|Home | About | Journals | Submit | Contact Us | Français|
Metal free formation of a P–C bond via addition of acetone to a fluoroaryl phosphinic acid is observed. The dynamic nature of the underlying equilibrium was investigated using H/D exchange and the resulting adduct forms an extensive hydrogen bonded 2D network in the solid state which was confirmed by X-ray diffraction.
The synthesis, structure and reactivity of the fluoroaryl phosphinic acid HF4C6–P(O)HOH is reported and compared to a sterically comparable yet non-fluorinated analog with similar size. The fluoroaryl phosphinic acid undergoes reversible P–H addition to the carbonyl functionality of ketones under formation of a P–C bond which is retained in the resulting α-hydroxy phosphinic acid. The latter shows an extended 2D hydrogen bonded network in the solid state.
Phosphinic acids are relevant for many fields of chemistry , biology  and medicinal chemistry . On the other side, also phosphorus compounds with electron withdrawing moieties attracted considerable attention in the last decade. Electron withdrawing groups are known to influence electronic and optical properties of the phosphorus containing compounds besides their reactivity [4–7]. It has been demonstrated that the phosphinic acid (CF3)2POH is the prevalent tautomeric structure over (CF3)2P(O)H, which is in sharp contrast to other known phosphinic acids [8,9]. Also C2F5 substitution leads to a similar behavior . By using 1,3 bis(trifluoro)methyl substituted aryl rings Hoge and co-workers showed that the corresponding phosphinic anhydrides can be stabilized over the tautomeric diphosphane monoxides which was attributed to the electronic nature of the fluorinated groups . In the last years the synthesis of fluorinated phosphanes aiming at phosphano-borane based “frustrated” Lewis acid/base pairs has flourished enormously looking at applications as e.g. hydrogen activation and storage [12,13]. The perfluorinated phosphinic acid (C6F5)2P(O)H forms an adduct with acetone in solution, which is however not retained in the solid state owing to its alleged kinetic instability . By increasing the Lewis acidity of the carbonyl component the adduct formation becomes irreversible as is evidenced on going from acetone to benzaldehyde . The resulting α-hydroxy phosphinic acids had been previously synthesized using alternative pathways [15–19]. For a non-fluorinated α-hydroxy phosphinic acid obtained by the latter route the isolation and characterization with X-ray diffraction of a single enantiomer (S) could be achieved . Applications of this class of compounds range from flame retardants  to asymmetric synthesis  and neutral amino peptidase (NAPN) inhibitors .
We investigated the P–H addition of a phosphinic acid to acetone where the partially fluorinated substituent (HF4C6–) carries a single hydrogen atom as spectator unit for spectroscopic purposes. A comparison with the non-fluorinated mesityl phosphinic acids shows the influence of the electron withdrawing substituent on the phosphinic acid, while the steric demand of the fluorine groups should be only slightly smaller than that of the methyl groups [24,25]. For the partially fluorinated phosphinic acid we found a reversible addition equilibrium with acetone forming the corresponding α-hydroxy phosphinic acid. Surprisingly the latter is also stable in the solid phase, unlike its previously reported perfluorinated counterpart.
The partially fluorinated substituent 2,3,5,6-tetrafluorophenyl (HF4C6–) turned out to be useful to track reactions employing the single hydrogen atom as a spectroscopic probe . The corresponding dichlorophosphane 1a which was recently published  should be a suitable precursor for the synthesis of phosphinic acid 2a. For HF4C6-compounds the electronic and steric situation should be very similar to their C6F5 substituted analogs. On the other hand for the corresponding mesityl (Mes = 2,4,6-trimethyl-phenyl) derivative 2b, the electronic – unlike the steric – situation at the adjacent phosphorus atom should be very different from the fluorinated counterparts. In order to explore the balance of steric and electronic effects for these compounds we prepared 2a and 2b to compare their structure and reactivity.
