Grégory Landelle

Etienne Schmitt

Armen Panossian

Jean-Pierre Vors

Sergiy Pazenok

Peter Jeschke

Oliver Gutbrod

Frédéric R Leroux
email: frederic.leroux@unistra.fr

Gregory Landelle

Tri-and difluoromethoxylated N-based heterocycles -Synthesis and insecticidal activity of novel F 3 COand F 2 HCO-analogues of Imidacloprid and Thiacloprid

Keywords: Trifluoromethoxy, difluoromethoxy, difluorocarbene, heterocycles, agrochemicals

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Introduction

Since some years ago, the electron-withdrawing trifluoromethoxy (F 3 C-O) and difluoromethoxy (F 2 HC-O) groups are becoming more and more important in modern crop protection but also in pharmaceutical chemistry [1][2][3][4][5][6], because they can protect an aromatic ring system against oxidative (or electrophilic) attacks. An increased stability towards degradation is observed for active ingredients or fragments containing this special substitution pattern. Based on its electronic properties, which are close to the halogen atoms chlorine and fluorine [7], the F 3 C-O group has been referred as a super- [8] or a pseudo [9]-halogen. The fluorinated carbon adjacent to an oxygen atom increases lipophilicity as shown by the high value of the F 3 C-O hydrophobic substituent parameter [START_REF] Hansch | Substituent Constants for Correlation Analysis in Chemistry and Biology[END_REF][START_REF] Leo | [END_REF][12]. It appears that the F 3 C-O substituent is far more lipophilic (p = +1.04) than the halogens and lies between a F 3 C (p = +0.88) and a F 3 C-S (p = +1.44) group. It may thus replace advantageously a fluorine atom (p = +0.14) in most molecules with the benefit of increased lipid solubility. The trifluoromethoxy substituent can induce particular conformational changes due to its anisotropic character (in difference to the isotropic trifluoromethyl group) [13] and adopt an orthogonal orientation with respect to an arene plane, in contrast to the methoxy group, which normally lies in the plane of the arene [14,15]. In fact, the electron density of the non-bonding p-orbitals at oxygen is very low. The electrons of the oxygen p-orbital are delocalized into the antibonding orbitals of the trifluoromethyl C-F bonds [16]. As a consequence, the oxygen non-bonding orbitals are not conjugated with the aromatic ring system; therefore the F 3 Cgroup of F 3 C-O lies out of the arene plane, and the rotational barrier is significantly lower than that for a methoxy group [17][18][19]. This behaviour can be used to tune the binding affinity in drug-target complexes. The use of the F 3 C-O-motif in pharmaceuticals led to major breakthroughs; Riluzole was the first drug approved for amylotropic lateral sclerosis treatment; Delamanid is included in the World Health Organization List for essential medicines as prodrug for tuberculosis treatment; Celikalim is a vasorelaxing agent protecting cardiac muscles. In addition, marketed agrochemicals bearing the F 3 CO-motif display various possible MoAs; Indoxacarb is a Voltage-gated sodium channel (VgSoCh) blocker; Thifluzamide is a fungicide (SDH Complex II inhibitor); Flurprimidol is Plant Growth Regulator (or PGR) (Figure 1). The difluoromethoxy group shares several key properties with its renowned trifluoromethoxy analogue (high electronegativity, excellent lipophilicity, specific electronic distribution, thermal/chemical stability), but is not as bulky and displays an additional H-bonding capacity. This combination of properties makes the F 2 CH-O-group more and more popular. It is found in medicinally relevant compounds that include enzyme inhibitors (e.g.: Roflumilast, a selective and long-acting phosphodiesterase-4 inhibitor, anti-HIV agents and antimicrobial agents). Pantoprazole is a nice example of F 2 CH-O-containing drug found in the top 100 selling drugs in 2013, as well as several cardiovascular medications, such as Riodipine (Figure 1) [1]. Surprisingly, most of marketed drugs are commonly bearing an aryl-OCHF 2 motif, but no example is known with heteroaryl-OCHF 2 motif. Difluoromethoxy compounds are less described in marketed agrochemicals; only several examples containing a F 2 CH-O-heteroaryl moiety are currently on the market: Diflumetorim is a fungicide (SDH Complex I inhibitor); Pyroxasulfone is a VLCFAs (Very Long Chain Fatty Acids) biosynthesis inhibitor; Flucythrinate, an insecticide acting as Voltage-gated sodium channel blocker, also contains this group (Figure 1) [2]. These examples clearly illustrate the large potential of both F 3 CO-and F 2 HCO-substituents for the development of new bioactive ingredients. Therefore, we became interested in preparing new analogues of pyridine-containing neonicotinoid insecticides Imidacloprid and Thiacloprid, containing either 6-trifluoromethoxy-or 6-difluoromethoxy-pyridin-3-yl-methyl moieties.

Results and discussion

Trifluoromethoxy-derivatives

Our group was the first to report on the modular synthesis of a library of trifluoromethoxylated pyridines [17]. This approach has been applied in the synthesis of

Difluoromethoxy-precursors

The synthesis of F 2 HCO-compounds was reported either by the use of ozone-depleting CHF 2 Cl gas, or by means of many other difluorocarbene precursors. The generated difluorocarbene is reacted with an alkoxide/phenoxide to provide the corresponding F 2 HCOproduct. Elevated temperatures or poor functional group tolerance were sometimes important drawbacks of these approaches [20]. Hartwig reported a new approach for the preparation of difluoromethoxylated aromatics by means of a non-ODS-based reagent, namely difluoromethyl triflate (TfO-CHF 2 ), which displays difluorocarbene reactivity [21]. This reagent can be conveniently prepared from the Ruppert-Prakash reagent (TMSCF 3 ) and triflic acid, and can be used as an air-stable liquid. The difluoromethylation of a diversity of phenols (and sulphides) was reported with good to excellent yields within minutes in aqueous solvent.

A broad functional group tolerance and mild reaction conditions enabled the difluoromethylation of phenols generated in situ by catalytic and oxidative processes (from aryl boronic acids, arenes or aryl halides), despite slightly lower yields. Surprisingly, only two examples of hydroxychromenones and that of 8-hydroxyquinoline (i.e. where the OH group is borne by the benzo ring, not the pyrido one) were included into this report; the difluoromethylation of other hydroxylated heterocycles thus remained untapped, and it seemed important to complete the study. Therefore, we developed the difluoromethylation of a variety of hydroxylated heterocycles, including pyridines, pyridazines, pyrazines, pyrazoles or quinolines. desired product in 85% yield (Table 1, entry 8). Attempts to deviate from these conditions, in terms of solvent, base or amount of base could not provide any improvement (Table 1). Difluoromethyl triflate was prepared using Dilman's procedure [22].

After this first study, the scope extension was achieved using a selection of hydroxypyridines, -pyrazoles, -pyrazine, -pyridazine and -quinoline (11a-o, Table 2). The difluoromethylation reaction of these substrates using difluoromethyl triflate was achieved with moderate to good yields. Interestingly, all heterocycles used to illustrate this study were successfully difluoromethylated, showing the versatility of this method. The possibility of using difluoromethyl-nonaflate (F 2 HC-ONf) to avoid the formation of aryl triflate sideproducts was not investigated in this case (as previously achieved by Hartwig's group). The low yields observed in the cases of light substrates can be explained by the volatility of the corresponding products (e.g.: entries 7, 8, 12, Table 2). Reactions were performed on a 0.5 mmol scale and the yields were determined by 19 F NMR spectroscopic analysis on the crude product using PhCF 3 as internal standard. a: 0.5mL KOH instead of 1.0 mL.

It is important to note that several reports have recently described the preparation of difluoromethoxylated heterocycles using different difluorocarbene precursors ([Cu(phen) 2 ][O 2 CCF 2 Cl] or fluoroform). In the majority of cases, the reported yields were lower, heating the reaction mixture was required, as well as the use of less environmentally friendly organic solvents [23,24]. The reactions were performed on a 1 mmol scale. a: yield measured by 19 F NMR spectroscopic analysis on the crude product using PhCF 3 as internal standard.

O F F S F 3 C O O N N KOH (6M) solvent, rt, 30 min OH Cl O Cl F F (3 equiv.) 11a 10
As previously mentioned, the F 2 HC-O-group possesses similar electronic properties to those of F 3 C-O, but with specific features (H-bonding capacity, different conformational behaviour, size). Therefore, we decided to apply this approach to the synthesis of F 2 HC-O-analogues of Imidacloprid and Thiacloprid.

For this purpose, the key intermediate 14 was prepared starting from readily available 6hydroxynicotinic acid. First, this starting material was converted into 5-(hydroxymethyl)pyridin-2(1H)-one (12) after esterification in acidic medium followed by ester reduction. The resulting product 12 was then O-protected via a TBS group, in order to successfully achieve the O-difluoromethylation of the pyridine core providing intermediate 13. After a TBAF-mediated O-desilylation, the chlorination of the resulting primary alcohol using thionyl chloride was performed providing the desired product 14. This product was further coupled with 4,5-dihydro-N-nitro-1H-imidazol-2-amine or N-(4,5-dihydro-2-thiazolyl) cyanamide, to provide the two desired difluoromethoxy analogues of Imidacloprid and Thiacloprid (15 and 16) in 74% and 72 % yield respectively (Scheme 2).

N N F 2 HC OH N N F 2 HC OCHF 2 N N Br OH CO 2 Et N N Br OCHF 2 CO 2 Et N N OH N N OCHF 2 N N Cl OH N N Cl OCHF 2 N N Br OH N N Br OCHF 2 N OH N OCHF 2
Scheme 2. Synthesis of F 2 HCO-Imidacloprid (15) and Thiacloprid (16).

F 3 CO-and F 2 HCO-analogues of Imidacloprid and Thiacloprid -Biological evaluation

The activity of neonicotinoids towards inhibition of an enzymatic reaction can be approximately evaluated as the pI 50 index (I 50 = quantity of neonicotinoid required for 50% inhibition) [25]. Both 6-difluoromethoxy-(15; logP-value = 1.59) and 6-trifluoromethoxyanalogues (8; logP-value = 1.82) of Imidacloprid have the same low pI 50 -values (5.3 vs 5.2) in vitro, which are significantly lower than the one measured for Imidacloprid (logP-value = 0.6; pI 50 = 9.1). Despite the fact that 15 (100 g a.i. ha -1 ) is 5 times more active in vivo against green-peach aphid (M. persicae) than 8 (500 g a.i. ha -1 ), both derivatives are much less active (by a factor of 625) than Imidacloprid (0.16 g a.i. ha -1 ). A similar result was obtained for the two Thiacloprid analogues (9 and 16). Both 6-difluoromethoxy-(16; logP-value = 1.92) and 6-trifluoromethoxy-analogues (9; logP-value = 2.08) have the same low pI 50 -values (4.9 vs 4.8) in vitro, which are significantly lower than the one measured for Thiacloprid (logP-value = 1.6; pI 50 = 9.2). Contrary to the case of Imidacloprid and of its derivatives 8 and 15, the OCF 3 -Thiacloprid analogue 9 (100 g a.i. ha -1 ) is 5 times more active in vivo against M. persicae than the OCHF 2 -one (16; 500 g a.i. ha -1 ); however -as for 8 and 15 compared to Imidacloprid-both derivatives 9 and 16 are much less active (by a factor of 125) than Thiacloprid (0.8 g a.i. ha -1 ) (Table 3). Parts of the cysteine loop covering the active site were undisplayed to allow a complete view on the ligand orientations. The images shown above were generated using the molecular modeling software suite SYBYLx2.2. [26] While it has been difficult to obtain crystals of any nAChR of sufficient quality to conduct high-resolution X-ray crystallography, both the crystal structure of a soluble homopentameric acetylcholine binding protein isolated from the seawater mollusc Aplysia californica (Ac-AChBP) and the only recently added crystal structure of the human a4b2 acetylcholine receptor [27] can be used to provide considerable support to the understanding of ligandreceptor interactions [28]. Figure 2 compares the mode of binding of Imidacloprid and its 6difluoromethoxy-analogue (15) as well as Thiacloprid and its 6-trifluoromethoxy-analogue (9) to Ac-AChBP from A. californica. The Figure 2 has been created from PDB entry 3C79 (Imidacloprid in complex with Ac-AChBP) [START_REF] Talley | Proc. Natl. Acad. Sci[END_REF] following the procedure described by Beck et al. [START_REF] Beck | [END_REF]. In both cases, the positively polarized N-nitroguanidine and N-cyano-amidine πsystems of Imidacloprid and 15 as well as Thiacloprid and 9 demonstrate a perfect overlay as shown in Figures 2b and2d.

