Among the organic semiconductors with applications in organic electronics, pentacene (Pc) has been widely studied for its charge transport qualities. [1,2] Its high field-effect mobility arising from its high molecular order and large grain sizes in films makes it suitable for devices such as low-voltage organic thinfilm transistors, [3,4] organic light-emitting diodes, [5] and fieldeffect transistors.[6] Its regular crystal structure makes it a good material for efficient organic photovoltaic cells. [7] However, its poor solubility in organic solvents and its sensitivity to oxidation, together with the interest in achieving better device performance, encouraged the design of new pentacene derivatives. [8,9] Functionalization of organic molecules is used as a strategy to change their stability, reduction/oxidation potentials, as well as their electrical and optical properties, since introduction of substituents alters the molecular energy levels, and-depending on the type, number and position of the substituents-also the supramolecular arrangement.[10-13] Two functionalization strategies in particular are currently under debate: alkoxylation [8] and fluorination. [14][15][16] While the former method is expected generally to destabilize the frontier molecular orbitals (MOs) due to the strong positive mesomeric effect of oxygen (+ M, electron donating), the latter is expected to stabilize the frontier MOs due to the strong inductive effect of fluorine (-I, electron withdrawing). This has indeed been demonstrated for a number of (per)fluorinated compounds in a recent quantum-chemical study.[17] Interestingly, an intuitive prediction of the resulting (optical) bandgaps of these compounds is not possible; thus, depending on the molecular backbone, hypsochromic (e.g. oligothiophenes) or bathochromic shifts (oligoacenes) are observed and reproduced by (time-dependent) density functional theory, (TD)DFT, calculations.[17]Herein we raise the question of whether it is possible to control the HOMO and LUMO levels independently by site-specific substitution, due to its high practical relevance for the rational design of molecular materials. In particular, we investigate the impact of two different substituents on the frontier MOs and (optical) bandgaps of pentacene by quantum-chemical methods. We choose methoxy and fluorine, as they represent two extremes of electronic manipulation and we systematically vary the number and position of the substituents. In doing so, a conceptual approach is provided, which should eventually lead synthetic chemists to the design of molecules with maximum electronic manipulation while minimizing structural modification.The molecular structures, HOMO and LUMO energies, and first optical transition for methoxy-and fluorine-substituted pentacenes are shown in Figure 1. As a first approximation, the effect of substitution with electron-withdrawing substituents on pentacene is explained by Hückel theory.[18] If the LCAO coefficients in HOMO and LUMO at the substituent positions are similar, both ele...