Exploiting photooxygenations mediated by porphyrinoid photocatalysts under continuous flow conditions

Article abstract of DOI:10.1039/c6ra00285d

Photooxygenation reactions are a powerful synthetic tool to produce oxidized organic compounds; however, these reactions often exhibit experimental limitations including the production of complex mixtures that hinder desired product isolation and scale-up. Herein, we present a photocatalysed protocol under continuous flow conditions using a simple home built photoreactor and porphyrinoids as photocatalysts. Reaction conditions, long-term experiments, and scope demonstrate a protocol that is cost-effective, safe, reproducible and robust, thus allowing the production of relevant substituted naphthoquinones with interest in natural product synthesis and biological activity.

Full text of DOI:10.1039/c6ra00285d

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Exploiting photooxygenations mediated by
porphyrinoid photocatalysts under continuous
Cite this: RSC Adv., 2016, 6, 12717
flow conditions†
ab
a
a
*
*
L. Zane Miller and D. Tyler McQuade
Kleber T. de Oliveira,
Photooxygenation reactions are a powerful synthetic tool to produce oxidized organic compounds;
however, these reactions often exhibit experimental limitations including the production of complex
mixtures that hinder desired product isolation and scale-up. Herein, we present a photocatalysed
protocol under continuous flow conditions using a simple home built photoreactor and porphyrinoids as
photocatalysts. Reaction conditions, long-term experiments, and scope demonstrate a protocol that is
cost-effective, safe, reproducible and robust, thus allowing the production of relevant substituted
naphthoquinones with interest in natural product synthesis and biological activity.
Received 5th January 2016
Accepted 22nd January 2016
DOI: 10.1039/c6ra00285d
www.rsc.org/advances
most prominent processes since signicant improvements have
been accomplished at the micro- and meso-scale, and success-
Introduction
ful reaction classes improved using these techniques due to the
high efficiency of light irradiation and enhanced safety.10
Regarding the photooxygenations of naphthols, previous
work performed in batch conditions has been published,13 as
Photooxygenation reactions have an important role in synthetic
chemistry due to their high atom-economy and low cost.1 Over
the last ve decades researchers have recognized that singlet
oxygen is the key excited intermediate for generating oxygen-
ated compounds such as hydroperoxides,2 peroxides,3 dioxe-
tanes,4 endoperoxides5 and sulfoxides.6
well as preliminary versions of photochemical ow devices. The
14
¨
pioneering work of Oelgemoller and co-workers showed the
possibility to use both plug-ow and parallel falling lms for
photooxygenations under different continuous ow conditions.
However, both methodologies and devices of these previous
work displayed limitations and required many reaction cycles,
high concentrations of photosensitizers (up to 5 mol%) with low
conversions in some cases,14c inspiring us to explore improved
and cost-competitive conditions for this continuous ow
photooxygenation.
Herein, we have built and applied a simple, yet effective in-
house engineered photoreactor to perform a comprehensive
study of the photooxygenation of naphthols (Scheme 1).
Different porphyrinoid and phthalocyanine derivatives were
evaluated as photosensitizers (0.1–0.5 mol%), achieving high
efficiency. Scope, robustness, and most importantly, scalability
with a 24 h extended experiment are presented under contin-
uous ow conditions, which allowed the production of relevant
substituted naphthoquinones of interest in natural product
synthesis and with well-recognized biological activities.15
The generation of singlet oxygen using photosensitizers is
well-known.7 While many photosensitizers have been
described,8 porphyrin derivatives are one of the most efficient
classes of compounds for this purpose as supported by recent
and relevant applications in organic synthesis.5,9
Since their discovery, photooxygenation processes have pre-
sented restrictions for their use in large scale reactors due to
limitations imposed by the potential to form explosive inter-
mediates, thus requiring the use of high dilutions and small
scales. However, this limitation has recently been addressed by
utilization of ow-based approaches to carry out photochemical
transformations.10 Current advances in chemical synthesis
under continuous ow conditions have in fact changed the way
in which reactions are developed and scaled up in the phar-
maceutical industry and research laboratories.11 Numerous
advantages have been provided such as controlled mixing, fast
heat transfer, control of residence time and process automa-
tion.12 Particularly, photochemical and photocatalysed trans-
formations accelerated under continuous ow are one of the
Results and discussion
aFlorida State University, Department of Chemistry and Biochemistry, Tallahassee, FL,
First, in order to elucidate the best conditions for these pho-
tooxygenations, we constructed the photoreactor shown in
Fig. 1 and S1 (ESI†). We used a reexive aluminium-plate
adapted with connections for a lamp with fan cooling, and
a glass cylinder to coil the PFA (peruoroalkoxy) tubing (for
32306-4390, USA. E-mail: tylermcquade@gmail.com
b
˜
´
˜
Universidade Federal de Sao Carlos, Departamento de Quımica, 13565-905, Sao
Carlos, SP, Brazil. E-mail: kleber.oliveira@ufscar.br; Web: http://www.lqbo.ufscar.br
† Electronic supplementary information (ESI) available: Copy of 1H and 13C NMR
spectra. See DOI: 10.1039/c6ra00285d
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Scheme 1 Photocatalytic cycle and photosentizers for the photooxygenation of 1.
