Porphyrins as Photoredox Catalysts: Experimental and Theoretical Studies

Article abstract of DOI:10.1021/jacs.6b09036

Metalloporphyrins not only are vital in biological systems but also are valuable catalysts in organic synthesis. On the other hand, catalytic properties of free base porphyrins have been less explored. They are mostly known as efficient photosensitizers for the generation of singlet oxygen via photoinduced energy transfer processes, but under light irradiation, they can also participate in electron transfer processes. Indeed, we have found that free base tetraphenylporphyrin (H₂TPP) is an efficient photoredox catalyst for the reaction of aldehydes with diazo compounds leading to α-alkylated derivatives. The performance of a porphyrin catalyst can be optimized by tailoring various substituents at the periphery of the macrocycle at both the β and meso positions. This allows for the fine tuning of their optical and electrochemical properties and hence their catalytic activity.

Full text of DOI:10.1021/jacs.6b09036

Subscriber access provided by EPFL | Scientific Information and Libraries
Article
Porphyrins as Photoredox Catalysts - Experimental and Theoretical studies
Katarzyna Rybicka-Jasi#ska, Wenqian Shan, Katarzyna Zawada, Karl Kadish, and Dorota Gryko
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b09036 • Publication Date (Web): 02 Nov 2016
Downloaded from http://pubs.acs.org on November 2, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 10
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Porphyrins as Photoredox Catalysts - Experimental and
Theoretical studies
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Katarzyna Rybicka-Jasińska,1 Wenqian Shan,2 Katarzyna Zawada,3* Karl Kadish,2* Dorota
Gryko1*
1 Institute of Organic Chemistry Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
2 University of Houston, Department of Chemistry, Houston, Texas 77204-5003, USA
3 Medical University of Warsaw, Faculty of Pharmacy with the Laboratory Medicine Division, Department of Physi-
cal Chemistry, Banacha 1, 02-097 Warsaw, Poland
Keywords: photochemistry, photoredox catalysis, alkylation, diazo compounds, aldehydes, organocatalysis
ABSTRACT: Metalloporphyrins are not only vital in biological systems but also valuable catalysts in organic synthesis. On
the other hand, catalytic properties of free base porphyrins are less explored. They are mostly known as efficient photo-
sensitizers for the generation of singlet oxygen via photoinduced energy transfer processes but under light irradiation,
they can also participate in electron transfer processes. Indeed, we have found that free-base tetraphenylporphyrin
(H2TPP) is an efficient photoredox catalyst for the reaction of aldehydes with diazo compounds leading to α-alkylated
derivatives. The performance of a porphyrin-catalyst can be optimized by tailoring various substituents at the periphery
of the macrocycle at both the β- and meso-positions. This allows for the fine tuning of their optical and electrochemical
properties, hence their catalytic activity.
INTRODUCTION
(photosensitization) or electrons (photoredox cataly-
sis).13,15
Efficient C-C bond formation in a green, non-toxic and
inexpensive way has always been a challenge. To this end,
the development of visible light-promoted methodologies
is one of the means to achieve such a goal.1-5 Photoredox
catalysis is based on a photo-induced electron transfer
process (PET) between a substrate and a photoredox
catalyst, commonly Ru- or Ir-complexes.6-8 Though organ-
ic dyes have been well known for their ability to partici-
pate in photo-induced electron transfer processes, their
use as catalysts in such reactions is less explored.9 The
replacement of Ir- and Ru-complexes with known organic
dyes is not always possible but a recent comprehensive
review by Romero and Nicewicz compiles a list of organic
photoredox catalysts including: xanthenes, cyanoarenes,
benzophenones, quinones, and thiazines, to name few.10
Surprisingly, porphyrinoid compounds, though known as
pigments of life, are not mentioned.
There are numerous reports describing the use of metal-
loporphyrins as artificial photosynthesis models and en-
zyme mimics as well as in catalyzing chemical reactions.16-
18 Particular attention has been paid to the aliphatic C-H
hydroxylation reaction which in nature is catalyzed by the
heme-containing enzyme, cytochrome P450.19.20 Other
developed reactions include amination, alkylation, olefin
epoxidation, cyclopropanation, olefination, oxidative
amine coupling, oxidative Mannich reaction, Diels-Alder
reactions, and functional group transformations.21-23
Conversely, in organic synthesis free-base porphyrins
have been mainly applied as photosensitizers for singlet
oxygen generation.24 Under light irradiation porphyrins
are excited to a singlet state, after which they can undergo
ISC to produce a triplet state, and as such via energy
transfer, singlet oxygen is formed or electron transfer
leads to the formation of reactive oxygen species.25 Using
this methodology various compounds including olefins,
aromatic compounds, amines, enamines, and aldehydes
were oxidized.26 For example, Nagata and coworkers re-
ported photooxidation of alcohols to aldehydes via pho-
toinduced electron transfer from a porphyrin (free-base
or zinc) to the quinone.27 Moreover, free-base porphyrins
were shown to catalyze photooxidative hydroxylation of
arylboronic acids, although in this case the corresponding
Zr-organic framework containing substituted-porphyrin
groups turned out to be more efficient. This reaction is
These beautiful macrocycles are vital for our life, playing a
key role in energy and electron transfer processes notably
including photosynthesis, transport and storage of respir-
atory gases, methyl transfer, rearrangement reactions,
etc.11,12 Among them, porphyrins are of particular im-
portance due to their 18 π-electron aromatic ring, small
singlet-triplet splitting, high quantum yield for intersys-
tem crossing, and long triplet state lifetime making them
perfectly suited for being robust electron mediators.13,14
Under light irradiation porphyrins can absorb photons
and in the excited state they are able to transfer energy
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 10
believed to proceed via a reductive quenching mecha-
properties of porphyrins as well as their simple synthesis,
nism.28
we wondered whether under light-irradiation free base
porphyrins could be employed as photoredox catalysts
under light-irradiation.