The fluoroaryl phosphinic acid 2a is obtained in a clean reaction by controlled hydrolysis of 1a in chloroform solution as an oily material, which solidifies at 4 °C upon prolonged cooling after removal of the solvent in almost quantitative yields. In a similar way, the mesityl analog 2b is obtained in 75% by a clean reaction from 1b (Scheme 1). The IR data of solid 2a,b show the presence of the P–H and the PO functionalities . For both compounds the tautomeric form present in the solid state is the phosphorane form 2 of the phosphinic acid rather than the phosphane tautomer 2′ as was clearly confirmed by X-ray diffraction on suitable single crystals.
Compound 2a crystallizes in the monoclinic space group P21/c as colorless plates. The phosphinic acid group in 2a is oriented to near coplanarity of the P–H bond relative to the aryl ring (C6–C1–P1–H1 1.8(7)°) leading to a close contact with an F atom (H1F6 2.58(2) Å). The P–H and O–H bonds are 1.28(2) Å and 0.87(3) Å, respectively, which is in the typical range for these bonds. In general phosphinic acids form strong hydrogen bonds owing to the polarity of the P–O unit. In 2a this is further enhanced resulting in very short donor acceptor distances, which is significantly shorter than in phenyl phosphinic acid (4) , but also shorter than in [2,4,6-tris(trifluoromethyl)phenyl]-phosphinic acid (5) . A summary of the donor acceptor geometry parameters is given in Table 1. The formation of a linear chain is typical for phosphinic acid with little steric shielding , while phosphinic acids with bulky substituents usually form dimers [30,31]. Short contacts of neighboring chains via the aromatic hydrogen atom exhibit weak vdW interactions H4–F2 (2.44(2) Å and H4–O1 2.70(2) Å). A graphical representation of the structure of 2a is depicted in Fig. 1 and details of the data acquisition and structure solution are summarized in Table 2.
The mesityl substituted analog 2b crystallizes in the monoclinic space group P21/n as colorless needles. The phosphinic acid shows an orientation in a way that the PO bond is arranged almost coplanar with the phenyl ring (O2–P1–C1–C2 10.0(1)°). The quality of the crystal of 2b allowed the analysis of the hydrogen bond system which forms a zig-zag arranged linear chain. Also in non-fluorinated 2b shorter donor acceptor distances than in (4) and (5) are observed which indicates that the electron withdrawing properties of the substituent in fluorinated 2a are only in part responsible for the strong donor–acceptor interaction. Other structural parameters of 2b show no peculiarities (Fig. 2).
To check how compounds 2a,b behave in solution we performed NMR measurements in acetone. Based on 31P NMR measurements the phosphinic acid R–PH(O)OH is the only detectable tautomer for fluorinated 2a and non-fluorinated 2b. The chemical shifts and coupling constants are with 2.2 ppm (d, 1JPH = 630 Hz) (2a) and 24.2 (d, 1JPH = 562 Hz) (2b) in the expected range for the phosphorane form of phosphinic acids. One significant difference between 2a and 2b is the reaction behavior towards acetone. Unexpectedly, we found a dynamic H/D exchange for fluorinated 2a in acetone–d6 while no such behavior was observable for non-fluorinated 2b. In the case of 2a the stepwise exchange of both protons of the –PH(O)OH functionality can be monitored with 1H NMR where the presence of the C–H proton turns out to be especially useful. Initially, the P–OH resonance of 2a can be observed, but already after 5 min integrals are no longer in agreement with the intensity of the other signals (e.g. HF4C6–). After 12 h both proton resonances of the phosphinic acid have disappeared, owing to complete exchange with deuterium. The transfer of the more acidic OH proton to the less acidic P–H position (H/D scrambling) can be explained by a successive tautomeric equilibrium involving a sequential change of the formal oxidation state from P(V) to P(III) and vice versa as summarized in Scheme 2. As known from the literature electron withdrawing substituents favor the trivalent P(III) intermediate 2′ which explains why such an exchange is observed for 2a but not for 2b [8,9]. Based on DFT calculations (B3LYP/6-311G**) the preference for the phosphorane structure 2 over the phosphane structure 2′ can be quantified and as expected the energy difference is smaller for the electron-withdrawing HF4C6-substituent (2′a → 2a |ΔG298 = −1.9 kcal/mol and 2′b → 2b |ΔG298 = −6.5 kcal/mol).