In addition, a strikingly conserved water molecule mediates a hydrogen bridge between the pyridine nitrogen atoms of all neonicotinoids and the loop D backbone, which is known to be important for ligand binding. However, the overlay of Imidacloprid and 15 with the focus on 6-F 2 HC-O-and 6-Cl-pyridin-3-yl residues (Figure 2c) as well as Thiacloprid and 9 with the focus on 6-F 3 C-O-and 6-Cl-pyridin-3-yl residues (Figure 2e) clearly demonstrates the differences between the two commercial neonicotinoids and their fluoroalkoxy-containing analogues. Both the F 2 HCO-and F 3 CO-groups in 6-position of the pyridine are much larger (see dotted circles in Figure 2c and2e) compared to a chlorine atom and therefore disruptive for the ligand-receptor interaction. In addition, the groups tend to adopt perpendicular position as described for (hetero)aromatic ring systems [31,32]. As a consequence of these structural modifications the insecticidal activity of 15 and 9 decreased remarkably.

Conclusion

To illustrate the potential of the F 3 CO-and F 2 HCO-groups as emergent fluorinated substituents (EFS), analogues of Imidacloprid and Thiacloprid displaying a replacement of the key chlorine atom by these two groups have been prepared and evaluated. For the preparation of the key intermediates, we have developed an efficient synthetic route to prepare the desired F 3 CO-intermediate; in a second hand, we have developed a novel strategy to prepare F 2 HCOsubstituted heterocycles, and this strategy was applied to the preparation of the desired F 2 HCO-intermediate. With both key intermediates, F 3 CO-and F 2 HCO-analogues of Imidacloprid and Thiacloprid were prepared. While the in-vitro activity of these analogues is promising, their in-vivo activity revealed to be much less elevated. However, this investigation opens the route to a new access to analogues of bioactive ingredients and their further evaluation, which could possibly lead to large activity enhancements.

Experimental

General

All reactions were performed in flame-dried glassware using sealed tube or Schlenk tube. Liquids and solutions were transferred with syringes. Air-and moisture-sensitive materials were stored protected and handled under an atmosphere of argon, with appropriate glassware. Solvents were purified and dried following standard procedures: tetrahydrofuran (THF) was distilled from sodium or sodium + benzophenone prior to use. Anhydrous MeCN was used from commercial source and was stored under Argon. Technical grade solvents for extraction and chromatography (cyclohexane, dichloromethane, n-pentane, ether, toluene, and ethyl acetate) were used without purification. All reagents were purchased from standard suppliers (Sigma Aldrich, ABCR, Alfa Aesar and Apollo scientific). Starting materials, if commercial, were purchased and used as such, provided that adequate checks (NMR) had confirmed the claimed purity. Analytical thin-layer chromatography (TLC) was performed on silica gel. Flash column chromatography was performed on silica gel 60 (40-63 μm, 230-400 mesh, ASTM) by Merck using the indicated solvents. 1 H, 13 C, and 19 F-NMR spectra were recorded in CDCl 3 on Bruker AV 400 instruments ( 1 H: 400MHz, 19 F: 376MHz, 1) Thiophosgene (3.0 mL, 39 mmol, 1 equiv.) in dichloromethane (24 mL) was added dropwise to a solution of 2-chloro-6-hydroxypyridine (5.0 g, 39 mmol) in aqueous sodium hydroxide (5%, 34 mL) at 0 °C. The reaction mixture was vigorously stirred for 2 h at 0 °C before being extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with 1M HCl (20 mL) and water (20 mL) and dried with sodium sulphate before being evaporated. The crude product was taken up in chloroform (40 mL) and the reaction mixture was then saturated with chlorine at 25 °C until the reaction mixture began to warm up. After 2 h at 25 °C, excess chlorine was again added until a yellow solution was obtained. After 24 h at 25 °C, excess chlorine was removed with a stream of argon and the solution was concentrated. The crude pale-yellow oil was distilled under reduced pressure to afford pure 2-chloro-6trichloromethoxypyridine (1). Colourless oil (5.7 g, 60% yield), b.p. = 80-82 °C (1 mbar); 1 H NMR (CDCl 3 , 300 MHz, 25 °C): δ 7.70 (t, 1 H, J = 7.9 Hz, H-4), 7.19 (d, 1 H, J = 7.9 Hz, H-5), 7.02 (d, J = 7.9 Hz, 1 H, H-3) ppm; 13 2-Chloro-6-trifluoromethoxypyridine (2) 2-Chloro-6-trichloromethoxypyridine (1, 5.9 g, 24 mmol, 1 equiv.) was added dropwise at 120 °C to a mixture of SbF 3 (8.7 g, 48 mmol, 2 equiv.) and SbCl 5 (0.60 mL, 4.8 mmol, 0.2 equiv.) and the mixture was stirred for 3 h at 140 °C. GC monitoring indicated 100% conversion and disappearance of the -OCF 2 Cl byproduct. The mixture was then cooled to room temperature and dissolved in dichloromethane (100 mL). The solution was washed with 2M HCl (150 mL) and the aqueous layer was extracted with dichloromethane (2 x 50 mL). The combined organic layers were dried over sodium sulphate and the solvent was evaporated at atmospheric pressure. The crude product was distilled under reduced pressure to afford pure 2-chloro-6-trifluoromethoxypyridine (2). Colourless oil (2.5 g, 53% yield), b.p. = 42-44 °C (20 mbar); 1 H NMR (CDCl 3 , 300 MHz, 25 °C): δ 7.67 (t, 1 H, J = 7.9 Hz, H-4), 7. 18 (d,1 H, J = 7.9 Hz, H-5), 6.87 (d, 1 H, J = 7.9 Hz, H-3) ppm; 13

2-Chloro-6-(trifluoromethoxy)-5-(trimethylsilyl)pyridine (3)

Butyllithium (1.56 M in hexanes, 5.7 mL, 8.9 mmol, 1.1 equiv.) was added dropwise at 0 °C to a solution of diisopropylamine (1.2 mL, 8.9 mmol, 1.1 equiv.) in THF (15 mL). A solution of 2-chloro-6-(trifluoromethoxy)pyridine 2 (1.6 g, 8.1 mmol, 1 equiv.) in THF (5 mL) was added dropwise at -78 °C, and the reaction mixture was stirred for 2 h at this temperature. Chlorotrimethylsilane (1.0 g, 1.13 mL, 8.9 mmol, 1.1 equiv.) was then added dropwise and the mixture was allowed to reach 25 °C before being neutralised with water (20 mL) and extracted with diethyl ether (3 x 10 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo. The crude product was distilled under reduced pressure to afford pure 2-chloro-6-(trifluoromethoxy)-5-(trimethylsilyl)pyridine (3). Colourless oil (1.5 g, 68%), b.p. = 89-93 °C (14 mbar); 1 H NMR (CDCl 3 , 300 MHz, 25 °C): δ 7.78 (d, 1 H, J = 7.6 Hz, H-3), 7.22 (d, 1 H, J = 7.6 Hz, H-4), 0.34 (s, 9 H, SiMe 3 ) ppm. Spectroscopic data were in agreement with literature values [17].

2-Chloro-6-trifluoromethoxynicotinic acid (4)

Butyllithium (1.56 M in hexanes, 3.7 mL, 5.7 mmol, 1.1 equiv.) was added dropwise at 0 °C to a solution of 2,2,6,6-tetramethylpiperidine (1.0 mL, 5.7 mmol, 1.1 equiv.) in THF (10 mL). A solution of 2-chloro-6-(trifluoromethoxy)-5-(trimethylsilyl)pyridine 3 (1.4 g, 5.2 mmol, 1 equiv.) in THF (5 mL) was added dropwise at -78 °C, and the reaction mixture was stirred for 2 h at this temperature. The mixture was then poured onto an excess of freshly crushed dry ice before being treated with an aqueous solution of sodium hydroxide (5%, 10 mL). The resulting aqueous layer was collected, washed with diethyl ether (10 mL), and acidified to pH = 1 by dropwise addition of 6M HCl (4 mL). After extraction with ethyl acetate (3 x 10 mL), the combined organic layers were dried over sodium sulphate and evaporated. The crude oil was treated with tetrabutylammonium fluoride (1M in THF, 5.7 mL, 5.7 mmol, 1.1 equiv.) for 20 h at 25 °C. The mixture was then neutralised by addition of 2M HCl (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over sodium sulphate and evaporated to afford pure 2-chloro-6-(trifluoromethoxy)nicotinic acid (4). Colourless powder (0.92 g, 70%); 1 H NMR (CD 3 OD, 300 MHz, 25 °C): δ 8.44 (d, 1H, J = 8.3 Hz, H-4), 7.21 (d, 1 H, J = 8.3 Hz, H-5) ppm. Spectroscopic data were in agreement with literature values [17].

6-Trifluoromethoxynicotinic acid (5)

Palladium (10% on charcoal, 2.1 g, 2.0 mmol, 10 mol%) was added at 25 °C with stirring to a solution of 2-chloro-6-trifluoromethoxynicotinic acid 4 (4.8 g, 20 mmol, 1 equiv.) and ammonium formate (2.5 g, 40 mmol, 2 equiv.) in methanol (40 mL). The reaction mixture was stirred for 16 h at room temperature before being filtered on Celite ® , the filtrate was concentrated and the residue was taken up in ethyl acetate (50 mL). The organic layer was washed with 2M HCl (2 x 20 mL) and water (20 mL). The organic layer was dried over sodium sulphate and evaporated in vacuo to afford pure 6-(trifluoromethoxy)nicotinic acid (5). Colourless powder (3.2 g, 76%); 1 THF (1M in THF, 36 mL, 36 mmol, 5 equiv.) was added dropwise to 6-trifluoromethoxy nicotinic acid 5 (1.5 g, 7.3 mmol, 1 equiv.) in solution in THF (25 mL) at 0 °C. The reaction mixture was stirred 30 min at this temperature, and allowed to reach room temperature overnight. It was quenched with methanol (25 mL), diluted with diethyl ether (100 mL) and the organic layer was washed with brine (2 x 100 mL). The combined organic layers were dried with sodium sulphate and the solvent was distilled off. The crude product was purified by column chromatography on silica gel with pentane/diethyl ether (6:4 to 3:7) as eluent, which afforded 6. Colourless oil (1.0 g, 70%); 1

3-(Chloromethyl)-6-(trifluoromethoxy) pyridine (7)

