Unusual ionization of phosphine-boranes under RP-HPLC-HRMS conditions disclose a potential system for reduction of C=O bond

HRMS analysis of a set of phosphine-boranes using RP-HPLC-HRMS has been performed using an acetonitrile/water mixture. The data show that all compounds undergo ionization under the measurement conditions to afford cations of [M-H]+, [2M-H]+, [2M-3H]+, [2M-5H]+ or [2M 6H]2+ type. A detailed analysis of their structures led to the conclusion that these species might act as carbonyl-group activators.


Introduction
Phosphine-boranes have emerged as a new and valuable class of organophosphorus compounds in the past few decades. 1,2 Due to the presence of a weak P−B bond, these compounds are regarded as good substitutes for free phosphines because they lack the disadvantages of the latter. Their utility as substrates has been proven many times, especially in the synthesis of P−stereogenic diphosphine ligands for asymmetric catalysis. [3][4][5][6] The presence of a weak phosphorus-boron bond frequently raises the problem of the complete analysis of phosphine−boranes, however, especially when the data are collected for the preparation of a manuscript. Contrary to NMR, which is regarded as a non-destructive analytical method, MS analysis, especially the coupled LC−MS or GC−MS techniques, causes cleavage of the P−B bond predominantly, leading to the corresponding free phosphines during measurements. The latter may undergo oxidation, affording a completely different compound which enters the mass analysis. As a consequence, a detailed description of mass peaks should be included in the analysis. An analogous problem is associated with the identity confirmation, which is usually associated with either elemental analysis or high-resolution mass spectrometry (HRMS). Many phosphine−boranes exist as oils which strongly influence results reliability using elemental analysis. Therefore, HRMS should be the method of choice for identity confirmation for these compounds.
Herein, we present the results concerning the HRMS analysis of a set of structurally-different phosphine−boranes using a RP−HPLC−HRMS technique, along with some interesting consequences associated with the discussed observations.

Results and Discussion
All compounds used for RP−HPLC−HRMS analysis are presented in Figure 1. Some of them have been prepared as presented in Scheme 1.
In Scheme 1, the phosphine−boranes 20 and 21, possessing a hydroxy substituent at the  carbon atom, were prepared from 2 using a deprotonation/epoxide-addition sequence. Phosphine−boranes 27 and 28 were obtained from 1-indanone, which was subjected to a reaction with a base followed by an addition of Ph2PCl and BH3 complex. The obtained compound 27 was treated with NaBH4 in methanol, affording the final phosphine−borane 28. Phosphine−borane 29, with an ester functionality, has been obtained from the corresponding secondary phosphine−borane 32 by treatment with ethyl chloroacetate in the presence of a base. Finally, triarylphosphine−borane 30 has been prepared by simple reaction of a free phosphine 33 with BH3 complex.

AUTHOR(S)
All phosphine−boranes were subjected to HRMS analysis using a RP−HPLC−HRMS technique. Samples were dissolved in MeOH and subjected to HPLC analysis with 5% or 30% MeCN in water as eluent in an isocratic mode, followed by HRMS analysis with ESI mode and IT−TOF mass-peak analysis. For better ionization of the analyzed compounds, formic acid was added to each solvent (1mL/L). The analysis of each compound shows an interesting feature which is depicted in detail for diphenylmethylphosphine−borane 6 in Figure 2. The results presented in Figure 2 show that none of the mass peaks found for phosphine−borane 6 are of M+H−type. The mass peak closest to the molecular mass of 6 was m/z 213.1001 which corresponds to the molecular peak of Ph2MeP(BH2) cation I (Figure 2b). This peak, however, was weak compared to the other peaks found in the spectrum. The most intensive peak was found at m/z 427.2091, which corresponds to III, an adduct of the starting phosphine−borane 6 and Ph2MeP(BH2) cation ( Figure 2d). There are two more mass peaks found in this region. The first was found at m/z 425.1934, and corresponds to the compound IV derived through the formal elimination of a hydrogen molecule from III ( Figure 2e). The second mass peak was found at m/z 423.1778, which corresponds to the compound V, derived through the formal elimination of a hydrogen molecule from IV ( Figure 2f). Finally, there was still one weak mass peak found at m/z 211.0845 which was ascribed to a dication II. This dication is formally formed by hydrogen-molecule elimination from cation I, followed by dimerization of the formed intermediates ( Figure 2b). The analysis of the spectra shown in Figure 2a revealed that the most intense mass peaks corresponded to a few dimers of different composition. Moreover, it seemed that hydrogen abstraction is a quite facile process, at least under the measurement conditions.
In order to understand the mechanism of the transformation of 6, DFT calculations have been performed (Scheme 2).  It has been assumed that the first step is the reaction of phosphine−borane 6 with H3O + . This reaction should involve the hydrogen atom bonded to boron since the most negative electrostatic potential in the molecule is found there according to DFT calculations (Figure 3a), as indicated by blue translucent spheres surrounding hydrogen atoms. The reaction between 6 and H3O + proceeds without any activation barrier, leading to the adduct A. This intermediate undergoes water and hydrogen elimination which leads to the formation of cation I with only slight increase of energy. In the next step, the formation of dimer III occurs through a reaction of cation I with phosphine−borane 6. The formation of this intermediate is very favorable, as judged from the remarkable stabilization of the system.
