Thomas Castanheiro

Angèle Schoenfelder

Morgan Donnard

Isabelle Chataigner

Mihaela Gulea

Synthesis of sulfur-containing exo-bicyclic dienes and their Diels-Alder reactions to access thiacycle-fused polycyclic systems

The stereocontrolled synthesis of unprecedented sulfur-containing exo-bicyclic 1,3-dienes is reported through a palladium-catalyzed reductive cyclization of sulfur-linked 2-bromoenynes. The fused bicyclic structure provides a better stability to the thiacyclic diene, compared to the simple 3,4dimethylenetetrahydrothiophene. Their reactivity towards several dienophiles has been investigated and various original thiacycle-fused polycyclic systems have been obtained, with high or total diastereoselectivity. Moreover, they are the first exo-bicyclic dienes used in Diels-Alder reactions. The relative configurations of four cycloadducts have been unambiguously assigned by X-ray crystallographic analysis. Mechanistic details of the cycloadditions have been examined by computational means.

Introduction

Sulfur-heterocycles (often called thiacycles) are important constituents of biologically active molecules for pharmaceutical industry. 1 Therefore, providing new complex structures containing a thiacycle as potential drug candidates, represents a topical research subject. As part of our interest in accessing various S-heterocycles, we have envisioned to access new sulfur-containing fused polycyclic systems via [4+2] cycloadditions involving exo-thiacyclic 1,3-dienes. Indeed, exo-cyclic 1,3-dienes 2 are widely used partners in Diels-Alder (DA) reactions, due both to their high reactivity provided by their fixed s-cis conformation, and their synthetic usefulness consisting in the direct access to fused bicyclic structures, which are often found in natural products. 3 Various efficient methodologies have been developed to synthesize exo-cyclic dienes, including palladium-catalyzed 4 and radical cyclizations. 5 As far as the sulfur series is concerned, exo-thiacyclic 1,3-diene I, namely the 3,4dimethylenetetrahydrothiophene (Figure 1), has been prepared by Gaoni and Sadeh from 2,3bis(bromomethy1)-1,3-butadiene and sodium sulfide, then used in a Diels-Alder reaction with dimethyl acetylenedicarboxylate (DMADC) as dienophile. 6 The authors noted the instability of this diene resulting mostly in its transformation into the corresponding 3,4dimethylthiophene and its very fast polymerization in the free states. Exo-bicyclic Scontaining dienes of type II (Figure 1) should provide a better stability due to hyperconjugation effect brought by the substituents on the double bonds and the bicyclic structure. Therefore, we decided to synthesize these hitherto unknown 1,3-dienes and to investigate their reactivity in [4+2] cycloadditions. Access to these bicyclic structures bearing a stereogenic carbon center next to the sulfur atom was first envisaged in the racemic form.

After cycloaddition, the thiacycle-fused polycyclic cycloadducts thereby produced should have interesting 3D-structures, the stereochemistry of the newly formed stereogenic centers being governed both by the existing stereocenter and by the cycloaddition process itself, in line with modern concepts in drug discovery. A literature survey revealed that while exo-monocyclic dienes are abundant, exobicyclic dienes are rarely encountered. Only a few examples of these 1,3-dienes have been reported (Scheme 1): the carbo-bicyclic (Eq. 1), 8 and aza-bicyclic (Eq. 2) 9 dienes were obtained via an intramolecular Heck reaction, and the oxacyclic dienes were generated via radical cyclizations using Bu3SnH/AIBN system or SmI2 (Eq. 3). 10 These methods afforded

I S II (n = 1,2) S R ( ) n *
the 1,3-dienes as a mixture of E/Z isomers. 11 Noteworthy, the reactivity in Diels-Alder reactions of these exo-bicyclic dienes has not been examined so far.

The powerful synthetic tool represented by the palladium-catalyzed domino cyclizations 12 together with our experience in using sulfides as substrates for these reactions, 13 prompted us to envisage 5-or 6-exo-dig syn-cyclocarbopalladation/reduction sequences to generate the sulfur containing exo-bicyclic 1,3-dienes. This process should lead to an exclusive Zgeometry of the generated double bond, as a result of the well established syncarbopalladation mechanism. 4 We report herein the preparation of racemic dienes II and their use in Diels-Alder or hetero-Diels-Alder (HDA) reactions to access unprecedented Scontaining polycyclic compounds (Scheme 1, Eq. 4). Azacyclic series: Grigg et al. 9 Carboxyclic series: Tietze et al. 8 Oxacyclic series: Sha, Zhan et al. 10 not used in DA

Scheme 1. Syntheses of exo-bicyclic dienes

Results and discussion

We first prepared thioacetic ester 1 from 1,6-dibromocyclohex-1-ene and potassium thioacetate, then used it as the starting material to access sulfur-linked 2-bromo-1,6-and 2bromo-1,7-enynes 2, which are the suitable precursors of the desired dienes 3 (Scheme 2).

Sulfides 2a-f have been synthesized with satisfactory yields from 1 and the corresponding propargyl or homopropargyl halide, with different R substituents on the triple bond. Sulfide 2f was obtained by introducing a phenyl group on the terminal alkyne of 2e via a Sonogashira cross-coupling. These substrates have been then reacted under Pd-catalyzed reaction conditions in the presence of ammonium formate as the hydrogen donor. 14 Gratifyingly, the reductive cyclization sequence led to the desired exo-bicyclic dienes 3a-d,f in moderate to good yields. The Z-geometry of the newly formed double bond is assumed considering the syn-carbopalladation/reduction process, and no trace of another isomer of the diene was detected by NMR analysis. Once again the use of sulfur-containing compounds was compatible with the Pd-catalysis conditions. Only diene 3e (R = H) was obtained in a disappointing yield (22% by 1H NMR) and could not be isolated in a pure form. This is probably due to competitive S-depropargylation reaction in the presence of the palladium catalyst, occurring more easily on the terminal alkynyl substrate 2e. 15 The method is efficient for both accessing 5-and 6-membered rings bearing either alkyl, phenyl or hydroxymethyl terminal groups. Indeed, the fused bicyclic dienes provide a better stability to these thiacyclic dienes, compared to 3,4-dimethylenetetrahydrothiophene I, as they can be isolated by column chromatography and stored at least one week at room temperature. First, all isolated dienes were reacted with maleic anhydride D1, in dichloromethane, at 40 °C (Scheme 3). A complete consumption of the diene was observed within 2 to 4 hours.

Theoretically, the cycloaddition between diene 3 and dienophile D1 can lead to four couples of diastereomeric cycloadducts 4A-D, arising from the four possible approaches: two from the top/bottom face of the diene and two according to the endo/exo orientations. The reaction with 3a led to a mixture of two inseparable diastereomers in 8:2 ratio (91% yield). NMR analyses (NOEDIFF correlations) indicated that the major cycloadduct resulted from the expected endo-attack, however it was difficult to distinguish between 4aA and 4aB. In the case of the phenyl substituted diene 3b, the formation of a single diastereomer was observed. The relative stereochemistry of the isolated adduct 4bA (50% yield) was unambiguously assigned by an X-ray crystallographic analysis (Figure 2) and confirmed the favored endo approach from the less hindered face of the diene (top-face), opposite to the Scontaining ring. Then, in the reaction between D1 and diene 3c the product 4'cA was obtained as the only adduct in 90% yield. In this case the cycloaddition was followed by an intramolecular lactonization occurring on cycloadduct 4cA and leading to 4'cA. 16 X-Ray crystallographic analysis on a monocrystal also confirmed the structure and the relative stereochemistry of the product in this case (Figure 3). The cycloaddition of D1 with the 6membered ring exo-bicyclic dienes 3d and 3f led to a single diastereomer, 4dA (47% yield) and 4fA (41% yield), respectively. Crystals obtained from 4fA allowed to obtain an X-ray structure (Figure 4), which revealed that its relative stereochemistry was similar to 4bA. The relative configurations of 4aA and 4dA were then assigned by analogy with the previous results. N-Phenylmaleimide D2 was then reacted with dienes 3a and 3b under the same reaction conditions. In both cases only one diastereomer was formed and we assume that they are respectively 5aA (93% yield) and 5bA (97% yield), having the same relative configurations than those obtained with D1 (Scheme 4). Dimethylacetylene dicarboxylate D3 was then reacted with dienes 3a, 3b, and 3d.

Heating in toluene at 80 °C overnight was necessary to get completion in this case.

Cycloadducts 6a and 6d were obtained as a mixture of two diastereomers (A/B) in 10:3 and 2:1 ratio, respectively (Scheme 5). Very probably, similarly to the previous cases, the major products are respectively 6aA and 6dA, resulting from the top-face approach of the diene.

The product resulting from 3b decomposed and could not be characterized. Hetero-Diels-Alder (HDA) reactions have been then attempted with an aza-dienophile, the 4phenyl-3H-1,2,4-triazole-3,5(4H)-dione D4 (Scheme 6). The reactions were performed in dichloromethane, at room temperature, until complete consumption of the substrates was observed (0.5 to 1 hour). Both 5-membered ring dienes 3a and 3b led to a mixture of two separable products in 1:2 and 1:1 ratio, respectively. The two products derived from 3a have been identified as cycloadduct 7aA (22% yield) and the corresponding thiophene derivative 8a (45% yield), formed by a dehydrogenative aromatization of the dihydrothiophene ring of the cycloadduct 7a. Dienophile D4 is probably involved in this latter transformation and further studies will be done to propose a plausible mechanism. Similarly, products 7bA and 8b resulting from diene 3b have been isolated in 22% and 26% yield, respectively. The structure of 8b was confirmed by X-ray crystallographic analysis (Figure 5). In the cases of 6membered ring exocyclic dienes, the oxidation of the thiacycle did not occurred, and only the expected cycloaddition products were obtained. The reaction between D4 and diene 3d led to a 20:1 mixture of diastereomers, whereas diene 3f led to a single diastereomer, which was isolated in 60% yield. By adding D4 at room temperature to the crude diene 3e, the expected product was also obtained as a single diastereomer, however with a low isolated yield of 15%.

Assignments of the relative configurations of the major (or single) cycloadducts (7aA, 7bA, 7dA, 7eA, 7fA) were done by analogy with the previous results, which correspond to a topface approach of the diene (Scheme 6). We finally explored the more challenging HDA-reaction with the dithioester heterodienophile D5, 17 in order to obtain structures containing two sulfur-heterocycles 7). As this dienophile is non-symmetric, two regioisomeric cycloadducts can be expected, each one with four relative stereochemistries mentioned before. The reaction was performed in dichloromethane, at room temperature, in the presence of BF3.Et2O as Lewis acid to activate the dienophile. An inseparable mixture of two products in 3:1 ratio, was obtained with diene 3a, however we were not able to determine their structures, since the products decomposed fast. The reactions of D5 with dienes 3b and 3f also afforded mixtures of two products in a ratio of 10:1 and 10:3, respectively. In the case of the two cycloadducts resulted from 3f, a series of NMR experiments indicate that they correspond to two diastereomers of regioisomer 10f, of which the relative configurations differ at the CHS 1 carbon-stereocenter, as the result of the top/bottom approaches. It was however difficult to categorically conclude on the relative configurations at the CHS 2 carbon-stereocenter (endo vs exo approach relative to pyridyl), although several NOESY-2D and selective NOESY-1D experiments match well with products 10fA (major) and 10fB (minor) having pyridyl and phenyl substituents in a cis relationship (endo approach). Geometry optimization of 10fA and 10fB (DFT calculations) is also in agreement with this assignment (see in Supporting Information).

The overall results showed that the stereochemical course of the Diels-Alder reaction involving exo-bicyclic dienes 3 did not depend on the tethered ring-size, as both five and sixmembered thiacyclic dienes give high selectivities. The cycloadducts resulting from fivemembered thiacyclic dienes and aza-dienophile D4 are prone to aromatization into the corresponding thiophene derivatives. Concerning the nature of the substituent on the triple bond, a phenyl substituent led to slightly better selectivity than an alkyl one.

Scheme 7. thia-Diels-Alder reactions of exo-bicyclic dienes 3 (ratio diene/D5 1.1:1)

Theoretical study

In order to get a better insight into the mechanistic details of these cycloadditions, we then examined the course of the reaction by computational means. DFT calculations were performed at the wB97XD/6-31+G(d,p) level of theory, including dispersion terms, which proved appropriate for similar organic systems 18 (see SI for the results obtained with other functionals, basis sets and inclusion of solvent effects). Computations were first effected with diene 3b and maleic anhydride (D1) as dienophile. Optimization of the diene conformation expectedly showed a half-chair conformational preference for the cyclohexenyl moiety. An energy minimum was found for the conformer with a C=C-C=C dihedral angle of 42.2°.

