Aggregation effects in visible-light flavin photocatalysts: Synthesis, structure, and catalytic activity of 10-arylflavins

Article abstract of DOI:10.1002/chem.201202488

A series of 10-arylflavins (10-phenyl-, 10-(2′,6′- dimethylphenyl)-, 10-(2′,6′-diethylphenyl)-, 10-(2′,6′- diisopropylphenyl)-, 10-(2′-tert-butylphenyl)-, and 10-(2′,6′- dimethylphenyl)-3-methylisoalloxazine (2 a-f)) was prepared as potentially nonaggrega

Full text of DOI:10.1002/chem.201202488

DOI: 10.1002/chem.201202488
Aggregation Effects in Visible-Light Flavin Photocatalysts:
Synthesis, Structure, and Catalytic Activity of 10-Arylflavins
[a, b]
ˇ
Jitka Dadovꢀ,
Susanne Kꢁmmel,[a] Christian Feldmeier,[a] Jana Cibulkovꢀ,[c]
Richard Pazout,[c] Jaroslav Maixner,[c] Ruth M. Gschwind,[a] Burkhard Kçnig,[a] and
ˇ
Radek Cibulka*[b]
ꢀ
Abstract: A series of 10-arylflavins (10-
phenyl-, 10-(2’,6’-dimethylphenyl)-, 10-
(2’,6’-diethylphenyl)-, 10-(2’,6’-diisopro-
pylphenyl)-, 10-(2’-tert-butylphenyl)-,
and 10-(2’,6’-dimethylphenyl)-3-methyl-
isoalloxazine (2a–f)) was prepared as
potentially nonaggregating flavin pho-
tocatalysts. The investigation of their
structures in the crystalline phase com-
bined with 1H-DOSY NMR spectro-
scopic experiments in CD3CN, CD3CN/
D2O (1:1), and D2O confirm the de-
creased ability of 10-arylflavins 2 to
form aggregates relative to tetra-O-
acetyl riboflavin (1). 10-Arylflavins 2a–
d do not interact by p–p interactions,
which are restricted by the 10-phenyl
ring oriented perpendicularly to the
isoalloxazine skeleton. On the other
weak C H···O bonds and weak p–p in-
teractions were found. 10-Arylflavins 2
were tested as photoredox catalysts for
the aerial oxidation of 4-methoxyben-
zyl alcohol to the corresponding alde-
hyde (model reaction), thus showing
higher efficiency relative to 1. The
quantum yields of 4-methoxybenzyl al-
cohol oxidation reactions mediated by
arylflavins 2 were higher by almost one
order of magnitude relative to values
in the presence of 1.
ꢀ
hand, N3 H···O hydrogen bonds were
detected in their crystal structures. In
the structure of 10-aryl-3-methylflavin
(2 f) with a substituted N3 position,
Keywords: aggregation · flavins ·
noncovalent interactions · organo-
catalysis · oxidation · photocatalysis
Introduction
that cannot be oxidized thermally.[5–14] Until now, flavins
have been applied to the photooxidation of benzyl alco-
hols,[5] benzyl amines,[6] and methylbenzenes[7] to benzalde-
hydes; the photooxidation of benzyl methyl ethers to methyl
benzoates;[7] the photooxidation of dopamine,[8] amino
acids,[9] indols,[10] unsaturated lipids and fatty acids,[11] glu-
cose,[12] and phenols;[13] and the selective photocatalytic re-
moval of benzylic protecting groups.[14] The photooxidation
reactions mentioned are usually performed in the presence
of air, thus allowing the regeneration of the flavin catalyst
Fl from its dihydro form Fl-H2, which is formed from flavin
in the excited state Fl* in the presence of a substrate
(quencher) by a subsequent two-electron reduction and pro-
tonation process. Therefore, only a catalytic amount of
flavin is required (Scheme 1). Flavins are also known to sen-
sitize singlet oxygen production.[15] Until now, flavin-mediat-
ed sulfoxidation reactions[16] and oxidation reactions of un-
saturated lipids[17] that are proceeded by a singlet-oxygen
mechanism have been reported.
Flavins (isoalloxazines) are biologically active compounds
that are responsible for redox processes in many types of
enzyme, mostly in the form of flavin mononucleotide or
flavin adenin dinucleotide cofactors.[1] Besides, synthetic
flavin analogues are the subject of intensive research as or-
ganocatalysts of oxidation and reduction reactions.[2,3] The
redox activity of flavin derivatives is dramatically enhanced
by absorption of visible light; the longest wavelength ab-
sorption maximum is at around lmax =450 nm.[4] Thus, the
photoexcitation of flavins enables the oxidation of substrates
ˇ
[a] J. Dadovꢀ, S. Kꢁmmel, C. Feldmeier, Prof. Dr. R. M. Gschwind,
Prof. Dr. B. Kçnig
Institute of Organic Chemistry
University of Regensburg
Universitꢂtsstrasse 31, 93040 Regensburg (Germany)
ˇ
[b] J. Dadovꢀ, Dr. R. Cibulka
In almost all studies, the photooxidation of benzyl alco-
hols to benzaldehydes in acetonitrile was studied as a typical
procedure to elucidate the efficiency of the flavin photocata-
lyst. The activity of simple flavins, for example, tetra-O-
acetyl riboflavin (1) and lumiflavin (see Figure 1 for the
structures), in the oxidation of 4-methoxybenzyl alcohol in
acetonitrile is very low, with quantum yields of up to
0.03%.[5c,18] Several attempts to improve the efficiency of
flavins have recently been reported. Substantially higher
quantum yields of the oxidation of benzyl alcohol were ach-
Department of Organic Chemistry
Institute of Chemical Technology, Prague
Technickꢀ 6, 166 28 Prague (Czech Republic)
Fax : (+420)220-444-288
E-mail: cibulkar@vscht.cz
ˇ
[c] J. Cibulkovꢀ, Dr. R. Pazout, Dr. J. Maixner
Central Laboratories
Institute of Chemical Technology, Prague
Technickꢀ 6, 166 28 Prague (Czech Republic)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202488.
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Chem. Eur. J. 2013, 19, 1066 – 1075

FULL PAPER
Figure 2. Structure of 10-arylflavins synthesized and investigated as pho-
tocatalysts.
eton due to ortho substitution, thus making p–p interactions
between flavins less possible. Compound 2a, without substi-
tution on the phenyl ring, and the 3-methyl derivative 2 f
were prepared for comparison. The photochemical, electro-
chemical, and aggregation properties; crystal structures; and
ability to mediate the photooxidation of 4-methoxybenzyl
alcohol (model reaction) of arylflavins 2 were studied and
compared with those of 1.
Scheme 1. Catalytic cycle for the aerobic photooxidation of a substrate S
mediated by flavin Fl.
