Water-Soluble O-, S- and Se-Functionalized Cyclic Acetyl-triaza-phosphines. Synthesis, Characterization and Application in Catalytic Azide-alkyne Cycloaddition

The 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane (DAPTA) derivatives, viz. the already reported 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane 5-oxide (DAPTA=O, 1), the novel 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane-5-sulfide (DAPTA=S, 2), and 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane-5-selenide (DAPTA=Se, 3), have been synthesized under mild conditions. They are soluble in water and most common organic solvents and have been characterized using 1H and 31P NMR spectroscopy and, for 2 and 3, also by single crystal X-ray diffraction. The effect of O, S, or Se at the phosphorus atom on the structural features of the compounds has been investigated, also through the analyses of Hirshfeld surfaces. The presence of 1–3 enhances the activity of copper for the catalytic azide-alkyne cycloaddition reaction in an aqueous medium. The combination of cheaply available copper (II) acetate and compound 1 has been used as a catalyst for the one-pot and 1,4-regioselective procedure to obtain 1,2,3-triazoles with high yields and according to ‘click rules’.


Synthesis and Characterization of 1-3
Oxidation of DAPTA with hydrogen peroxide in ethanol leads to the formation of DAPTA=O (1) in 79% yield (Scheme 2, route I). Reaction of DAPTA with sulphur or selenium in methanol, under ultrasonic irradiation for 1h and at room temperature afforded DAPTA=S (2) or DAPTA=Se (3) Molecules 2020, 25, 5479 3 of 16 in good yields, 94 and 64%, respectively (Scheme 2, routes II and III). Compounds 1-3 exhibit high solubility in water, dimethyl sulfoxide, methanol, and chloroform, whereas they are not soluble in diethyl ether, benzene, and hexane.

Synthesis and Characterization of 1-3
Oxidation of DAPTA with hydrogen peroxide in ethanol leads to the formation of DAPTA=O (1) in 79% yield (Scheme 2, route I). Reaction of DAPTA with sulphur or selenium in methanol, under ultrasonic irradiation for 1h and at room temperature afforded DAPTA=S (2) or DAPTA=Se (3) in good yields, 94 and 64%, respectively (Scheme 2, routes II and III). Compounds 1-3 exhibit high solubility in water, dimethyl sulfoxide, methanol, and chloroform, whereas they are not soluble in diethyl ether, benzene, and hexane.

Scheme 2. Synthesis of compounds 1-3.
All compounds were characterized by elemental analysis, NMR ( 1 H, 31 P{ 1 H}) spectroscopies and ESI-MS, which support the proposed formulations. In addition, their structures were authenticated by SCXRD analysis. The obtained crystal structure of 1 was in agreement with that already reported [8].
The 1 H and 31 P{ 1 H} NMR spectroscopic data were obtained in DMSO-d6 (see Supplementary Figures S1, S2, S4, S5, and S7). In all cases, the observation of four resonances for the acyl groups in the 1 H NMR spectra and three independent signals in the 31 P{ 1 H} NMR indicates the presence of the compounds in solution in three rotameric forms ( Figure 2). The 1 H NMR spectrum of 3 (Supplementary Figure S7) shows four singlets for the acyl groups at 2.07, 2.02, 1.97 and 1.94 ppm, with an integration ratio of 1:2.6:7.8:7.8. The resonances at 2.07 and 2.02 ppm are assigned to the two syn isomers (minor) of the compound, where each signal represents the equivalent acetyl groups in the same isomer. The pair of more intense signals at 1.97 and 1.94 ppm represent the two nonequivalent acetyl groups of the anti isomer (major). The 31 P{ 1 H} NMR spectrum of 3 ( Figure 3) shows three singlets, namely those at −10.98 and −13.9 for the syn isomers, and that at −14.06 ppm for the anti isomer. The intense ratio is 2.6:1:15.6, which is in fair agreement with that observed in the 1 H NMR spectrum. The calculated first order 77 Se− 31 P coupling constant ( 1 JSe−P) is of 934 Hz. It is well established that the observation of 1 JSe−P values for phosphine-based compounds allows the assessment of the phosphorus basicity. With DAPTA=Se having a 1 JSe−P value higher than that of its PTA analogue (1,3,5-triaza-7-phosphaadamantane-7-selenide, PTA=Se, 760 Hz), [15] it appears that DAPTA is a weaker σ donor when compared to PTA. Similarly, the 1 H and 31 P{ 1 H} NMR spectra in DMSO-d6 for compounds 1 and 2 (Supplementary Figures S1, S2, S4, and S5) are consistent with the presence of the three rotamers in each case, with the anti isomer being the major component. All compounds were characterized by elemental analysis, NMR ( 1 H, 31 P{ 1 H}) spectroscopies and ESI-MS, which support the proposed formulations. In addition, their structures were authenticated by SCXRD analysis. The obtained crystal structure of 1 was in agreement with that already reported [8].
