The neutral cluster V2O5 is generated and detected in the gas phase. Its reactivity toward butane is studied both experimentally and theoretically. Experimental results show dearly that neutral V2O5 can react with n-butane (C4H10) to generate V2O5H2, indicating double hydrogen atom transfer from C4H10 to V2O5 to produce C4H8. Further experimental evidence indicates that V2O5 is only partially reacted even at very high concentrations of C4H10. Density functional theory (DFT) studies show that the lowest energy triplet state of V2O5 is reactive toward C4H10, whereas the ground state singlet V2O5 is inert. Calculated results are in agreement with experimental findings, and a detailed reaction mechanism is provided. Reactions of V2O5H2 with several oxidants are also studied theoretically to find a path to regenerate V2O5. Neutral (V2O5)-V-3 can also react with C2H6 to form V2O5H2 and C2H4, but only as a minor reaction channel; the major product is the adsorption product V2O5(C2H6).