Results and Discussion
Synthesis: The synthesis of 10-arylisoalloxazines
2
(Scheme 2) was started by converting commercially availa-
ble substituted anilines 3a–e with 6-chlorouracil (4a) into 6-
arylaminouracils 5a–e. It is evident from the reaction condi-
Figure 1. Structure of the flavin compounds typically used in photocataly-
sis.
ieved if the flavin photocatalyst was protonated or coordi-
nated to rare-earth metal ions, with the highest value of
17% in the case of a scandiumACHTNUGRTNEUNG
(III) complex.[5g,h,l] Also, thio-
urea accelerated the photooxidation of benzyl alcohol medi-
ated by flavins and reached a high turnover number (TON)
of up to 580.[5c] A remarkable improvement in the catalytic
efficiency of the flavin moiety was achieved by its covalent
attachment to ZnII–cyclen or a b-cyclodextrin substrate-
binding site.[5d,f] The reaction medium enhances the photo-
oxidation if performed in sodium dodecyl sulfate (SDS) mi-
celles.[5e] A positive effect of water on the rate of photooxi-
dation reactions mediated by flavins has also been de-
scribed.[5a,d,18] Immobilization of flavins on fluorinated silica
gel stabilizes the chromophore.[5b]
Scheme 2. Synthesis of 10-arylflavins 2.
Besides hydrogen bonding, flavins are known to interact
with several molecules by p–p stacking,[19] donor–p interac-
tions,[20] and cation or anion–p interactions.[21] These interac-
tions are essential not only for the binding of flavin cofac-
tors in proteins, but also to modulate their redox properties
and, consequently, the reactivity of flavin moieties in biolog-
ical systems.[19f,21] The effect of noncovalent interactions on
the properties of flavins in artificial systems is also well
documented.[19,20] There is evidence for flavin dimer forma-
tion, even in dilute solutions,[22] and such intermolecular ag-
gregation may decrease the photocatalytic efficiency of fla-
vins by quenching excited states or alter their redox proper-
ties.[5a] With the aim of minimizing the ability of flavins to
aggregate, we prepared a series of derivatives 2b–e, with an
ortho-substituted phenyl ring in position 10 (Figure 2). The
aryl ring should be oriented perpendicular to the flavin skel-
tions and yields (Table 1) that the substitution becomes
more difficult with increasing steric hindrance of the sub-
stituents on C2 and C6 of the phenyl ring. Although the
nonsubstituted phenyl derivative 5a was obtained almost
Table 1. Reaction conditions and yields for the preparation of 6-aminour-
acils 5 by the reaction of 6-chlorouracil (4a) with substituted anilines 3.[a]
6-Aminouracil
T [8C]
Reaction time [h]
Yield [%]
5a
5b
5c
5d
5e
150
180
180
200
180
1
1
7
24
10
98
74
58
75
57
[a] A mixture of 4a and 3 was heated in a nitrogen atmosphere (see the
Supporting Information for further details).
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1067

R. Cibulka et al.
quantitatively, sterically hindered aminouracils were isolated
only in moderate yields (i.e., 5c and 5e) or after a substan-
tially longer reaction time (i.e., 5d).
The analysis of the X-ray crystallographic data showed
ꢀ
pairs of symmetrical hydrogen N H···O bonds between the
pyrimidine rings of two adjacent molecules of flavins 2a–d
ꢀ
The prepared aminouracils 5a–e were converted into the
target flavins 2a–e by reaction with nitrosobenzene in acetic
acid/acetic anhydride (1:1). Although this synthetic ap-
proach was effective for the synthesis of other sterically hin-
dered flavins,[3c,23] derivatives 2 were obtained in relatively
low yields (13–25%). Unfortunately, the yield did not in-
crease even when acetic acid and acetic anhydride in other
ratios were used as the solvent. The 3-methyl derivative 2 f
was prepared in an analogous process by using 6-chloro-3-
methylaminouracil (4b; Scheme 2). Interestingly, the conver-
sion of 6-arylamino-3-methyluracil (5 f) into 3-methylflavin
(2 f) proceeded in a substantially higher yield relative to the
formation of 2b (44 versus 23%, respectively), which pos-
sesses a nonsubstituted N3 position.
(Figure 3a–d). Additionally,
H···O12A hydrogen bond in the structure of 2c and weak
a
relatively short N3B
ꢀ
C H···O interactions in 2a–d contribute to the aggregation.
ꢀ
ꢀ
Hydrogen bonds C16 H···O11 in 2b (Figure 3b) and C22
H···O12 in 2d (Figure 3d), with participation of the hydro-
gen atoms on the (alkyl)phenyl ring on one hand, and hy-
ꢀ
drogen bond C7B H···O11B in 2a (Figure 3a), with partici-
pation of the hydrogen atoms on the isoalloxazine skeleton
on the other hand, can be given as examples (see the Sup-
porting Information for all the hydrogen-bonding data). In
ꢀ
contrast to flavins with a free N3 H bond (2a–d), com-
pound 2 f cannot form N-H···O bonds, and thus relatively
ꢀ
weak C H···O interactions dominate in the crystal structure
of 2 f (Figure 3e). Methyl groups on both the N3 atom and
ꢀ
the aryl ring participate in these C H···O bonds. However,
Crystal structures: The interaction of flavin molecules in the
crystal can provide information about the aggregation be-
havior in the solution. For this purpose, crystals for single-
crystal analysis were prepared of 2a–d and 2 f. Interestingly,
of the five structures only two 2b and 2d exhibited one mol-
ecule in the asymmetric unit, as could be expected. Three
structures 2a, 2c, and 2 f possessed two different molecules
A and B in the asymmetric unit. A close inspection of the
structures with A and B molecules showed that a significant
difference between the two molecules was displayed only by
2c, in which one ethyl group of the ortho-substituted phenyl
ꢀ
despite the presence of the ortho,ortho-disubstituted phenyl
ring with perpendicular orientation toward the isoalloxazine
skeleton (Table 2), little overlap of the flavin subunits that
results in a weak p–p interaction was found in the structure
of 2 f (Figure 3 f). The distance between the neighboring
planes in the stack is about 3.5 ꢄ.
The investigation of the structure in the crystalline phase
confirms that 10-arylflavins 2 have no structural prerequi-
sites to interact by mean of strong p–p interactions and to
form stacks in a similar manner to simple flavin mole-
cules.[24] One could speculate about the situation in solution
due to the conformational flexibility of the molecules.