Fig. 1 Flow chemistry setup for photooxygenations.
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details, Fig. S1†). For process optimization we selected 5-
hydroxynaphthol (1) to yield juglone (2) (Scheme 1).
We began the optimization by pumping of 100 mL of 3 mM
solution of 1 with 0.1 mol% of the photocatalyst tetraphe-
nylporphyrin (3) under three different plug-ow conditions
(Table 1) in order to select the best ow rate and light source for
the transformations (Scheme 1 and Fig. 1).
Using the FLC lamp (45 W) the best result was obtained with
a ow rate of 0.75 mL minꢀ1 (entry 2, Table 1) considering the
yield, residence time, and space-time yield (STY). Similarly, the
use of white LED lamp (24 W) and a ow rate of 0.75 mL minꢀ1
(entry 5, Table 1) produced the best result in terms of yield,
residence time and STY, and requiring approximately half of the
energy compared to the FLC source (24 W vs. 45 W). The
superiority of the white LED lamp can be explained by the
comparison of the emission and absorption spectra (Fig. 2) for
each light source and the porphyrin 3. Specically, the broad
emission band of white LED source (480–700 nm) encompasses
the entire visible region of the absorption spectrum of 3 (500–
670 nm).
Fig. 2 Comparison between the emission spectra of light sources and
absorption spectra of 3.
Another parameter which highlights this preference is the
productivity of the photocatalyst which is almost two times
greater for 0.3 mol% photocatalyst loading. The selected
conditions to proceed with the methodology study are shown in
entry 4, Table 3, since greater concentrations of substrate (up to
10 mM) required amounts of photocatalyst 3 (mol%) which
caused precipitation to occur (entries 5, 8 and 9, Table 3). It is
Thus, from the rst six experiments it was possible to
suggest the ow rate of 0.75 mL minꢀ1 as the most adequate
due to the productivity, and also because the most signicant
increase of STY was found in the range of 0.5 to 0.75 mL minꢀ1
.
It is important to highlight that the reproducibility was also
evaluated by performing each reaction twice (Table 1) with only
minor variations of 1–3% yield, as observed in Table 1.
Aer establishing the best light source, different photo-
catalyst concentrations were examined from 0.1 to 0.5 mol% at
three different ow rates (Table 2). From the results we
conclude that 0.3 and 0.5 mol% are the best photosensitizer
concentrations, but it was not clear if the use of 0.5 mol% would
furnish the best cost-benet.
important to highlight that this optimized amount of TPP (3)
(0.3 mol%, US dollars 33.1 mmolꢀ1
)
is advantageous
16
compared to similar photooxygenation procedures found in the
literature14 using bengal rose ($5 mol%, US dollars 40.4
mmolꢀ1).16
Aer screening to nd the best ow rate and substrate/
photocatalyst concentrations we decided to evaluate different
photocatalysts including additional porphyrinoids 4–6 and the
phthalocyanine 7 (Table 4). Different photoactivities were
observed most likely due to the different ability of these
photosensitizers (3–7) to produce singlet oxygen since nearly
the entire absorption spectra of 3–7 (Q-bands, 500–700 nm)
were covered by the emission spectra of the LED lamp (430–700
nm). Clearly, the simplest and most cost-competitive photo-
catalyst 3 proved to be the most efficient giving us all of the
Subsequently, different concentrations of substrate
1
(Table 3) were assessed from 3.0 to 12.0 mM while maintaining
the ow rate at 0.75 mL minꢀ1 and employing two different
photocatalyst concentrations (0.3 and 0.5 mol%). Comparing
the experiments from entries 1–5 and 6–9, very similar yields
and STY were observed between all comparable entries,
however, the use of lower amounts of photocatalyst (0.3 mol%,
entries 1–5, Table 3) were decisive for the choice of 0.3 mol% as
the most ideal catalyst loading.