1
2
3
4
5
6
7
8
We envisaged that following photooxidation-like path-
ways, porphyrins could be broadly used as photoredox
catalysts for C-C bond forming reactions. After light ab-
sorption, in the excited state they could then serve as
oxidants by accepting electrons from a substrate or trans-
form into a long-lived radical cation, enabling reduction
of the starting material (Scheme 1).29,30
We have found that under light irradiation porphyrins are
indeed able to participate in both energy and electron
transfer processes generating an enamine cation radical
and a carbene in the triplet state, thus facilitating func-
tionalization of aldehydes at the α-position. To the best of
our knowledge, this is the first example of the use of por-
phyrins as photoredox catalysts in C-C bond forming reac-
tions.
9
Scheme 1. Energy and electron transfer processes
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Electrochemical studies. Given that the crucial step in
all light-induced reactions involves absorption of a pho-
ton by a photocatalyst to transform it into high energy
excited state, it is the reduction potential of the excited
state that should be taken into account. This potential
cannot be directly measured but it can be estimated from
cyclic voltammetry (CV) and spectroscopic data. An ap-
proximation of excited-state potentials (both in the sin-
glet and triplet state) of a catalyst relates to a ground state
potential and its zero-zero excitation energy (E0,0).6a,15
RESULTS AND DISCUSSION
There are only a few reports describing photoinduced
electron transfer from free-base porphyrins in polymeri-
zation processes.31 To the best of our knowledge, the only
successful example of free-base porphyrin catalyzing a C-
C bond forming reaction, has been recently described by
Kanai and co-workers.32 They found that tetra(4-
diethylaminophenyl)porphyrin is effective in promoting
C(3)-H arylation of coumarins with aryl diazonium salts.
The porphyrin reduces aryl diazonium tetrafluoroborate
affording an aryl radical and nitrogen. The resulting por-
phyrin radical cation then oxidizes the benzyl radical
intermediate. Interestingly, the reaction is not affected by
the presence or absence of light.
Available data and our experiments suggested that in the
studied reaction, porphyrin acts as a photoredox catalyst.
The electroreduction of tetraphenylporphyrin (4, H2TPP)
and Zn-4 were investigated in both DMSO and
DMSO:buffer (pH = 4) solvents containing TBAP as a
supporting electrolyte and potentials are reported vs.
saturated calomel electrode (SCE). The reduction of
H2TPP (4) is located at E1/2 = - 1.03 and -1.46 V while the
oxidation at 1.03 V. For ZnTPP (Zn-4) the respective po-
tentials are slightly higher, at E1/2 = - 1.32, -1.71 V and 0.86,
and 1.06 V. In DMSO:buffer (pH = 4) solution, the reac-
tion medium, we have only observed peaks corresponding
to the reduction of buffer. Therefore, data from experi-
ments in DMSO were used for calculations of approxi-
mate reduction potentials of H2TPP (4) and ZnTPP (Zn-4)
in both excited states:
The seminal work on photoredox catalysis describes pho-
toinduced functionalization (trifluoromethylation33, ben-
zylation34, alkylation35) of aldehydes in the presence of
well-known photoredox catalysts – ruthenium or iridium
metal complexes. As an alternative to transition metal
complexes, organic dyes have been also applied in photo-
redox catalysis,36-38 with eosin Y being the most com-
mon.39
Oxidative Quenching:
Eox*[Por•+/Por*] = Eox[Por•+/Por] - E0,0
in the singlet state
Eox*[TPP•+/TPP*] = 1.03 V – 1.94 V= - 0.91V
Eox*[ZnTPP•+/ZnTPP*] = 0.86 V – 2.04 V = -1.18 V
in the triplet state15
Eox*[TPP•+/TPP*] = 1.03 V – 1.45 V= - 0.42 V
Eox*[ZnTPP•+/ZnTPP*]= 0.86 V – 1.59 V = -0.73 V
Reductive Quenching:
Recently, we have reported light induced α-alkylation of
aldehydes with diazoesters catalyzed by Ru(bpy)3Cl2
(Scheme 2).40
Scheme 2. Light-induced reaction of aldehydes with
EDA
Under the developed conditions, other photoredox cata-
lysts – organic dyes such as eosin Y, methylene blue, fluo-
resceine, and rose bengal were tested, but only eosin Y
and rose bengal gave the desired product 3 in reasonable
yields. However, in general, it is not always possible to
replace Ir- and Ru-complexes with known organic dyes
and therefore the search for new, suitable catalysts is
ongoing. Given the promising optical and electrochemical
Ered*[Por*/Por•-] = Ered[Por/Por•-] + E0,0
in the singlet state
Ered*[TPP*/TPP•-] = - 1.03 V + 1.94 V= 0.91 V
Ered*[ZnTPP*/ZnTPP•-] = -1.32 V + 2.04 V = 0.79 V
in the triplet state15
ACS Paragon Plus Environment

Page 3 of 10
Journal of the American Chemical Society
Ered*[TPP*/TPP•-] = - 1.03 V + 1.45 V= 0.42 V
Ered*[ZnTPP*/ZnTPP•-] = -1.32 V + 1.59 V = 0.27 V
Table 1. The reaction of aldehyde 1 with EDA (2) –
background reactionsa
1
2
3
4
5
6
7
8
entry
catalyst b
amine
yield
(%)b
In the excited state H2TPP (4, singlet 0.91 V, triplet 0.42
V) and Zn-4 (singlet 0.79 V, triplet 0.27 V) reduction
potentials in DMSO are similar to those calculated for
Ru(bpy)32+ (0.67 V) and eosin Y (0.83 V),6 but apparently
both are strong enough to act as efficient catalysts in our
model reaction. It is well documented that, once exited,
H2TPP (4) can function as both an oxidant and a reduct-
ant and its redox properties can be tuned by electronic
effects of the substituents on the macrocycle.41,42 This
suggests that porphyrins can also be used as photoredox
catalysts and their catalytic properties can be improved if
required.