Mesyl chloride (0.28 mL, 3.6 mmol, 1.5 equiv.) was added dropwise to a solution of (6-(trifluoromethoxy)pyridin-3-yl)methanol 6 (0.50 g, 2.4 mmol, 1 equiv.) in dichloromethane (8 mL) in presence of triethylamine (0.60 g, 0.79 mL, 5.7 mmol, 2.4 equiv.) at 0 °C. The reaction mixture was allowed to reach room temperature overnight. It was then poured into a saturated solution of sodium hydrogen carbonate (10 mL). The aqueous layer was extracted with dichloromethane (3 x 15 mL) and washed with water (2 x 10 mL). The combined organic layers were dried over sodium sulphate and the solvent was distilled off. The crude product was purified by column chromatography on silica gel with pentane/diethyl ether (9:1) as eluent, which afforded 7. Pale yellow oil (0.31 g, 56%);

N-(1-((6-(Trifluoromethoxy)pyridin-3-yl)methyl)-4,5-dihydro-1H-imidazol-2yl)nitramide (8)

3-(Chloromethyl)-6-(trifluoromethoxy)pyridine 7 (0,15 g, 0.69 mmol, 0.90 equiv.) was added dropwise to a solution of 4,5-dihydro-N-nitro-1H-imidazol-2-amine (0,10 g, 0.76 mmol, 1 equiv.), potassium carbonate (0.10 g, 0.73 mmol, 0.96 equiv.) and caesium chloride (5.0 mg, 0.030 mmol, 0.03 equiv.) in acetonitrile (5 mL) at room temperature. The reaction mixture was stirred 5 hours at room temperature. It was then filtrated and the solvent was distilled off. The crude product was purified by HPLC on reverse phase with water/acetonitrile gradient, which afforded 8 (89.0 mg, 38% yield); 1

N-(3-((6-(Trifluoromethoxy)pyridin-3-yl)methyl)thiazolidin-2ylidene)cyanamide (9)

3-(Chloromethyl)-6-(trifluoromethoxy)pyridine 7 (0.15 g, 0.69 mmol, 0.90 equiv.) was added dropwise to a solution of N-( 4,5-dihydro-2-thiazolyl)cyanamide (98 mg, 0.76 mmol, 1 equiv.), potassium carbonate (0.10 g, 0.73 mmol, 0.96 equiv.) and caesium chloride (5.0 mg, 0.030 mmol, 0.03 equiv.) in acetonitrile (5 mL) at room temperature. The reaction mixture was stirred 5 hours at room temperature. It was then filtrated and the solvent was distilled off. The crude product was purified by HPLC on reverse phase with water/acetonitrile gradient, which afforded 9 (172.6 mg, 74% yield); 1

F 2 HCO-Imidacloprid and F 2 HCO-Thiacloprid Preparation of 2-chloro-6-(difluoromethoxy)pyridine (11a). General procedure for the difluoromethylation of hydroxyl-substituted heteroaromatics

To a vigorously stirred solution of 2-chloro-6-hydroxypyridine (0.13 g, 1.0 mmol) in acetonitrile (2 mL) at room temperature was added a 6M aqueous solution of potassium hydroxide (2 mL). Difluoromethyltriflate (0.38 mL, 3.0 mmol, 3 equiv.) was added dropwise to the reaction mixture which was maintained at room temperature by means of a water bath (the reaction is exothermic), and the medium was stirred for 30 min. The mixture was diluted with water (20 mL) and extracted with diethyl ether (2 x 10 mL) and ethyl acetate (3 x 10 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and evaporated under reduced pressure. The crude material was purified by column chromatography on silica gel with pentane/diethyl ether (100:0 to 70:30) as eluent to afford the pure title compound (129 mg, 72% yield); 1 H-NMR (400 MHz, CDCl 3 ): δ 7.62 (t, 1H, J = 7.9 Hz), 7.37 (t, 1H, J = 72.2 Hz), 7.07 (d, 1H, J = 7.9 Hz), 6.76 (d, 1H, J = 8.0 Hz) ppm. 13

2-Chloro-5-(difluoromethoxy)pyridine (11b).

The crude material was purified by column chromatography on silica gel with pentane/diethyl ether (100:0 to 70:30) as eluent to afford the pure title compound (133 mg, 74%). 1 H-NMR (400 MHz, CDCl 3 ): δ 8.16 (d, 1H, J = 2.8 Hz), 7.37 (dd, 1H, J = 8.8 Hz, J = 2.8 Hz), 7.24 (d, 1H, J = 8.8 Hz), 6.44 (t, 1H, J = 72.2 Hz) ppm. 13 C-NMR (101 MHz, CDCl 3 ): δ 147.8, 146.2, 141.9, 130.8, 124.9, 115.1 (t, J = 266 Hz) ppm. 19 F-NMR (376 MHz, CDCl 3 ): δ -81.9 (d, 2F, J = 72.5 Hz) ppm. HRMS (ESI) calcd for C 6 H 5 ClF 2 NO [M+H] + : 180.002. Found: 180.004. Spectroscopic data were in agreement with literature values [17].

2-Chloro-4-(difluoromethoxy)pyridine (11c).

The crude material was purified by column chromatography on silica gel with pentane/diethyl ether (100:0 to 70:30) as eluent to afford the pure title compound (74 mg, 41%).

2-Bromo-3-(difluoromethoxy)pyridine (11d).

The crude material was purified by column chromatography on silica gel with pentane/diethyl ether (100:0 to 70:30) as eluent to afford the pure title compound (170 mg, 76%).

3-Bromo-2-(difluoromethoxy)pyridine (11e).

The crude material was purified by column chromatography on silica gel with pentane/diethyl ether (100:0 to 70:30) as eluent to afford the pure title compound (101 mg, 45%).

2,4-Dichloro-5-(difluoromethoxy)pyridine (11f).

The crude material was purified by column chromatography on silica gel with pentane/diethyl ether (100:0 to 70:30) as eluent to afford the pure title compound (141 mg, 66%).

5-(Difluoromethoxy)-2-methylpyridine (11g).

The crude material was purified by column chromatography on silica gel with pentane/diethyl ether (100:0 to 70:30) as eluent to afford the pure title compound (49 mg, 31%).

3-(Difluoromethoxy)pyridine (11h).

The crude material was purified by column chromatography on silica gel with pentane/diethyl ether (100:0 to 70:30) as eluent to afford the pure title compound (46 mg, 32%). Spectroscopic data were in agreement with literature values [17].

Ethyl 2-(difluoromethoxy)nicotinate (11i).

The crude material was purified by column chromatography on silica gel with pentane/diethyl ether (100:0 to 60:40) as eluent to afford the pure title compound (61 mg, 28%).

5-(Difluoromethoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole (11j).

The crude material was purified by column chromatography on silica gel with pentane/diethyl ether (100:0 to 60:40) as eluent to afford the pure title compound (149 mg, 75%). 1 H-NMR (400 MHz, CDCl 3 ): δ 6.48 (t, 1H, J = 55.0 Hz), 6.47 (t, 1H, J = 71.9 Hz), 6.04 (s, 1H), 3.69 (s, 3H) ppm. 13

Ethyl 3-bromo-5-(difluoromethoxy)-1-methyl-1H-pyrazole-4-carboxylate (11k).

The crude material was purified by column chromatography on silica gel with pentane/diethyl ether (100:0 to 60:40) as eluent to afford the pure title compound (120 mg, 40%). 1 H-NMR (400 MHz, CDCl 3 ): δ 6.98 (t, 1H, J = 74.0 Hz), 4.34 (q, 2H, J = 7.5 Hz), 3.78 (s, 3H), 1.38 (t, 3H, J = 7.5 Hz) ppm. 13 C-NMR (101 MHz, CDCl 3 ): δ 160.5, 146.8 (t), 126.9, 116.7 (t), 101.9, 61.1, 35.3, 14.1 ppm. 19

5-(Difluoromethoxy)-1,3-dimethyl-1H-pyrazole (11l).

The crude material was purified by column chromatography on silica gel with pentane/diethyl ether (100:0 to 60:40) as eluent to afford the pure title compound (57 mg, 35%). 1 H-NMR (400 MHz, CDCl 3 ): δ 6.47 (t, 1H, J = 72.5 Hz), 5.65 (s, 1H), 3.66 (s, 3H), 2.21 (s, 3H) ppm.

3-Chloro-6-(difluoromethoxy)pyridazine (11m).

The crude material was purified by column chromatography on silica gel with pentane/diethyl ether (100:0 to 60:40) as eluent to afford the pure title compound (107 mg, 59%).

2-Bromo-5-(difluoromethoxy)pyrazine (11n).

The crude material was purified by column chromatography on silica gel with pentane/diethyl ether (100:0 to 60:40) as eluent to afford the pure title compound (119 mg, 53%).

4-(Difluoromethoxy)quinoline (11o).

The crude material was purified by column chromatography on silica gel with pentane/diethyl ether (100:0 to 60:40) as eluent to afford the pure title compound (61 mg, 31%).

5-(Hydroxymethyl)pyridin-2-ol or 5-(hydroxymethyl)pyridin-2(1H)-one (12).

To a stirred solution of 6-hydroxynicotinic acid (10 g, 72 mmol) in absolute ethanol (500 mL) was added sulfuric acid (4 mL) at room temperature. The mixture was heated to reflux for 48 h. After cooling down to room temperature, water (50 mL) was added and the reaction mixture was neutralized to pH = 6-7 by portionwise addition of sodium hydrogen carbonate (caution: gas evolution). The mixture was evaporated under reduced pressure (most of ethanol was removed), and the residue was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with brine, dried over Na 2 SO 4 and evaporated under reduced pressure leading to the pure ethyl 6-hydroxynicotinate [START_REF] Beck | [END_REF] (10 g, 86%). 1 H-NMR (400 MHz, CDCl 3 ): δ 13.07 (s, 1H), 8.14 (s, 1H), 7.94 (d, 1H, J = 9.9 Hz), 6.51 (d, 1H, J = 9.4 Hz), 4.25 (q, 2H, J = 7.1 Hz), 1.29 ppm.

To a stirred solution of lithium aluminium hydride (1.4 g, 37 mmol, 1.2 equiv.) in anhydrous THF (20 mL) at room temperature was added dropwise over 1 h a solution of ethyl 6hydroxynicotinate (5.1 g, 31 mmol) in anhydrous THF (150 mL) at the same temperature. The mixture was stirred at room temperature for 2 h and then heated to reflux for 30 min. The reaction mixture was cooled down to 0 °C and quenched with ethyl acetate (12 mL) and water (6 mL). The solvents were removed and the residue was taken up in refluxing ethanol (200 mL). The solution was filtered through Celite ® and ethanol was evaporated under reduced pressure. The crude material was purified by column chromatography on silica gel with ethyl acetate/methanol (75:25) as eluent to afford the pure title compound 12 (2.3 g, 60%).

5-(((tert-Butyldimethylsilyl)oxy)methyl)-2-(difluoromethoxy)pyridine (13).

To a stirred solution of 5-(hydroxymethyl)pyridin-2-ol (1.3 g, 10 mmol) and imidazole (1.7 g, 25 mmol, 2.5 equiv.) in DMF (2.5 mL) was added tert-butyldimethylsilyl chloride (1.8 g, 12 mmol, 1.2 equiv.) at room temperature, and the reaction medium was stirred overnight. Water (20 mL) was added and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with brine, dried over Na 2 SO 4 and evaporated under reduced pressure. The crude material was purified by column chromatography on silica gel with pentane/diethyl ether (100:0 to 80:20) as eluent to afford pure 5-(((tertbutyldimethylsilyl)oxy)methyl)pyridin-2-ol (1.3 g, 54%). 1 H-NMR (400 MHz, DMSO-d 6 ): δ 11.36 (s, 1H), 7.31 (dd, 1H, J = 9.4 Hz, J = 2.7 Hz), 7.20 (m, 1H), 6.27 (d, 1H, J = 9.4 Hz), 4.36 (s, 2H), 0.81 (s, 9H), 0.00 (s, 6H) ppm. 13 To a vigorously stirred solution of 5-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-ol (0.48 g , 2 mmol) in acetonitrile (4 mL) at room temperature was added a 6M aqueous solution of potassium hydroxide (4 mL). Difluoromethyltriflate (0.76 mL, 6 mmol, 3 equiv.) was added dropwise to the reaction mixture which was maintained at room temperature by means of a water bath (the reaction is exothermic), and the medium was stirred for 30 min. The mixture was diluted with water (20 mL) and extracted with diethyl ether (2 x 10 mL) and ethyl acetate (3 x 10 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and evaporated under reduced pressure. The crude material was purified by column chromatography on silica gel with pentane/diethyl ether (100:0 to 90:10) as eluent to afford the pure title compound 13 (0.40 g, 70%).