Table 1 Screening of light source and flow rate for the continuous flow photooxygenation of 1a,b
Juglone (2) yield (%)
Visible light
source
Solution ow
Residence time
(min)
STY (2)c
(g per day)
Entry
rate (mL minꢀ1
)
1st
2nd
Avg
1
2
3
4
5
6
FLC, 45 W
FLC, 45 W
FLC, 45 W
LED, 24 W
LED, 24 W
LED, 24 W
0.50
0.75
1.00
0.50
0.75
1.00
52
58
48
75
58
43
55
60
49
72
56
43
53
59
48
74
57
43
25.0
16.7
12.5
25.0
16.7
12.5
0.20
0.33
0.36
0.28
0.32
0.32
a
Reactions performed by using 100 mL of a solution of the substrate 1 at 3.0 mmol Lꢀ1, photocatalyst 3 at 0.1 mol% in CH3CN : CH2Cl2 (95 : 5), 1
b
cm plug-ow (regular oxygen and solution) in a 25 mL PFA tubing photoreactor (0.125 in (OD) ꢁ 0.065 in (ID)). Isolated yield by column
chromatography. c Considering the average yield (Avg).
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Table 2 Screening of photocatalyst 3 mol% by using 24 WLED lamp for the continuous flow photooxygenation of 1a
Juglone (2)
Juglone (2)
Juglone (2)
Juglone (2)
Solution ow
yield (%) using TPP
(3) at 0.1 mol%
yield (%) using TPP
(3) at 0.2 mol%
yield (%) using TPP
(3) at 0.3 mol%
yield (%) using TPP
(3) at 0.5 mol%
Entry
rate (mL minꢀ1
)
1
2
3
0.50
0.75
1.00
73
57
43
81
71
60
85
80
75
85
83
81
a
Reactions performed by using 100 mL of a solution of the substrate 1 at 3.0 mmL Lꢀ1, photocatalyst 3 in different concentrations in
CH3CN : CH2Cl2 (95 : 5), 1 cm plug-ow (regular oxygen and solution) in a 25 mL PFA tubing photoreactor (0.125 in (OD) x 0.065 in (ID)).
Table 3 Screening of the substrate concentration using LED 24 W lamp for the continuous flow photooxygenation of 1a
Substrate
TPP (3) as
photocatalyst (mol%)
Juglone (2)
yield (%)
STY (2)
(g per day)
Productivity mmol product
per mmol catalyst per h
Entry
1 mmol Lꢀ1
1
2
3
3.0
6.0
9.0
10.0
12.0
3.0
6.0
9.0
12.0
0.3
0.3
0.3
0.3
0.3
0.5
0.5
0.5
0.5
80
85
85
82
78
83
83
83
78
0.45
0.96
1.44
1.54
1.76
0.47
0.93
1.41
1.76
120
128
128
123
117
75
75
75
70
4
5b
6
7
8b
9b
a
Reactions performed by using 100 mL of a solution of the substrate 1, photocatalyst 3 at 0.3 mol% or 0.5 mol% in CH3CN : CH2Cl2 (95 : 5),
solution ow rate (0.75 mL minꢀ1), 1 cm plug-ow (regular oxygen and solution) in a 25 mL PFA tubing photoreactor (0.125 in (OD) ꢁ 0.065 in
b
(ID)). In these conditions it was observed a small amount of TPP (3) as a precipitate aer the experiment with no serious blockage of the
pump system.
