Phenazine-Based Donor Acceptor Systems as Organic Photocatalysts for "metal-free" C-N/C-C Cross-Coupling

Article abstract of DOI:10.1021/acs.joc.9b03407

With an aim to achieve a balance between ground-state and excited-state reduction potential of donor acceptor systems for efficient C-N/C-C cross-coupling, a series of donor acceptor systems DA1-DA4 have been synthesized by varying the donor strength and connecting positions. With an increase in donor strength, systematic elevation in the ground-state reduction potential and decrease in the HOMO-LUMO gap was observed. Interestingly, all the derivatives DA1-DA4 could catalyze the C-N bond formation reaction between activated aryl halides and amines at low catalytic loading under metal-free conditions without the need of any external base upon irradiation with white LED. A balance was realized in the case of derivative DA2, which exhibits high efficiency in C-N couplings. Different control experiments support the validity of the energy as well as electron transfer pathways in the visible light-mediated C-N bond formation. This study further reveals the potential of derivative DA1 in "metal-free"Sonogashira coupling involving activated aryl halides which is attributed to its high excited-state reduction potential.

Full text of DOI:10.1021/acs.joc.9b03407

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Article
Phenazine Based Donor Acceptor Systems as Organic
Photocatalysts for ‘Metal-Free’ C-N/C-C Cross Coupling
Harnimarta Deol, Gurpreet Singh, Manoj Kumar, and Vandana Bhalla
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03407 • Publication Date (Web): 23 Jul 2020
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Phenazine Based Donor Acceptor Systems as
Organic Photocatalysts for ‘Metal-Free’ C-N/C-C
Cross Coupling
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Harnimarta Deol, Gurpreet Singh, Manoj Kumar and Vandana Bhalla*
Department of Chemistry, UGC Centre of Advanced Study
Guru Nanak Dev University, Amritsar 143005, and Punjab, India
KEYWORDS: C-N coupling, donor acceptor system, photoredox,
reduction potential, Sonogashira Coupling.
ABSTRACT: With an aim to achieve a balance between ground state
and excited state reduction potential of donor acceptor systems
for efficient C-N/C-C cross coupling, a series of donor acceptor
systems DA1-DA4 have been synthesized by varying the donor
strength and connecting positions. With an increase in donor
strength, systematic elevation in the ground state reduction
potential
and
decrease
in
HOMO-LUMO
gap
was
observed.
Interestingly, all the derivatives DA1-DA4 could catalyze C-N
bond formation reaction between activated aryl halides and
amines at low catalytic loading under metal-free conditions
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without need of any external base upon irradiation with white
LED. A balance was realized in case of derivative DA2 which
exhibits high efficiency in C-N couplings. Different control
experiments support the validity of the energy as well as
electron transfer pathways in the visible light mediated C-N
bond formation. This study further reveals the potential of
derivative DA1 in ‘metal free’ Sonogashira coupling involving
activated aryl halides which is attributed to its high excited
state reduction potential.
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1.
INTRODUCTION
The C-N/C-C bond formation via palladium catalyzed coupling
reaction
is
an
of
introductory
method
to
access
and
complex
architectures
natural,
pharmaceutical
functional
materials.1-5 Unfortunately, wide spread use of palladium based
catalytic systems is hampered by a few reaction elements such as
high cost/toxic nature/sensitive handling of palladium, need for
high equivalents of base and high reaction temperature.6,7 The
pursuit for alternate ‘green’ catalytic systems for efficient
and ecofriendly aminations of aryl halides encouraged the
researchers to design copper based catalytic platforms. Over the
years, a variety of copper based catalytic systems for Ullmann
type coupling reaction have been developed which have undergone
tremendous improvisation to construct C-N bond under controlled
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thermal conditions (100 0C).8,9 To get rid of thermal heating,
photoinduced C-N bond formation has been reported in which Cu-
amine complex facilitated the aryl amination through single
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electron
transfer
(SET)
under
photocatalytic
conditions.
In 201611
However, the reaction conditions require the presence of high
1
0
energy UV radiation as energy source.
Building on pioneering
R
5 mol% NiX .glyme
2
Br
N
R' 0.02 mol% Ir photocatalyst
R'
photocataly
R
tic aminoH Na rylation via elec
R
tron transfer processes,
0
DABCO, DMA, rt or 55 C
Y
R
Y
blue LED
Ni based
photocatalytic
systems
have
been
developed
by
Scheme 1. Nickel in combination with Ir as
integrating nickel complex with different photocatalysts for C-N
In 201815
11-13
bond formation with a good substrate scope (Scheme 1).
Very
R
R
recently a nickel based catalytic system has been reported which
R
5
mol% NiBr .3H O, rt
2 2
HN
catalyzed C-N coupling
R
througBl
h
ue L
en
D,ergy transfer pathway and works
E
no base or 1.5 eq quinuclidine,
X
N
N , DMAc
2
R
R
efficiently with electron deficient aryl halides and secondary
Scheme
2.
