Sonogashira coupling

The Sonogashira coupling, sometimes Sonogashira - Hagihara coupling, is a modern name reactions of organic chemistry. It involves a palladium-catalyzed cross-coupling between aryl halides and terminal alkynes. It was developed in the 70s by Kenkichi Sonogashira and Hagihara Nobue and published in 1975. It represents a further development of the Stephens - Castro coupling

The Cacchi coupling differs from the Sonogashira coupling in the starting material and reaction sequence: So triflates instead of aryl halides are used. The reaction mechanism proceeds instead of a neutral complex with a positively charged Pd complex and the negatively charged triflate anion.

Catalysts

This type of cross-coupling reactions need two catalytic converters, a zerovalent palladium complex and a copper halide. In this case, the palladium is activated by oxidative addition of the aryl halide or aryl triflate bond, while the copper salt and the alkyne to react at an intermediate stage to an organic copper compound. Then the copper is replaced by palladium. Examples are known in which the coupling can run without copper salt.

Mechanism

The reaction requires a basic solvent such that Sonogashira and Cacchi couplings are often performed in amines such as triethylamine, diisopropylamine or ethyldiisopropylamine. As a result of instability of the palladium complex to air, the reaction is carried out usually under an inert gas atmosphere, wherein the inert gas (eg, argon, nitrogen) to prevent a possible dimerization of oxygen supported alkyne used. The driving force of the reaction is the formation of the salt CuX, since this is a thermodynamic sink and thus the formation is energetically favorable.

Palladium - cycle

• Reactive palladium ( 0) species, the 14 electron complex is Pd (0 ), L2 A ( for example, with two triphenylphosphine ligand ). This reacts with the aryl halide or triflate R1X in an oxidative addition to a Pd (II ) complex B
• The following rate-determining step of the transmetalation of the formed complex B reacts with the copper acetylide to complex C. The copper acetylide was previously generated in situ in the copper cycle, with release of a copper halide ( CuX here ).
• The two organic ligands are trans to each other, now following a cis -trans isomerization provides complex D.
• In the product- forming step, the product, an unsymmetrically substituted alkyne, followed by reductive elimination and regenerates the Pd (0 ) catalyst.

Copper cycle

• The biggest limitation of the Sonogashira coupling is the deprotonation of the terminal alkyne. This is due to the fact that the amines used ( for example, triethylamine ) to have a low basicity. Presumably, it is still possible deprotonation even after the initial formation of the Pi -alkyne complex E.
• The copper acetylide F reacts after their formation with the palladium intermediate B, regenerating the copper halide CuX G.
• It is believed that the copper acetylide is involved in the reduction of Pd ( II) species. Here, a dialkyne - PdL2 complex is formed initially. Subsequently, by reductive elimination of the regeneration of the Pd ( 0) species, and the release of a diacetylene as product. Therefore, the Glaser coupling ( coupling of two acetylenes ) can be regarded as a side reaction.

Developments

Newer air-stable palladium complexes allow reactions under normal atmosphere. More recent research serve the copper-free or even solvent-free synthesis. As a further extension, the use of dilute aqueous ammonia solution (c = 0.5 mol / L) are considered as the reaction medium.