Relativistic functional groups: Aryl carbon-gold bond formation by selective transmetalation of boronic acids

Article abstract of DOI:10.1002/anie.200603350

(Chemical Equation Presented) Gilded organometallics: Carbon-gold bond formation occurs selectively and in high yields upon reaction of gold(I) bromides with arylboronic acids in the presence of Cs₂CO₃. The reaction is broadly tolera

Full text of DOI:10.1002/anie.200603350

Communications
ꢀ
C Au Bond Formation
DOI: 10.1002/anie.200603350
Relativistic Functional Groups: Aryl Carbon–
Gold Bond Formation by Selective
Transmetalation of Boronic Acids**
David V. Partyka, Matthias Zeller, Allen D. Hunter, and
Thomas G. Gray*
The rational design of triplet-state sensitizers for the photo-
dynamic therapy of cancers[1–3] and other diseases[4] remains
an obdurate challenge. A prominent strategy[5–7] is the
modification of existing photosensitizers with bromine (Z =
35) or iodine (Z = 53); the resulting heavy-atom effects
1
potentiate the generation of therapeutic Dg O2. The (phos-
phane)gold(I) fragment is s-isolobal with the proton. Termi-
nal substitution of aromatic organic molecules with gold (Z =
79) has clear desirability for developing phototherapy medi-
ators. What is missing are mild means of carbon–gold bond
formation in the presence of sensitive functional groups. We
describe here a selective protocol that installs gold(I)–carbon
bonds along the peripheries of organic molecules. Reducible,
polar moieties are tolerated, including nitro groups, alde-
hydes, ketones, and esters. The organometallic compounds
described here withstand air and water indefinitely. The
ability to modify organic fluorophores with gold raises
immediate
opportunities
in
metallopharmaceuticals
design.[8–10] Finally, the new protocol affords organogold(I)
compounds more rapidly and in higher yield than by tradi-
tional methods[11] of arylating gold.
In the palladium-catalyzed Suzuki–Miyaura cross-cou-
pling,[12,13] carbon–carbon bond formation is believed to
follow transmetalation from boron to palladium. The reaction
often requires an auxiliary base, which is thought to quater-
nize boron and promote transmetalation.[14] Related prece-
dents include observations by the groups of Schmidbaur[15]
and Fackler[16] of phenyl-group transfer from BPh4ꢀ to gold(I)
in aqueous and non-aqueous media.
[*] Dr. D. V. Partyka, Prof. Dr. T. G. Gray
Department of Chemistry
Case Western Reserve University
Cleveland, OH 44106 (USA)
Fax: (+1)216-368-3006
E-mail: tgray@case.edu
Dr. M. Zeller, Prof. Dr. A. D. Hunter
Department of Chemistry
Youngstown State University
Youngstown, OH 44555 (USA)
[**] We thank Case Western Reserve University and the donors of the
Petroleum Research Fund, administered by the American Chemical
Society (grant 42312-G3 to T.G.G.) for support. The diffractometer
was funded by NSF grant 0087210, the Ohio Board of Regents grant
CAP-491, and Youngstown State University.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or fromthe author.
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Table 1: Arylgold(I) products, reaction conditions, and isolated yields.
Transmetalation of (triphenylphospha-
ne)gold(I) bromide with o-tolylboronic acid
in isopropyl alcohol in the presence of
cesium carbonate causes disappearance
over 24 h of the 31P NMR resonance at d =
35.2 ppm, with concomitant growth of a
singlet at d = 44.4 ppm attributable to 1
(Scheme 1). No other products were dis-
cernible by 31P NMR spectroscopy. For
comparison, an independent synthesis of 1
from Ph3PAuBr and (o-tol)MgBr in toluene
achieved less than 50% conversion after
3 days. Similar reactions proceed for a range
of arylboronic acids, all in moderate to
excellent yields. Gold(I) bromide com-
plexes of triaryl, trialkyl, and mixed alkyl-
aryl phosphanes transmetalate effectively.
The reaction tolerates steric bulk and
accommodates o-biphenyl, o-tolyl, and
mesityl substituents, affording gold aryls in
61% (4), 79% (5), and 65% (6) yields upon
isolation (Table 1). Transmetalation also
proceeds for substrates bearing electron-
withdrawing groups (7, 9, and 10). The
protocol is not limited to substituted phe-
nylboronic acids as witnessed by transme-
talation of ferrocenyl and 2-thienyl boronic
acids (11 and 12). Control experiments
found no reaction in the absence of base.
