Accurate Redox Potentials of Mononuclear Iron, Manganese, and Nickel Model Complexes ARTUR GALSTYAN, ERNST-WALTER KNAPP Department of Biology, Chemistry, and Pharmacy, Institute of Chemistry and Biochemistry, Free University of Berlin, Fabeckstr. 36a, D-14195 Berlin, Germany Received 19 November 2007; Accepted 11 April 2008 DOI 10.1002/jcc.21029 Published online 11 June 2008 in Wiley InterScience (www.interscience.wiley.com). Abstract: Density functional theory (DFT) was combined with solution of the Poisson equation for continuum dielectric media to compute accurate redox potentials for several mononuclear transition metal complexes (TMCs) involving iron, manganese, and nickel. Progress was achieved by altering the B3LYP DFT functional (B4(XQ3)LYP-approach) and supplementing it with an empirical correction term G X having three additional adjusta- ble parameters, which is applied after the quantum-chemical DFT computations. This method was used to compute 58 redox potentials of 48 different TMCs involving different pairs of redox states solvated in both protic and aprotic solvents. For the 58 redox potentials the root mean square deviation (RMSD) from experimental values is 65 mV. The reliability of the present approach is also supported by the observation that the energetic order of the spin multi- plicities of the electronic ground states is fulfilled for all studied TMCs, if the influence from the solvent is consid- ered as well. q 2008 Wiley Periodicals, Inc. J Comput Chem 30: 203–211, 2009 Key words: density functional theory; hypothetical functional B4XLYP; redox potential computation; iron/manganese/ nickel model complexes; low/high spin states Introduction Transition metal complexes (TMCs) often serve as cofactors in the active centers of proteins involved in enzymatic reactions. Therefore, it is important to characterize the redox properties of these cofactors in order to understand the electron-transfer (ET) reactions in such biochemical systems. A direct measurement of cofactor redox potentials in proteins is generally limited to equi- librium situations by establishing contact with the redox poten- tial prevailing in the solvent. If the cofactor is deeply buried in the protein, this contact is hampered, which may have an influ- ence on the measured redox potential. Furthermore, action redox potentials referring to nonequilibrium situations, which are typi- cal of ET reactions and transient redox states occurring in chem- ical reactions, cannot be measured directly. In such instances one can only estimate the action redox potential of an electron- donor group from measured ET rates, assuming the validity of standard ET theory, knowing the redox potential of the electron- acceptor group and approximating the reorganization energy. Because of these limitations the development of reliable theoret- ical methods to calculate redox potentials of TMCs is of great interest. Recent works 1–5 on the calculation of the redox poten- tials of TMCs are based on density functional theory (DFT), which has proved to be highly suitable. 6–10 The concept to com- bine DFT with continuum dielectric theories was implemented by Chen et al. 11 and used effectively in several studies, 1–5 where the smallest mean absolute deviation (MAD) between a com- puted and measured redox potential was found to be about 150 mV, corresponding to 3.46 kcal mol 21 . 2 However, ET in biolog- ical systems often proceed between redox-active species with energy gaps of less than 0.100 eV. Hence, enhancement of the accuracy of the DFT-continuum hybrid approach so that it may be applied reliably to ET reactions of biological relevance is a challenging task. Recent procedures 12–15 to compute redox potentials of differ- ent organic compounds (excluding TMCs) showed agreement with experiment in a range of 170 mV 12 (calibrated method of combined DFT and electrostatics computation) or 58 mV 14 (ab initio quantum chemistry with independent continuum electro- statics). DFT has proved to be an efficient and relatively accu- rate tool for the description of large molecular systems. Of the number of the DFT functionals that have been developed over Additional Supporting Information may be found in the online version of this article. Contract/grant sponsor: Deutsche Forschungsgemeinschaft; contract/grant numbers: Sfb 498 Project A5, GRK 80/2, GRK 268, GRK 788/1 Correspondence to: E. W. Knapp; e-mail: knapp@chemie.fu-berlin.de q 2008 Wiley Periodicals, Inc.