5-(Chloromethyl)-2-(difluoromethoxy)pyridine (14).

To a stirred solution of 5-(((tert-butyldimethylsilyl)oxy)methyl)-2-(difluoromethoxy)pyridine 13 (1.4 g, 5 mmol) in THF (10 mL) was added a solution of TBAF (1.0 M solution in THF, 10 mmol, 2 equiv.) at room temperature, and the mixture was stirred for 4 h. The reaction was quenched with saturated ammonium chloride and brine, and extracted with ethyl acetate (3x 20 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and evaporated under reduced pressure. The crude material was purified by column chromatography on silica gel with ethyl acetate/pentane (60:40) as eluent to afford pure (6-(difluoromethoxy)pyridin-3yl)methanol (761 mg, 87%). To a stirred solution of thionyl chloride (0.16 mL, 2.2 mmol, 1.1 equiv.) in toluene (1 mL) at room temperature was added dropwise a solution of (6-(difluoromethoxy)pyridin-3yl)methanol (0.35 g, 2 mmol) in toluene (2 mL). After 1 h at room temperature, vacuum was applied leading to the pure title compound 14 (0.34 g, 89%) without further purification. 1 H-NMR (400 MHz, CDCl 3 ): δ 8.18 (d, 1H, J = 2.6 Hz), 7.78 (dd, 1H, J = 8.5 Hz, J = 2.6 Hz), 7.46 (t, 1H, J = 72.8 Hz), 6.92 (d, 1H, J = 8.5 Hz), 4.56 (s, 2H) ppm. 13 C-NMR (101 MHz, CDCl 3 ): δ 158.9, 146.7, 140.6, 129.8, 114.0 (t, J C-F = 256.7 Hz), 111.4, 42.5 ppm. 19

N-(1-((6-(Difluoromethoxy)pyridin-3-yl)methyl)-4,5-dihydro-1H-imidazol-2yl)nitramide (15)

5-(Chloromethyl)-2-(difluoromethoxy)pyridine 14 (0.13 g, 0.69 mmol, 0.90 equiv.) was added dropwise to a solution of 4,5-dihydro-N-nitro-1H-imidazol-2-amine (0.10 g, 0.76 mmol, 1 equiv.), potassium carbonate (0.10 g, 0.73 mmol, 0.96 equiv.) and caesium chloride (5.0 mg, 0.030 mmol, 0.03 equiv.) in acetonitrile (5 mL) at room temperature. The reaction mixture was stirred 5 hours at room temperature. It was then filtrated and the solvent was distilled off. The crude product was purified by HPLC on reverse phase with water/acetonitrile gradient, which afforded 15 (163.9 mg, 74%);

Receptor binding studies (pI 50 -values in vitro)

Radioligand [ 3 H]imidacloprid displacement studies were conducted according to established protocols by using membranes isolated from frozen (-80 °C) housefly (Musca domestica L.) heads. [33,34] Briefly, 5 g heads were homogenised in 100 mL of 0.1 MK-phosphate buffer, pH 7.4, 320 mM of sucrose and 1 mM of EDTA using an Ultra Turrax at 4 °C. After centrifugation for 15 min at 1200 × g and 4 °C, the pellet was resuspended and centrifuged again. Both supernatants were combined and filtered through Miracloth, and the filtrate was subsequently centrifuged at 105.000 × g for 60 min at 4 °C. The resulting pellet was resuspended in buffer and adjusted to approximately 0.5 mg protein mL -1 . The assay was conducted in a total volume of 1 mL, consisting of 850 µL of homogenate and 50 µL of [ 3 H]imidacloprid (25.000 dpm; 1.406 GBq µmol -1 ) in 0.1 MK-phosphate buffer, pH 7.4, containing 1 g L -1 of BSA and 5% ethanol (0.25% final concentration). After 5 min, different concentrations of the F 3 CO-and F 2 HCOanalogues of imidacloprid (8,15) and thiacloprid (9,16) were added (1000, 100, 10, 3, 1, 0.3, 0.1 and 0.01 nM, containing up to 0.1% DMSO). After incubation for 60 min at 22 °C while shaking, the samples were filtered through prewetted Whatman GF/C glass fibre filters, followed by two rinseswith 3 mL of ice-cold 0.1 MK-phosphate buffer (pH 7.4). Subsequently, the filters were dried (55 °C, 40 min), and 3.5 mL of scintillation cocktail was added. After 16 h at room temperature, the samples were subjected to liquid scintillation counting.

Myzus persicae -spray test (in vivo)

Solvent:

78.0 parts by weight acetone 1.5 parts by weight N,N-dimethylformamide Emulsifier: alkylarylpolyglycol ether To produce a suitable preparation of active compound, 1 part by weight of the F 3 CO-and F 2 HCO-analogues of imidacloprid (8,15) and thiacloprid (9, 16) is mixed with the stated amount of solvents and is diluted with water, containing an emulsifier concentration of 1000 ppm, to the desired concentration. Further test concentrations are prepared by dilution with emulsifier containing water.

Chinese cabbage (Brassica pekinensis) leaf disks infected with all instars of the green peach aphid (Myzus persicae), are sprayed with a preparation of the active ingredient of the desired concentration.

After 5-6 days mortality in % is determined. 100 % means all aphids have been killed and 0 % means none of the aphids have been killed.

In this test, for example, the compounds 8 and 16 from the preparation examples showed good activity of 100 % at an application rate of 500 g ha -1 and the compounds 9 and 15 from the preparation examples showed good activity of 100 % at an application rate of 100 g ha -1 .

Figure 1 .

 1 Figure 1. F 3 CO-and F 2 HCO-bearing drugs and agrochemicals.

F 3 Scheme 1 .

 31 Scheme 1. Synthesis of F 3 CO-Imidacloprid (8) and Thiacloprid(9).

Figure 2 .

 2 Figure 2. Binding modes of Imidacloprid and Thiacloprid to Ac-AChBP. a) Overlay of two neighbouring monomers generated from PDB entry 3C79. The remaining panels zoom into the respective structures, but adopt similar perspectives. b) Overlay of Imidacloprid and its 6trifluoromethoxy-analogue (8) with the focus on the [O 2 N-N=]-pharmacophores. c) Overlay of Imidacloprid and its 6-difluoromethoxy-analogue(15) with the focus on 6-F 2 HC-O-and 6-Cl-pyridin-3-yl residues. d) Overlay of Thiacloprid and its 6-difluoromethoxy-analogue(16) with the focus on the [NC-N=]-pharmacophores. e) Overlay of Thiacloprid and its 6trifluoromethoxy-analogue (9) with the focus on 6-F 3 C-O-and 6-Cl-pyridin-3-yl residues. Parts of the cysteine loop covering the active site were undisplayed to allow a complete view on the ligand orientations. The images shown above were generated using the molecular modeling software suite SYBYLx2.2.[26]

  13 C: 100MHz,11 B: 128MHz). Chemical shifts are reported in parts per million (ppm) downfield from tetramethylsilane and are referenced to the residual solvent resonance as the internal standard (chloroform (δ [ 1 H] 7.26 and accordingly δ [ 13 C] 77.16 ppm), CD 3 CN (δ [ 1 H] 1.94 and accordingly δ [ 13 C] 1.32 ppm, MeOD-d 4 (δ [ 1 H] 3.31 and accordingly δ [ 13 C] 49.00 ppm), DMSO-d 6 (δ [ 1 H] 2.50 and accordingly δ [ 13 C] 39.52 ppm) or Acetone-d 6 (δ [ 1 H] 2.05 and accordingly δ [ 13 C] 29.84 ppm). Data are reported as follows: chemical shift, multiplicity (br s = broad singlet, s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, m = multiplet, br d = broad doublet), coupling constant (Hz) and integration. Fluorobenzene (d [ 19 F] -113.15 ppm) was used as internal standard to measure yields in-situ. The spectra were processed with the program NMR Notebook (Version 2.70, NMRtec). Experiments under microwave irradiation were carried out on an Initiator TM apparatus from Biotage, exact parameters are given with the procedures. Melting points (M.p.) were determined for crystalline or solid compounds with a Melting Point Apparatus M-560 and are not corrected. High resolution mass spectrometry (HRMS) analysis and elemental analysis (Anal.) were performed by the analytical facility at the University of Strasbourg (measurement accuracy ≤ 15 ppm). Spectral data were recorded from samples purified by Hickmann distillation when necessary.

F 3

 3 CO-Imidacloprid and F 3 CO-Thiacloprid 2-Chloro-6-trichloromethoxypyridine (

  C NMR (CDCl 3 , 75 MHz, 25 °C): δ 151.8 (C), 149.0 (C), 141.7 (CHarom), 122.2 (CHarom), 112.7 (CHarom), 109.1 (OCCl 3 ). Spectroscopic data were in agreement with literature values[17].

  C NMR (CDCl 3 , 75 MHz, 25 °C): δ 155.6 (C), 149.3 (C), 142.0 (CHarom), 122.2 (CHarom), 119.8 (q, J C-F = 262.1 Hz, OCF 3 ), 111.1 (CH); 19 F NMR (CDCl 3 , 282 MHz, 25 °C): δ -57.2 ppm. Spectroscopic data were in agreement with literature values[17].

  H NMR (CD 3 OD, 300 MHz, 25 °C): δ 8.91 (d, 1 H, Jm = 2.3 Hz, H-2), 8.48 (dd, 1 H, Jo = 8.4, Jm = 2.3 Hz, H-4), 7.24 (d, 1 H, Jo = 8.4 Hz, H-5) ppm. Spectroscopic data were in agreement with literature values[17].(6-(Trifluoromethoxy)pyridin-3-yl)methanol (6) BH 3 .

  H NMR (CDCl 3 , 300 MHz, 25 °C): δ 8.28 (d, J = 2.4 Hz, 1 H, H-2), 7.82 (dd, 1 H, Jo = 8.4 Hz, Jm = 2.4 Hz, H-4), 7.03 (d, 1 H, J = 8.4 Hz, H-5), 4.73 (s, 2H, CH 2 ), 2.36 (brs, 1H, -OH) ppm.; 13 C NMR (CDCl 3 , 75 MHz, 25 °C): δ 156.5 (C-6), 146.7 (C-2), 139.7 (C-4), 135.6 (C-3), 120.6 (q, J C-F = 259.2 Hz, OCF 3 ), 62.1 (CH 2 ) ppm; 19 F NMR (CDCl 3 , 282 MHz, 25 °C): δ -56.7 ppm; HRMS (ESI Positive) for C 7 H 7 F 3 NO 2 [M+H]: calcd. 194.043; found 194.044.

  1 H NMR (CDCl 3 , 300 MHz, 25 °C): δ 8.32 (d, 1 H, J = 2.4 Hz, H-2), 7.85 (dd, 1 H, Jm = 2.4 Hz, Jo = 8.4 Hz, H-4), 7.03 (d, 1 H, J = 8.4 Hz, H-5), 4.59 (s, 2H, CH 2 ) ppm; 13 C NMR (CDCl 3 , 75 MHz, 25 °C): δ 156.5 (C-6), 147.4 (C-2), 140.6 (C-4), 131.6 (C-3), 120.0 (q, OCF 3, J C-F = 260.1 Hz), 42.0 (CH 2 ) ppm; 19 F NMR (CDCl 3 , 282 MHz, 25 °C): δ -56.6 ppm; MS (EI): m/z = 211.1 [M + ], 176.0 [M + -Cl].

