September 7, 2007

Putting fluorine in its place

A three-component catalytic system enables the formation of carbon–fluorine bonds at precise positions in organic molecules

Figure 1: A three-component catalyst system comprising (i) a nickel (Ni) metal ion complexed to an organic ligand, (ii) a nitrogen (N)-containing base, and (iii) a silicon (Si)-containing acid can be used, in conjunction with a fluorinating agent, to switch a specific hydrogen atom (white) in an aryl acetic acid substrate with a fluorine atom (yellow).

Organic molecules produced by living systems are often referred to as ‘natural products’, and are a rich source of biologically active substances that can sometimes be used as drugs themselves or, alternatively, offer a convenient starting point for designing and making others. These compounds generally have hydrocarbon skeletons and contain a small number of atoms of other elements—so-called heteroatoms.

Whereas nitrogen and oxygen, and, to a lesser extent, sulfur and phosphorus, are relatively common heteroatoms found in natural products, many of the other elements that comprise the periodic table rarely feature. A case in point is fluorine, which, points out Mikiko Sodeoka from RIKEN’s Discovery Research Institute in Wako, “is not popular in chemicals produced by organisms.”

Substituting a hydrogen atom with fluorine can, however, often confer beneficial properties on a particular compound, such as a drug, by increasing its stability or making it more easily absorbed in the body. Consequently, as many as 20% of therapeutic pharmaceuticals and 30–40% of agrochemicals, made by the chemical industry, contain a fluorine atom.

Many researchers have, therefore, investigated reactions to make carbon–fluorine bonds in an efficient and selective manner. Sodeoka and co-workers1 have made many contributions in this area and the most recent describes a new three-component catalytic system that enables the fluorination of a family of molecules known as aryl acetic acids.

After screening a range of reaction conditions, it was found that a cocktail of three different chemicals could be used, in conjunction with a fluorinating agent (N-fluorobenzenesulfonimide (NFSI)), to replace a hydrogen atom with a fluorine atom in a range of aryl acetic acid substrates (Fig. 1). Each component of the ternary mixture has a specific function: an acid activates the NFSI, a metal-ligand complex activates the substrate, and the base removes the hydrogen atom that is being substituted.

In principle, this fluorination reaction can produce two different mirror-image forms (enantiomers) of a given compound. The process developed by Sodeoka and co-workers is particularly powerful, however, because it can be intentionally biased to produce greater amounts of either of these closely related products—simply by choosing which mirror-image form of the metal catalyst is used in the reaction.

The ability to introduce fluorine atoms into molecules that can be made selectively in either left- or right-handed form is a powerful and generic synthetic strategy which Sodeoka hopes could make a significant contribution to the field of medicinal chemistry.


  1. Suzuki, T., Hamashima, Y. & Sodeoka, M. Asymmetric fluorination of α-aryl acetic acid derivatives with the catalytic system NiCl2–binap/R3SiOTf/2,6-lutidine. Angewandte Chemie International Edition 46, 5435–5439 (2007). |  | (Link)