1
2
H2TPP (4)
Zn-4
morpholine
morpholine
morpholine
no
84
88
0
3
no
9
4
5c
H2TPP (4) or Zn-4
H2TPP (4) or Zn-4
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
morpholine
0
aReaction conditions: aldehyde 1 (0.5 mmol), morpholine (0.4
equiv.), catalyst (1 mol%, c = 1.25 x 10-3 M), EDA (2, 1 equiv.),
DMSO: buffer pH = 4 (5 mL, 9:1 mixture), 5 h. b Yields were
determined by GC. cNo light
Moreover, Rehm-Weller formalism allows for estimating
the thermodynamic driving force, -ΔGPET(0), for PET be-
tween the enamines and the excited-state porphyrins (see
SI). Because of the irreversible electrochemical oxidation
of the enamines, and solvents used (DMSO:buffer), we do
not have exact values for the potentials for their oxida-
tion. For acetonitrile, the voltammograms show peak
potentials between about 0.3 and 0.6 V vs. SCE for oxida-
tion of enamines.43 For irreversible oxidation the inflec-
tion points, rather than the peak potential, are repre-
sentative for the standard reduction potentials.44 There-
fore, we can assume that the reduction potentials for
oxidation of enamines ranges between about 0.2 and 0.6
V vs. SCE. Furthermore, an increase in the media polarity
causes negative shifts in the potentials of oxidation, mak-
ing the enamines better electron donors; there are also
positive shifts in the potentials of reduction, making the
porphyrins better electron acceptors.45 Therefore, for PET
initiated from the singlet-excited state of the porphyrins,
ΔG most likely assumes negative values of a tens of elec-
tronvolts, making it thermodynamically favorable. Con-
versely, the triplet excited states of the sensitizers lie
about half an electron volt below their singlet states,
which may or may not results in positive values for the
ΔGPET(0) estimates. Therefore, we cannot necessarily claim
a triplet manifold for PET.
Moreover, as porphyrins are able to generate singlet oxy-
gen and/or reactive oxygen species ROS from oxygen,
their presence should diminish the reaction yield.
100
50
0
1
2
3
4
Influence of oxygen
1 - degassed, under Ar 2 - only degassed 3 - open to air 4 - under O2
Figure 1. Influence of oxygen on the yield of the reaction
to give functionalized aldehyde 3a
aReaction conditions: aldehyde 1 (0.5 mmol), morpholine (0.4
equiv.), H2TPP (4, 1 mol%), EDA (2, 1 equiv.), DMSO:buffer pH
= 4 (5 mL, 9:1 mixture), 5 h. Yields were determined by GC.
Indeed, the reaction open to air gave functionalized alde-
hyde 3 in much lower yield (Fig. 1).
In the next step, the reaction conditions were optimized
with respect to the photocatalyst, amine46, pH of the buff-
er used, as well as reaction time and solvents utilized.
The nature of substituents at the periphery of the macro-
cycle greatly affects the value of the half-wave potentials
as well as the magnitude of the HOMO-LUMO gap.41,42,47
Hence porphyrins possessing both electron-withdrawing
and electron-donating substituents were tested as cata-
lysts. Almost all of the free-base porphyrins studied, 4, 6-
13, catalyzed the model reaction of 3-phenylpropanal (1)
with EDA (2), leading to desired the product 3 (Table 2).
However, due to solubility issues (porphyrins are, to a
large extend, poorly soluble in the utilized reaction medi-
um), a direct correlation between reaction yield and elec-
tronic nature of the substituents was not unequivocal.
Free base porphyrin 4 and its zinc complex were found to
be the most effective in catalyzing the model reaction.
Optimization studies. In a preliminary experiment we
tested free base tetraphenylporphyrin (4) and the Zn-
complex as photoredox catalysts for the reaction of 3-
phenylpropanal (1) with ethyl diazoacetate (2, EDA) un-
der conditions developed for the Ru-catalyzed reaction.40
Notably, both reactions gave the desired product 3 in 84
and 88% respectively (Table 1, entries 1, 2). Control exper-
iments confirmed that all reaction components are essen-
tial as the exclusion of any of them halted the reaction
completely (entries 3-5), the aldehyde remained intact
while EDA decomposed or polymerized. Thus, contrary to
the arylation of cumarins, the alkylation reaction is in-
deed induced by white visible light.
As seen in Table 2, the influence of porphyrin ring sub-
stituents Zn-6, Zn-7, and Zn-9 series is clear; as the mac-
rocycle became more electron rich (-CO2Me, Me, -OMe)
the catalytic efficacy of the porphyrin increases (entries 5,
8, 11). The β-substituted protoporphyrin IX, derivative 13,
furnished the product with a reasonable yield of 54%.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 10
Zinc complex Zn-4 exhibiting the best solubility, allowed Subsequently, various amines were studied (Table 4).
1
2
3
4
5
6
7
8
for the use of very low catalytic loading (0.1 mol%) with
only a slight decrease in yield (Table 3, entries 7, 13). This
fact also emphasizes the advantage of porphyrins over Ru-
and Ir- complexes.
Only in the presence of secondary amines did the reaction
furnish the desired product 3. DABCO and NEt3 did not
catalyze the reaction, thus confirming the proposed role
of an amine in the catalytic cycle e.g. the formation of
enamine (entries 6, 7). Surprisingly, among the secondary
amines tested, morpholine proved to be the best with
respect to the reaction yield although it is pyrrolidine that
furnishes more reactive enamines.
Table 2. Porphyrins tested in alkylation reaction.