Nickel
based
amine.14 Despite the environmental benefits, the nickel centered
1
6
photoredox system could not attain the target of sustainable
In 2019
X= Br, Cl
chemical process due to use of organic
R R
bases, blue LED as
X
N
R
mpg-CN, NiBr .glyme
2
irradiation source and high cost of iridium salts. To overcome
HN
R
R
DMA, Base, N
2
R
0
25 C, 455 nm
some of these limitations ‘photocatalyst free’ nickel centered
Scheme 3. Nickel in combination with carbon nitride
catalytic system has been developed (Scheme 2) but high energy
source
(blue
LED)
was
still
needed
to
catalyze
the
Present work
1
5
transformations.
X= I, Br
1. Metal free catalysis
2. Organic donor acceptor system as photocatalyst.
R
R
X
N
R
3. No external Base.
DA (0.1 mol%), White LED
HN
4. White LED as source of irradiation.
R
R
R
0
DMF, N , rt or 40 C
5. Low catalytic loading
2
Scheme
4.
Metal
free
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Encouraged by economical and sustainable advantages of pure
organic photocatalysts in organic transformations, very recently
a ‘metal free’ organic semiconductor mesoporous carbon nitride
(mpg-CN) material has been reported which catalyzes C-C/C-N bond
formation through oxidative and reductive electron transfer
processes (Scheme 3).16 Though mpg-CN could catalyze the
formation of C-C bond under ‘metal free’ conditions but for
construction of C-N bond, the assistance of Ni-complex was
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needed. Thus, it is still a challenge to prepare pure organic
photoredox catalyst for efficient formation of C-N bond under
‘metal free’ conditions.
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Our interest in the development of organic photocatalytic
systems motivated us to develop ‘metal free’ photoredox systems
for C-N bond formation.17 For convenient C-N bond formation,
activation of substrate i.e. aryl halide and nucleophile (amine)
is vital. We visualized a catalytic cycle for C-N bond formation
reaction involving organic photocatalyst18,19 (Scheme 5) which is
analogues to that of metal based photoredox catalysts.11,16 As per
hypothesized
mechanism,
upon
excitation
the
organic
photocatalyst (DA*) will undergo reduction in the presence of
R
NH
electron donor (nucleophile) to generate a stable radical anion
R
-.
R
(
DA ) which will activate C-X bond of aryl halide to form
NH
R
A
radical anion ‘B’ wh
D
ich on cleavage to generate aryl radical ‘C’
DA
A
*
Photooxidant
Photoreductant
before returning to the ground state (DA) (Scheme 5).
Ar + X
Ar
X
hv, ISC
B
C
DA
Ar
X
Scheme 5. The proposed electron transfer process for ‘metal
free’ C-N coupling under visible light irradiation.
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For successful realization of the proposed mechanistic pathway,
the designed organic photoredox catalytic system should have (i)
high absorption in the visible region to ensure requirement of
low catalytic loading in the organic transformations, (ii) high
excited state reduction potential to easily accept the electron
from amine in the excited state, (iii) sufficient ground state
potential to activate aryl halide for the generation of aryl
radical, (iv) effective intersystem crossing (ISC) and reverse
intersystem crossing (RISC) for maximum transfer of the absorbed
photons to excited state.20,21
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For preparing materials having high absorption in the visible
region and sufficient redox potential, donor-acceptor (DA)
platform showing ICT state are the best. In literature,
a
variety of photocatalysts having either high excited state or
high ground state redox potential have been reported, however,
there are few reports available regarding organic materials
having sufficient excited state as well as ground state redox
potential.20,21 Generally, materials having high ground state
redox potential have low excited state redox potential and the
other way round, however, for efficient C-N bond construction, a
balance between excited state and ground state reduction
potential of organocatalyst should be maintained. The donor
acceptor system having strong donor groups usually have high
ground state reduction potential and by directly connecting the
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donor group to acceptor unit (without spacer) ground state
reduction potential is further enhanced with decrease in HOMO-
LUMO gap. We envisaged that by appropriate choice of donor units
and by controlling the conformation of the DA system a balance
between ground state and excited state reduction potential may
be realized. For acceptor unit, we chose dibenzo[a, c] phenazine
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(
DBPZ) derivative due to its known light harvesting22,23 and
efficient ISC-RISC.24,25 To understand the structure-activity
relationship for achieving balanced reduction potential in
excited and ground state, we planned to examine the catalytic
potential of DA systems having different donor groups (variable
strength) with different connectivity (through spacer or direct)
in C-N coupling reactions. To begin with, we planned to couple
DBPZ core with anisole group and envisaged that resulting donor
acceptor system DA1 may exhibit ICT characteristics. Further, by
connecting carbazole unit directly to DBPZ core through
arylation, we expect derivative DA2 to show twisted
conformation. As test of our hypothesis, we carried out
N
a
computational studies of derivatives DA1 and DA2. In derivative
DA1 overlapping between HOMO-LUMO orbitals was observed whereas
well separated HOMO-LUMO orbitals with twist angle of 660 were
observed (vide infra) in case of derivative DA2. After carrying
out DFT studies for derivatives DA1 and DA2, we synthesized
donor acceptor systems DA1 and DA2, and to examine the effect of
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donor strength on the catalytic efficiency, we also prepared
derivatives DA3 and DA4 having relatively stronger donor units.
