residue of lime stemming from the hydration and then transported with the water) [START_REF] Viallis | Interaction between Salts (NaCl, CsCl) and Calcium Silicate Hydrates (C-S-H)[END_REF].

It should be noted that the difference in conductivity values and thus in the quantities of water accumulating at the concrete/formwork interface of the various concretes had absolutely no impact on facing quality. At 20°C, the same polarization conditions were applicable to concretes featuring distinct mix designs.

Facing wall aesthetics at a temperature of 8°C

Figure 9 reveals the photographs of facings obtained after concrete formwork removal. The pertinent notations are given in Table 8. Application of a 3-V voltage for the NC1 mixture yielded an appearance of facings and mold walls free of any attachment points. The quantity of water transported at the concrete/formwork interface was thus sufficient. A 3-V voltage was more appropriate for a concrete electrical conductivity on the order of 4 mS/cm. An increase in this voltage could lead to modifying the microstructure [START_REF] Goudjil | Electro-osmosis applied for formwork removal of concrete[END_REF][START_REF] Goudjil | Impact of temperature on the demoulding of concrete elements with a polarization process[END_REF]. On the other hand, a voltage drop can entail concrete stripping following formwork removal.

Both the NC2 and SCC mixtures displayed high-quality facing without any attachment points on the mold surface. Dusting was present however on the mold surface for the two concretes, as previously observed for the SCC concrete at 20°C. These hydration-induced lime residues were easily cleaned upon formwork removal. Let's also note for the NC2 mixture a slight bubbling along with a few extremely dispersed compaction voids, most definitely correlated with the comparatively high yield stress. Air bubble mobility and, consequently, the ease of air bubble discharge during vibration actually decreased as yield stress rose.

Despite its ease, formwork removal exposed, against all expectations, fouling on the concrete surface for the NC2 mixture. At the time of formwork removal, the aging of concretes NC2 and SCC mixtures (designed using CEMI) was more advanced than that of NC1 mixture (made with CEMIII). The film thickness, which provides for effective formwork removal and high-quality facings, might therefore have been less than that for the NC1 mixture.

Even though the voltage values had been adapted to the electrical conductivity of the concretes tested, other mix design-related parameters (e.g. zeta potential and cement paste volume) also need to be considered. It is thus critical to consider the concentration of ions present in the transported water subjected to the polarization effect.

Chromatography analysis of water migration

Transporting water under the polarization effect may be accompanied by the transport of dissolved ions during hydration reactions. This phenomenon would then cause the concrete to leach. To ensure the absence of such a risk, ion chromatography tests on the water being transported were conducted under optimal conditions. A Metrohm 883 Basic IC-Plus chromatograph, equipped with a conductivity detector, was used to determine both the anions (fluorine, chlorine, bromine and sulfur) and cations (sodium, lithium, potassium, calcium and magnesium) in the concrete pore solution. These tests were performed in the MIA Laboratory at the University of La Rochelle. The pore solution was extracted from concrete using a filter-press apparatus. The solution was then placed in a 4-mm diameter, 100-mm high cylinder. A pressure of 5.5 MPa was applied to force the mobile phase through the column at typical flow rates of 0.7 ml/min. The results of concentration (Ci) and electrolytic conductivity (k) obtained from the NC mixture by means of chromatography are reported in Table 9.

This characterization of the concrete pore solution can be compared with the water transported by polarization at the concrete/formwork interface. The absence of any risk of transporting dissolved ions, capable of disrupting polarization-related hydration reactions, could thus be assessed.

Results indicate that regardless of the concrete mixture, the ion concentration present in the water being transported under the effect of polarization was of the same order of magnitude as that found in the concrete pore solution. These results provide the grounds for concluding that the risk of concrete leaching has been averted.