9
Table 3. Optimization of the catalyst loading a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
entry
catalyst
H2TPP (4)
H2TPP (4)
H2TPP (4)
H2TPP (4)
H2TPP (4)
Zn-4
loading, mol%
yield, %b
1
2
1.5
1.0
0.7
0.4
0.1
2.0
1.5
73
84
63
65
61
3
4
5
6
7
84
90
88
86
86
80
Zn-4
8
9
10
11
Zn-4
1.0
0.8
0.4
0.1
Zn-4
Zn-4
Zn-4
aReaction conditions: aldehyde 1 (0.5 mmol), morpholine (0.4
equiv.), porphyrin (1 mol%), EDA (2, 1 equiv.), DMSO:buffer
pH = 4 (5 mL, 9:1 mixture), 5 h. b Yields were determined by
GC.
Table 4. The influence of an amine useda
48
entry
catalyst
amine
pKb
yield,
%b
entry
catalyst
yield (%)b
1
H2TPP (4)
H2TPP (4)
H2TPP (4)
H2TPP (4)
pyrrolidine
piperidine
piperazine
2.89
2.73
4.19
4.87
57
59
26
24
2
3
4
1
2
H2TPP (4)
84
traces
44
14
5
N
-
3
6
methylpiperazine
morpholine
DABCO
4
7
5
6
H2TPP (4)
H2TPP (4)
H2TPP (4)
Zn-4
5.6
5.2
84
0
5
8
10
6
9
60
8
7
NEt3
3.3
0
7
10
8
pyrrolidine
piperidine
piperazine
2.89
2.73
4.19
4.87
68
83
79
73
8
11
15
9
Zn-4
9
PP-IX, 12
15
10
11
Zn-4
10
11
12
13
14
PP-IX diethyl ester, 13
54
88
0
Zn-4
N-
Zn-4
Zn-6
Zn-7
Zn-9
methylpiperazine
12
Zn-4
morpholine
5.6
88
54
75
aReaction conditions: aldehyde 1 (0.5 mmol), morpholine (0.4
equiv.), porphyrin (1 mol%), EDA (2, 1 equiv.), DMSO:buffer
pH = 4 (5 mL, 9:1 mixture), 5 h. b Yields were determined by
GC.
aReaction conditions: aldehyde 1 (0.5 mmol), morpholine (0.4
equiv.), porphyrin (1 mol%), EDA (2, 1 equiv.), DMSO:buffer
pH = 4 (5 mL, 9:1 mixture), 5 h. b Yields were determined by
GC.
We confirmed that the addition of buffer at pH = 4 as-
sured the highest yield and any deviation from this value
ACS Paragon Plus Environment

Page 5 of 10
Journal of the American Chemical Society
photosensitizers we assumed that such a carbene is
diminished the amount of product formed (Fig. 2). The
1
2
3
4
tendency was even more pronounced for the ZnTPP-
catalyzed reactions, which is understandable as demetal-
lation can occur in acidic conditions.
100
formed.
Scheme
functionalization of aldehydes
3.
Scope
and
limitations
of
α-
5
6
7
8
9
50
0
3
3.5
4
4.5
pH of a buffer
5
5.5
6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
TPP, 4 (1 mol%)
Zn-TPP, Zn-4 (1 mol%)
Figure 2. Influence of pH buffer used in the reactiona
aAldehyde 1 (0.5 mmol), morpholine (0.4 equiv.), H2TPP, (4,
1 mol%), EDA (2, 1 equiv.), DMSO: buffer pH = 4 (5 mL, 9:1
mixture), 5 h. c Yields were determined by GC.
As the reactions are pH dependent, the final step in our
study involved examining Brönsted and Lewis acids as co-
catalysts (for details see SI). The addition of common
Brönsted acids lowered the reaction yield, in the case of
ascorbic acid, which is a known radical scavenger, and no
product formation was observed. Gratifyingly, the addi-
tion of LiBF4 led to further increase in the yield up to
90%.
Scope and limitations studies. Under the described
conditions: aldehyde (1 mmol), morpholine (0.4 mmol),
H2TPP (4) (1 mol%), LiBF4 (20 mol%), EDA (2, 1 mmol), a
mixture of DMSO/buffer (9:1, 10 mL, buffer pH = 4, c = 0.1
M), 5 h, 4 ’household’ LEDs, the scope and limitations of
α-alkylation of aldehydes with diazoesters were explored
(Scheme 3). In general, the reactions gave good yields in
C-H alkylation of aldehydes with diazoesters with differ-
ent functional groups being well tolerated (-Cl and -
OMe). It is noteworthy that unsaturated aldehydes fur-
nished only C-H alkylated compounds (26-29) with no
cyclopropane product being formed. The observed
chemoselectivity creates great possibilities for further
functionalization of compounds possessing double bonds.
However, generation of a quaternary center proved diffi-
cult under the developed conditions and requires further
studies.
Scheme 4. Proposed mechanism for light-induced
functionalization of aldehydes with EDA in the pres-
ence of porphyrin (4)
Mechanistic Considerations
A proposed mechanism for the functionalization of alde-
hydes involves two interrelated catalytic cycles as shown
in Scheme 4. Each reaction component, the amine, pho-
tocatalyst and light, play an important role (Table 1, en-
tries 3-5). It is assumed that the porphyrin acts as both a
photosensitizer and photoredox catalyst. Firstly, H2TPP
(4) under light irradiation is excited from the singlet
ground state to the excited state and as such it can trans-
fer energy to EDA (2) forming carbene in the triplet state
(biradical C) with simultaneous extrusion of nitrogen. It is
known that in the presence of light, carbenes in a singlet
ground state are generated via direct photolysis, while in
the presence of triplet-sensitizers less reactive triplet
carbenes are formed.49 As porphyrins are known triplet
Moreover, EDAs quench porphyrin luminescence as
demonstrated by the Stern-Volmer analysis (Fig. 3). The
reaction yields are inversely proportional to the EDA
quenching rates. This feature is consistent with the pro-
posed mechanism, which requires two parallel processes
involving the sensitizer: 1) the PET for forming the oxi-
dized enamine and 2) the intersystem crossing (ISC) for
the energy transfer needed for the formation of a triplet
carbene. As such, neither of these processes should have
rates which are too fast. If PET is fast and outcompetes
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 10
the processes, energy transfer will not occur efficiently ciently fast PET steps. For the concentrations used in this
1
2
3
4
5
6
7
8
and the C-C bond cannot be formed (no carbene). On the
other hand, if ISC is too fast, PET will not occur hence the
enamine will not be oxidized.
study, the rates of PET are comparable to the nanosecond
decay times of the singlet-excited porphyrins.
