Air-Stable, Highly Fluorescent Primary Phosphanes

Light without fright: a synthetic route to fluorescent primary phosphanes (RPH(2)) that are resistant to air oxidation both in the solid state and in chloroform solution is described. These versatile precursors undergo hydrophosphination to give tripodal ligands and subsequently fluorescent transition-metal complexes.

Primary phosphanes (RPH 2 ) have a reputation as noxious compounds which are spontaneously flammable in air. [1] We have recently demonstrated, however, that they can be stabilized to air oxidation without any need for steric protection, providing sufficient p conjugation is incorporated into the organic R group; thus we were able to prepare the first air-stable chiral primary phosphanes. [2] Since then, we have been developing a working model based on DFT, which indicates that, contrary to popular belief, many primary phosphanes will be air-stable if the molecule contains a high degree of conjugation (see below). [3] As such, the model predicted that the incorporation of the phosphino group onto a boron dipyrromethene (Bodipy [4] ) skeleton would also produce air-stable primary phosphanes. These phosphanes should provide a highly versatile gateway into a vast range of fluorescent phosphane derivatives, which are currently sorely underrepresented, despite the importance of phosphanes in catalytic and biomedical applications. To explore this exciting possibility, we commenced a synthetic study based on the strategy shown in Scheme 1. The fluorescent aryl bromide derivative of Bodipy, 1, was synthesized in a one-pot reaction. [5] Following difficulties with retaining the two fluorine atoms in the later reduction step, [6] we treated 1 with two equivalents of phenyllithium to give the novel derivative 2 a, which was characterized by X-ray crystallography ( Figure S1 in the Supporting Information). A palladium-catalyzed coupling reaction of 2 a with diethylphosphite yielded the fluorescent phosphonate 3 a, which was also analyzed by X-ray crystal-lography ( Figure S3 in the Supporting Information). Phosphonate 3 a was then reduced quantitatively to the primary phosphane 4 a by using a combination of lithium aluminum hydride and chlorotrimethylsilane. As predicted by the model, 4 a was found to be stable to oxidation; when exposed to air both in the solid state and in chloroform solution over seven days, no decomposition was observed. Importantly, incorporation of the phosphonate and the phosphino group did not dramatically alter the photophysical properties of the molecules when compared to the parent aryl bromide 2 a (Table 1). This finding was not unexpected, as the results from our DFT calculations show that the highest occupied molecular orbitals (HOMOs), up to the HOMO-6 of 2 a, do not incorporate the phosphorus atom, although they are affected by the phenyl rings on the boron atom ( Figure S6 in the Supporting Information). It is noteworthy that, after the aryl substitution of 1, the quantum yield (F) of aryl bromide 2 a drops from 0.65 to 0.079. In an effort to maintain the high quantum yield of 1, but to still allow the reduction step, we treated 1 with two equivalents of methyllithium to give the dimethyl aryl bromide derivative 2 b, which was also characterized by X-ray crystallography ( Figure S2 in the Supporting Information). Substitution of the fluorine atoms by methyl groups has a less detrimental effect on the quantum yield (compare F values for 1, 2 a, and 2 b, Table 1). We then adopted the previous methodology to prepare the corre-  sponding phosphonate 3 b and the primary phosphane 4 b, which also retain generally better quantum yields and molar absorption coefficients (F and e and Table 1). [7] The primary phosphane 4 b is air-stable as a solid and in solution over seven days; Figure 1 depicts its crystallographically determined molecular structure.
Again this air stability is in accord with that predicted by the model; the high degree of p conjugation raises the orbital energies of both the neutral molecule and the associated radical cation, which was found to correlate with a higher resistance to air oxidation. [3] For 4 b, the phosphino group is not incorporated in any orbital above HOMO-3 ( Figure S7 in the Supporting Information). The two methyl groups on the boron of 4 b are involved in the HOMO-1, but in contrast to the diphenyl substitution on 4 a, the dimethyl substitution has a much lower impact on the quantum yield of 4 b (see above, Table 1), which has a value almost eight times that of 4 a. Having demonstrated that both 4 a and 4 b are air-stable and that 4 b possesses desirable photophysical properties common to the Bodipy scaffold, [4,7] we next sought to measure the reactivity of the phosphino group, to establish if the resistance to air oxidation impinges on the behavior of the normally reactive PÀH bonds. One of the classical reactions of a primary phosphane is the hydrophosphination reaction across a double bond. Zubieta, Valliant et al. have shown that fluorescent, tripodal, quinoline-derived complexes of rhenium and technetium have tremendous potential as radiopharmaceutical imaging agents. [8] With this in mind, we treated 4 b with two equivalents of vinyldiphenylphosphane, using [Pt(nbd) 3 (Table 1); modification at the phosphorus center is not detrimental. Having established that the air stability of 4 b does not impede on the reactivity of its phosphino group, we sought to study some preliminary coordination chemistry of the tripodal phosphane 5 b. Reaction of 5 b with [ReCl(CO) 3 (PPh 3 ) 2 ] in mesitylene generated the octahedral rhenium complex 6 b (Scheme 2).
A sample of 6 b was analyzed by X-ray crystallography, and the molecular structure is depicted in Figure 3. This structure shows that the tripodal phosphane adopts a mer configuration about the rhenium center, with the central phosphorus atom trans to a carbonyl ligand and the terminal phosphorus atoms of the ligand 5 b trans to each other. Of particular note is the elongated metal-carbon bond length of the carbonyl ligand trans to the phosphorus atom, relative to that of the carbonyl ligand trans to the chlorine atom   .