In situ testing

Once this technique had been developed in the laboratory on molds of dimensions 300×300×200 mm, it was subsequently applied on a formwork measuring 1×1×0.2 m [START_REF] Goudjil | Electro-osmosis applied for formwork removal of concrete[END_REF] and ultimately at full scale (2.4×2.8×0.2 m) in a concrete-mixing plant (Fig. 10) for the purpose of observing the scaling effect. Two K30 formworks, supplied by the company Outinord and regularly implemented on worksites to cast vertical elements, were used in the concretemixing plant. Each formwork was composed of two stainless steel form panels vertically connected by means of two insulated end pieces (covered by a plastic film).

The reinforcement was an HA ST20 placed at the center of the formwork (100 mm coating layer) in order to study the most unfavorable case (Fig. 11). The voltage was applied simultaneously between the latticework and the upper part of walls opposite the formwork.

The concretes employed on the worksites were identical to those studied in the laboratory (Table 10). To enable casting each wall with the same batch, a sufficient quantity of concrete (1,500 liters) was produced at the time of each test. The mixing mode was the same as that practiced at the mixing plant and compliant with Standard NF 033, referred to as "ready-mix concrete".

All material ingredients were poured into the mixer before adding the water and admixture.

The mixing step lasted approximately 1 minute. Once produced, the concretes were characterized relative to their consistency: Abrams cone slump tests for the NC1 and NC2 mixtures, and a spreading flow test for SCC mixture. These characteristics, along with the corresponding experimental conditions, are indicated in Table 10. The concrete was then poured from the top, for both concretes, using a 1-m 3 bucket fitted with a sleeve tube. Various 0.5-m concrete layers, with a maximum concrete falling distance of 1 m, were produced; vibration was applied for the conventional concrete.

The formwork and concrete walls were separated for 24 hours and 20 hours, respectively, once the concrete had been cast for NC1, NC2 and SCC mixtures. This test was conducted at temperatures of 8±2°C (detrimental conditions for the electro-osmosis technique) and 20±3°C.

Table 11 provides the scores assigned to concrete facings and the formwork wall, as determined from French standard criteria. Figure 12 shows pictures of the concrete facing and formwork surface after demoulding for NC1 mixture.

For the NC1 mixture, the formworks were easily removed, thus yielding satisfactory facing quality. For the conventional concrete, the criteria were in general completely satisfied with no sign of attachment points. The water film thickness was enough to ensure separation between the concrete element and the formwork; however, a few traces of water stemming from polarization did leave a very slight fouling on the formwork wall after evaporation. The implementation step had caused no segregation, disorganization or porosity.

The second test was carried out with the NC2 mixture at an ambient temperature of between 3° and 6°C, i.e. less than the lowest temperature tested in the laboratory (8° ± 2°C). The formwork was removed 24 hours after casting. The photographs of shell facings and formwork walls are provided in Fig. 13. Heavy concrete stripping and poor facing quality were observed. This stripping was due to an insufficient quantity of water being transported at the concrete/formwork interface and/or to an insufficient concrete curing period, the latter of which would be correlated with the slowing of hydration reactions caused by the low temperature, thus inducing a drop in the concrete conductivity value. This value would no longer lie within the conductivity interval determined during testing on the effect of conductivity with respect to the concrete mix design. It would have been possible to increase the voltage value, yet by not knowing the conductivity value, the choice of which voltage to apply had to be random. A low conductivity value complicates the penetration of water into concrete. Regardless, a higher voltage would not necessarily have solved the problem. To derive the voltage value most likely to yield good results, it's essential to know the concrete conductivity value at the test temperature, wherein lies the need to conduct preliminary tests in the laboratory.

The third wall was cast with self-compacting concrete (SCC); its placement did entail a few difficulties. More specifically, during placement of the first concrete layer in the formwork, the bin could not be properly shut, which caused the entire concrete batch, i.e. the equivalent of approx. four layers, to fall. So, this concrete was cast using just two layers (one of roughly 2 m, the other of 500 mm) (Fig. 14).