Flavin 2a may show rotation of the phenyl ring; however,
this behavior is strongly limited by the ortho substituents in
2b–f. Therefore, only partial overlap of the isoalloxazine
skeletons (e.g., by one ring) that results in a weak p–p inter-
action could be expected in solution. As was shown in fla-
voenzyme models, the binding constants based on the over-
lap of one or three rings of the flavin skeleton with an aro-
matic compound can differ by a factor of 30.[19g]
ring of the molecule B was rotated around the CACTHNUTRGNEUG(N phenyl)
CH2 bond by 83.9(1)8 (Figure 3c). In the structure of 2 f,
molecules A and B differed only by a slightly different rota-
tion of the phenyl ring (Table 2). In the case of the structure
2a, no marked difference between molecules A and B was
observed.
Structures of several simple flavin derivatives have al-
ready been investigated by X-ray diffraction.[24] In most
cases, p-stacking interactions between the isoalloxazine moi-
eties were recognized, which results in the packing of flavin
molecules with distances of between 3.3 and 3.6 ꢄ. In such
stacked systems, flavin molecules adopt an alternating orien-
tation, and the benzene ring of one flavin moiety overlaps
with the pyrimidine ring of the adjacent one (and vice
versa). Tetra-O-acetyl riboflavin (1),[24d] 3-methyl-tetra-O-
acetyl riboflavin,[24a] 3-benzyllumiflavin,[24b] and 10-methyli-
soalloxazine[24e] are examples of such stacked structures in
the crystal phase. As expected, no p–p interactions between
flavin moieties were found in the structures of 10-arylflavins
2b–d, even in the case of 2a with the unsubstituted phenyl
ring, in which a coplanar orientation of the phenyl and isoal-
loxazine subunits was still allowed. In the structures of fla-
vins 2a–d, the aryl ring is almost perpendicular to the mean
plane of the isoalloxazine fragment, with a dihedral angle
that ranges from 78.4 to 86.58, thus preventing the stacking
of flavins (see Table 2, Figure 3, and the Supporting Infor-
mation). A similar value of the dihedral angle of 79.78 was
reported for 10-(2-hydroxyphenyl)-3-methylisoalloxazine.[25]
Aggregation properties determined by 1H-DOSY NMR
spectroscopy: H-DOSY NMR experiments[26] were used to
1
measure the diffusion coefficients of 1 and arylflavins 2 in
CD3CN, D2O, and CD3CN/D2O (1:1). The resulting aggrega-
tion numbers calculated from the experimental diffusion co-
efficients (see the Experimental Section and Supporting In-
formation) are presented in Table 3. A significant aggrega-
tion for 1 was detected in CD3CN, with an average aggrega-
tion number of 3.0, which decreased upon the addition of
water down to monomers in pure D2O. Next, the aggrega-
tion trends for arylflavins 2a–f were investigated. For all the
compounds, a significantly decreased aggregation number
was found in CD3CN relative to 1. Again, the addition of
water led to disaggregation for arylflavins 2a–f. These data
show that the basic idea to decrease p–p interactions in the
aggregates by the introduction of an aryl ring with sterically
demanding substituents works. However, there was no
direct correlation between the steric demand of the substitu-
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Development of Highly Efficient Flavin Photoredox Catalysts
FULL PAPER
Figure 3. Hydrogen bonding in the crystal structures of 10-arylflavins a) 2a, b) 2b, c) 2c, d) 2d, and e) 2 f and f) a fragment that shows p stacking of the
molecules 2 f. The hydrogen bonds are shown as dashed lines, and the non-hydrogen atoms that participate in the hydrogen bonds are labeled. See the
Supporting Information for a colour version, hydrogen-bonding data, and more images.
ents in 2a–f and the aggregation number detected experi-
mentally. For example, 2c shows decreased aggregation rela-
tive to 2b, as expected for ethyl groups relative to methyl
Table 2. Dihedral angles between the aryl and isoalloxazine planes in the
crystal structures.
Flavin
Angle [8]
groups as substituents; however, a further increase in the
steric demand in 2d and 2e did not lead to decreased aggre-
gation numbers. This finding suggests that not only p–p in-
teractions between the isoalloxazine moieties contribute to
the aggregation, but also additional stabilizing dispersion
forces between the bulkier substituents[27] and other nonco-
2a
2b
2c
2d
2 f
79.73(5),[a] 78.43(4)[b]
83.25(4)
86.48(4),[a] 83.48(4)[b]
85.69(5)
79.49(5),[a] 82.02(5)[b]
[a] Molecule A. [b] Molecule B.
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R. Cibulka et al.
Table 3. Aggregation numbers of 1 and 10-arylflavins 2 in different sol-
absorption intensity in the UV/Vis spectra. Substitution at
the N3 position of the 10-arylisoalloxazine ring effects the
position of the absorption maxima more significantly (cf. fla-
vins 2b and 2 f), than it was observed in the case of lumifla-
vin and 10-methylisoalloxazine.[29] All flavins 2 show inten-
sive fluorescence with a maximum at around lmax =500 nm.
A small effect of the aryl substitution on the fluorescence
maxima was only observed in the case of 2a, which bears a
nonsubstituted phenyl ring. However, the fluorescence
quantum yield of 2a is significantly decreased by half rela-
tive to 1 and 2b–d. Similarly, substitution at N3 decreases
the fluorescence quantum yield of arylflavins, which corre-
sponds to the observed effect of N3 substitution in 1[24a,30]
and 10-methylisoalloxazine.[29b] On the other hand, the fluo-
rescence quantum yields reported for lumiflavin and 3-meth-
yllumiflavin are almost the same.[29a]
vents.[a]
Flavin
Aggregation number
CD3CN/D2O (1:1)
CD3CN
D2O
1
3.0
2.4
2.6
1.9
2.1
2.2
2.4
1.7
1.2
1.4
1.0
1.2
1.0
1.3
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2a
2b
2c
2d
2e
2 f
[a] Conditions: T=300 K, c=5ꢅ10ꢀ3 molLꢀ1 of flavins 1 and 2 in solu-
tion with CD3CN and CD3CN/D2O (1:1) or a saturated solution in D2O.
valent interactions play an important role. Interestingly,
ꢀ
analysis of the crystal structures of 2a–d revealed N H···O
hydrogen bonding as the dominant noncovalent interaction
for these arylflavins and not p–p interactions, as found for
1. In the 3-methyl derivate 2 f, hydrogen bonding through
The reduction potentials of the synthesized flavin deriva-
tives in acetonitrile that correspond to one-electron reduc-
[30]
Cꢀ
ꢀ
the N3 H bond is blocked. However, the diffusion measure-
tion (Fl!Fl )
were determined by cyclic voltammetry
ments showed only a slightly decreased aggregation number
relative to 2b. This outcome is in accordance with the crys-
tal structure of 2 f, which shows p–p interactions again be-
(CV) relative to ferrocene/ferrocenium. Moreover, the
change in the Gibbs free energy DGET of the electron trans-
fer from the substrate 4-methoxybenzyl alcohol to the excit-
ed flavins in the singlet state (Table 5) were calculated from
the observed reduction potentials by using the Rehm–
Weller equation (1):[31]
ꢀ
sides weaker C H···O interactions. The solvent-dependent
disaggregation of arylflavins 2a–e going from CD3CN to
CD3CN/D2O (1:1) and D2O correlates with the relative hy-
drogen-bond acceptor properties of these solvents in terms
of better solute/solvent interactions toward pure D2O.[28] In-
terestingly, the aggregates driven by p–p-interactions show a
similar solvent dependence, thus demonstrating that the sol-
vent dependence in flavins cannot be used as an indicator of
the intermolecular interaction mode. Thus, the combination
of aggregation numbers and crystal-structure analysis re-
veals that both p–p interactions and hydrogen bonding play
a decisive role in the aggregation of the flavins, and their
relative contribution can be tuned by the structure of the
synthesized flavins.
