Visible light flavin photo-oxidation of methylbenzenes, styrenes and phenylacetic acids

Article abstract of DOI:10.1039/c0pp00202j

We report the photocatalytic oxidation of benzylic carbon atoms under mild conditions using riboflavin tetraacetate as photocatalyst and blue-emitting LEDs (440 nm) as light source. Oxygen is the terminal oxidant and hydrogen peroxide appears as the only byproduct in most cases. The process oxidizes toluene derivatives, stilbenes, styrenes and phenylacetic acids to their corresponding benzaldehydes. A benzyl methyl ether and acylated benzyl amines are oxidized directly to the corresponding methyl ester or benzylimides. The mechanism of the reactions has been investigated and the results indicate that oxygen addition to benzyl radicals is a key step of the oxidation process in the case of phenylacetic acids.

Full text of DOI:10.1039/c0pp00202j

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www.rsc.org/pps | Photochemical & Photobiological Sciences
Visible light flavin photo-oxidation of methylbenzenes, styrenes and
phenylacetic acids†
Robert Lechner, Susanne Ku¨mmel and Burkhard Ko¨nig*
Received 29th June 2010, Accepted 5th August 2010
DOI: 10.1039/c0pp00202j
We report the photocatalytic oxidation of benzylic carbon atoms under mild conditions using riboflavin
tetraacetate as photocatalyst and blue-emitting LEDs (440 nm) as light source. Oxygen is the terminal
oxidant and hydrogen peroxide appears as the only byproduct in most cases. The process oxidizes
toluene derivatives, stilbenes, styrenes and phenylacetic acids to their corresponding benzaldehydes. A
benzyl methyl ether and acylated benzyl amines are oxidized directly to the corresponding methyl ester
or benzylimides. The mechanism of the reactions has been investigated and the results indicate that
oxygen addition to benzyl radicals is a key step of the oxidation process in the case of phenylacetic acids.
method was used for the selective photocatalytic removal of benzyl
Introduction
protecting groups,4a and is now extended to flavin-mediated photo-
catalytic oxidation to methylbenzenes, styrenes and phenylacetic
acids. Riboflavin tetraacetate (RFT, see Scheme 1)6 is used as a
readily available and non-toxic photocatalyst; blue light-emitting
high power LEDs serve as a selective and efficient light source.
Flavins have attracted much attention since they are involved in a
large number of biological processes acting as redox co-factors,
such as flavin adenine dinucleotide (FAD) or flavin mononu-
cleotide (FMN)1 and photoreceptors. Besides the application as
flavoenzyme models for biochemical processes,2 synthetic flavin
derivatives have been used as organocatalysts in thermal3 and
photochemical4 oxidation reactions. The latter processes utilize the
increased oxidation power of the isoalloxazine chromophore in its
oxidized form 1 upon excitation by light.5 When an electron donor
is present, the excited triplet form of 1 can undergo subsequent
two electron reduction and protonation to yield dihydroflavin 2,
which is oxidized back to 1 by molecular air oxygen as the terminal
oxidant. In this catalytic process hydrogen peroxide is obtained as
sole stoichiometric by-product (Scheme 1).4
Oxidation of methylbenzenes
The aerobic photochemical oxidation of methylbenzenes under
heterogeneous7 and homogeneous8 reaction conditions has been
described. Yet the use of purely visible light is still the exception.8b,c
Quenching of the excited state of flavin by methyl- and methoxy-
benzenes via electron transfer (ET) has been known for some
time,9 but no products of the ET reactions have been described
so far. We therefore investigated the reaction as a possible C–H
activation pathway to functionalize electron-rich arenes at their
benzyl position.
First encouraging results were obtained by subjecting 4-
methoxytoluene 3a to standard flavin photocatalysis conditions:
0.01 mmol of substrate and 10 mol% RFT were dissolved in 1 mL
solvent and irradiated with blue light (440 nm, 3 W LED) and
the course of the reaction was monitored by GC analysis. Besides
4-methoxybenzaldehyde 3b, the only side product that could be
detected in small amounts by 1H NMR was 4-methoxybenzyl
alcohol 5 as a likely intermediate of the benzyl oxidation.
Starting from this initial result, we optimized the reaction
conditions by varying the solvent and oxygen content (see Table 1).
