the alkyne group for this ligand exchange, which is why the amine is generally added in excess to promote preferential substitution. Protecting groups Trimethylsilylacetylene is a commonly used reagent in Sonogashira couplings. Being a liquid it is a more convenient reagent than the gaseous acetylene, and the trimethylsilyl group prevents addition onto the other end of the acetylene group. The trimethylsilyl group can then be removed using TBAF, yielding a monosubstituted acetylene. It may also be removed using DBU in a one-pot synthesis, allowing the monosubstituted acetylene to react further with another aryl halide to form diphenylacetylene and derivatives. Reaction variations Copper-free Sonogashira coupling While a copper co-catalyst is added to the reaction to increase reactivity, the presence of copper can result in the formation of alkyne dimers. This leads to what is known as the Glaser coupling reaction, which is an undesired formation of homocoupling products of acetylene derivatives upon oxidation. As a result, when running a Sonogashira reaction with a copper co-catalyst, it is necessary to run the reaction in an inert atmosphere to avoid the unwanted dimerization. Copper-free variations to the Sonogashira reaction have been developed to avoid the formation of the homocoupling products. There are other cases when the use of copper should be avoided, such as coupling reactions involving substrates which potential copper ligands, for instance free-base porphyrins. Inverse Sonogashira coupling In an inverse Sonogashira coupling the reactants are an aryl or vinyl compound and an alkynyl halide. Catalyst variations Silver co-catalysis In some cases stoichiometric amounts of silver oxide can be used in place of CuI for copper-free Sonogashira couplings. Nickel catalysts Recently, a nickel-catalyzed Sonogashira coupling has been developed which allows for the coupling of non-activated alkyl halides to acetylene without the use of palladium, although a copper co-catalyst is still needed. It has also been reported that gold can be used as a heterogeneous catalyst, which was demonstrated in the coupling of phenylacetylene and iodobenzene with an Au/CeO2 catalyst. In this case, catalysis occurs heterogeneously on the Au nanoparticles, with Au(0) as the active site. Selectivity to the desirable cross coupling product was also found to be enhanced by supports such as CeO2 and La2O3. Additionally, iron-catalyzed Sonogashira couplings have been investigated as relatively cheap and non-toxic alternatives to palladium. Here, FeCl3 is proposed to act as the transition-metal catalyst and Cs2CO3 as the base, thus theoretically proceeding through a palladium-free and