  H NMR (DMSO-d 6 , 150 MHz): δ 3.50 (m, 2H, CH 2 ), 3.63 (m, 2H, CH 2 ), 4.50 (s, 2H, CH 2 ), 7.31 (d, 2H, C-H, Py, J = 8.4 Hz), 7.96 (dd, 1H, C-H, Py, J = 8.4 Hz, J = 2.5 Hz), 8.32 (d, 1H, C-H, Py, J = 2.5 Hz), 9.00 (s, 1H, NH); 13 C NMR (proton-decoupled) (DMSO-d 6 , 150 MHz): δ 41.8, 44.6, 45.3 (CH 2 ), 113.4 (C-H, Ph), 119.9 (OCF 3 ), 131.5 (C, Ph), 141.3, 147.3 (C-H, Ph), 155.5 (C-O, Ph), 160.5 (C=N) ppm; 19 F NMR (DMSO-d 6 , 566 MHz): δ = -54.7 ppm. HRMS (ESI) calcd for C 10 H 11 F 3 N 5 O 3 [M+H] + : 306.0814. Found: 306.0816.

  H NMR (CD 3 CN, 150 MHz): δ 3.41 (m, 2H, CH 2 ), 3.85 (m, 2H, CH 2 ), 4.61 (s, 2H, CH 2 ), 7.12 (d, 2H, C-H, Py, J = 8.4 Hz), 7.87 (dd, 1H, C-H, Py, J = 8.4 Hz, J = 2.5 Hz), 8.23 (d, 1H, C-H, Py, J = 2.5 Hz); 13 C NMR (proton-decoupled) (CD 3 CN, 150 MHz): δ 28.3, 47.4, 53.6 (CH 2 ), 114.1 (C-H, Py), 121.1 (OCF 3 ), 131.0 (C, Py), 142.0, 148.4 (C-H, Py), 157.1 (C-O, Py), 176.3 (C=N); 19 F NMR (CDCN, 566 MHz): δ = -55.8 ppm. HRMS (ESI) calcd for C 10 H 10 F 3 N 4 OS [M+H] + : 303.0527. Found: 303.0526.

  C-NMR (101 MHz, CDCl 3 ): δ 158.3, 148.5, 142.1, 120.1, 113.8 (t, J = 259 Hz), 109.6 ppm. 19 F-NMR (376 MHz, CDCl 3 ): δ -89.3 (d, 2F, J = 71.4 Hz) ppm. HRMS (ESI) calcd for C 6 H 5 ClF 2 NO [M+H] + : 180.002. Found: 180.000. Spectroscopic data were in agreement with literature values[17].

  1 H-NMR (400 MHz, CDCl 3 ): δ 8.36 (d, 1H, J = 5.6 Hz), 7.08 (s, 1H), 6.99 (m, 1H), 6.65 (t, 1H, J = 71.6 Hz) ppm. 13 C-NMR (101 MHz, CDCl 3 ): δ 158.9, 152.9, 151.1, 114.6 (t, J C-F = 265.2 Hz), 113.7, 112.4 ppm. 19 F-NMR (376 MHz, CDCl 3 ): δ -83.6 (d, 2F, J = 72.6 Hz) ppm. HRMS (ESI) calcd for C 6 H 5 ClF 2 NO [M+H] + : 180.0022. Found: 180.0038.

  1 H-NMR (400 MHz, CDCl 3 ): δ 8.28 (d, 1H, J = 4.6 Hz), 7.56 (d, 1H, J = 8.4 Hz), 7.31 (m, 1H), 6.60 (t, 1H, J = 73.0 Hz) ppm. 13 C-NMR (101 MHz, CDCl 3 ): δ 146.7, 145.1, 135.9, 129.3, 123.5, 115.3 (t, J C-F = 264.5 Hz) ppm. 19 F-NMR (376 MHz, CDCl 3 ): δ -82.0 (d, 2F, J = 72.6 Hz) ppm. HRMS (ESI) calcd for C 6 H 5 BrF 2 NO [M+H] + : 223.952. Found: 223.952. Spectroscopic data were in agreement with literature values[17].

  1 H-NMR (400 MHz, CDCl 3 ): δ 8.13 (d, 1H, J = 4.6 Hz), 7.94 (d, 1H, J = 7.7 Hz), 7.46 (t, 1H, J = 72.4 Hz), 7.01 (dd, 1H, J = 7.5 Hz, J = 4.8 Hz) ppm. 13 C-NMR (101 MHz, CDCl 3 ): δ 155.5, 145.5, 143.2, 121.1, 114.2 (t, J C-F = 257.2 Hz), 106.8 ppm. 19 F-NMR (376 MHz, CDCl 3 ): δ -89.3 (d, 2F, J = 72.1 Hz) ppm. HRMS (ESI) calcd for C 6 H 5 BrF 2 NO [M+H] + : 223.952. Found: 223.952.

  1 H-NMR (400 MHz, CDCl 3 ): δ 8.32 (s, 1H), 7.47 (s, 1H), 6.60 (t, 1H, J = 72.1 Hz) ppm. 13 C-NMR (101 MHz, CDCl 3 ): δ 148.5, 143.1, 138.8, 125.7, 115.0 (t, J C-F = 267.1 Hz), 110.2 ppm. 19 F-NMR (376 MHz, CDCl 3 ): δ -81.8 (d, 2F, J = 72.0 Hz) ppm. HRMS (ESI) calcd for C 6 H 4 Cl 2 F 2 NO [M+H] + : 213.964. Found: 213.963.

  1 H-NMR (400 MHz, CDCl 3 ): δ 8.20 (s, 1H), 7.23 (m, 1H), 7.00 (d, 1H, J = 8.8 Hz), 6.35 (t, 1H, J = 73.0 Hz), 2.40 (s, 3H) ppm. 13 C-NMR (101 MHz, CDCl 3 ): δ 154.5, 143.9, 140.1, 126.8, 122.3, 114.1 (t, JC-F = 262.1 Hz), 22.4 ppm. 19 F-NMR (376 MHz, CDCl 3 ): δ -81.2 (d, 2F, J = 74.8 Hz) ppm. HRMS (ESI) calcd for C 7 H 8 F 2 NO [M+H] + : 160.057. Found: 160.058.

  1 H-NMR (400 MHz, CDCl 3 ): δ 8.32 (dd, 1H, J = 4.8 Hz, J = 2.0 Hz), 8.27 (dd, 1H, J = 7.7 Hz, J = 2.0 Hz), 7.53 (t, 1H, J = 72.4 Hz), 7.19 (dd, 1H, J = 7.6 Hz, J = 4.8 Hz), 4.41 (q, 2H, J = 7.3 Hz), 1.41 (t, 3H, J = 7.2 Hz) ppm. 13 C-NMR (101 MHz, CDCl 3 ): δ 163.9, 157.1, 150.2, 142.1, 119.7, 115.4, 114.0 (t, J C-F = 251.8 Hz), 61.8, 14.1 ppm. 19 F-NMR (376 MHz, CDCl 3 ): δ -89.3 (d, 2F, J = 71.7 Hz) ppm. HRMS (ESI) calcd for C 9 H 9 F 2 NNaO 3 [M+Na] + : 240.0443. Found: 240.0414.

  C-NMR (101 MHz, CDCl 3 ): δ 145.3, 145.1 (t, JC-F = 29.8 Hz), 114.9 (t, J C-F = 268.2 Hz), 111.0 (t, JC-F = 235.6 Hz), 89.4, 34.8 ppm. 19 F-NMR (376 MHz, CDCl 3 ): δ -83.9 (d, 2F, J = 71.8 Hz), -112.3 (d, 2F, J = 55.0 Hz) ppm. HRMS (ESI) calcd for C 6 H 7 F 4 N 2 O [M+H] + : 199.049. Found: 199.050.

  F-NMR (376 MHz, CDCl 3 ): δ -83.3 (d, 2F, J = 74.7 Hz) ppm. HRMS (ESI) calcd for C 8 H 9 BrF 2 N 2 NaO 3 [M+Na] + : 320.966. Found: 320.965.

  13 C-NMR (101 MHz, CDCl 3 ): δ 147.3, 145.2, 115.1 (t, J C-F = 264.2 Hz), 90.8, 34.0, 14.3 ppm. 19 F-NMR (376 MHz, CDCl 3 ): δ -83.6 (d, 2F, J = 72.3 Hz) ppm. HRMS (ESI) calcd for C 6 H 9 F 2 N 2 O [M+H] + : 163.0677. Found: 163.0674.

  1 H-NMR (400 MHz, CDCl 3 ): δ 7.52 (t, 1H, J = 71.1 Hz), 7.48 (d, 1H, J = 9.0 Hz), 7.06 (d, 1H, J = 9.0 Hz) ppm. 13 C-NMR (101 MHz, CDCl 3 ): δ 160.9, 153.9, 132.4, 119.9, 113.4 (t, J C-F = 259.2 Hz) ppm. 19 F-NMR (376 MHz, CDCl 3 ): δ -88.9 (d, 2F, J = 71.0 Hz) ppm. HRMS (ESI) calcd for C 5 H 4 ClF 2 N 2 O [M+H] + : 180.997. Found: 180.997.

  1 H-NMR (400 MHz, CDCl 3 ): δ 8.19 (d, 1H, J = 1.2 Hz), 8.10 (d, 1H, J = 1.2 Hz), 7.25 (t, 1H, J = 71.8 Hz) ppm. 13 C-NMR (101 MHz, CDCl 3 ): δ 155.0, 143.4, 135.2, 134.5, 113.8 (t) ppm. 19 F-NMR (376 MHz, CDCl 3 ): δ -89.1 (d, 2F, J = 72.0 Hz) ppm. HRMS (ESI) calcd for C 5 H 4 BrF 2 N 2 O [M+H] + : 224.9470. Found : 224.9473.

  1 H-NMR (400 MHz, CDCl 3 ): δ 8.73 (d, 1H, J = 4.8 Hz), 8.10 (d, 1H, J = 8.4 Hz), 8.02 (d, 1H, J = 8.4 Hz), 7.68 (t, 1H, J = 7.2 Hz), 7.50 (t, 1H, J = 7.8 Hz), 6.93 (s, 1H), 6.75 (t, 1H, J = 72.2 Hz) ppm. 13 C-NMR (101 MHz, CDCl 3 ): δ 154.4, 150.7, 149.8, 130.5, 129.2, 127.0, 121.5, 120.8, 115.3 (t, J C-F = 261.1 Hz), 105.8 ppm. 19 F-NMR (376 MHz, CDCl 3 ): δ -82.9 (d, 2F, J = 72.6 Hz) ppm. HRMS (ESI) calcd for C 10 H 8 F 2 NO [M+H] + : 196.057. Found: 196.058.

  1 H-NMR (400 MHz, DMSO-d 6 ): δ 11.56 (s, 1H), 7.43 (dd, 1H, J = 9.1 Hz, J = 2.5 Hz), 7.25 (d, 1H, J = 2.5 Hz), 6.30 (d, 1H, J = 9.1 Hz), 5.22 (t, 1H, J = 5.6 Hz), 4.20 (d, 2H, J = 5.6 Hz) ppm. 13 C-NMR (101 MHz, DMSO-d 6 ): δ 162.6, 142.0, 133.0, 120.1, 119.6, 60.1 ppm. HRMS (ESI) calcd for C 6 H 8 NO 2 [M+H] + : 126.056. Found: 126.055.