The oxidation reaction depends heavily on the water content:
nearly no conversion was obtained in pure MeCN, whereas the
yield of aldehyde 4a increased with the increasing portion of water
to reach a maximum at a 1 : 1 mixture of H2O–MeCN. At higher
water content the yield decreased again.10
Scheme 1 Catalytic cycle of aerobic riboflavin tetraacetate (RFT: R =
C13H19O8) mediated photo-oxidation of benzyl alcohols or benzyl amines.
In previous studies we used flavin-mediated photocatalysis for
the oxidation of benzyl alcohols4b,c,e and benzyl amines.4a The
Complete consumption of 3a in H2O–MeCN 1 : 1 required the
addition of another 10 mol% RFT after 20 min of irradiation
time. After 40 min of irradiation 3a was consumed completely and
aldehyde 4a was obtained in 58% yield. Since no other side product
could be detected in appreciable amounts, a parasitic side reaction,
Institute of Organic Chemistry, University of Regensburg, Universita¨tsstr.,
31, 93040, Regensburg, Germany. E-mail: burkhard.koenig@chemie.uni-
regenburg.de; Fax: +49-941-943-1717; Tel: +49-941-943-4575
† Electronic supplementary information (ESI) available: UV-Vis absorp-
tion spectra of RFT 1 during the photo-oxidation of 4-methoxytoluene
3a. See DOI: 10.1039/c0pp00202j
1
giving products that could not be detected by GC and H NMR
analysis, is proposed. From earlier studies it is known that phenolic
compounds are oxidized to not detectable,11 presumable polymeric
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Table 1 Photocatalytic oxidation of 4-methoxytoluene 3a
Yield (%)b
H2O–MeCN/mL
Conditionsa
Irradiation time/min
Aldehyde 4a
Alcohol 5
Starting material 3a
0/1.0
10
10
10
10
10
10
40c
5
10
20
20
20
20
20
5
2
0
0
0
0
4
0
0
4
0
6
0
0
0
0
0
95
49
9
11
29
49
0
33
1
0
65
69
88
90
11
0.2/0.8
0.4/0.6
0.5/0.5
0.6/0.4
0.7/0.3
0.5/0.5
0.5/0.5
0.5/0.5
0.5/0.5
0.5/0.5
0.5/0.5
0.5/0.5
0.5/0.5
0.5/0.5
16
18
28
24
19
58
29
21
51
0
0
0
0
10
O2
O2
O2
no RFT/O2
dark/O2
no RFT
dark
D2O/MeCN-d3/O2
The bold row shows optimized conditions with the best results.a O2: oxygen saturated solution. b Determined by GC. c 20 mol% RFT.
products under flavin-mediated photo-oxidation conditions.4a,12
Hence hydroxylation of the aromatic core by water and subsequent
oxidation to polymeric compounds is proposed.13
The reaction proceeded faster and RFT did not bleach when
the photocatalysis was done in an oxygen-saturated system, but
there was no beneficial effect on the yield of 4a.
Without irradiation as well as when the reaction mixture was
irradiated in the absence of RFT no benzaldehyde 4a was formed.
In some oxidation reactions, 4-methoxybenzyl alcohol 5 was
detected as a side product. Since alcohol 5 is oxidized faster to
aldehyde 4a than toluene 3a,4b alcohol 5 might be an intermediate
in the oxidation of toluene 3a.
To exclude a singlet oxygen oxidation pathway, which flavins can
mediate under photo-irradiation,14 the photo-oxidation reaction
was performed in deuterated solvents. Since the lifetime of
singlet oxygen is significantly prolonged in deuterated solvents
compared to the same non-deuterated solvents,15 the photo-
oxidation reaction should be accelerated in deuterated solvents,
if singlet oxygen formation is involved. The yield of aldehyde 4a
was lower in deuterated compared to non-deuterated solvents at
identical irradiation times, disfavouring a singlet oxygen reaction
pathway and indicating the role of water as reactant. The change
of pKa by changing from H2O to D2O is not decisive since the
reaction is not dependent on the pH value in a certain range.16
The quantum yield of the flavin-mediated photo-oxidation of 4-
methoxytoluene 3a was determined to be 1.1% [c = 0.01 mol L-1
in 2 mL of H2O–MeCN 1 : 1, O2 purged].
