During the past decade, two-dimensional (2D) nanomaterials have provided a broad platform for a wide variety of applications and have been the focus of numerous studies due to their unique properties. The most common 2D materials are of hexagonal or trigonal symmetry, with structures that can be grown on inexpensive substrates like Si and sapphire. The ability to grow 2D materials on additional substrates with a larger variety of symmetries and surface terminations, such as metals, glass, and complex metal oxides, can be regarded as a big and necessary step in the design of new functional materials. However, there is a dearth of knowledge on 2D materials beyond hexagonal and trigonal symmetries, their synthesis, and epitaxy. Here, we present a procedure to rationalize the aqueous exfoliation of known 3D materials as a route to create stable tetragonal 2D materials with tunable lattice parameters and electronic structures. We develop a model using first-principles density functional theory plus thermodynamics to propose an ecofriendly synthesis of 2D materials using aqueous media and use it to investigate a class of previously synthesized tetragonal ABX compounds. Then, we predict the thermodynamics of their exfoliation in water by combining surface slab models, their subsequent surface transformations, and experimentally determined changes in free energy. The atomistic results obtained here are correlated to periodic properties and are used to elucidate trends in electronic structure and the thermodynamics of aqueous exfoliation.