  1 H-NMR (400 MHz, CDCl 3 ): δ 8.02 (m, 1H), 7.59 (dd, 1H, J = 8.1 Hz, J = 2.5 Hz), 7.35 (t, 1H, J = 73.1 Hz), 6.73 (d, 1H, J = 8.4 Hz), 4.60 (s, 2H), 0.82 (s, 9H), 0.00 (s, 6H) ppm. 13 C-NMR (101 MHz, CDCl 3 ): δ 158.3, 144.8, 138.5, 133.2, 114.1 (t, J C-F = 255.4 Hz), 111.1, 62.2, 25.9, 18.3, -5.3 ppm. 19 F-NMR (376 MHz, CDCl 3 ): δ -88.6 (d, 2F, J = 72.9 Hz) ppm. HRMS (ESI) calcd for C 13 H 22 F 2 NO 2 Si [M+H] + : 290.139. Found: 290.138.

  1 H-NMR (400 MHz, CDCl 3 ): δ 8.15 (d, 1H, J = 2.5 Hz), 7.76 (dd, 1H, J = 8.5 Hz, J = 2.5 Hz), 7.45 (t, 1H, J = 73.7 Hz), 6.90 (d, 1H, J = 8.5 Hz), 4.68 (m, 2H), 2.04 (m, 1H) ppm. 13 C-NMR (101 MHz, CDCl 3 ): δ 158.7, 145.6, 139.4, 132.5, 114.1 (t, J C-F = 253.9 Hz), 111.4, 62.1 ppm. 19 F-NMR (376 MHz, CDCl 3 ): δ -88.7 (d, 2F, J = 73.5 Hz) ppm. HRMS (ESI) calcd for C 7 H 8 F 2 NO 2 [M+H] + : 176.0518. Found: 176.0530.

  F-NMR (376 MHz, CDCl 3 ): δ -89.1 (d, 2F, J = 72.5 Hz) ppm. HRMS (ESI) calcd for C 7 H 7 ClF 2 NO [M+H] + : 194.018. Found: 194.018.

  1 H (DMSO-d 6 , 150 MHz): δ 3.47 (m, 2H, CH 2 ), 3.62 (m, 2H, CH 2 ), 4.45 (s, 2H, CH 2 ), 7.10 (d, 2H, C-H, Py, J = 8.4 Hz), 7.70 (t, 1H, OCHF 2 , J C-F = 72.8 Hz), 7.86 (dd, 1H, C-H, Py, J = 8.4 Hz, J = 2.5 Hz), 8.22 (d, 1H, C-H, Py, J = 2.5 Hz); 8.96 (s, 1H, NH); 13 C NMR (proton-decoupled) (DMSO-d 6 , 150 MHz): δ 41.7, 44.6, 45.1 (CH 2 ), 111.5 (C-H, Ph), 114.9 (OCHF 2 ), 128.9 (C, Ph), 141.0, 146.7 (C-H, Ph), 158.1 (C-O, Ph), 160.5 (C=N); 19 F NMR (DMSO-d 6 , 566 MHz): δ = -86.8 (d, 2F, J = 72.9 Hz) ppm. HRMS (ESI) calcd for C 10 H 12 F 2 N 5 O 3 [M+H] + : 288.0908. Found: 288.0917.N-(3-((6-(Difluoromethoxy)pyridin-3-yl)methyl)thiazolidin-2ylidene)cyanamide (16) 5-(Chloromethyl)-2-(difluoromethoxy)pyridine 14 (0.13 g, 0.69 mmol, 0.90 equiv.) was added dropwise to a solution of N-(4,5-dihydro-2-thiazolyl)cyanamide (98 mg, 0.76 mmol, 1 equiv.), potassium carbonate (0.10 g, 0.73 mmol, 0.96 equiv.) and caesium chloride (5.0 mg, 0.030 mmol, 0.03 equiv.) in acetonitrile (5 mL) at room temperature. The reaction mixture was stirred 5 hours at room temperature. It was then filtrated and the solvent was distilled off. The crude product was purified by HPLC on reverse phase with water/acetonitrile gradient, which afforded of 16 (158.5 mg, 72%); 1 H (DMSO-d 6 , 150 MHz): δ 3.49 (m, 2H, CH 2 ), 3.90 (m, 2H, CH 2 ), 4.62 (s, 2H, CH 2 ), 7.11 (d, 2H, C-H, Py, J = 8.4 Hz), 7.71 (t, 1H, OCHF 2 , J C-F = 72.7 Hz), 7.85 (dd, 1H, C-H, Py, J = 8.4 Hz, J = 2.5 Hz), 8.23 (d, 1H, C-H, Py, J = 2.5 Hz); 13 C NMR (proton-decoupled) (DMSO-d 6 , 150 MHz): δ 27.5, 46.4, 52.9 (CH 2 ), 111.5 (C-H, Py), 114.9 (OCHF 2 ), 128.0 (C, Py), 141.2, 147.0 (C-H, Py), 158.2 (C-O, Py), 174.8 (C=N); 19 F NMR (DMSO-d 6 , 566 MHz): δ = -86.88 (d, 2F, J = 72.8 Hz) ppm. HRMS (ESI) calcd for C 11 H 11 F 2 N 4 OS [M+H] + : 285.0622. Found: 285.0618.

Table 1 :

 1 Optimization of the reaction conditions for the difluoromethylation of 6chloropyridin-2-ol using difluoromethyl triflate.

	Entry	Base	Solvent	Yield [11a]
	1	KOH	DMSO	6%
	2	KOH	DMF	8%
	3	KOH	iPrOH	34%
	4	KOH	acetone	67%
	5	KOH	DME	66%
	6	KOH	dioxane	76%
	7	KOH	THF	83%
	8	KOH	MeCN	85%
	9	KOH a	MeCN	71%
	10	LiOH	MeCN	36%
	11	NaOH	MeCN	55%

Table 2 :

 2 Difluoromethylation of various N-based heterocycles using difluoromethyl triflate.

	Entry	Substrate	Product	Yield
	1	11a		72%
	2	11b		74%
	3	11c		41%
	4	11d		76%
	5	11e	(+	45%

50% N-CHF 2 )

	6	11f		66%
	7	11g		31%
	8	11h		32%
	9	11i	(+	28%

15% N-CHF 2 )

	10	O O S O F 3 C	F	F	10	11j	75%
			(3 equiv.)
	Het OH 11		KOH (6M)			Het OCHF 2 11k	11a-o	40%
		solvent, rt, 30 min
	12							11l	35%
		Cl	N	OH			Cl	N	OCHF 2
	13							11m	59%
				OH			OCHF 2
	14	Cl	N					11n	Cl	N	53%
			OH				OCHF 2
	15	Cl	N					11o	Cl	N	51% a
			OH				OCHF 2
		N	Br				N	Br
			Br				Br
		N	OH				N	OCHF 2
			Cl					Cl
				OH			OCHF 2
		Cl	N					Cl	N
			OH			OCHF 2
		N					N
			OH				OCHF 2
		N						N
			CO 2 Et			CO 2 Et
		N	OH					N	OCHF 2

Table 3 .

 3 Biological evaluation of the F 3 CO-and F 2 HCO-analogues of imidacloprid(8,15) and thiacloprid(9,16).

	Compound	Activity in vitro	Activity in vivo
		(pI50-value)	(Myzus persicae) [in g a.i. ha -1 ]
	Imidacloprid	9.1	0.16
	8	5.2	500
	9	4.8	100
	Thiacloprid	9.2	0.8
	15	5.3	100
	16	4.9	500

  C-NMR (101 MHz, DMSO-d 6 ): δ 162.5, 141.3, 133.0, 120.4, 118.2, 61.8, 26.3, 18.4, -4.7 ppm. HRMS (ESI) calcd for C 12 H 22 NO 2 Si [M+H] + : 240.142. Found: 240.141.

Acknowledgment

The authors thank the Centre National de la Recherche Scientifique (CNRS) France and are very much grateful to Bayer for grants to E. S. and G. L. The French Fluorine Network (GIS Fluor) is also acknowledged. The authors thank the analytical platform (GDS3648) and the mass spectroscopy service of the Chemistry Institute of Strasbourg for both microanalysis and HRMS results.


Alexander V Neimark
email: aneimark@rutgers.edu

François-Xavier Coudert
email: fx.coudert@chimie-paristech.fr

Anne Boutin

Alain H Fuchs

Stress-based model for the breathing of metal-organic frameworks

deformation and structural transitions associated with stepwise expansion and contraction of the material, known as breathing transitions between large pore (lp) and narrow pore (np) phases. We present here a simple yet instructive model for the physical mechanism of this enigmatic phenomenon considering the adsorption-induced stress exerted on the material as a stimulus that triggers breathing transitions. The proposed model implies that the structural transitions in MOFs occur when the stress reaches a certain critical threshold. We showcase this model drawing on the example of Xe adsorption on MIL-53 (Al) at 220 K, which exhibits two consecutive hysteretic breathing transitions between lp and np phases. We also propose an explanation for the experimentally observed coexistence of np and lp phases in MIL-53 materials. KEYWORDS: MOF, metal-organic frameworks, MIL-53, adsorption, structural flexibility, adsorption stress.

TOC graphic.