We then applied the oxidation conditions to a variety of methyl-
benzenes. The results are summarized in Table 2. The conversion
rate of methylbenzenes depends on the electronic character of the
arene: benzene rings bearing electron donating substituents lead
to a faster conversion, while more electron poor arenes are not
active at all. This is in accordance with previous observations on
flavin-mediated photo-oxidation of benzyl alcohols and benzyl
amines.4a,b Toluene, benzyl bromide and ethyl benzene are not
electron rich enough to be oxidized by flavin photo-oxidation.
Fluorene 3d gave fluorenone 4d as oxidation product in 16% yield.
Tetrahydronaphthalene 3e was oxidized to a-tetralone 4e in 34%
yield. Unreacted starting material was only partly recovered, which
indicates competing polymerization processes as described above.
Treating of triphenylmethane as well as triphenylmethanol
with these oxidation conditions did not yield any oxidation
products, whereas more electron rich 4-methoxytriphenylmethane
3f underwent oxidative degradation to benzophenone 4f in 24%
and 4-methoxybenzophenone 4g in 35% yield. This kind of
oxidative degradation is known from triphenylmethane radicals
derived from triphenylmethyl halides17 or triphenylmethane.18 It
was proposed that the triphenylmethane radical cation that is
formed after initial ET to excited flavin loses a proton to form
a triphenylmethyl radical. This is quenched by oxygen to form a
peroxy radical that collapses into benzophenone and phenol.18
To gain more data on possible intermediates formed during the
flavin-mediated photo-oxidation of 3a, we followed the course of
the UV-Vis absorption of RFT under aerobic, oxygen saturated
and anaerobic conditions (see ESI†). Strong bleaching of the RFT
1 absorption in the visible region with elongated irradiation times
was observed. A 50% bleach of the absorption band at 446 nm
is obtained after about 90 s of irradiation. No recovery of the
bleached signals was obtained when the system was purged with
air after the irradiation. Therefore the obtained flavin species is not
reduced RFT 2. The same course of RFT 1 bleaching was observed
when the reaction was followed in an oxygen saturated system,
besides bleaching of RFT 1 slowing down. The 50% bleach of RFT
1 was retarded to roughly 150 s irradiation time. The irradiation
of the reaction mixture under anaerobic conditions showed a fast
bleaching of RFT 1. When the mixture then was purged with air a
blue flavin species developed, exhibiting two absorption maxima
at 601 nm and 629 nm. We assign this spectrum to a neutral N5
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Table 2 Photocatalytic oxidation of methylbenzenes in MeCN–H2O 1 : 1
Entry
1
Irradiation timea/min
165
Starting material
Product(s)
Yield (%)b
40c
2
3
270
100
43c
16
4
5
100
60
34
24c,d
35
a The reaction mixtures were irradiated until RFT was completely bleached. b Determination of yield by GC. c 20 mol% RFT. d MeCN–H2O 3 : 2.
Scheme 2 Proposed mechanism for flavin-mediated photo-oxidation of methylbenzenes.
alkyl flavin radical.19 This radical was stable in the dark at least
for some minutes, but decayed quickly under irradiation.
Scheme 2 and 3 show possible pathways of flavin-mediated
methylbenzene photo-oxidation by considering the presented
results.
The initial step in the photo-oxidation process is an ET from
methylbenzene 3a to RFT in the triplet excited state.9 The so-
formed radical ion pair of radical cation 6 and RFT∑- can either
collapse via back ET to 3a and RFT 1 or follow two different
productive pathways: Either the attack of water on the radical
cation 6 to give phenol 7 that is further oxidized by flavin to
presumable polymeric compounds or the radical cation 6 that is a
strong acid (pKa of toluene radical cation in MeCN was estimated
by Arnold20a to be -13 and -12 by Green20b) loses a proton to
∑
give benzyl radical 8 (Scheme 2). Benzyl radical 8 and RFT- can
recombine to form covalent intermediates.19 The C4a adduct 9
collapses under irradiation and oxygen present to aldehyde 4a and
RFT.19j,k The N5 adduct 10 is oxidized by oxygen in a dark reaction
to form the observed neutral radical 11. The radical is undergoing
an ET and subsequently fragments to RFT 1 and benzyl alcohol
5 (Scheme 3).19j,k Whether benzyl alcohol 5 is the outcome of an
intermediate benzyl cation that is trapped by water or generated
via a concerted mechanism is not known.
