In this paper, HFC-161 is proposed as a substitution of HFC-134a used in small automobile air-conditioning. According to the previous work, HFC-161 has some excellent thermal physical characteristics. Theoretical cycle analysis was firstly developed to analyze the feasibility of replacing HFC-134a with HFC-161 at evaporation temperatures ranging from −5°C to 10°C, and condensation temperatures ranging from 50°C to 65°C. Based on the theoretical results, the experimental comparison of the cycle performance for HFC-161 and HFC-134a was conducted. The experiment was performed on a single-stage compression refrigeration system with a compressor designed for HFC-134a. In theory, the COPs of HFC-161 were quite close to those of HFC-407C; the specific refrigerating effects and volumetric refrigerating effects of HFC-161 were about 50% and 38% larger than those of HFC-134a, respectively. Experimental results showed that the COPs of HFC-161 were higher than those of HFC-134a at evaporation temperatures of −5°C, 0°C, 5°C; the refrigeration capacities and compressor power consumptions of HFC-161 were about 56% and 47% larger than those of HFC-134a; the compressor discharge temperatures of HFC-161 were higher than that of HFC-134a by 20–35°C. The experimental data agreed with the theoretical data. Considering the good environmental performance of HFC-161, it is highly significant to analyze the possibility of HFC-134a being substituted by HFC-161.
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