Squaric acid and esters: Analysis for contaminants and stability in solvents

Two squaric acid diesters, squaric acid diethyl ester (SADEE) and squaric acid dibutyl ester (SADEE), have been suggested as replacements for 2,4-dinitrochlorobenzene in the treatment of alopecia areata and alopecia totalis. We synthesized these squaric acid diesters and examined them for the presence of carcinogenic contaminants, hexachlorobutadiene and tetrachloro-2-cyclobutene-1-one, by gas chromatography-mass spectrometry (GC-MS). The stability of SADBE to hydrolysis by water in acetone, butanol, isopropanol, and absorbent ointment with and without molecular sieves was examined. The stability of SADEE in ethanol and acetone, with and without molecular sieves, was also studied. Hydrolysis products were detected by their formation of a colored complex with ferric chloride. This complex absorbs in the visual range at 480 nm, thus affording a convenient method for determination of the concentration of free squaric acid in a solution. No contaminants were found by positive or negative ion detection in our GC-MS system. At the end of 3 weeks the extent of hydrolysis was greater in alcohols than in acetone when 10 and 100 molar excess of water were added to the solutions. In the presence of molecular sieves, hydrolysis was reduced even at 100 molar excess of added water in alcohol or acetone. However, under storage conditions without sieves, acetone solutions and alcohol solutions were equally stable over a period of 2 months. Molecular sieves reduce hydrolysis of squarate esters in the presence of a large molar excess of water, regardless of solvent.