Acridinium-Based Photocatalysts: A Sustainable Option in Photoredox Catalysis

Article abstract of DOI:10.1021/acs.joc.6b01240

The emergence of visible light photoredox catalysis has enabled the productive use of lower energy radiation, leading to highly selective reaction platforms. Polypyridyl complexes of iridium and ruthenium have served as popular photocatalysts in recent ye

Full text of DOI:10.1021/acs.joc.6b01240

Article
pubs.acs.org/joc
Acridinium-Based Photocatalysts: A Sustainable Option in
Photoredox Catalysis
Amruta Joshi-Pangu,† Francois Levesque,† Hudson G. Roth,‡ Steven F. Oliver,† Louis-Charles Campeau,†
̧
́
David Nicewicz,‡ and Daniel A. DiRocco*,†
†Process Research & Development, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, United States
‡Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, United States
S
* Supporting Information
ABSTRACT: The emergence of visible light photoredox catalysis has enabled
the productive use of lower energy radiation, leading to highly selective
reaction platforms. Polypyridyl complexes of iridium and ruthenium have
served as popular photocatalysts in recent years due to their long excited state
lifetimes and useful redox windows, leading to the development of diverse
photoredox-catalyzed transformations. The low abundances of Ir and Ru in the
earth’s crust and, hence, cost make these catalysts nonsustainable and have
limited their application in industrial-scale manufacturing. Herein, we report a
series of novel acridinium salts as alternatives to iridium photoredox catalysts
and show their comparability to the ubiquitous [Ir(dF-CF3-ppy)2(dtbpy)](PF6).
redox window (E1/2(Ir(III*/II)) = 1.21 V and E1/2(Ir(III*/IV))
= −0.89 V). Owing to the low abundance of iridium in earth’s
crust (0.001 ppm),4 Ir-based photocatalysts are viewed as
neither cost-effective nor sustainable. From an industrial
perspective, organic-based photocatalysts represent a cost-
effective and sustainable approach to photoredox catalysis.
Inspired by the unique reactivity of [Ir(dF-CF3-ppy)2(dtbpy)]-
(PF6) (1), we were interested in developing an organic
photoredox catalyst scaffold that is robust, has a useful redox
window, and is easily synthesized on a commercial scale. Highly
reducing organic photoredox catalysts, such as 10-phenyl-
phenothiazine (PTH; E1/2* = −2.1 V vs SCE) have shown
utility in replacing transition-metal complexes such as Ir(ppy)3
(E1/2* = −1.7 V vs SCE) in reductively initiated reactions, due
to their similar excited state reduction potentials.5 No similar
scaffold has been demonstrated to replace [Ir(dF-CF3-
ppy)2(dtbpy)](PF6) in reactions initiated via oxidation.6
INTRODUCTION
■
In the past decade, visible light photoredox catalysis has
revolutionized the manner in which chemists approach new
bond formations. Polypyridyl complexes of ruthenium and
iridium are among the most widely utilized photocatalysts due
to their unique photophysical properties such as long excited
state lifetimes and large redox windows (Figure 1).1 For
Initially, we considered using the traditional xanthene-based
scaffold upon which fluorescein, rose bengal, and eosin Y are
based.7 However, their narrow redox window, low solubility in
typical organic solvents, pH dependence, and susceptibility to
bleaching have rendered this class of catalysts less effective.
Acridinium-based photocatalysts appear to obviate many of
these pitfalls, as they have extended redox windows in
comparison to other organo-photocatalysts, are insensitive to
the pH of the reaction medium, and are soluble in a range of
organic solvents. 9-Mesityl-10-methylacridinium perchlorate
(3), pioneered by Fukuzumi,8 has been utilized effectively in
Figure 1. Commonly used photocatalysts Ir(dF-CF3-ppy)2(dtbpy)-
(PF6), Ru(bpy)3(2PF6), and 9-mesityl-10-methylacridinium perchlo-
rate.
example, the photophysical properties of ruthenium tris-
2+
(bipyridine) (2) have been thoroughly studied. Ru(bpy)3
has a long-lived excited state lifetime (1100 ns) and excited
state redox potentials of E1/2(III/*II) = −0.81 V and E1/2(*II/
I) = +0.77 V vs SCE (Table 1) that allow it to engage in a
variety of oxidative and reductive processes.2
[Ir(dF-CF3-ppy)2(dtbpy)](PF6) (1), initially reported for
OLED and water-splitting applications,3 has likewise become
one of the most widely used photocatalysts in recent years.
