Pyrimidopteridine N-Oxide Organic Photoredox Catalysts: Characterization, Application and Non-Covalent Interaction in Solid State

Article abstract of DOI:10.1002/chem.201900118

Herein we report the photo- and electrochemical characterization of pyrimidopteridine N-oxide-based heterocycles. The potential of their application as organic photoredox catalysts is showcased in the photomediated contra-thermodynamic E→Z isomerization of cinnamic acid derivatives and oxidative cyclization of 2-phenyl benzoic acid to benzocoumarin using molecular oxygen as a mild oxidant. Furthermore, unprecedented intermolecular non-covalent n–π-hole interactions in solid state are discussed based on crystallographic and theoretical data.

Full text of DOI:10.1002/chem.201900118

A Journal of
Accepted Article
Title: Pyrimidopteridine N-Oxide Organic Photoredox Catalysts:
Characterization, Application and Non-Covalent Interaction in
Solid State
Authors: Richy Hauptmann, Andranik Petrosyan, Franziska Fennel,
Miguel André Argüello Cordero, Annette-Enrica Surkus, and
Jola Pospech
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10.1002/chem.201900118
Chemistry - A European Journal
COMMUNICATION
Pyrimidopteridine N-Oxide Organic Photoredox Catalysts:
Characterization, Application and Non-Covalent Interaction in
Solid State
Richy Hauptmann†,[a] Andranik Petrosyan†,[a] Franziska Fennel,[b] Miguel A. Argüello Cordero,[a,b]
Annette-E. Surkus,[a] and Jola Pospech*[a]
Abstract: Herein we report the photo- and electrochemical
characterization of pyrimidopteridine N-oxide based heterocycles.
The potential of their application as organic photoredox catalyst is
showcased in the photomediated contra-thermodynamic E→Z
isomerization of cinnamic acid derivatives and oxidative cyclization
of 2-phenyl benzoic acid to benzocoumarine using molecular oxygen
as a mild oxidant. Furthermore, unprecedented intermolecular non-
covalent n–π hole interactions in solid state are discussed based on
crystallographic and theoretic data.
and robustness
as
compared to commonly used
photosensitizers. In addition, the solid state analysis of N-oxides
1-4 reveal interesting non-covalent intermolecular interactions
that are indicative of lone-pair−π-hole interaction based on
crystallographic and theoretic data.
Recently there has been convincing evidence that flavin-N5-
oxide serves as a viable intermediate in enzyme-catalyzed
oxygenation reactions besides the well-established flavin-C4a-
peroxide.[1] Based on spectroscopic and spectrometric studies,
the stable flavin-N5-oxide has been postulated to participate in
reactions involving EncM monooxygenase, provoking oxidative
carbon rearrangement,[2] dibenzothiophene catabolism[3] and
oxidative cleavage of uracil amides.[4] However, till date the
actual catalytic potential of flavin-N5-oxides remains largely
unexplored.[5] The structurally related 1,3,7,9-tetrabutyl-2,4,6,8-
tetraoxo-[5,4-g]pteridine 5-oxide (BuPPT N-oxide, 3) has first
been reported by the group of Maki in 1986 and has been
applied in various photo-mediated oxygen atom transfer
reactions leading to N-demethylation,[6] C−H oxygenation[7] and
oxidative C−C bond scission reactions[8] as a stoichiometric
oxygen atom transfer reagent. Since the initial reports, no further
investigation concerning its photoredox properties and
applicability in catalytic reactions has been attempted. In view of
the latest findings in flavin chemistry, these structures may serve
as an important link between organic photoredox catalysis and
chemical biology. We have optimized the synthesis of 4 different
PPTNO photosensitizers on gram-scale. Besides the previously
reported BuPPT N-oxide (3), we prepared its tetramethyl
(MePPT N-oxide, 1), tetrapropyl (PrPPT N-oxide, 2), and
tetraphenyl (PhPPT N-oxide, 4) derivatives via modified
procedure.[9] Photo- and electrochemical analysis revealed that
all compounds have large excited state energies, and are
capable of oxidizing compounds with oxidation potentials
exceeding +2.0 V. Furthermore, the radical anions resulting from
photoinduced electron transfer are moderate to good reductants,
and turnover with mild oxidants such as dioxygen. The
heteroarene based photosensitizers display excellent stability
Scheme 1. Structural, electro- and photochemical properties of
photosensitizers 1−4.