The new organogold(I) compounds are
stable to air, water, and laboratory lighting
over periods of months.
Gold(I)
precursor
Arylboronic
acid
Boronic
acid
t [h]
Product
Yield
[%][a]
[equiv]
Ph3PAuBr
1.8
24
1
86
Ph3PAuBr
Cy3PAuBr
1.9
1.9
24
24
2
3
59
89
Cy3PAuBr
Cy3PAuBr
1.8
1.9
24
24
4
5
61
79
Cy3PAuBr
Cy3PAuBr
2.6
2.5
48
36
6
7
65
94
Cy3PAuBr
Cy3PAuBr
2.5
2.0
30
36
8
9
85
90
Cy3PAuBr[b]
2.2
36
10
80
Cy3PAuBr
Cy3PAuBr
2.3
1.8
48
24
11
12
85
86
Products were characterized by multi-
nuclear NMR spectroscopy and elemental
analysis. Figure 1 depicts crystal structures
of representative organogold(I) species.[17,18]
In complex 11 an expected two-coordina-
tion about gold is found. The P-Au-Cs-aryl
angle is 173.74(10)8; the gold–carbon bond
length is 2.040(3) Š; and the gold–phospho-
rus separation is 2.2970(9) Š. No intermo-
lecular contacts between gold atoms are
observed.
Cy3PAuBr
1.9
2.0
24
30
13
14
86
84
2.3
30
15
74
[a] Isolated material of ꢁ95% purity. [b] Reaction run in ethanol. Cy=cyclohexyl.
Complexes of sterically imposing phos-
phane ligands transmetalate efficiently. Dia-
Scheme 1. Syntheses of 1 fromboronic acid and Grignard reagent
Figure 1. Crystal structures of 11 and 14 (50% probability ellipsoids
precursors.
shown).
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lkylbiarylphosphanes[19,20] undergo widespread use in palla-
allowed. Both orbitals have predominant naphthyl character.
A fragment orbital calculation finds the LUMO of 13’ to be
87.5% derived from the LUMO of the naphthyl monoanion,
and the HOMO is 93.2% composed of naphthyl anion
HOMOꢀ1. The HOMOꢀ1 of 13’ is the primary C–Au s-
bonding combination. This orbital carries a 42.4% contribu-
tion from the a1 LUMO of Me3PAu+, which is an sd hybrid
orbital of s symmetry.[28] The lower energy of the gold-heavy
HOMOꢀ1 (of 13’), 0.63 eV below the HOMO, effectively
precludes luminescence deactivation by electron transfer
from AuI. A Dapprich–Frenking charge decomposition anal-
ysis[29,30] finds a net charge donation of 0.33e from the
naphthyl ligand to the (phosphane)gold fragment. The Au–C
Wiberg bond order[31] in the Löwdin basis is 0.970; that of the
dium-catalyzed reactions; they are increasingly applied in
gold(I) catalysis.[21] Transmetalation of biarylphosphane com-
plexes with phenylboronic acid proceeded smoothly and in
high yields; reaction times are comparable to those of other
entries in Table 1. The crystal structure of 14 is shown in
Figure 1. Close approaches occur between gold and two
carbon atoms of the pendant aryl ring (non-phosphorus-
ꢀ
bound) of each biarylphosphane: 3.3063(18) Š (Au Cipso) and
ꢀ
3.2469 (19) Š (Au Cortho). The P-Au-Cs-aryl bond angle is a
modestly nonlinear 174.18(6)8.
The new organogold(I) compounds do not significantly
absorb visible light except for ferrocenyl complex 11 (orange)
and 13 (pale yellow). Complex 13 is luminescent in THF
solution upon excitation with UV light. A conflated absorp-
tion and emission spectrum of 13 is shown in Figure 2.
ꢀ
Au P bond is 0.984.
Time-dependent DFT calculation[32] of the low-lying
singlet excited states of 13’ indicates an allowed excitation
at 324.3 nm of mixed parentage, deriving mainly from a
!
LUMO HOMO transition with an admixed LUMO +
1
!
!
HOMO excitation; both are p* p transitions. The
calculated oscillator strength is f = 0.209. Weaker absorption
transitions are calculated at 258 and 254 nm, with f = 0.0201
and 0.0489, respectively. No other singlet–singlet transitions
of significant oscillator strength were calculated in the
absorption window of THF. The lowest-energy triplet state
(computed for the singlet geometry) is calculated at 452.1 nm.