The most positive electrostatic potential in III is placed around positively charged phosphorus atoms (red color), and is mostly concentrated around the part found around B−H−B bridge. The stability of the dimeric cation is also evident from HOMO analysis in which the orbital involving B−H bonds can be found at HOMO−8 level (Figure 3b).  The formation of dication II is proposed to proceed via a different mechanism as shown in Scheme 3.  In this case, dimerization of cation I should proceed through the transition state I−TS in which the formation of a four−membered B−H−B−H− ring is the crucial step. The activation energy for this transformation was found to be +43.0 kcal/mol which leads to the cyclic dication VI with −23.7 kcal/mol of overall stabilization. Dication VI resembles the structure typical for boranes, especially for the diborane B2H6, the structure of which has been definitively proved by Hedberg and Schomaker. 7 This dication undergoes a concerted process in which two hydrogen molecules are cleaved from the dication leading to the final dication II. This process was found to proceed without any activation barrier, as dissociation of two hydrogen molecules from VI occurs with a steady destabilization of the system. Overall, this process is highly energy demanding (+91.1 kcal/mol) which can explain a generally low intensity of these mass peaks. The same process could potentially occur via step-wise elimination of hydrogen molecules. In this case, however, a mass peak around m/z 212 should be detected, as the formation of this dication should occur more readily than dication II. The lack of mass peak m/z 212 has been attributed to a synchronous elimination of two H2 molecules from VI.
The behavior discussed for phosphine−borane 6 reflects, to some extent, the behavior of other compounds possessing dative phosphorus−boron bonds. The data of RP−HPLC−HRMS analyses of compounds 1−30 are presented in Table 1.   The ease of formation of [M−H] + and [2M−H] + cations raised the question of whether these species could be obtained under milder or even standard conditions. It is known that liberation of free phosphines from their borane complexes can be achieved by a reaction with a strong acid, especially for electronically-rich phosphines. 8,9 In this case, however, at least a 5-fold excess has been used to assure complete transformation of phosphine−borane into free phosphine. It was, therefore, decided to check the reactivity of stoichiometric amounts of strong acids towards a model phosphine−borane.
NMR experiments were performed using the triphenylphosphine−borane 34 which was subjected to a reaction with two strong acids, HBF4 and TfOH, in two different stoichiometries (0.5 and 1 equiv.) ( Figure 5).
Addition of either 0.5 or 1 equivalent of HBF4 to a solution of Ph3P(BH3) 34 in DCM−d2 led to a vigorous evolution of gas which ceased shortly thereafter. 31 P NMR spectra of the reaction mixture performed after mixing showed the presence of two signals at 20.5 ppm (major) and 5.5 ppm (minor), respectively. The same signals (but at a different rate) were observed in the spectrum obtained 12 h later ( Figure 5A, top). The first could be attributed to the substrate, however, hydrogen evolution at the beginning of the reaction led to a conclusion that the formation of Ph3P−BH2, followed by an immediate formation of [Ph3P−BH2−H−BH2−PPh3] + , should occur under the reaction conditions. Therefore, it should be assumed that the signal in the 31 P NMR corresponding to the cationic dimer should appear in the same region as substrate, which is the consequence of a bridgehead hydrogen atom present in the dimeric cation.
Apart from this signal, the presence of a peak at 5.5 ppm was observed in the 31 P NMR spectrum of the reaction mixture which evolved over time. This signal has been ascribed to Ph3PH + cation according to the literature. 10 In the 1 H NMR, a signal at 8.70 ppm was found with JP−H 520. 8 Hz, which supports the structure of this cation. In the 11 B NMR, the presence of two signals at −0.7 ppm and −37.7 ppm (multiplet), respectively, was detected ( Figure 5A, bottom). The first signal may be assigned to BF3 or BF4 − derived from HBF4. The multiplet at −37.7 ppm should be, in consequence, ascribed to both the substrate and cationic species [Ph3P−BH2−H−BH2−PPh3] + .