Evaluation of the frontier orbitals energies confirmed the preferential interaction between the HOMO of diene 3b and the LUMO of dienophile D1, and thus the normal electron demand character of the cycloaddition process. Quantitative evaluation of the preferred pathway on the activation energy was then undertaken, by localization of the transition states (TS) of the cycloaddition. Four arrangements were considered, depending on the face approach:

top/bottom approach of the dienophile and the endo/exo orientations (Figure 6). The cycloaddition proved exergonic in each case. The most favored transition states were found to be 20.57 kcal.mol -1 above the reactants for the top-endo approach (A) and 23.57 kcal.mol -1 for the top-exo one (C). The bottom-endo TS (B) was slightly higher in energy (24.37 kcal.mol-1) while the bottom-exo (D) one proved to be the least favorable (27.68 kcal.mol -1 ). Considering the reaction is under kinetic control, the 3.00 kcal.mol -1 difference between the two most favoured TS should thus allow for a good if not complete stereocontrol of the cycloaddition. Experimentally, the only stereoisomer formed and isolated when interacting 3b

with D1 proved to be 4bA. These DFT calculations are thus in line with these results since the top-endo TS indeed leads to cycloadduct 4bA. The process appeared to be concerted and slightly asynchronous, the lengths of the forming bonds CH cyclo -C dienophile and CH Ph -C dienophile being in the same range, 2.10 Å and 2.36 Å, respectively for the most favored top-endo TS.

The phenyl substituent of the diene moiety was not conjugated with the double bond but the dihedral angle C diene =C diene H-C Ph =C Ph H was small (23.95°). All attempts to find zwitterionic intermediates were unsuccessful. Computations involving the 6-membered ring diene 3f and diene D1 led to similar results. In this case also the top-endo approach (A) is the also most favored one, in line with the experimental results, albeit a much lower energy difference between the two most favorable TS is observed (Figure 7). Interestingly, the phenyl moiety of the diene is not conjugated with the dienic part (with a C diene =CH-C=C(Ph)H dihedral angle of 54.5°) in the optimized diene and is quasi perpendicular to the dienic part in the top/endo most favored TS (the C diene =C diene H-C Ph =C Ph H dihedral angle being 78.48°), in sharp contrast with the 5-membered ring system. The process remains a concerted, asynchronous one with the lengths of the forming bonds being 2.47 Å and 2.08 Å CH cyclo -C dienophile and CH Ph -C dienophile , respectively for the most favored top-endo TS. Noteworthy, the asynchronicity is more important, with the 6membered ring system, and the smallest forming bond is not the same, highlighting the strong influence of the thiacycle on the cycloaddition reaction.

Conclusions

In summary, we developed a stereocontrolled synthesis of new sulfur-containing exo-bicyclic 1,3-dienes, based on palladium-catalyzed reductive cyclization of sulfur-linked 2bromoenynes. The method is efficient for both accessing 5-and 6-membered thiacyclic dienes. They have been reacted with several electron-deficient dienophiles leading to various original thiacycle-fused polycyclic systems, with high or total diastereoselectivity. Mechanistic details of the cycloadditions have been examined by computational means and the conclusions were in agreement with the experimental results.

Experimental Part

General information. Reagents were obtained from commercial sources and used without any further purification. Thin layer chromatography was performed on silica gel 60 F254 plates.

NMR spectra were recorded at 400 or 500 MHz for 1 H and at 100 or 125 MHz for 13 C. Chemical shifts are reported in parts per million (ppm) relative to residual solvent and coupling constants (J) are reported in hertz (Hz). CDCl3 was filtered previously on basic alumina. Assignments of 1 H and 13 (2-bromocyclohex-2-en-1-yl) ethanethioate (1). To a solution of 1,6-dibromocyclohex-1-ene (240 mg, 1 mmol, 1 equiv) in acetone (200 mL), potassium thioacetate (126 mg, 1.1 mmol, 1.1 equiv) was added. The reaction mixture was stirred at room temperature for one night. After filtration of the potassium bromide salts, the filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (heptane) to afford thioacetate 1 (235 mg, 100% yield).

Synthesis and characterization of sulfides (2a-f)

(2-bromocyclohex-2-en-1-yl)(pent-2-yn-1-yl)sulfane (2a) To a solution of KOH (657 mg, 11.7 mmol, 1.5 equiv) in ethanol (130 mL), thioacetate 1 (1.83 g, 7.80 mmol, 1 equiv) and 3-(ethyl)propargyl bromide (1.26 g, 8.58 mmol, 1.1 equiv) were added successively. The reaction mixture was stirred at room temperature for 15 min. After evaporation of the solvent, hydrolysis by water and extraction with ether, the organic layers were separated, dried with MgSO4 and the solution was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluent: heptane) to afford 2a (1.6 g, 80% yield).

1 H NMR (CDCl3, 400 MHz) d 1.16 (t, J = 7.5 Hz, 3H, CH3), 1.71 (m, 1H), 1.86 (m, 1H), 2.04-2.17 (m, 4H, 2xCH2), 2.24 (tq, J = 2.3, 7.6 Hz, 2H, CH3CH2), 3.39 (t, J = 2.3 Hz, 2H, SCH2), 3.70 (s, 1H, SCH), 6.16 (t, J = 3.8 Hz, 1H, BrC=CH). 13 C NMR (CDCl3, 100.6 MHz) d 12.5 (CH3), 14.0 (CH3CH2), 13.3 (SCH2), 20.9 (CH2), 20.5 (CH2), 30.9 (CH2), 49.4 (SCH), 74.9 (Cq), 85.4 (Cq),122.4 (CBr),132.5 (BrC=CH). HRMS (FI+eiFi) m/z: [M + ] calculated for C11H15BrS 258.0078, found 258.0083.

(2-bromocyclohex-2-en-1-yl) (3-phenylprop-2-yn-1-yl)sulfane (2b) To a solution of KOH (716 mg, 12.8 mmol, 1.5 equiv) in ethanol (78 mL), thioacetate 1 (2 g, 8.5 mmol, 1 equiv) and (3-chloroprop-1yn-1-yl)benzene (1.28 g, 8.5 mmol, 1 equiv) were added successively. The reaction mixture was stirred at room temperature for one hour. After evaporation of the solvent, hydrolysis by water and extraction with ether, the organic phases were separated, dried with MgSO4 and the solution was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (heptane) to afford 2b (1.43 g, 55% yield).

4-((2-bromocyclohex-2-en-1-yl)thio)but-2-yn-1-ol (2c)

To a solution of KOH (286 mg, 5.10 mmol, 1.5 equiv) in ethanol (40 mL), thioacetate 1 (800 mg, 3.40 mmol, 1 equiv) and 4-chlorobut-2-yn-1-ol (391 mg, 3.74 mmol, 1.1 equiv) were added successively. The reaction mixture was stirred at room temperature for 5 hours. After evaporation of the solvent, hydrolysis by NH4Cl and extraction with ether, the organic layers were separated, dried on Na2SO4 and the solution was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (heptane/ AcOEt 80/20) to afford 2c (789 mg, 89%). (2-bromocyclohex-2-en-1-yl)(pent-3-yn-1-yl)sulfane (2d) To a solution of KOH (260 mg, 4.6 mmol, 1.5 equiv) in ethanol (40 mL), S-(2-bromocyclohex-2-en-1-yl) thioacetate 1 (730 mg, 3 mmol, 1 equiv), 18-crown-6 (170 mg ; 0,46 mmol, 0,15 equiv), and then 5-bromopent-2-yne (670 mg, 3.7 mmol, 1.2 equiv) were added successively. The reaction mixture was stirred at room temperature for 3 hours. After evaporation of the solvent, ether was added, then the insoluble solid removed by filtration. The solution was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (heptane/AcOEt 99:1) to afford 2d (653 mg 81% yield). (2-bromocyclohex-2-en-1-yl)(but-3-yn-1-yl)sulfane (2e). To a solution of KOH (358 mg, 6.3 mmol, 1.5 equiv) in ethanol (40 mL), S-(2-bromocyclohex-2-en-1-yl) thioacetate 1 (1 g, 4.25 mmol, 1 equiv), 18-crown-6 (169 mg, 0.63 mmol, 0.15 equiv), and 4-bromobut-1-yne (566 mg, 4.25 mmol, 1 equiv) were added successively. The reaction mixture was stirred at room temperature for 3 hours. After evaporation of the solvent, ether was added, then the insoluble solid was removed by filtration. The solution was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (heptane/AcOEt) to afford 2e (791 mg 76% yield). (2-bromocyclohex-2-en-1-yl) (4-phenylbut-3-yn-1-yl)sulfane (2f). Under argon atmosphere, were added successively copper iodide (0.1 equiv, 0.04 mmol, 7.7 mg), Pd(OAc)2 (4.6 mg, 0.02 mmol, 0.05 equiv), PPh3 (10.7 mg, 0.04 mmol, 0.1 equiv), phenyl iodide (120 mg, 0.4 mmol, 1 equiv), then the mixture was dissolved in distilled diisopropylamine (1 mL). Then, homopropargyl sulfide 2e (107 mg, 0.4 mmol, 1 equiv) was added and the mixture was stirred at room temperature for 12h. The reaction mixture was then filtered through Celite to eliminate the metal traces and then concentrated under reduced pressure. The crude product was purified by flash column chromatography (eluent: heptane/AcOEt 95/5), to afford pure 2f (108 mg 84% yield).

Synthesis and characterization of dienes (3a-f). General procedure:

To a solution of sulfide 2 (1 equiv) in DMF, were successively added ammonium formate (1.5 equiv), Pd(OAc)2 (0.1 equiv) and PPh3 (0.2 equiv). After 2 h at 100 °C, the reaction mixture was cooled to room temperature and water was added to remove the DMF. After extraction with ethyl acetate, the combined organic phases were washed with brine, dried with MgSO 4 , filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (cyclohexane/toluene 95/5) to give diene 3.

(Z)- 3-propylidene-2,3,5,6,7,7a-hexahydrobenzo[b]thiophene (3a). Following the general procedure, sulfide 2a (456 mg, 1.76 mmol, 1 equiv) was used with ammonium formate (166 mg, 2.64 mmol, 1.5 equiv), Pd(OAc)2 (39 mg, 0.18 mmol, 0.1 equiv) and PPh3 (92 mg, 0.35 mmol, 0.2 equiv) to afford diene 3a as colorless oil (217 mg, 68%). (Z)- 3-benzylidene-2,3,5,6,7,7a-hexahydrobenzo[b]thiophene (3b). Following the general procedure, sulfide 2b (498 mg, 1.63 mmol, 1 equiv) was used with ammonium formate (154 mg, 2.44 mmol, 1.5 equiv), Pd(OAc)2 (36 mg, 0.16 mmol, 0.1 equiv) and PPh3 (85 mg, 0.32 mmol, 0.2 equiv) to afford diene 3b as colorless oil (223 mg, 60%). (Z)-2- (5,6,7,7a-tetrahydrobenzo[b]thiophen-3(2H)-ylidene)ethan- 1-ol (3c). Following the general procedure, sulfide 2c (100 mg, 0.38 mmol, 1 equiv) was used with ammonium formate (36 mg, 0,57 mmol, 1.5 equiv), Pd(OAc)2 (9 mg, 0.04 mmol, 0.1 equiv) and PPh3 (20 mg, 0.07 mmol, 0.2 equiv) to afford diene 3c as colorless oil (32 mg, 46%).

1 H NMR (CDCl3, 400 MHz) d 2H),1.55 (m,1H),1.90 (m,1H),3H),3.54 (s,2H,SCH2),3.72 (m,1H,SCH),4.24 (d,J = 6.8 Hz, 2H, OCH2), 5.93, (t, J = 7.0 Hz, 1H, C=CH), 6.01 (bs, 1H, C=CH). 13 C NMR (CDCl3, 100.6 MHz) d 22.1 (CH2), 24.9 (CH2), 29.2 (CH2), 31.4 (CH2), 45.9 (SCH), 60. 5 (OCH2),118.4 (C=CH),119.7 (C=CH),140.3 (Cq),140.6 (Cq). HRMS (ESI/Q-TOF) m/z: [M+H + ] calculated for C10H15OS 183.0838, found 183.0829.

(E) -4-ethylidene-3,4,6,7,8,8a-hexahydro-2H-thiochromene (3d) . Following the general procedure, sulfide 2d (286 mg, 1.1 mmol, 1 equiv) was used with ammonium formate (104 mg, 1.65 mmol, 1.5 equiv), Pd(OAc)2 (24 mg, 0.11 mmol, 0.1 equiv) and PPh3 (58 mg, 0.22 mmol, 0.2 equiv), in 1 mL DMF, to afford diene 3d as colorless oil (110 mg, 55%). CDCl3,400 MHz) d 1 1H),1.62 (d,J = 6.7 Hz,3H,CH3),1H),2H),2.11 (m,1H),2.28 (m,1H),3H),2.90 (m,1H) 4-methylene-3,4,6,7,8,8a-hexahydro-2H-thiochromene (3e). Following the general procedure, sulfide 2e (100 mg, 0.41 mmol, 1 equiv) was used with ammonium formate (39 mg, 0.61 mmol, 1.5 equiv), Pd(OAc)2 (9 mg, 0.041 mmol, 0.1 equiv) and PPh3 (21 mg, 0.082 mmol, 0.2 equiv), in 2 mL DMF, to afford diene 3e. The crude product obtained (characterized by 1 H-NMR) after extraction was directly used in cycloaddition.