Table 4 Screening of the different photocatalysts 3–6 in the photooxygenation of 1a
Photocatalysts
at 0.3 mol%
Juglone (2)
yield (%)
STY juglone (2)
(g per day)
Productivity mmol product
per mmol catalyst per h
Entry
1
2
3
4
5
3
4
5
6
7
82
15
72
6
1.54
0.28
1.35
0.11
0.34
123
22
108
9
18
27
a
Reactions performed by using 100 mL of a solution of the substrate 1 at 10.0 mmol Lꢀ1, different photocatalysts at 0.3 mol% in CH3CN : CH2Cl2
(95 : 5), solution ow rate (0.75 mL minꢀ1), 1 cm plug-ow (regular oxygen and solution) in a 25 mL PFA tubing photoreactor (0.125 in (OD) ꢁ 0.065
in (ID)).
optimized parameters required to advance the scope of this naphthol derivatives containing electron-donating groups are
photooxygenation protocol. Before continuing with the scope of invariably more reactive than the ones with electron-
this protocol, we decided to showcase the robustness of this withdrawing groups, which is consistent with the accepted [4
method and performed two 24 h experiments using the opti- + 2] pericyclic mechanism for this photooxygenation.1,13
mized conditions (substrate 1 at 10 mM, TPP 3 at 0.3 mol%, ow
Comparing entries 1 and 3 (Table 5) the starting materials 1
rate at 0.75 mL minꢀ1 in CH3CN : CH2Cl2 95 : 5, and 1 cm plug- and 8 yielded the expected corresponding naphthoquinones 2
ow of oxygen and solution). Juglone (2) was obtained in both and 19, respectively, with the same yield (82%) under contin-
experiments in 72% (1.35 g) and 74% (1.40 g) yield, respectively, uous ow conditions, compared to 59% yield obtained for 18
proving this protocol as reproducible and in agreement with (entry 2, Table 5). Also, the yields for batch conditions (using the
STY (1.54 g) for these conditions (entry 4, Table 3).
same residence time, 16.7 min) were substantially lower than
In order to evaluate the scope, we selected different naphthol under continuous ow, providing a real advantage with the use
derivatives 8–17 containing various substituent groups in of this photoreactor.
different positions (Table 5). The rst general result is that
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Table 5 Scope of the photooxygenations under continuous flow and batch conditionsa
Entry
Substrate
Product and yield (%) under continuous ow conditionsb
Product and yield (%) in batch conditionsb,c
1
2
3
4
5
No reactiond
No reactione
6
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Table 5 (Contd.)
Entry
Substrate
Product and yield (%) under continuous ow conditionsb
Product and yield (%) in batch conditionsb,c
7
No reactionf
No reactionf
8
9
No reactionf
No reactionf
10
11
a
All the reactions under continuous ow conditions were performed using the optimized conditions: LED lamp 24 W, 10 mM solutions of the
substrates in CH3CN : CH2Cl2 (95 : 5) (100 mL), TPP (3) at 0.3 mol%, solution ow rate ¼ 0.75 mL minꢀ1, 1 cm plug-ow (oxygen-solution),
b
c
residence time ¼ 16.7 min, 25 mL photoreactor. Isolated yields by using column chromatography. Reactions performed using the residence
d
time of the comparable continuous ow conditions (16.7 min). An attempt to run this reaction under continuous ow conditions was
e
performed, but due to the low solubility of the starting material it was not possible to nish it because the blockage of the system. An attempt
to perform this reaction in batch conditions was performed but no products were observed aer 1 h. f Starting material totally recovered.
The activated 6-hydroxynaphthol (10) (entry 4, Table 5) yiel- unreactive in both ow and batch reactions, but the equivalent
ded 20 in 46% yield under continuous ow conditions together reduced compound 14 furnished the corresponding product 22
with minor by-products which were difficult to separate. In an under both ow (75% yield) and batch (7% yield) conditions
identical reaction performed using batch conditions only traces (entry 8, Table 5). The deactivated compound 15 also did not
of 20 could be identied.
react (entry 9, Table 5), however, both compounds 16 and 17
Compound 11 was submitted to photooxygenation under yielded the corresponding naphthoquinone 18 (8 and 26% yield,
both ow and batch conditions, but unsuccessfully, most likely respectively) under continuous ow conditions together with
due to the very low solubility of this compound (entry 5, Table 5). many by-products (entries 10 and 11, Table 5). It is important to
On the other hand, the corresponding acetylated compound 12 highlight in entry 11 (Table 4) that we were able to isolate the
yielded the corresponding naphthoquinone 21 in both ow brominated derivative 23 in 22% yield under continuous ow
(72% yield) and batch (8% yield) conditions (entry 6, Table 5). conditions, and we conclude that this was most likely possible via
Similarly, the deactivated naphthol 13 (entry 7, Table 5) was reaction of 18 and HOBr produced during the process.
