In 1872
Adolf von Baeyer mixed various aldehydes, including formaldehyde, with phenols in a strongly acidic solution. The resultant tars defied characterization; but represented the typical products of a phenol/formaldehyde polymerization.
Leo Baekeland discovered that these tars could be cured into a brittle substance which he marketed as "
Bakelite". This polymer was the first commercial synthetic plastic. The success of Bakelite spurred scientific investigations into the chemistry of the phenol/formaldehyde reaction. One result was the discovery made in 1942 by
Alois Zinke, that p-alkyl phenols and formaldehyde in a strongly basic solution yield mixtures containing cyclic tetramers. Concomitantly,
Joseph Niederl and H. J. Vogel obtained similar cyclic tetramers from the acid-catalyzed reaction of resorcinol and aldehydes such as benzaldehyde. A number of years later,
John Cornforth showed that the product from p-tert-butylphenol and formaldehyde is a mixture of the cyclic tetramer and another ambiguous cyclomer. His interest in these compounds was in the tuberculostatic properties of their oxyethylated derivatives. In the early 1970s
C. David Gutsche recognized the calix shape of the cyclic tetramer and thought that it might furnish the structure for building an enzyme xenologue. He initiated a study that lasted for three decades. His attention to these compounds came from acquaintance with the
Petrolite company's commercial
demulsifiers, made by
ethoxylation of the still ambiguous products from p-alkylphenols and formaldehyde. He introduced the name "calixarene": from "calix", the Greek name for a chalice, and "arene" for the presence of aryl groups in the cyclic array. He also determined the structures for the cyclic tetramer, hexamer, and octamer, along with procedures for obtaining these materials in good to excellent yields. He then established procedures for attaching functional groups to both the upper and lower rims and mapped the conformational states of these flexible molecules. Additionally, he proved that the cyclic tetramer can be frozen into a cone conformation, by the addition of measurably large substituents to the lower "rim" of the calix shape. Concomitant with Gutsche's work was that of the Hermann Kämmerer and Volker Böhmer. They developed methods for the stepwise synthesis of calixarenes. Chemists of
University of Parma, Giovanni Andreetti, Rocco Ungaro and Andrea Pochini were the first to resolve
X-ray crystallographic images of calixarenes. In the mid 1980s, other investigators joined the field of calixarene chemistry. It has become an important aspect of supramolecular chemistry and attracts the attention of hundreds of scientists around the world. The Niederl cyclic tetramers from resorcinol and aldehydes were studied in detail by
Donald J. Cram, who called the derived compounds "
cavitands" and "
carcerands". An accurate and detailed history of the calixarenes along with extensive discussion of calixarene chemistry can be found in Gutsche's monograph. ==Medical uses==