Development of efficient molecular photoacoustic contrast agent plays significant role in the next generation biomedical imaging techniques. This article demonstrates a design criterion for small molecules to exhibit large photoacoustic effect by density functional theory (DFT) and its experimental validation. The method relies on controlling the effect of resonating structures on the vibrational energies of small molecules such that rapid thermalization pathways exist near higher-order unoccupied molecular orbitals. A series of Zn(II)porphyrin derivatives (Por-Cn-RAm, where n=12 or 8 and m=1–4) is designed as a model system by DFT and demonstrated a systematic variation in the absorption coefficients of C-H vibrational modes occurring at high-frequency spectral region. A systematic decrease in absorption coefficients was observed; and therefore, a similar variation in the photoacoustic signals is predicted. To …