The 1 H and 31 P{ 1 H} NMR spectroscopic data were obtained in DMSO-d 6 (see Supplementary Figures S1, S2, S4, S5, and S7). In all cases, the observation of four resonances for the acyl groups in the 1 H NMR spectra and three independent signals in the 31 P{ 1 H} NMR indicates the presence of the compounds in solution in three rotameric forms ( Figure 2). The 1 H NMR spectrum of 3 (Supplementary Figure S7) shows four singlets for the acyl groups at 2.07, 2.02, 1.97 and 1.94 ppm, with an integration ratio of 1:2.6:7.8:7.8. The resonances at 2.07 and 2.02 ppm are assigned to the two syn isomers (minor) of the compound, where each signal represents the equivalent acetyl groups in the same isomer. The pair of more intense signals at 1.97 and 1.94 ppm represent the two non-equivalent acetyl groups of the anti isomer (major). The 31 P{ 1 H} NMR spectrum of 3 ( Figure 3) shows three singlets, namely those at −10.98 and −13.9 for the syn isomers, and that at −14.06 ppm for the anti isomer. The intense ratio is 2.6:1:15.6, which is in fair agreement with that observed in the 1 H NMR spectrum. The calculated first order 77 Se− 31 P coupling constant ( 1 J Se−P ) is of 934 Hz. It is well established that the observation of 1 J Se−P values for phosphine-based compounds allows the assessment of the phosphorus basicity. With DAPTA=Se having a 1 J Se−P value higher than that of its PTA analogue (1,3,5-triaza-7-phosphaadamantane-7-selenide, PTA=Se, 760 Hz), [15] it appears that DAPTA is a weaker σ donor when compared to PTA. Similarly, the 1 H and 31 P{ 1 H} NMR spectra in DMSO-d 6 for compounds 1 and 2 (Supplementary Figures S1, S2, S4, and S5) are consistent with the presence of the three rotamers in each case, with the anti isomer being the major component.    In all cases, the 1 H NMR spectrum shows seven sets of signals arising from the ten aliphatic methylene protons, observed between 5.6 to 3.2 ppm. Their splitting patterns are traceable through the diastereotopic nature of the NCH2N and PCH2N moieties. These resonances were assigned based on COSY experiments. Figure 4 shows a comparison of the 1 H NMR spectra of DAPTA and of compounds 1-3 in DMSO-d6 in the 5.7-3.0 ppm region. A comparison of the 31 P{ 1 H} NMR spectra these compounds in the same solvent is depicted in Supplementary Figure S9. In all cases, the 1 H NMR spectrum shows seven sets of signals arising from the ten aliphatic methylene protons, observed between 5.6 to 3.2 ppm. Their splitting patterns are traceable through the diastereotopic nature of the NCH 2 N and PCH 2 N moieties. These resonances were assigned based on COSY experiments. Figure 4 shows a comparison of the 1 H NMR spectra of DAPTA and of compounds 1-3 in DMSO-d 6 in the 5.7-3.0 ppm region. A comparison of the 31 P{ 1 H} NMR spectra these compounds in the same solvent is depicted in Supplementary Figure S9.

