John C. Sheehan

American chemist

• Born: September 23, 1915
• Birthplace: Battle Creek, Michigan
• Died: March 21, 1992
• Place of death: Key Biscayne, Florida

Sheehan developed the first total synthesis of penicillin, opening the way for the production of the antibiotic in a pure form and for the production of specialized penicillins for a wide range of diseases.

Primary fields: Chemistry; medicine and medical technology

Primary invention: Synthetic penicillin

Early Life

John Clark Sheehan was one of three boys born to Leo C. and Florence Sheehan. Leo was the sports editor and political writer for the Battle Creek Enquirer, where he later became managing editor. He died of cancer at age fifty. Florence worked as a genealogist. John was interested in chemistry at an early age and had a traditional chemistry kit, which grew into a basement laboratory. His other interests included rocketry, model airplanes, yo-yos (he was a champion), tennis, and the Boy Scouts of America. He received awards in tennis, both in singles and in doubles with his brother Joseph. He attended St. Philip High School in Battle Creek and then Battle Creek College, graduating with honors with degrees in chemistry and political science. As valedictorian of the 1937 class, he was awarded a scholarship to attend the graduate school of his choice. He received his master’s and doctoral degrees from the University of Michigan in 1938 and 1941, respectively. His doctoral research was in the synthesis of phenanthrene derivatives.

In 1941, Sheehan married a high school classmate, Marion Jennings, and began postdoctoral work with his mentor, Werner E. Bachmann. Bachmann had a national defense grant to develop a synthesis for an explosive, cyclotrimethylenetrinitroamine, code-named RDX and called cyclonite. Bachmann and Sheehan developed a method to synthesize large quantities of RDX by nitration of hexamethylenetetramine. RDX was a very useful explosive, replacing trinitrotoluene (TNT) as the main explosive in rockets, bombs, and torpedoes. Sheehan also isolated another explosive, cyclotetramethylenetetranitramine (HMX), as a by-product of the RDX project.

Sheehan went to work for Merck and Company in Rahway, New Jersey, in 1941. While at Merck, Sheehan was involved in several outstanding projects, including the new synthesis of calcium pantothenate, the purification of streptomycin, and the purification of penicillin. In 1946, he became an assistant professor at the Massachusetts Institute of Technology (MIT) for half his salary at Merck. By 1950, Sheehan had proven that he was one of the most capable scientists in the field of organic synthesis. He was promoted to associate professor in 1948 and full professor in 1952.

Life’s Work

Sheehan worked on many projects besides penicillin. He developed a new method to synthesize peptides—the carbodiimide method for forming amides. Further studies with the carbodiimides (molecules with a carbon double-bonded to two nitrogen atoms) led Sheehan to develop a gelatin that would not melt at room temperature. Gelatin, a form of collagen, is held together by weak hydrogen bonds and will remain semisolid at low temperature. The carbodiimide caused amide bonds to form, making the gelatin more stable at room temperature. Sheehan also proved that carbodiimides will cure leather. He developed three new methods to synthesize beta-lactam rings, and he did research in amino acids, alkaloids, steroids, and the synthesis of high explosives.

Sheehan began working on the synthesis of penicillin in 1948, receiving funding from Bristol Laboratories in Syracuse, New York. Nine years later, he and his team successfully synthesized penicillin V. Among his most important discoveries was ampicillin, a penicillin derivative that could be taken orally. Unlike ampicillin, penicillin is acid-sensitive and so cannot be taken orally. Ampicillin became an important antibiotic, as it had broad-spectrum antibacterial activity. For many years, Sheehan and MIT fought over the patent rights to penicillin synthesis. The rights were finally granted to MIT and generated millions of dollars for the institute. In 1992, the year Sheehan died, MIT named a professorship for him.

Although penicillin is not a large molecule, it is unstable, with a beta-lactam ring that can be easily opened. A beta-lactam ring has a carbonyl group: a carbon double-bonded to an oxygen atom, which is bonded to a nitrogen atom, forming an amide bond. Two additional carbons make up the remainder of the ring. In the penicillin molecule, the nitrogen and one carbon are also part of a second five-element ring consisting of the nitrogen and carbon in the beta-lactam ring, a sulfur atom, and two carbons. One carbon has a carboxylic acid group attached to it; the other has two methyl groups attached. The carbon in the beta-lactam ring that is not part of both rings has a nitrogen atom attached to it that is part of an amide group. A side-chain group is then attached to the carbonyl carbon of the amide group. Penicillin works by attaching to an OH group in an enzyme that forms cell walls for bacteria. Human cells do not have the same type of cell walls and are not attacked by penicillin. The amide bond in the beta-lactam ring breaks to allow the carbonyl group to attach to the oxygen of the OH group on the enzyme. Thus, the beta-lactam ring is the key to the action of penicillin.

