Hydrosoluble Complexes Bearing Tris(pyrazolyl)methane Sulfonate Ligand: Synthesis, Characterization and Catalytic Activity for Henry Reaction Hydrosoluble Complexes Bearing Tris(pyrazolyl)methane Sulfonate Ligand: Synthesis, Characterization and Catalytic Activity for Henry Reaction

: The catalytic activity of the water-soluble scorpionate coordination compounds towards the (Henry) reaction between nitromethane nitroethane in aqueous medium a respectively, 2-nitro-1-phenylethanol or 2-nitro-1-phenylpropanol, the latter in the syn and the anti diastereoisomeric forms. Complex 1 exhibited the highest activity under the optimum experimental conditions and was used to broaden the scope of the reaction to include several aromatic aldehydes achieving yields up to 94%. Abstract: The catalytic activity of the water-soluble scorpionate coordination compounds [Cu( κ NN’O -Tpms) 2 ] ( 1 ), [Mn(Tpms) 2 ] ( 2 ) and Li[FeCl 2 ( κ - NN’N’’ -Tpms)] ( 3 ) [Tpms = tris(pyrazolyl)-methane sulfonate, O 3 SC(pz) 3 − ], were studied towards the (Henry) reaction between benzaldehyde and nitromethane or nitroethane in aqueous medium to afford, respectively, 2-nitro-1-phenylethanol or 2-nitro-1-phenylpropanol, the latter in the syn and the anti diastereoisomeric forms. Complex 1 exhibited the highest activity under the optimum experimental conditions and was used to broaden the scope of the reaction to include several aromatic aldehydes achieving yields up to 94%.


Introduction
Scorpionate is a term coined by Trofimenko [1] to describe a special class of poly(pyrazolyl) compounds, which are derived from two or more N-deprotonated pyrazole rings bound to a main group atom (e.g., boron, carbon, aluminium, indium, gallium, silicon, and germanium) through one of the ring nitrogens [1][2][3][4][5][6]. Tris(pyrazolyl)methanes (Tpm, Figure 1) were reported for the first time in 1937 [7]. However, up to mid-90s, their properties and coordination chemistry remained unexplored due to the difficulties of their preparation in good yields, until Reger has reviewed some effective synthetic protocols to prepare Tpm compounds in high yields [8][9][10].  The hydrophilic nature of Tpms and its complexes makes them potentially useful in the area of enzyme modelling and catalysis, where systems that operate in aqueous solution are actively sought after due to the inherently potential sustainable processes [11]. Although the coordination properties of Tpms have been well studied towards diverse metal centers, the use of Tpms-containing hydrosoluble complexes in aqueous medium catalysis is limited to scarce examples, in particular for oxidation [16,[33][34][35], hydroformylation [19], and hydrogenation [20] reactions. The catalytic activity of Tpms-metal complexes for nitroaldol (Henry) reaction has not yet been investigated.
On the basis of the above considerations, herein we report the catalytic performance of welldefined hydrosoluble Cu(II), Mn(II), and Fe(II) complexes 1-3 bearing a Tpms ligand for Henry reaction in a homogeneous aqueous medium, for which a high Lewis acid character of the catalyst should constitute a favorable feature.
The hydrophilic nature of Tpms and its complexes makes them potentially useful in the area of enzyme modelling and catalysis, where systems that operate in aqueous solution are actively sought after due to the inherently potential sustainable processes [11]. Although the coordination properties of Tpms have been well studied towards diverse metal centers, the use of Tpms-containing hydrosoluble complexes in aqueous medium catalysis is limited to scarce examples, in particular for oxidation [16,[33][34][35], hydroformylation [19], and hydrogenation [20] reactions. The catalytic activity of Tpms-metal complexes for nitroaldol (Henry) reaction has not yet been investigated.
On the basis of the above considerations, herein we report the catalytic performance of well-defined hydrosoluble Cu(II), Mn(II), and Fe(II) complexes 1-3 bearing a Tpms ligand for Henry reaction in a homogeneous aqueous medium, for which a high Lewis acid character of the catalyst should constitute a favorable feature.