Single Crystal X-ray Diffraction Analysis
Single crystals of 2 and 3 were obtained from methanol solution by slow evaporation at room temperature. Compound 2 crystalized in the orthorhombic space group Pbcn, and 3 in the monoclinic space group P21/n. Crystallographic data and structure refinement details are provided in Table S1. Thermal ellipsoid representations are depicted in Figure 5. Table 1 shows the selected bond distances and angles for compounds 2 and 3 and, for comparative reasons, those of DAPTA and DAPTA=O (1)

Single Crystal X-ray Diffraction Analysis
Single crystals of 2 and 3 were obtained from methanol solution by slow evaporation at room temperature. Compound 2 crystalized in the orthorhombic space group Pbcn, and 3 in the monoclinic space group P21/n. Crystallographic data and structure refinement details are provided in Table S1. Thermal ellipsoid representations are depicted in Figure 5. Table 1 shows the selected bond distances and angles for compounds 2 and 3 and, for comparative reasons, those of DAPTA and DAPTA=O (1) obtained from their reported SCXRD structures [8].

Single Crystal X-ray Diffraction Analysis
Single crystals of 2 and 3 were obtained from methanol solution by slow evaporation at room temperature. Compound 2 crystalized in the orthorhombic space group Pbcn, and 3 in the monoclinic space group P21/n. Crystallographic data and structure refinement details are provided in Table S1. Thermal ellipsoid representations are depicted in Figure 5. Table 1 shows the selected bond distances and angles for compounds 2 and 3 and, for comparative reasons, those of DAPTA and DAPTA=O (1) obtained from their reported SCXRD structures [8].
The presence of an additional substituent on the phosphorus atom leads to considerable differences in bonding geometry of the crystal structures of DAPTA and its homologs, compounds 1-3. The largest differences in bonding geometry were observed in the bonds that involve the P atom and the adjacent C atoms. The presence of a substituent on the P atom is accompanied by an elongation of the P-C bond distances, an opening of the C-P-C angles and a decreasing of the P-C-N angles ( Table 1).
The magnitude of the P-X (X = O, S or Se) bond distances should depend on the electronegativity of X which assumes values of 3.44 (O) >> 2.58 (S) ≈ 2.55 (Se) [16].Consequently, the P-O bond length in 1 is much shorter than those of P-S (in 2) and P-Se (in 3). The differences in bonding geometry observed for the DAPTA P III molecule and the oxidized P V species 1-3 are consistent with the different oxidation states of phosphorus and electronegativities of X.
In all the compounds the acetyl groups adopt the anti orientation. The N-C carbonyl bond distances in 2 and 3 (in the 1.350(6)-1.362(6) Å range; Table 1) are shorter than the other N-C bonds (between 1.429(6) and 1.486(6) Å; Table 1), which confirm the double bond character of such Schiff base type moiety (Scheme 3) and justify the solubility in water of the respective compounds. The same was observed for DAPTA and 1 [8].
120.0 (9) 114.5(2) P1-C3-N4 113.5(2) P1-C1-N1 114.2 (4) The presence of an additional substituent on the phosphorus atom leads to considerable differences in bonding geometry of the crystal structures of DAPTA and its homologs, compounds 1-3. The largest differences in bonding geometry were observed in the bonds that involve the P atom and the adjacent C atoms. The presence of a substituent on the P atom is accompanied by an elongation of the P-C bond distances, an opening of the C-P-C angles and a decreasing of the P-C-N angles ( Table 1).
The magnitude of the P-X (X = O, S or Se) bond distances should depend on the electronegativity of X which assumes values of 3.44 (O) >> 2.58 (S) ≈ 2.55 (Se) [16].Consequently, the P-O bond length in 1 is much shorter than those of P-S (in 2) and P-Se (in 3). The differences in bonding geometry observed for the DAPTA P III molecule and the oxidized P V species 1-3 are consistent with the different oxidation states of phosphorus and electronegativities of X.
In all the compounds the acetyl groups adopt the anti orientation. The N-Ccarbonyl bond distances in 2 and 3 (in the 1.350(6)-1.362(6) Å range; Table 1) are shorter than the other N-C bonds (between 1.429(6) and 1.486(6) Å ; Table 1), which confirm the double bond character of such Schiff base type moiety (Scheme 3) and justify the solubility in water of the respective compounds. The same was observed for DAPTA and 1 [8]. Scheme 3. Schiff base N=C bond formation through the π electronic resonance of the amide group.

Hirshfeld Structural Comparison of DAPTA and Derivatives 1-3
The 3D Hirshfeld analysis and 2D fingerprint plots of DAPTA and compounds 1-3 were performed with the CrystalExplorer version 17.5 software [17] and were mapped (Supplementary Scheme 3. Schiff base N=C bond formation through the π electronic resonance of the amide group.