The electron donating methoxy group on the arene in the case of
4-methoxytoluene 3a stabilizes the initially formed radical cation
6.8c,9,21,22 The proposed ET pathway is further supported by the
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Table 3 Photocatalytic oxidation of trans-stilbene
Yield (%)b
H2O–MeCN/mL
Conditionsa
Irradiation time/min
Benzaldehyde 4h
cis-Stilbene 13
trans-Stilbene 12a
0/1.0
5
5
1
5
5
1
1
5
69
19
0
Traces
13
Traces
42
2
10
Traces
5
11
28
38
2
72
98
88
70
70
0.4/0.6
0.4/0.6
0.4/0.6
0.4/0.6
0.4/0.6
0.4/0.6
no RFT
in dark
O2
D2O/MeCN-d3
a O2: oxygen saturated solution. b Determination of yield by GC.
Scheme 3 Formation of covalent intermediates and decomposition to products in the photo-oxidation of methylbenzenes.
critical role of water as solvent: the triplet reduction of flavin
proceeds via a dipolar intermediate. The degree of ET product
formation depends on the extent of solvent interaction. With its
high dielectric constant, water is stabilizing the formed separated
radical cations 6 and RFT∑-.23 Secondly, when the proton is not
directly transferred from radical cation 6 to RFT∑-, water acts as
a base or proton relay, promoting the rate limiting deprotonation
step of radical cation 6 to form benzyl radical 8.22a,b Additional the
reoxidation of flavin from its reduced state 2 to its oxidized state 1
is faster in water compared to MeCN.24
benzaldehyde 4h in 69% yield (considering the production of 2 eq.
of benzaldehyde 4h from the oxidation of 1 eq. stilbene 12a) within
5 min of irradiation time, leaving only 2% of starting material 12a
and 2% of cis-stilbene 12b (Table 3).
When the oxidation was performed in pure MeCN only 5% of
benzaldehyde 4h was detected within 5 min irradiation time, but
42% of cis-stilbene 13 was observed. The formation of 10% cis-
stilbene 13 already after 1 min is indicative that trans-stilbene 12a
is oxidized to benzaldehyde 4h as well. Whether cis-stilbene 13
is a general intermediate in the photo-oxidation process cannot
be concluded from this data. No reaction was observed when
the reaction mixture was irradiated without RFT and only traces
of benzaldehyde 4h were formed when the reaction mixture was
stirred in the dark. Oxygen saturation of the solution had no
beneficial effect on the reaction rate of the photo-oxidation and
only traces of benzaldehyde 4h were formed when the reaction was
done in deuterated solvents for 1 min. The non-dependency on the
oxygen content and the large effect of the solvent are indicative that
water, but not oxygen is participating in the rate determining step.
The quantum yield of the flavin-mediated photo-oxidative
cleavage of trans-stilbene 12a was determined to be 1.1% [c =
0.01 mol L-1 in MeCN–H2O 4 : 3].
Oxidation of phenylenes
The photo-oxidative cleavage of stilbenes and styrenes has been
of great interest for some time.25 Studies towards the flavin-
photosensitization of stilbene have been undertaken, but only the
trans-cis isomerisation of stilbene has been observed.26 An example
of double bond oxidation by flavin sensitization is the oxidation of
unsaturated fatty acids in MeCN that yielded hydroperoxides of
fatty acids. It was proposed that the oxidation proceeds by a type
II (singlet oxygen) mechanism.27 To our delight, applying flavin
photo-oxidation conditions to trans-stilbene 12a, we obtained
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Table 4 Photocatalytic oxidation of phenylenes
at least partially, as oxygen atom source in the flavin-mediated
oxidation of tolane 14 to benzil 15.
Oxidation of stilbene 12a in a MeOH–MeCN mixture yielded
benzaldehyde 4h as main product, but benzoic acid methyl ester
16 and O-methylbenzoin 17 could be detected by GC-MS as well.
A comparable reactivity was observed when the reaction was
performed in an AcOH–MeCN mixture: benzaldehyde 4h was
obtained as the main product, but diester 18 and O-acetylbenzoin
19 were formed as well (Scheme 5). These results clearly indicate
the role of the solvent acting as a nucleophile in the course of the
oxidation reactions.