Description of the X-Ray Crystal Structure
The molecular structure of 1 was established by single crystal X-ray diffraction (SCXRD) analysis. The crystals were obtained as described in the experimental section. Selected Complexes 1-3 are stable in air both in the solid state and in solution. While 2 and 3 show a good solubility in water, DMSO and MeCN, 1 can be dissolved only in hot water after stirring for several hours, or upon addition of few drops of 0.1 M NH 4 OH to raise the pH to 9. The formulations of 1-3 were confirmed by spectroscopic and analytical data (see experimental section). As expected, compounds 1 and 2 are paramagnetic.
The IR spectra of the compounds exhibit a set of bands with diverse intensities typical of the Tpms ligand [66], in particular the ν(C=C) and ν(C=N) vibrations of the pyrazolyl groups in the range of ca. 1651-1506 cm −1 , in addition to the ν(S=O) in the range of 1064-1036 cm −1 .
ESI-MS spectra for the complexes were obtained in water solutions. In the negative mode a common peak corresponding to [O 3 SC(pz) 3 ] − is revealed and represents the base peak; in the positive mode the spectra of the complexes do not show the [M] + molecular ion peak, but a set of other peaks assigned to the compounds fragmentations.

Description of the X-ray Crystal Structure
The molecular structure of 1 was established by single crystal X-ray diffraction (SCXRD) analysis. The crystals were obtained as described in the experimental section. Selected crystallographic data and structure refinement details are provided in Table S1. Selected bond distances and angles are listed in Table S2.
Complex 1 crystallized in the orthorhombic space group Pbca, its asymmetric unit comprising the copper metal cation and one Tpms unit ( Figure 2). The metal presents a slightly distorted N 4 [65], on account of the metal lower oxidation state in the latter. However, it is also lower than those found in the copper(II) complex with 2,2,2-tris(pyrazol-1-yl)ethyl methanesulfonate ligands, working as NNN-chelators [1.999(3)-2.347(3) Å] [67]. Although the long Cu-O dimension in 1 can be due to Jahn-Teller distortion [68][69][70], it is similar to that found in the Cu(I) complex [65]. The coordinated pyrazolyl rings and sulfonate group restrict the intra-ligand N-Cu-N and N-Cu-O angles to the range 83.32(7) • -86.28(7) • , it is therefore shorter than the expected 90 • .
Catalysts 2019, 9, x FOR PEER REVIEW 4 of 14 crystallographic data and structure refinement details are provided in Table S1. Selected bond distances and angles are listed in Table S2. Complex 1 crystallized in the orthorhombic space group Pbca, its asymmetric unit comprising the copper metal cation and one Tpms unit ( Figure 2). The metal presents a slightly distorted N4O2 octahedral geometry, with the ligands exhibiting κ-NNʹO coordination modes. The N-donor atoms occupy the equatorial positions with Cu-N bond distances of 1.9829 (16) [65], on account of the metal lower oxidation state in the latter. However, it is also lower than those found in the copper(II) complex with 2,2,2-tris(pyrazol-1-yl)ethyl methanesulfonate ligands, working as NNN-chelators [1.999(3)−2.347(3) Å] [67]. Although the long Cu-O dimension in 1 can be due to Jahn-Teller distortion [68][69][70], it is similar to that found in the Cu(I) complex [65]. The coordinated pyrazolyl rings and sulfonate group restrict the intra-ligand N-Cu-N and N-Cu-O angles to the range 83.32(7)º−86.28(7)º, it is therefore shorter than the expected 90°.

Catalytic Activity
Compounds 1-3 were tested, under atmospheric mild homogeneous reaction conditions, as catalysts for nitroaldol coupling of nitromethane with benzaldehyde in water to afford 2-nitro-1phenylethanol. Using as a model the reaction of benzaldehyde with nitromethane (see Table 1), using 5 mol% of catalyst in water as sole solvent for 24 h and at 75 °C, the Cu(II) complex 1 exhibited the highest catalytic activity for the Henry reaction (Table 1, entries 1-3). Therefore, it was employed for further exploration of several reaction variables in order to find the optimum conditions to afford the highest yield of the product.  Figure 2. ORTEP diagram of 1 with displacement ellipsoids shown at 40% probability level and partial atom labelling scheme. Symmetry operation (i) to generate the equivalent atoms: -x,-y,1-z.

