Sondheimer was born at Stuttgart in Germany but moved with his family to Britain in 1937. He was educated at Imperial College, London, where he obtained his PhD in 1948. After serving as a research fellow with Robert Woodward at Harvard from 1949 to 1952 he spent a brief period as associate director of chemical research with Syntex in Mexico City before being appointed in 1956 professor of organic chemistry at the Weizmann Institute, Rehovoth, Israel. In 1964 Sondheimer returned to Britain where he held a Royal Society research professorship first at Cambridge and from 1967 at University College, London.

In 1952, while with Syntex, Sondheimer collaborated with Carl Djerassi in the synthesis of an oral estronelike compound, the precursor of the contraceptive pill. In the 1960s Sondheimer deployed his synthetic skills on the annulenes, monocyclic hydrocarbons with alternating double and single bonds like the familiar benzene ring. Such molecules were important in theoretical chemistry following the formulation in 1931 by Erich Hückel of his rule claiming that compounds with monocyclic planar rings containing (4n + 2)π electrons should be aromatic. The rule obviously held for benzene (n = 1).

In 1956 Sondheimer and his colleagues discovered a relatively simple way to synthesize large-ring hydrocarbons and by the early 1960s they had produced annulenes with 14 and 18 carbon atoms, n = 2 and n = 4 respectively. 14–annulene is a highly unstable compound, which is not planar because of the positions of the hydrogen atoms on the molecule. 18–annulene has a planar ring obeying the Hückel rule and does have aromatic properties. The group also synthesized 30–annulene – a planar compound (n = 7). In 1981 while a visiting professor at Stanford, Sondheimer was found dead in his laboratory beside an empty cyanide bottle. He had apparently been suffering from depression.