MW irradiation and ionic liquids as green tools in hydrolyses and alcoholyses

The optimized HCl-catalyzed hydrolysis of alkyl diphenylphosphinates is described. The reaction times and pseudo-first-order rate constants suggested the Pr > Me > Et ∼ Pr ∼ Bu order of reactivity in respect of the alkyl group of the phosphinates. The MW-assisted p-toluenesulfonic acid (PTSA)-catalyzed variation means a better alternative possibility due to the shorter reaction times, and the alkaline hydrolysis is another option. The transesterification of alkyl diphenylphosphinates took place only in the presence of suitable ionic liquids, such as butylmethylimidazolium hexafluorophosphorate ([bmim][PF6]) and butyl-methylimidazolium tetrafluoroborate ([bmim][BF4]). The application of ethyl-methylimidazolium hydrosulfate ([emim][HSO4]) and butyl-methylimidazolium chloride ([bmim][Cl]) was not too efficient, as the formation of the ester was accompanied by the fission of the O–C bond resulting in the formation of Ph2P(O)OH. This surprising transformation may be utilized in the phosphinate → phosphinic acid conversion.


Introduction
The esters of phosphinic acids (alkyl phosphinates) prepared in most cases by the reaction of the corresponding phosphinic chloride with alcohol [1,2], or recently, by the microwave-assisted direct esterification of the phosphinic acids in the presence of an IL additive [2][3][4][5] are widely applied starting materials and intermediates in syntheses [2]. They may also be the precursors of (potentially) biologically active derivatives [6][7][8][9]. Hydrolysis of the alkyl phosphinates (and in general P-esters including dialkyl phosphonates) is an often used and rather common transformation that may be performed under acidic conditions [10][11][12][13], but also in the presence of a base [14][15][16][17]. We have recently investigated the acidic hydrolysis of a series of cyclic alkyl phosphinates in detail [18]. Optimum conditions for the acidic hydrolysis of dialkyl arylphosphonates and α-hydroxy-benzylphosphonates were also explored [19,20]. The reactivity of the starting P-esters along with the kinetics was also evaluated. In this paper, the acidic-or base-catalyzed hydrolyses of alkyl diphenylphoshinates are investigated and compared. We wished to find the optimum conditions and to characterize the processes by rate constants. The other purpose was to elaborate the transesterification of our "Ph 2 P(O)OR" model compounds by reaction with series of alcohols. We have had some experience on MWassisted alcoholysis of dialkyl phosphites, which may lead to fully transesterified products via the intermediate with two different alkoxy groups [21,22]. Continuous flow accomplishments were also developed by us [23].

General
The 31 P, 13 C, 1 H NMR spectra were taken on a Bruker DRX-500 spectrometer operating at 202.4, 125.7, and 500 MHz, respectively. The couplings are given in Hz. LC-MS measurements were performed with an Agilent 1,200 liquid chromatography system coupled with a 6,130 quadrupole mass spectrometer equipped with an ESI ion source (Agilent Technologies, Palo Alto, CA, USA). High resolution mass spectrometric measurements were performed using a Thermo Velos Pro Orbitrap Elite hybrid mass spectrometer in positive electrospray mode.

Preparation of the starting alkyl diphenylphosphinates
The C 1 -C 4 alkyl diphenylphosphinates (1a-e) were synthetized by the reaction of diphenylphosphinoyl chloride with the corresponding alcohols at 26°C in the presence of triethylamine in toluene (Scheme 1). Identification of the starting material (1a) and the ester products (1c-h), as well as the acid (2), can be found in Table 1.

Use of the 31 P NMR spectra during monitoring the hydrolyses and alcoholyses
The composition of the reaction mixtures was determined by integration of the areas under the corresponding peaks of the starting material and product in the 31 P NMR spectra.

Curve fitting on the timerelative quantity data pairs
The acidic hydrolyses were modelled assuming pseudofirst-order kinetics. The concentration of water and hydrochloric acid was constant during the reaction. The calculated time-composition curves were fitted to the experimental data using nonlinear least-squares method. The pseudofirst-order rate constants were optimized so that the sum of squares of the residuals (i.e., the difference of the experimental and the calculated composition) be the minimal. The approximate values of the rate constants were found iteratively, using the nonlinear generalized reduced gradient method of Microsoft Excel Solver.
3 Results and discussion

