A clear understanding of the formation mechanism of single atom M-N4 sites (M represents transition metals such as Fe, Co, Ni, etc) is required for rational synthesis of M-N-C catalysts for the oxygen reduction reaction (ORR) in fuel cells. On the basis of multi-component characterizations, especially in-temperature x-ray absorption spectroscopy (XAS), we unraveled that in the conventional synthesis route of M-N-C catalysts wherein the M, N, and C precursors are mixed for high temperature pyrolysis, the metal compound transforms to metal oxides, followed by the formation of tetrahedral M-O4 moieties as the temperature increases. The M-O4 releases single free atom M1, which is captured by the N-doped cavity nearby forming in-plane M-N4 moieties. The threshold transform temperature of the conversion from the tetrahedral M-O4 to in-plane M-N4 appear to increase with the oxophicility of the M, as it essentially determined by the difference in the thermodynamic stability of the tetrahedral M-O4 and in-plane M-N4 moieties. This transform temperature largely defines the optimal pyrolysis temperature of M-N-C ORR catalysts, such as 1000 ± 100 ℃ for Fe-N-C. The ultra-short mean free path of M1 in the inert gaseous environment and mild temperature range requires close proximity between the M-O4 and the N-doped cavity to form M-N4, which requires a well mix of the M, N, and C precursors prior to pyrolysis. As a result, the M-N4 sites are formed throughout the whole N-doped carbon matrix, and only a portion is electrochemically active accessible by air. If the metal precursor is not in physical contact with the N and C precursors during pyrolysis, M1 is generated upon the thermal decomposition of the M precursor, and nucleates forming small nanoparticles that land onto the N-C substrate rather than forming M-N4. Therefore, relatively high pyrolysis temperature and well mix of the M, N, and C precursors are two salient features and limitations of the conventional synthesis route. These two limitations can be overcome by chemical vapor deposition of metal chlorides onto the N-C substrate that is not in physical contact with the metal chlorides. The gas phase metal chlorides are formed at relatively low temperature. They have much longer mean free paths than the corresponding M1 since the M is isolated by few Cl- ions. As a result, M-N4 sites are formed exclusively on the surface of the N-C substrate via deposition of gas phase metal chlorides into N-doped cavities. In addition, the optimal pyrolysis temperature of M-N-C is generally much lower than the conventional synthesis route owing to the absence of the M-O4 intermediates as the generators of M1. Consequently, we demonstrate a highly active Fe-N-C ORR catalyst synthesized via CVD at 750 ℃ with a surface Fe-N4 site density of 1.8 wtFe%. Acknowledgements This work was supported by the US Department of Energy under award number DE-EE0008416 and DE-EE0008075. The authors acknowledge the support from the DOE Energy Efficiency and Renewable Energy Fuel Cell Technologies Office (DOE-EERE-FCTO) ElectroCat consortium. This research used beamline 6-BM and 8-ID (ISS) of the National Synchrotron Light Source II, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Brookhaven National Laboratory under Contract No. DE-SC0012704. Argonne is a U.S. Department of Energy Office of Science Laboratory operated under Contract No. DE-AC02-06CH11357 by UChicago Argonne, LLC.