Recent attempts to find energy-efficient thermal management systems for electric and plug-in hybrid electric vehicles have led to secondary loop systems as an alternative approach to meet dynamic heating and cooling demands and to reduce refrigerant charge. The choice of refrigerant for the primary refrigeration cycle is an important issue regarding the overall system performance. In this work, an HFC refrigerant (R-134a) and a natural refrigerant (R-744) are evaluated regarding a potential use in secondary loop systems. To meet the demands of R-744 cycles such as higher system pressure, most components have to be redeveloped. Nonetheless the use of the environmentally friendly refrigerant has advantages such as better applicability and performance in heat pump systems under cold ambient conditions. This work presents Modelica-based design and simulations of secondary loop automotive refrigeration systems with the HFC refrigerant in a subcritical and R-744 in a transcritical primary cycle. Under defined use cases and environmental conditions, both primary cycles are compared resulting in a better performance for HFC in a summer scenario and for R-744 under winter conditions.