DGET ¼ 96:4ðEox1=2ꢀEred1=2Þꢀe2=eaꢀE0ꢀ0
ð1Þ
where Eox and Ered are the oxidation potentials of the
1/2
1/2
substrate (Eox1/2 = +1.19 V for 4-methoxybenzyl alcohol)[5d]
and the reduction potential of the flavin (Table 5); e2/ea is
the Coulomb term (5.4 kJmolꢀ1);[30] E0–0 is the flavin excita-
tion energy (given in kJmolꢀ1), which was estimated as the
average of absorption (hc/l1) and emission (hc/lF) energies
with l1 and lF values derived from the flavin absorption
and fluorescence spectra (Table 4); h is the Planck constant
(6.63ꢅ10ꢀ34 m2 kgsꢀ1); and c is the velocity of light (2.99ꢅ
108 msꢀ1). The redox potential of arylflavins 2 shifts to more
positive values, but by only 60 mV relative to 1, which did
not seem to be enough to influence the oxidation power of
the flavin significantly. According to Gibbs free energy
Spectral and electrochemical properties: The spectral and
electrochemical properties of the newly prepared 10-arylfla-
vins 2 in acetonitrile were studied and compared to those of
1 (see Table 4 and the Supporting Information). The aryl
substituent in position 10 of the isoalloxazine causes a small
blue shift of the absorption maxima and a decrease in the
Table 5. Redox potentials of flavins
1 and 2, estimated free-energy
changes DGET, and Stern–Volmer KS constants for the electron transfer
Table 4. Spectroscopic data for flavins 1 and 2 in acetonitrile.
from 4-methoxybenzyl alcohol to flavins 1 and 2 in acetonitrile.
[c]
[b]
Flavin l2 [nm]
l1 [nm]
lF [nm][b] FF
Flavin
Ered [V][a]
DGET [kJmolꢀ1
]
KS [molꢀ1 dm3]
1/2
(e [molꢀ1 dm3 cmꢀ1])[a] (e [molꢀ1 dm3 cmꢀ1])[a]
1
ꢀ1.18
ꢀ1.12
ꢀ1.11
ꢀ1.10
ꢀ1.11
ꢀ1.10
ꢀ1.11
ꢀ42
ꢀ46
ꢀ51
ꢀ52
ꢀ51
ꢀ51
ꢀ53
26
25
42
44
35
36
33
1
343
335
330
331
330
332
321
A
440
436
437
434
436
437
427
U
505
517
498
500
501
502
498
0.499
2a
2b
2c
2d
2e
2 f
2a
2b
2c
2d
2e
2 f
A
U
0.244
0.447
0.537
0.434
0.328
0.282
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
[a] Values obtained in acetonitrile at a scan rate of 50 mVsꢀ1 in solutions
of the flavins (1ꢅ10ꢀ3 molLꢀ1) with Bu4NPF6 (1ꢅ10ꢀ2 molLꢀ1) at 208C
versus ferrocene/ferrocenium. [b] Free-energy changes calculated from
Equation (1) using Eox1/2 =1.19 V for 4-methoxybenzyl alcohol versus fer-
rocene/ferrocenium.[5d]
[a] l1 and l2 are the positions of the two lowest-energy bands in the ab-
sorption spectra. [b] The maximum of the fluorescence emission spec-
trum, lex =l1. [c] The fluorescence quantum yield determined with quini-
dine sulfate as a standard.
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Development of Highly Efficient Flavin Photoredox Catalysts
FULL PAPER
Table 6. Photooxidation of 4-methoxybenzyl alcohol to 4-methoxybenzal-
dehyde in CD3CN catalyzed by 1 and 10-arylflavins 2a–f.
changes, electron transfer between 4-methoxybenzyl alcohol
and flavins 1 and 2 in their singlet excited state is exergonic,
and thus favorable (DGET <0). The DGET values are less
negative for 1 and 10-phenylisoalloxazine (2a) by about
10 kJmolꢀ1 relative to 2b–f.
Entry
Flavin
Conversion
[%][a]
Relative
absorbance
[%][b]
Quantum yield[c]
F [%] of
aldehyde formation
1
2
3
4
5
6
7
1
5
9
94
74
83
27
72
56
87
0.0034 (0.0041)[d]
0.0045 (0.0042)[d]
0.0204 (0.0210)[d]
0.0179 (0.0149)[d]
0.0126 (0.0125)[d]
0.0102 (0.0086)[d]
0.0118 (0.0113)[d]
Fluorescence quenching for the newly synthesized deriva-
tives 2 with 4-methoxybenzyl alcohol was studied in acetoni-
trile. Stern–Volmer plots constructed from the results are
linear in all the cases (see the Supporting Information). The
values of Stern–Volmer constants KS (KS =kQtF, where kQ is
the apparent rate constant and tF is the fluorescence life-
time) were calculated as the slope of Stern–Volmer depend-
ence (I0/I=1+KS[Q]), that is, as the slope of the ratio of
the fluorescence intensities I0/I in the absence and presence
of 4-methoxybenzyl alcohol (quencher Q) plotted against
concentration [Q]. Interestingly, for almost all the newly
prepared flavins bearing substituted phenyl rings 2b–f,
higher quenching KS constants were measured relative to 1.
Only the value for 10-phenylisoalloxazine (2a) is equal to
that of 1. The observed decreased values of Stern–Volmer
KS constants for 1 and 2a probably result from the de-
creased rate of electron transfer kQ, which corresponds to
the decreased Gibbs free energy changes DGET (Table 5).