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stabilization of the plug-ow (ca. 1 cm each) using the desired
ow rate of acetonitrile and oxygen. The product was also pro-
tected from external light and collected until the end of
pumping process, when pure acetonitrile was used to clean the
photoreactor maintaining the same initial ow rate. Aer
recovering all of the reaction mixture, acetonitrile was distilled
off under vacuum followed by purication by simple silica-gel
plug ltration using CH2Cl2 as eluent or mixtures of solvents
as specied in each example. In general, 50–70% of the pho-
tocatalyst was recovered, and the main product was easily iso-
lated aer the solvent evaporation.
Conclusions
In summary, we have developed an optimized protocol for
photooxygenation of activated naphthols, screening some por-
phyrinoids as photocatalysts and many parameters under
continuous ow conditions. In addition, we have shown the
applicability and safety of this very simple device in process
intensication by using mild and cost-competitive conditions to
produce valuable compounds in gram-scale. Previous efforts
described in the literature presented limitations requiring
many reaction cycles due to the engineered devices or the
photocatalysts which were used. Herein we have presented
a simple and efficient solution for these problems allowing the
production of relevant naphthoquinone derivatives in only one
reaction cycle with short optimized residence time (16.7 min).
General procedure for experiments under batch conditions
A solution of naphthol (1 or 8–17) (1.0 mmol) was prepared in 10
mL of acetonitrile and sonicated for 2 min. Aer this was
completed, 85 mL of oxygenated acetonitrile (previously
bubbled with oxygen for 10 min) was added, and a solution of
photocatalyst (0.3 mol%) in 5 mL of CH2Cl2 was added last. The
reactions were carried out in a 250 mL Pyrex® round-bottom
ask using the same LED lamp (24 W) from the ow photo-
reactor kept as close as possible to the round-bottom ask (see
Fig. S3 – ESI†). A slow magnetic stirring and oxygen bubbling
was used and the reaction maintained under irradiation for 16.7
min (the same residence time for comparison – Table 5). Aer
the reaction, acetonitrile was distilled off under vacuum fol-
lowed by purication by simple silica-gel plug ltration using
CH2Cl2 as eluent or mixtures of solvents as specied in each
example. When obtained, the main product was easily isolated
aer the solvent evaporation.
Experimental section
All reagents and solvents were purchased from Aldrich or
national US suppliers. When necessary, solvents and reagents
were puried using standard procedures.17 Porphyrins 3–6 were
obtained as described in the literature.7f,11r Phthalocyanine 7
was purchased from Sigma-Aldrich.
1H and 13C NMR spectra were recorded with a Bruker Avance
600 spectrometer at 600 and 150 MHz, respectively. CDCl3 or
DMSO-d6 was used as solvent and TMS (tetramethylsilane) as
the internal reference. The chemical shis are expressed in
d (ppm) and coupling constants (J) are given in Hertz (Hz). The
UV-vis spectra were recorded with a Perkin-Elmer Lambda 25
spectrophotometer using 1 cm optical length quartz cuvettes at
25 ꢂC and dichloromethane as solvent. Emission spectra of FLC
and LED lamps were recorded an Ocean Optics Spectrometer
HR2000CG-UV-NIR. MS analysis were performed using HP
model 5973 mass selective detector with HP model 6890 + gas
General data and yields reported for results from Table 5
5-Hydroxynaphthalene-1,4-dione (2).14 Purication over
silica gel using CH2Cl2 as eluent, Rf ¼ 0.52, 82% yield (142.5 mg,
ꢂ
chromatograph; scanned from 50 to 550 amu; T ¼ 70 C for 3
1
ꢀ1
0.819 mmol). H NMR (600 MHz, CDCl3) d (ppm): 6.96 (s, 2H);
min and then to 300 C at 30 ꢂC min
.
