Ionic liquid matrices (ILMs) have great contributions and showed high improvements for the protein analysis using matrix assisted laser desorption/ionization mass spectrometry (MALDI-MS). The physicochemical properties of these materials are important to understand the ILM performance and design the effective ILMs. The present study represented the relationships of the chemical structure and the physicochemical properties of ILMs. Different organic bases for two common organic matrices called 2,5-dihydroxy benzoic acid (DHB) and 3,5-dimethoxy-4-hydroxycinnamic acid (Sinapinic acid, SA) were calculated. The two series showed the same profile for molar refractivity, molar volume, Parachor, index of refraction, polarizability and surface tension. However, ionic liquids based on sinapinic acid showed higher values than DHB for all parameters except index of refraction and surface tension. These parameters may explain the high performance of SA-ILs for protein analysis compared to DHB-ILs. The present results are important for one who is looking for a new design of ILMs.