2a
2b
2c
2d
2e
2 f
37
36
29
28
25
[a] After irradiation for 90 min. Conditions:
c
c ,
alcohol =4ꢅ10ꢀ3 molLꢀ1
flavin =4ꢅ10ꢀ4 molLꢀ1, irradiation with 1 W LED (lmax =450 nm), T=
258C, monitoring by 1H NMR. [b] Relative absorbance of the reaction
mixture at l=443 nm after irradiation for 60 min relative to the absorb-
ance at the beginning of the experiment. [c] Determined by independent
experiments with monitoring by GC. [d] Determined in CH3CN.
portant for the efficiency of the flavin photocatalysts. The
diethyl derivative 2c showed nearly the same activity as 2b
(compare entries 3 and 4 in Table 6), whereas the activity of
2d and 2e with branched isopropyl and tert-butyl substitu-
ents is slightly decreased (Table 6, entries 5 and 6). Interest-
ingly, the alkylation of the N3 atom also decreases the effi-
ciency of the flavin chromophore in the photooxidation re-
actions (Table 6, entry 7). The conversion of the photooxida-
tion reactions in the presence of 2b–f are relatively high
after 1.5 hours of irradiation, but they are not remarkably
increased during the next irradiation period. This behavior
is caused by degradation of the flavin photocatalysts during
photooxidation reactions, which was evidenced from bleach-
ing of the reaction mixtures (see Table 6 and the Supporting
Information). Nevertheless, the photostability is not the
most important factor that influences the activity of flavin
photocatalysts. The least stable flavin 2c showed relatively
high efficiency. Interestingly, all the synthesized catalysts 2
are less photostable than flavin 1.
Photooxidation of 4-methoxybenzyl alcohol: The ability of
the prepared flavins 2 to mediate the photooxidation of 4-
methoxybenzyl alcohol with oxygen to the corresponding al-
dehyde was investigated under standard conditions, namely,
10 mol% of photocatalyst in deuterated acetonitrile at 258C
under the atmospheric pressure of air (Scheme 3). A high-
Scheme 3. Model photooxidation reaction.
The results of quantum-yield measurements are in accord-
ance with the observed conversions (Table 6). The introduc-
tion of disubstituted aryl rings at position 10 of the isoallox-
azine ring causes a substantial increase in the quantum yield
of the oxidation of 4-methoxybenzyl alcohol, which is, in the
case of 2b, by almost one order of magnitude higher than
the photooxidation in the presence of 1. However, the in-
crease in the quantum yield of the flavin photocatalyst is ap-
proximately half with bulky isopropyl or tert-butyl substitu-
ents or if the N3 position of isoalloxazine is substituted by a
methyl group. As expected, the quantum yields of the oxida-
tion reactions are not affected by deuteration of the solvent,
thus indicating that a singlet-oxygen pathway is not in-
volved.[32]
One could speculate that the lower efficiency of 2a rela-
tive to 2b–f is a result of its smaller oxidation power, but
the differences in reduction potentials and in estimated
DGET values are not sufficient to explain the observed signif-
icant differences in reactivity. The low activity of 2a can
also be attributed to the possible free rotation of the non-
power light-emitting diode was used for the irradiation of
the reaction mixture. A comparison of the efficiencies of fla-
vins in the photooxidation reactions was made by determin-
1
ing 1) conversion after 90 minutes determined by H NMR
spectroscopic analysis of the reaction mixture and 2) quan-
tum yield of the photooxidation reactions determined inde-
pendently. Importantly, the oxidation reaction does not pro-
ceed in the absence of flavin or light.
With 1 as a photocatalyst, only 5% conversion was ach-
ieved after 90 minutes of irradiation (Table 6, entry 1). The
use of 2a without substitution on the phenyl ring led to only
a small improvement of the conversion (Table 6, entry 2).
On the other hand, the introduction of an phenyl ring with
substituents in ortho positions resulted in a substantial in-
crease in flavin efficiency to mediate photooxidation, thus
reaching conversions of up to 37% after 90 minutes of irra-
diation in the presence of 2b (Table 6, entry 3). The charac-
ter of the alkyl substituents on the aryl ring seems to be im-
Chem. Eur. J. 2013, 19, 1066 – 1075
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1071

R. Cibulka et al.
substituted aryl ring, thus allowing its coplanar arrangement
relative to the isoalloxazine plane. This effect may increase
the ability of 2a to aggregate in solution with flavins or sub-
strates, thus supporting fast unproductive charge recombina-
DOSY NMR spectroscopic experiments. Nevertheless, it
was shown that there is no direct correlation between the
steric demand of the substituents in 2a–f and the aggrega-
tion numbers, which is probably due to the contributions of
tion.[5a] Interestingly, the N3 H···O hydrogen bonds that
other noncovalent interactions; for example, the N H···O
ꢀ
ꢀ
dominate among the intermolecular interactions of flavins
2b–e seem to have no negative effect on the catalytic activi-
ty of flavin photocatalysts, as evidenced by the comparison
of 2b and 2 f (compare entries 3 and 7 in Table 6).
hydrogen bonds in the case of 2a–e or dispersion forces be-
tween the bulkier substituents in the case of 2d and 2e.
Flavins 2b–f are far more effective photocatalysts for the
photooxidation of 4-methoxybenzyl alcohol than tetra-O-
acetyl riboflavin (1). The observed quantum yield of this ox-
idation in the presence of 2b (the best photocatalyst among
10-arylflavins 2) exceeds that of 1 by almost one order of
magnitude. Unfortunately, the increased reactivity of 2 is ac-
companied by their lower photostability. Although the con-
versions of the photooxidation reactions of 4-methoxybenzyl
alcohol in acetonitrile catalyzed by flavins 2b–f are not
quantitative, they are among the most active flavins tested
so far in the photooxidation reactions of benzyl alcohols.
The efficiency of flavins 2 can be significantly enhanced by
water as reported for 1.[5a,18]
Significantly enhanced quantum yields (by a factor of 80)
were reported for the oxidation of 4-methoxybenzyl alcohol
catalyzed by 1 by changing the solvent from pure acetoni-
trile to acetonitrile/water (1:1).[5a,18] In the case of arylflavin
2b, the effect of water content on the quantum yield is even
higher and a factor of 220 was reached (Table 7). Conse-
Table 7. Photooxidation of 4-methoxybenzyl alcohol to 4-methoxybenzal-
dehyde in CD3CN/D2O (1:1) catalyzed by 1 and 10-arylflavin 2b.
[c]
Flavin
Conversion after
irradiation [%][a]
Relative
F/FCD CN
3
absorbance [%][b]
5 min
15 min
The results show that the efficiency of a flavin photocata-
lyst can be altered and improved by changing the structural
elements that influence aggregation properties. However,
there is no simple correlation as to how intermolecular in-
teractions affect the ability of flavins to mediate the photo-
oxidation of 4-methoxybenzyl alcohol. Although p–p inter-
actions decrease the activity of flavin photocatalysts, the
effect of hydrogen bonding seems to be positive. Therefore
p–p interactions and hydrogen bonding should both be
taken into account in the design of the structure of new fla-
vins for photocatalysis. Additionally, photophysical proper-
ties (e.g., the quantum yields of singlet and triplet flavin ex-
cited-state formation) are influenced by substitution.