EDA
y = 7.7164x + 0.9792
R² = 0.9855
1.45
4-(3-phenylprop-1-enyl)morpholine
3-phenylpropanal
morpholine
3.4
y = 31.284x + 0.8975
R² = 0.9888
2.9
y = 3.2711x + 1.002
R² = 0.9874
y = 22.664x + 0.9953
R² = 0.9887
2.4
1.9
1.4
0.9
y = 0.0212x + 1
R² = 0.9722
y = 0.0095x + 1
R² = 0.9916
9
y = 7.042x + 0.987
R² = 0.9799
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
0.95
0
0.01
0.02
0.03
0.04
0.05
0.06 0.07
[M]
0
0.02
0.04
0.06
0.08
0.1
Figure 4. Stern–Volmer quenching experiment for
H2TPPa
[M]
Porphyrin 9
TPP (4)
Porphyrin 5
aExperiment conditions: for 3-phenylpropanal (1), EDA,
enamine (4-(3-phenylprop-1-enyl)morpholine), and morpho-
line samples were prepared by adding solutions of substrates
to H2TPP (4) in DMSO (total volume 2 mL) and degassed
with Ar. The concentration of H2TPP (4) in DMSO was 3.6 x
10-5 M.
Figure 3. Stern–Volmer quenching experiments for
porphyrinsa
aExperimental conditions: for EDA samples were prepared by
adding solutions of substrates to porphyrins 4, 5, and 9 in
DMSO (total volume 2 mL) and degassed with Ar. The con-
centration of porphyrins 4, 5, and 9 in DMSO were 3.6 x 10-5
M, 3.8 x 10-5 M 3.4 x 10-5 M respectively. For H2TPP τ0 = 9.95
Conversely, for these types of sensitizers, ISC is the prin-
cipal pathway of non-radiative deactivation of their sin-
glet-excited states. Still, because of the inherently long
lifetimes of the triplet excited states, even small quantum
yields of porphyrin triplets will prove sufficient for the
bimolecular energy transfer essential for the formation of
the carbenes for the proposed mechanism. That is, while
the PET, occurring in the nanosecond time domain from
the singlet-excited states of the sensitizers, generates the
oxidized enamines; the triplet energy transfer from the
sensitizer, occurring with considerably smaller rates,
provides the carbenes.
ꢄ ꢅ ꢇꢂꢉ
ꢆ
ꢇꢂꢈ , for porphyrin 9 τ0 = 8.6 ns, kq =
ns, kq = ꢀ. ꢁ ∙ ꢂꢃ
ꢊ. ꢋꢂ ꢌ ꢂꢃꢍꢅꢆꢇꢂꢈꢇꢂꢉ, for porphyrin 5 τ0 = 10.1 ns, kq
ꢂ. ꢃ ꢌ ꢂꢃꢍ ꢅꢆꢇꢂꢈꢇꢂꢉ (for calculations see SI).
=
When both the singlet and triplet exited porphyrin (4)
were quenched with benzoquinone, the model reaction
stopped completely, thus confirming the involvement of a
carbene in the triplet state.49,50 It can react with other
molecules such as radicals or undergo ISC. Concomitantly
an aldehyde reacts with a secondary amine furnishing an
intermediary enamine A which was detected by ESI-MS
1
In accordance with the proposed mechanism reactive
radicals are formed. To confirm their presence, EPR spec-
troscopy experiments were performed.
and H NMR analyses. In MS, the corresponding peak at
204.14 Da [M+H]+ was observed not only when aldehyde 1
was treated with morpholine but also in the reaction
mixture. The 1H NMR spectrum clearly showed character-
istic proton resonances for enamine at 5.95 and 4.56 ppm.
Subsequently, H2TPP (4) in its excited state oxidizes
enamine A to form a porphyrin (4) radical anion and an
active cation radical B which reacts with biradical C fur-
nishing the new radical D. After electron transfer from
the porphyrin radical anion and protonation, the final
product of the reaction is formed. In addition, chain
propagation reactions may likely be also involved.51 The
presence of cation radical B was confirmed by EPR exper-
iments and Stern-Volmer quenching experiments.
11000
1000
-9000
-19000
329
330
331
332
333
334
335
measured
simulated
Figure 5. EPR spectra of the reaction mixture in the
presence of DMPOa
The Stern-Volmer analyses for each of the reaction com-
ponents clearly shows that enamine A and EDA (2) exhib-
it strong, in comparison with morpholine and 3-
phenylpropanal (1), quenching of H2TPP (Fig. 4). This
indicates that the reaction of H2TPP with enamine and
ethyl diazoacetate play a crucial role in the mechanism of
the α- alkylation reaction. Furthermore, the highly effi-
cient quenching of the porphyrin luminescence by
enamines, i.e., the bimolecular quenching constants are
comparable with diffusion-limited rates, indicating suffi-
aReaction conditions: aldehyde 1 (1 equiv., 1 mmol), morpho-
line (0.4 equiv.), H2TPP (4, 1 mol%), EDA (2, 1 equiv.),
DMSO:buffer pH = 4 (10 mL, 9:1 mixture), spin trap DMPO
after 10 min of irradiation with LED.