Hydrolysis of alkyl diphenylphosphinates under acidic conditions on conventional heating
The hydrolyses of alkyl diphenylphosphinates (1a-e) were performed in water medium containing 12% of hydrochloric acid at reflux (Scheme 2). The reactions were monitored by 31  The curves were fit by the nonlinear least-squares method. It can be seen that the reaction time fell in the range of 3-7 h. The pseudo-first-order rate constants calculated are listed in Table 2. The hydrolysis of the methyl ester (1a) was significantly faster (t r = 4 h and k = 1.36 h −1 ) than that of the n-alkyl esters (1b,c,e) (t r = 6.5-7 h and k = 0.57-0.62 h −1 ). It is noteworthy that the i Pr ester (1d) was hydrolyzed more than twice as much faster than the n Pr derivative (1c) (compare t r = 3 to 7 h, and k = 1.6 h −1 to k = 0.62 h −1 ). In the latter case, obviously the A Al 1 mechanism operates.      The HCl-catalyzed hydrolyses of phosphinates 1a-e furnished diphenylphosphinic acid (2) in yields of 90-94%; however, the reaction times were in most cases (1b-d) as long as 7-8 h. The hydrolysis of the Me and i Pr diphenylphosphinate (1a and 1e) was complete after 4 and 3 h, respectively.

Hydrolysis of alkyl diphenylphosphinates under acidic conditions on microwave irradiation
In the second phase of our study, the alkyl diphenylphosphinates (1a-e) were hydrolyzed under microwave (MW) irradiation. To avoid corrosion problems caused by the HCl, in these experiments PTSA served as the catalyst. The experimental data are summarized in Table 3. Applying 1 equivalent of PTSA, the hydrolysis of methyl phosphinate 1a was complete at 140°C after 3.75 h or at 160°C after 0.75 h ( Table 3, entries 1 and 2). Using only 0.5 equivalents of PTSA at 160°C, the completion required 1.5 h ( Table 3, entry 3). Decreasing the quantity of the catalyst to 0.1 equivalents, there was need for a reaction time of 4 h ( Table 3, entry 4). Increasing the temperature to 180°C, an irradiation of 1.5 h was enough ( Table 3, entry 5). The hydrolysis of the ethyl ester (1b) was somewhat slower; in the presence of 0.1 equivalents of PTSA at 160°C and 180°C, the completion took 6 and 2 h, respectively ( Table 3, entries 6 and 7). Similar results were obtained for the hydrolysis of the n-propyl and the n-buthyl phosphinate (1c and 1e) ( Table 3, entries 8, 9, 12, and 13). In the Me (1a), Et (1b), n Pr (1c), and Bu (1e) cases, the hydrolyses were about 3-times faster at 180°C than at 160°C. It is noteworthy that the hydrolysis of isopropyl diphenylphosphinate (1d) was again significantly faster: at 160°C and 180°C, the completion required 2 and 0.5 h, respectively ( Table 3, entries 10 and 11). This is the consequence of the A Al 1 mechanism.
A comparative thermal experiment corresponding to entry 5 of Table 3 afforded phosphinic acid 2 in a significantly lower conversion of 24% referring to the role of MWs. This observation may be the consequence of local overheatings [27] and the better MW absorbing ability of PTSA. Earlier, the beneficial effect of onium salts was demonstrated [28].
The MW-assisted hydrolyses performed at 180°C in the presence of 10% of PTSA can be regarded as robust and green affording diphenylphosphinic acid (2) practically quantitatively (in yields of 93-97%) after removing the PTSA catalyst by washing with water.
To determine the corresponding pseudo-first-order rate constants, the hydrolyses of phosphinates 1a, 1b, and 1d performed at 160°C in the presence of 0.1 equivalents of PTSA were monitored by 31 P NMR (Figures 6-8). The rate constants are listed in Table 2.
It can be seen that the rate constants obtained under MW conditions at 160°C applying 0.1 equivalents of PTSA were significantly higher than those determined on conventional heating at 100°C in the presence of 12% aqueous HCl.
As a comparison, the MW-assisted PTSA-catalyzed hydrolyses seem to be more advantageous than the HCl-promoted conversions on conventional heating, as

Alkaline hydrolysis of alkyl diphenylphosphinates
Beside acidic hydrolysis, the alkaline version is also a good option to convert P-esters to P-acids. The methyl and ethyl diphenylphosphinates (1a and 1b) were hydrolyzed at 50°C using aqueous 5% NaOH solution in different portions ( Table 4). Applying 1.1, 1.2, and 2 equivalents of NaOH in reaction with methyl diphenylphosphinate (1a), the hydrolysis was complete after 45, 35, and 15 min, respectively ( Table 4, entries 1-3). It is noteworthy that the conversion of the ethyl ester (1b) to diphenylphosphinic acid (2) was much slower under similar conditions and took 7 and 4 h using 1.2 equivalents and 2 equivalents of NaOH, respectively ( Table 4, entries 4 and 5). The sensitivity of the basic hydrolysis on the substituents is in accord with earlier observations [29]. Two selected cases marked by entries 1 and 4 of Table 4 were monitored by 31 P NMR. The resulting curves are shown in Figures 9 and 10, respectively. The second order rate constants were obtained as 4.31 and 0.31 dm 3 /mol h, respectively. The alkaline hydrolysis is an alternative possibility to the option performed in the presence of an acid. It required a lower temperature of 50°C, but the rate was sensitive to the nature of the alkyl substituent: the