As indicated by computational studies, the derivative DA1 has
ICT state whereas presence of TICT state was found in case of
derivatives DA2-DA4. Furthermore, all the derivatives exhibit
strong absorption in the visible region and systematically
elevated reductive potential (-1.25 to -1.71 V) with a gradual
decrease in their HOMO-LUMO gap upon increasing the donor
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strength.
Interestingly,
C-N
coupling
between
1-iodo-4-
nitrobenzene and pyrrolidine progressed well using low loading
(0.1 mol %) of pure organic photocatalysts and the desired
product was obtained in excellent yield. To the best our
knowledge, this is the first report which demonstrates ‘metal
free’ approach for carrying out successful C-N coupling under
visible light using organic photocatalyst without using any
external base (Scheme 4). In all the DPBZ derivatives, due to
their low HOMO-LUMO gap low energy of light source (white LED)
was sufficient for excitation and presence of base was not
needed. Different control experiments support the validity of
the energy as well as electron transfer pathways in the visible
light mediated C-N bond formation. Among all the photocatalysts
examined, DA2 exhibits excellent efficiency towards amination of
activated aryl halides (electron deficient) due to contribution
of energy as well as electron transfer pathways. The derivative
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DA1 fails to catalyze the organic transformations involving
relatively less activated aryl halides such as 1-bromo-3,5-
difluorobenzene and 4-bromobenzonitrile due to its insufficient
ground state reduction potential. On the other hand, despite the
highest ground state reduction potential, derivative DA4 shows
relatively poor catalytic activity due to its low excited state
reduction potential. To sum up, a balance between ground and
excited state potential was realized in case of derivative DA2.
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We
also
examined
the
catalytic
efficiency
of
these
photocatalysts in ‘metal free’ Sonogashira coupling in the
presence of weak electron donor i.e. triethylamine. Though we
were not disappointed by the weak catalytic activity of DA2-DA4
under optimized conditions, we were delighted at good efficiency
of DA1 in Sonogashira coupling involving activated aryl halides
as coupling partners. The high excited state reduction potential
of DA1 is the reason behind its good catalytic activity in
Sonogashira coupling reaction.
2.
RESULTS AND DISCUSSION
2.1Synthesis and properties of DPBZ based donor acceptor
systems.
The Suzuki Miyaura coupling between dibromo derivative of
dibenzo [a, c] phenazine26 A1 and 4-methoxy phenyl boronic acid
furnished the DA1 in 80% yield (Chart 1) (Figures S70-72, SI).
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Further, Ullman coupling between dibromo derivative of dibenzo
[
a, c] phenazine A1 and different donors such as carbazole, 3,6-
Di-tert-butyl-9H-carbazole and diphenylamine furnished DPBZ
derivatives DA2, DA3 and DA4 in 70%, 70% and 80% yields,
respectively (Chart 1) (Figures S73-S81, SI).
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OCH3
N
N
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OCH3
DA1
DA2
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N
DA3
DA4
Chart 1. Molecular structure of donor acceptor
systems DA1-DA4.
We carried out UV-vis studies of all the derivatives in DMF
(
Figure 1) and it was found that all the derivatives absorb
strongly in the visible region due to intramolecular charge
transfer (ICT) state (Table 1). Further, it was observed that
ICT band is red shifted from 420 nm (DA1) to 470 nm (DA4) on
changing the donor groups from anisole to diphenylamine. We also
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carried out fluorescence studies of these derivatives in
different solvents (non-polar to polar) and these studies
confirm the existence of twisted intramolecular charge transfer
state in case of derivatives DA2-DA4 (Figures S1-S4, SI).
Further, the emission band is red shifted from 510 nm to 605 nm
on changing the donor groups from anisole to diphenylamine
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4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(Figure S5, SI). The quantum yields of all donor acceptor
systems are given in table 1 and from these values it is clear
that all the donor acceptor systems (DA1-DA4) are emissive in
solution. The time resolved emission studies of derivatives DA1-
DA4 (Figures S6-S9, SI) show that DA2 shows highest singlet
excited state lifetime among all the derivatives (Table 1).
