Tomislav Pintauer and Krzysztof Matyjaszewski from Duquesne University and Carnegie Mellon University, in Pittsburgh, US, reveal the magic ingredient that turns radical reactions 'green'

Morris Selig Kharasch, known for revolutionising radical reactions, first reported the addition of halogenated compounds to alkenes or alkynes in the 1940s.  This process - coined an atom transfer radical addition (ATRA) reaction - is today considered to be a fundamental reaction in organic synthesis.

ATRA reactions work with a variety of alkyl halides and alkenes, and can be conducted inter- and intra-molecularly.  The intramolecular version is particularly attractive because it enables the synthesis of functionalised cyclic systems, important building blocks for complex organic molecules from natural products to pharmaceuticals. 

The first ATRA reactions were conducted in the presence of light or radical initiators.  These were later replaced with more efficient halogen-transfer agents based on transition metals such as copper, iron, ruthenium or nickel.  However, to form the desired product selectively, large amounts of metal catalyst are needed (several million ppm).  This causes problems in product separation and catalyst regeneration, making the process environmentally unfriendly and expensive.  Limiting its use for making complex molecules and natural products, especially on the large scale. 

 

Adding a reducing agent means the amount of metal catalyst needed is so small the reaction mixture is colourless

 

Similar problems are also encountered with the copper-mediated atom transfer radical polymerisation (ATRP) reaction, which was discovered in 1995. Mechanistically similar to ATRA, the reaction conditions are modified so that the product of the initial addition reaction can be reactivated. The repetitive addition step is what makes ATRP a polymerisation process.  It is a powerful, robust, and easy to conduct method that allows polymeric materials to be prepared with well-defined composition, architecture and functionality.

In copper-catalysed ATRA and ATRP, the transition metal in its lower oxidation state activates the dormant alkyl halide species, generating radicals which are then deactivated by the metal in its higher oxidation state.  Nevertheless, because the radical deactivation - known as termination - reactions cannot be totally suppressed, the higher oxidation state metal complex accumulates as the reaction proceeds. This means larger metal quantities are required as the catalyst is 'used up'.  A recently discovered solution to this problem uses environmentally friendly reducing agents to continuously regenerate the metal complex in the lower oxidation state.  These reducing agents include radical initiators, amines, glucose, ascorbic acid and tin(II) compounds.

These ARGET (activators regenerated by electron transfer) and ICAR (initiators for continuous activator regeneration) ATRP processes allow polymerisation to be conducted using very small amounts of copper catalyst (1-100 ppm).  Generally the amount of catalyst required to carry out a reaction is reduced 500-10 000 times. The methodology also reduces catalyst-based side reactions. 

A procedure developed for catalyst regeneration in copper- and ruthenium-catalysed ATRA reactions has also been successfully used here, achieving one of the highest turnover numbers for any metal mediated ATRA process.

These recent developments could have profound implications for the large-scale industrial synthesis of small organic molecules and well-defined polymeric materials.

Read Pintauer and Matyjaszewski's tutorial review on 'Atom transfer radical addition and polymerization reactions catalyzed by ppm amounts of copper complexes' in issue 6, 2008 of Chemical Society Reviews