Hirshfeld Structural Comparison of DAPTA and Derivatives 1-3
The 3D Hirshfeld analysis and 2D fingerprint plots of DAPTA and compounds 1-3 were performed with the CrystalExplorer version 17.5 software [17] and were mapped (Supplementary Figure S10, top) with the d norm property where the blue, white and red colours reveal the long, at van der Waals and the short interatomic contacts, respectively. A comparison of the Hirshfeld volumes expectedly shows the consequence of functionalization, with a slight growth upon oxidation of DAPTA (an increase from 262 to 273 Å 3 was calculated, upon formation of DAPTA=O) and more effective for 2 and 3 (volumes of 303 and 306 Å 3 , in this order) conceivably due to the relatively larger dimensions of S and Se against O. In view of the weak interactions in the crystals, more informative representations could be obtained by means of shape-index measurements in which the convex blue areas identify the donors, and the red concavities the acceptors, as shown in Supplementary Figure S10 (bottom) for the most effective O···H contacts.
The 2D fingerprint plots [18] in Figure 6 quantitatively describe the nature and type of the intermolecular contacts in the compounds, where d i and d e represent the distances from the surface to the nearest atom inside or outside the surface, respectively. The overall 2D plots for DAPTA and 1 are similar (Figure 6), although with a more compact pattern in the latter conceivably due to an increase of the OH contributions to the overall surface (see also Figure 7) and a decrease of the HH ones upon the P-functionalization. The 2D plots for 2 and 3 also have common general features with the higher number of points at larger distances in the latter being due to HH interactions with a short tail at (2.6, 2.4).
The graph in Figure 7 compares the contacts that more extensively contribute to the Hirshfeld volumes in every structure, expectedly showing a much greater influence of the OH contacts in 1 (36.8%) relatively to those in DAPTA (23.6%), compound 2 (17.7%) or 3 (17.3%). The SH and the SeH interactions contribute to 21.0 and 21.4%, respectively.
to the nearest atom inside or outside the surface, respectively. The overall 2D plots for DAPTA and 1 are similar (Figure 6), although with a more compact pattern in the latter conceivably due to an increase of the OH contributions to the overall surface (see also Figure 7) and a decrease of the HH ones upon the P-functionalization. The 2D plots for 2 and 3 also have common general features with the higher number of points at larger distances in the latter being due to HH interactions with a short tail at (2.6, 2.4).  The graph in Figure 7 compares the contacts that more extensively contribute to the Hirshfeld volumes in every structure, expectedly showing a much greater influence of the OH contacts in 1 (36.8%) relatively to those in DAPTA (23.6%), compound 2 (17.7%) or 3 (17.3%). The SH and the SeH interactions contribute to 21.0 and 21.4%, respectively.

Catalytic Performances of 1-3 in CuAAC Reaction
With the aim to develop a highly efficient catalytic system in aqueous medium for CuAAC, cheap and available copper (I) or copper (II) salts were mixed with any of the compounds 1-3 and tested for this reaction, first by following well established reaction conditions (see Table 2, legend)

Catalytic Performances of 1-3 in CuAAC Reaction
With the aim to develop a highly efficient catalytic system in aqueous medium for CuAAC, cheap and available copper (I) or copper (II) salts were mixed with any of the compounds 1-3 and tested for this reaction, first by following well established reaction conditions (see Table 2, legend) which were then adjusted to try to the optimum reaction conditions for this system (Table 2). volumes in every structure, expectedly showing a much greater influence of the OH contacts in 1 (36.8%) relatively to those in DAPTA (23.6%), compound 2 (17.7%) or 3 (17.3%). The SH and the SeH interactions contribute to 21.0 and 21.4%, respectively.