ꢂ
7.28 (dd, J ¼ 7.8 Hz and J ¼ 1.5 Hz, 1H); 7.62 (dd, J ¼ 7.8 Hz and J
¼ 1.5 Hz, 1H); 7.65 (t, J ¼ 7.8 Hz, 1H); 11.91 (s, 1H). 13C NMR
(150 MHz, CDCl3) d (ppm): 114.9; 119.1; 124.5; 131.7; 136.5;
138.6; 139.6; 161.4; 184.2; 190.2.
All continuous ow experiments were carried out using
a micro HPLC pump from ThalesNano and an in-house engi-
neered photoreactor as specied in the ESI.† Analytical thin-
layer chromatography was performed on glass plates (3 ꢁ 6
cm, 1 mm thick), Merck TLC silica-gel 60 F254.
Naphthalene-1,4-dione (18).18 Purication over silica gel
using CH2Cl2 : hexanes 6 : 4 as eluent, Rf ¼ 0.38, 59% yield (94.0
1
mg, 0.594 mmol). H NMR (600 MHz, CDCl3) d (ppm): 6.99 (s,
General procedure for experiments under continuous ow
conditions
2H); 7.75–7.79 (m, 2H); 8.08–8.12 (m, 2H). 13C NMR (150 MHz,
CDCl3) d (ppm): 126.4; 131.9; 133.9; 138.7; 185.0.
A solution of naphthol (1 or 8–17) (0.3–1.2 mmol) was prepared
2-Methylnaphthalene-1,4-dione (19).19 Purication over
in 10 mL of acetonitrile and sonicated for 2 min. Aer this was silica gel using CH2Cl2, Rf ¼ 0.65, 82% yield (141.1 mg, 0.819
1
completed, 85 mL of oxygenated acetonitrile (previously mmol). H NMR (600 MHz, CDCl3) d (ppm): 2.21 (s, 3H); 6.84–
bubbled with oxygen for 10 min) was added, and a solution of 6.86 (m, 1H); 7.71–7.76 (m, 2H); 8.05–8.08 (m, 1H); 8.09–8.12
photocatalyst (0.1–0.5 mol%) in 5 mL of CH2Cl2 was added last. (m, 2H). 13C NMR (150 MHz, CDCl3) d (ppm): 16.4; 126.1; 126.5;
The reaction mixture was protected from light with an 132.2; 132.3; 133.6 (2C); 135.7; 148.2; 185.0; 185.6.
aluminium foil and the solution pumped into the photoreactor
6-Hydroxynaphthalene-1,4-dione (20).20 Purication over
in different ow rates, as specied. The plug-ow was per- silica gel using CH2Cl2 : MeOH 9.5 : 0.5, Rf ¼ 0.50, 46% yield
1
formed using a commercial oxygen cylinder adapted with (79.3 mg, 0.455 mmol). H NMR (600 MHz, DMSO-d6) d (ppm):
a manometer (0–250 bar) and an intermediate valve for the ne 6.97 (d, J ¼ 10.2 Hz, 1H); 7.00 (d, J ¼ 10.2 Hz, 1H); 7.18 (dd, J ¼
adjustment of oxygen pressure (1.5–2.0 bar depending on the 8.7 Hz, J ¼ 2.5 Hz, 1H); 7.28 (d, J ¼ 2.5 Hz, 1H); 7.86 (d, J ¼ 8.7
solution ow). All reactions were started only aer previous Hz; 1H); 11.0 (br s, 1H). 13C NMR (150 MHz, DMOS-d6) d (ppm):
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111.6; 120.8; 123.7; 128.9; 133.7; 138.2; 139.0; 162.8; 183.6;
185.0.