The test was performed at a temperature ranging between 6° and 9°C. The optimal conditions identified in the laboratory for this particular concrete, i.e. at a temperature of 8° ± 2°C, were thus applied. Photographs of the results obtained are presented in Fig. 15.

With self-compacting concrete (SCC), the formwork surface received the same scores as the conventional concrete for both fouling and attachment points. The small increase in dusting was probably due to the quantity of fines in the mix. This dusting had also been observed when using demoulding oil (vegetable or mineral oil) [START_REF] Caro | Influence of the nature of the demoulding agent on the properties of the formwork[END_REF][START_REF] Libessart | Influence of the type of release oil on steel formwork corrosion and facing Aesthetics[END_REF]. As regards the concrete facing, the appearance was very good with no dusting on the surface. However, the quantity of bubbling was high, especially over the bottom part of the concrete wall (Fig. 15). 'Microbubbling', as defined in the standard, was not really applicable here, hence the difficulty in establishing a score. This phenomenon can be tied to the concrete casting process.

The concrete was in fact poured over two levels, and the concrete descent was considerable (more than 1 meter). Some bubbles could be trapped both at the interface and inside the SCC mixture, despite its low plastic viscosity and yield stress. This same experiment was carried out in the laboratory on formwork measuring 300×300×200 mm at the same temperature; in this case, the concrete surface displayed no bubbling.

Given these observations and visual comparisons of the facing parameters, the polarization technique presented herein has produced highly satisfactory results at low temperatures.

Overall, the results are encouraging. The formwork was straightforward to remove, and the facings were of high quality. No trace of stripping was visible on either the shell facing or formwork walls. Nonetheless, considerable bubbling was detected on the concrete walls, most likely correlated with concrete placement and the presence of dusting on the formwork walls. This dusting on formwork walls did make cleaning necessary, using water and a soft brush, after each use.

Conclusions

This study has primarily examined the impact of mix design on the quality of facings and formwork removal. The technique presented herein was found to be perfectly transposable to the worksite. The optimal polarization conditions determined in previous studies have been tested here with various mix designs and readjusted whenever necessary. The formwork removal tests have demonstrated that at 20°C, slight deviations in the quantity of water transported exert absolutely no influence on facing quality. The same voltage value (1 V) has, for all mix designs tested, resulted in a satisfactory quality of both the facings and formwork removal. At 8°C, it's essential to conduct preliminary test to adapt the voltage value according to the electrical conductivity. As seen on site with the NC2 mixture, a decreasing of the temperature (compared to the preliminary tests) can entail some problems to remove the formwork successfully and achieving high-quality facings.

Chromatography tests did make it possible to ensure the absence of any leaching risk due specifically to polarization. It was found that conductivity is not the lone parameter to be considered in the determination of optimal conditions. Other mix design-related parameters (e.g. cement paste volume, zeta potential) must also be considered. Upon completion of this

Fig. 1 . 3 . 21 Fig. 4 . 5 .Fig. 6 . 7 .Fig. 12 .Fig. 13 . 14 .Fig. 15 .

 1321456712131415 Fig. 1. Mixing sequence for concrete mixtures

Table 4

 4 Setting time and electrical conductivity values of concrete mixtures at 8 and 20°C

	Mixture	Setting time at 20±2°C	Setting time at 8±2°C	Conductivity at 20±2°C (mS/cm)	Conductivity at 8±2°C (mS/cm)
	NC1	2h25	2h35	6.60	3.83
	NC2	2h15	1h45	7.52	6.80
	SCC	2h	1h30	8.20	6.99
	*Conductivity value measured at the start of the setting time

Table 5

 5 Codification used to evaluate the demoulding performances

Code

Concrete facing Code Mould surface

study, it can be concluded that the research performed has provided the basis for using this new formwork removal process with various concrete mix designs at different temperatures.

CRediT authorship contribution statement

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.