The optimal design of reactive complex distillation systems is a highly nonlinear and multivariable problem, and the objective function used as optimization criterion is generally nonconvex with several local optimums and subject to several constraints. The esterification of lauric acid and methanol is explored using thermally coupled distillation sequences with side columns and with a minimum number of reboilers. The product of the esterification can be used as biodiesel. This is a major step forward since thermally coupled reactive distillation sequences with side columns and with a minimum number of reboilers offer significant benefits, such as the following: reductions on both capital investment and operating costs due to the absence of the reboilers and higher conversion and selectivity since products are removed as they are produced as well as no occurrence of thermal degradation of the products due to a lower temperature profile in the column. In this work, we have studied the design of reactive distillation with thermal coupling with a minimum number of reboilers, using differential evolution with restrictions coupled to AspenONE Aspen Plus. Also, we have analyzed the control properties of the reactive distillation schemes studied, and the results indicate that the energy requirements and the total annual cost of the complex distillation sequences with a minimum number of reboilers are reduced significantly in comparison with the conventional reactive distillation process and can be also achieved without significant control problems.