H NMR (

1 H NMR (CDCl3, 400 MHz) d 1.5 (t, J = 7.5 Hz, 1H), 2H),2H),2H),2H),1H),1H),4.66 (s,1H,=CH),4.86 (s,1H,=CH),5.78 (s,1H,=CH).

(E) -4-benzylidene-3,4,6,7,8,8a-hexahydro-2H-thiochromene (3f). Following the general procedure, to a solution of sulfide 2f (264 mg, 0.8 mmol, 1 equiv) in DMF (5 mL), were successively added ammonium formate (78 mg, 1.2 mmol, 1.6 equiv, 0.5 mmol), Pd(OAc)2 (18 mg, 0.08 mmol, 0.1 equiv) and PPh3 (43 mg, 0.2 mmol, 0.2 equiv). After 2 h at 100 °C, the reaction mixture was cooled to room temperature and water was added to remove the DMF. After extraction with ethyl acetate, the combined organic phases were washed with water, dried with MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by chromatography (cyclohexane/toluene 95/5) to afford diene 3f as colorless oil (151 mg, 78%). ),123.8 (CH),125.7 (CH),126.7 (CH),128.3 (2xCH),129.4 (2xCH),137.8 (Cq),140.8 (Cq), 142.1 (Cq). HRMS (ESI/Q-TOF) m/z: [M+H + ] calculated for C16H19S 243.1207, found 243.1195.

Diels-Alder reactions. Synthesis and characterization of cycloadducts (4-10)

Cycloadditions of diene (3a) 6-ethyl-1,2,3,3a,6,6a,9a,9b-octahydro-5H-thieno[4',3',2':4,5]naphtho [1,2-c]furan -7,9-dione (4aA) A mixture of diene 3a (50 mg, 0.28 mmol, 1.1 equiv) and maleic anhydride D1 (27 mg, 0.25 mmol, 1 equiv) was stirred 2 h at 40 °C in dichloromethane (0.5 mL). The product was then purified by flash chromatography (heptane/ethyl acetate 9/1) and obtained as an inseparable mixture of two diastereomers in 8/2 ratio, as a white paste (63 mg, 91%).

Major stereoisomer 4aA: 1 H NMR (CDCl3, 400 MHz) d 1.12 (t, J = 7.2 Hz, 3H, CH3), 1.73 (m, 1H), 1.78 (m,1H),2H),2H),2H),2H),3.43 (m,1H,Hc),3.54 (dd,J = 4.5,9.0 Hz,1H,Hb),2H,SCH2),4.26 (bs,1H,SCHe). 6-ethyl-8-phenyl-2,3,3a,5,6,6a,9a,9b-octahydrothieno[4',3',2':4,5]naphtho [1,2-c]pyrrole-7,9(1H,8H)dione (5aA). A mixture of diene 3a (43 mg, 0.24 mmol, 1.1 equiv) and N-phenylmaleimide D2 (35 mg, 0.2 mmol, 1 equiv) was stirred 2 h at 40 °C in dichloromethane (0.5 mL). The product 5aA was then purified by flash chromatography (heptane/ethyl acetate 9/1) and obtained as single diastereomer, as a white paste (65 mg, 93%). 4.6,8.1 Hz,1H),2H,SCH2),4.27 (bs,1H,SCH),2H),7.38 (m,1H),2H). 13 C NMR (CDCl3, 100.6 MHz) d 13.1 (CH3), 21.3 (CH2CH3), 21.9 (CH2), 22.5 (CH2), 30.5 (CH), 36.5 (CH2), 39.2 (SCH2), 40.4 (CH), 44.2 (CH), 44.7 (CH), 49.8 (SCH),126.8 (2xCH),128.8 (CH),129.3 (2xCH), 132.0 (Cq), 135.8 (C=C), 139.9 (C=C), 176.1 (C=O), 176.7 (C=O).

HRMS (ESI/Q-TOF) m/z: [M+H +

] calculated for C21H23NO2S 354.1522, found 354.1530.

dimethyl 3-ethyl-3,5a,6,7,8,8a-hexahydro-2H-naphtho[1,8-bc]

thiophene-4,5-dicarboxylate (6a)

A mixture of diene 3a (50 mg, 0.28 mmol, 1 equiv) and dimethyl acetylenedicarboxylate D3 (60 mg, 0.42 mmol, 1.5 equiv) was stirred overnight at 80 °C in toluene (3 mL). The product was then purified by flash chromatography (heptane/ethyl acetate 9/1) and obtained as an inseparable mixture of two diastereomers in 10/3 ratio, as a colorless oil (57 mg, 65%).

Major stereoisomer 6aA: 1 H NMR (CDCl3, 400 MHz) d 0.63 (t, J = 7.5 Hz, 3H, CH3), 1.39 (m, 1H), 1.52-1.60 (m, 2H), 1.63-1.73 (m, 2H), 1.78-1.93 (m, 2H) Minor stereoisomer 6aB: 1 H NMR (CDCl3, 400 MHz) characteristic signals different from 6aA: d 0.70 (t, J = 7.5 Hz, 3H, CH3), 3.97 (m, 1H, SCH). 13 C NMR (CDCl3, 100.6 MHz) d 8.5, 22.9, 25.8, 33.7, 39.5, 39.6, 39.9, 52.2, 54.9, 127.1, 136.6, 137.1, 137.8, 167.8, 168.5. 6aA/B: HRMS (ESI/Q-TOF) m/z: [M+H + ] calculated for C17H23O4S 323.1312, found 323.1308. 6-ethyl-9-phenyl-1,2,3,3a,6,11a-hexahydro-5H,8H-thieno[4,3,2-de][1,2,4]triazolo [1,2-a]cinnoline-8,10(9H)-dione (7aA) and 6-ethyl-9-phenyl-1,2,3,11a-tetrahydro-6H,8H-thieno[4,3,2de][1,2,4]triazolo [1,2-a]cinnoline-8,10(9H)-dione (8a)

A mixture of diene 3a (23 mg, 0.13 mmol, 1 equiv) and 4-phenyl-3H-1,2,4-triazole-3,5(4H)-dione D4

(43 mg, 0.26 mmol, 2 equiv) was stirred 1 h, at room temperature, in dichloromethane ( 0.5 mL). The product was then purified by flash chromatography (heptane/ethyl acetate 9/1) and obtained as a mixture of 7aA and 8a in 1:2 ratio. Each one was isolated as a single diastereomers: 7aA as an amorphous white solid (11 mg, 22%) of and 8a as a viscous oil (23 mg, 45%).

Product 7aA:

Cycloaddition between diene (3a) and dithioester (D5). 2-(Methylsulfanyl)carbothioylpyridine D5

(47 mg, 0.28 mmol, 1 equiv) and boron trifluoride diethyl etherate (0.035 mL, 0.28 mmol, 1 equiv)

were mixed in dichloromethane (0.6 mL). After 5 min, diene 3a (54 mg, 0.3 mmol, 1.1 equiv) was added in dichloromethane (0.2 mL). Then the reaction mixture was stirred 1 h at 40 °C in DCM. The mixture was washed with a saturated solution of NaHCO3 and the product was extracted with dichloromethane. The organic layers were then dried with MgSO4 and evaporated under vacuum.

After purification by flash chromatography (heptane/ethyl acetate 9/1) the product was obtained as an inseparable mixture of two cycloadducts (ratio 3:1), as an orange oil (70 mg, 72%). The structures have been not assigned.

Major cycloadduct 10a: Cycloadditions of diene (3b) 6-phenyl-1,2,3,3a,6,6a,9a,9b-octahydro-5H-thieno[4',3',2':4,5]naphtho [1,2-c]furan-7,9-dione (4bA)

A mixture of diene 3b (21 mg, 0.09 mmol, 1.1 equiv) and maleic anhydride D1 (8 mg, 0.08 mmol, 1 equiv) was stirred 2 h at 40 °C in dichloromethane (1 mL). The product 4bA was then purified by trituration in pentane and obtained as single diastereomer, as a white solid with mp = 137 °C (13 mg, 50%). 6,8-diphenyl-2,3,3a,5,6,6a,9a,9b-octahydrothieno[4',3',2':4,5]naptho [1,2-c]pyrrole-7,9(1H,8H)-dione (5bA)

A mixture of diene 3b (30 mg, 0.13 mmol, 1.1 equiv) and N-phenylmaleimide D2 (15 mg, 0.09 mmol, 1 equiv) was stirred 2 h at 40 °C in dichloromethane (1 mL). The product 5bA was then purified by flash chromatography (heptane/ethyl acetate 9/1) and obtained as a single diastereomer, as an amorphous white solid (35 mg, 97%). 6,9-diphenyl-1,2,3,3a,6,11a-hexahydro-5H,8H-thieno[4,3,2-de][1,2,4]triazolo [1,2-a]cinnoline-8,10(9H)-dione (7bA) and 6,9-diphenyl-1,2,3,11a-tetrahydro-6H,8H-thieno[4,3,2de][1,2,4]triazolo [1,2-a]cinnoline-8,10(9H)-dione (8b)

A mixture of diene 3b (30 mg, 0.13 mmol, 1 equiv) and 4-phenyl-3H-1,2,4-triazole-3,5(4H)-dione D4

(46 mg, 0.26 mmol, 2 equiv) was stirred 30 min, at room temperature, in dichloromethane ( 0.5 mL).

The product was then purified by flash chromatography (heptane/ethyl acetate 9/1) and obtained as a mixture of 7bA and 8b in 1:1 ratio. Each one was isolated as a single diastereomer: 7bA as a viscous oil (11 mg, 22%) and 8b as a white solid with mp = 184 °C (13 mg, 26%).

(7bA): 2-(4-(methylthio)-3-phenyl-2,3,4,5a,6,7,8,8a-octahydrothieno[4,3,2-de]thiochromen-4-yl)pyridine

(10b)

2-(Methylsulfanyl)carbothioylpyridine D5 (17 mg, 0.1 mmol, 1 equiv) and boron trifluoride diethyl etherate (0.0127 mL, 0.1 mmol, 1 equiv) were mixed in dichloromethane (0.2 mL). After 5 min, diene 3b (25 mg, 0.11 mmol, 1.1 equiv) was added in dichloromethane (0.2 mL). Then the reaction mixture was stirred 1 h at 40 °C in DCM. The mixture was washed with a saturated solution of NaHCO3 and the product was extracted with dichloromethane. The organic layers were then dried with MgSO4 and evaporated under vacuum. After purification by flash chromatography (heptane/ethyl acetate 9/1) the product was obtained as an inseparable mixture of two cycloaducts (ratio 10:1), as a yellow oil (20 mg, 51%).

Major cycloadduct 10b:

Cycloaddition of diene (3c)

7 -oxo-2a,3,4,5,5a,6,6a,7,9,9a-decahydro-1H-thieno[2',3',4':8,1]naphtho [2,3-c]

Cycloadditions of diene (3d)

7-methyl -1,2,3,3a,5,6,7,7a,10a,10b-decahydrobenzo[8,1]isothiochromeno [6,7-c]furan-8,10-dione (4dA)

A mixture of diene 3d (40 mg, 0.22 mmol, 1.1 equiv) and maleic anhydride D1 (25 mg, 0.22 mmol, 1 equiv) was stirred 2.5 h at 40 °C in dichloromethane (0.3 mL). The product 4dA was then purified by flash chromatography (pentane/diethyl ether 8/2) and obtained as single diastereomer, as an amorphous white solid (29 mg, 47%). dimethyl-4-methyl-2,3,4,6a,7,8,9,9a-octahydrobenzo[de]thiochromene-5,6-dicarboxylate (6dA/6dB)

A mixture of diene 3d (50 mg, 0.28 mmol, 1 equiv) and dimethyl acetylenedicarboxylate D3 (59 mg, 0.42 mmol, 1.5 equiv) was stirred overnight at 80 °C in toluene (1 mL). The resulted product was obtained as an inseparable mixture of two diastereomers in 2/1 ratio, as a colorless oil (49 mg, 54%) and purified by flash chromatography (heptane/ethyl acetate 9/1). A small fraction enriched in minor isomer 6dB was isolated (ratio 2/10).