Figure 1. UV-vis spectra of DA1 to DA4
Table 1. Photophysical properties of
Photocatalyst Absorption Emission Quantum
Singlet
state
lifetime
Reduction
potential
(V)
Calculated
Excited state LUMO gap
Reduction
potential (V)
HOMO-
maxima
maxima
Yield
(eV)
2.8
2.5
DA1
DA2
420 nm
426 nm
510 nm
560 nm
0.62
0.38
5 ns
8 ns
-1.25, -0.88
-1.49, -1.09
1.55
1.01
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2
3
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6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
DA3
DA4
440 nm
470 nm
595 nm
605 nm
0.22
0.32
3.5 ns -1.55, -1.23
3 ns -1.71, -1.27
0.90
0.65
2.3
2.1
The DFT studies of derivative of DA1 indicate the overlapping
between its HOMO-LUMO molecular orbitals (Figures S10, SI) while
DFT studies of derivatives DA2-DA4 corroborate with their
twisted geometry as is evident from the large dihedral angle
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
between
donor
and
acceptor
units
with
complete
spatial
separation between HOMO-LUMO molecular orbitals (Figures S11-
S13, SI). We observed that HOMO-LUMO gap reduced with increase
in donor strength (Table 1). Further, the ground state reduction
potential of all derivatives was evaluated by cyclic voltammetry
studies in DMF using Ag/AgCl as reference electrode (Figures S14-S17,
SI). The increase in the ground state reduction potential was
observed with increase in the donor strength. Among all the
derivatives, derivative DA4 has highest reduction potential in
ground state. Further, we calculated excited state reduction
potential using Rehm Weller equation27 and derivative DA1 was
found to have highest excited state reduction potential (Table
1). All the derivatives DA1-DA4 show reversible reduction peaks
which indicates high stability of their corresponding radical
anion.19 The formation of stable radical anion is vital for
smooth completion of the catalytic cycle.
(
A)
0
5
min
min
(B)
0
min
5
min
N+
+N
TEOAox
TEOA
DA1
ACS Paragon Plus Environment
2+
MV
+
e
-e
12
N+
.
N

Page 13 of 52
The Journal of Organic Chemistry
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Next, we checked the validity of our proposed mechanistic
hypothesis i.e ability of DA1-DA4 to act as photooxidants in
the excited state and photoreductant in the ground state. We
chose three component system in which triethanolamine (TEOA)
2+
as sacrificial donor, methyl viologen (MV ) as acceptor and
donor acceptor systems (DA) as electron transporter. We
examined the electron transfer from triethanolamine to
2+
methyl viologen (MV ) using donor acceptor system as
transporters. We begin with DA1 system and the solution
2+
containing methyl viologen (MV ), DA1 and TEOA was exposed
to visible light radiations under inert atmosphere. Within 5
min colour of the solution changed from colorless to
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
greenish blue. The whole event was also followed by UV-vis
spectroscopy.
The UV-vis spectrum of the irradiated sample containing
methyl viologen, DA1 and TEOA exhibits presence of two new
bands at λ = 395 and 603 nm corresponding to the reduced
species MV•+ of methyl viologen (Figure 2A). We believe that
derivative DA1* was reductively quenched by sacrificial
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-
donor in the excited state to generate DA1 which eventually
reduces MV2+ to MV•+ (Figure 2B).28-30 Similar behaviour was
observed when the same experiment was repeated with other
donor acceptor systems (DA2-DA4) (Figures S18-S20, SI).
2
.2 Metal Free C-N Cross Coupling.
After completing the initial monitoring, we examined the test
reaction between 1-iodo-4-nitrobenzene (1 equiv.) and
pyrrolidine (5 equiv.) in DMF under irradiation of white LED (16
W), at room temperature and under inert atmosphere using
photocatalyst DA1. To our pleasure, the reaction was complete in
7
h and the desired product was obtained in 68% yield (Table 2,
entry 1). To facilitate the reaction kinetics of model reaction
catalyzed by DA1, we increased the temperature of model reaction
mixture to 40 oC. The kinetics was accelerated and product
formation was observed within 15 min (monitored by TLC) and a
notable enhancement in the yield of target product was observed
(92%) (Table 2, entry 2). Further increase in temperature did
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Page 15 of 52
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9
not affect the yield significantly (Table 2, entry 3).