Special Issue: Photocatalysis
Received: May 24, 2016
+
While it bears many similarities to Ru(bpy)3 , it offers a longer-
lived excited state lifetime (2300 ns) and greatly expanded
© XXXX American Chemical Society
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Table 1. Photophysical Properties of Photocatalysts 1−8
a
b
E1/2(C+/C*)
E
1/2(C*/C−)
E1/2(C+/C)
E
1/2(C/C−)
(V)
excited state lifetime τ
excitation
λmax (nm)
emission
λmax (nm)
entry
1
photocatalyst
(V)
(V)
(V)
(ns)
[Ir(dF-CF3-ppy)2(dtbpy)]
(PF6) (1)
−0.89
+1.21
+1.69
−1.37
2300
380
470
2
3
4
5
6
[Ru(bpy)3](PF6)2 (2)
acridinium (3)
acridinium (4)
acridinium (5)
acridinium (6)
−0.81
+0.77
+2.06
+2.08
+1.90
+2.01
+1.29
−1.33
−0.57
−0.59
−0.57
−0.71
1100
452
430
420
466
407
615
570
517
545
525
tF = 6.4 ns
tF = 14.4 ns
tF = 18.7 ns
tF1 = 3.0 ns,
tF2 = 10.1 ns
7
8
acridinium (7)
+1.65
−0.82
tF1 = 1.3 ns, tF2 = 12.3
414
412
550
550
ns
acridinium (8)
+1.62
-0.84
tF1 = 1.3 ns, tF2 = 8.9
ns
a
Excited state reduction potentials were estimated from ground state redox potentials and the intersection of the absorption and emission bands.
Determined by cyclic voltammetry in acetonitrile versus SCE. See the Supporting Information.
b
a variety of transformations, most notably in the anti-
Markonikov addition of nucleophiles to olefins.9 While
uniquely applicable to chemistries that require strong single
electron oxidants, it is limited in many transformations due to
its weakly negative ground state reduction potential (E1/2(C/
C−) = −0.57 V vs SCE). Furthermore, its strongly positive
excited state reduction potential (E*1/2 = +2.06 V vs SCE) can
lead to substrate decomposition through unselective oxidation
processes. Studies have shown that catalyst 3 undergoes
demethylation and is prone to nucleophilic attack, leading to
degradation and bleaching of the catalyst chromophore.10 We
hoped to overcome these shortcomings by designing
acridinium catalysts with enhanced stability and attenuated
excited state reduction potentials. Herein, we describe a
modular series of readily accessible novel acridinium photo-
catalysts with increased physical stability and expanded redox
windows.
(Scheme 1).11 In the presence of the Fukuzumi catalyst 3, very
low conversion to product was observed. Given the measured
Scheme 1. Decarboxylative Conjugate Addition of Cbz-
Proline to Dimethyl Maleate
RESULTS AND DISCUSSION
■
A series of substituted acridinium salts were synthesized to
probe the relationship between structure and the physical
properties of these novel catalysts. The acridinium nitrogen was
arylated to avoid the competitive demethylation previously
observed with the corresponding N-methyl catalyst. The
presence of electron-donating substituents on the acridinium
core results in longer excited state lifetimes (8.9−18.7 ns) and,
in the case of catalysts 6−8, a more negative ground state
reduction potential in comparison to the parent catalyst 3
(Table 1). In particular, tetramethoxy-substituted acridinium 8
was measured to possess a ground state redox potential
(E1/2(C/C−) = −0.84 V vs SCE) comparable to the excited
state redox potential of [Ir(dF-CF3-ppy)2(dtbpy)](PF6)
(E1/2(C+/C*) = −0.89 V vs SCE).
photophysical properties of the new acridinium catalysts, base-
promoted deprotonation of Cbz-proline and single electron
transfer of the carboxylate (hexanoate, E1/2(red) = +1.16 V vs
SCE) and single electron reduction of the resultant α-acyl
radical (α-acyl radical, E1/2(red) = −0.60 V vs SCE) upon
Michael addition should be thermodynamically favorable
(Figure 2).11 Gratifyingly, high yields were obtained when
Cbz-proline was reacted with dimethyl maleate in acetonitrile
using the substituted acridinium salts 4−8 (Scheme 1).
Catalysts 7 and 8 performed exceptionally well, consistent
with their more negative ground state reduction potentials
(Table 1, entries 7 and 8).
