Natural gas consists mainly of methane, an important resource that can unfortunately have a significant impact on our climate if released into the atmosphere. Methane can, however, be used to produce another important base chemical: methanol. Methanol is currently synthesized from methane through the creation of syngas, a thermodynamically inefficient process, as it requires high temperatures and pressures to overcome the reaction energy of +206 kJ/mol in steam reforming. Due to the need for intermediate syngas creation, the on-site usage of methane at smaller and remote sources of methane is greatly hindered, and the methane at such remote sites is often simply flared, as its transport to other locations is not easily achieved. Methanol, however, can be stored and transported with much less effort, as it is a liquid under ambient conditions. A direct and selective pathway from methane to methanol, usable at small and large scales, would therefore greatly decrease the environmental impact of remote methane sources, as well as methanol-derived substances and methanol-based fuels. A key challenge is achieving high selectivity in the direct methane to methanol reaction. Burning methane is easy, stopping at methanol is not. Recently, many advances in the field of methane activation have been made. Inspired by enzymes, many biomimetic, homogeneous catalysts have been designed to achieve the goal of high selectivity combined with high yield. However, industrially, heterogeneous catalysts provide many advantages. From a chemical perspective, metal-organic frameworks (MOFs) offer an intriguing possibility to create catalysts that combine the best features of homogeneous catalysts, namely their atomically precise structures and vast possibilities for tuning, with the advantages of a solid material. MOFs are also an ideal platform to understand reaction mechanisms in detail and then propose new design strategies for further investigation. Two important design goals for a MOF catalyst for the selective conversion of methane to methanol are suggested by economics and prior work: 1) the catalyst should be active under mild conditions and 2) the obtained methanol should be protected to prevent overoxidation. Metaloxo centers are active species for the activation of the C-H bond of methane and other alkanes and can be designed into a variety of MOF structures. Also, the secondary interactions and geometric effects of the host system (sometimes called second-sphere effects) can be exploited to control reaction mechanisms in nanoporous materials as recently shown by Snyder et al. The mobility of the CH3 radical involved in many mechanisms for methane activation proved to be a key factor in the activity of zeolites incorporating metal-oxo centers, which have already been shown to be active for continuous methane oxidation using N2O and H2O. In MOFs, iron-oxo centers (Fe=O) have been successfully incorporated into the Fe2(dobdc) family (Fe-MOF-74, dobdc 4-=2,5-dioxido-1,4-benzenedicarboxylate) and have been shown to be catalytically active towards C-H bond cleavage in experiment and theory. For the case of ethane to ethanol conversion, this MOF exhibited a high selectivity due to the strong binding of the product to the open metal sites, resulting, however, in a low yield in both flow-through and batch operation modes as the reactive sites become blocked by the strongly bound product. Many other systems incorporating metal-oxo centers have since then been investigated for the oxidation of methane by computational means. Also, our group recently investigated metal-oxo species in MOFs for the activation of the C-H bond by identifying structure-activity relationships in MOFs based on DFT calculations, screening a MOF database to identify promising MOF systems, and investigating triazolate based MOFs with varying metals and anions theoretically. Based on their studies of triazolate based MOFs for C-H bond activation, Rosen et al., proposed the MOF Zn5Cl4(BTDD)3, where H2BTDD = bis(1,2,3-triazolo [4,5-b],[4′,5′-i])dibenzo [1,4]dioxin, also known as MFU-4l, as a platform material. This MOF is known to be chemically and thermally stable. Furthermore, four of the five Zn ions contained in the metal node can be post-synthetically exchanged with other transition metals and even lithium to obtain Mx-MFU-4l (M being the introduced metal and x the number of exchanged ions per unit cell). The exchanged metal sites can in turn provide a basis for a desired catalytic application. Besides the metal itself, also the counter-anion located at the metal node is subject to post-synthetic exchange. In this work, we focus on the exchange of Cl -to OH -, which has already been experimentally achieved for a range of transition metal substituted M-MFU-4l(OH) materials (M=Cu, Co, Ni). See Figure for a representation of the Fe1-MFU-4l(OH) MOF structure. We limit this investigation to N2O as the oxygen source for practical reasons and only consider the homolytic methane activation pathway, as it is the most relevant one for iron-oxo active sites. The goal of this work is to achieve insight into the C-H bond activation in methane and the factors that affect the selectivity using a fully periodic model of the MFU-4l platform, including non-local second-sphere effects.