Barton reaction

The Barton reaction, also known as the Barton nitrite ester reaction, is a photochemical reaction that involves the photolysis of an alkyl nitrite to form a δ-nitroso alcohol. The Barton reaction, also known as the Barton nitrite ester reaction, is a photochemical reaction that involves the photolysis of an alkyl nitrite to form a δ-nitroso alcohol. Discovered in 1960, the reaction is named for its discoverer, Nobel Laureate Sir Derek Barton. Barton's Nobel Prize in Chemistry in 1969 was awarded for his work on understanding conformations of organic molecules, work which was key to realizing the utility of the Barton Reaction. The Barton reaction involves a homolytic RO–NO cleavage, followed by δ-hydrogen abstraction, free radical recombination, and tautomerization to form an oxime. Selectivity for the δ-hydrogen is a result of the conformation of the 6-membered radical intermediate. Often, the site of hydrogen atom abstraction can be easily predicted. This allows the regio- and stereo-selective introduction of functionality into complicated molecules with high yield. Due to its then unique ability to derivitize otherwise inert substrates Barton used this reaction extensively in the 1960s to create a number of unnatural steroid analogues. While the Barton reaction has not enjoyed the popularity or widespread use of many other organic reactions, together with the mechanistically similar Hofmann–Löffler reaction it represents one of the first examples of C-H activation chemistry, a field which is now the topic of much frontline research in industrial and academic chemistry circles. The unusual alkyl nitrite starting material of the Barton reaction is prepared by attack of an alcohol on a nitrosylium cation generated in situ by dehydration of doubly protonated nitrous acid. This series of steps is mechanistically identical to the first half of the mechanism formation of the more well-known aryl and alkyl diazonium salts. While the synthesis of alkyl nitrites from nitrosyl chloride is known and oft-employed in the context of complex molecule synthesis, the reaction is reversible and the products are in thermodynamic equilibrium with the starting material. Furthermore, nitrosyl chloride is a powerful oxidizing agent, and oxidation of the alcohols with concomitant chlorination has been observed. The reaction of nitrosyl chloride with aromatic alcohols generally yields nitroso compounds and other over-oxidation products. The Barton reaction commences with a photochemically induced cleavage of the nitrite O-N bond, typically using a high pressure mercury lamp. This produces an alkyoxyl radical which immediately abstracts a hydrogen atom from the δ-carbon. In the absence of other radical sources or other proximal reactive groups, the alkyl radical recombines with the nitrosyl radical. The resultant nitroso compounds undergoes tautomerization to the isolated oxime product. The carbon centered radical can be intercepted by other radical sources such as iodine or acrylonitrile. The first instance results in the δ-hydrogen being replaced with iodine, then subsequent cyclization to a tetrahydrofuran by an SN2 reaction. The second example results in a chain elongation product with the oxime formed 2 carbon units further from the oxygen than normal. This mechanistic hypothesis is supported by kinetic isotope effect experiments. Isotopic labeling of the nitrite with 15N has shown the mechanism non-‘caged’ and that the nitrosyl radical formed from a given nitrite recombines randomly with other alkyl radicals. However, recombination of the nitrosyl radical with the alkoxyl radical (a reversal of the homolytic cleavage) has been shown to proceed without scrambling of isotope labels. This lack of tight radical pairing is also supported by the observation that alkyl radicals generated by Barton conditions can undergo radical cyclization while analogous intermediates generated by lead tetraacetate oxidation do not.