Interestingly, the control reaction carried out under optimized
conditions without any photocatalyst furnished the final product
in 35% yield after 12 h (Table 2, entry 4) (vide infra). We
repeated the model reaction without any photocatalyst and after
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
h when spot corresponding to product appeared on TLC, we
removed the light source for next 6 h, however, the reaction did
not proceed further (Table 2, entry 5). This study proves that
continuous
irradiation
of
light
is
necessary
as
no
photocatalytically active species is generated in dark to
further proceed the reaction. Further, to understand the
importance of continuous irradiation of visible light, we
repeated the model reaction under above mentioned conditions
using DA1 as photocatalyst. The reaction proceeds and after 4 h
significant amount of product was formed (monitored by TLC),
thereafter, we removed the light source for next 4 h, but no
significant increase in the yield of product was observed during
this time (monitored by TLC) (Table 2, entry 6). These studies
prove the role of continuous irradiation of reaction mixture
with light to achieve the target product in good yield. The
model reaction when repeated under dark did not proceed (Table
2, entry 7). We also carried out EDX studies of DA1 system but
no palladium content was found. These studies clearly rule out
the possibility of traces of palladium in DA1 system to act as
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5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
catalyst (Figure 21, SI). Next, we examined the influence of
number of equivalents of the amine substrate on reaction
kinetics/yield. The model reaction using 3 equiv. of pyrrolidine
shows a significant decrease in the yield of the target product
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(Table 2, entry 8). Thus, besides acting as one of the coupling
partners, the amine substrate also acts as a sacrificial donor.
Next, we screened different solvents such as toluene, ACN, THF,
DMSO and glycerol as reaction media (Table 2, entries 9-13). The
highest yield was obtained in case of DMF as solvent (Table 2,
entry 2). We carried out several control reactions to examine
influence of the presence/absence as well as nature of base on
reaction outcome (Table 2, entries 14-16). Interestingly, the
presence and absence of base had insignificant effect on the
kinetics/yield of test reaction.
Table 2. Optimization of reactions conditions for
I
H
N
DA (0.1 mol%)
O N
N
2
o
DMF, N , 40 C or rt
2
NO2
1
2
3
Entry Photocatalyst solvent
Base
Temp. Time Yield%
1.
DA1
DA1
DA1
DMF
DMF
DMF
-
-
-
rt
7 h
3 h
3 h
68%
92%
95%
o
2
3
.
.
40 C
o
60 C
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2
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5
6
7
8
9
o
4
5
.
.
-
DMF
-
40 C
12 h
12 h
8 h
3 h
3 h
3 h
3 h
3 h
3 h
3 h
3 h
3 h
3 h
3 h
3 h
3 h
3 h
3 h
35%
o
20%a
-
DMF
-
40 C
6.
DA1
DA1
DA1
DA1
DA1
DA1
DA1
DA1
DA1
DA1
DA1
DA1
DA1
DA2
DA3
DA4
DMF
-
rt
rt
46%b
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
tracesc
7
8
9
.
.
.
DMF
-
o
65%d
80%
70%
68%
78%
70%
90%
92%
93%
20%e
50%e
90%
82%
78%
DMF
-
40 C
o
Toluene
ACN
-
40 C
o
10.
-
40 C
o
1
1
1
1.
2.
3.
THF
-
40 C
o
DMSO
Glycerol
DMF
-
40 C
o
-
40 C
o
14.
K
2
CO
3
40 C
o
1
1
1
1
5.
6.
7.
8.
DMF
t-BuOK 40 C
o
DMF
DABCO 40 C
o
DMF
-
-
-
-
-
40 C
o
glycerol
DMF
40 C
o
19.
40 C
o
2
2
0.
1.
DMF
40 C
o
DMF
40 C
a. switch on light for 6 h and switch off for next 6 h.; b. switch on light for
h and switch off for next 4 h; c. dark conditions; d. 3 equiv. of
4
pyrrolidine; e. aerial conditions
To understand the need of inert reaction atmosphere, we repeated
the test reaction under aerial conditions, however, the yield of
desired
product
reduced
to
20%
(Table
2,
entry
17).
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Surprisingly, only in case of glycerol as reaction media, the
desired product was obtained in 50% yield under aerial
conditions (Table 2, entry 18). We believe that in the presence
of highly viscous glycerol the diffusion of oxygen is
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
restricted.
All
these
control
experiments
confirm
the
requirement of light source, inert atmosphere and photocatalyst
to achieve the rapid formation of product in high yield.
Further, we repeated the test reaction using the photocatalysts
DA2, DA3 and DA4 (Table 2, entries 19-21). Among all the
photocatalysts examined, the derivatives DA1 and DA2 furnished
the target compound in excellent yield (Table 2, entries 2 and
19) and relatively lower yield of product was obtained when DA4
was used as catalyst (Table 2, entry 21).
With optimized conditions in hand, we examined the substrate
scope
with
regard
to
nucleophiles
i.e.
cyclic
amines
(secondary), aliphatic amines and aromatic amines (aniline). In
all the cases, the reactions proceed conveniently and desired
products were obtained in good to moderate yield (Table 3,
entries 1-6). Out of morpholine and piperidine, piperidine
substituted product was obtained in relatively higher yield in
case of all the photocatalysts (Table 3, entry 1).
