The mechanisms of chemical reactions of molybdenum suboxide clusters Mo2On- (n = 2-5) with methane are investigated using B3LYP hybrid density functional theory and polarized basis sets. In particular, we focus on the reactions of the most stable structural isomers of Mo2O2,3,4,5- that lead to single molybdenum species such as HMoO2CH3-, as seen in the recent experimental study of Jarrold and co-workers. We find that, while all experimentally observed products are unfavorable due to the high amount of energy required to cleave the metal oxide, the formation of HMoO2CH3- is least endothermic. Even in this case, the thermodynamics of these reactions is very unfavorable when a single methane is reacted with the metal oxide. However, we find that the sequential addition of two methanes produces HMoO2CH3- (and another neutral molecule whose identity depends on the number of oxygens in the metal oxide) at a much lower thermodynamic cost. Further, the overall reaction barriers are much lower when the second methane adds prior to the Mo2O2,3,4,5- cleavage. The methane addition at each metal center oxidizes the metals to produce a species that is then stable enough to afford the Mo-Mo cleavage.