As the concentration of free radicals in the reaction mix-
ture was too low to be detected directly, EPR measure-
ments were performed with two spin traps N-tert-butyl-α-
ACS Paragon Plus Environment

Page 7 of 10
Journal of the American Chemical Society
(Fig. 7). Two components are present in the simulated
phenylnitrone (PBN) and 5,5-dimethyl-1-pyrroline N-
1
2
3
4
5
6
7
8
oxide (DMPO). The spectra were also simulated using the
EasySpin package in Matlab. First, EPR spectra of the
reaction mixture were recorded after 10 min of irradiation
(Fig. 5 for DMPO, Fig. S1 for PBN in SI). Spectral simula-
tions indicate the presence of three paramagnetic species
with the intensity ratio of the two corresponding compo-
nents being very similar (See SI Fig. S4). To identify these
radical species present, the EPR spectrum of H2TPP (4),
morpholine, and aldehyde (1) with no EDA added was
registered in the presence of spin traps after light irradia-
tion (Fig. 6 and SI Fig. S10).
EPR spectrum. It is known that the thermal decomposi-
tion of diazo compounds leads to the formation of car-
bon-centered radicals that with PBN give adducts with aN
= 1.54 mT and aH = 0.4 mT.52 Our measured parameters of
a dominating component (aN = 1.49 mT and aH = 0.4 mT)
are very similar thus suggesting that the signal corre-
sponds to a radical formed during photolysis of EDA (2),
e.g. radical C. Its hyperfine splitting constants are also
similar to those obtained for PBN-benzoyl radical adduct
in DMSO solution (aN = 1.45 mT and aH = 0.47 mT)53, so its
presence can be considered as an alternative.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 5. Experiment with TEMPO
4400
2400
400
-1600
-3600
-5600
329
330
331
measured
332
333
334
simulated
335
Figure 6. EPR spectra for the mixture of porphyrin (4)
with aldehyde (1) and morpholine in DMSO: buffer
with DMPOa
Hence, the use of two different spin-traps in the EPR
experiments proved beneficial, allowing the detection of
two paramagnetic species B and C, thus supporting the
proposed mechanism. We were not able to detect the
radical D using this technique but the addition of
TEMPO, a radical scavenger, to the reaction mixture
stopped the reaction completely, providing evidence for
the formation of three radical species (B, C, D) as
TEMPO-adducts (30, 31, 32) in the reaction mixture as
detected by MS (Scheme 5).
aReaction conditions: aldehyde 1 (1 equiv., 1 mmol), morpho-
line (0.4 equiv.), H2TPP (4, 1 mol%), DMSO:buffer pH = 4 (10
mL, 9:1 mixture), spin trap DMPO after 10 min of irradiation
with LED.
1100
600
100
CONCLUSIONS
-400
-900
We have demonstrated that porphyrins are effective in
catalyzing the reaction of aldehydes with diazo com-
pounds under light irradiation. Mechanistic studies con-
firmed that the effective reaction requires a dual catalytic
system composed of a photocatalyst and an organocata-
lyst. It is assumed that the porphyrin acts both as a pho-
toredox catalyst and as a photosensitizer.
331
331
332
332
333
333
334
334
335
measured
simulated
Figure 7. EPR spectra of the mixture of TPP (4) with
EDA (2) and PBN
aReaction conditions: H2TPP (4, 1 mol%), EDA (2, 1 mmol
mmol), DMSO:buffer pH = 4 (10 mL, 9:1 mixture), spin
trap PBN after 10 min of irradiation with LED.
Porphyrins can now be added to the list of photoredox
catalysts that are suitable for photoredox catalysis. As
these compounds are easy to synthesize and their optical
and electrochemical properties can be tuned by placing a
variety of electron-donating or electron-withdrawing
substituents at the periphery of the macrocycle, they are
perfectly suited for this role. These findings demonstrate
unexplored venues in both porphyrin chemistry and pho-
tocatalysis.
Two components are present in the simulated EPR spec-
trum. The first one, responsible for 63% of intensity in the
presence of DMPO (aN = 1.40 mT, aHβ = 1.47 mT and aHγ
=
0.20 mT), corresponds to a carbon-centered radical ad-
duct as indicated by the value of aHβ higher than aN value
and a small difference between them suggests the bulki-
ness of a radical. It can be ascribed as an enamine radical
B.
ASSOCIATED CONTENT
Supporting Information is available free of charge via the
Internet at http://pubs.acs.org.
Subsequently the EPR spectrum was measured for a mix-
ture of H2TPP (4) and EDA (2) in the presence of PBN
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 10
Full description of optimization and mechanistic studies,
general procedure, for the α-alkylation of aldehydes, com-
pound characterization (NMR, HRMS, AE), copies of NMR
and EPR spectra
(17) a) Fukuzumi, S. Bull. Chem. Soc. Jpn. 2006, 79, 177. b) Fu-
1
2
3
kuzumi, S.; Mizuno, T.; Ojiri, T. Chem. Eur. J. 2012, 18,
15794. c) Fukuzumi, S., Ohkubo, K., Suenobu, T. Acc.
Chem. Res. 2014, 47, 1455.
(18) Chang, C.-H., Hu, Y.-T., Lo, C.-F., Luo, L., Lin, H.-M., Lin,
C.-Y., Diau, E. W.-G., Wu, T.-K. Int. J. Biol. Sci. 2011, 7,
1203.
4
5
6
7
8
9
AUTHOR INFORMATION
Corresponding Author
(19) Liu, W., Groves, J. T. Acc. Chem. Res. 2015, 48, 1727.
(20)Maldotti, A., Andreotti, L., Molinari, A., Carassiti, V. JBIC
1999, 4, 154.