A reaction of either 0.5 or 1 equivalent of TfOH with Ph3P(BH3) 34 in DCM−d2 proceeded in a similar manner, affording a mixture of compounds ( Figure 5B). 31 P NMR spectra of the reaction mixture recorded after mixing showed the presence of three signals at 20.5 ppm, 5.5 ppm, and 2.3 ppm, respectively. The same signals (but at a different rate) were observed in the spectrum obtained 12 h later ( Figure 5B, top). Signals at 20.5 ppm and 2.3 ppm were both broad which suggests the presence of P−B bond in the molecule. Signals at 20.5 ppm and 5.5 ppm were also present in the reaction of 34 with HBF4, while the signal at 2.3 ppm appeared as a new peak. This signal corresponds most probably to the Ph3P−BH2OTf molecule as a reaction between 34 and TfOH proceeded with vigorous evolution of hydrogen, generating a Ph3P−BH2 cation which undergoes immediate coordination to the triflate anion. The same trend in chemical shift was observed when trimethylphosphine−borane (−1.8 ppm) 11 was allowed to react with methanesulfonic acid (MsOH), affording Me3P−BH2OMs (−13.9 ppm). 12 In the 11 B NMR, the presence of two signals at −8.4 ppm and −37.7 ppm (multiplet), respectively, was detected ( Figure 5B, bottom). The first signal may be assigned to Ph3P−BH2OTf, whereas, the multiplet at −37.7 ppm belongs to the substrate. The presence of the cationic species [Ph3P−BH2−H−BH2−PPh3] + was deemed probable, but not definitive, as it gives the same shift in the 11 B NMR spectrum.
Interesting Organophosphorus compounds of R3P−BH3 and R2P−BH2 types can be regarded as borohydride and borane analogues, at least theoretically. In organic synthesis, NaBH4 and BH3 are often reagents of choice for reduction of carbon−heteroatom double bonds. Compounds of R2P−BH2 type possess quite interesting properties as they can be regarded both as Lewis base and Lewis acid due to the presence of a free-electron pair (at phosphorus) and electron vacancy (at boron). As a consequence, they readily undergo oligomerization 13,14 and cyclooligomerization [15][16][17] reactions, affording products with multiple −P−B− linkage. When considering reducing properties of either R3P−BH3 or R2P−BH2 type compounds, the only mention found in the literature was either intermolecular 18 or intramolecular [19][20][21] hydroboration of a C=C bond with R3P−BH3 type compounds. A combination of these molecules, i.e., R3P−BH3 or R2P−BH2, however, can serve as a system for reduction of multiple bonds in which the P−BH2 fragment activates multiple bonds and R3P−BH3 provides a hydride anion (Figure 7). The best model reaction to test the hypothesis stated above is the reduction of the C=O bond, as boron forms a strong dative bond with the carbonyl oxygen, thus, activating the carbonyl group and facilitating a hydride transfer from the second boron functionality. For a test reaction, acetophenone has been used as the model carbonyl compound which was then reacted with a monocation derived from the diphosphine−diborane 24 and TfOH (Scheme 4). The reaction was performed in a NMR tube using stoichiometric amounts of reagents; the progress of the reaction was followed by 1 H, 31 P and 11 B NMR analyses as shown below (Figure 8).
The 1 H NMR spectrum, recorded after 30 min, revealed the presence of two major compounds: acetophenone and ethylbenzene 35 in 0.41:1.00 ratio. Apart from these two compounds, traces of styrene were detected in the olefinic region. The presence of a minor amount of DPPE diborane (singlet at 2.44 ppm) and major amount of Ph2P(BH3)CH2CH2P(BH2OTf)Ph2 (multiplets at 2.43-2.71 ppm) have been confirmed as well. Additionally, other multiplets in the 2.73-3.46 ppm region started to appear, which could be ascribed to the products of the DPPE-diborane transformation. During the time, the amount of acetophenone constantly decreased with a simultaneous increase of the amount of ethylbenzene.
In the 31 P NMR spectra, the initial shifts of Ph2P(BH3)CH2CH2P(BH2OTf)Ph2 were at 18.5 and 0.7 ppm, respectively. After 30 minutes, additional signals at 9.4 ppm (JP-P 52 Hz), 10.5 (singlet) and 26.9 ppm (broad multiplet), respectively, were found. The intensity of the latter increased over time with simultaneous decrease in the intensity of the signals of the parent compound. The presence of the doublet at 9.4 ppm with a relatively large coupling constant suggests the formation of a cationic intermediate with the possible structure like Ph2P(BH3)CH2CH2P(H)Ph2, and the signal at 10.5 ppm might correspond to the dicationic Ph2P(H)CH2CH2P(H)Ph2.
In the 11 B NMR, the signals of the initial Ph2P(BH3)CH2CH2P(BH2OTf)Ph2 appear at -40.4 ppm and -9.3 ppm, respectively. Apart from this, a characteristic and very broad peak around 0 ppm appeared, corresponding to B2O3 oxide, along with a peak at -34.5 ppm. The latter corresponds to a phosphine-borane different from the substrate. Over time, the intensity of the signals of the starting borane decreased with a steady increase of a broad B2O3 signal.
A detailed analysis of the reaction mixture revealed one surprising observation which was the lack of the most obvious reduction product, 1-phenylethanol. Instead, ethylbenzene is the major reaction product as deduced from NMR and GC-MS analysis, formed in almost 86% yield. In this regard, the reaction could be regarded as a hydrodeoxygenation, but the presence of trace amounts of styrene points toward a more complex mechanism. This most probably involves reduction of acetophenone to 1-phenylethanol, followed by its dehydration to styrene. The latter most likely undergoes hydroboration of the double bond, followed by hydrolysis of the boron-oxygen bond with water formed in the previous step.