A new ligand, 5-diethylphosphonoisophthalic acid ((HOOC) 2C 6H 3-PO 3(C 2H 5) 2, H 2Et 2L), for the hydrothermal synthesis of inorganic–organic hybrid compounds was prepared and characterized by NMR-spectroscopy. Its in situ hydrolysis leads to the corresponding 5-phosphonoisophthalic acid ((HOOC) 2C 6H 3-PO 3H 2, H 4L). Applying high-throughput methods, different di- and trivalent metal salts for the synthesis of crystalline metal phosphonates based on H 2Et 2L have been screened. From the resulting discovery library, single-crystals of four new compounds, [Sm 2(H 2O) 4(H(OOC) 2C 6H 3-PO 3) 2]·2H 2O ( 1), [Cu 3(H 2O)(H(OOC) 2C 6H 3-PO 3) 2]·2H 2O ( 2), Ca 2(H 2O)[H(OOC) 2C 6H 3-PO 3H] 2 ( 3), and Ba 2(H 2O) 3(OOC) 2C 6H 3-PO 3 ( 4), have been isolated. The single-crystal structure determination of the title compounds shows H 4L to be a versatile ligand, exhibiting different types of coordination modes between the functional groups and the metal ions. A comparison of the structural features of the title compounds shows a varying degree of M–O–M connectivities. Thus, isolated metal–oxygen clusters (compounds 1 and 2), infinite M–O–M chains (compound 3), and infinite M–O–M layers (compound 4) are observed. The title compounds 1, 2, and 3 were further characterized by IR-spectroscopy, TG-, EDX-, and elemental chemical analysis.