1
2b
17
58
51
quant.
94
49
80
220
[a] Conditions: calcohol =4ꢅ10ꢀ3 molLꢀ1, cflavin =4ꢅ10ꢀ4 molLꢀ1, irradiation
with 1 W LED (lmax =450 nm), T=258C, monitoring by 1H NMR.
[b] Relative absorbance of the reaction mixture at l=443 nm after irradi-
ation for 10 min relative to the absorbance at the beginning of the experi-
ment. [c] Relative values of the quantum yields in CD3CN/D2O (1:1) rel-
ative to the quantum yields in pure CD3CN (Table 6).
quently, quantitative conversion was observed after only
15 minutes of photooxidation catalyzed by 2b, whereas only
37% conversion was achieved in pure CD3CN after 90 mi-
nutes (compare Table 7 with Table 6, entry 3). Unfortunate-
ly, the decomposition of 2b was also relatively fast in
CD3CN/D2O (1:1; see Table 7 and the Supporting Informa-
tion).
Experimental Section
Materials and methods: NMR spectra were recorded on a Varian Mercu-
ry Plus 300 (299.97 and 75.44 MHz for 1H and 13C, respectively), Bruker
Avance 300 (300.13 and 75.03 MHz for 1H and 13C, respectively), Bruker
Avance 400 (400.13 and 100.03 MHz for 1H and 13C, respectively), and
Conclusion
1
Bruker Avance 600 (600.13 and 150.03 MHz for H and 13C, respectively)
10-Arylisoalloxazines 2a–f were prepared as potentially
nonaggregating flavin photocatalysts by condensation of the
appropriately substituted aminouracils 5a–f with nitrosoben-
zene. The investigation of their structures in the crystalline
phase confirms that 10-arylflavins 2 have no structural pre-
requisites to interact by means of strong p–p interactions
and to form stacks in a similar manner to simple flavin mol-
ecules, which is caused by steric hindrance of the substituted
phenyl ring oriented perpendicularly to the flavin skeleton.
spectrometers. Chemical shifts d are given in ppm with the residual sol-
vent or tetramethylsilane (TMS) as an internal standard. Coupling con-
stants are reported in Hz. UV/Vis spectra were recorded on a Varian
Cary 50 spectrophotometer and fluorescence spectra on a Varian Cary
Eclipse fluorescence spectrophotometer. TLC analyses were carried out
on DC Alufolien Kieselgel 60 F254 and on DC Silicagel 60 RP-18 F254
s
(Merck). Preparative column-chromatography separations were per-
formed on silica gel Kieselgel 60 0.040–0.063 mm (Merck). Melting
points were measured on a Boetius melting point apparatus or SRS
MPA100 OptiMelt and are uncorrected. Elemental analyses (C, H, N)
were performed on a Perkin–Elmer 240 analyzer. MS spectra were re-
corded on a ThermoQuest Finnigran TSQ 7000 mass spectrometer in
tandem with a Janeiro LC system. HPLC analyses were carried out on an
Ingos HPLC System (column: Phenomenex Luna 5u Silica, 150ꢅ4.6 mm)
with a UV/Vis spectrophotometric detector. The starting materials and
reagents were purchased from Sigma–Aldrich, Eurorad (deuterated sol-
vents: CDCl3, [D6]DMSO, CD3CN), and Lach-Ner (acetonitrile, propan-
2-ol, and n-heptane for HPLC). The solvents were purified and dried by
using standard procedures.[34]
ꢀ
X-ray diffraction studies also revealed that N H···O hydro-
gen bonding dominates in the crystals of 2a–d. Blocking the
N3 position with a methyl group in 2 f inhibits the formation
ꢀ
ꢀ
of N H···O bonds; instead, C H···O hydrogen bonds and
weak p–p interactions shape the structure of the molecules
in the solid state. The significantly lower tendency of flavins
2a–f to aggregate in acetonitrile was confirmed by 1H-
1072
www.chemeurj.org
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 1066 – 1075

Development of Highly Efficient Flavin Photoredox Catalysts
FULL PAPER
Tetra-O-acetyl riboflavin (1),[35] 6-chlorouracil (4a),[36,37] 6-chloro-3-meth-
yluracil,[3c] and nitrosobenzene[38] were prepared according to the report-
ed procedures. The experimental details about the synthesis and charac-
terization of 6-aminouracils 5a–f are provided in the Supporting Informa-
tion.
(400 MHz, CDCl3, 258C, TMS): d=0.97 (d, J
1.15 (d, J(H,H)=6.8 Hz, 6H; CH3), 2.16 (m, 2H; CH), 6.82 (dd, J-
(H,H)=8.5, 1.0 Hz, 1H; Ar-H), 7.40 (d, J(H,H)=7.8 Hz, 2H; Ar-H),
7.75–7.50 (m, 3H; Ar-H), 8.37 (dd, J(H,H)=8.1, 1.3 Hz, 1H; Ar-H),
ACHTUNGTREN(NNUG H,H)=6.8 Hz, 6H; CH3),
AHCTUNGTRENNUNG
N
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
8.79 ppm (s, 1H; NH); 13C NMR (100 MHz, CDCl3, 258C, TMS): d=
23.84, 24.09, 29.18, 117.20, 125.54, 127.22, 130.65, 131.34, 132.97, 134.44,
135.87, 138.47, 144.52 ppm; UV/Vis (CH3CN): lmax (e)=330 (6200),
436 nm (8900 molꢀ1 dm3 cmꢀ1); MS (ESI): m/z (%): 375 (100) [M+H]+;
749 (24) [2M+H]+; HRMS (ESI): m/z calcd for C22H22N4O2 [M+Na]+:
397.16350; found: 397.16345; elemental analysis calcd (%) for
C22H22N4O2: C 69.57, H 5.92, N 14.96; found: C 69.86, H 6.06, N 15.25.
Synthesis of 10-arylisoalloxazines 2a–f: Nitrosobenzene and the substitut-
ed 6-arylaminouracil 5 were dissolved in acetic acid/acetic anhydride (1:1,
10 mL). The reaction mixture was heated under reflux and stirred for
1.5 h (monitoring by TLC analysis with dichloromethane/methanol (10:1)
as the mobile phase). The solvent was evaporated under reduced pres-
sure and the crude product was purified by column chromatography with
dichloromethane/methanol as the eluent (10:1 for 2a–c and 2 f; 8:1 for
2d and 2e) or/and by recrystallization from ethanol. The resulting isoal-
loxazine derivative was dried in vacuo.