To gain more insight into the mechanism of the oxidative
cleavage of stilbenes, trans-stilbene oxide, meso-hydrobenzoin 25
and benzoin 31 as potential intermediates, were subjected to the
standard reaction conditions. All three compounds did not yield
benzaldehyde 4h as oxidation product within 1 min irradiation
time, excluding the compounds as possible intermediates. In the
case of trans-stilbene oxide no benzaldehyde 4h was formed even
after 60 min irradiation, whereas meso-hydrobenzoin 25 was
oxidatively cleaved in 60% to benzaldehyde 4h within the same
irradiation time. Benzoin 31 did not react even after 60 min
irradiation as judged by TLC. Since meso-hydrobenzoin 25 is not
a likely intermediate in the flavin-mediated photo-oxidation of
stilbene 12a, the proposed mechanism by Fry et al.29 for anodic
cleavage of stilbenes is not valid for our system.
A singlet oxygen reaction pathway can be excluded, since it is
known that stilbene is not oxidized by singlet oxygen.25j,k
Quenching of the radical cation 21 of stilbene radical cation
20 is not likely since oxygen hardly reacts with radical cations of
aromatic olefins.30 It has been shown that alkene radical cations
behave as cations when reacting with nucleophiles,31 which are in
our case water, MeOH or acetic acid. The so-formed benzyl radical
22 can now react with oxygen yielding peroxy radical 23, which
undergoes fragmentation to benzaldehyde 4h (Scheme 6). The
reaction mechanism is in accordance to the proposed mechanism
of Velasco et al. for the oxidative cleavage of stilbene in aqueous
solution under aerobic conditions.32
Entry
Starting material
Product/s
Yield (%)a
1
2
R1: OMe, R2: C6H4-4-OMe 12b
R1:NO2, R2: C6H4-4-OMe 12c
R: OMe 4a
R: OMe 4a
R: NO2 4i
R: H 4h
36b
69c
64
3
R1: H, R2: COOH 12d
68d
a Determination of yield by GC. b MeCN–H2O 24 : 1. c MeCN–H2O 5 : 3.
d 20 mol% RFT.
Next, we applied flavin-mediated photocatalytic oxidation to
electron rich symmetrical stilbene 12b and unsymmetrical stilbene
12c (Table 4). As expected, the symmetrical stilbene 12b was
oxidized to 4-methoxybenzaldehyde 4a in 36% yield within 80 min
irradiation time. The slow conversion and the low yield might be
attributed to the poor solubility of 12b and hence the low water
content of the reaction mixture. The unsymmetrical stilbene 12c
was oxidized within the same time to 4-methoxybenzaldehyde 4a
in 69% and 4-NO2 benzaldehyde 4i in 64% yield.
Styrene, a-methyl styrene and 4-methoxystyrene did not yield
the desired benzaldehydes. No products or starting material could
be detected with GC-MS, due to polymerization of the starting
compounds under the experimental conditions. When b-nitro
styrenes were subjected to the photocatalytic oxidation conditions,
oxidative cleavage did not take place.
Photocatalytic oxidation reaction of tolane 1428 gave benzil 15
as sole oxidation product in 28% yield leaving 2% of starting tolane
14 (Scheme 4). When the oxidation of tolane 14 was done in 18
O
labelled water (10.5% 18O content), the isotope peak with m/z =
212.1 (benzil m/z = 210.1) was found in a relative abundance of a
factor 5.8 higher compared to a sample obtained from non-labelled
water as confirmed by EI-MS. This indicates that water is acting,
A second ET from benzyl radical 22 to flavin seems not likely
since the so-formed carbocation 24 would give meso-hydrobenzoin
25 upon reaction with water or stilbene oxide which were excluded
as intermediates.
For the oxidation of tolane 14 to benzil 15, meso-hydrobenzoin
25 and trans-stilbene oxide were excluded as intermediates, since
submitting these compounds to our oxidation conditions did not
yield benzil 15. From these results a reaction pathway in analogy
to stilbene oxidation is proposed (Scheme 7). Here, peroxy radical
Scheme 4 Photocatalytic oxidation of tolane 14.
Scheme 5 Photocatalytic oxidation of stilbene 12a in organic solvents.
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Scheme 6 Proposed mechanism for flavin-mediated photo-oxidation of stilbene 12a.
Scheme 7 Proposed mechanism for flavin-mediated photo-oxidation of tolane 14.
ketone 29 instead of the alcohol 23 is formed, which collapses to
benzil 15.