We chose catalyst 7 for further studies due to its high
catalytic activity and straightfoward synthesis (Scheme 2, Figure
3, and Tables 2 and 3).12 To determine the feasibilty of using
this catalyst on a larger scale and avoid problems associated
with scale in batch photochemistry, we further studied the
reaction using a flow reactor.13 In an attempt to improve
With these promising results in hand, we next investigated
the reactivity of these catalysts in the decarboxylative conjugate
addition of Cbz-proline (9) to dimethyl maleate (10), which is
known to be catalyzed by [Ir(dF-CF3-ppy)2(dtbpy)](PF6)
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Figure 3. Reaction progress analysis: Cbz-proline (1 mmol), dimethyl
maleate (1.5 mmol), catalyst 7 (0.012 mmol), 2,6-lutidine (1.2 mmol),
biphenyl (0.1 mmol), acetonitrile (10 mL). The reaction yield was
calculated via HPLC using biphenyl as internal standard.
Figure 2. Proposed mechanism of the photocatalyzed decarboxylative
conjugate addition of Cbz-proline to dimethyl maleate.
a
Table 2. Initial Reaction Optimization in Flow
b
entry
(M)
amt of cat. (mol %)
temp (°C)
yield (%)
productivity, higher reaction concentrations were examined but
proved detrimental to the reaction rate. Catalyst loading had
little to no effect (Table 2), characteristic of a light-limited
process. The reaction rate and yield increased with increasing
reaction temperature, albeit with significant concomitant
catalyst degradation.14 Furthermore, the observed rate of
Cbz-proline consumption was significantly faster than that of
dimethyl maleate (Figure 3). Ultimately, increasing the amount
of dimethyl maleate from 1.0 to 1.5 equiv while running the
reaction at 40 °C resulted in optimal conditions for the flow
process (Table 3). We obtained an 89% yield (HPLC assay) of
the desired product with a 60 min residence time (Figure 3).
To gain a further understanding of the large difference in
reactivity between the Fukuzumi catalyst 3 and catalyst 7, we
monitored their respective concentrations at different residence
times. While catalyst 7 did show some decomposition over the
course of the reaction, Fukuzumi catalyst 3 was completely
degraded within 2 min (Figure 4). This observation further
underscores the effectiveness of the alterations to the parent
mesitylacridinium scaffold to enhance the stability of this
important class of photoredox catalysts.
In conclusion, we have developed a series of 1,3,5,6-
substituted acridinium salts as organic alternatives to
transition-metal-based photocatalysts that combine a useful
redox window and higher chemical stability. The tetrasub-
stituted catalysts can be obtained in a single step from the
corresponding triarylamine and have shown catalytic perform-
ance comparable to that of [Ir(dF-CF3-ppy)2(dtbpy)](PF6) in
the decarboxylative conjugate addition of Cbz-proline to
dimethyl maleate. Given the sustainable, cost-effective, and
robust nature of these novel catalysts, we plan to continue
1
2
3
4
5
6
7
8
0.08
0.16
0.4
1
30
30
30
30
30
30
40
60
43
30
18
33
30
29
63
80
1
1
0.16
0.16
0.16
0.08
0.08
0.5
1
2
1
1
a
Standard reaction conditions: Cbz-proline (1 mmol), dimethyl
maleate (1 mmol), 2,6-lutidine (1.2 mmol), biphenyl (0.1 mmol), in
acetonitrile, 30 min residence time. Flow experiments were carried out
using a Vapourtec R2S equipped with a UV-150 photoreactor (10 mL,
FEP tubing, 1.3 mm i.d.). Reaction yield calculated via HPLC using
biphenyl as internal standard.
b
Table 3. Reaction Optimization Results in Flow (τ = 60
min)
a
b
entry amt of 9 (equiv) amt of 10 (equiv) temp (°C) yield (%)
1
2
3
1.0
1.2
1.0
1.0
1.0
1.5
60
40
40
80
82
89
a
Flow experiments were carried out using a Vaportec R2S equipped
with a UV-150 photoreactor (10 mL, FEP tubing, 1.3 mm i.d.).
Reaction yield calculated via HPLC using biphenyl as internal
standard.
b
evaluating their performance in photochemical reactions with
an eye toward their future implementation in manufacturing
processes.
Scheme 2. Synthesis of Acridinium Salt Photocatalyst 7
C
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desired residence time (for example, 0.333 mL/min for 30 min
residence time). In every case, 10 mL of the stock solution was
pumped through the reactor, but only the middle portion was
collected (2 mL) to minimize dilution effects. A sample of the reaction
mixture was taken, diluted in acetonitrile, and analyzed by LC/MS.
The reactor was flushed with acetonitrile, and the parameters were set
for the next experiment.