*dorota.gryko@icho.edu.pl,
Homepage: http://ww2.icho.edu.pl/gryko_group
(21) a) Zhou, C.-Y., Lo, V. K.-Y., Che, C.-M. Handbook of por-
phyrin science. Vol. 21, Chapter 101: Metalloporphyrin-
Catalyzed C-C Bond Formation, World scientific, 2012,
Singapore. b) Rybicka-Jasińska, K.; Ciszewski, Ł. W.;
Gryko, D. J. Porphyrins Phtalocyanines 2016, 20, 76-95. c)
Barona-Castaño, J. C.; Carmona-Vargos, C. C.; Brocksom,
T. J.; de Oliveira, K. T. Molecules 2016, 21, 310. d) Lu, H.-J.;
Zhang, X. P. Chem. Soc. Rev. 2011, 40, 1899. e) Anding, B.
J.; Woo, L. K. Handbook of porphyrin science. Vol. 21,
Chapter 100: An overview of Metalloporphyrin-Catalyzed
Carbon and Nitrogen Group Transfer Reactions, World
scientific, 2012, Singapore.
Author Contributions
Funding Sources
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The support of the Ministry of Science and Higher Education
(DG, grant number N NT204 187139) and the Robert A.
Welch Foundation (K.M.K Grant E-680) are gratefully
acknowledged.
ACKNOWLEDGMENT
Dedicated to Prof. Jonathan S. Lindsey on his 60th birthday.
The authors greatly acknowledge prof. V. Vullev for helpful
discussions.
(22)a) Subbarayan, V.; Jin, L.-M.; Cui, X.; Zhang, X. P. Tetra-
hedron Lett. 2015, 56, 3431. b) Lu, H.-J.; Jiang, H.-L., Hu,
Y.; Wojtas, L.; Zhang, X. P. Chem. Sci. 2011, 2, 2361.
REFERENCES
(23)Du, G.; Mirafzal, G. A.; Woo, L. K. Organometallics 2004,
23, 4230.
(1) Fontecave, M. Angew. Chem. Int. Ed. 2015, 54, 6946.
(2) Peńa-López, M.; Rosas-Hernándes, A.; Beller, M. Angew.
Chem. Int. Ed. 2015, 54, 5006.
(24)Clennan, E. L.; Pace, A. Tetrahedron 2005, 61, 6665.
(25)DeRosa, M. C.; Crutchley, R. J. Coord. Chem. Rev. 2002,
(3) Angnes, R. A.; Li, Z.; Correia, C. R. D.; Hammond, G. B.
351.
Org. Biomol. Chem. 2015, 13, 9152.
(26)Berlicka, A.; Kӧnig, B. Photochem. Photobiol. Sci. 2010, 9,
(4) Meggers, E. Chem. Commun. 2015, 51, 3290.
(5) Brimioulle, R.; Lenhart, D.; Maturi, M. M.; Bach, T. An-
gew. Chem. Int. Ed. 2015, 54, 2.
1359.
(27)Nagasawa, T.; Allakhverdiev, S. I.; Kimura, Y.; Nagata, T.
Photochem. Photobiol. Sci. 2009, 8, 174.
(6) a) Tucker, J. W.; Stephenson, C. R. J. J. Org. Chem. 2012,
77, 1617. b) Douglas, J. J.; Sevrin, M. J.; Stephenson, C. R. J.
Org. Process. Res. Dev. 2016, 20, 1134. c) Staveness, D.;
Bosque, I. B.; Stephenson, C. R. J. Acc. Chem. Res. 2016,
(28)Toyao, T.; Ueno, N.; Miyahara, K.; Matsui, Y.; Kim, T.-H.;
Horiuchi, Y.; Ikeda, H.; Matsuoka, M. Chem. Commun.
2015, 51, 16103.
(29)Lazarides, T.; Sazanovich, I. V.; Simaan, A. J.; Kafentazi,
M. C.; Delor, M.; Mekmouche, Y.; Faure, B.; Reglier, M.;
Weinstein, J. A.; Coutsolelos, A. G.; Tron, T. J. Am. Chem.
Soc. 2013, 135, 3095.
49, 2295-2306. d) Teegardin, K.; Day, J. I.; Chan, J.; Weav-
er, J. Org. Process Res. Dev. 2016, 20, 1156. e) Demissie, T.
B.; Ruud, K.; Hansen, J. H. Orgnometallics 2015, 34, 4218.
(7) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem.
Rev. 2013, 113, 5322.
(30)Inisan, C.; Saillard, J.-Y.; Guilard, R.; Tabard, A.; Le Mest,
Y. New. J. Chem. 1998, 823.
(8) Skubi, K. L.; Blum, T. R.; Yoon, T. P. Chem. Rev. 2016, 116,
(31) a) Xu, J.; Shanmugam, S.; Boyer, C. ACS Macro Lett. 2015,
4, 926. b) Shanmugam, S.; Xu, J.; Boyer, C. J. Am. Chem.
Soc. 2015, 137, 9174. c) Xu, J.; Shanmugam, S.; Fu, C.;
Aguey-Zinsou, K.-F.; Boyer, C. J. Am. Chem. Soc. 2016,
138, 3094.
10035-10074.
(9) a) Nicewicz, D. A.; Nguyen, T. M. ACS Catal. 2014, 4, 355.
b) Fukuzumi, S.; Ohkubo, K. Org. Biomol. Chem. 2014, 12,
6059. c) Pitre, S. P.; McTiernan, C. D.; Scaiano, J. C. ACS
Omega 2016, 1, 66.
(32)Kojima, M.; Oisaki, K.; Kanai, M. Chem. Commun. 2015,
51, 9718.
(10) Romero, N. A.; Nicewicz, D. A. Chem. Rev. 2016, 116,
10075-10166.
(33)Nagib, D. A.; Scott, M. E.; McMillan, D. W. C. J. Am.
Chem. Soc. 2009, 131, 10875.