Catalytic Performances of 1-3 in CuAAC Reaction
With the aim to develop a highly efficient catalytic system in aqueous medium for CuAAC, cheap and available copper (I) or copper (II) salts were mixed with any of the compounds 1-3 and tested for this reaction, first by following well established reaction conditions (see Table 2, legend) which were then adjusted to try to the optimum reaction conditions for this system (Table 2). For screening the potential catalytic activity of Cu (I) halide salts as a starting point, phenylacetylene and benzyl azide were mixed in water and the system stirred for 24 h. The experiments were performed at room temperature in the presence of 1 mol% of the salt. Under these conditions, the Cu (I) halides were not active ( Table 2, entries 1-3), which is not surprising in view of their poor solubility in water. However, the solubility of the copper (I) sources increased upon the addition of compounds 1-3 to the reaction media (2 mol%). Under these conditions, a significant catalytic activity was observed ( Table 2, entries 4-12), with the mixture of CuI and 1 being the most active one, leading to 62% of the triazole yield ( Table 2, entry 4).
Water-miscible organic co-solvents were used to improve the homogeneity of the reaction system by increasing the solubility of the organic reactants ( Table 2, entries 26-30). Using 1:1 water-alcohol mixtures (MeOH, EtOH or t BuOH; entries 26-28) did not improve the yield when compared to that obtained using water as the sole solvent (entry 22). However, a mixture of water and DMF or MeCN significantly increased the conversion to 88% and 97%, respectively (entries 29 and 30). In H 2 O:MeCN (1:1) solvent mixture the completion of the reaction was reached in 8 h when the temperature was raised to 80 • C ( Table 2, entry 31).
Since the combination of copper acetate and compound 1 gave an optimum catalytic performance for the CuAAC reaction, and the well-defined previously obtained complex [Cu(µ-CH 3 COO) 2 (κO-DAPTA=O)] 2 [11] (4, Figure 8) was included in this study. Using the aforementioned model reaction in H 2 O:MeCN (1:1) solvent mixture, the effects of catalyst loading, reaction time and temperature were investigated (Table 3).  Performing the reaction at room temperature for 24 h, the yield increased from 54% to almost quantitative conversion with increasing the catalyst loading from 0.5 to 5 mol%, while the TON (turnover number = number of moles of product per mol of catalyst) was gradually attenuated ( Table  3, entries 1-4). Using 1 mol% of catalyst 4 at room temperature, the reaction yield increased with time to reach 88% after 48 h (Table 3, entries 5-8). The reaction was completed in 6 h with a quantitative conversion when the temperature was raised to 80 °C (Table 3, entry 9). In view of the resemblance of the results (compare entry 31 in Table 2 with entry 9 in Table 3), the active catalytic species in both cases (with 4 or with Cu(CH3COO)2.H2O + 1) can be the same.
Relying on the optimization studies, the scope of the catalytic system was broadened to include several acetylenes. Various terminal alkynes were reacted with benzyl azide to produce the corresponding 1,4-disubstituted-1,2,3-triazoles (5), and the results are summarized in Table 4. The    Performing the reaction at room temperature for 24 h, the yield increased from 54% to almost quantitative conversion with increasing the catalyst loading from 0.5 to 5 mol%, while the TON (turnover number = number of moles of product per mol of catalyst) was gradually attenuated ( Table  3, entries 1-4). Using 1 mol% of catalyst 4 at room temperature, the reaction yield increased with time to reach 88% after 48 h (Table 3, entries 5-8). The reaction was completed in 6 h with a quantitative conversion when the temperature was raised to 80 °C (Table 3, entry 9). In view of the resemblance of the results (compare entry 31 in Table 2 with entry 9 in Table 3), the active catalytic species in both cases (with 4 or with Cu(CH3COO)2.H2O + 1) can be the same.
Relying on the optimization studies, the scope of the catalytic system was broadened to include several acetylenes. Various terminal alkynes were reacted with benzyl azide to produce the corresponding 1,4-disubstituted-1,2,3-triazoles (5), and the results are summarized in Table 4. The reactions were performed in water: MeCN (1:1)  Performing the reaction at room temperature for 24 h, the yield increased from 54% to almost quantitative conversion with increasing the catalyst loading from 0.5 to 5 mol%, while the TON (turnover number = number of moles of product per mol of catalyst) was gradually attenuated (Table 3, entries 1-4). Using 1 mol% of catalyst 4 at room temperature, the reaction yield increased with time to reach 88% after 48 h (Table 3, entries 5-8). The reaction was completed in 6 h with a quantitative conversion when the temperature was raised to 80 • C (Table 3, entry 9). In view of the resemblance of the results (compare entry 31 in Table 2 with entry 9 in Table 3), the active catalytic species in both cases (with 4 or with Cu(CH 3 COO) 2 .H 2 O + 1) can be the same.