Experimental Procedure for Catalyst Preparation. 9-Mesityl-
2,7-dimethoxy-10-phenylacridin-10-ium Tetrafluoroborate (5). A
mixture of 4-methoxyaniline (7.52 g, 61.0 mmol) and 2-bromo-5-
methoxybenzoic acid (10 g, 43.3 mmol) with anhydrous K2CO3 (8.49
g, 61.5 mmol) and copper (0.495 g, 7.79 mmol) in anhydrous 1-
pentanol (150 mL) was heated at 160 °C for 3 h. The solvent was
evaporated under reduced pressure, and the residue was dissolved in
hot water (800 mL) and filtered through Celite. The Celite was
washed with water (250 mL), and the filtrate was acidified with
concentrated HCl to pH 6. A solid precipitated, which was isolated by
filtration and washed with water (2 × 150 mL). The solid was
crystallized from CHCl3 (100 mL) to give 5-methoxy-2-((4-
methoxyphenyl)amino)benzoic acid (10.8 g, 39.5 mmol, 91% yield)
as a light brown solid.
A mixture of 5-methoxy-2-((4-methoxyphenyl)amino)benzoic acid
(10.8 g, 39.5 mmol) and polyphosphoric acid (32.4 mL) was heated to
110 °C for 3 h. The solution was poured onto ice (1000 mL), and the
precipitate was filtered and washed with water (2 × 200 mL). The
precipitate was dissolved in hot EtOH (1.5 L), filtered, and evaporated
to afford 2,7-dimethoxyacridin-9(10H)-one (6.6 g, 25.9 mmol, 65.4%
yield) as a dark green solid.
In an oven-dried 250 mL round-bottom flask were charged 2,7-
dimethoxyacridin-9(10H)-one (5.6 g, 21.94 mmol), iodobenzene
(3.75 g, 18.38 mmol), copper(I) iodide (0.350 g, 1.838 mmol),
2,2,6,6-tetramethylheptane-3,5-dione (0.677 g, 3.68 mmol), and
K2CO3 (5.08 g, 36.8 mmol) in DMF (86 mL). The round-bottom
flask was equipped with a condenser, sparged with N2 for 20 min, and
heated at 120 °C under N2 for 48 h. The reaction mixture was cooled
to room temperature, diluted with water, transferred to a separatory
funnel, acidified with aqueous HCl, extracted with dichloromethane,
and concentrated. The crude residue was purified by chromatography
on silica gel using 20% EtOAc/hexanes to yield 2,7-dimethoxy-10-
phenylacridin-9(10H)-one (4.2 g, 12.67 mmol, 69.0% yield) as a
yellow powder.
Figure 4. Catalyst degradation analysis for catalysts 3 and 7: Cbz-
proline (1 mmol), dimethyl maleate (1.5 mmol), catalyst (0.012
mmol), 2,6-lutidine (1.2 mmol), biphenyl (0.1 mmol), acetonitrile (10
mL). The reaction yield was calculated via HPLC using biphenyl as
internal standard.
EXPERIMENTAL SECTION
■
General Methods. All reactions were carried out under nitrogen
outside the glovebox. 3,6-Di-tert-butyl-9-mesityl-10-phenylacridin-10-
ium was synthesized via a reported method.11 9-Mesityl-10-
methylacridinium perchlorate was purchased from TCI. 1H NMR
spectra were recorded on either a 500 or 600 MHz spectrometer at
ambient temperature. Data are reported as follows: chemical shift in
parts per million (δ, ppm) from residual CHCl3 (7.26 ppm),
multiplicity (s = singlet, bs = broad singlet, d = doublet, t = triplet,
q = quartet, m = multiplet, om = overlapped multiplet, and dd =
doublet of doublets), coupling constants (Hz), and number of protons
(H). 13C NMR spectra were recorded on either a 500 or 600 MHz
spectrometer at ambient temperature. Chemical shifts are reported in
ppm from CDCl3 (77.16 ppm). Reactions were monitored using
UPLC-MS. Crude reactions were purified using flash column
chromatography.
General Procedure for Reactions in Scheme 1. In a 1 dram vial
equipped with a stir bar were placed (S)-1-((benzyloxy)carbonyl)-
pyrrolidine-2-carboxylic acid (20 mg, 0.08 mmol), dimethyl maleate
(11 μL, 0.088 mmol), catalyst (2 mol %, 1.605 μmol), and K2HPO4
(16.77 mg, 0.096 mmol) in acetonitrile (2 mL). The reaction was
degassed by bubbling nitrogen through the reaction mixture for 15
min. Seven reactions for catalysts 2−8 and catalyst 1 were set up in
parallel inside a Dewar flask. The 450 nm blue LED lamp was placed
over the Dewar, and the setup was covered with aluminum foil. The
reaction temperature was maintained between 30 and 35 °C by
adjusting the flow of nitrogen through the Dewar. Reaction mixtures
were irradiated for 20 h and assayed via HPLC against internal
standard to calculate the assay yield.