Further, the primary aliphatic amines such as dimethylamine and
n-butylamine furnished the desired products in comparatively
lower yields in case of photocatalysts DA3 and DA4 (Table 3,
ACS Paragon Plus Environment
Table 3. The C-N coupling between 1-iodo-4-nitrobenzene and
18
different amines using photocatalyst DA1-DA4 under optimized

Page 19 of 52
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entries 3 and 4). These studies show that reaction kinetics and
yield is strongly dependent upon nucleophilic strength of the
amine substrate.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Entry
Aryl Halide
Amine
Time
Product
Yield%
DA1 DA2 DA3 DA4
1.
3
h
h
9
1% 89% 84% 80%
O N
N
5
O N
I
HN
2
2
4
1
2
3
4
.
.
.
8
O N
I
HN
O
2
N
7
O
75% 72% 58% 55%
82% 80% 65% 60%
O N
2
6
1
5 h
O N
I
I
2
H N
O2N
N
H
2
8
1
1
9
O N
H
3 h
3 h
88% 85% 66% 60%
90% 85% 75% 68%
2
N
O N
N
2
10
11
5.
NH3
12
O N
I
2
O N
NH2
2
1
13
H
6
.
10 h
O N
I
H2N
2
O N
N
2
68% 60% 40% 30%
1
14
15
Next, we investigated the reaction of 1-iodo-4-nitrobenzene with
ammonia using photocatalyst DA1-DA4 (Table 3, entry 5). Again,
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
the derivatives DA1 and DA2 furnished target product in good
yield, however, comparatively lower yield was obtained in case
of derivatives DA3 and DA4.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The C-N coupling between 1-iodo-4-nitrobenzene and aniline
yields the desired product in 68% and 60% yield respectively in
case of DA1 and DA2, moderate yield (40%) in case of DA3 and
lower yield (30%) in case of DA4 (Table 3, entry 6).
Next, we examined the effect of leaving group on the reaction
kinetics.
Interestingly,
the
coupling
between
1-bromo-4-
nitrobenzene with pyrrolidine progressed conveniently to furnish
the target product in same yield and time as observed in case of
1-iodo-4-nitrobenzene using DA1-DA4 as photocatalysts (Table 4,
entry 1). We believe that due to the same reduction potential of
-bromo/iodo-1-nitrobenzene derivative (-0.98 V),31 the rate of
4
catalyst mediated
Table 4. The C-N coupling between electron withdrawing aryl
halides and different amines using photocatalyst DA1-DA4 under
Entry
Aryl Halide
Amine
Time
Product
Yield%
DA1 DA2 DA3 DA4
1
.
3
h
O N
N
92%
90% 86% 80%
HN
O N
Br
2
2
2
3
16
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9
2
.
24 h
-
-
-
-
I
HN
N
1
7
18
2
3.
12 h
Traces 75% 65% 60%
Traces 72% 54% 50%
Traces 60% 50% 45%
NC
Br
HN
NC
N
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
20
1
9
4
5
.
.
12 h
12 h
3 h
NC
NC
Br
Br
N
NC
HN
HN
1
9
21
4
O
NC
N
O
6
19
F
2
2
F
F
F
F
6.
93%
90%
90% 85% 82%
HN
HN
HN
F
Br
F
N
2
F
F
F
24
F
2
3
7
8
.
.
F
F
3 h
F
90% 82% 80%
F
Br
F
N
F
F
F
F
F
F
F
F
4
2
3
25
3 h
82%
80% 70% 65%
O
F
Br
F
N
O
6
F
F
F
F
F
2
3
26
9
1
.
3 h
3 h
Traces 82% 78% 74%
F
F
HN
HN
N
Br
2
F
F
28
27
0.
F
Traces 80% 70% 68%
Br
N
F
F
4
29
27
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
1.
F
F
5 h
F
F
Traces 65% 58% 50%
Br
HN
O
N
0
O
6
3
27
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
substrate
activation
is
same,
thus,
kinetics
remained
unaffected. Furthermore, the reaction between iodobenzene and
pyrrolidine did not proceed under optimized conditions (Table 4,
entry 2). We believe that due to high reduction potential of
iodobenzene (Ered
>
-2.1 V)32,33
,
the ground state reduction
potential of photocatalysts DA1-DA4 is not sufficient to
activate the C-X bond of aryl halide to generate aryl radical.
To confirm this assumption, we examined several electron
deficient aryl halides as coupling partners using photocatalysts
DA1-DA4 (Table 4, entries 3-11).
Upon replacing nitro group with nitrile, the photocatalysts DA2-
DA4 furnished the desired products in relatively lower yields
(
Table 4, entries 2-5), however, to our surprise, photocatalyst
DA1 failed to catalyze the transformation in case of 4-
bromobenzonitirile as coupling partners. By using 1-
bromopentafluorobenzene as reaction partner, the target products
were attained in high yield (Table 4, entries 6-8), however, in
case of 1-bromo-3,5-difluorobenzene the yields were affected and
photocatalyst DA1 again failed to catalyze the transformations
(
Table 4, entries 9-11).