Catalytic Activity
Compounds 1-3 were tested, under atmospheric mild homogeneous reaction conditions, as catalysts for nitroaldol coupling of nitromethane with benzaldehyde in water to afford 2-nitro-1-phenylethanol. Using as a model the reaction of benzaldehyde with nitromethane (see Table 1), using 5 mol% of catalyst in water as sole solvent for 24 h and at 75 • C, the Cu(II) complex 1 exhibited the highest catalytic activity for the Henry reaction (Table 1, entries 1-3). Therefore, it was employed for further exploration of several reaction variables in order to find the optimum conditions to afford the highest yield of the product. catalysts for nitroaldol coupling of nitromethane with benzaldehyde in water to afford 2-nitro-1-phenylethanol. Using as a model the reaction of benzaldehyde with nitromethane (see Table 1), using 5 mol% of catalyst in water as sole solvent for 24 h and at 75 °C, the Cu(II) complex 1 exhibited the highest catalytic activity for the Henry reaction (Table 1, entries 1-3). Therefore, it was employed for further exploration of several reaction variables in order to find the optimum conditions to afford the highest yield of the product.  Figure S3). d Moles of 2-nitro-1-phenylethanol per mol of catalyst. e In the presence of 5 mol% triethylamine.
The reaction progression with time has been monitored in water using 5 mol% of the catalyst, at 75 • C ( Table 1, entries 1 and 4-9). 2-Nitro-1-phenylethanol yield raised gradually with time up to 77% upon 48 h, and a further extension of the reaction time did not lead to a significant change. Performing the reaction in different solvents (Table 1, entries 10-20, and Figure 3) revealed the following points: using solely a protic solvent (e.g., water, methanol, or ethanol) led to higher 2-nitro-1-phenylethanol yields than the use of other organic solvents for the same period of time (Table 1, entries 10-15); MeOH gave the highest yield of 61%. Generally, by using a 1:1 combination of water and organic co-solvent (Table 1, entries [16][17][18][19][20] better yields were obtained. A 1:1 mixture of water and MeOH gave a yield (59%) very close to that obtained using MeOH alone (Table 1, entries 10  and 16). Finally, the use of a 1:1 immiscible mixture of CH 2 Cl 2 or toluene with water in a bi-phasic catalytic system gave lower product yields (28% and 31%, respectively) when compared to other miscible aqueous combinations (Table 1, compare entries [16][17][18][19][20]. It was observed that in a mixture of water and MeOH, the rise in temperature up to 100 °C led to an increase in the reaction yield to 89% after 48 h (Table 1, entries 21-23). Also, increasing the catalyst loading from 0.5 mol% to 5 mol% raised the reaction yield from 14% to 78% (Table 1, entries 22 and [24][25][26]. In the presence of an additional catalytic amount of a base (i.e., 5 mol% of catalyst 1 and a similar amount of triethylamine), the conversion was quantitative after only 12 h in water, at room temperature ( By replacing nitromethane in the model reaction with nitroethane, the β-nitro alcohol is produced in the diastereoisomeric syn and the anti forms of 2-nitro-1-phenylpropanol (Table 2). In a water/MeOH (1:1) mixture, using 5 mol% of catalyst 1 at 100 °C a yield of 85% (maximum) was reached in 48 h exhibiting superior selectivity for the syn isomer ( Table 2, entries 1-4). The presence of 5 mol% of triethylamine improved the reaction performance in terms of yield (97%) at ambient temperature and in a shorter time and but with a significant decrease in selectivity (Table 2, entry 5).  It was observed that in a mixture of water and MeOH, the rise in temperature up to 100 • C led to an increase in the reaction yield to 89% after 48 h (Table 1, entries 21-23). Also, increasing the catalyst loading from 0.5 mol% to 5 mol% raised the reaction yield from 14% to 78% (Table 1, entries 22 and 24-26).
In the presence of an additional catalytic amount of a base (i.e., 5 mol% of catalyst 1 and a similar amount of triethylamine), the conversion was quantitative after only 12 h in water, at room temperature ( By replacing nitromethane in the model reaction with nitroethane, the β-nitro alcohol is produced in the diastereoisomeric syn and the anti forms of 2-nitro-1-phenylpropanol (Table 2). In a water/MeOH (1:1) mixture, using 5 mol% of catalyst 1 at 100 • C a yield of 85% (maximum) was reached in 48 h exhibiting superior selectivity for the syn isomer ( Table 2, entries 1-4). The presence of 5 mol% of triethylamine improved the reaction performance in terms of yield (97%) at ambient temperature and in a shorter time and but with a significant decrease in selectivity (Table 2, entry 5). By replacing nitromethane in the model reaction with nitroethane, the β-nitro alcohol is produced in the diastereoisomeric syn and the anti forms of 2-nitro-1-phenylpropanol (Table 2). In a water/MeOH (1:1) mixture, using 5 mol% of catalyst 1 at 100 °C a yield of 85% (maximum) was reached in 48 h exhibiting superior selectivity for the syn isomer ( Table 2, entries 1-4). The presence of 5 mol% of triethylamine improved the reaction performance in terms of yield (97%) at ambient temperature and in a shorter time and but with a significant decrease in selectivity (   Figure S4). d Moles of 2-nitro-1-phenylpropanol per mol of catalyst. e In the presence of triethylamine (5 mol%).
In accordance with previous studies, [71][72][73][74] the mechanism of the reaction involves metal assisted (upon coordination) deprotonation of nitroalkane to produce the nitronate species, and activation of the aldehyde for its electrophilic attack to the nitronate. Therefore, the Cu(II) complex 1 acts efficiently as a Lewis acid for the aforementioned activation process and, furthermore, the Tpms ligand can behave as a base to enhance the nitroalkane deprotonation.
Based on the study of several variables, it was found that the best reaction conditions to obtain the highest possible yield of β-nitro alcohols using catalyst 1 (5 mol%) is by heating the reaction mixture at 100 • C for 48 h in a mixture of water and MeOH.
The scope of the catalytic reaction was broadened to include different para-substituted aromatic aldehydes (Table 3) under the aforementioned optimum conditions.
Using either nitromethane or nitroethane, the reaction proceeded smoothly to afford the corresponding β-nitro alcohols with yields up to 94%, exhibiting higher selectivity towards the syn isomer if nitroethane was employed. The results show that the aromatic aldehydes with electron-donating substituents (OCH 3 or CH 3 , Table 3, entries 1-4) exhibit a lower reactivity than those bearing electron-withdrawing groups (NO 2 , Br or Cl, Table 3, entries 7-12) due to the higher electrophilicity of the aldehyde in the latter case. In comparison to the scarce examples found in the literature for the catalytic nitroaldol reaction in water, using catalysts based on different metals (Table S3), the conversions obtained in this work are comparable, or better in some cases, taking into consideration the indicated reaction conditions such as temperature, amount of catalyst, and reaction time [43,44,[60][61][62][75][76][77][78][79][80]. Based on the study of several variables, it was found that the best reaction conditions to obtain the highest possible yield of β-nitro alcohols using catalyst 1 (5 mol%) is by heating the reaction mixture at 100 ºC for 48 h in a mixture of water and MeOH.
The scope of the catalytic reaction was broadened to include different para-substituted aromatic aldehydes (Table 3) under the aforementioned optimum conditions. Using either nitromethane or nitroethane, the reaction proceeded smoothly to afford the corresponding β-nitro alcohols with yields up to 94%, exhibiting higher selectivity towards the syn isomer if nitroethane was employed. The results show that the aromatic aldehydes with electrondonating substituents (OCH3 or CH3, Table 3, entries 1-4) exhibit a lower reactivity than those bearing electron-withdrawing groups (NO2, Br or Cl, Table 3, entries 7-12) due to the higher electrophilicity of the aldehyde in the latter case. In comparison to the scarce examples found in the literature for the catalytic nitroaldol reaction in water, using catalysts based on different metals (Table S3), the conversions obtained in this work are comparable, or better in some cases, taking into consideration the indicated reaction conditions such as temperature, amount of catalyst, and reaction time [43,44,[60][61][62][75][76][77][78][79][80].