General Setup for Reactions in Flow. A Vaportec R2S
(peristaltic pump, blue tube) and R4 modules equipped with a UV-
150 photoreactor (10 mL, FEP tubing, 1.3 mm i.d.) were used. The
photoreactor was fitted with a 450 nm LED lamp (input power 60 W,
radiant power 24 W). The photoreactor was either cooled (Vaportec
cooling module) or heated. The exiting stream was connected to a UV
detector (Knauer, Detector 50D) to trigger collection. A variable back-
pressure regulator was attached, and the internal pressure was
maintained around 2.1 bar. Finally, a switch valve was used to direct
the exiting stream toward a Gilson fraction collector (FC-203B) or a
waste bottle. Flow Commander software allowed sequential runs of
multiple reaction conditions in an automated fashion.
General Procedure for Reactions in Flow. A solution of Cbz-
proline (1 mmol), dimethyl maleate (1.5 mmol), catalyst 7 (0.012
mmol), 2,6-lutidine (1.2 mmol), and biphenyl (0.1 mmol) in
acetonitrile (total volume of the solution 10 mL, volumetric flask)
was prepared. The resulting yellow solution was degassed by bubbling
dry nitrogen for 15 min. The stock solution was kept under dry
nitrogen (40 mbar) to prevent introduction of oxygen. The reactor
was flushed with pure acetonitrile at a flow rate of 4.00 mL/min, the
lamp was ignited, and the reactor was either heated or cooled. Upon
temperature stabilization, the flow rate was readjusted to reach the
In an oven-dried 1000 mL round-bottom flask under nitrogen were
charged 2,7-dimethoxy-10-phenylacridin-9(10H)-one (4.2 g, 12.67
mmol) and THF (420 mL, dried over 4A MS), and the reaction
mixture was stirred for 30 min. A solution of mesitylmagnesium
bromide (65 mL, 65.0 mmol) was added slowly at room temperature.
The reaction mixture was stirred at room temperature for 24 h and at
50 °C for 24 h and then cooled to room temperature. The solution
was quenched with dilute NaHCO3 solution. This solution was
extracted with DCM (3 × 200 mL). The combined organic extracts
were washed with brine, dried over Na2SO4, and filtered, and the
solvent was evaporated under reduced pressure. The residue was
purified by column chromatography on silica gel, with CH2Cl2/MeOH
as eluent, to afford a brown solid. This solid was dissolved in Et2O
(150 mL) and stirred while a solution of tetrafluoroboric acid diethyl
etherate (660 μL, 20 mL of diethyl ether, 1.2 equiv) was added slowly.
The residue was purified by preparative reverse phase HPLC (C-18),
with MeOH/water + 0.1% TFA as eluent, to give 0.8 g of a yellow
solid, which was stirred with a solution of tetrafluoroboric acid diethyl
etherate (300 μL, 20 mL of diethyl ether, 1.2 equiv) twice. After
filtration 9-mesityl-2,7-dimethoxy-10-phenylacridin-10-ium tetrafluor-
oborate (0.65 g, 1.247 mmol, 9.84% yield) was obtained as a yellow
solid.
1H NMR (500 MHz, CDCl3): δ 7.94−7.82 (om, 3H), 7.77 (br s,
2H), 7.67 (br s, 2H), 7.50 (br s, 2H), 7.18 (s, 2H), 6.87 (s, 2H), 3.78
(s, 6H), 2.49 (s, 3H), 1.90 (br s, 6H). 13C NMR (126 MHz, CDCl3):
δ 159.1, 157.5, 140.2, 137.6, 137.3, 136.2, 132.1, 131.8, 131.5, 129.8,
129.4, 128.5, 128.1, 122.2, 103.6, 56.4, 21.5, 20.5. 19F NMR (470 MHz,
+
CDCl3) δ −153.2. HRMS: calcd for C30H29BF4NO2 , 434.2115;
found, 434.2140.
D
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9-Mesityl-3,6-dimethoxy-10-phenylacridin-10-ium Tetrafluoro-
borate (6). In a 500 mL three-neck round-bottom flask was placed
a mixture of 3-methoxyaniline (12.78 g, 104 mmol), 2-bromo-4-
methoxybenzoic acid (17 g, 73.6 mmol), anhydrous K2CO3 (14.44 g,
104 mmol), and copper (0.842 g, 13.24 mmol) in anhydrous 1-
pentanol (255 mL). The reaction mixture was heated at 160 °C for 3
h. The solvent was evaporated under reduced pressure, and the residue
was dissolved in hot water (2000 mL) and filtered through Celite. The
Celite was washed with water (250 mL), and the filtrate was acidified
with concentrated HCl to pH 6. A solid precipitated, which was
isolated by filtration and washed with water (2 × 200 mL). The solid
was crystallized from CHCl3 (300 mL) to give 4-methoxy-2-((3-
methoxyphenyl)amino)benzoic acid (17 g, 62.2 mmol, 85% yield).