10-(2’-tert-Butylphenyl)isoalloxazine (2e): Following the general proce-
dure, aminouracil 5e (390 mg, 1.50 mmol) and nitrosobenzene (483 mg,
4.50 mmol) were heated to reflux to yield 10-(2’-tert-butylphenyl)isoallox-
azine (2e). The pure product was obtained after recrystallization from
ethanol as an orange powder (65 mg, 13%). M.p. 3008C (decomp);
1H NMR (400 MHz, CDCl3, 258C, TMS): d=1.12 (s, 9H; CH3), 6.83 (dd,
10-Phenylisoalloxazine (2a): Following the general procedure, aminoura-
cil 5a (0.68 g, 3.35 mmol) and nitrosobenzene (1.00 g, 10.4 mmol) were
heated to reflux to yield 10-phenylisoalloxazine (2a) as a green-yellow
powder (0.32 g, 33%). M.p. 2158C; 1H NMR (400 MHz, [D6]DMSO,
J
N
ACHTUNGTREN(NUNG H,H)=7.9 and 1.4 Hz,
258C, TMS): d=6.75 (dd, J
(H,H)=5.2, 3.2 Hz, 2H; Ar-H), 7.85–7.54 (m, 5H; Ar-H), 8.19 (dd, J-
ACHTUNGTRENNUNG
(H,H)=8.1, 1.3 Hz, 1H; Ar-H), 11.43 ppm (s, 1H; NH); 13C NMR
(100 MHz, [D6]DMSO, 258C, TMS): d=116.71, 125.93, 127.78, 129.75,
130.26, 131.33, 134.00, 134.69, 136.05, 139.46, 151.68, 155.46, 159.47 ppm;
UV/Vis (CH3CN): lmax (e)=335 (6200), 436 nm (8900 molꢀ1 dm3 cmꢀ1);
MS (ESI): m/z (%): 291 (100) [M+H]+; 581 (32) [2M+H]+; HRMS
(ESI): m/z calcd for C16H10N4O2 [M+H]+: 291.08765; found: 291.08764;
elemental analysis calcd (%) for C16H10N4O2: C 66.20, H 3.47, N 19.30;
found: C 66.24, H 3.15, N 18.86.
ACHTUNGTRENN(UNG H,H)=8.5, 0.8 Hz, 1H; Ar-H), 7.44 (dd, J-
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
13C NMR (100 MHz, CDCl3, 258C, TMS): d=31.75, 36.70, 118.24, 127.03,
128.73, 129.34, 130.76, 131.15, 132.81, 135.49, 135.62, 135.77, 138.16,
146.29, 152.66, 154.80, 159.11 ppm; UV/Vis (CH3CN): lmax (e)=332
(7000), 437 nm (9900 molꢀ1 dm3 cmꢀ1); MS (ESI): m/z (%): 347 (100)
[M+H]+; 693 (60) [2M+H]+; HRMS (ESI): m/z calcd for C20H18N4O2
[M+Na]+: 369.13220; found: 369.13213; elemental analysis calcd (%) for
C20H18N4O2: calcd C 69.35, H 5.24, N 16.17; found: C 68.93, H 5.62, N
16.42.
10-(2’,6’-Dimethylphenyl)isoalloxazine (2b): Following the general proce-
dure, aminouracil 5b (360 mg, 1.56 mmol) and nitrosobenzene (500 mg,
4.67 mmol) were heated to reflux to yield 10-(2’,6’-dimethylphenyl)isoal-
loxazine (2b). The pure product was obtained after recrystallization from
ethanol as an orange powder (115 mg, 23%). M.p. 3508C (decomp);
1H NMR (400 MHz, CDCl3, 258C, TMS): d=1.93 (s, 6H; CH3), 6.80 (dd,
10-(2’,6’-Dimethylphenyl)-3-methylisoalloxazine (2 f): Following the gen-
eral procedure, aminouracil 5 f (100 mg, 0.41 mmol) and nitrosobenzene
(200 mg, 1.87 mmol) were reacted to yield isoalloxazine 2 f. The pure
product was obtained after recrystallization from ethanol as an orange
powder (60 mg, 44%). M.p. 3508C (decomp); 1H NMR (400 MHz,
CDCl3, 258C, TMS): d=1.92 (s, 6H; CH3), 3.52 (s, 3H; CH3), 6.86–6.73
(m, 1H; Ar-H), 7.30 (d, J
7.4 Hz, 1H; Ar-H), 7.64–7.56 (m, 1H; Ar-H), 7.68 (dd, J
1.4 Hz, 1H; Ar-H), 8.39 ppm (dd, J(H,H)=8.1 and 1.4 Hz, 1H; Ar-H);
J
N
ACHTUNGERTN(NUNG H,H)=7.7 Hz, 2H; Ar-H),
E
ACHTUNGTRENNUNG(H,H)=
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
1H; Ar-H), 8.83 ppm (s, 1H; NH); 13C NMR (100 MHz, CDCl3, 258C,
TMS): d=17.81, 116.19, 127.26, 129.79, 130.57, 133.09, 133.58, 134.38,
135.98, 136.47, 138.64, 150.46, 155.15, 159.18 ppm; UV/Vis (CH3CN): lmax
(e)=330 (7000), 437 nm (10000 molꢀ1 dm3 cmꢀ1); MS (ESI): m/z (%): 319
(100) [M+H]+; 637 (82) [2M+H]+; HRMS (ESI): m/z calcd for
C18H14N4O2 [M+Na]+: 341.10090; found: 341.10087; elemental analysis
calcd (%) for C18H14N4O2: C 67.91, H 4.43, N 17.60; found: C 67.91, H
4.29, N 17.72.
AHCTUNGTRENNUNG
13C NMR (100 MHz, CDCl3, 258C, TMS): d=17.66, 28.87, 115.84, 126.79,
129.60, 130.38, 132.81, 132.85, 133.30, 134.42, 135.87, 135.94, 137.93,
148.73, 155.81, 159.70 ppm; UV/Vis (CH3CN): lmax (e)=321 (5500),
427 nm (6500 molꢀ1 dm3 cmꢀ1); MS (ESI): m/z (%): 333 (100) [M+H]+;
665 (86) [2M+H]+; HRMS (ESI): m/z calcd for C19H16N4O2 [M+H]+:
333.13460; found: 333.13457; elemental analysis calcd (%) for
C19H16N4O2: C 69.35, H 5.24, N 16.17; found: C 69.20, H 5.20, N 16.55.