The synthesis of the pyrimidopteridine N-oxides 1-3 was
accomplished by radical dimerization of the corresponding 6-
amino-5-nitrosouracils (5’), which according to spectroscopic
data is better described as 5-hydroimino-6-imino tautomer 5.
The dimerization is provoked by phenyliodine(III) diacetate
(PIDA) and the desired condensed heterocycles were isolated in
60-65% yield on gram-scale by recrystallization. The phenyl
derivative 4 was obtained in significantly higher yield when lead
tetraacetate was used as oxidant.[10]
Scheme 2. Synthesis of PPT N-oxides 1-4. [a] All yields are isolated yields
purified by crystallization. [b] Pb(OAc)4 was used instead of PhI(OAc)2.
[a]
M.Sc. R. Hauptmann, Dipl.-Chem. A. Petrosyan, M.Sc. M. A.
Argüello Cordero, Dr. A.-E. Surkus, Dr. J. Pospech
Leibniz Institute for Catalysis at University of Rostock, Department
Albert-Einstein-Strasse 29a, D-18059 Rostock, Germany.
E-mail: Jola.Pospech@catalysis.de
Dr. F. Fennel, M.Sc. M. A. Argüello Cordero
Department of Physics, Rostock University, Albert-Einstein-Str.
23-24, 18059 Rostock, Germany.
Next, we investigated the photophysical properties of the
pyrimidopteridine N-oxide photosensitizers. The oxygenated
PPTNOs 1−4 showed absorption maxima around 368−375 nm
and 267−273 nm, associated with the n→π* and π→π*
[b]
†
These authors contributed equally
Supporting information for this article is given via a link at the end of
the document.
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Table 1. Photophysical and Electrochemical Properties of PPTNO
Photosensitizers.
high excited state energies of +3.25 V for 1−4 turn the
compounds into very potent excited state oxidants with excited
state reduction potentials of +2.30 V and higher. Thus, the N-
oxides 1−4 are well-suited for the activation of a great number of
substrates in there excited state. At the same time, the reduced
PPTNO•− [퐸1푟/푒2푑 (PPTNO/PPTNO•−) = −0.91 eV for 1 vs SCE in
MeCN] are oxidized by mild oxidants, such as molecular oxygen
excited
state
ground state
redox potentials
(V vs SCE)
excited state
redox potentials
(V vs SCE)

푎푏푠
휆
energy
푚푎푥
휙푓
a
푆1
퐸
0,0
표푥
c
d
푟푒푑
퐸
compound
[eV]
퐸
퐸푟∗푒푑
퐸표∗푥
[nm]
368
370
371
366
[퐸 (O2/O2•−) = −0.87 eV vs SCE in MeCN].[12] In comparison,
1/2
푟푒푑
1/2
1/2
the reduction potential of riboflavin is −0.43 V with an excited
0.69
1.86
0.40
0.24
+3.24
+3.25
+3.25
+3.25
−0.91
−0.95
−0.92
−0.93
+2.42
+2.42
+2.47
+2.33
+2.33
+2.30
+2.33
+2.32
−0.82
−0.83
−0.78
−0.92
1
2
3
4
state reduction potential of +1.50 V (vs SCE in water).[13] Overall,
the photo- and electrochemical properties render the studied
compounds excellent candidates for applications in organic
photoredox catalysis.
[a] E0,0 values corresponding to the energy at the intersection of the excitation
and emission spectra. [b] Potentials were measured using cyclic voltammetry
(CV) and differential pulse voltammetry (DPV) relative to Fc+/Fc; referenced to
SCE by adding 0.42 V to the value relative to Fc+/Fc.[11] [c] Calculated by
1/2
푟푒푑
1/2
푆1
푆1
푆1
퐸
= 퐸푆1 + 퐸 . [d] Calculated by 퐸 = E표푥 − E
.