T. Glasnov and C. O. Kappe, Chem.–Eur. J., 2015, 21, 4368;
(f) T. S. A. Heugebaert, C. V. Stevens and C. O. Kappe,
ChemSusChem, 2015, 8, 1648; (g) Z. Amara, J. F. B. Bellamy,
R. Horvath, S. J. Miller, A. Beeby, A. Burgard, K. Rossen,
M. Poliakoff and M. W. George, Nat. Chem., 2015, 7, 489.
N-(5,8-Dioxo-5,8-dihydronaphthalen-1-yl)acetamide (21).21
Purication over silica gel using hexanes : ethyl acetate 6 : 4, Rf
1
¼ 0.60, 72% yield (154.9 mg, 0.720 mmol). H NMR (600 MHz,
´
´
¨
CDCl3) d (ppm): 2.31 (s, 3H); 6.93 (d, J ¼ 10.2 Hz); 6.96 (d, J ¼
10.2 Hz, 1H); 7.74 (dd, J ¼ 8.5 Hz, J ¼ 1.1 Hz); 7.83 (dd, J ¼ 7.5
Hz, J ¼ 1.1 Hz, 1H); 9.09 (dd, J ¼ 8.5 Hz, J ¼ 1.1 Hz); 11.87 (br s,
1H). 13C NMR (150 MHz, CDCl3) d (ppm): 25.6; 116.0; 121.9;
126.0; 132.2; 135.7; 138.0; 139.9; 141.3; 169.9; 184.4; 189.1.
2-(1-Hydroxyethyl)naphthalene-1,4-dione (22).22 Purication
over silica gel using CH2Cl2 : ethyl acetate 9.5 : 0.5, Rf ¼ 0.30,
6 J. Dad'ova, E. Svobodova, M. Sikorski, B. Konig and
R. Cibulka, ChemCatChem, 2012, 4, 620.
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A. J. Bortoluzzi, Y. Iamamoto and O. A. Serra, J. Org. Chem.,
2011, 76, 8824; (b) C. M. B. Carvalho, T. J. Brocksom and
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1
75% yield (152.1 mg, 0.752 mmol). H NMR (600 MHz, CDCl3)
d (ppm): 1.52 (d, J ¼ 6.4 Hz, 3H); 2.49 (d, J ¼ 4.9 Hz, 1H); 5.02
(ddq, J ¼ 6.4 Hz, J ¼ 4.9 Hz, J ¼ 1.5 Hz, 1H); 7.01 (d, J ¼ 1.5 Hz,
1H); 7.74–7.78 (m, 2H); 8.06–8.12 (m, 2H). 13C NMR (150 MHz,
CDCl3) d (ppm): 22.6; 65.3; 126.2; 126.5; 131.9; 132.2; 132.9;
133.8; 134.0; 152.7; 185.3; 185.6.
¨
V. F. Ferreira, S. Hackbarth, B. Roder, T. T. Tasso,
2-Bromonaphthalene-1,4-dione (23).23 Purication over silica
gel using CH2Cl2, Rf ¼ 0.69, 22% yield (42.0 mg, 0.265 mmol).
1H NMR (600 MHz, CDCl3) d (ppm): 7.53 (s, 1H); 7.75–7.82 (m,
2H); 8.08–8.12 (m, 1H); 8.17–8.20 (m, 1H). 13C NMR (150 MHz,
CDCl3) d (ppm): 126.9; 127.8; 130.9; 131.7; 134.1; 134.4; 140.1;
140.4; 177.9; 182.4. MS: m/z (relative intensity): [M+] 238 (90);
[M+] 236 (90); 157 (100); 129 (90); 101 (70).
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Acknowledgements
The authors would like to thank (McQuade projects: Clinton
Health Access Initiative, Corning Glass, Gates Foundation, and
˜
¨
NSF (CHE-1152020)), and the Sao Paulo Research Foundation 10 (a) M. Oelgemoller and O. Shvydkiv, Molecules, 2011, 16,
(FAPESP) for the nancial support for K. T. de Oliveira (BPE
fellowship 2014/25538-6) and laboratory founding in Brazil
(2013/06532-4 and 2013/07276-1). Thalesnano is thanked for
providing the micro HPLC pump used in this work. Thanks are
also due to Prof. T. J. Brocksom (UFSCar) and R. O. M. A. de
Souza (UFRJ) for helpful discussions and to MsC. P. B. Momo
and Dr M. C. Donatoni for the porphyrin synthesis.
7522; (b) J. P. Knowles, L. D. Elliott and K. I. Booker-
Milburn, Beilstein J. Org. Chem., 2012, 8, 2025; (c)
K. Gilmore and P. H. Seeberger, Chem. Rec., 2014, 14, 410;
¨
(d) Y. Su, N. J. W. Straathof, V. Hessel and T. Noel, Chem.–
Eur. J., 2014, 20, 10562; (e) M. Hurevich, J. Kandasamy,
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