Angewandte
Communications complexes, [ReCl(CO) 2 (triphos)] (triphos = bis(2-diphenylphosphanoethyl)phenylphosphane). [9] The complex 6 b retains a similar absorption-emission profile (l abs 513 nm; l em 527 nm) to that of the uncomplexed tripodal phosphane 5 b and, although the molar absorption coefficient and quantum yield are lowered relative to 5 b, these values are not dramatically affected; thus the molar absorption coefficient e is lowered from 90 000 to 64 000 m À1 cm À1 , and the quantum yield is reduced from 0.34 to 0.28. The high quantum yield value is of significance; the aforementioned rhenium tripodal nitrogen complexes give quantum yields of 0.015 to 0.003 (depending on the solvent), as do many other transitionmetal fluorescence probes. [10] Therefore the results indicate that the rhenium phosphane core is straightforward to prepare and retains a highly desirable photophysical profile. Because of the similar coordination chemistry, rhenium is a frequently used mimic of 99m Tc, which is the most widely used radionuclide in medicinal diagnoses. [8,11] Thus cores such as 6 b offer the potential for correlating fluorescence studies with radioimaging data to better understand and improve the imaging and targeting of diseases. Fluorescence microscopy would facilitate an understanding of cellular activity in vitro, which could then be used in conjunction with information garnered from living specimens that had been subjected to nuclear imaging techniques after treatment with the gammaemitting 99m Tc analogues. Our studies are now focused in this area.

Experimental Section
Apart from the air stability studies, reactions were carried out using standard Schlenk-line techniques in anhydrous solvents. Full characterization data for compounds 1-6 are given in the Supporting Information.
2 a: Phenyllithium (4.57 mL, 9.15 mmol, 2.0 m solution in dibutyl ether) was added dropwise to a tetrahydrofuran solution (100 mL) of 1 (2.00 g, 4.36 mmol). The solution was stirred at room temperature until complete consumption of the starting material was observed by TLC. The reaction was quenched with water (20 mL), extracted with dichloromethane (2 100 mL), and the combined organic fractions were washed with water (40 mL) and brine (40 mL) and dried over magnesium sulfate. Column chromatography on silica (petroleum ether/toluene, 4:1) gave an orange solid (1.10 g, 44 %).
4 a: Lithium aluminum hydride (3.16 mL, 3.16 mmol, 1.0 m solution in tetrahydrofuran) was added to a Schlenk flask and cooled to À78 8C in a dry ice/acetone bath. Chlorotrimethylsilane (0.40 mL, 3.16 mmol) was added to the resultant white suspension, and the mixture was allowed to warm to room temperature over 30 min. A colorless solution was evident which was then cooled to À40 8C in a dry ice/acetonitrile bath, and a solution of 3 a (1.00 g, 1.58 mmol) in tetrahydrofuran (100 mL) was added dropwise. The reaction was allowed to warm to room temperature and stirred overnight. The solution was concentrated in vacuo and then quenched in an ice-bath with degassed water (20 mL). The product was extracted with diethylether (3 20 mL) and dried over magnesium sulfate. Column chromatography on silica (dichloromethane/petroleum ether, 1:2) gave 4 a as an orange solid (0.77 g, 92 %). 4 b: The compound was prepared in a similar fashion to 4 a, by using lithium aluminum hydride (3.93 mL, 3.93 mmol, 1.0 m solution in tetrahydrofuran), chlorotrimethylsilane (0.50 mL, 3.93 mmol), and 3 b (1.00 g, 1.97 mmol) in tetrahydrofuran (100 mL). Column chromatography on silica (chloroform/n-hexane, 1:4) gave 4 b as an orange solid (0.74 g, 93 %). [12] 5 b: Vinyldiphenylphosphane (0.16 mL, 0.78 mmol), [Pt(nbd) 3 ] (0.018 g, 0.037 mmol), and 4 b (0.150 g, 0.37 mmol) were dissolved in toluene (10 mL), and the reaction was stirred at reflux for five days. Column chromatography on silica (dichloromethane/n-hexane, 1:1) gave 5 b as an orange solid (0.21 g, 70 %).