The synthesis and design of reactive distillation columns separating reacting mixtures with the most unfavorable relative volatilities (i.e., the reactants are the heaviest and lightest components with the products being the intermediate ones) are described. The unfavorable thermodynamics poses great difficulties in combining the reaction operation and the separation operation involved and limits severely the potential of reactive distillation columns in the reduction of capital investment (CI) and operating cost. To remove the limitation, we propose two strategies for facilitating the synthesis and design of this kind of reactive distillation columns in this article. One is to arrange prudentially the reactive section so as to strengthen internal energy integration between the reaction operation and the separation operation involved; that is, while the reactive section should be placed at the bottom of the reactive distillation columns separating exothermic reactions, it should be at the top of the reactive distillation columns separating endothermic reactions. The other is to introduce an external recycle flow between the two ends of the reactive distillation columns to reinforce internal mass integration and internal energy integration between the reaction operation and the separation operation involved; that is, whereas the external recycle flow should be directed from the top to bottom of the reactive distillation columns separating exothermic reactions, it should be from the bottom to top of the reactive distillation columns separating endothermic reactions. Separation of four hypothetical ideal (i.e., two quaternary and two ternary systems, respectively) and two real nonideal (i.e., two quaternary systems) reacting mixtures is chosen to evaluate the proposed strategies. The results show that they can considerably lower energy requirement besides a further reduction in CI. (c) 2012 American Institute of Chemical Engineers AIChE J, 59: 20152032, 2013