Metal-organic frameworks (MOFs) represent a rapidly expanding class of nanoporous materials that display an extremely wide range of crystal structures and host-guest properties due to the tunable porosity allowed by coordination chemistry, and the versatility enabled by functionalisation of organic linkers. It is anticipated that MOFs may have a major impact in many areas of science and technology. [START_REF] Yaghi | Synthetic Strategies, Structure Patterns, and Emerging Properties in the Chemistry of Modular Porous Solids[END_REF] A number of these materials exhibit an exceptional flexibility and stimulus-responsive behavior, [START_REF] Kitagawa | Dynamic porous properties of coordination polymers inspired by hydrogen bonds[END_REF][START_REF] Férey | Large breathing effects in three-dimensional porous hybrid matter: facts, analyses, rules and consequences[END_REF][START_REF] Kitagawa | Functional Porous Coordination Polymers[END_REF][START_REF] Ashleugh | Flexibility in metal-organic framework materials: Impact on sorption properties[END_REF][START_REF] Liu | Reversible Structural Transition in MIL-53 with Large Temperature Hysteresis[END_REF] reacting to changes in temperature, pressure, and adsorption of guest molecules by undergoing structural transformations. Such materials have promising applications as sensors and actuators, as well as in adsorptive separation. [START_REF] Férey | Large breathing effects in three-dimensional porous hybrid matter: facts, analyses, rules and consequences[END_REF][START_REF] Ashleugh | Flexibility in metal-organic framework materials: Impact on sorption properties[END_REF][START_REF] Li | Selective gas adsorption and separation in metal-organic frameworks[END_REF] The stimulus-responsive MOFs can be classified in two distinct categories. In some cases, variations in structure are progressive, as is the case of the swelling of MIL-88 upon exposure to water and various alcohols. [START_REF] Mellot-Draznieks | Very Large Swelling in Hybrid Frameworks: A Combined Computational and Powder Diffraction Study[END_REF] In other materials, the structural response is displayed by an abrupt transition between two distinct structures of the framework. A particularly remarkable example of MOFs exhibiting this bistability is the MIL-53 materials family, [START_REF] Millange | structure determination and properties of MIL-53as and MIL-53ht: the first Cr III hybrid inorganic-organic microporous solids: Cr III (OH)•{O 2 C-C 6 H 4 -CO 2 }•{HO 2 C-C 6 H 4 -CO 2 H} x[END_REF][START_REF] Loiseau | A Rationale for the Large Breathing of the Porous Aluminum Terephthalate (MIL-53) Upon Hydration[END_REF][START_REF] Serre | An Explanation for the Very Large Breathing Effect of a Metal-Organic Framework during CO 2 Adsorption[END_REF] which have recently attracted a lot of attention due to their prominent flexibility and the occurrence of a double, guest-induced structural transition ("breathing") upon adsorption of some gases (see Fig. 1). The MIL-53 framework is made of parallel one-dimensional M(OH) chains (M = Al 3+ , Cr 3+ ), linked together by 1,4-benzenedicarboxylate (BDC) ligands to form linear diamond-shaped channels that are wide enough to accommodate small guest molecules. This structure may oscillate (or "breathe") between two distinct conformations called a large-pore phase (lp) and a narrow-pore phase (np; see Fig. 1), which have a remarkable difference in cell volume of up to 40%. This breathing is clearly displayed on the adsorption-desorption isotherm of Xe at 220 K with two distinct hysteresis loops (Fig. 2). [START_REF] Boutin | Breathing Transitions in MIL-53(Al) Metal-Organic Framework Upon Xenon Adsorption[END_REF] At room temperature and in the absence of guest molecules, lp phase is the most stable form. [START_REF] Liu | Reversible Structural Transition in MIL-53 with Large Temperature Hysteresis[END_REF] However in the course of Xe adsorption, lp phase is transformed into np phase at low pressures and the reverse transformation occurs at high pressures. The conditions, at which the breathing of MIL-53 happens, have been widely studied earlier, and it was shown in particular to be triggered by changes in temperature, [START_REF] Liu | Reversible Structural Transition in MIL-53 with Large Temperature Hysteresis[END_REF] as well as adsorption of some gases and gas mixtures, but not others. [START_REF] Serre | An Explanation for the Very Large Breathing Effect of a Metal-Organic Framework during CO 2 Adsorption[END_REF][START_REF] Coudert | Thermodynamics of Guest-Induced Structural Transitions in Hybrid Organic-Inorganic Frameworks[END_REF] Recent work, that considered the issue from the point of view of thermodynamics, has been successful in rationalizing the conditions for the occurrence of breathing in MIL-53. [START_REF] Coudert | Thermodynamics of Guest-Induced Structural Transitions in Hybrid Organic-Inorganic Frameworks[END_REF] It was shown that, upon gas adsorption at a given temperature, the occurrence of breathing is conditioned by the relative adsorption affinities of the gas for the two host phases, lp and np, measured by the ratio of the Henry constants, K H lp /K H np , and by the intrinsic stability of the two respective framework conformations, characterized by the free energy difference !F host between the lp and np phases. [START_REF] Coudert | Double Structural Transition in Hybrid Material MIL-53 upon Hydrocarbon Adsorption: The Thermodynamics Behind the Scenes[END_REF] This thermodynamic analysis was then extended to fluid mixtures [START_REF] Coudert | Prediction of Breathing and Gate-Opening Transitions Upon Binary Mixture Adsorption in Metal-Organic Frameworks[END_REF] and to an investigation of temperature dependence, which allowed to predict complete pressure-composition and pressure-temperature phase diagrams for various adsorbates in MIL-53. 12,15 The thermodynamic approach described above is useful in understanding whether breathing occurs or not and in calculating the equilibrium vapor pressures, at which the structural transitions may take place.

However, it makes no assumption about and gives no insight into physical mechanisms of structural transitions associated with breathing, nor does it explain the hysteresis loops experimentally observed.

Numerous structural chemistry studies reported on MIL-53 are extremely useful for a general understanding of the phenomenon, but provide no direct insight into the transition mechanisms. [START_REF] Férey | Large breathing effects in three-dimensional porous hybrid matter: facts, analyses, rules and consequences[END_REF] In this letter, we present a simple yet instructive model for the structural transformations undergone by MIL-53 upon gas adsorption, considering the adsorption-induced stress as a stimulus that triggers these transformations. We describe how this model inherently accounts for the adsorption hysteresis observed experimentally and showcase, drawing on the example of Xenon adsorption in MIL-53 (Al) at 220 K, [START_REF] Boutin | Breathing Transitions in MIL-53(Al) Metal-Organic Framework Upon Xenon Adsorption[END_REF] that the model is coherent with the experimental data available so far. Finally, we propose an explanation for the existence of mixtures of np and lp phases observed in XRD experiments of CO 2 adsorption in MIL-53. 16 The proposed model relates the stress, exerted by the adsorbed phase on the adsorbent framework, with the adsorption isotherm. From the thermodynamic standpoint, the adsorption stress " s can be quantified by derivative of the grand thermodynamic potential ! c of the adsorbed phase per unit cell with respect to the unit cell volume V c at fixed temperature T and adsorbate chemical potential µ, [START_REF] Ravikovitch | Density Functional Theory Model of Adsorption Deformation[END_REF][START_REF] Kowalczyk | Adsorption-Induced Deformation of Microporous Carbons: Pore Size Distribution Effect[END_REF] " s V c

( ) = # $% c $V c & ' ( ) * + µ,T (1)
In pores of simple geometries of slit, cylindrical, or spherical shapes, the adsorption stress has a simple physical interpretation as a normal to the pore wall component of the stress tensor in the adsorbed phase. [START_REF] Evans | Phase-Equilibria and Solvation Forces for Fluids Confined Between Parallel Walls[END_REF][START_REF] Balbuena | Solvation Pressures for Simple Fluids in Micropores[END_REF][START_REF] Frink | Stress Isotherms of Porous Thin Materials: Theoretical Predictions from a Nonlocal Density Functional Theory[END_REF] In anisotropic materials like MOFs this interpretation is no longer valid, and one needs to introduce tensor quantities. However, the adsorption stress defined by Eq. 1 can serve as an overall scalar measure of the magnitude of the adsorption forces acting on the porous framework. The difference between the adsorption stress, " s , and the external pressure represents the so-called solvation or disjoining pressure, P s , which determines the magnitude of framework elastic deformation in terms of the volumetric strain # (# = "V c /V c , where "V c is the variation of the cell volume), assuming the linear Hooke law with an effective framework bulk modulus K, , where " 0 is a prestress in the reference state at which the cell volume V c is defined. [START_REF] Ravikovitch | Density Functional Theory Model of Adsorption Deformation[END_REF] The linear elasticity theory describes adsorption-induced deformations of microporous materials like zeolites and activated carbons, when the strain is small, typically in fractions of percent. [START_REF] Tvardovskiy | Sorbent Deformation[END_REF] . For breathing MOFs, experiencing structural transitions with the volume changes in tens of percent, the stress-strain linearity should hold only for the stable lp and np phases. In the vicinity of the transition, the stressstrain relationship becomes necessarily nonlinear and it may even diverge at the onset of the transition.

We hypothesize that the structural transition occurs when the solvation pressure approaches a certain critical stress " * that the framework cannot resist. The critical stress " * lp associated with the lp!np transitions should be negative, because this transition corresponds to a framework contraction, while the critical stress of lp!np transition " * np should be positive. As shown below, this hypothesis explains the hysteric behavior of structural transitions in breathing MOFs and is consistent with the existence of two breathing transitions in MIL-53 at low and high adsorptive pressures.

As shown earlier, the adsorption isotherms of Xe and some other vapors in lp and np structures of MIL-53 can be described by Langmuir equations with reasonable accuracy. [START_REF] Boutin | Breathing Transitions in MIL-53(Al) Metal-Organic Framework Upon Xenon Adsorption[END_REF][START_REF] Coudert | Thermodynamics of Guest-Induced Structural Transitions in Hybrid Organic-Inorganic Frameworks[END_REF][START_REF] Coudert | Double Structural Transition in Hybrid Material MIL-53 upon Hydrocarbon Adsorption: The Thermodynamics Behind the Scenes[END_REF] The Xe isotherm, plotted in Fig. 2 (upper panel) in logarithmic pressure coordinates, fits two Langmuirian isotherms for lp and np structures. These isotherms are presented by broken lines. It is remarkable that the same Langmuirian isotherm adequately describes the adsorption in lp structure at low pressures prior to the lp!np transition and adsorption at high pressures after np!lp transition. This observation complies with a picture of Xe adsorption in MIL-53 as a homogeneous filling of the pore channels, without distinctive, preferential adsorption sites. The saturation uptakes of Xe at 220 K are compatible with a single-file filling in np channels (about 3 atoms per np unit cell), and a dense stack of alternating pairs of atoms in lp channels (about 9 atoms per lp unit cell), see schematics in Fig. 1.

For a generic Langmuirian isotherm, N( p) = N 0 K H p /(N 0 + K H p), where N 0 is the unit cell capacity and K H is the Henry constant, the adsorption stress can be directly calculated invoking the general integral relationship between the grand thermodynamic potential and the adsorption isotherm,

" c p ( ) = #RT N 0 p $ ( p) d(ln p) = #RTN 0 ln(1+ K H p /N 0 ). (2)
From equations 1 and 2, the adsorption stress as a function of the vapor pressure is expressed as

(3)

In addition to N 0 and K H , the adsorption stress depends on the variations of these quantities with respect to the cell volume, and It is noteworthy, that while is apparently positive, in general negative. This gives rise to a nonmonotonic variation of the adsorption stress and, respectively, the solvation pressure in the course of adsorption, as seen from Eq. 3. In the Henry region at low pressures, is negative and decreasing, that corresponds to the sample contraction.

In the saturation region at high pressures, increases and may even become positive, leading to the sample expansion. Similar nonmonotonic isotherms of solvation pressure have been calculated by using the density functional theory [START_REF] Ravikovitch | Density Functional Theory Model of Adsorption Deformation[END_REF] and Monte Carlo simulations [START_REF] Kowalczyk | Adsorption-Induced Deformation of Microporous Carbons: Pore Size Distribution Effect[END_REF] to explain nonmonotonic deformation in the course of adsorption on zeolites and activated carbons, which is typical for many microporous materials. [START_REF] Tvardovskiy | Sorbent Deformation[END_REF] Schematics of structure transformations upon adsorption and desorption is presented in Fig. 2. The isotherms of solvation pressure for Xe adsorption at 220 K in lp and np phases of MIL-53 are given in the lower panel; the parameters employed for calculations are reported in Table 1. Since the parameters dN 0 dV c and dK H dV c for lp and np phases as well as pre-stresses are not known, and we do not pretend here to discuss the magnitude of the adsorption deformation (which would require knowledge of the framework elasticity), the solvation pressure is given in arbitrary units, that allows us to present a qualitative scenario of structural breathing transitions observed in experiments.

Host structure K H N 0 dK H /dV c dN 0 /dV c lp 50.1 bar -1 9.0 -2.6 10 -2 bar -1 Å -3 1.0 10 -2 Å -3 np 778.2 bar -1 2.8 -8.26 bar -1 Å -3 4.8 10 -3 Å -3

Table 1. Model parameters for adsorption of Xe in MIL-53 (Al) at 220 K: Langmuir parameters (K H and N 0 ) are taken from Ref. 12, and their derivatives with respect to unit cell volume were optimized to reproduce the experimental pressures of adsorption and desorption steps. [START_REF] Boutin | Breathing Transitions in MIL-53(Al) Metal-Organic Framework Upon Xenon Adsorption[END_REF] According to the adopted model, adsorption starts in lp phase. At low vapor pressures, the solvation pressure decreases causing sample contraction in an elastic fashion; the volume changes may be very minor. Once the critical value of " * lp is reached, the lp phase becomes unstable and the first structural transition occurs, from lp to np, causing an "abnormal breathing" -the sample contracts while inhaling. This results in a sharp uptake step on the adsorption isotherm; the sample volume decreases by ~40% (line A1 in Fig. 2). Upon further increase of vapor pressure, adsorption proceeds in np phase and the solvation pressure varies gradually, as is typical for the saturation region of Langmuir isotherm. At a certain point, the solvation pressure starts to increase, causing elastic expansion of the sample. Once the critical stress " * np , which np phase cannot withhold, is attained, a second structural transition, from np to lp, occurs, causing a "normal breathing" -the sample expands while inhaling. The sample volume increases by ~40%. This is displayed by the second step on the adsorption isotherm (line A2). As adsorption occurs further in lp phase, the solvation pressure increases, causing elastic expansion of the sample, which remains stable.