As in the case of photo-oxidation of methylbenzenes and
styrenes, the oxidation of diphenylacetic acid 32a to benzophenone
4f was dependent on the water content: the higher the water
content, the higher the reaction rate. Oxygen saturation of the
system had an inhibitory effect and the yield of benzophenone 4f
decreased (Table 5).
The reaction was accelerated when it was performed open to
air in a non-closed sample vial as compared to the closed system.
Full conversion of diphenylacetic acid 32a to benzophenone 4f in
an open reaction system was achieved within 20 min irradiation
time. Whether the oxygen availability or the rising partial pressure
of CO2 in the head space upon expelling of CO2 from the
substrate is the limiting factor cannot be concluded from the
collected data. No incorporation of 18O was observed when the
reaction was done in 18O labelled water (10.5% 18O content).
Deuteration of the solvents did not have any impact on the photo-
oxidation. These findings are different to the observations on
the flavin-mediated oxidations of methylbenzenes, styrenes and
tolane and indicate that dissolved oxygen is acting as oxygen
The parasitic side reaction of hydroxylation of intermediate rad-
ical cations as it was proposed for the oxidation of methylbenzenes
(Scheme 2) seems to be true for the flavin mediated oxidation of
phenylenes and tolane as well. These reaction pathways are not
shown in the Schemes.
Oxidation of phenylacetic acids
Phenylacetic acid 32b was photo-oxidized yielding aldehyde 4h.
This decarboxylative photo-oxidation reaction of phenylacetic
acids is known.33 Anaerobic photo-decarboxylation of phenylac-
etate by excited flavin with accompanying benzylation of the flavin
core19j,k,34 and oxidative decarboxylation of dihydrophthalates35
has been described. Photo-decarboxylation of a-hetero carboxylic
acids by flavin has been reported as well.36 We have optimized the
reaction conditions of this flavin-mediated decarboxylation for
synthetic preparative use.
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Table 5 Oxidation of phenylacetic acids
H2O–
Irradiation
Starting material MeCN/mL Conditionsa
time/min Yield (%)b
R1: H, R2:Ph 32a 0/1.0
0.25/0.75
5
5
5
5
5
5
5
5
2
4
24
34
11
8
0.5/0.5
0.7/0.3
0.5/0.5
0.5/0.5
0.5/0.5
0.5/0.5
0.5/0.5
0.5/0.5
O2
HCl
NaOH
open to air
open to air
22
32
>99
no 18
20
H218O (10.5%) 20
O
Scheme 8 Proposed mechanism for flavin-mediated photo-oxidation of
diphenylacetic acid 33.
labelled 4fc
0.5/0.5
0.5/0.5
R1: OMe, R2:H 32c 0.5/0.5
D2O/MeCN-d3
open to air
open to air
5
30
10
31
45
43
R1: H, R2:H 32b
oxygen present in solution yielding peroxy radical 36, which
yields benzophenone 4f under these reaction conditions. The
decarboxylation is very efficient and the yield of the reaction is
nearly quantitative. No parasitic side reaction as described for the
oxidation of methylbenzenes, phenylenes and tolane was observed.
The occurrence of intermediate benzyl radical 35 is supported
by the anaerobic photo-oxidation of diphenyl acetic acid in dry
MeCN (Scheme 8).37 Tetraphenyl ethane 37 was identified as main
product that most likely results from the dimerization of two
diphenylmethyl radicals 35.
Benzyl ether 38a and the acylated benzyl amines 38b and 38c
were investigated for comparison. They are photo-oxidized to
yield the ester or imides as summarized in Table 6. The acylated
benzylamine 38b was converted in an acetonitrile–water mixture
into imide 39b in 83% yield, while the methyl ether 38a and the
tetrahydroisoquinoline derivative 38c showed less conversion and
lower yields under these conditions. Using methanol as solvent and
a O2: oxygen saturated solution, HCl: 0.001 N HCl instead of H2O, NaOH:
0.001 N NaOH instead of H2O. b Determination of yield by GC. c 18O was
not incorporated into benzophenone 4f.
source in the flavin-mediated photo-oxidation of diphenylacetic
acid 32a.
With the same protocol phenylacetic acid 32b was oxidized
to benzaldehyde 4h in 45% yield within 30 min. The more
electron rich 2-methoxyphenylacetic acid 32c was oxidized to the
corresponding aldehyde 4j in 43% yield already within 10 min of
irradiation.
