In this research, at first, a comparative DFT study on hydride or fluoride release from a number of known orthoamides, their fluorine derivative having a central C-F bond and some simple organic compounds, is reported. The obtained data show that orthoamides release hydride or fluoride anions much easier than do other known organic compounds studied here. Interestingly, three simulated orthoamides having a central C-F bond, spontaneously and like an inorganic compound, release fluoride anion upon dissolving in polar solvents. The calculations confirmed that hyperconjugation interactions in the initial orthoamides facilitate the anion release from these compounds. However, the data clearly show that the proper overlap of an empty p orbital of the central carbon atom with adjacent lone-pair orbitals of nitrogen atoms ( lpN → lp*C or, in other words, the pπ-pπ interaction) in the resulting carbocations is a more important factor that must be taken into consideration when designing the hydride, fluoride, or other anion releasing agents. In addition, for the first time, a mechanism of hydride and fluoride removal from the orthoamides either through their reaction with BH3 and BF3 molecules, respectively, or upon their protonation is provided. To continue and for generalization of results to other groups attached to the central carbon atom of orthoamides, the reactions of H+ with orthoamides having the CH3, OH, CN, NH2, or C5H5 substituents were studied. The results showed that in all cases and in both gas and solution phases the above substituents easily leave the carbon atom as an anion and bond to H+. Thus, we have to conclude that upon the reaction of orthoamides with usual Lewis acids, many types of substituents on their central carbon atom can leave these compounds as anions.