Major stereoisomer 6dA: 7-phenyl-1,2,3,3a,5,6,7,7a,10a,10b-decahydrobenzo[8,1]isothiochromeno [6,7-c]furan -8,10-dione (4fA). A mixture of diene 3f (50 mg, 0.2 mmol, 1.1 equiv) and maleic anhydride D1 (20 mg, 0.2 mmol, 1 equiv) was stirred 5 h at 40 °C in dichloromethane (0.3 mL). The product 4fA was then purified by flash chromatography (pentane/diethyl ether 8/2) and obtained as single diastereomer, as a white solid, mp = 142 °C (28 mg, 41%). 7-methyl-10-phenyl-1,2,3,3a,5,6,7,12a-octahydro-9H-thiopyrano[4,3,2-de][1,2,4]triazolo [1,2a]cinnoline-9,11(10H)-dione (7fA). A mixture of diene 3f (30 mg, 0.13 mmol, 1 equiv) and 4-phenyl-3H-1,2,4-triazole-3,5(4H)-dione D4 (45 mg, 0.26 mmol, 2 equiv) was stirred 1 hour, at room temperature, in dichloromethane ( 0.5 mL). The product was then purified by flash chromatography (heptane/ethyl acetate 9/1) to afford 7fA as a single diastereomer, as a white powder (30 mg, 60%). 2- (2-(methylthio)-3-phenyl-3,4,5,6a,7,8,9,9a-octahydro-2H-thiopyrano[4,3,2-de]thiochromen-2yl)pyridine (10f). 2-(Methylsulfanyl)carbothioylpyridine D5 (39 mg, 0.2 mmol, 1 equiv) and boron trifluoride diethyl etherate (0.0152 mL, 0.1 mmol, 1 equiv) were mixed in dichloromethane (0.5 mL).

After 5 min, diene 3f (62 mg, 0.22 mmol, 1.1 equiv) was added in dichloromethane (0.2 mL). Then the reaction mixture was stirred 1.5 h at 40 °C in DCM. The mixture was washed with a saturated solution of NaHCO3 and the product was extracted with dichloromethane. The organic layers were then dried with MgSO4 and evaporated under vaccum. After purification by flash chromatography (heptane/ethyl acetate 9/1) the product was obtained as an inseparable mixture of two cycloadducts (ratio 10:3), as a yellow oil (54 mg, 65%).

The regio-and stereochemical assignments of these cycloadducts have been made on the basis of the following NMR experiments: ADEQUATE: correlation between CHPh and Cq-(SMe); selective NOESY-1D on CHS 2 -major: correlation with SCH3-major; weak correlation with CHS 1 -major;

selective NOESY-1D on CHS 2 -minor: correlation with SCH3-minor; strong correlation with CHS 1minor; selective NOESY-1D on SCH3: similar correlations with CHS 2 -major and CHS 2 -minor;

7

 7

Figure 1 .

 1 Figure 1. Known exo-thiacyclic diene I and envisaged more stable exo-bicyclic dienes II

Scheme 2 .

 2 Scheme 2. Synthesis of sulfur-containing exo-bicyclic dienes 3

Scheme 3 .

 3 Scheme 3. Diels-Alder reactions of exo-bicyclic dienes 3 with D1 (ratio diene/D1 1.1:1)

Figure 2 .Figure 3 .

 23 Figure 2. X-ray structure of 4bA (50% probability ellipsoids)

Figure 4 .

 4 Figure 4. X-ray structure of 4fA (50% probability ellipsoids)

Scheme 4 .

 4 Scheme 4. Diels-Alder reactions of exo-bicyclic dienes 3a,b with D2 (ratio diene/D2 1.1:1)

Scheme 5 .

 5 Scheme 5. Diels-Alder reactions of exo-bicyclic dienes 3 with D3 (ratio diene/D3 1:1.5)

Figure 5 .

 5 Figure 5. X-ray structure of 8b (50% probability ellipsoids)

Figure 6 .TSFigure 7 .

 67 Figure 6. Schematic representation of the energy profile for the cycloaddition between 3b and D1

  C signal were made by DEPT, COSY, HSQC, HMBC, ADEQUATE, NOESY-2D, and selective NOESY-1D experiments. HRMS were performed with a Q-TOF analyzer Agilent 1200, using either electrospray ionization (ESI) at Tsource = 340 °C, Vcap = 4000 V, or atmospheric pressure chemical ionization (APCI) at Tgas = 300 °C, Tvap = 380 °C, Vcorona = 4µA, or with an Agilent 7890 analyzer by using GC-MS (FI or EI). Melting points were determined in open capillary tubes and are uncorrected.

1 H 9 (

 19 NMR (CDCl3, 400 MHz) d 1.59 (m, 1H), 1.75 (m, 1H), 1.96 (m, 1H), 2.09-2.18 (m, 3H), 2.35 (s, 3H, CH3), 4.37 (bs, 1H, SCH), 6.19 (t, J = 4.0 Hz, 1H, C=CH). 13 C NMR (CDCl3, 100.6 MHz) d 17.CH3), 27.4 (CH2), 30.5 (CH2), 31.7 (CH2), 48.2 (SCH), 120.3 (CBr), 133.8 (C=CH), 194.6 (C=O).

1 H

 1 NMR (CDCl3, 400 MHz) d 1.70 (m, 1H), 1.85 (m, 1H), 1.94-2.17 (m, 4H, CH2), 3.62 (s, 2H, SCH2), 3.77 (bs, 1H, SCH), 6.11 (t, J = 4.0 Hz, 1H, BrC=CH),7.21-7.26 (m, 3H), 7.37-7.39 (m, 2H).

13 C

 13 NMR (CDCl3, 100.6 MHz) d 17.5 (SCH2), 21.5 (CH2), 27.74 (CH2), 31.19 (CH2), 49.90 (SCH), 83.70 (Cq), 85.54 (Cq), 122.37 (Cq), 123.1 (Cq), 128.4 (CH), 128.5 (2xCH), 131.9 (2xCH), 133.0 (CBr). HRMS (ESI/Q-TOF) m/z: [M+H + ] calculated for C15H16BrS 307.0151, found 307.0143.

1 H

 1 NMR (CDCl3, 400 MHz) d 1.71 (m, 1H), 1.83 (m, 1H), 2.04-2.17 (m, 4H, 2xCH2), 3.41 (s, 2H, SCH2), 3.66 (s, 1H, SCH), 4.30(d, J = (5.1 Hz, 2H, OCH2), 6.15 (dd, J = 4.6, 3.5 Hz, 1H, BrC=CH).

13 C

 13 NMR (CDCl3, 100.6 MHz) d 17.5 (CH2), 20.7 (CH2), 27.7 (CH2), 31.1 (SCH2), 49.7 (SCH), 51.5 (OCH2), 81.7 (Cq), 82.1 (Cq), 122.2 (CBr), 133.0 (C=CH). HRMS (ESI/Q-TOF) m/z: [M+H + ] calculated for C10H14BrOS 260.9943, found 260.9938.

1 H

 1 NMR (CDCl3, 400 MHz) δ 1.67 (m, 1H),1.77 (s, 3H, CH3), 1.79 (m, 1H), 4H, 2xCH2), 2H, CH2), 2.75 (t, J = 7.4 Hz, 2H, SCH2), 3.46 (s, 1H, SCH), 6.08 (t, J = 3.8 Hz, 1H, CBr=CH).13 C NMR (CDCl3, 100.6 MHz) δ 3.7 (CH3), 17.5 (CH2), 20.7 (CH2), 27.6 (CH2), 31.7 (CH2), 32.3 (CH2), 50.1 (SCH), 70.0 (≡C), 76.9 (≡C), 122.9 (CBr),132.3 (=CH). HRMS (ESI/Q-TOF) m/z: [M+H + ] calculated for C11H16BrS 259.0151, found 259.0141.

1 H

 1 NMR (CDCl3, 400 MHz) δ 1.67 (m, 1H), 1.83 (m, 1H), 2.03-2.12 (m, 5H, 2xCH2 & C≡CH), 2.49-2.56 (m, 2H, CH2), 2.82 (t, J = 7.4 Hz, 2H, SCH2), 3.47 (s, 1H, SCH), 6.11 (t, J = 3.8 Hz, 1H, CBr=CH). 13 C NMR (CDCl3, 100.6 MHz) δ 17.4 (CH2), 20.4 (CH2), 27.6 (CH2), 31.7 (2xCH2), 50.2 (SCH), 69.6 (HC≡), 82.7 (≡C), 122.7 (CBr), 132.5 (=CH). HRMS (APCI/Q-TOF) m/z: [M+H + ] calculated for C10H14BrS 245.0000, found 244.9987

1 H

 1 NMR (CDCl3, 400 MHz) δ 1.67 (m, 1H),1.86 (m, 1H), 4H, 3xCH2), 2H, CH2), 2H, SCH2), 3.54 (s, 1H, SCH), 6.15 (t, J = 3.8 Hz, 1H, CBr=CH), 3H), 2H).13 C NMR (CDCl3, 100.6 MHz) δ 17.5 (CH2), 21.5 (CH2), 27.6 (CH2), 31.7 (CH2), 32.0 (CH2), 50.2 (SCH), 81.8 (≡C), 88.3 (PhC≡), 122.9(Cq), 123.7 (Cq), 128.0 (CH),128.4 (2xCH), 131.8 (2xCH), 132.5 (CH). HRMS (ESI/Q-TOF) m/z: [M+H + ] calculated for C16H18BrS 321.0313, found 321.0309.

1 H

 1 NMR (CDCl3, 400 MHz) d 1.01 (t, J = 7.6 Hz, 3H, CH3), 1.38 (m, 1H), 1.50 (m, 1H), 1.90 (m, 1H), 2.05-2.11 (m, 2H, CH2CH3), 2.13-2.22 (m, 3H), 3.49 (s, 2H, SCH2), 3.74 (m, 1H, SCH), 5.75 (t, J = 7.5 Hz, 1H, C=CH), 5.89 (bs, 1H, C=CH). 13 C NMR (CDCl3, 100.6 MHz) d 14.0 (CH3), 22.4 (CH2), 22.9 (CH2), 25.0 (CH2), 29.5 (CH2), 31.7 (SCH2), 46.4 (SCH), 117.6 (C=CH), 122.5 (Cq), 137.7 (C=CH), 140.8 (Cq). HRMS (APCI/Q-TOF) m/z: [M+H + ] calculated for C11H17S 181.1045, found 181.1041.

1 H

 1 NMR (CDCl3, 400 MHz) d 1.39-1.49 (m, 1H, CH2), 1H, CH2), 1H, CH2), 3H, CH2), 1H, SCH), 3.84 (s, 2H, SCH2), 6.13 (s, 1H, C=CH),6.77 (s, 1H, C=CH), 1H), 4H). 13 C NMR (CDCl3, 100.6 MHz) d 17.5 (CH2), 21.5 (CH2), 27.7 (CH2), 31.2 (SCH2), 49.9 (SCH), 122.4 (C=CH), 123.2 (C=CH), 128.4 (CH), 128.5 (2xCH), 128.6 (C=CH), 129.0 (Cq), 131.9 (2xCH), 133.0 (C=CH). HRMS (ESI/Q-TOF) m/z: [M+H + ] calculated for C15H17S 229.1045, found 229.1044.

  , 3.49 (m, 1H, SCH), 5.44 (q, J = 7.2 Hz, 1H, C=CH), 5.65 (bs, 1H, C=CH). 13 C NMR (CDCl3, 100.6 MHz) d 13.3 (CH3), 21.1 (CH2), 25.9 (CH2), 29.2 (CH2), 30.0 (CH2), 30.7 (CH2), 40.5 (SCH), 119.8 (CH), 122.1 (CH), 140.2 (Cq), 141.0 (Cq). HRMS (APCI/Q-TOF) m/z: [M+H + ] calculated for C11H17S 181.1045, found 181.1041.

1 H

 1 NMR (CDCl3, 400 MHz) d 1.53-1.59 (m, 2H), 1.81 (m, 1H), 2.08-2.20 (m, 3H), 2.44-2.80 (m, 3H), 3.16 (m, 1H, SCHH), 3.59 (m, 1H, SCH), 5.88 (bs, 1H, C=CH), 6.49 (s, 1H, C=CH), 7.21-7.26 (m, 3H), 7.32-7.34 (m, 2H). 13 C NMR (CDCl3, 100.6 MHz) d 22.0 (CH2), 26.1 (CH2), 29.3 (CH2), 30.0 (CH2), 32.2 (CH2), 40.4 (SCH

  100.6 MHz) d 12.7 (CH3), 20.9 (CH2CH3), 21.5 (CH2), 22.1 (CH2), 30.2 (CH2), 35.5 (CH), 39.1 (CH2), 39.6 (CH), 44.7 (CHb), 45.0 (CHc), 49.7 (SCHe), 136.1 (C=C), 140.2 (C=C), 170.9 (C=O), 171.4 (C=O). HRMS (ESI/Q-TOF) m/z: [M+H + ] calculated for C15H18O3S 279.1049, found 279.1057. Minor stereoisomer (characteristic signals different from 4a): 1 H NMR (CDCl3, 400 MHz), d 1.02 (t, J = 7.2 Hz, 3H, CH3), 4.00 (bs, 1H, SCHe). 13 C NMR (CDCl3, 100.6 MHz) d 12.4 (CH3), 23.4 (CH2CH3), 26.3 (CH2), 29.8 (CH2), 31.3 (CH2), 34.1 (CH), 36.1 (CH2), 38.2 (CH), 39.7 (CH), 43.3 (CH), 55.5 (CH), 131.0 (C=C), 137.0 (C=C), 170.70 (C=O), 170.72 (C=O).