0,0
푟푒푑
0,0
표푥
transitions, respectively. The aromatic π→π* transition in the
phenyl derivative are visible but structureless. The emission
spectra of N-alkyl substituted derivatives 1−3 show an emission
maximum at 398 nm resulting in a Stokes shift of approximately
30 nm (0.25 eV). The emission spectra of 1, 2 and 3 exhibited
close to mirror-image symmetry and the quantum yields are
between 0.4% and 1.86%. In contrast, the emission spectra of
phenyl-bearing 4 had a broad shape with a maximum at 423 nm,
indicative of an enhanced charge transfer character in the
excited state in the presence of aryl substituents on the pyrimido
pteridine core. The strong charge transfer character of the
excited state is supported by the further reduced quantum yield
of 0.23%. Nevertheless, E0,0 values corresponding to the energy
at the intersection of the absorption and emission spectra and
were close to unity for all PPTNOs 1−4 at 382 (1) nm (3.25 eV)
and are listed in Table 1. Cyclic voltammetry (CV) was employed
to determine the ground state redox potentials (Eox and Ered) of
compounds 1−4. All compounds exhibit an irreversible anodic
oxidation at potentials above +2.20 V. The heteroarene N-oxides
1−4 experience two consecutive reductions around −0.93 V and
−1.20 V which could not be separated from one another. As a
consequence, the re-oxidation peaks were ill-defined which
compromises the correct determination of the half-wave
Figure 2. UV-vis absorption and emission spectra (top); Cyclo
voltammogramm (CV) (bottom left); Differential pulse voltammogramms (DPV)
of PPTNOs 1-4 against the Fc+/Fc redox couple.
Herein, we showcase the catalytic activity of the synthesized
pyrimidopteridiine N-oxides in representative reactions that have
previously been reported using (−)-riboflavin as organic
photoredox catalyst. For instance, the PPTNO photocatalyst
demonstrate a similar behavior as compared to the (−)-
riboflavin-based system by inducing a contra-thermodynamic E
→Z isomerization of cinnamic acid derivatives via productive
energy transfer (ET).[14],[15] Methyl cinnamate (6) was isomerized
to a mixture of E- and Z-methyl cinnamate (7) in a 43:57 ratio
using phenyl derivative 4. In comparison, (−)-riboflavin promoted
the same reaction in a 41:59 isomeric ratio. The isomerization of
E to Z ethyl 3-(4-bromophenyl)but-2-enoate (8) proceeds in
lower selectivity of a maximum of 21:79 (E:Z) using MePTTNO
(1) as compared to riboflavin system but still exemplifies the
proof of concept. To our delight, a cyclization of [1,1'-biphenyl]-2-
carboxylic acid (10) to benzocoumarine 11 was accomplished in
86% isolated yield under unoptimized reaction conditions.
potential. This is
measurements. Figure
a
common problem in electrochemical
shows the differential pulse
2
voltammogramms (DPV) of the reduction and oxidation waves of
the pyrimidopteridine N-oxides against the Fc+/Fc redox couple.
The diagrams show the measurements of the cathodic reduction
(left) and anodic oxidation (right). DPV uses a series of voltage
pulses superimposed on the linear sweep potential and the
current change is plotted against the potential. The signal
maximum is a good approximation of the half wave potential E1/2
and can be determined without the prerequisite of showing
defined peaks for the anodic and cathodic current as required in
CV measurements and thus allows a more facile determination
of redox potentials. The potentials listed in Table 1 were
referenced to SCE by adding 0.42 V to the value relative to
Fc+/Fc.[11] The excited state potentials 퐸푟∗푒푑 and 퐸표∗푥 were
determined by employing optical and electrochemical data. The
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Noteworthy, the (−)-riboflavin-based system suffers from catalyst
degradation in course of the SET reaction, necessitating the
iterative addition of catalyst in batches of 5.0 mol% every 12
hours.[16] The experiments presented herein, were conducted on
a 0.5 mmol scale using only a single batch of 5.0 mol% of the
organocatalyst.
applied DFT calculations for MePPTNO (1) on a B3LYP/6-
31G(d,p) level of theory.[21] The differences in the charge
distributions within the molecule were visualized by an
electrostatic potential (ESP) map depicted in Figure 3. The red
color represents an excess of electron density and electron-
deficient regions are colored in blue. Accordingly, the electron
density accumulates at the carbonyl−N-oxide−carbonyl portion
of the molecule whereas the center of the aromatic rings are
Scheme 1. Photo-mediated E/Z-isomerization and benzocoumarin synthesis.