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To understand the mechanism of reaction, we begin with the
control reaction between 1-iodo-4-nitrobenzene and pyrrolidine
without using any photocatalyst under irradiation of visible
light. The control experiment was repeated in the presence of 1
equiv. of TEMPO as radical scavenger. The reaction did not
proceed and the mass spectrometric studies confirm the formation
of TEMPO adduct (Figure S22, SI). This study supports the
formation of aryl radical under reaction conditions (Scheme S6,
SI). Further, we monitored the control reaction by absorption
spectroscopy. The absorption spectrum of 1-iodo-4-nitrobenzene
and pyrrolidine in DMF under inert atmosphere exhibits the
formation of two bands at 500 nm and 600 nm which suggests the
formation of electron donor acceptor (EDA) complex between 1-
iodo-4-nitrobenzene (acceptor) and pyrrolidine (donor) in ground
state34,35 (Figure S23, SI). The formation of EDA complex was
visible to naked eye with clear change of color of the solution
from colorless to light green. We believe that EDA complex is
acting as light harvesting antenna and is catalyzing the
reaction in the forward direction.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
To understand the role of photocatalyst, we prepared EDA complex
(between 1-iodo-4-nitrobenzene and pyrrolidine) and introduced
it to solution of DA1 system in DMF, complete quenching of the
emission was observed in the fluorescence spectrum (Figure S24,
SI) and a good spectral overlap between absorption spectrum of
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
EDA complex and emission spectrum of DA1 system was also
observed
(Figure
S25,
SI).
These
results
indicate
the
possibility of energy transfer from DA1 systems to EDA complex.14
Next, we also examined the fluorescence behaviour of donor
acceptor system DA1 (5 µM, DMF) in the presence of pyrrolidine.
Interestingly, in the presence of 10 equiv. of pyrrolidine, the
derivative DA1 shows quenching of the emission intensity (Figure
S26, SI), however, no spectral overlap was observed between the
emission of DA1 system and absorption spectrum of pyrrolidine
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(Figure S27, SI). The quenching of emission may be attributed to
photoinduced electron transfer (PET) from electron rich amine to
DA1 system36,37 which indicates the possibility of electron
transfer pathway.
Similar behaviour was observed in case of DA2 and DA3 donor
acceptor systems (Figures S28 and S31, SI) except in case of DA4
(vide infra) (Figures S32 and S33, SI).
To get deep insight into the mechanistic pathway in case of
other aryl halides, we examined the formation of EDA complex in
case of 1-bromopentafluorobenzene, bromobenzonitrile and 3,5-
difluoro bromobenzene using absorption spectroscopy (Figures
S34-S36, SI). Among all, EDA complex was formed only in case of
1-bromopentafluorobenzene. These observations indicate that in
case of relatively more electron deficient aryl halide (1-iodo-
4-nitrobenzene and 1-bromopentafluorobenzene) reaction proceeds
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through both electron as well as energy transfer pathways,
however, in case of bromobenzonitrile, 3,5-difluoro bromobenzene
the reaction proceeds through electron transfer pathway only.
These results also clearly explain the inability of DA1 to
catalyze the reactions involving bromobenzonitrile, 3,5-difluoro
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Energy Transfer Pathway
bromobenzene as one of the substrates due to insufficient ground state
*
R
H
R
2
1
red
R
uction potential of DA
R
H
1
1
. A
R
m
2
ong all the donor accep
N
tor systems, donor acceptor system DA2
N
R
R
2
1
N
X
R
shows high efficiency in case of all aryl
H
X
R
X
Photoexcited
EDA complex
EDA complex
A
R1
NH
R2
DA*
DA
R1
R2
Electron Transfer Pathway
N
H
B
X
R
D
C
R1 R2
DA
N
H
R1
NH
R2
X
R
R1
R1
R2
X
R
N
N
R2
H
2
B
E
R1
N
R2
R1
R
2 X
R
N
H
2
Scheme 6.
The proposed energy transfer/electron transfer
pathways for ‘metal free’ C-N coupling under visible light
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6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
halides which was due to more spectral overlap with absorption of EDA complex which
enhances the rate through energy transfer pathway and the balanced reduction potential in
excited and ground state enhances the rate of reaction through electron transfer pathway.
Further, we carried out model reaction in the presence of
different equivalents of TEMPO using DA1 as photocatalyst under
optimized conditions. Upon introducing 0.5 equiv. of TEMPO to
the reaction the yield of target product reduced to 30%, while
upon introducing 1 equiv. of TEMPO, the progress of model
reaction was inhibited and formation of TEMPO adduct was
detected using mass spectrometric analysis (Figure S37, SI).