1 H

 1 NMR (CDCl3, 400 MHz) d 1.16 (t, J = 7.3 Hz, 3H, CH3), 1.58-1.68 (m, 2H), 1.77-1.96 (m, 3H), 1.99 (m, 1H), 2.18 (m, 1H), 2.27 (m, 1H), 2.38-2.49 (m, 2H), 3.31 (t, J = 8.1 Hz, 1H), 3.42 (dd, J =

  , 2.19 (m, 1H),3.18 (m, 1H), 3.36 (m, 1H), 3.54 (m, 1H), 3.72 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 3.78 (m, 1H), 4.18 (m, 1H, SCH). 13 C NMR (CDCl3, 100.6 MHz) d 8.6 (CH3), 21.0 (CH2), 23.2 (CH2CH3), 23.5 (CH2), 25.9 (CH2), 36.3 (CH), 38.8 (SCH2), 39.2 (CH), 49.8 (SCH), 52.1 (2xOCH3), 129.7 (C=C), 135.1 (C=C), 138.6 (C=C), 139.5 (C=C), 167.8 (C=O), 168.5 (C=O).

1 H

 1 NMR (CDCl3, 500 MHz) d 1.44 (d, J = 7.5 Hz, 3H, CH3), 1.49-1.55 (m, 2H), 1.75 (m, 1H), 1.85-2.12 (m, 2H), 2.15-2.40 (m, 4H), 2.55-2.65 (m, 3H), 3.18-3.25 (m, 2H), 3.6 (m, 1H, SCH). 13 C NMR (CDCl3, 125.7 MHz) d 13.6 (CH3), 20.3 (CH2), 22.4 (CH2), 25.5 (CH2), 27.0 (CH2), 27.7 (CH2), 34.0 (CH), 35.2 (CH), 37.0 (CH), 46.9 (CH), 45.7 (CH), 134.0 (Cq), 135.3 (Cq), 171.7 (2xC=O). HRMS (APCI/Q-TOF) m/z: [M+H + ] calculated for C15H18O3S 279.1049, found 279.1037.

1 H

 1 NMR (CDCl3, 400 MHz) d 1.21 (d, J = 7.1 Hz, 3H, CH3), 1.55-2.1 (m, 4H), 2.15 (m, 2H), 2.43 (m, 2H), 2.95 (m, 2H), 3.15 (m, 2H), 3.30 (m, 1H), 3.76 (6H, 2xOCH3). 13 C NMR (CDCl3, 100.6 MHz) d 20.3 (CH2), 22.1 (CH3), 25.0 (CH2), 26.5 (CH2), 26.6 (CH2), 26.9 (CH2),

1 H

 1 NMR (CDCl3, 400 MHz) d 1.67 (m, 1H), 3H), 2H), 2.33 (m, 1H), 2.64 (m, 1H), 3.21 (m, 1H), 3.66 (m, 1H, SCH), 4.41 (m, 1H), 5.19 (s, 1H, CHPh), 10H). 13 C NMR (CDCl3, 100.6 MHz) d 18.8 (CH2), 23.9 (CH2), 27.1 (CH2), 27.0 (CH2), 28.3 (CH2), 37.2 (CH), 55.5 (CH), 59.2 (CH), 125.6 (CH), 126.8 (Cq), 128.1 (CH), 128.8 (2xCH), 128.9 (2xCH), 129.0 (CH), 129.1 (2xCH), 131.2 (Cq), 131.8 (Cq), 136.7 (Cq), 150.4 (C=O), 154.9 (C=O). HRMS (ESI/Q-TOF) m/z: [M+Na + ] calculated for C24H23N3O2SNa 440.1403, found 440.1436.

,d)A 6(a,d)B Scheme 6. Hetero

	S	( ) n	R	MeO 2 C	D3	CO 2 Me	S	( ) n	R	+	S	( ) n	R
	3a,d			toluene, 80 °C, overnight 6(a		CO 2 Me CO 2 Me		CO 2 Me CO 2 Me
						R = Et, n = 1: 6aA/ 6aB (10/3 ratio, 65%)
						R = Me, n= 2: 6dA/ 6dB (2/1 ratio, 54%)

-Diels-Alder reactions of exo-bicyclic dienes 3 with D4 (ratio diene/D4 1:2)

  NMR (CDCl3, 500 MHz) d1.49-1.68 (m, 2H),1.85-2.12 (m, 6H), 2.48 (m, 1H), 2.57 (m, 1H), 2.68 (m, 1H), 3.42 (t, J = 8.5, 1H), 3.71 (bs, 1H), 3.64 (m, 1H), 3.84 (dd, J = 9.0, 4.2 Hz, 1H), 7.31-7.39(m, 3H),7.44-7.46 (m, 2H). 13 C NMR (CDCl3, 125.7 MHz) d 20.4 (CH2), 22.8 (CH2), 25.4 (CH2), 27.8 (CH2), 27.7 (CH2), 35.4 (CH), 36.6 (CH), 45.6 (CH), 46.1 (CH), 47.2 (CH), 134.3 (Cq), 130.2 (2xCH), 128.5 (2xCH), 127.6 (CH), 136.9 (Cq), 135.2 (Cq), 171.0 (C=O), 171.5 (C=O). HRMS (APCI/Q-TOF) m/z: [M+H + ] calculated for C20H21O3S 341.1206, found 341.1216.

1 H

Acknowledgements

We thank the ''Centre National de la Recherche Scientifique (CNRS)'' and the University of Strasbourg (IdEX Unistra grant for T. C.) for financial support. We thank Dr. Bruno Vincent (GDS 3648) and Dr. Karolina Flidrova (PACSI, GDS 3670) for NMR analyzes, Dr. Lydia Karmazin and Corinne Bailly (GDS 3648) for X-ray analyses, Dr. Delphine Garnier (PACSI,

Author Information

Corresponding Author* E-mail: gulea@unistra.fr


domain: chim chim.cata sde

text:
Thomas Pigeon

Céline Chizallet

P Raybaud
email: pascal.raybaud@ifpen.fr

Revisiting -alumina surface models through the topotactic transformation of boehmite surfaces

Keywords: gamma-alumina, boehmite, topotactic transformation, density functional theory, surfaces, hydroxyls

The rational understanding of -alumina (-Al2O3) supported catalysts requires an ever more improved atomic scale determination of the support's surface properties. By using density functional theory (DFT) calculations, we show how the structural and energetic surface properties of alumina crystallites intrinsically depend on its synthesis pathway. Considering the case study of the topotactic transformation of boehmite (-AlOOH) into -Al2O3 taking place during calcination, we propose a methodology to mimic this pathway by reconstructing relevant slabs of boehmite into -alumina slabs following 3 steps : dehydration, contraction/translation and Al migration into spinel or non-spinel sites. On the one hand, we confirm the reliability of some earlier (1 0 0), (1 1 0) and (1 1 1) surface structures determined by standard bulk cleavage approach. Moreover, we find new -alumina surfaces harboring Brønsted acid sites (BAS) and Lewis acid sites (LAS) of specific local structure. More strikingly, we find that the basal (1 1 0) b surface of alumina inherited from the (010) basal surface of boehmite, exhibits a larger number of isolated µ2-OH groups than the lateral (1 1 0) l surface. For the lateral (1 1 0) l orientation (respectively (1 1 1) orientation), four (respectively three) thermodynamically competing surfaces are identified, including models earlier proposed. These results are induced by crystallites finite size and morphology effects during the topotactic transformation. Thanks to thorough comparative analysis of morphology and nature of BAS and LAS as a function of thermal treatment and water pressure for each surface, we identify coherent chemical families of surfaces across the main crystallographic orientations. These features open the door to a better differentiation of the reactivity of the basal alumina surfaces from the lateral ones.

Introduction

Alumina (Al2O3) is an inorganic oxide material existing as various polymorphs. Among these, the γ-polymorph is a chemically versatile transition alumina of high surface area exhibiting interesting Brønsted and Lewis acid-basic sites. [START_REF] Euzen | Handbook of Porous Solids[END_REF][START_REF] Busca | [END_REF] Hence, the γ-alumina surface sites are very useful to promote its intrinsic acid-basic catalytic reactivity [START_REF] Busca | [END_REF] as expected for biomass conversion, [3] or to allow the anchoring and dispersion of metallic active phases of various forms such as organometallic, [4] reduced, [START_REF] Boudart | Catalysis by Supported Metals[END_REF][START_REF] Batista | [END_REF] oxidized [7] or sulfided [START_REF] Toulhoat | Catalysis by Transition Metal Sulfides. From molecular theory to industrial applications[END_REF] ones. In the case of Mo sulfided active phase, γ-alumina is considered as the most widely used support, where the nature of the exposed surfaces was shown to influence key physico-chemical features [START_REF] Bara | [END_REF][10][11] and catalytic activities [12] of the active phase. The location of inorganic dopant (phosphates) or metallic aggregates was also proposed to be surface sensitive. [13,14] Hence, the continuous improvement of atomistic models of γ-alumina surfaces are necessary for the better control of the catalyst properties from the preparation steps [15] to the reaction conditions. [16] In order to better characterize the local surface structure of these sites, numerous analytic experiments (IR, NMR, gravimetry) [17][18][19][20][21][22][23] and theoretical investigations [24][25][26][27][28] have been undertaken. The γ-polymorph is a transition alumina metastable within a specific temperature range below ~750°C. At higher temperatures, its crystallographic structure may evolve toward other polymorphs with lower surface area. [START_REF] Euzen | Handbook of Porous Solids[END_REF] One of the most industrially used synthesis pathway of -alumina is the dehydration of the boehmite precursor (-AlOOH): following this thermal treatment process, the -alumina polymorph is formed at ~450°C. [START_REF] Euzen | Handbook of Porous Solids[END_REF] The -AlOOH → -Al2O3 transformation is topotactic [START_REF] Euzen | Handbook of Porous Solids[END_REF][29][30][31] which means that simple relationships exists between the crystallographic axes of -AlOOH and those of -Al2O3. Such a topotactic transformation was also invoked for the synthesis of other materials such as iron oxides from their hydroxide precursor, e.g. -FeOOH goethite and -FeOOH lepidocrite into -Fe2O3 hematite and -Fe2O3 respectively. [32][33][34] Moreover, the shape of the individual platelets of both materials is conserved, as represented in Figure 1a for one hypothetical shape of boehmite platelet. Indeed, the shape of the boehmite and resulting alumina particles may depend on the boehmite synthesis conditions (such as pH or presence of organic surfactant). [35] For the present study, we will refer to this topotactic dehydration process. Obviously, other processes for the synthesis of alumina may be used such as oxidation of Al foil [36] or mechanochemistry [37] which transformation process might differ from the topotactic one. Figure 1a also shows the correspondence between the (ℎ 𝑘 𝑙) facets of the starting boehmite material and those of alumina, according to the topotactic transformation. Since the earlier studies on the γ-alumina structure suggested that it may be similar to a spinel, [31,38] the Miller indices for alumina facets reported in Figure 1 are chosen according to this reference. The fact that alumina is not a perfectly defined crystalline material makes its structural determination difficult, even if theoretical models have been proposed which improved our understanding of this material. Indeed, thanks to the possible applications of density functional theory (DFT) to -alumina supported catalytic systems of growing complexity, [16,39,40] the knowledge of this structure has been pushed forward, even if open questions remain. [41,42] Two different families were proposed for the γ-Al2O3 bulk structure: the defective spinel-like models in which only spinel positions are allowed [27,43,44] and non-spinel ones in which both spinel and non-spinel positions. [30,45] The non-spinel model earlier proposed by Krokidis et al. [30] is based on an ideal mechanism of dehydration of boehmite and proposed to involve three key steps: dehydration of boehmite, translation/contraction of layers and Al migration from octahedral into tetrahedral sites. For the present study, we will use the latter, assuming that this topotactic process can be applied to build models for the (ℎ 𝑘 𝑙) surfaces of γ-alumina starting from surface models of boehmite, whereas the initial model of Krokidis et al. only considered the transformation of bulk boehmite into bulk γ-Al2O3. [30] The true determination of these surfaces is critical for predicting the energetics of the particles (surface energy), which is a key descriptor of the reactivity and stability of the nanomaterials. In particular, the surfaces bear the Brønsted or Lewis acid sites (BAS/LAS) involved in reactivity. BAS are constituted of aluminols (Alx-OH), hydroxyl groups bonded to one or multiple surface LAS (aluminum ions) with flexible coordination numbers (4, 5, 6 when hydrated). Their reactivity depends on their local architecture depending itself on their location on the γ-alumina facets. [20] More recently, some edge models have also been proposed and revealed alternative accessible sites of alumina. [26] To simulate and investigate these surface sites by periodic density functional theory (DFT) approach, the most widely applied method in computational surface science is to cleave the bulk model of the material along the desired (ℎ 𝑘 𝑙) crystallographic orientations. This method was applied to the determination of -alumina surfaces from models of -alumina bulk by numerous previous studies. [24,25,27,44,46] However, this theoretical approach may be questioned when dealing with topotactic transformation such as the one depicted in Figure 1a, where crystallographic parentage affects not only the bulk structures of the starting material and final one, but also the shape and the surface structures.

