Guidelines for Sonogashira cross-coupling reactions

As a synthetic organic chemist you will have built many carbon-carbon bonds and most probably in some occasions this will have been between sp2 and sp carbons. The so called Sonogashira cross-coupling reaction (Scheme 1), the most important of the latter carbon-carbon bond formations, is the reaction between an aryl or vinyl halides with a terminal acetylene catalysed generally by a palladium catalyst.

sono1Scheme 1.

 However, if one is to perform such reaction, the search for the ideal conditions can be difficult as addressed by a recent review (Chem. Soc. Rev. 2011, 40, 5084) where a search in SciFinder with the topic ‘Sonogshira’ revealed more than 1500 hits for the period 2007-2010.

Some general rules have previously been published by Hartwig in 2007 (Inorg. Chem. 2007, 46, 1936) which were derived from studies of the electronics and the bulkiness of the substrates and catalysts:

  1. The oxidative addition in Ar-X is promoted by electron-withdrawing groups at the aryl halide.
  2. Steric bulk of phosphines or NHC ligands coordinated to Pd promote the formation of a monoligated complex, which turns out to be highly active for oxidative addition.
  3. There is a pronounced steric effect in the transmetalation, while the ligand bite angle and the electronic effect are less important.
  4. Reductive elimination tends to be favoured by less electron donating ligands and steric bulk.

More recently Plentio has presented a guide on the performance of the Sonogashira cross-coupling (J. Org. Chem. 2012, 77, 2798) based on about 200 reactions (Scheme 2), where he correlates the stereoelectronic properties of the substituents in aryl bromides, acetylenes and phosphines.

 sono2Scheme 2.

  His conclusions can be summarized:

  •  The most important factor for choosing the ideal Pd/phosphine catalyst is the steric bulk of the phenylacetylene and Plentio reaches an ideal combination for the optimum steric bulk on the acetylene and phosphine. In short, the higher the steric bulk on the arylacetylene and the lower is the bulk of the phosphine ligand will promote the most efficient transformations.
  • Electron-withdrawing groups on the arylacetylene also increases the reactivity and this effect is more pronounced when the electron-withdrawing group is located on the acetylene rather than on the aryl bromide.
  • The more electron-rich the phosphine is, the higher the reactivity is.
  • The steric bulk on the aryl bromide, alpha to the bromo substituent, is more detrimental for the reaction than steric bulk on the acetylene.


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