The thermally coupled distillation configuration (TCDS) could reduce energy consumption and capital investment compared with conventional distillation sequences. But their use was still limited. The five kinds of conventional distillation sequences and five kinds of thermally coupled distillation sequences were performed in separation of quaternary mixtures with distillation rigorous simulations. The energy savings of a series of thermally coupled distillation sequences were compared. The results showed that the feed composition and ease of separation of the composition have great effect on the choice of the thermally coupled sequences. In the most cases, the TCDS with side rectifier or striper had the more energy saving effect.