As illustrated in Figure 1, the experimentally observed surfaces of -alumina particles are the (0 0 1), (1 1 0), (1 1 ̅ 0), (1 ̅ 1 1) and (1 ̅ 1 1 ̅ ) and their negative counterparts. The symmetry rules of the perfect spinel imply that all the surfaces having the same colors in Figure 1b are equivalent. If a topotactic transformation from common boehmite platelets (Figure 1a)

is not used to synthesize -alumina and if the spinel symmetry holds, the equilibrium shape of the -alumina particles would be isotropic such as illustrated in Figure 1b. Such models have been proposed by previous studies [27,42,47] without considering that the synthesis pathway involved a topotactic transformation generating -alumina from its parent boehmite material.

On the contrary, the alumina surfaces by Digne et al. [24,25] were based on a bulk structure constructed on the basis of the topotactic transformation of the boehmite into alumina as suggested by Krokidis et al. [30] This method is illustrated by the top path of Scheme 1 where the topotactic transformation is applied to 3D-periodic boundary conditions of the boehmite bulk cell (infinite material) and leads to the 3D-cell of bulk -alumina. Then, it is followed by the building of the slab model obtained by directly cleaving the alumina bulk in (ℎ 𝑘 𝑙)

directions. In this case, no obvious distinction was made for the various possible surfaces belonging to one given (ℎ 𝑘 𝑙) family. In addition, it did not take into account the effect of finite size of the starting boehmite particles on the topotactic transformation mechanism. Considering the platelet morphology (Figure 1a) often invoked for boehmite nano-materials, [48] the (0 1 0) corresponds to the basal facet while (0 0 1), (1 0 0), and (1 0 1) surfaces correspond to lateral ones. The various (1 1 0) surfaces of -alumina are thus inherited from two parent boehmite surfaces which are not identical: the basal (0 1 0) and the lateral (1 0 0) surfaces. So, it may be legitimately questioned why the two daughter alumina surfaces, called in what follows

(1 1 0) l (label l stands for lateral) and (1 1 0) b (label b stands for basal), should become identical (Figure 1a) after a topotactic transformation (since the spinel symmetry of Figure 1b is not recovered).

In the present work, we investigate an alternative way of building such surface models (bottom path in Scheme 1). We will consider the initial boehmite slab models representing the most commonly exposed boehmite surface (Figure 1a) and we will build the alumina surfaces by applying the topotactic transformation to the slab models explicitly (being inspired by the Krokidis process, [30] but starting from boehmite slab models instead of boehmite bulk). The starting boehmite surfaces considered here will be the inequivalent (0 1 0), (0 0 1), (1 0 0), and (1 0 1) surfaces (Figure 1a). Their various possible hydration states were thoroughly investigated by DFT methods. [35,49] Our work will analyze how the structural and energetic properties of the (1 1 0) b , (1 1 0) l , (0 0 1), (1 1 1) -alumina surfaces may differ according to the two approaches described in Scheme 1. In particular, we will quantitatively compare surface energies and nature of sites (BAS and LAS) exposed on each surface, as a function of relevant operating conditions (temperature, water partial pressure). For some of these orientations, we will propose surface models which differ from previous proposals, and which are likely to provide new understanding on surface acido-basicity of -alumina.

Scheme 1: Two ways of forming γ-Al2O3 surfaces involving the topotactic transformation from boehmite. Top path: topotactic transformation applied to the bulk, bottom path: topotactic transformation applied to the slabs. The topotactic transformation method is taken from Ref.

[30]

Methods

The study has been conducted at the quantum level, on the basis of periodic Density Functional Theory (DFT) calculations. We used a plane-wave basis set with a 400 eV energy cutoff. We used the projector augmented wave (PAW) method for the pseudopotentials [50] as implemented in the Vienna Ab-initio Simulation Package (VASP). [51,52] The exchange correlation functional used was the one proposed by Perdew, Burke and Ernzerhof (PBE) [53] with density dependent dispersion correction according to dDsC formalism. [54,55] The energy of the reference water molecule has been computed at the same level of approximation (PBE-dDsC) in a cubic box of 10 Å at the gamma point. As expected, the use of dispersion corrections induced a systematic positive shift of surface energy values with respect to the previous work by Digne et al. [24,25] A Gaussian smearing was used with a width of 0.05 eV and the convergence criterion for the SCF cycles was set at 10 -7 eV. The non-spinel bulk model from ref. [30] had been fully relaxed with a 2x2x4 gamma point centered K-point grid and a 800 eV cutoff for the plane waves and a convergence criterion for the structure of 10 -5 eV. The K point grid density for the slabs were identical to the bulk except in the direction in which the vacuum was introduced where it was set to 1. To build the slabs in the (1 1 1) orientation, the bulk structure has been firstly re-optimized in a reoriented cell containing 16 Al2O3 units with a 4x4x4 gamma point centered K-point grid. Then, as for all slab supercells, the relaxation of the atomic positions only has been performed with a 400 eV cutoff, before and after cleavage of the slabs. The convergence criterion for geometric relaxation was set to 0.01 eV Å -1 on each atom of the bulk and slab models. The atomic coordinates of the most relevant atomic structures of -alumina surfaces are available from [START_REF] Pigeon | Atomic structures of the gamma-alumina surfaces[END_REF].

The thermodynamic diagrams were computed assuming that the only temperature dependent value was the water free energy, through its translational and rotational enthalpy and entropy. For selected systems, the vibrational components were taken into account both for gas phase water and hydroxylated slabs and showed a negligible influence on the computed surface dehydratation temperatures (Supporting Information SI.1). As we only computed free energy differences, this is equivalent to assuming that vibrational contributions balance out for the competing structures which would exhibit similar vibrational modes. Therefore, we compare the stability of the various structures on the basis on the electronic energy calculated at 0 K.

The water adsorption free energy ∆ 𝐴𝑑𝑠 𝐺 and the surface energy 𝛤 (𝑘ℎ𝑙) were computed according to equations (1) and ( 2) respectively. In some cases, we also considered dehydration free energies which are computed by the same equations given ∆ 𝐴𝑑𝑠 𝐺 = -∆ 𝑑𝑒ℎ𝑦𝑑𝑟𝑎𝑡𝑖𝑜𝑛 𝐺.

where 𝐴 stand for the surface area exposed on each side of the slabs, 𝑁 the number of bulk units in the slab and 𝑛 the number of water molecules adsorbed. ∆ 𝐴𝑑𝑠 𝐺 stands for successive hydration energies.

The surface energies were computed according to equation ( 2), to determine bulk energy we computed it separately in a cell having the same orientations as the slab of interest. We assumed that vapor water is an ideal gas and thus included its rotational and translational free energies in gas phase. We must underline that all thermodynamic diagrams reported in this study are only valid for the domain where water can be considered in a gaseous state. For that reason, we recall in all (T, p) diagrams the liquid/vapor, solid/vapor and solid/liquid equilibria to identify the frontiers beyond which our thermodynamic model is not valid anymore. For the domain where water exists in liquid or solid state, this would require explicit or implicit simulation of water as undertaken in some dedicated studies with more sophisticated approaches beyond the scope of present work. [11,[START_REF] Ngouana-Wakou | [END_REF]58] 3. Results

(𝟏 𝟏 𝟎) 𝐛 surface models

The first part of our work consists in applying the two construction methods explained previously (Scheme 1) to build the alumina surfaces. If we focus first on the (1 1 0) family of surfaces exposed on alumina particle, the corresponding slabs can be obtained by a topotactic transformation of the (0 1 0) slab of boehmite according to the mechanism proposed in the bottom path of Scheme 1. As the (0 1 0) surface is generally the lowest energy surface exposed by boehmite particles, it is also the predominant one considered as the basal surfaces embracing the boehmite platelets. [35,49] Since the boehmite to γ-alumina transformation is topotactic, the alumina surface and its corresponding slab created from the boehmite (0 1 0) surface (slab) necessarily consecutive in reality, some of these may take place jointly. A preliminary question is whether the dehydration of the surface occurs before or after the dehydration of the interlayers. As described in Supporting information SI.2, we found that the surface dehydration energies are twice larger than the bulk dehydration energy. This dehydration of interlayer is further stabilized by the translation/contraction steps involved in the topotactic transformation of boehmite, before Al migrations occur in the bulk (Figure 2).[30] Hence, we will assume that during the first dehydration step, the bulk transforms first.

Following the internal slab reconstruction, we considered the possible migrations of Al atoms that can take place on the surface itself, which could lead to the surface reconstruction.

Being inspired by the surface migration of Al atoms proposed by Wischert et al. [46], we investigated all the possible surface migrations and found that only two of them are possible to avoid too short Al-Al distances (Figure 3). For this reason, the two Al migrations represented by both blue arrows (respectively by green arrows) must occur simultaneously, while the green migrations must occur independently from the blue ones. The two types of migrations lead to two distinct surfaces induced by the coordination of sub-layer oxygen atoms (Supporting Information SI.3). Moreover, since the orientation of the bridging hydroxyls has an impact on the stability, eight surface configurations have optimized. Among all possible configurations detailed in Supporting Information SI.3, the most stable one is illustrated in Figure 3b. oxygen, grey balls: aluminum, white balls: hydrogen. The axis system corresponds to the boehmite Cmcm orientation so the normal to the surface is given by y.

At this stage, it is required to investigate the stability of this surface as a function of temperature and water pressure as it was proposed by Digne et al. for the original alumina

(1 1 0) surface models. [24,25] For that we systematically screened the removal of water molecules, and identified the thermodynamically most favorable hydrated states of this surface.

The resulting surface energy curves (Figure 4a) show that this (1 1 0) b surface requires a treatment at high temperature (T> 850 K) even at low water pressure (< 10 -6 bar) to be fully dehydrated. At water pressure higher than 10 -2 bar, the surface remains hydrated (Figure S5).

As it will be discussed later in detail, the fully hydrated surface exhibits an important number of isolated (non H-bond donor) bridging OH-µ2-(AlVI,AlVI). No other alumina surface model proposed so far, exhibits such amount of stable OH-µ2 species directly reminiscent of the boehmite (0 1 0) surface. As we will discuss it in the next section, this behavior differs from the (1 1 0) surface model earlier proposed by Digne et al. [24,25] Thanks to the topotactic mechanism directly applied to -alumina bulk as proposed by

Krokidis, [30] it is also possible to identify the (1 1 0) direction in the alumina bulk corresponding to the basal surface inherited from the (0 1 0) direction of the boehmite. [49] This protocol follows the top part of Scheme 1. There is only one possibility to construct a stoichiometric and symmetric slab (Supporting information SI.4). As it is not straightforward to calculate the surface energy of asymmetric slabs, we did not consider them. This is not the cleavage orientation that was formally chosen by Digne et al., [24,25] the later corresponding to the lateral (1 1 0) orientation, developed in the following section. After cleaving the bulk along the direction corresponding to the basal (1 1 0) orientation, the dehydrated surface is composed of two AlIV-Ss sites, two O(AlIV-Td)(AlIV-Ss) and two O(AlIV-Ss)(AlVI-Oh)2 (Figure S6).

Notably, the first index after an Al atom is its coordination number and the second its VSEPR geometry (Oh: Octahedral, Td: Tetrahedral, Ss: Seesaw, SP: Square pyramidal). The thermodynamic diagrams (Figure 4b

(𝟏 𝟏 𝟎) 𝐥 surface models

As shown in Figure 1, the fully hydrated (1 0 0) boehmite surface [35,49] leads to the genesis of a (1 1 0) γ-alumina surface during the topotactic transformation. As the (1 0 0) surface is a lateral facet of the boehmite particles, we will call the corresponding alumina surface as (1 1 0) lateral, and label it as (1 1 0) l . Following the mechanism described on the bottom path of Scheme 1, the dehydration of the boehmite slab is presented in Figure 5. As detailed in Supporting information SI.5, four different surface models can be obtained by this method, depending on the type of bulk and surface Al atoms migrations involved during the last step of the transformation. Unlike the (1 1 0) b surface, our analysis reveals that this approach leads to the same models as the approach going through bulk alumina (top path of Scheme 1) that we will describe in what follows. Indeed, building a surface model corresponding to the same orientation by cleaving the bulk -alumina model leads to considering four distinct slab models as illustrated in Figure 6.