Relying on the optimization studies, the scope of the catalytic system was broadened to include several acetylenes. Various terminal alkynes were reacted with benzyl azide to produce the corresponding 1,4-disubstituted-1,2,3-triazoles (5), and the results are summarized in Table 4. The reactions were performed in water:MeCN (1:1) solvent mixture, in the presence of catalyst 4 or the mixture of Cu(CH 3 COO) 2 ·H 2 O and compound 1, under air at 80 • C. The reactions proceeded smoothly to give 5, usually with similar yields (with 4 or with Cu(CH 3 COO) 2 .H 2 O + 1) from 81% up to quantitative conversion. The products precipitated from the reaction mixture. After removing the solvent under vacuum, the triazole solids were isolated by filtration, washed, and dried.  Although the position (meta-or para-) of the substituent group of phenylacetylene seems not to have an influence on the yield of the reaction (compare entries 3-4, with entries 7-8, Table 4), increasing its electron-donating character can decrease that yield (compare entries 7-10 with entries [15][16]. However, this is not a general behaviour since the alkyl substituted catalysts lead to higher yields than the fluoro catalyst (compare entries 7-10 and 13-14 with entries [11][12]. In comparison with the copper (I) catalysts with DAPTA=NO(OR)2S core ligands for CuAAC reaction, [19] our catalytic system revealed a high catalytic activity to obtain triazoles with quantitative conversions in water/acetonitrile solution after only 6 h, without any added reducing agents or bases. Lower conversions were, however, obtained with water as the sole solvent, but the Cu(I) complexes bearing the iminophosphorane DAPTA derivatives [19] required 10 mol% of 2,6dimethylpyridine for the reaction to proceed. The Cu (I) complexes [CuX(DAPTA)3] and [Cu(μ-X)(DAPTA)2]2 (X = Br or I) also proved to be of high efficiency with quantitative conversions in aqueous medium under microwave irradiations in 15 min [12]. Despite the high activity of these latter catalysts in terms of very short reaction time, the required copper complex loading was relatively high (5 mol%). The catalyst loading in the present study is low and thus beneficial from the economic point of view, but the higher reaction time is, in this respect, a disadvantage.
Although several N-donor and phosphine ligands were found to form efficient and highly active copper catalysts for CuAAC reactions, [20,21,22] DAPTA=O is notable in view of its high solubility in water, and thus the corresponding complex can be separated easily from the organic product by simple solvent extraction procedures. Unfortunately, complex 4 and the copper (II)/1 system exhibit poor recyclability as the yield of the triazole product diminished considerably on the following cycles. The obtained yields were 61% and 58% in the second cycle, 15% and 22% in the third cycle for complex 4 and the copper (II)/1 catalytic systems, respectively.
A mechanism for the CuAAC reaction has been proposed (Scheme 4) based on fundamental steps established by computational [23,24,25] and experimental methods [26,27,28]. As a starting point, the catalytically active Cu(I) species are generated through an oxidative homocoupling of terminal alkynes (Glaser reaction) [ Although the position (meta-or para-) of the substituent group of phenylacetylene seems not to have an influence on the yield of the reaction (compare entries 3-4, with entries 7-8, Table 4), increasing its electron-donating character can decrease that yield (compare entries 7-10 with entries [15][16]. However, this is not a general behaviour since the alkyl substituted catalysts lead to higher yields than the fluoro catalyst (compare entries 7-10 and 13-14 with entries [11][12]. In comparison with the copper (I) catalysts with DAPTA=NO(OR) 2 S core ligands for CuAAC reaction, [19] our catalytic system revealed a high catalytic activity to obtain triazoles with quantitative conversions in water/acetonitrile solution after only 6 h, without any added reducing agents or bases. Lower conversions were, however, obtained with water as the sole solvent, but the Cu(I) complexes bearing the iminophosphorane DAPTA derivatives [19] required 10 mol% of 2,6-dimethylpyridine for the reaction to proceed. The Cu (I) complexes [CuX(DAPTA) 3 ] and [Cu(µ-X)(DAPTA) 2 ] 2 (X = Br or I) also proved to be of high efficiency with quantitative conversions in aqueous medium under microwave irradiations in 15 min [12]. Despite the high activity of these latter catalysts in terms of very short reaction time, the required copper complex loading was relatively high (5 mol%). The catalyst loading in the present study is low and thus beneficial from the economic point of view, but the higher reaction time is, in this respect, a disadvantage.