The pyrimidopteridine heterocycles can be stored under ambient
conditions, without any signs of degradation as crystalline
material.[17] Crystals suitable for single crystal analysis were
obtained for the N-oxide derivatives 1−4. The PPTNOs showed
interesting non-covalent interactions. The view perpendicular (A)
and along (B) the heteroarene plane is depicted in Figure 2. The
molecules are arranged in a stair-like fashion in which the N-
oxide oxygen atom interacts with the heteroarene core of the
adjacent molecule. This interaction is most pronounced in the
propyl and methyl derivatives 1 and 2, resulting in a near
perpendicular arrangement of the single molecules in the crystal
package of 85° and 76°, respectively between the planes
defined by the C(4a)−N(5)−C(5a) plane of two neighboring
molecules (Table 2). The more bulky butyl substituents tame the
interaction. The neighboring molecules of 3 are tilted in an angle
of 29°. However, in each case, the N-oxide oxygen and
pyrimidine core are in close contact of a mean value of 2.76 Å.
The intramolecular interactions in the solid state are reminiscent
of lone-pair−π hole or anion−π hole interactions that are often
apparent between electron-rich species and electron-deficient
arenes.[18] Such non-covalent interactions (NCI) have recently
attracted much attention particularly regarding ion transport in
biomolecular structures and catalysis.[19],[20] In order to clarify the
origin of the molecular arrangement in the crystal structure, we
Figure 3. Crystal structures of PPTNOs 1-4 in (A) top and (B) side view.
Figure 4. Electrostatic potential map of MePPTNO (1) showing electron-rich
(red) and electron-poor regions (blue).
electron deprived regions and are thus well suited for anion or
lone-pair interaction.
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In the pyrimidopteridines N-oxides, the d(N−O) bond lengths are
relatively short, with a mean value of about 1.26 Å. In
comparison with typical N–O single bonds in hydroxylamines
(1.45 Å) and N=O double bonds in nitrosoalkanes (1.27 Å), the
crystallographic data suggests that this bond should be
considered as a strong non-polar dative N−O bond, stabilized by
π-type N−O back-donation, rather than a polar covalent bond
N+−O−.[22] Thus, we propose that the NCI originates from lone-
pair−π-hole rather than anion− π -hole interaction.
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d(N-O) [Å]
1.257
d(O-pyr) [Å][a]
2.719
angle[b]
76°
1
2
3
4
1.256
2.797
85°
[8]
[9]
1.263
2.783
29°
1.257
2.765
68°
[a] Distance between O(5) atom and plane defined by C(4a)–N(5)–C(5a); [b]
angle between two planes defined by C(4a)–N(5)–C(5a) of neighbouring
molecules.
The synthesis involves a radical dimerization of a nitrosoamino
intermediate. In the seminal report, this step was accomplished
using lead(IV) tetraacetate. We have successfully revised this
sequence using phenyliodo diacetate (PIDA) as radical initiator.
A detailed comparison on the preformance of PhI(OAc)2 vs
Pb(OAc)4 is reported in the SI.
In summary, we report the photo- and electrochemical
characterization
of
pyrimidopteridine
N-oxide
based
[10]
[11]
[12]
[13]
[14]
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excellent stability and robustness as compared to commonly
used photosensitizers and can be synthesized on gram-scale
from inexpensive starting material. Here, we demonstrated its
application as potent organic photoredox catalyst for the first
time. Furthermore, unprecedented intermolecular non-covalent
n–π hole interactions of the pyrimidopteridine N-oxides based on
crystallographic data is described and is supported by DFT
calculations.
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Acknowledgements
This work was funded by the Deutsche Forschungsgemeinschaft
(DFG, German Research Foundation) – 401007518 and by the
European Union (ESF/14-BM-A55-0049/16). We thank Dr. Anke
Spannenberg (LIKAT) and Dr. Alexander Villinger (Rostock
University) for crystallographic measurements and Dr. Nils
Rockstroh for assistance with the measurements of emission
spectra. Moreover, we would like to express our gratitude to the
LIKAT for excellent support.
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Keywords: Organo Photoredox Catalysis • Non-Covalent
Interactions • Heteroarene N-oxides • Heterocycles
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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Richy Hauptmann, Andranik Petrosyan,
Franziska Fennel, Miguel A. Argüello
Cordero, Annette-Enrica Surkus, Jola
Pospech*
Page No. – Page No.
Pyrimidopteridine N-Oxide Organic
Photoredox Catalysts:
Characterization, Application and
Non-Covalent Interaction in Solid
State
Pyrimidopteridine N-oxide based heterocycles exhibit excellent excited state
reduction potentials paired with a suitable ground state reduction potential allowing
for catalyst turnover with mild oxidants. The structural similarity between
pyrimidopteridines and recently uncovered flavine N-oxides may draw an important
link between organic photoredox catalysis and chemical biology.
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