# Combination of Chemo- and Biocatalysis: Conversion of Biomethane to Methanol and Formic Acid
## 1 Introduction
\[\mathrm{CH_{4}+0.5~{}O_{2}\to CH_{3}OH} \mathrm{\Delta G^{\circ}=-27.7~{}kcal\cdot mol^{-1}} \tag{1}\] \[\mathrm{CH_{4}+O_{2}\to CH_{2}O+H_{2}O} \mathrm{\Delta G^{\circ}=-69.1~{}kcal\cdot mol^{-1}}\] (2) \[\mathrm{CH_{4}+1.5~{}O_{2}\to CO+2~{}H_{2}O} \mathrm{\Delta G^{\circ}=-134.0~{}kcal\cdot mol^{-1}}\] (3) \[\mathrm{CH_{4}+2~{}O_{2}\to CO_{2}+2~{}H_{2}O} \mathrm{\Delta G^{\circ}=-195.5~{}kcal\cdot mol^{-1}} \tag{4}\]  
However, the direct formation of formaldehyde from methane and oxygen has been known for years and satisfying selectivities can be achieved at low conversion (\(X_{\mathrm{CH_{4}}}<10\%\)) [6]. At very low residence times the reaction can be controlled partially. During recent years, researchers focused their studies on methods to increase the productivity of this reaction [29; 30; 31] and found that a CH\({}_{2}\)O space-time yield above 5 kg\({}_{\mathrm{CH_{2}O}}\)'kg\({}_{\mathrm{cat}}\)\({}^{-1}\)-h\({}^{-1}\) is possible by using an optimized mesoporous silica supported VO\({}_{\mathrm{x}}\) catalyst [32; 33]. [PERSON] and [PERSON] transformed methane directly to methanol and formic acid via chlorine dioxide radicals under photoirradiation [34]. Moreover, self-disproportionation of formaldehyde to methanol and formic acid under hydrothermal or supercritical conditions occurs spontaneously [35; 36]. However, both the products can be obtained under much milder conditions applied in an enzymatic conversion of formaldehyde. Formaldehyde dismutase (FDM; EC 1.2.99.4) is an enzyme which converts formaldehyde into methanol and formic acid [37; 38]. By a so-called flip-flop mechanism, formaldehyde is disproportionated to formic acid and methanol. Initially, hydrated formaldehyde is oxidized to formic acid. Thereafter the reduction equivalents are transferred to the enzyme bound cofactor NAD\({}^{+}\) which is regenerated by the reduction of another formaldehyde molecule to methanol. As described by [PERSON] [39], the enzyme is independent of further cofactors and very robust. The associated and self-regenerating cofactor makes the FDM interesting to use as a technical enzyme because neither an additional cofactor has to be added nor an alternative regeneration path has to be developed. Most importantly, the specific activity of FDM can be up to 6000 times higher compared to MMO (138,000 \(\pm\) 16,000 nmol\({}_{\mathrm{CH_{3}OH}}\)-mg\({}^{-1}\)-min\({}^{-1}\) vs. 22.9 \(\pm\) 6.1 nmol\({}_{\mathrm{CH_{3}OH}}\)-mg\({}^{-1}\)-min\({}^{-1}\) over FDM [38] and pMMO [24], respectively). This led us to the idea to combine highly productive chemocatalytic methane oxidation with fast biocatalytic conversion of the formaldehyde intermediate to generate methanol and formic acid in equimolar amounts. Scheme 1 compares the different routes for methanol production: (i) in industrial scale including formic acid synthesis, (ii) via direct oxidation routes and (iii) the here presented chemo-/biocatalytic oxidation cascade. The latter, our approach, uses molecular oxygen in the chemocatalytic methane activation step followed by a relatively fast (selective) biocatalytic methanol production, additionally yielding formic acid in equimolar amounts. Moreover, methane from mimicked biogas (CH\({}_{4}\):CO\({}_{2}\) = 1:1) was utilized in this work to further explore this renewable feedstock, which is produced at a scale of Gm\({}^{3}\) a\({}^{-1}\)[41]. The following results should be also set into context of presently discussed methanol production routes from biogas which follow the conventional syngas strategy [42] or might use the hydrogenation of carbon dioxide [43; 44; 45; 46]. Clearly, the following results represent insights of a new, alternative route to already existing methods from biomethane to methanol.