In a 250 mL three-necked round-bottom flask was placed a mixture
of 4-methoxy-2-((3-methoxyphenyl)amino)benzoic acid (17 g, 62.2
mmol) and PPA (102 mL). The mixture was heated to 110 °C for 3 h.
The solution was poured onto ice (2000 mL), and the precipitate was
filtered and washed with water (2 × 250 mL). The precipitate was
dissolved in hot EtOH (1.5 L) and filtered to afford a mixture of 1,6-
dimethoxyacridin-9(10H)-one and 3,6-dimethoxyacridin-9(10H)-one
(14 g, 54.8 mmol, 88% yield).
In an oven-dried 100 mL round-bottom were charged a mixture of
1,6-dimethoxyacridin-9(10H)-one and 3,6-dimethoxyacridin-9(10H)-
one (14 g, 54.8 mmol), iodobenzene (9.4 g, 46.1 mmol), copper(I)
iodide (0.878 g, 4.61 mmol), 2,2,6,6-tetramethylheptane-3,5-dione
(1.698 g, 9.22 mmol), and K2CO3 (12.74 g, 92 mmol) in DMF (216
mL). The round-bottom flask was equipped with a condenser, sparged
with N2 for 20 min, and heated at 120 °C under N2 for 48 h. The
reaction mixture was cooled to room temperature, diluted with water,
transferred to a separatory funnel, acidified with aqueous HCl,
extracted with dichloromethane, and concentrated. The crude residue
was purified by chromatography on silica gel using 20% EtOAc/
hexanes to yield 14 g of product (crude, contains about 5% isomer).
The crude mixture was purified by preparative Combi-Flash reverse
phase HPLC (C-18), with acetonitrile/water + 0.05%NH4HCO3 as
eluent, to give 3,6-dimethoxy-10-phenylacridin-9(10H)-one (5.8 g,
17.50 mmol, 38.0% yield) as a yellow powder.
10-(3,5-Dimethoxyphenyl)-9-mesityl-1,3,6,8-tetramethoxyacri-
din-10-ium Tetrafluoroborate (7). Chloro[(tri-tert-butylphosphine)-
2-(2-aminobiphenyl)]palladium(II) (0.844 g, 1.714 mmol), 1-bromo-
3,5-dimethoxybenzene (49.6 g, 228 mmol), and 3,5-dimethoxyaniline
(17.5 g, 114 mmol) were placed in a two-neck round-bottom flask and
purged with nitrogen. Tetrahydrofuran (600 mL) was added and the
solution degassed by subsurface nitrogen sparging for 15 min. A
solution of sodium tert-butoxide (2 M, 230 mL) was added rapidly
under nitrogen, and the reaction mixture was heated to 60 °C. After 19
h, the reaction mixture was cooled and 1 L of water added followed by
1.5 L of MTBE. Layers were separated and washed with MTBE and
brine to obtain tris(3,5-dimethoxyphenyl)amine as a brown solid (39
g) in 81% yield.
Tris(3,5-dimethoxyphenyl)amine (41 g, 96 mmol) and 2,4,6-
trimethylbenzoyl chloride (37 g, 202 mmol) were dissolved in
chlorobenzene (300 mL). Triflic acid (8.51 mL, 96 mmol) was added
slowly, and the mixture was heated to 80 °C. After 18 h the reaction
mixture was cooled and washed with NaBF4 (0.2 M, 3 × 200 mL) and
water (2 × 600 mL). To the organic layer was added MTBE (2400 mL
slowly) until a precipitate started to form. The mixture was seeded,
and then an additional 3000 mL of MTBE was added slowly and this
mixture was stirred for 30 min. The mixture was filtered, and the solid
was washed with MTBE and dried under nitrogen stream, yielding a
bright orange solid (44 g, 71% yield).
1H NMR (600 MHz, CDCl3): δ 6.90 (s, 2H), 6.83 (t, J = 2.1 Hz,
1H), 6.61 (d, J = 2.2 Hz, 2H), 6.48 (d, J = 2.1 Hz, 2H), 6.18 (d, J = 2.2
Hz, 2H), 3.92 (s, 6H), 3.85 (s, 6H), 3.48 (s, 6H), 2.37 (s, 3H), 1.83 (s,
6H). 13C NMR (151 MHz, CDCl3): δ 168.4, 163.3, 162.4, 160.8,
144.9, 140.0, 137.7, 136.6, 132.2, 127.2, 113.5, 105.7, 103.0, 97.7, 92.9,
57.2, 56.7, 56.4, 21.3, 20.3. 19F NMR (470 MHz, CDCl3): δ −153.4.