Although several N-donor and phosphine ligands were found to form efficient and highly active copper catalysts for CuAAC reactions, [20][21][22] DAPTA=O is notable in view of its high solubility in water, and thus the corresponding complex can be separated easily from the organic product by simple solvent extraction procedures. Unfortunately, complex 4 and the copper (II)/1 system exhibit poor recyclability as the yield of the triazole product diminished considerably on the following cycles.
The obtained yields were 61% and 58% in the second cycle, 15% and 22% in the third cycle for complex 4 and the copper (II)/1 catalytic systems, respectively.
A mechanism for the CuAAC reaction has been proposed (Scheme 4) based on fundamental steps established by computational [23][24][25] and experimental methods [26][27][28]. As a starting point, the catalytically active Cu(I) species are generated through an oxidative homocoupling of terminal alkynes (Glaser reaction) [29][30][31][32][33]. The catalytic cycle should start with (1) π-coordination of the alkyne to a Cu (I) species, thus increasing the acidity of the terminal alkyne (pKa drops from~25 to~15), and allowing the subsequent (2) formation of a Cu (I) σ-coordinated acetylide, thus generating an intermediate that resembles the known µ-coordination mode of Cu (I) acetylides [34]. (3) A triazolide intermediate is formed upon the coordination of the azide to the π-coordinated Cu (I) center, potentially either through the substituted nitrogen (π-donating) or the terminal one (π-accepting). However, (4) the regioselectivity for the 1,4-isomer was attributed to the π-coordination to Cu (I) of the α-carbon of the acetylide, raising the electron density on the metal centre, directing a nucleophilic attack of the β-carbon at the electrophilic terminal nitrogen and ensuing oxidative coupling. Thus, (5) a six-membered bimetallic cupra-cycle intermediate was proposed, [25] stabilized by a geminal bimetallic coordination. Finally, (6) in an exothermic reductive elimination process, Cu (I) triazolide is formed [25,27], and its protonation releases the 1,4-disubstituted 1,2,3-triazole product.
Molecules 2020, 25, x FOR PEER REVIEW 12 of 17 thus generating an intermediate that resembles the known µ -coordination mode of Cu (I) acetylides [34]. (3) A triazolide intermediate is formed upon the coordination of the azide to the π-coordinated Cu (I) center, potentially either through the substituted nitrogen (π-donating) or the terminal one (πaccepting). However, (4) the regioselectivity for the 1,4-isomer was attributed to the π-coordination to Cu (I) of the α-carbon of the acetylide, raising the electron density on the metal centre, directing a nucleophilic attack of the β-carbon at the electrophilic terminal nitrogen and ensuing oxidative coupling. Thus, (5) a six-membered bimetallic cupra-cycle intermediate was proposed, [25] stabilized by a geminal bimetallic coordination. Finally, (6) in an exothermic reductive elimination process, Cu (I) triazolide is formed [25,27], and its protonation releases the 1,4-disubstituted 1,2,3-triazole product. The catalytic activities of the mixtures of Cu (I) halide salts CuX (I − > Br − > Cl − ) with 1-3 may follow the inverse of the general trend in the spectrochemical series (I − < Br − < Cl − ), reflecting the πelectron donor ability of the halide, which can promote the oxidation addition step in the catalytic cycle. In the case of mixtures of Cu (II) salts and DAPTA=O (1), the highest catalytic activity is observed for the acetate salt. Since the acetate anion is the strongest base in the group, the importance for promoting step (1) of the catalytic cycle is evident. Moreover, acetate readily bridges two copper ions, forming the {Cu2(μ-CH3COO)4} dicopper core (4), which promotes the formation of dicopper intermediates involved in the catalytic cycle (Scheme 4).