X-ray diffraction studies: Single crystals of 2a, 2b, 2d, and 2 f suitable
for X-ray analysis were prepared by slow evaporation of the solvent from
solutions of 2a (2.6 mg, 0.009 mmol), 2b (1.6 mg, 0.005 mmol), 2d
(4.4 mg, 0.012 mmol), and 2 f (1.0 mg, 0.003 mmol) in ethanol (1.46, 1.00,
0.50, and 0.20 mL, respectively). A single crystal of 2c was prepared by
10-(2’,6’-Diethylphenyl)isoalloxazine (2c): Following the general proce-
dure, aminouracil 5c (405 mg, 1.56 mmol) and nitrosobenzene (500 mg,
4.67 mmol) were heated to reflux to yield 10-(2’,6’-diethylphenyl)isoallox-
azine (2c). The pure product was obtained after recrystallization from
ethanol as an orange powder (110 mg, 20%). M.p. 3508C (decomp);
1H NMR (400 MHz, CDCl3, 258C, TMS): d=1.06 (t, J
6H; CH3), 2.07 (dq, J(H,H)=15.1, 7.5 Hz, 2H; CH2), 2.24 (dq, J
15.2, 7.6 Hz, 2H; CH2), 6.78 (dd, J(H,H)=8.5, 1.1 Hz, 1H; Ar-H), 7.36
(d, J(H,H)=7.7 Hz, 2H; Ar-H), 7.52 (t, J(H,H)=7.7 Hz, 1H; Ar-H),
7.65–7.59 (m, 1H; Ar-H), 7.69 (ddd, J(H,H)=8.6, 7.3, 1.5 Hz, 1H; Ar-H),
8.37 (dd, (H,H)=8.1, 1.5 Hz, 1H; Ar-H), 8.96 ppm (s, 1H; NH);
(H,H)=7.6 Hz,
(H,H)=
slow cooling of
a solution of 2c (3.2 mg, 0.009 mmol) in ethanol
(0.50 mL) from 608C to ambient temperature.
N
ACHTUNGTRENNUNG
N
X-ray diffraction data for yellow-to-ruby crystals of flavin derivatives 2a–
d and 2 f were measured at 170 K on a four-circle CCD diffractometer
Gemini of Oxford Diffraction Ltd. with graphite monochromated CuKa
radiation (l=1.5418 ꢄ). Data reduction including empirical absorption
correction by using spherical harmonics were performed with CrysAlis-
Pro[39] (Oxford Diffraction). The crystal structure was solved by the
charge-flipping method using the program Superflip[40] and refined with
the Jana2006 program package[41] by full-matrix least-squares technique
on F. The non-hydrogen atoms were refined anisotropically and the hy-
drogen atoms were positioned geometrically and refined by using the
riding model. The molecular-structure plots were prepared by using
ORTEP III,[42] and the intermolecular interactions were viewed in Mer-
cury.[43] Selected data for 2a–d and 2 f are collected in the Supporting In-
formation.
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
JACHTUNGTRENNUNG
13C NMR (100 MHz, CDCl3, 258C, TMS): d=13.41, 23.85, 116.76, 127.21,
127.46, 130.87, 132.55, 132.97, 133.84, 135.91, 136.17, 138.59, 139.49,
151.05, 155.14, 159.24 ppm; UV/Vis (CH3CN): lmax (e)=331 (7000),
434 nm (10100 molꢀ1 dm3 cmꢀ1); MS (ESI): m/z (%): 347 (100) [M+H]+;
693 (70) [2M+H]+; HRMS (ESI): m/z calcd for C20H18N4O2 [M+Na]+:
369.13220; found: 369.13216; elemental analysis calcd (%) for
C20H18N4O2: C 69.35, H 5.24, N 16.17; found: C 69.20, H 5.20, N 16.55.
10-(2’,6’-Diisopropylphenyl)isoalloxazine (2d): Following the general pro-
cedure, aminouracil 5d (200 mg, 0.70 mmol) and nitrosobenzene (224 mg,
2.09 mmol) were reacted to yield 10-(2’,6’-diisopropylphenyl)isoalloxazine
(2d). The pure product was obtained after recrystallization from ethanol
as an orange powder (50 mg, 19%). M.p. 3508C (decomp); 1H NMR
CCDC-887842 (2c), CCDC-887843 (2a), CCDC-887844 (2b), CCDC-
887845 (2d), and CCDC-887846 (2 f) contain the supplementary crystal-
Chem. Eur. J. 2013, 19, 1066 – 1075
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1073

R. Cibulka et al.
lographic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
c.uk/data_request/cif.
GC analysis with chlorobenzene as an internal standard, and the quan-
tum yield was determined as an average from all these measurements.
1H-DOSY NMR: The 1H-DOSY NMR spectroscopic measurements
were conducted on a Bruker Avance 600 spectrometer (600.13 Hz) equip-
ped with a triple-resonance broadband inverse (TBI) 31P/13C selective
probe. Temperature stability was ensured by a BVT 3000 unit. The data
were processed and evaluated with Bruker Topspin 2.1 with the software
package t1/t2. The measurements were conducted at 300 K with solutions
of cflavin =5ꢅ10ꢀ3 molLꢀ1 in CD3CN and CD3CN/D2O (1:1) and saturated
solutions in D2O (cflavin = <5ꢅ10ꢀ3 molLꢀ1). The aggregation numbers
are based on diffusion coefficients measured by 1H-DOSY NMR experi-
ments by using a convection-compensating pulse sequence developed by
Jerschow and Mꢁller.[44] Diffusion coefficients of TMS served as a viscosi-
ty reference. By assuming a spherical shape of the molecules and consid-
ering a microfriction factor, calculation of the hydrodynamic volumes
from experimental diffusion coefficients was carried out according to the
reported procedure.[26,45] The comparison of this experimental determined
hydrodynamic volumes with theoretical volumes calculated according to
Zhao et al.[46] show that all the experimental hydrodynamic volumes for
the flavins in water are smaller than the theoretically expected values
with a factor of 0.7–0.8. This factor is in accordance with previous studies
on experimental diffusion coefficients of aromatic systems[47,48] and shows
that the flavins appear as monomers in D2O. The aggregation numbers
were calculated as the ratio between the experimentally determined hy-
drodynamic volumes of the flavins in the respective solvent and the ex-
perimentally determined hydrodynamic volumes of their monomers in
D2O. An experimental hydrodynamic volume of flavin 2 f in D2O was not
accessible due to its poor solubility. Therefore, this value was calculated
by adding the theoretical volume of a methyl group[46] to the experimen-
tal hydrodynamic volume of flavin 2b (see the Supporting Information
for data).
Acknowledgements
We thank the graduate research training group GRK 1626 “Chemical
Photocatalysis” of the German National Science Foundation (DFG),
Deutsche Bundesstiftung Umwelt (DBU, German Environmental Foun-
dation), and Ministry of Education, Youth and Sports of the Czech Re-
public (specific university research No. 21/2012) for financial support of
this work.
[1] a) Chemistry and Biochemistry of Flavoenzymes (Ed.: F. Mꢁller),
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Received: July 12, 2012
Revised: September 14, 2012
Published online: November 29, 2012
Chem. Eur. J. 2013, 19, 1066 – 1075
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1075