The alcoholysis of alkyl diphenylphosphinates
Phosphinic esters may also participate in alcoholysis reactions. The first model reaction was the transesterification of methyl diphenylphosphinate (1a) with pentanol. The results are summarized in Table 5. As can be seen, at 220°C, there was no reaction between phosphinate 1a and PentOH after a 2 h MW irradiation ( Table 5, entry 1). On the basis of our earlier experiences, ionic liquid additives promoted the direct esterification of P-acids [4,5,30]. For this, the alcoholysis was also attempted in the presence of 10 mol% of the selected ionic liquids. ] is the method of choice for an efficient transesterification. The latter reaction was monitored by 31 P NMR ( Figure 11). The pseudo-first-order rate constant was obtained as 1.    additive was so efficient that the ratio of the ester (1g) and acid (2) was 18:82. In other words, instead of transesterification, the fission of the ester function took place with a selectivity of 82%. This novel transformation can be regarded as an alternative for hydrolysis and will be studied in detail in due course.
In the next stage, methyl diphenylphosphinate (1a) was reacted with different alcohols under MW irradiation in the presence of 10 mol% of [bmim][PF 6 ] ( Table 6). The alcoholysis of phosphinate 1a with n-propyl alcohol was complete after a 2 h heating at 200°C ( Table 6, entry 1). At the same time, the similar reaction with i-propyl alcohol was not successful, as the product (1d) formed decomposed almost quantitatively under the conditions of the reaction ( Table 6, entry 2). The unstability of i-propyl diphenylphosphinate (1d) on heating has been described [31]. Completion of the transesterification of phosphinate 1a with nand i-butyl alcohol required 2 h at 220°C ( Table  6, entries 3 and 4). The similar reaction of ester 1a with cyclohexanol required a longer reaction time of 3.5 h at 220°C ( Table 6, entry 5). This is the consequence of steric hindrance. After flash column chromatography, the phosphinates were obtained in yields of 89-92%.
Finally, different alkyl phosphinates (1b-e) were subjected to alcoholysis with n-pentanol in the presence of 10 mol% of [bmim] [PF 6 ]. The case starting from the methyl ester (1a) is recalled ( Table 5, entry 3). The alcoholysis of the ethyl phosphinate 1b hardly proceeded after a treatment at 220°C for 4 h ( Table 7, entry 1). However, after an irradiation at 225°C for 4 h in the presence of 20 mol% of the additive, the conversion was 97% ( Table 7, entry 2). Alcoholyses of the n-propyl and n-butyl esters (1c and 1e) at 225°C remained incomplete after 4 h, when only 10 mol% of the additive was used. The conversions were ca. 43% ( Table 7, entries 3 and 6). Repeating the reaction at 225°C using 20 mol% of the additive, the conversion amounted to 80% (Table 7, entry 7). As regards the transesterification of i-propyl phosphinate 1d, it was faster than that of the n-propyl derivative (1c) ( Table 7, entries 4 and 5 vs entry 3). Performing the reaction at  220°C for 4 h, only 16% starting material (1d) remained in the mixture, while at 225°C all 1d was consumed. This surprising result can be explained assuming a different mechanism. In the case under discussion, the i-propyl ester (1d) is converted to the corresponding acid (2), and the latter species take part in a direct MW-assisted and IL-catalyzed esterification. This was confirmed by the fact that some Ph 2 P(O)OH could be detected in the crude mixtures (see footnotes "b" and "c" of entries 4 and 5 of Table 7). The reactivity of the ethyl, n-propyl, and n-butyl phosphinates 1a, 1b, and 1e seemed to be comparable (see entries 1, 3, and 6, as well as entries 2 and 7 of Table 7).

Conclusions
In summary, from among the three possibilities of the hydrolysis of alkyl diphenylphosphinates, the MWassisted and PTSA-catalyzed method seems to be the best due to the shorter reaction times, but the HCl-promoted option on conventional heating, as well as the alkaline hydrolysis, may also be applied as these are also efficient, but, with one exception, are somewhat slower. The reactivity of the alkyl phosphinates was also mapped and rate constants were determined. In case of the i-propyl ester, the A Al 1 mechanism was substantiated.  4 ] led to the fission of the ester moiety to the acid function. This novel reactivity will be explored in due course.