On the desorption pass, the isotherm displays a striking hysteresis. Desorption starts and proceeds in lp phase until the solvation pressure, which decreases as the vapor pressure decreases, reaches the critical stress " * lp that triggers the structural transition from lp to np. This is displayed by a sharp downward step on the desorption isotherm (line D1). We assume here that the critical stress " * lp does not depend on the adsorbed phase and is the same as that for the first lp!np transition at low pressure adsorption. At the same time, the vapor pressure that corresponds to the critical stress " * lp exerted in lp phase in the process of desorption is lower than the vapor pressure that corresponds to the critical stress " * np exerted in np phase in the process of adsorption: this is the origin of hysteresis in the system under consideration. After the first desorption-induced transition, desorption proceeds further in accord with the np Langmuirian isotherm, until the solvation pressure reaches the critical stress " * np , leading to a final low-pressure transition back to lp phase and the second downward step on the desorption isotherm (line D2). This transition happens at a pressure lower than that of the first lp!np adsorption-induced transition, explaining the low-pressure hysteresis loop, assuming again that the critical stress " * np does not depend on the adsorbed phase and is determined by the mechanical properties of the np framework itself.

In addition to providing a plausible stress-based mechanism for the breathing structural transitions of MIL-53 upon guest adsorption, the proposed model sheds some light into the existence of lp/np phase mixtures at pressure close to the breathing pressures. According to ref. 16, the coexistence of phases occurs to some proportion in all of the adsorption systems studied so far such as MIL-53. Thus, while no X-ray diffraction study of the Xe-loaded MIL-53 has yet been performed, the coexistence of lp and np phases within certain pressure ranges of vapor pressures may be expected. Based on the proposed model, the simplest explanation for a possible phase coexistence can be suggested assuming that the experimental sample of MIL-53 is composed of a large number of crystallites of different sizes. If we hypothesize that the size of a given crystallite influences the critical stress that it can withhold being in the particular phase, the existence of a distribution of crystallite sizes induces a certain distribution of " * np and " * lp values. As such, not all crystallites will undergo phase transitions at the same vapor pressure, leading to the coexistence of the two phases within a certain pressure range. This effect causes rounding the isotherm steps in the vicinities of structural transitions. We show in Fig. 3 The present model can be tested against a variety of other guest-host systems at different temperatures. We also expect that this model may be applied to other types of flexible hybrid materials, such as the coordination polymers, which exhibit the so-called "gate opening" phenomenon.

ACKNOWLEDGMENT. A.V.N. acknowledges the ARO grant W911NF-09-1-0242 and the Région Île-de-France for the support via a Blaise Pascal International Research Chair, administered by the Fondation de l'École normale supérieure.

Figure 1 .

 1 Figure 1. Schematic representation of the breathing phenomenon of MIL-53 (Al), exhibiting two successive structural transitions upon adsorption of some gases (here, Xe at 220 K). The two possible states of bistable MIL-53 (Al) are called np (narrow pore) and lp (large pore).

Figure 2 .

 2 Figure 2. Upper panel: experimental adsorption and desorption isotherms of Xe in MIL-53 (Al) at 220 K 12 (in blue), in logarithmic pressure scale, along with Langmuirian fits of the parts of the isotherm corresponding to the lp and np structures (black and red). Lower panel: adsorption stress for both host phases (black: lp; red: np) and critical stress ! * np and ! * lp determining the structural transitions upon adsorption and desorption (blue arrows, and pressures noted as A1, A2, D1 and D2).

  an example of quantitative predictions based on this hypothesis with Gaussian distributions of " * np and " * lp chosen to be compatible with the experimental spread of the adsorption and desorption steps; the upper panel shows the calculated isotherms, while the lower panel shows the lp-np phase composition as a function of pressure.

Figure 3 .

 3 Figure 3. Calculated adsorption and desorption isotherms (upper panel) and lp phase composition (lower panel) for a model representing an assembly of crystallites of different sizes and critical stress values.

Llewellyn, P. L.; Maurin, G.; Devic, T.; Loera-Serna, S.; Rosenbach, N.; Serre, C.; Bourrelly, S.;


Guillermo López Quesada

Giorgos Tatsios

Stéphane Colin

Dimitris Valougeorgis

Lucien Baldas

Christine Barrot

Marcos Rojas-Cárdenas

Guillermo Lopez Quesada

Marcos Rojas-Cardenas

Computational study of a novel Knudsen pump design exploiting drilling and 3D printing techniques in low thermal conductivity materials

Keywords: Vacuum micropump, thermal transpiration, kinetic modeling

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

Over the past two decades a large number of MEMS and micro-devices have been developed. These miniaturized systems, such as lab-on-chip sensors, gas chromatography analyzers, etc., require micro-pumps for air sampling through the testing stages of the device. Additionally, some microscale components such as radio frequency switches, microscopic vacuum tubes and other parts that depend on electron or ion optics, require certain vacuum environment for proper operation. Simply sealing the devices is not sufficient because leaks and outgassing are excessively detrimental in vacuum devices at microscale level. Accordingly, such components may need vacuum pumping to maintain proper functionality. The thermal transpiration phenomenon has been extensively investigated; however, functional prototypes based on this phenomenon have been only recently developed. The Knudsen pump, which is one of the devices exploiting this well-known phenomenon, is able to generate a macroscopic gas flow by solely exploiting a tangential temperature gradient along a surface without requiring any external pressure gradient [START_REF] Colin | Single-phase gas flow in microchannels. Heat transfer and fluid flow in minichannels and microchannels[END_REF]. Still, fabricating a Knudsen pump is not a trivial task mainly due to microfabrication difficulties and constraints linked to the control of local thermal gradients [START_REF] Qin | Arrayed architectures for multi-stage Si-micromachined high-flow Knudsen pumps[END_REF][START_REF] An | A Si-micromachined 162-stage two-part Knudsen pump for on-chip vacuum[END_REF]. In this work, a novel Knudsen pump is proposed. Instead of following the typical process of etching along the substrate surface, the microchannels are fabricated by laser drilling or 3D printing techniques across the thickness of the wafer, as shown in Fig. 1. In this novel layout of the Knudsen pump, the microfabrication process is fundamentally simplified. Furthermore, the implementation of low thermal conductivity materials such as glass or polymers decreases the overall power consumption of the device and increases the thermal gradient that can be achieved along the wall of the channels. Additionally, by manufacturing the channels through the thickness of the device, the hot and cold regions of the Knudsen pump are spatially separated resulting to an easier temperature control. Using this design, three different configurations can be developed (Fig. 1): A. Multiple parallel channels for high mass flow rate and low pressure difference. B. Multistage assembly of single channels in series for high pressure difference and low mass flow rate. C. Combination of the two previous configurations to find a compromise between achieved pressure difference and mass flow rate. The two important performance metrics for these micropumps are the mass flow rate ṁ and the pressure difference ΔP between the inlet and the outlet of the pump. Depending on the target application of the Knudsen pump, the required performance can vary considerably. The idea is that for a particular surface area, depending on the application of the Knudsen pump, channels can be arranged all in parallel to maximize ṁ (configuration A), all in series to maximize ΔP (configuration B) or to compromise between the limiting conditions (configuration C). Atlanta,USA, 9-12 September 2018 The numerical study is based on the linearized Shakhov kinetic model subject to diffuse boundary conditions. The deduced kinetic coefficients are introduced in a mass balance equation to yield the flow rate and the pressure difference [START_REF] Tatsios | Computational investigation and parametrization of the pumping effect in temperature driven flows through long tapered channels[END_REF]. The computational investigation involves the analysis of configurations A and B, so that their solutions are combined to characterize configuration C. Here, results for a representative configuration C are presented. Each pumping sub-stage is taken to be a square area of 200 μm x 200 μm with 100 channels of diameter D = 10 μm in parallel (easily achieved by various microfabrication processes). Each backflow sub-stage is also a square area of 200 μm x 200 μm with a single channel of diameter D = 100 μm. The length of the channels is L = 300 μm (following the typical thickness of glass wafers). The temperatures at the cold and hot sides of the channels are TC = 300 K and TH = 400 K respectively (following previous experimental experience [START_REF] Rojas-Cárdenas | Temperature gradient induced rarefied gas flows[END_REF]). The numerical simulations have been performed for various operating inlet pressures Pin = 1 kPa, 5 kPa, 10 kPa, 20 kPa, 50 kPa and 100 kPa and considering argon as the working gas. As it was expected from previous analysis in multistage systems with orthogonal channels [START_REF] Tatsios | Computational investigation and parametrization of the pumping effect in temperature driven flows through long tapered channels[END_REF], in most cases ΔP increases almost linearly with the number of stages (Fig 2 -top). Only, in the case of the lowest operating pressure of 1 kPa, the pressure difference is not increased in an exactly linear manner in the first stages due to the non-linearity at higher rarefaction flow regimes (transitional regime). Depending on the size of the channel, the maximum ΔP is found at a gas rarefaction parameterr δ = 4-8, which for the channel diameter D = 10 μm corresponds to an operating inlet pressure around 5 kPa. This finding has been also experimentally observed [START_REF] Rojas-Cárdenas | Temperature gradient induced rarefied gas flows[END_REF]. This remark also justifies the fact that ΔP increases as the inlet pressure in P decreases until reaching the maximum performance at Pin = 5 kPa and then, for Pin = 1 kPa is slightly decreased. This is more evident for a small number of stages, where δ is small, while as the number of stages increases and δ is also increased the difference in ΔP is decreased and finally, by the 100 th stage both cases of Pin = 1 and 5 kPa provide about the same performance. Regarding the mass flow rate ṁ (Fig 2 -bottom), it drops rather rapidly as the number of stages is increased from one up to ten stages and then, as the number of stages is further increased, it is reduced very slowly in an asymptotic manner. The reduction of the mass flow rate depends on the operating pressure, being bigger when the flow regime is more rarefied (at 1 kPa the reduction is 25%) in opposition to the very low reduction closer to the hydrodynamic regime (at 100 kPa the reduction is only 1%). This evolution of ΔP and the mass flow rate with the number of stages is interesting for designing a multistage pump since by increasing the number of stages to more than ten the pressure difference grows linearly, while the mass flow rate remains almost constant. As a conclusion, a novel design for a Knudsen pump has been presented and computationally explored by taking into consideration tentative manufacturing and experimental constraints. The proposed design aims to achieve particular performances for targeted applications by tailoring the pumping stages (either increasing the parallel channels for enhancing the mass flow rate or increasing the number of stages to boost the pressure difference). It is noted that the presented results up to 100 stages only needs a footprint of 8 mm 2 , which is more than four thousand times smaller than previous designs [START_REF] Qin | Arrayed architectures for multi-stage Si-micromachined high-flow Knudsen pumps[END_REF][START_REF] An | A Si-micromachined 162-stage two-part Knudsen pump for on-chip vacuum[END_REF]. Therefore, the compactness of the design is very good. Finally, a prototype is being manufactured and corresponding experimental work is expected to begin shortly.

Figure 1 .

 1 Figure 1. Representative view of the three different configurations; yellow arrows denote the pumping flow direction.

Acknowledgements

This project has received funding from the European Union's Framework Programme for Research and Innovation Horizon 2020 (2014-2020) under the Marie Skłodowska-Curie Grant Agreement No. 643095.