+
HRMS: calcd for C34H37BF4NO6 , 554.2537; found, 554.2568.
9-Mesityl-1,3,6,8-tetramethoxy-10-phenylacridin-10-ium Tetra-
fluoroborate (8). A dried three-necked round-bottom flask was
charged with 1-bromo-3,5-dimethoxybenzene (50.0 g, 230 mmol), 3,5-
dimethoxyaniline (42.3 g, 276 mmol), potassium 2-methylpropan-2-
olate (83 g, 737 mmol), reactant 5 (47.7 g, 46.1 mmol), and [1,1′-
biphenyl-2-yl]di-tert-butylphosphine (6.87 g, 23.04 mmol). The
reagents were dried under reduced pressure, and the vessel was
back-filled with argon. Then anhydrous toluene (750 mL) was added
and the reaction mixture was heated at 80 °C for 3 h. Then
iodobenzene (94 g, 461 mmol) was added and the mixture heated at
80 °C for 48 h. The mixture was cooled to room temperature and
diluted with water (250 mL), and the organic layer was concentrated
in vacuo. The crude product was recrystallized from MTBE/heptane
in the ratio of 1/3 (2 V/6 V), affording N-(3,5-dimethoxyphenyl)-3,5-
dimethoxy-N-phenylaniline (65.0 g, 164 mmol, 71.0% yield) as a gray
solid.
In an oven-dried 500 mL round-bottom flask was charged 3,6-
dimethoxy-10-phenylacridin-9(10H)-one (5.5 g, 16.60 mmol) in THF
(275 mL) that was dried under 4A MS under nitrogen and stirred for
30 min. A solution of mesitylmagnesium bromide (55 mL, 55.0 mmol)
was added slowly at room temperature. The reaction mixture was
stirred at room temperature for 24 h and then at 50 °C for 24 h and
cooled to room temperature, and this solution was quenched with
dilute NaHCO3 solution. This solution was extracted with 3 × 200 mL
of DCM. The combined organic fractions were washed with brine,
dried (Na2SO4), and filtered, and the solvent was evaporated under
reduced pressure. This solid was dissolved in 150 mL of Et2O and
stirred while a solution of tetrafluoroboric acid diethyl ether complex
(4.86 mL, 20 mL diethyl ether, 1.2 equiv) was added slowly. The
residue was purified by preparative reverse phase HPLC (C-18), with
MeOH/water + 0.1% TFA as eluent, to give 0.8 g of a yellow solid
which was stirred with a solution of tetrafluoroboric acid diethyl ether
complex (300 μL, 20 mL of diethyl ether, 1.2 equiv) two times. After
filtration 2.4 g of 9-mesityl-2,7-dimethoxy-10-phenylacridin-10-ium
trifluoroacetate was obtained as a yellow solid, which was dissolved in
100 mL of Et2O and stirred while a solution of tetrafluoroboric acid
diethyl ether complex (1.35 mL, 20 mL diethyl ether, 1.2 equiv) was
added slowly. The solid was collected by filtration to afford 9-mesityl-
3,6-dimethoxy-10-phenylacridin-10-ium tetrafluoroborate (6; 1.45 g,
2.493 mmol, 15.02% yield) as a yellow solid.
In a 500 mL round-bottom flask were placed N-(3,5-dimethox-
yphenyl)-3,5-dimethoxy-N-phenylaniline (10.00 g, 27.4 mmol) and
trifluoromethanesulfonic acid (4.11 g, 27.4 mmol) in 1,4-dioxane (100
mL). To this solution was added 2,4,6-trimethylbenzoyl chloride
(10.50 g, 57.5 mmol), and the mixture was stirred at 80 °C for 48 h.
After rotation the crude mixture was separated by gel column
chromatography (EA including 1% TFA/PE = 75/25) and 14.0 g of
the crude TFA salt obtained. This was purified by reversed phase
Combi-Flash HPLC (column C18-2 330 g; detector 210 nm; mobile
phase A water/0.05% TFA; mobile phase B MeOH; flow rate 140 mL/
min; gradient 45% B to 80% B in 20 min), and 7.40 g of the TFA salt
was obtained. This TFA salt was dissolved in methanol (5 V) and the
solution stirred while a solution of tetrafluoroboric acid diethyl ether
complex (3.3 mL, 1.1 equiv) was added slowly. The mixture was
concentrated under vacuum. After ether was added (5 V), the solid
was collected after 12 h by filtration to give 9-mesityl-1,3,6,8-
tetramethoxy-10-phenylacridin-10-ium tetrafluoroborate (5.70 g, 9.51
mmol, 34.8% yield) as a red-brown solid.