Moreover, the proton exchange is presumably facilitated via a dimeric intermediate . To the best of our knowledge no evidence for P–H/P–D exchange in acetone–d6 at ambient temperature has been reported so far. By contrast H/D exchange of primary phosphanes in D2O is well established . We assume that acetone–d6 acts as the deuterium source owing to the α-acidity of carbonyl compounds involving the corresponding enol. The fact that H/D exchange only occurs for 2a but not 2b might point to the higher acidity of 2a which may lead to protonated acetone–d6 which then on deprotonation would be able to transfer D+ to the conjugated base of 2a.
In the course of the H/D exchange, the initial doublet of the 31P signal of 2a (1JPH 630 Hz) turns into a triplet of constant intensity due to the 31P–D coupling (1JPD 92 Hz). The ratio of the coupling constants is ~6.85, which roughly matches the ratio of the gyromagnetic constants (42.58:6.54 = 6.51). The aromatic proton in para position offers the possibility for easy detection of the aromatic carbon atom signals in HMBC 13C NMR measurements and additionally the P-bonded Caryl resonance (116.4 ppm) could be detected in D2O/H2O solution. Detection of these signals by more simple 13C NMR experiments is often limited by small and broad signals owing to CF couplings over more than one bond.
In the course of the NMR measurements in acetone–d6, we observed a broad-unresolved-signal around 46 ppm in the 31P spectra, but no additional signals in the proton spectra. Hoge and co-workers described the formation of an acetone adduct of (C6F5)2P(O)H in acetone in solution with a 31P chemical shift at 29.2 ppm. However the latter turned out to be kinetically unstable and upon evaporation of the solvent also the incorporated acetone molecule was removed and the adduct could not be obtained and isolated in the solid state . By contrast, we could easily isolate the analogous adduct 3a in crystalline form from solutions of phosphinic acid 2a in non-deuterated acetone, which is formed as depicted in Scheme 3. Attempts to crystallize 2a from any other organic solvent than acetone failed however. X-ray structure analysis of these crystals confirms the presence of the phosphinic acid–acetone adduct (3a) in the solid state (Fig. 3). The acetone adduct was isolated in 52% yield.
Compound 3a crystallizes in the monoclinic space group P21/c as colorless plates. The P–Caryl bond lengths are in the upper range (1.822(1) Å–1.830(1) Å) comparable to the benzaldehyde adduct of phenyl phosphinic acid (1.818(4) Å–1.821(3) Å)  and (2,6-CF3C6H4)2P(O)H (1.819(2) Å–1.822(2) Å) . The phosphorus oxygen bonds are also in the typical range 1.482(1) Å–1.488(1) Å and 1.549(1) Å–1.554(1) Å for double and single bonds, respectively. The aliphatic hydroxyl group shows significantly shorter O–H distances (0.77(2) Å–0.81(2) Å) compared to the more acidic phosphinic OH group (0.89(2) Å–0.95(2) Å). The packing of the molecules in the solid state is dominated by the formation of a hydrogen bonded network. Compound 3a forms an extended 2-dimensional hydrogen bonded network orthogonal to the crystallographic b-axis (0 1 0). Hexagonal cycles are formed by six individual molecules resulting in a honey-comb-like structure (six membered cycles A and B). Two pairs of molecules form a dimeric unit by two POHO–C hydrogen bonded motifs (C) with OH distances of 1.82(2) Å. These dimers are bridged by further 2 molecules via single hydrogen bonds (D: OH 1.86(2) Å), E: OH 1.59(2) Å). A second dimeric hydrogen bonded motif (F) of OH 1.67(2) Å completes the comb like structure. Weak interactions of fluorine atoms with the phenyl rings (F6–C11 3.000(1) Å, F6–C12 2.934(1) Å, F3–C2 2.973(1) Å, F3–C3 3.155(1) Å) shows stacking between the layers formed by the H-bonded network. Relevant crystallographic details for 3a are summarized in Table 2 and a graphical representation of the 2-dimensional network is depicted in Fig. 4.
