The selective separation of strongly hydrophilic structurally related compounds in aqueous solutions is a long-standing challenge due to a trade-off between separation selectivity and capacity. This work shows a new method to separate strongly hydrophilic structurally related compounds through hydrophobic ionic solution-based liquid-liquid extraction, with L-ascorbic acid 2-glucoside (AA-2G) and L-ascorbic acid as model compounds. Extraordinary distribution coefficient, superb molecular selectivity, large extraction capacity and good recyclability without using strong acids and salts were all achieved, with a small consumption of phosphonium bromide ionic liquid and aprotic molecular diluent. The essence of this method is the successful combination of both strong hydrogen-bond basicity and good hydrophobicity along with significant preferential solvation phenomena of the constructed ionic solutions. Even if at a high feed concentration of 100 mg/mL, the purity of AA-2G could be greatly elevated from 50% to 96.2% with an ultrahigh yield of almost 100% after five-stage countercurrent extraction. (c) 2017 American Institute of Chemical Engineers AIChE J, 64: 1373-1382, 2018