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studied;[6–55] the early literature up to 1983 has been discussed
in book chapters and review articles.[6–8] A wide range of elec-
trode materials and supports were investigated in these stud-
ies. This corpus of literature work, however, has mostly focused
on natural flavins (i.e., riboflavin, FAD, FMN) and much less is
known about their synthetic counterparts. The few studies on
synthetic flavins, on the other hand, were directed toward un-
derstanding substituent effects on redox potentials by theoret-
ical and experimental means.[22,28,43,46] The present study, in
contrast, differentiates itself from the extensive prior body of
work on natural flavins by focusing on freely-diffusing synthet-
ic flavin molecules, and their redox properties, especially from
electrocatalysis and photocatalysis perspectives. Thus this
study focuses on the reductive (i.e., cathodic) electrochemical
behavior of four synthetic flavin derivatives in aqueous media.
The distinguishing side groups of riboflavin, FMN, and FAD
(Figure 1) are also a potential source of instability for applica-
tions such as in fuel cells and in heterogeneous photocatalysis.
Flavins 1–4 (Figure 1) were thus designed for enhanced redox
stability and aqueous solubility over a broad pH range. Fur-
thermore and, most importantly, these species avoid intramo-
lecular proton-transfer events[22] stemming from the acidic N3
imide proton in the natural flavins during redox cycling.
ments[36,40,59] for mechanistic elucidations related to proton-
coupled electron transfer (PCET). Important aspects related to
PCET such as electron/proton stoichiometry and its sensitivity
to solution pH, and proton starvation effects at the electrode-
solution interface are discussed below, as is the influence of N-
alkyl substitution (at N1/N10 and N3) on the redox potential of
1-4. Finally, a preliminary assessment of the electrocatalytic
properties of 1 for the dioxygen reduction reaction (ORR) is
also presented. Follow-up collaborative studies will address
tethered synthetic flavins on metallic and oxide semiconductor
electrode supports, and their applicability to targeted multie-
lectron transfer for ORR and solar water splitting.
Results and Discussion
Synthesis of aqueous soluble flavin derivatives
The preparation of ammonium-substituted flavins is detailed in
Figure 2 and 3. Alloxazine (5) and N10-phenylisoalloxazine (12)
core structures (Figures 2 and 3) were prepared as previously
described.[60,61] N-alkylation to directly install quaternary ammo-
nium groups was achieved by a rather specific procedure.
Methylation of alloxazines at N-1 and N-3 is commonly ach-
ieved by standard single-step methods with methyl iodide.[67]
However, the ammonium species pose obvious differences in
reactivity and thermal stability compared to simpler haloal-
kanes. Figure 2 shows the major product (N1,N3-dimethylallox-
azine, 8) of one-step approaches to the desired products from
commercially available halides 6 and 7. Attempts to install an
N,N-dimethylated substituent from compound 9 led us to in-
termolecular product 10 under a variety of one-pot conditions.
Quaternary ammonium containing flavins were successfully
prepared by a simple two-step procedure from commercially
available materials. Nucleophilic dipotassium alloxazine 11 was
achieved by heating alloxazine with potassium carbonate in
DMF. Subsequent treatment of the isolated salt with bromoalk-
yl ammonium species 6 in DMF produced the desired water-
Alloxazine 1 (Figure 1), the primary focus of this study, was
selected because it has a more thermodynamically favorable
interaction with dioxygen (O2) after electrochemical reduction,
in comparison to isoalloxazines 2-4, which have more positive
redox potentials. While all reduced flavin mimics are thermody-
namically disposed to reduce O2, initial electron transfer from
reduced flavin to O2 is the kinetic barrier to this interaction. In
biological oxidoreductases, where constitutive formation of re-
active oxygen species should be limited, the protein structure
and environment serve to accelerate the redox process.[56,57]
Furthermore, the relative synthetic ease with which two per-
manent cationic species can be installed in 1, with comparison
to the monoionic isoalloxazine systems, imparts excellent solu-
bility over a wide range of pH.
While 1–4 are incompletely described as azaquinones
(Figure 1, redox active bisimines), both species have resonance
forms that contribute to an azaquinone, or quinone-like,
system. Further, their redox properties are similar to the qui-
none systems, and changes in pKas and relative redox poten-
tials between alloxazines and isoalloxazines are related to the
different alkylation sites, and consequently the relative proto-
nation sites of the chemically reduced flavins (N1ÀH for isoal-
loxazines and N10ÀH for alloxazines). The nature of these Ns
(N10, anilino- and N1, amido-) alters the electron density and
distribution of the system in a predictable manner, resulting in
a >150 mV negative shift in redox potentials for isomerization
of the C=N double bond from the amido-N1 site to the ani-
line-N10 site. Such aspects are highlighted in the comparative
voltammetry behavior of 1–4 presented in the following.
In line with the extreme versatility of voltammetry in its var-
iant modes (linear sweep, cyclic, or hydrodynamic) for the elec-
trochemical study of organic molecules,[57] this technique was
primarily employed in the present study on 1–4 (Figure 1) in
conjunction with UV/Vis spectroelectrochemical (SPEC) experi-
Figure 2. Outcome of single-step attempts to prepare desired flavin mimics.
Chem. Eur. J. 2016, 22, 9209 – 9217
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