The IR spectra of solid 3a show a strong band 1248 cm−1 which can be assigned to PO stretching modes based on calculated IR data. The strong band at around 1600 cm−1 can be attributed to different aromatic stretch and methyl bending modes. The different hydroxyl groups give weak broad bands around 3120 cm−1. The measured bands with the exception of OH modes can be assigned reasonably based on calculated ones. The deviation for the OH vibrations may be attributed to the associated hydrogen bond network present in the experimental sample as compared to the isolated molecules in vacuo used for calculations.
A solution of crystalline 3a in acetone–d6 shows a singlet at 46.4 ppm in the 31P NMR spectra. Furthermore, minor amounts of phosphinic acid 2a are observed as well which is likely to be derived from elimination of acetone from 3a. In the 1H NMR spectra one signal for the aromatic proton (7.77 ppm) and a doublet for the methyl groups (1.39 ppm, 16.0 Hz) are observed for 3a. According to 2D-NMR (HMBC/HSQC) measurements the proton signal of these methyl groups shows a correlation to the quaternary carbinol carbon atom (δ(13C) = 70.11 ppm) which proves the connection of the methyl groups to the latter also in solution. The integrals of the proton signals of the methyl groups in 3a are smaller than expected, which can be explained assuming a fast (on the NMR time scale) exchange of the non-deuterated acetone unit in the addition product with the deuterated acetone used as a solvent. To suspend this exchange we dissolved 3a in tetrahydrofurane–d8 giving a single resonance at 34.3 ppm in the 31P NMR spectra, which is at rather high field compared to other α-hydroxy phosphinic acids . The difference of the 31P chemical shifts of 3a in acetone and THF underlines the significance of solvent effects for this system. Similar adducts of 2a with other ketones can be formed as well and the corresponding methylethylketone adduct shows a 31P chemical shift of 38.1 ppm in chloroform solution.
An investigation of the thermodynamic balance of the adduct formation has been performed with computational methods (B3LYP/6-311G**). The surprising result is that the adduct formation of 2a and acetone leading to 3a is in fact an endergonic reaction (ΔG298 = 11.1 kcal/mol). Since the calculations refer to the gas phase, the relevant driving force for the formation of 3a may be the formation of the extended hydrogen bonded network as found in the solid state. Nevertheless the parameters (i.e. geometry, spectroscopic data) calculated for an isolated molecule of 3a in vacuo are in good agreement with the experimental data measured for the solid (H-bridged) compound.
In summary, we prepared a phosphinic acid with a fluorinated aryl group (2a) in comparison to its mesityl substituted analog (2b) where the steric situation is similar while the electronic situation differs. The behavior of these phosphinic acids was studied in solution indicating the exclusive presence of the phosphorane tautomer 2, or a fast equilibrium on the NMR time scale in which the latter is dominant over the corresponding phosphane tautomer 2′. In the solid state molecules of 2a and 2b are connected via their phosphorane functionalities to infinite chains via strong hydrogen bonds. Besides these similarities, their reactivity towards acetone differs substantially. A characteristic reaction of compound 2a is the addition of the P–H unit to the carbonyl group of acetone under formation of 3a, which occurs in solution and persists also in the solid state. Its mesityl analog 2b does not show a reaction with acetone at all. Moreover, in solution 2a is also involved in a dynamic proton exchange with acetone as evidenced by H/D scambling. Again its mesityl analog 2b does not show similar behavior. According to our findings, the energetically lower accessibility of the phosphane tautomer 2′a along with the higher acidity of 2a are likely to be responsible for this different behavior. In summary the unique reactivity observed in the formation of 3a allows the facile formation of a P–C bond without involvement of salt elimination or expensive or sensitive organometallic coupling reagents. An obvious perspective for future work will be the control of the reversibility of this addition also exploring the possibility to induce an enantiomeric excess for the asymmetrically substituted phosphorus center formed during this addition.
CCDC-753926 (for 2a), -754559 (for 2b) and -754558 (for 3a) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: (internat.) +44 1223 336 033; E-mail: email@example.com. ac.uk].
