Air-stable, highly fluorescent primary phosphanes

Article abstract of DOI:10.1002/anie.201108416

Light without fright: A synthetic route to fluorescent primary phosphanes (RPH₂) 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. Copyright

Full text of DOI:10.1002/anie.201108416

Angewandte
Chemie
DOI: 10.1002/anie.201108416
Phosphaorganic Chemistry
Air-Stable, Highly Fluorescent Primary Phosphanes**
Laura H. Davies, Beverly Stewart, Ross W. Harrington, William Clegg, and Lee J. Higham*
Primary
phosphanes
(RPH2) have a reputation
as noxious compounds
which are spontaneously
flammable in air.[1] We
have recently demon-
strated, however, that
they can be stabilized to
air oxidation without any
need for steric protection,
Scheme 1. Synthetic procedure for the novel compounds 2a/2b, 3a/3b, and 4a/b. DPPB=1,4-bis(diphenylphos-
phino)butane, DMSO=dimethyl sulfoxide.
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 2a, which was
characterized by X-ray crystallography (Figure S1 in the
Supporting Information). A palladium-catalyzed coupling
reaction of 2a with diethylphosphite yielded the fluorescent
phosphonate 3a, which was also analyzed by X-ray crystal-
lography (Figure S3 in the Supporting Information). Phos-
phonate 3a was then reduced quantitatively to the primary
phosphane 4a by using a combination of lithium aluminum
hydride and chlorotrimethylsilane. As predicted by the
model, 4a 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 2a
(Table 1). This finding was not unexpected, as the results from
our DFT calculations show that the highest occupied molec-
Table 1: Photochemical data of compounds 2a/b, 3a/b, and 4a/b.[a]
labs [nm]
lem [nm]
e [mÀ1 cmÀ1
]
F
1
526
519
514
518
513
518
512
513
513
540
531
524
534
527
532
526
528
527
78000
80000
87000
83000
91000
79000
79000
90000
64000
0.65
0.079
0.36
0.039
0.29
0.042
0.33
0.34
0.28
2a
2b
3a
3b
4a
4b
5b
6b
[a] Determined in THF at room temperature.
[*] L. H. Davies, Dr. B. Stewart, Dr. R. W. Harrington, Prof. W. Clegg,
Dr. L. J. Higham
ular orbitals (HOMOs), up to the HOMO-6 of 2a, 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 2a
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 2b, which was also charac-
terized 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, 2a, and 2b, Table 1). We then
adopted the previous methodology to prepare the corre-
School of Chemistry, Bedson Building, Newcastle University
Newcastle upon Tyne, NE1 7RU (UK)
E-mail: lee.higham@ncl.ac.uk
Homepage: http://www.ncl.ac.uk/chemistry/staff/profile/
lee.higham
[**] We thank Newcastle University for funding (L.H.D.) and the EPSRC
for a Career Acceleration Fellowship (L.J.H.), an equipment grant
(W.C.), their National Mass Spectrometry Service Centre, Swansea
(UK), and the Newcastle-operated synchrotron component of their
National Crystallography Service. We also thank STFC for access to
synchrotron facilities at Diamond Light Source.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201108416.
Re-use of this article is permitted in accordance with the Terms and
Conditions set out at http://angewandte.org/open.
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sponding phosphonate 3b and the primary phosphane 4b,
which also retain generally better quantum yields and molar
absorption coefficients (F and e and Table 1).[7] The primary
phosphane 4b is air-stable as a solid and in solution over
seven days; Figure 1 depicts its crystallographically deter-
mined molecular structure.
Figure 2. The absorption and emission photochemical profiles of 4a
and 4b in THF; Stokes’ shifts of 14 nm are evident.
spectrum in [D]chloroform gave a doublet at d = À12.2 ppm
and a triplet at d = À16.4 ppm in a 2:1 ratio (3JPP = 27.3 Hz).
The phosphane also retains the photophysical characteristics
of its precursor 4b (Table 1); modification at the phosphorus
center is not detrimental. Having established that the air
stability of 4b does not impede on the reactivity of its
phosphino group, we sought to study some preliminary
coordination chemistry of the tripodal phosphane 5b. Reac-
tion of 5b with [ReCl(CO)3(PPh3)2] in mesitylene generated
the octahedral rhenium complex 6b (Scheme 2).
Figure 1. View of the molecular structure of 4b with 50% probability
displacement ellipsoids. Hydrogen atoms bound to carbon atoms have
been omitted for clarity. Selected bond distances [ꢀ] and angles [8]:
P1–H1A 1.42(4), P1–H1B 1.23(4), P1–C21 1.8289(17), C5–C18
1.493(2), C5–C6 1.397(2), N2–C6 1.400(2), B1–N1 1.591(2), B1–N2
1.593(2), B1–C24 1.615(3); H1A-P1-H1B 87(2), C4-C5-C6 122.60(15),
N1-B1-C24 110.61(15), N1-B1-N2 104.89(12).