(11) Kadish, K. M.; Smith, K. M.; Guilard, R. Handbook of
porphyrin science. Vol. 4. Phototherapy, radioimmuno-
theraphy and imaging, World Scientific, 2010, Singapore.
(34)Shih H.-W.; Vander, M. N.; Wal, R. L.; Grange; MacMil-
lan D. W. C. J. Am. Chem. Soc. 2010, 132, 13600.
(12) Imahori, H.; Mori, Y.; Matano, Y. J. Photochem. Photobiol.
C 2003, 4, 51.
(35)Nicewicz, D. A; MacMillan, D. W. C. Science 2008, 322,
77-80.
(13) Whitten, D. G. Rev. Chem. Intermed. 1978, 2, 107.
(14) Fukuzumi, S.; Honda, T.; Kojima, T. Coord. Chem. Rev.
2012, 256, 2488.
(36)Neumann, M.; Füldner, S.; Kӧnig B.; Zeitler K. Angew.
Chem. Int. Ed. 2011, 50, 951.
(37)Arceo, E.; Jurberg, I. D.; Álvarez-Fernández, A.; Melchior-
(15) a) Seely, G. R. Photochem. Photobiol. 1978, 27, 639. b) Ril-
lema, D. P.; Nagle, J. K.; Barringer, L. F.; Meyer, T. J. J.
Am. Chem. Soc. 1981, 103, 56.
re, P. Nat. Chem. 2013, 5, 750-756.
(38)Silvi, M.; Arceo, E.; Jurberg, I. D.; Cassni, C.; Melchiorre,
P. J. Am. Chem. Soc. 2015, 137, 6120.
(16) Gust, D.; Moore, T. A.; Moore, A. L. Acc. Chem. Res.
2009, 42, 1890.
ACS Paragon Plus Environment

Page 9 of 10
Journal of the American Chemical Society
(39)a) Hari, D. P.; Kӧnig, B. Chem. Commun. 2014, 50, 6688.
(45) a) Bao D.; Ramu, S.; Contreras, A.; Upadhyayula, S.;
Vasquez, J. M.; Beran, G.; Vullev, V. J. Phys. Chem. B 2010,
114, 14467; b) Bao D.; Millare, B.; Xia, W.; Steyer, B. G.;
Gerasimenko, A. A.; Ferreira, A.; Contreras, A.; Vullev, V.
I. J. Phys. Chem. A 2009, 113, 1259.
1
2
3
4
5
6
7
8
b) Hari, D. P.; Kӧnig, B. Org. Lett. 2011, 13, 3852.
(40)Rybicka-Jasińska, K.; Ciszewski, Ł. W.; Gryko, D. Adv.
Synth. Catal. 2016, 358, 1671.
(41) Kadish, K. M.; Morrison, M. M. Bioinorg. Chem. 1977, 7,
(46) Kempf, B.; Hampel, N.; Ofial, A. R.; Mayr, H. Chem.
Eur. J. 2003, 9, 2209.
107.
(42) a) Kadish, K. M.; Van Caemelbecke, E. J. Solid State Elec-
trochem. 2003, 7, 254. b) Williams, R. F. X.; Hambright,
P. Bioinorg. Chem. 1978, 9, 537. c) Cui, Y.; Zeng, L.; Fang,
Y.; Zhu, J.; Devillers, C. H.; Lucas, D.; Desbois, N.; Gros,
C. P.; Kadish, K. M. ChemElectroChem 2016, 3, 228. d) Tu,
Y.-J.; Cheng, H. C.; Chao, I.; Cho, C.-R.; Cheng, R.-J.; Su,
Y. O. J. Phys. Chem. A 2012, 116, 1632. e) Xue, S.; Ou, Z.;
Ye, L.; Lu, G.; Fang, Y.; Jiang, X.; Kadish, K. M. Chem. Eur.
J. 2015, 21, 2651. f) Fang, Y.; Bhyrappa, P.; Ou, Z.; Kadish,
K. M. Chem. Eur. J. 2014, 20, 524.
(47)Morrison, M. M.; Kadish, K. M. J. Am. Chem. Soc. 1976,
98, 3326.
(48) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem.
Rev. 2007, 107, 5471.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(49)L’Esperance, R. P.; Ford, T. M.; Jones, M. J. Am. Chem.
Soc. 1988, 110, 209.
(50)Osuka, A.; Maruyama, K. J. Chem. Research 1987, 2401.
(51) Cismesia, M. A.; Yoon, T. P. Chem. Sci. 2015, 6, 5426.
(52)Hiramoto, K.; Johkoh, H.; Sako, K.; Kikugawa, K. Free
Radic. Res. Commun. 1993, 19, 323.
(43)Schoeller, W. W.; Niemann, J.; Rademacher, P. J. Chem.
Soc. Perkin Trans 2 1988, 369.
(53)Janzen, E.G.; Coulter, G.A.; Oehler, U.M.; Bergsma, J.P.
(44) a) Espinoza, E. M.; Larsen, J. M.; Vullev, V. L. J. Phys.
Lett. 2016, 7, 758; b) Larsen, J. M.; Espinoza, E. M.; Hart-
man, J. D.; Lin, Ch-K.; Wurch, M.; Maheshwari, P.;
Kaushal, R. K.; Marsella, M. J.; Beran, G. J. O.; Vullev, V.
L. Pure Appl. Chem. 2015, 87, 779.
Can. J. Chem. 1982, 60, 2725.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 10
Authors are required to submit a graphic entry for the Table of Contents (TOC) that, in conjunction with the man-
uscript title, should give the reader a representative idea of one of the following: A key structure, reaction, equation,
concept, or theorem, etc., that is discussed in the manuscript. Consult the journal’s Instructions for Authors for
TOC graphic specifications.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Insert Table of Contents artwork here
10
ACS Paragon Plus Environment