General Procedures and Instrumentation
All synthetic procedures were performed in air. Reagents and solvents were obtained from commercial sources and used without further purification. Li(Tpms) [32] and complex 3 [33] were synthesized using the reported procedures.
C, H, N and S elemental analyses were carried out by the Microanalytical services of the Instituto Superior Técnico. Infrared spectra (4000-400 cm −1 ) were obtained in a Cary 630 FTIR spectrometer (Agilent, Santa Clara, CA, USA); wavenumbers are in cm −1 ; abbreviations: s, strong; m, medium; w, weak. Electrospray mass spectra were obtained with a Varian 500 MS LC Ion Trap Mass Spectrometer equipped with an electrospray (ESI) ion source. For electrospray ionization, the drying gas and flow rate were optimized according to the particular sample with 35 p.s.i. nebulizer pressure. The compounds were observed in the negative and positive modes (capillary voltage = 80-105 V). 1 H spectra were obtained using Bruker Advance III 300 or 400 MHz UltraShield Magnet spectrometer (Bruker, Billerica, MA, USA), at ambient temperature.
X-ray quality crystals of 1 were obtained after dissolving the compound (25 mg) in an acetonitrile: 0.1 M NH 4 OH aqueous solution (10:1.5 mL) following slow evaporation in air. Compound 1 was