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 4b, 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 4b are involved in the HOMO-1, but in contrast to
the diphenyl substitution on 4a, the dimethyl substitution has
a much lower impact on the quantum yield of 4b (see above,
Table 1), which has a value almost eight times that of 4a.
Figure 2 plots absorption coefficient e and fluorescence
intensity versus wavelength l to illustrate the absorption
and emission maxima of 4a and 4b.
Scheme 2. The synthesis of cis,mer-[ReCl(CO)2(5b)].
A sample of 6b 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 5b 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
(1.943(5) versus 1.904(6) ꢀ) and the wider bond angle present
for the rhenium–phosphorus–Bodipy carbon junction
(122.08(18)8) when compared to the corresponding angles
when the carbon atoms form part of a metallocyclic ring
(110.61(18) and 109.18(19)8). The parameters compare well
with the only other known tripodal phosphane rhenium
Having demonstrated that both 4a and 4b are air-stable
and that 4b 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
À
normally reactive P H 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 rhe-
nium and technetium have tremendous potential as radio-
pharmaceutical imaging agents.[8] With this in mind, we
treated 4b with two equivalents of vinyldiphenylphosphane,
using [Pt(nbd)3] as catalyst (nbd = norbornadiene), to gen-
erate the tripodal ligand 5b in high yield. The 31P{1H} NMR
2
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2a: Phenyllithium (4.57 mL, 9.15 mmol, 2.0m 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%).
2b: The compound was synthesized in a similar fashion to the
above procedure from 1 (2.00 g, 4.36 mmol) and methyllithium
(5.72 mL, 9.15 mmol, 1.6m solution in diethyl ether). Column
chromatography on silica (petroleum ether/toluene, 9:1) gave an
orange solid (0.79 g, 40%).
3a: Compound 2a (1.00 g, 1.74 mmol) was dissolved in dimethyl
sulfoxide (40 mL), and palladium acetate (0.117 g, 0.17 mmol),
diethyl phosphite (0.25 mL, 1.91 mmol), N,N-diisopropylethylamine
(0.91 mL, 5.21 mmol), and 1,4-bis(diphenylphosphino)butane
(0.074 g, 0.17 mmol) were added. The mixture was degassed for
20 min, before being heated at 908C for three days. The reaction was
diluted with dichloromethane (100 mL) and washed with water
(40 mL) and brine (40 mL) and dried over magnesium sulfate.
Column chromatography on silica (ethyl acetate/petroleum ether,
2:1) gave an orange solid (0.96 g, 87%).
3b: The compound was prepared in a similar fashion to 3a, by
using 2b (1.00 g, 2.22 mmol), toluene (40 mL), bis(dibenzylideneace-
tone)palladium (0.128 g, 0.22 mmol), diethyl phosphite (0.34 mL,
2.66 mmol), N,N-diisopropylethylamine (1.16 mL, 6.66 mmol), and
1,4-bis(diphenylphosphino)butane (0.095 g, 0.22 mmol). Column
chromatography on silica (ethyl acetate/n-hexane, 3:1) gave an
orange solid (0.60 g, 53%).
4a: Lithium aluminum hydride (3.16 mL, 3.16 mmol, 1.0m
solution in tetrahydrofuran) was added to a Schlenk flask and
cooled to À788C 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
À408C in a dry ice/acetonitrile bath, and a solution of 3a (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/petro-
leum ether, 1:2) gave 4a as an orange solid (0.77 g, 92%).
4b: The compound was prepared in a similar fashion to 4a, by
using lithium aluminum hydride (3.93 mL, 3.93 mmol, 1.0m solution
in tetrahydrofuran), chlorotrimethylsilane (0.50 mL, 3.93 mmol), and
3b (1.00 g, 1.97 mmol) in tetrahydrofuran (100 mL). Column chro-
matography on silica (chloroform/n-hexane, 1:4) gave 4b as an orange
solid (0.74 g, 93%).[12]
Figure 3. View of the molecular structure of 6b with 50% probability
displacement ellipsoids. Hydrogen atoms have been omitted for clarity.
Selected bond distances [ꢀ] and angles [8]: Re–P1 2.3890(14), Re–P2
2.4068(13), Re–P3 2.3877(13), Re–C24 1.904(6), C24–O1 1.128(6),
Re–C25 1.943(5), C25–O2 1.138(6), Re–Cl 2.5220(13), P2–C21
1.827(5), C5–C6 1.379(9), C6–N2 1.402(6), N2–B 1.591(9), B–C54
1.630(13); Cl-Re-P1 81.39(5), Cl-Re-P2 84.53(4), P1-Re-P3 155.18(5),
C24-Re-C25 86.3(2), Re-C25-O2 178.0(5), Re-P2-C21 122.08(18), C4-C5-
C6 122.5(5), N1-B-N2 105.5(5).[12]
complexes, [ReCl(CO)2(triphos)] (triphos = bis(2-diphenyl-
phosphanoethyl)phenylphosphane).[9] The complex 6b
retains a similar absorption–emission profile (labs 513 nm;
lem 527 nm) to that of the uncomplexed tripodal phosphane
5b and, although the molar absorption coefficient and
quantum yield are lowered relative to 5b, these values are
not dramatically affected; thus the molar absorption coef-
ficient e is lowered from 90000 to 64000mÀ1 cmÀ1, 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 transition-
metal 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 99mTc, which is the most widely
used radionuclide in medicinal diagnoses.[8,11] Thus cores such
as 6b 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 gamma-
emitting 99mTc analogues. Our studies are now focused in this
area.
