1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 Redox Properties and Interchromophoric Electronic Interactions in Isoalloxazine  Anthraquinone Dyads Giovanni Valenti, [a] Matteo Iurlo, [a] Rosa Marı ´a Claramunt, [b] Gianluca Accorsi, [c] Francesco Paolucci, [a] M. A ´ ngeles Farra ´n,* [b] and Massimo Marcaccio* [a] The electrochemistry of a family of recently synthesized isoalloxazine cyclophanes containing anthraquinones, variously substituted and linked by aliphatic chains of different lengths, has been studied. The redox behavior of such species was elucidated by complementing the voltammetric studies with DFT molecular modelling. In these cyclophanes (mimicking the active centers of enzymes), the distance between chromophores and their reciprocal orientations were found to significantly modify their redox properties. Inter-moiety p  p stacking plays an important role in the electrochemical behavior by modulat- ing the orbital energies, which leads to an inversion of the localization of the first reduction, with the anthraquinone being reduced before the more electron-accepting flavine. 1. Introduction Flavins are undoubtedly a kind of very versatile redox cofactors found in flavoenzymes, enzymes that catalyze a wide range of redox reactions. They are derivatives of vitamin B2, riboflavin, that is the biosynthetic precursor of FAD (Flavin Adenine Dinucleotide) and FMN (Flavin Monononucleotide). Both cofac- tors are composed of a isoalloxazine (AL) unit bearing either a ribityl adenine group or a ribityl phosphate chain. The isoalloxazine takes part in several important biological pro- cesses comprising, cell apoptosis, oxygen activation, dehydro- genation of metabolites, redox reactions, DNA repair. [1] The catalytic mechanism of flavoenzymes proceeds via the oxida- tion of the substrate with formation of the reaction product, assisted by NADPH. Then, the reduced flavin reacts with an electron-accepting substrate (e. g., oxygen) regenerating the oxidized state, being the process reversible in many cases. Flavoproteins also mediate between single-electron redox processes, involving iron-heme and iron sulfur clusters, and the obligate two-electron redox processes of NADH. [2] The conjugated structure of isoalloxazine, combined to the surrounding proteic environment that favors the interaction with the isoalloxazine itself, allows an exceptional chemical versatility through hydrogen bonding, p  p stacking or steric effects and charge transfer interactions. Quinone Reductase (QR) enzyme family represents one of the interesting type of flavoenzymes. These flavin-containing quinone reductases are involved in the protection of organisms from redox stress. Quinone Reductase 1 (QR1) is a chemo- protective enzyme involved in cellular defense against the electrophilic and oxidizing metabolites of xenobiotic quinones; while quinone reductase 2 (QR2) is a quinone reducing enzyme which does not use NAD(P)H as QR1 does. X-ray structures of both reductases with different substrates are available in the literature, [3,4] showing structures with different relative orienta- tions of FAD-quinone complexes, for which the quinone lies above the isoalloxazine central ring. These enzymes are capable of catalyzing the two-electron reduction directly to the hydro- quinone form, thus bypassing the generation of semiquinone, which can give oxidative stress [5] through production of super- oxide radicals. The large variability in the redox potentials and activity of the flavin in different enzymes, [6,7,8,9] mostly depends by the role of the environment that surrounds the isoalloxazine system, as evidenced by many studies in the literature where this aspect has been thoroughly investigated. Amongst the interactions studied the most interesting includes hydrogen bonding, [10,11] aromatic p-p stacking, [12] steric effects, [13] change transfer interactions [14] and complexation with metal ions. [15] Herein we have turned our attention towards closed cyclophane-like structures in order to somehow control the distance and orientation of the two chromophores involved in a simple model of the QR active centers. [16,17,18] Reports on cyclophanes containing isoalloxazines [19,20] and dyads of iso- alloxazines bridged with naphthalene, anthracene and pyrene are available [20] and we have recently reported a series of cyclophanes containing isoalloxazine with naphthalene, anthra- quinone and anthracene. [17,18,21] To tackle such important issues, we have then chosen to investigate supramolecular, systems made of flavins and aromatic moieties, comparing the behavior [a] Dr. G. Valenti, Dr. M. Iurlo, Prof. Dr. F. Paolucci, Prof. Dr. M. Marcaccio Department of Chemistry “ G. Ciamician” University of Bologna,Via Selmi 2, 40126, Bologna (Italy) E-mail: massimo.marcaccio@unibo.it [b] Dr. R. M. Claramunt, Prof. Dr. M. . Farrµn Departamento de Química Orgµnica y Bio-Orgµnica, Facultad de Ciencias, Universidad Nacional de Educación a Distancia (UNED), Paseo Senda del Rey 9, 28040 Madrid, Spain E-mail: afarran@ccia.uned.es [c] Dr. G. Accorsi CNR NANOTEC Institute of Nanotechnology c/o Campus Ecotekne University of Salento, Via Monteroni, 73100 Lecce (Italy) Supporting information for this article is available on the WWW under https://doi.org/10.1002/celc.201701374 An invited contribution to the Alan Bond Festschrift 1 ChemElectroChem 2018, 5,1–7  2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim These are not the final page numbers! ÞÞ Articles DOI: 10.1002/celc.201701374