For compounds 2a,b, 2′a,b and 3 output summaries for the DFT calculations (optimized geometries, total energies (E, in hartree)) have been provided as supplementary material.
Reactions are carried out under ambient atmosphere unless otherwise noted. NMR measurements were performed on a Varian UnityInova 400 and a BrukerAvanceIII 300 operating at proton frequencies of 399.9 MHz and 300.1 MHz, respectively. 1H and 13C shifts are given in ppm and referenced to residual solvent signal. 19F and 31P shifts are given in ppm and are referenced externally to C6H5CF3 (−63.7 ppm) and H3PO4 (85%), respectively. Dichlorophosphanes 1a, Mes–PCl2, and Mes–PH(O)OH were synthesized according to published procedures [26,36,37]. Freshly bought acetone–d6 (0.02% water) was dried over P4O10 and stored in a Schlenk-tube after distillation. DFT calculations were performed with the Gaussian program package . The B3LYP hybrid functional with a 6-311G** basis set was used for all calculations. All structures are fully optimized and determined to be local minima by inspection of their harmonic frequencies having no imaginary frequency. Frequencies were used without scaling factors for determination of thermal correction at 298.15 K.
To a solution of 1a (240 mg, 0.96 mmol) in CHCl3 (1.3 ml) ca. 2 equivalents of H2O (40 mg, 2.2 mmol) are added. The resulting suspension is dried by slow evaporation under ambient conditions. The phosphinic acid is insoluble in typical organic solvents, with the exception of acetone and water. Compound 2a is an oily material which solidifies upon standing at 4 °C. Yield: 203 mg (0.95 mmol, 99%). Mp. 27 °C. 1H NMR (CD3COCD3, 400 MHz): δ = 7.67 (1H, m, aryl), 7.90 (1H, d, 1JPH = 629.5 Hz), 8.37 (s, 1H, exchanges rapidly with acetone–d6); 13C NMR (CD3COCD3, 100 MHz): δ = 110.61 ppm, 146.00 (dm, 1JCF 235.7 Hz), 147.53 (dm, 1JCF 259.3 Hz), Caryl–P 116.4 (from freshly prepared D2O/H2O solution). 31P NMR (CD3COCD3, 162 MHz): δ = 2.2 ppm (d, 1JPH = 630 Hz) after 12 h. 1H was completely exchanged by 2H. The initial doublet becomes a triplet of constant intensity. 2.2 ppm (t, 1JPD = 92 Hz). 19F NMR (THF–d8, 282.4 MHz): δ = −141.09 (br. s, 4F). IR(KBr [cm−1]): 3104 (w, Carom.–H), 2469 (w, P–H), 2090 (m br.), 1610 (m arom.), 1484 (str, arom.), 1375 (m), 1246 (str, PO), 863 (m, P–OH).
To a solution of Mes–PCl2 (0.65 g, 2.9 mmol) in chloroform 2.5 equiv of H2O are added at 0 °C. The mixture is stirred for 1 h. The organic phase is dried over MgSO4 and the solvent removed in vacuum yielding 0.40 g pure product (2.2 mmol, 75%). Colorless crystals suitable for X-ray diffraction are obtained by slow evaporation of chloroform solutions. Mp: 143 °C. 1H NMR (CDCl3, 300 MHz): δ = 8.03 (1H, d, 1JPH = 562.0 Hz), 6.76 (2H, d, 4JPH 4.3 Hz, aryl), 2.57 (6H, s, o-CH3), 2.28 (3H, s, p-CH3). 13C NMR (CDCl3, 75.5 MHz): δ = 142.64 (s, Cpara) 141.47 (d, 11.7 Hz, Cmeta), 139.11 (d, 12.2 Hz, Cortho), 124.03 (d, 1JPC 138.1 Hz, Cipso), 20.96 (d, 3JPC 8.9 Hz, m-CH3), 14.21 (s, p-CH3). 31P NMR (CDCl3, 121.5 MHz): δ = 24.2 (d, 1JPH 562 Hz). IR(KBr [cm−1]): 2942 (w, Carom.–H), 2920 (w, Methyl), 2408 (w, P–H), 2155 (m. br.), 1605 (str., arom. stretch), 1561 (str., arom. stretch), 1457 (m, CH3 bent), 1190(m, PO stretch), 1092 (m), 964 (m), 853 (m, P–OH stretch).