These results indicate that energy transfer/electron transfer
mechanistic route proceeds through the formation of radical
intermediates (Scheme 6). In energy transfer pathway, DA system
absorbs energy upon irradiation of visible light and transfers
it to EDA complex. The photoexcited EDA complex ‘A’ complex then
undergoes cleavage to form amino radical cation ‘B’ and aryl
radical anion ‘C’, whereas, in case of electron transfer
pathway, DA system absorbs visible light and is excited to form
DA* (photooxidant) which then accepts electron from the amine to
form radical anion DA-. and amino radical cation ‘B’. The radical
anion DA-. activates aryl halide by electron transfer to form
anion radical ‘C’. In both pathways, the radical anion ‘C’
undergoes cleavage to generate aryl radical D. On other hand,
amino radical cation ‘B’ reacts with another molecule of amine
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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to form amino radical ‘E’. Finally, aryl radical ‘D’ combines
with amino radical ‘E’ to form the desired product.
Another interesting observation in C-N coupling reaction is that the reaction kinetics depends on
nucleophilic strength of amine. In case of strong nucleophile, the reaction proceeds at faster rate
to furnish the target product in high yield.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The distinct photophysical behaviour of DA4 in comparison to
DA1-DA3 in the presence of EDA complex and pyrrolidine suggests
an alternative mechanistic pathway for completion of the
reaction. To examine the possibility of oxidative quenching, we
examined the emission behavior of DA4 in the presence of 1-iodo-
4-nitrobenzene. No change in the emission behavior was observed
which rules out any possibility of oxidative quenching in the
excited state (Figure S38, SI). However, different control
experiments show that reaction kinetics is strongly dependent
upon the number of equivalents of pyrrolidine (Figure S39, SI).
Based on all the above experiments and literature reports, we
believe that in case of DA4, ISC is efficient and the
energy/electron transfer is operative through triplet state.38
Furthermore, regardless of high molar extinction coefficient, lower HOMO-LUMO gap and high
reduction potential in ground state, derivative DA4 shows low catalytic activity in all the
reactions. We believe that due to the presence of strong donor groups in DA4, electron density
on acceptor part is high and hence its ability to accept the electron from the amine substrate upon
3
9
excitation is reduced. Moreover, the DA4 has emission at longer wavelength (605 nm) due to
which spectral overlap with EDA complex was decreased.
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
.3 Metal Free Photocatalytic Sonogashira Coupling.
Classical Method 40-44
X
Pd, Cu, Ligand
R
R
R
Base, Organic Solvent
High Temp
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
R
Metal Free Approach45
X
UV light
R
R
R
H
Trifluoroethanol,
Only aliphatic
alkynes
Me CO
2
R
Present Work
X
DA1 (0.1 mol%), Et N
3
R
Toluene
R
R
o
4
0 C, N , Visible light
2
R
Scheme
7.
Catalytic
systems
for
The ability of all the photocatalysts to accelerate aryl halides
in ground state prompted us to examine their catalytic
efficiency in Sonogashira coupling involving activated aryl
halide and triethylamine (TEA) as electron donor due to its good
basicity. To begin with, we chose the reaction between 1-iodo-4-
nitrobenzene and phenylacetylene as model reaction using DA1 as
photocatalyst under optimized reaction conditions of C-N
coupling. The desired product was obtained in 40% yield (Table
5, entry 1). Upon switching the solvent from DMF to non-polar
toluene the yield of target product increased to 62% (Table 5,
entry 2). Though we are unable to provide a clear answer for
this observations but polarity of the solvent is significantly
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affecting the kinetices of coupling reaction. Thus, we chose
toluene as reaction media for further transformations. The
present approach for carrying out Sonogashira coupling is better
than the approaches reported in the literature40-46 (Scheme 7).
Next, we examined the photocatalytic activity of photocatalysts
DA2-DA4 towards Sonogashira coupling under optimized conditions.
In case of DA2, the target compound was obtained only in 35%
yield (Table 5, entry 3) while with DA3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 5. Optimization of reactions conditions for Sonogashira
coupling between aryl halide and phenylacetylene
I
DA1 (0.1 mol%), Et N
3
NO2
Toluene, N , 40 oC
2
NO2
1
31
32
Entry Photocatalyst Solvent Yield
1.
DA1
DA1
DA2
DA3
DA4
DMF
40%
2
3
4
5
.
.
.
.
Toluene 62%
Toluene 35%
Toluene 20%
Toluene 15%
and DA4 the
desired products were
20% and 15% yields,
obtained
in
6.
-
Toluene Traces
Toluene Traces
7
8
.
.
DA1a
respectively
(Table 5, entries
4
DA1b
Toluene Traces
and 5). All
the control
a dark, b aerial
experiments show that presence of light, inert atmosphere,
sacrificial donor and photocatalyst DA1 are essential for the
reaction to proceed in the forward direction. No product
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