From the obtained data, a reaction pathway for the decar-
boxylative oxidation of phenylacetic acid is proposed as shown
in Scheme 8. The deprotonated diphenylacetic acid 33 under-
goes an ET to excited flavin. The so-formed radical cation
34 decarboxylates to give benzyl radical 35 that is trapped by
Table 6 Oxidation of 4-methoxybenzyl methyl ether and acylated benzylamines
Starting material
Product
Solvent
Irradiation time/min
Conversion (%)a
Yield (%)a
CH3CN–H2O 1 : 1
MeOH (abs.)
MeOH
30
180
3 d
95
100
100
55
76b
86c
CH3CN–H2O 1 : 1
MeOH (abs.)
30
180
100
95
83
69
CH3CN–H2O 1 : 1
MeOH (abs.)
30
180
49
100
28
70
a Determination of conversion and yield by GCMS. b 6% 4-methoxybenzyldehyde dimethylacetal as side product. c 7 times 10 mol% additional RFT, side
product: 14% 4-methoxybenzyldehyde dimethylacetal.
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applying longer irradiation times the conversion of the substrates
was complete and product yields increased significantly. However,
the conversion and yield of 38b decreased under these conditions.
We noticed a rapid fading of flavin in the methyl ether 38a photo-
oxidation in methanol and the reaction was performed adding
eight times RFT. This improves the yield of the reaction to 86%.
for 30 s through a canula. The capped vial was irradiated at 440 nm
(3 W LED).
For GC analysis the sample was diluted with water (1 mL) and
extracted with ethyl acetate (3 ¥ 1.5 mL). The organic layer was
subjected to GC measurements.
General procedure for flavin-mediated photo-oxidations in H218O
(10.5% 18O)
Conclusions
The sample was prepared as described above using H218O (10.5%
18O) instead of H2O. After irradiation, MeCN was removed under
a stream of nitrogen. The residue was diluted with water (1 mL)
and extracted with ethyl acetate (3 ¥ 1.5 mL). The organic layer
was dried over MgSO4 and filtered. The concentrated filtrate was
subjected to EI-MS measurements.
The flavin-mediated photo-oxidation of benzylic carbon atoms
in hydrocarbons, alkenes, carboxylates, ethers and amines was
investigated. The potential of methylbenzenes as quenchers for
excited flavins has been observed before, but the formation of
aldehydes or ketones as oxidation products has not been described
so far. The electron density of the arene moiety is crucial for the
rate of oxidation: electron poor and very electron rich arenes
are not converted to the corresponding aldehydes, whereas 4-
methoxytoluene 3a could be oxidized in 58% to anis aldehyde
4a.
The oxidative cleavage of stilbene 12a and cinnamic acid 12d
to benzaldehyde 4h and the oxidation of tolane 14 to benzil
15 by flavin mediated oxidation are reported for the first time.
However, the moderate yields of the photocatalytic oxidations due
to competing polymerization limit their synthetic application.
The photo-oxidative decarboxylation of phenyl acetic acids by
flavin has been known to produce aldehydes. Conditions to achieve
quantitative product yields have been found.
Based on literature evidence and the results presented here,
reaction mechanisms for the flavin photocatalyzed oxidation of
methylbenzenes, stilbenes, tolane and phenyl acetic acids are
proposed. For all compound classes reported here, the initial step is
ET from the substrate to the excited flavin. The experimental data
do not indicate an oxidation via singlet oxygen (Type II oxidation).
Other reaction mechanism after the initial ET step than the
suggested one cannot completely be excluded on the basis of
our data. In addition, it is likely that different reaction pathways
compete and ratios vary with changes in reaction conditions and
substrate.
While some of the described conversions may already find
application in organic synthesis, the majority is currently limited
by narrow applicability or moderate product yields. The use of
flavin photocatalysts with substrate binding sites may increase the
selectivity and efficiency of some of the photo-oxidations.
Acknowledgements
We thank the graduate research training group GRK 1626
“Chemical Photocatalysis” of the German National Science Foun-
dation (DFG) for support of this work. S.K. thanks the German
Environmental Foundation (DBU) for a graduate scholarship.
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under N2, irradiation with LED for 30 min (440 nm, 3 W).
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