1H NMR (600 MHz, CDCl3): δ 7.96 (t, J = 7.5 Hz, 2H), 7.87 (t, J =
7.7 Hz, 1H), 7.71 (d, J = 7.8 Hz, 2H), 7.66 (d, J = 9.4 Hz, 2H), 7.24
(dd, J = 9.5, 1.9 Hz, 2H), 7.14 (s, 2H), 6.59 (d, J = 1.9 Hz, 2H), 3.83
(s, 6H), 2.47 (s, 3H), 1.87 (s, 6H). 13C NMR (151 MHz, CDCl3): δ
167.6, 160.7, 144.9, 140.2, 137.1, 136.2, 132.2, 132.0, 130.9, 129.5,
129.1, 128.1, 121.1, 120.3, 99.0, 56.7, 21.4, 20.2. 19F NMR (470 MHz,
1H NMR (600 MHz, CDCl3): δ 7.90 (t, J = 7.7 Hz, 2H), 7.82 (t, J =
7.5 Hz, 1H), 7.49 (d, J = 7.5 Hz, 2H), 6.91 (s, 2H), 6.48 (d, J = 2.0 Hz,
2H), 6.01 (d, J = 2.1 Hz, 2H), 3.77 (s, 6H), 3.48 (s, 6H), 2.38 (s, 3H),
1.83 (s, 6H). 13C NMR (151 MHz, CDCl3): δ 168.4, 162.4, 160.9,
145.3, 138.4, 137.6, 136.7, 132.3, 132.1, 131.7, 127.8, 127.2, 113.5,
+
CDCl3): δ −154.2. HRMS: calcd for C30H29BF4NO2 , 434.2115;
found, 434.2134.
E
DOI: 10.1021/acs.joc.6b01240
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
97.9, 92.7, 57.2, 56.6, 21.3, 20.4. 19F NMR (470 MHz, CDCl3): δ
−153.5. HRMS: calcd for C32H33BF4NO4 , 494.2326; found,
494.2342.
(12) Both tetrasubstituted acridiniums can be prepared in a single
step from the corresponding triarylamine derivative. See the
Experimental Section.
+
(13) For seminal work on continuous flow chemistry, see: (a) Hook,
B. D. A.; Dohle, W.; Hirst, P. R.; Pickworth, M.; Berry, M. B.; Booker-
Milburn, K. I. J. Org. Chem. 2005, 70, 7558. For a recent review on the
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b01240.
topic, see: (b) Cambie,
́
D.; Bottecchia, C.; Straathof, N. J. W.; Hessel,
V.; Noel, T. Chem. Rev. 2016, DOI: 10.1021/acs.chemrev.5b00707.
̈
(c) Knowles, J. P.; Elliott, L. D.; Booker-Milburn, K. I. Beilstein J. Org.
Chem. 2012, 8, 2025. For a recent study comparing batch and flow
photochemistry, see: (d) Elliott, L. D.; Knowles, J. P.; Koovits, P. J.;
Maskill, K. G.; Ralph, M. J.; Lejeune, G.; Edwards, L. J.; Robinson, R.
I.; Clemens, I. R.; Cox, B.; Pascoe, D. D.; Koch, G.; Eberle, M.; Berry,
M. B.; Booker-Milburn, K. I. Chem. - Eur. J. 2014, 20, 15226.
(14) Catalyst degradation at 60 °C was much more rapid than that at
room temperature.
1H and 13C NMR spectra and photophysical and
electrochemical measurements of photocatalysts (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail for D.A.D.: daniel.dirocco@merck.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
A.J.-P. is a Merck Research Laboratories Postdoctoral fellow.
This research was supported by Merck Research Laboratories.
A.J.-P. thanks the catalysis and automation group for their
encouragement. We thank Rebecca Ruck (Merck) for helpful
discussions and proofreading of this paper. Photophysical
measurements were performed in the UNC-ERFC Instrumen-
tation Facility established by the UNC-EFRC (Center for Solar
Fuels, an Energy Frontier Research Center funded by the U.S.
Department of Energy, Office of Science, Office of Basic Energy
Sciences under Award Number DE-SC0001011).
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DOI: 10.1021/acs.joc.6b01240
J. Org. Chem. XXXX, XXX, XXX−XXX