Besides his work at MIT, Sheehan headed a research group at the Research Institute for Medicine and Chemistry in Cambridge, Massachusetts, where he researched water-soluble carbodiimides and the synthesis of aldosterone. He also set up the nonprofit John C. Sheehan Research Institute, funded by research grants. Though initially successful, it later suffered from poor management. During 1953-1954, Sheehan served as scientific liaison officer for the Office of Naval Research with the U.S. embassy in London. He was a scientific adviser to PresidentsJohn F. Kennedy and Lyndon B. Johnson from 1961 to 1965.

Sheehan received many awards for his work. He was awarded honorary doctorates from the University of Notre Dame and the Stevens Institute of Technology and was a member of the National Academy of Sciences. The American Chemical Society presented him the Award in Pure Chemistry (1951) and the Award for Creative Work in Pure Chemistry (1959). In 1964, the city of Philadelphia awarded Sheehan the John Scott Award and Medal, crediting him with “saving millions of lives.” Elias James Corey, who won a Nobel Prize in Chemistry (1990) for developing the theory and methods of chemical synthesis, credited Sheehan and his colleagues at MIT with beginning the work for which Corey won the Nobel Prize.

Sheehan published more than 150 research papers and was granted some forty patents during his career. In 1977, he retired and was named professor emeritus and senior lecturer. Sheehan died of congestive heart failure at his home in Key Biscayne, Florida, on March 21, 1992. He was survived by his wife and three children.

Impact

During World War II, about eleven hundred scientists in thirty-nine labs in Great Britain and the United States worked unsuccessfully (at a cost of $20 million) to synthesize penicillin. Sheehan undertook the task after the war and succeeded in 1957. The synthesis led to commercial mass production of purer and improved penicillin at a lower cost than fermentation penicillin. People could afford penicillin to treat their particular ailment. By changing the side-chain groups of penicillin, scientists could alter the penicillin to treat different strains of bacteria. Different penicillins could treat diseases for which there had been no antibiotic treatment before.

Fermentation penicillin could treat only gram-positive microorganisms such as staphylococci, but not gram-negative microorganisms such as salmonellae. A derivative of penicillin, ampicillin attacks both gram-positive and gram-negative microorganisms. Also, fermentation penicillin is deactivated by acid and cannot be taken orally. Ampicillin can be taken orally. Some microorganisms are resistant to penicillin because they deactivate penicillin by opening the beta-lactam ring. By adding molecular groups to protect the beta-lactam ring, scientists have been able to develop penicillins such as staphcillin, methicillin, and oxacillin that are less likely to be deactivated. The method of modifying a drug to treat a specific problem is still used today.

Bibliography

Adams, Roger. Organic Reactions. New York: John Wiley & Sons, 1957. Includes a chapter on the synthesis of beta-lactams written by John Sheehan and Elias Corey. Illustrations, bibliography, index.

Manhas, Maghar S., and Ajay K. Bose. Synthesis of Penicillin, Cephalosporin C, and Analogs. New York: Marcel Dekker, 1969. Discusses the chemical synthesis of penicillin. Illustrations, bibliography.

Mascaretti, Oreste A. Bacteria Versus Antibacterial Agents: An Integrated Approach. Washington, D.C.: ASM Press, 2003. Discusses how penicillin and other antibiotics work to kill bacteria. Illustrations, bibliography, index.

Nicolaou, K. C., and T. Montagnon. Molecules That Changed the World: A Brief History of the Art and Science of Synthesis and Its Impact on Society. Wienheim, Germany: Wiley-VCH, 2008. One of the molecules discussed in this book is penicillin. Illustrations, bibliography, index.

Sheehan, John C. The Enchanted Ring: The Untold Story of Penicillin. Cambridge, Mass.: MIT Press, 1982. Tells the full story of the discovery of penicillin, its use as an antibiotic, its large-scale production, and its synthesis. Illustrations, bibliography, index.

Williams, Trevor Illtyd. Howard Florey: Penicillin and After. New York: Oxford University Press, 1984. Covers Florey’s development of penicillin into a medicine. Includes a section on the synthesis of penicillin. Illustrations, bibliography, index.