The slab thicknesses are adjusted so that the slabs are symmetric. The previous DFT calculations on this family of (1 1 0) surfaces compared the energies of the dehydrated surfaces at 0 K to identify the most favorable termination. [24,25] In the present work, we propose to go further by comparing hydrated surface models also. Actually these four models could be split in two main groups based on the nature of surface hydroxyls, directly related to the surface Al arrangement: two models labelled "L" for which the surface AlIV-Ss are aligned in the y direction (using boehmite's axes, see Figure S8), and two models labelled "A" for which they are alternated. In addition, two Al distributions in subsurface may exist for each model type, labelled as Lx and Ax (x=1 and 2). In particular, the A1 surface corresponds to the one that has been studied by Digne et al. [24,25] and Wischert et al. [46] We built the full thermodynamic diagrams for the four models, accounting for their gradual hydration-dehydration structures. Figure S10 shows that the Ax surfaces exhibit a continuous hydration/dehydration process (from 0 to 18 OH/nm 2 ). They stepwise adsorb or desorb water as a function of the thermal conditions and behaves like a sponge. By contrast, the Lx surfaces have a constant hydration state (12 OH/nm 2 ) over a large temperature domain and exhibit a discontinuous hydration/dehydration process, losing 9 OH/nm 2 at once above 800 K. Considering the envelope of surface energy minima (with minimization over the hydroxyl coverages) for each surface, Figure 7 shows that all models are similarly stable in a rather large domain of reaction conditions. As previously shown by Digne et al. [24,25] we confirm that the non-hydrated A1 surface (as cleaved) is the most stable at 0 K. When considering hydration effect, the A2 surface would be slightly preferred at very low T (<200 K). However, since this temperature is below the domain of vapor water, we cannot fully trust our thermodynamic model which would require the simulation of liquid water. The L1 surface appears as slightly more stable from 150 K to 700 K (at 𝑃 𝐻 2 𝑂 =10 -6 bar), while the A1 (and to a less extent A2) surface becomes more stable above 700 K (including calcination conditions).

However, given the DFT accuracy and assumptions on vibrational components of enthalpy and entropy, various surfaces are competing. This trend remains globally true whatever the pressure (Figure 7b), although the A1 surface is destabilized with respect to L1 at high pressure (> 0.1 bar).

(𝟏 𝟏 𝟏) surface models

The topotactic transformation of boehmite (1 0 1) surfaces leads to the (1 1 1) alumina surfaces (Figure 1). The (1 0 1) and (1 0 1 ̅ ) boehmite surfaces are equivalent but a priori, we cannot assume that this will be the same for the inherited -alumina surfaces. As for the surfaces previously studied, depending on the choices made for the Al migrations steps, different surface models can be obtained. The interesting part here is that depending on these choices either a

(1 1 ̅ 1) or a (1 ̅ 1 1) surface will be built. These two surfaces are not equivalent in the nonspinel bulk model. We arbitrarily decided to name these different orientations: Dx for (1 1 ̅ 1)

and Px for (1 ̅ 1 1). Figure 8 illustrates the dehydration steps for the boehmite (1 0 1) slab leading to the D1 model. With this method we can build two models in direction D (which are symmetric if we start from a slab with four layers of Al atoms) and four models in direction P (which are symmetric if we start from a slab with five layers of Al atoms). We then compare these models to the ones obtained from the extended alumina bulk structure presented in Figure 9 illustrating the construction of Dx model ((1 1 ̅ 1) spinel orientation) and Px models ((1 ̅ 1 1) spinel orientation) slabs using bulk alumina structure as a basis.

(𝟎 𝟎 𝟏) surface models

As a preliminary remark, we underline that according to the spinel indexation used in previous works, [24,25] the (0 0 1) surface was considered to be equivalent to the (0 1 0) and

(1 0 0) surface. According to the revisited indexation explained in Figure 1, the (1 0 0) surface is called here (0 0 1) surface.

Due to the possible translation of the boehmite layers in the direction normal to the (0 0 1) surface, and depending on the layer stacking configuration of boehmite, the slab ends up with either a flat or a stepped surface (with stacking fault). Figure 11 illustrates the case of a stepped (0 0 1) boehmite surface as a starting structure. If such a stepped boehmite surface is assumed, a flat alumina (0 0 1) surface (similar to the one proposed by Digne et al. [24,25]) can be easily recovered according to the topotactic mechanism applied to the slab as shown in In this case, the last Al migration step present different possibilities leading to four different models which cannot be all obtained by simply cleaving the -alumina bulk as described in Supporting Information SI.7. Hence, in this case, the two methods proposed in Scheme 1 are not strictly equivalent. The most stable surface model between the four investigated is, however, exactly the same as the (1 0 0) surface one proposed by Digne et al., [24,25] with similar OH coverages stability domain as previously published.

Discussion

Impact of the topotactic transformation

Our previous results highlight one striking structural difference between the basal

(1 1 0) b and lateral (1 1 0) l surfaces of alumina. Until now the available model, [25] considered to represent any kind of (1 1 0) facets, was the (1 1 0) l A1 surface using the notation of the present work. Considering the two methods described in Scheme 1 to generate γ-alumina surface models, we were able to build two distinct (1 1 0) b basal models. On top of being linked to its precursor, the model built through dehydration of a boehmite (0 1 0) slab is more stable than the one that could be proposed by direct cleavage of the alumina bulk.

Concerning the (1 0 0) boehmite surface which dehydrates into a 'lateral' (1 1 0) surface, we showed that the two methods described in Scheme 1 are strictly equivalent. Pushing further the study of alternative (1 1 0) l terminations, we identified three alternative surface models that are completing the description of this (1 1 0) l surface:

(1 1 0) l A2, (1 1 0) l L1 and (1 1 0) l L2.
The Lx models present some isolated µ2-OH really similar to those observed on the (1 1 0) b model. The (1 1 0) l A2 is really similar to the model labeled (1 1 0) l A1 (corresponding to the one earlier proposed [25]), while the (1 1 0) l L2 (similar to (1 1 0) l L1) differs from the alignment of the AlIV sites.

Finally, for the (1 1 1) and (0 0 1) γ-alumina surfaces, the two methods are only partially equivalent, with differences due to slab's stoichiometry, symmetry and stacking conditions. We did not identify an improved model for the (0 0 1) surface with respect to the one already existing though some further investigations could lead to alternative models (including stepped surfaces). Concerning the (1 1 1) surface, dehydration of (1 0 1) boehmite models allowed to recover the existing model, [25] labelled as (1 1 1)D1, and to propose two alternative models called (1 1 1)D2 and (1 1 1)P1_2.

From a methodological point of view, these findings illustrate how the theoretical mechanisms used for describing topotactic transformation should include the finite size character of the precursor boehmite nano-crystallites.

Surfaces stability and morphology as a function of experimental conditions

From an application point of view, it is interesting to compare first the energetics of the four more relevant surfaces constructed in the present study (Figure 12). Indeed, the surface energy may be considered as a descriptor for the intrinsic reactivity of the surfaces generated through topotactic transformation. While the (0 0 1) surface exhibits the lowest surface energy over a large temperature range, it is not the predominant one and represents at most 20%, according to the rules of topotactic transformations. [29,59] As previously discussed by Digne et al. [25], we thus confirm that the morphology of the -alumina particles obtained by topotactic transformation after calcination at ~800 K, is obviously metastable. It is interesting to notice first that even if the (1 1 0) b surface becomes slightly more stable than (1 1 0) l for temperature greater than 400 K (for a water pressure of 10 -6 bar), the (1 1 0) b surface exhibits a higher surface energy than the (0 0 1) surface. So, the newly obtained (1 1 0) b surface does not strongly modify the stability ranking at 800 K. Moreover, since the (1 1 1) and (1 1 0) l surfaces exhibit the higher surface energies, we may suspect that these facets are prone to be involved in the sintering process of the -alumina platelets. If we now consider a lower temperature regime (~300 K), Figure 12 reveals that the surface energy ranking is completely different: the (1 1 0) b surface energy becomes now slightly higher than the (1 1 0) l surfaces. This effect is due to the energy gain of water adsorption on the (1 1 0) l and to a less extent to the (1 1 1) surfaces which exhibit more undercoordinated Al sites than the (0 0 1) surface (as discussed later). Hence, depending on the synthesis (T, P) conditions or whether a topotactic transformation is involved or not, the relative stability of facets is impacted which may thus modify the equilibrium morphology.

Interestingly, when increasing the water pressure, the stability domain of the (0 0 1) and shrinks at the profit of the (1 1 0) b , the (1 1 0) l or the (1 1 1) surface depending on T and 1.

The morphology trend is quantified in Figure 13 where the Gibbs-Curie-Wulff morphology [60,61] was determined for three relevant temperatures (350, 550 and 750 K) and two water pressures considering two different assumptions. The first one assumes that a topotactic process leads to a parallelepiped like morphology are inherited from boehmite crystallite, i.e. exhibiting the (1 1 0) b facet (also inherited from (0 1 0) boehmite) as a basal plane, all other facets being lateral (1 1 0) l , (0 0 1) and (1 1 1) ones, normal to the basal one.

Notably, for a strictly topotactic transformation, the equilibrium shape should be deduced from the surface energy of boehmite, and not that of γ-Al2O3. Using the DFT calculated surface energies of -alumina as defined in Figure 12 a), the basal (1 1 0) b surface represents 32-36% whatever the (T, P(H2O)) conditions (Table 1). The lateral (1 1 0) l is also rather constant (16- 20%). By contrast, the relative proportions of the two other lateral facets are much more sensitive to the conditions. For the lower temperature (350 K) and/or higher water pressure (1 bar), the proportion of the most hydroxylated (1 1 1) facets are predominant (~40%) at the detriment of the (0 0 1) lateral facet (~5%). As the temperature increases and/or water pressure decreases, the surface energy of the (0 0 1) is the one that increases the least, so that its proportion is enhanced, reaching ~37% for T=750 K and P(H2O)=10 Table 1. Proportion (%) of each facet for the parallelipedic morphology as a function of temperature and water pressure (corresponding to Figure 13).

In Supporting Information SI.8, we also discuss different morphologies obtained by two different methods which are not based on topotactic transformation but rather on -alumina and spinel bulk equilibrium shape. For T=550 K or P(H2O)=1 bar, it is observed that the shape is ovoid-like for -alumina bulk which is at variance with the one obtained for a pure spinel bulk (Figure S14) that leads to a more spherical shape at 550 K. Interestingly, parallelepipedic and ovoidal shapes have been observed experimentally by transmission electron microscopy (TEM) [26], which may imply that a purely defective spinel structure for -gamma polymorph must be ruled out as discussed in previous works. [26,41,45,62] As a corollary (valid for all morphologies), we observe that increasing the water pressure from 10 -6 bar to 1 bar induces a morphology change similar as for a temperature decrease from 750 K to 550 K, which is interpreted as an effect induced by the evolution of surface hydration state.

Such morphology changes may also occur also during catalytic reactions involving water formation as a byproduct at a given temperature. At T~500-550 K corresponding to some biomass conversion or Fischer-Tropsch synthesis process, at low water pressure (low conversion), the (0 0 1) facet would exhibit 26% (Table 1). When water is produced in the course of the reaction at higher conversion, the (1 1 1) facet becomes thermodynamically favored (40%) while the (0 0 1) is destabilized (5%).

As discussed in the next section, the hydroxyl coverages and sites exposed by these facets are also significantly different, so their reactivity might change impacting either the overall catalyst activity or the support stability as reported by many experimental studies. [63][64][65]

Nature of the surface sites

Our work has also significant implications for the surface properties of -alumina prepared from boehmite precursor, following a topotactic transformation during the calcination process.

We discuss in what follows how different BAS (OH groups) and LAS (exposed aluminum ions) can be identified on the different surface models. The various types of sites for the most relevant models are reported in Table S6, by choosing various sets of experimental conditions from low temperature close to mild thermal treatment such as drying conditions (400 K) to harsher thermal treatment such as calcination conditions (700-800 K). These conditions may also correspond to various reaction conditions applied during chemical processes using alumina supported catalysts. [3,4,7,[START_REF] Toulhoat | Catalysis by Transition Metal Sulfides. From molecular theory to industrial applications[END_REF][START_REF] Boudart | Catalysis by Supported Metals[END_REF] The vapor pressures were also chosen from 10 -2 to 10 -6 bar to screen various possible water containing environment.