Phosphinic acid 2a (174 mg, 0.81 mmol) was dissolved in acetone and placed in a screw top vial at room temperature. Small plates of 3a suitable for X-ray diffraction were obtained after 3 weeks of crystallization. After collecting the solid material and washing with chloroform pure crystalline material was obtained. Yield 116 mg (0.43 mol, 52%). Mp. 131 °C. 1H NMR (CD3COCD3, 400 MHz): δ = 7.77 (m, 1H, aryl), 1.39 (d, “6H”, 3JPH 16.0 Hz); 13C 1H-HMBC/HSQC (THF–d8, 100 MHz): 23.33 (CH3), 70.11 (d, 1JPC 13.8 Hz), 110.76 (p-Carom.), 145.02–148.61 (m, o- and m-C). Carom.–P could not be detected. 31P NMR (CD3COCD3, 121.5 MHz) δ = 46.4; 31P NMR (THF–d8, 121.5 MHz): δ = 34.3, 19F NMR (THF–d8, 282.4 MHz): δ = −131.64 (m, 2F, Cortho–F), −141.07 (m, 2F, Cmeta–F); IR(KBr [cm−1]): 3121 br.w. 1476 (s, str), 1248 (s, str., PO), 970 (s, m), 917 (s, m). 860 (w, P–OH).
The solid phosphinic acid 2a (27 mg, 0.13 mmol) is dissolved in 2-butanone (5 ml) and stirred at slightly elevated temperatures for 2 days. Complete conversion into the corresponding α-hydroxy phosphinic acid was checked by 31P NMR spectroscopy. After removal of the excess of 2-butanone the resulting oily material is extracted with chloroform. Spectroscopically pure product is obtained as viscous oil after removal of the solvent under vacuum (33 mg, 0.12 mmol, 91%).
1H NMR (CDCl3, 300 MHz): δ = 0.99 (br. t, 3JHH 7.1 Hz, 3H, CH2–CH3), 1.35 (d, 3JPH 17.2 Hz, 3H, CH3), 1.76 (m, 2H, CH2–CH3), 6.75 (br. S, OH), 7.26 (m, 1H, aryl). 13C NMR (CDCl3, 75 MHz): δ = 6.6 (CH2–CH3), 19.2 (CH2–CH3), 27.9 (CH3), 73.7 (d, 1JPC 147.0 Hz, C–OH), 111.2 (Caryl–H), 145.5 (dm, 1JCF 261.9 Hz, o, m-Caryl), P–Caryl n.d. 19F NMR (CDCl3, 282 MHz): δ = −128.73 (m), −136.99 (br. s). 31P NMR (CDCl3, 121 MHz): δ = +38.1 (br. s).
X-ray studies have been carried out with a Bruker Apex-III diffractometer equipped with a CCD detector. Structures are solved by direct methods using SHEL-XS and refined with SHEL-XL . In compounds 2b and 3a the H atoms of the methyl groups were refined with common isotropic displacement parameters for the H atoms of the same group and idealized geometry with tetrahedral angles, enabling rotation around the X–C bond, and C–H distances of 0.98 Å. Hydrogen atoms of the phenyl rings were put at the external bisector of the C–C–C angle at a C–H distance of 0.95 Å and common isotropic displacement parameters were refined for the H atoms of the same phenyl group. All other hydrogen atoms in 2a, 2b and 3a have been located on the difference Fourier map and were refined isotropically without any constraints. In Table 2, crystal and refinement data for 2a, 2b, and 3a are summarized.
Financial support by the Austrian Science Fund (FWF) (Grants P18591-B03 and P20575-N19) and the EU-COST Action CM0802 “PhoSciNet” are gratefully acknowledged.