Can Range-Separated and Hybrid DFT Functionals Predict Low-Lying Excitations? A Tookad Case Study Boxue Tian, † Emma S. E. Eriksson, † and Leif A. Eriksson* ,†,‡ School of Chemistry, National UniVersity of Ireland - Galway, Galway, Ireland and O ¨ rebro Life Science Center, School of Science and Technology, O ¨ rebro UniVersity, 701 82 O ¨ rebro, Sweden Received March 18, 2010 Abstract: The spectral properties of Tookad (Pd-bacteriopheophorbide, Pd-BPheid), an effective photosensitizer that targets mainly prostate tumors, and metal-free BPheid have been studied using time-dependent density functional theory (TD-DFT). The well-established B3LYP functional, which is known to overestimate excitation energies, was included in the study along with recently introduced range-separated and meta hybrid DFT functionals CAM-B3LYP, M06, M06-2X, M06HF, ωB97XD, ωB97X, ωB97, LC-ωPBE, and PBE0 (PBE1PBE). The main focus is the performance of the new functionals in predicting low-lying excitations (>600 nm), to explore their potential roles in drug development for photodynamic therapy. The data suggests that ωB97XD overall performs best for the Q y transition band (the red-most absorption), followed by CAM-B3LYP. LC-ωPBE, ωB97, B3LYP, and PBE1PBE all generated the Q y band far from the experimental position. The error in absorption energy for the Q y band was found to be at most 0.05 eV for ωB97XD, compared to 0.15-0.19 eV for B3LYP. The use of different basis sets used in excited-state calculations was shown to be of less importance as was the use of either B3LYP or M06 in geometry optimizations. 1. Introduction Photodynamic therapy (PDT), in which a photosensitizer, light, and oxygen are the major components, has been shown to be a promising method for treatment of various cancers as well as other diseases. In the reaction between the excited photosensitizer and oxygen in the tissue, reactive oxygen species (ROS), such as singlet oxygen, are formed and can readily react with the target tissue. Photosensitizers are light- absorbing molecules often made up by conjugated systems, such as porphyrins, chlorins (17,18-dihydroporphyrin), and bacteriochlorins (7,8,17,18-tetrahydroporphyrin). The first approved and most widely used photosensitizer is Photofrin that has been successfully used in PDT. However, Photofrin suffers from drawbacks, such as light absorption at wave- lengths below the optimal tissue penetration as well as long- lasting photosensitization, due to accumulation in the skin tissue (low-clearance rate). Additional photosensitizers are now available on the market, and new photosensitizers are continuously being developed with the aim to reduce the side effects and increase the efficiency of the treatment. One of the most important aspects in the development of photosensitizers is the absorption properties. The red-most absorption peak of porphyrin- and chlorin-based photosen- sitizers is in general positioned between 600 and 700 nm and is the one used in PDT to excite the photosensitizer. Although this is usually significantly weaker than absorptions occurring around 400 nm, it is used in PDT due to the increased tissue penetration of the light at these wavelengths. Bacteriochlorophylls (BChl) display relatively speaking very large extinction coefficients for the low-lying Q y band, and thus some BChls and their derivatives have been suggested to be utilized as photosensitizers in PDT. 1,2 Substitution of the central Mg 2+ in native BChl with other divalent tran- sition-metal ions, such as Pd 2+ , Co 2+ , Ni 2+ , Cu 2+ , Zn 2+ , and Mn 2+ has been carried out successfully, 3 and the spectroscopic properties of these synthesized compounds * Corresponding author. E-mail: leif.eriksson@nuigalway.ie. † National University of Ireland. ‡ O ¨ rebro University. J. Chem. Theory Comput. 2010, 6, 2086–2094 2086 10.1021/ct100148h  2010 American Chemical Society Published on Web 06/21/2010