As expected, and already shown by previous studies, Table S6 shows that the hydroxylation state (number and type of OH) and its thermal evolution clearly depend on the type of surfaces. (1 1 1)D1 are removed at mild temperature. One small exception to this rule is the (1 1 1)P1_2

surface which exhibits µ2-and µ3-OH groups. However, since the hydroxyl concentration is very high (14.8 OH.nm -2 ), this induces a destabilization of µ2-OH groups which recombine with proton of µ3-OH groups and leave the surface at mild temperature.

Among all the surface studied here, the family of (1 1 1) surfaces is the one which keeps the highest concentration of BAS (from 7.3 to 9.8 OH.nm -2 ) even for high temperature and/or low vapor pressure (Figures S10). The (1 1 0) l A1 model (Figure 14 d ande) is identical to the one proposed by Digne [24] and Wischert [46] while the (1 1 0) l A2 is similar. The three other models (1 1 0) b (Figures 14 g,i) (1 1 0) l L1 (Figures 14 a,c) and (1 1 0) l L2 are different because they present significantly more OH-µ2-AlxAlx BAS which are not H-bonded to another surface oxygen atom. This high number of isolated µ2-OH groups found on these (1 1 0) surfaces may corroborate observations made by 17 O NMR spectroscopy. [23] We also notice for the (1 1 0) b and (1 1 0) l L1 surfaces a close proximity between isolated µ2-OH groups which also corroborates other observations provided by 1 H-1 H DQ MAS NMR spectra. [START_REF] Taoufik | [END_REF] The isolated µ2-OH protons might be more accessible and more reactive than those involved in H-bonds. They might also play an important role for the Brønsted acidity of this material since the lability of protons will be enhanced with respect to H-bonded species.

Conclusion

By using periodic DFT calculations, we revisited the construction of -alumina surface models by two complementary methods based on the topotactic transformation of the boehmite precursor under thermal treatment process (such as calcination): the standard one, considering the cleavage of a bulk alumina model, and an alternative one, considering the finite size of boehmite crystallites. On the one hand, our work confirms the relevance of the three previous -alumina surface models [24,25] related to the (0 0 1) , (1 1 0) and (1 1 1) crystallographic orientations obtained by the two methods. On the other hand, the alternative method provides three new relevant surface models: (1 1 0) b , (1 1 0) l L1 and (1 1 1)P1_2. These surface models, which are thermodynamically stable as a function of temperature and water pressure, exhibit some new populations in terms of types of hydroxyls with respect to previous models, that could be crucial to better understand γ-alumina surface properties.

In particular, we highlighted the key discrepancy between the basal and lateral

(1 1 0) surfaces. Until now a unique model (labelled (1 1 0) l A1 in our notation) was representing both of them and corresponded to a lateral facet. Thanks to the alternative method, the basal (1 1 0) surface is directly inherited from the (010) basal surface of its boehmite precursor and is highly stable according to its surface energy. Moreover, this (1 1 0) b model exhibits isolated surface µ2-OH (free from H-bonds) that have seldom been found on the other surfaces.

Concerning the (1 0 0) boehmite surface which is transformed into a 'lateral' (1 1 0) γ-Al2O3 surface, we showed that the two methods are strictly equivalent. In both cases, we identified three alternative surface models that are completing the description of this (1 1 0) l surface: (1 1 0) l A2, (1 1 0) l L1 and (1 1 0) l L2. The Lx models present some isolated µ2-OH similar to those observed on the (1 1 0) b model, whereas the Ax models exhibit less isolated µ2-OH.

For the (1 1 1) and (0 0 1) γ-alumina surfaces, the two methods are partially equivalent only, due to slab's stoichiometry and symmetry problems for the slab's construction using the bulk cleavage approach. We did not identify an improved model for the (0 0 1) surface with respect to the one previously proposed. [24,25] However, we observe that the final model might be influenced by stacking fault withing the layers of boehmite which may be the subject of future investigations. Concerning the (1 1 1) γ-Al2O3 surface, the topotactic transformation (101) boehmite slabs allowed to recover the earlier proposed model, (1 1 1)D1 18,19 and to identify a relevant alternative model called (1 1 1)P1_2.

From a methodological point of view, our work demonstrated that the two applied methods for constructing the surfaces: cleavage of -alumina bulk vs. topotactic transformation of boehmite slabs are not equivalent. In the same spirit as the mechanism of Krokidis et al. for building non-spinel -alumina bulk, [30] the topotactic transformation applied to boehmite slabs implies dehydration, layers translation/contraction and Al migration processes leading to stable spinel or non-spinel positions in the inner slabs and at their surface. Moreover, since the topotactic transformation occurs on nano-crystallites of boehmite's precursor, finite size effects induced by these crystallites directly influence the structural filiation of surfaces exposed by the resulting alumina. As a corollary, the present work demonstrates that the simple cleavage of spinel model of alumina bulk to build -alumina surface as sometimes proposed in the literature [27,42,47] is not appropriate to describe the surfaces of alumina when alumina is synthesized through a boehmite calcination process involving the topotactic transformation.

The morphology based on Gibbs-Curie-Wulff construction revealed how the proportion of each facet evolves as a function of (T, P(H2O)) conditions and depending on the synthesis pathway: parallelepipedic and ovoidal shapes have been thus highlighted. In the case of a topotactic transformation, the proportion of the basal (1 1 0) b facet inherited from boehmite remains stable ~32-37% whatever the (T, P(H2O)) conditions considered here. In all cases, among the lateral facets, the (1 1 1) and (1 1 0) facets are predominant at low temperature or at high water pressure, whereas the (0 0 1) is favored at high temperature or low water pressure.

As a first perspective, we suggest that this methodology based on the structural filiation of the precursor slabs should be applied for any material (such as Fe2O3) synthesized through a topotactic transformation of a precursor material. This method is the only way to rigorously determine the structural and energetic features of the surfaces exposed by the final material inherited from the precursor one. As a second perspective, the identification of new families of -alumina surfaces should provide alternative ways to tune the reactivity of the support with respect to organic or inorganic adjuvants from the preparation steps to reaction conditions. Also, these surfaces will provide the opportunity to explore in more detail the nature of alumina edge sites located at the intersection of two neighboring facets, as it was recently initiated for the (1 1 0) l / (0 0 1) edge. [26]

Figure 1 :

 1 Figure 1: a) Topotactic transformation from a boehmite particle (left) to a γ-alumina particle

  is thus the (1 1 0) basal surface (slab), called (1 1 0) b in what follows (Figure1).

Figure 2 :

 2 Figure 2: From left to right are represented the 4 first schematic transformation steps of the

Figure 3 :

 3 Figure 3:a) The two possible surface migrations of Al atoms from octahedral to tetrahedral

  and S7a) reveals that this surface is more hydrated at low T (< 400 K) than the previous one, which leads to hydroxyl groups of µ2-OH-(AlIVAlVI), µ1-OH-(AlVI), µ1-H2O-(AlVI) types at 18 OH.nm -2 (FigureS6 e). It becomes dehydrated at lower T whatever the pressure. However, the comparison of the evolution of surface energies of the two surface models obviously reveals the much greater stability of the (1 1 0)b surface built from the (0 1 0) surface of boehmite over a wide range of realistic experimental conditions (Figure4c). This trend remains true for higher water pressure as illustrated on the (P, T) thermodynamic diagrams where the solid/liquid/vapor equilibria of water are also represented (FiguresS7 b). This shows that the (1 1 0) b model build by cleaving the bulk structure is never stabilized in the domain of vapor water.

Figure 4 :

 4 Figure 4: Surface energy curves as function of temperature at fixed water pressure (PH 2 O =10 - 6 bar) for the (𝟏 𝟏 𝟎) 𝐛 surface. a) Model built from the (𝟎 𝟏 𝟎) boehmite slab, b) model built

Figure 5 :

 5 Figure 5: From left to right are represented the 4 first schematic transformation steps of the

Figure 6 :

 6 Figure 6: Periodic structure of bulk γ-Al2O3 non-spinel model. The structure was multiplied

Figure 7 :

 7 Figure 7: a) Evolution of the surface energy for the (𝟏 𝟏 𝟎) 𝐥 surfaces as a function of temperature at PH 2 O = 10 -6 bar. Each broken line corresponds to one given hydroxyl coverage

Figure 8 :

 8 Figure 8: From left to right are represented the schematic transformation steps of the

Figure 9

 9 Figure9shows that depending on the orientation, 2 families of slabs can be built. Here we

Figure 9 :Figure 9 .

 99 Figure 9: Periodic structure of bulk γ-Al2O3 non-spinel model. The structure was multiplied in

Figure 10 :

 10 Figure 10: Lowest energy envelope of the different surface energies for the (𝟏 𝟏 𝟏) lateral

Figure 11 .

 11 Figure 11.For sake of clarity, we decided to limit here our study to this mechanism leading to

Figure 11 :

 11 Figure 11: From left to right are represented the first 4 schematic transformation steps of the

Figure 12 .

 12 Figure 12. a) Lowest energy envelope of the surface energies for different relevant orientations

  12 b). This implies that the environmental conditions might impact the morphology and type of facets exposed by the -alumina particles due to the preferential dissociative adsorption of water on some facets.

Figure 13 .

 13 Figure 13. -alumina crystallite morphologies deduced from DFT surface energies (Figure 12

  The surfaces (1 1 0) l A1, (1 1 0) l A2, (1 1 1)D2, (1 1 1)P1_2 and to a lower extent (1 1 1)D1 exhibit a rather continuous decrease of the hydroxyl concentrations with temperature increase, whereas the (1 1 0) b , (1 1 0) l L1 and (1 1 0) l L2 surfaces reveal a more discontinuous one and refrain the release of water till high treatment temperature. These continuous/discontinuous trends are also clearly illustrated in Figures14 b, e and hwhere the (P, T) diagrams of OH coverages are plotted for the three relevant (1 1 0) surfaces belonging to these 2 families. The discontinuous trend could not be found by previously published sets of (1 1 0) models and it is intrinsically linked to the coordination number of OH groups and of the Al sites to which they are bonded. µ2-OH (OH coordinated to two Al sites) and µ1-OH groups bonded to AlIV site are predominant on the surfaces (1 1 0) b , (1 1 0) l L1 and (1 1 0) l L2, and are stable at higher temperature and/or lower vapor pressure with respect to other surface orientations. By contrast, µ1-OH or µ1-OH2 bonded to AlVI sites present on the (1 1 0) l A1, (1 1 0) l A2, (1 1 1)D2, and

  They exhibit a high number of µ3-OH and µ2-OH BAS which may explain their intrinsic stabilities. These surface hydroxyls might present a high Brønsted acidity, due to the great lability of proton attached to highly coordinated O atoms such as of the µ3-OH-(AlVIAlVIAlx) on the (1 1 1)P1_2 surface. At high temperature, they also exhibit Lewis acidity borne by AlV-SP sites. Conversely, as it was already observed by Digne et al.[25], the (0 0 1) surface loses OH groups at low temperature and gives raise to Lewis acidity borne by AlV-SP site. The family of (1 1 0) surfaces (either lateral or basal), behaves intermediately and exhibits OH BAS with concentration of 3 to 6 OH nm -2 even at high temperature and low vapor pressure. The departure of OH groups induces the formation of LAS, the nature of which depends whether it is located on a (1 1 0) l or (1 1 0) b surface, as discussed in what follows. The comparison of the relevant local structures of the (1 1 0) b and (1 1 0) l models is illustrated in Figure 14.

Figure 14 .

 14 Figure 14. Three relevant (𝟏 𝟏 𝟎) surface models at different hydroxyl coverages : a)

Figures 14 a

 14 Figures 14 a and d clearly show the main difference between the A and L models: the

  -6 bar. Such a proportion is compatible with the one earlier reported by experimental studies.[29]

		350 K		550 K		750 K
	Surface -Multiplicity		10 -6 bar 1 bar	10 -6 bar 1 bar
	(1 1 0)b -2	36	36	36	32	37
	(0 0 1) -2	5	26	5	37	21
	(1 1 0)l -2	17	20	19	19	20
	(1 1 1) -4	42	18	40	12	22

Acknowledgements

Calculations were performed using HPC resources (Jean Zay and Occigen) from GENCI-CINES (Grant A0020806134) and ENER 440 from IFP Energies nouvelles. This work is part of the "RatiOnAl Design for CATalysis" (ROAD4CAT) industrial chair, project IDEXLYON funded by the French National Research Agency (ANR-16-IDEX-0005) and the Commissariat-General for Investment (CGI) within the framework of Investissements d'Avenir program ("Investment for the future"). The authors thank the SYSPROD project and AXELERA Pôle de Compétitivité for financial support (PSMN Data Center).