General Procedure for β-Nitro Alcohols Synthesis
In a typical experiment, a mixture of the nitroalkane (1.5 mmol), the catalyst (0.025 mmol) and 2 mL of solvent, was prepared with constant stirring for 15 minutes. Then, the aldehyde (0.5 mmol) was added. The solution stirred in atmospheric conditions and for the time intervals indicated in Tables 1-3. After the desired reaction time, 3 mL water were added to the solution and extracted with diethyl ether (3 × 10 mL). The combined extracts were dried over Na 2 SO 4 (anhydrous), and the mixture filtered off. The diethyl ether was removed using vacuum, and the organic residue was analyzed by 1 H NMR spectroscopy, in CDCl 3 , to calculate the yield of β-nitro alcohol as no other products were detected.

X-ray Structure Determination of Compounds
An X-ray quality crystal of 1 and of Li(Tpms) were immersed in cryo-oil, mounted in a Nylon loop and measured at ambient temperature. Intensity data were collected in a Bruker AXS-KAPPA APEX II PHOTON 100 diffractometer (Bruker, Billerica, MA, USA) with graphite monochromated Mo-Kα (0.71069 Å) radiation. Data were collected using omega scans of 0.5 • per frame and a full sphere of data was obtained. Cell parameters were retrieved using Bruker SMART [86] software and refined using Bruker SAINT [86] on all the observed reflections. SADABS program was used for applying absorption corrections [87]. The structure was solved by direct methods using SIR97 package [88] and refined with SHELXL-2014/7 [89]. The WinGX System-Version 2014.1 was used for the calculations [90]. Least square refinements with anisotropic thermal motion parameters for all the non-hydrogen atoms and isotropic ones for the remaining atoms were employed.
CCDC 1936856 (1) and 1936857 [Li(Tpms)] contain the supplementary crystallographic data for this paper. This data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

Conclusions
The tris(pyrazolyl)-methane sulfonate compounds [Cu(κ-NN'O-Tpms) 2 ] (1), [Mn(Tpms) 2 ] (2) and Li[FeCl 2 (κ-NN N"-Tpms)] (3) were the first Tpms complexes to be investigated as catalysts towards the nitroaldol (Henry) reaction between benzaldehyde and nitromethane to afford the corresponding 2-nitro-1-phenylethanol. Complex 1 was the most active (89% yield) under the following optimum reaction conditions: 5 mol% of catalyst, 1:1 water:MeOH solvent mixture, 100 • C, and for 48 h. Reacting benzaldehyde with nitroethane in the presence of 1, and under the given experimental conditions, produced 2-nitro-1-phenylpropanol in the syn and the anti diastereoisomeric forms, with a total yield of 85% and a higher selectivity towards the former. The scope of the reaction was broadened to include several aromatic aldehydes, which were reacted with any of the nitroalkanes. Higher yields (up to 94%) were obtained with aldehydes possessing electron-withdrawing groups.