5b: Vinyldiphenylphosphane (0.16 mL, 0.78 mmol), [Pt(nbd)3]
(0.018 g, 0.037 mmol), and 4b (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 5b as an orange solid (0.21 g, 70%).
6b: 5b (0.050 g, 0.060 mmol), [ReCl(CO)3(PPh3)2] (0.050 g,
0.060 mmol), and mesitylene (2 mL) were heated to reflux for four
hours. After passing the mixture through a silica pad, eluting first with
n-hexane and then with dichloromethane, an orange solid was
obtained (0.051 g, 82%).[12]
Experimental Section
Apart from the air stability studies, reactions were carried out using
standard Schlenk-line techniques in anhydrous solvents. Full charac-
terization data for compounds 1–6 are given in the Supporting
Information.
Received: November 29, 2011
Revised: January 10, 2012
Published online: && &&, &&&&
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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K. P. Maresca, J. D. Brennan, J. W. Babich, J. Zubieta, J. F.
Valliant, J. Am. Chem. Soc. 2004, 126, 8598 – 8599.
[9] A. M. Bond, R. Colton, R. W. Gable, M. F. Mackay, J. N. Walter,
Inorg. Chem. 1997, 36, 1181 – 1193.
[10] a) X.-Q. Guo, F. N. Castellano, L. Li, J. R. Lakowicz, Anal.
Chem. 1998, 70, 632 – 637; b) K. K.-W. Lo, W.-K. Hui, D. C.-M.
Ng, K.-K. Cheung, Inorg. Chem. 2002, 41, 40 – 46.
Keywords: fluorescence · phosphanes · rhenium ·
synthetic methods
.
[1] M. Brynda, Coord. Chem. Rev. 2005, 249, 2013 – 2034.
[2] R. M. Hiney, L. J. Higham, H. Mꢂller-Bunz, D. G. Gilheany,
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[3] B. Stewart, A. Harriman, L. J. Higham, Organometallics 2011,
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[4] A. Loudet, K. Burgess, Chem. Rev. 2007, 107, 4891 – 4932.
[5] A. C. Benniston, G. Copley, K. J. Elliott, R. W. Harrington, W.
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[6] The difluoride analogue of 3a/b was prepared, but reduction of
this compound with LiAlH4 resulted in decomposition of the
backbone.
[11] S. S. Jurisson, J. D. Lydon, Chem. Rev. 1999, 99, 2205 – 2218.
[12] Crystal data for 4b: C25H34BN2P, M = 404.32, monoclinic, space
group P21/n, a = 7.9693(6), b = 11.0597(7), c = 26.1232(16) ꢀ,
b = 90.343(6)8, V= 2302.4(3) ꢀ3, Z = 4, T= 150 K, 4902 reflec-
tions collected, merging of equivalent reflections prevented by
twinning, R(F, F2>2s) = 0.0401, Rw(F2, all data) = 0.1078, good-
ness of fit = 1.031. Crystal data for 6b: C55H60BClN2O2P3Re,
M = 1106.42, monoclinic, space group P21, a = 8.1749(4), b =
10.0931(4), c = 33.0892(12) ꢀ, b = 91.786(4)8, V= 2728.9(2) ꢀ3,
Z = 2, T= 150 K, 17360 reflections collected, 10027 unique,
[7] The quantum yield was referenced to 4,4-difluoro-8-phenyl-
1,3,5,7-tetramethyl-2,6-diethyl-4-bora-3a,4a-diaza-s-indacene,
F = 0.76 in THF. Other photophysical properties: labs = 524 nm,
R
int = 0.0381, R(F, F2>2s) = 0.0348, Rw(F2, all data) = 0.0749,
goodness of fit = 1.013. CCDC 849750, 849751, 849752, 849753,
849754 contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.
uk/data_request/cif.
lem = 537 nm, e = 86000mÀ1 cmÀ1
.
[8] K. A. Stephenson, S. R. Banerjee, T. Besanger, O. O. Sogbein,
M. K. Levadala, N. McFarlane, J. A. Lemon, D. R. Boreham,
4
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Angew. Chem. Int. Ed. 2012, 51, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Phosphaorganic Chemistry
Light without fright: A synthetic route to
fluorescent primary phosphanes (RPH2)
that are resistant to air oxidation both in
the solid state and in chloroform solution
is described. These versatile precursors
undergo hydrophosphination to give tri-
podal ligands and subsequently fluores-
cent transition-metal complexes.
L. H. Davies, B. Stewart,
R. W. Harrington, W. Clegg,
L. J. Higham*
&&&& — &&&&
Air-Stable, Highly Fluorescent Primary
Phosphanes
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!