To summarize, a general protocol for creating gold(I)
carbon bonds is presented. The reaction entails transmetala-
tion from boronic acids to (phosphane)gold(I) bromides in
the presence of base. Significant steric encumbrance is
supported, both in the phosphane and the transmetalating
aryl group. The gold(I) products are robust compounds that
are stable in air and water for prolonged periods. Terminal
(phosphane)gold(I) functionality is compatible with lumines-
cence of the aromatic parent compound. The ability to tether
gold(I) fragments to organic skeletons invites syntheses of
more potent photodynamic therapy mediators that operate at
reduced dosages. Gold(I) compounds that can be prepared by
the new method hold added potential as rheumatoid arthritis
prodrugs. Lipophilicity and cell permeability are adjustable in
principle through the ancillary phosphane. Transmetalation
from boronic acids proffers gold compounds bearing
Grignard- and organolithium-incompatible functional
groups. Further investigations of this process and applications
to photoactive organic species are ongoing.
Figure 2. Room-temperature absorption (c) and emission (a)
spectra of 13 in THF (10ꢀ8 m, lex =310 nm).
Absorption extends from ca. 340 nm to the solvent limit of
THF. Vibronic structure is apparent in the absorption at
293 nm, with an average spacing of 1050 cmꢀ1 (9.57nm).
Room-temperature emission of 13 extends from ca. 350–
600 nm. The absorption cutoff of 13, but not the emission
maximum, is red-shifted relative to that of the parent
hydrocarbon.[22] Upon increasing the sample concentration
to 10ꢀ6 m, emission features appear between 480–560 nm that
have no counterpart in the fluorescence (Supporting Infor-
mation). We attribute these emissions to oligomeric gold
species. Time-dependent characterization of new arylgold(I)
complexes is in progress.
Static and time-dependent density functional theory
(DFT) calculations were conducted on Me3PAu(1-naphthyl),
13’[23,24] (see the Supporting Information for full details).
Implicit THF solvation was included with the polarizable
continuum model of Tomasi and co-workers.[25–27] The calcu-
lated (observed) Au–C bond length is 2.066 (2.030(4)) Š, the
Au–P distance is 2.367(2.3008(10)) Š, and the P-Au-C angle
is 178.9 (176.52(12))8. A Kohn–Sham orbital energy diagram
of 13’ appears in the Supporting Information (Figure S2).
Images of selected orbitals are inset. The energy gap between
the highest occupied and lowest unoccupied Kohn–Sham
orbitals (HOMO and LUMO, respectively) is calculated to be
Experimental Section
13: Cs2CO3 (98 mg, 0.30 mmol) and 1-naphthylboronic acid (53 mg,
0.31 mmol) were suspended in isopropyl alcohol (5 mL). Cy3PAuBr
(88 mg, 0.16 mmol) was added to the suspension, and the mixture was
stirred at 508C for 24 h. After cooling, the solvent was evaporated in
vacuo, the residue was extracted into benzene, the solution was
filtered through celite, and the filtrate was concentrated by rotary
evaporation. The residue was triturated with pentane, and the
pentane was removed by rotary evaporation. The pale yellow solid
was washed with pentane, dried, and extracted into benzene. Then the
solution was filtered through celite and concentrated to saturation.
Vapor diffusion of pentane caused separation of a colorless crystalline
mass, which was washed with cold methanol and pentane, dried, and
!
3.290 eV, and the LUMO HOMO transition is optically
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Angewandte
Chemie
1
collected. Yield: 82 mg (86%). H NMR (C6D6): d = 9.10 (d, 1H, 1-
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naphthyl), 1.95–0.94 ppm (m, 33H, C6H11); 31P NMR (C6D6): d =
58.0 ppm; UV/Vis (THF, 10ꢀ6 m): l (e) = 283 (11800), 293 (13500),
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302 (10000), 321 nm (2300 cmꢀ1mꢀ1); emission (THF, 10ꢀ8 m, lex
=
310 nm): l = 363 nm; emission (THF, 10ꢀ6 m, lex = 310 nm): l = 363,
483, 494 (sh), 520, 560 nm. Elemental analysis (%) calcd for
C28H40AuP: C 55.63, H 6.67; found: C 55.60, H 6.83.
Received: August 16, 2006
Revised: September 22, 2006
Published online: November 17, 2006
Keywords: boron · gold · phosphane ligands ·
.
photodynamic therapy · transmetalation
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