A different type of effect possibly concerns the extension of OH interactions which decreases in the order DAPTA=O >> DAPTA=S > DAPTA=Se (see above). Such contacts can affect the catalytic cycle, namely assisting in alkyne deprotonation (Scheme 4). The catalytic activities of the mixtures of Cu (I) halide salts CuX (I − > Br − > Cl − ) with 1-3 may follow the inverse of the general trend in the spectrochemical series (I − < Br − < Cl − ), reflecting the π-electron donor ability of the halide, which can promote the oxidation addition step in the catalytic cycle. In the case of mixtures of Cu (II) salts and DAPTA=O (1), the highest catalytic activity is observed for the acetate salt. Since the acetate anion is the strongest base in the group, the importance for promoting step (1) of the catalytic cycle is evident. Moreover, acetate readily bridges two copper ions, forming the {Cu 2 (µ-CH 3 COO) 4 } dicopper core (4), which promotes the formation of dicopper intermediates involved in the catalytic cycle (Scheme 4).
A different type of effect possibly concerns the extension of O···H interactions which decreases in the order DAPTA=O >> DAPTA=S > DAPTA=Se (see above). Such contacts can affect the catalytic cycle, namely assisting in alkyne deprotonation (Scheme 4).

General Procedures
All synthetic procedures were performed in air. Reagents and solvents were obtained from commercial sources. The organic reactants for the cycloaddition reaction (alkynes and benzyl azide) were further purified prior to use by distillation. DAPTA was synthesized using the published procedure [8,10]. The ultrasound irradiation was accomplished with a high-intensity ultrasonic probe SONIC VCX 750 (Sonics & Materials Inc., Newtown, CT, USA) model (20 kHz, 750 W) using a titanium horn. Elemental analyses (C, H, and N) were carried out by the Microanalytical service of Instituto Superior Tecnico. 1 H and 31 P NMR spectra were obtained using a Bruker Advance (Bruker, Billerica, MA, USA) 400 and 500 MHz spectrometers at ambient temperature. Chemical shifts δ are quoted in ppm. 1 H chemical shifts were internally referenced to residual protio-solvent resonance and are reported relative to SiMe 4 . 31 P chemical shifts were referenced to external 85% phosphoric acid. Assignments of 1 H signals rely on COSY experiments. Electrospray mass (ESI-MS) spectra were obtained on a Varian 500-MS LC Ion Trap Mass Spectrometer (Agilent Technologies, Santa Clara, CA, USA) equipped with an electrospray ion source. All compounds were observed in the positive mode (capillary voltage = 80-105 V). A similar procedure was utilized for the synthesis of 2 and 3. A mixture of methanol (10 mL), DAPTA (500 mg, 2.18 mmol) and sulfur (flowers of sulfur, 96 mg, 3 mmol for 2) or selenium (220 mg, 2.8 mmol for 3) was placed in 100 mL round bottom flask. At room temperature, the mixture was allowed to sonicate for 1 h. The resulting powders were filtered off, washed with ethanol and benzene, and dried under vacuum.

Conclusions
Hydrosoluble DAPTA=X compounds 1-3 (X = O, S or Se, in the same order) were synthesized in high yields under mild conditions. The structural features of the compounds, including the presence of rotameric forms due to the turning around the N-C bond, were studied in solution by 1 H and 31 P NMR spectroscopy, and in solid state by SCXRD. Some crystal structure data of DAPTA and 1 were revisited for comparison with the novel compounds 2 and 3. The effect of hybridization differences of the phosphorus atom and the electronegativity of the substituents on the structural features of the compounds have been studied, with the most significant differences being observed in the bonds that involve the P and the adjacent C atoms. Comparative Hirshfeld studies of DAPTA and compounds 1-3 revealed that the OH interactions contribute to ca. 37-17% of the Hirshfeld volume, following the HH contacts that reach 63-54% of that volume.
Compounds 1-3 have demonstrated a moderate to high efficiency to enhance the catalytic activity of copper salts for the CuAAC reaction in aqueous medium. The in situ generated catalyst from a combination of copper acetate with ligand 1 is an efficient catalyst for the one-pot CuAAC reaction of terminal alkynes with benzyl azide to selectively obtain the corresponding 1,4-disubstituted-1,2,3-triazoles in yields ranging from 81 to 99% in 8 h at 80 • C. The catalytic activity of the well-defined copper (II) complex bearing the DAPTA=O ligand (4) has also been investigated, and under similar conditions, the triazoles were obtained in yield ranging from 86% to 99% in 6 h.