Sonogashira Coupling

What is Sonogashira Coupling?

Sonogashira cross-coupling is when a potential reaction takes place during the fabrication of carbon materials. It was first found during the investigation of the reaction between iodobenzene and phenylacetylene on a flat Au(111) atomic surface. After home coupling, the products, diphenylacetylene, a Sonogashira coupling is formed. This Sonogashira coupling reaction is further proved to be operative on flat surfaces like Ag(100) as well as roughened surfaces like Au(100). It is important to note that Palladium doesn't participate in Sonogashira coupling, and therefore its underlying reaction shall be uncovered.

History of Sonogashira Reaction

The Sonogashira coupling was initially proposed in 1975 by Kenkichi Sonogashira, Nobue Hagihara and Yasuo Tohda in their publications. The reaction is termed as an extension to the original Cassar, Dieck and Heck reactions which carry out the coupling of compounds using palladium as a catalyst. But Sonogashira uses both copper and palladium together, for an enhanced coupling.

Sonogashira Cross-Coupling Reaction

It is a cross-coupling reaction that is mostly used in the coupling of vinyl or aryl halides - during the organic synthesis of carbon-carbon bonds. It is used in a variety of fields and has become an essential step in the synthesis of compounds in product chemistry, nanomaterials and material science pharmaceuticals. It also can be implemented in mild room temperature to synthesize even the most complex molecules.

Sonogashira Coupling Reaction Mechanism

Songashira mechanism is not entirely comprehended as it is difficult to analyse and isolate the organometallic compounds, precisely. These compounds are usually present in the reactions as intermediates. The mechanism is predicted around the palladium cycle and copper cycle. The formation of complex E and pi-alkyne complex is dependent on the presence of the base. The base acidifies the proton on the alkyne. The compound F reacts with the palladium to generate the copper halide. 

Steps of Sonogashira Coupling Reaction Mechanism

Palladium and copper involved Sonogashira coupling happens in two independent catalytic cycles.

Catalytic Cycle of Palladium and Copper Sonogashira Reaction

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Before the actual oxidative addition, the 14-electron PdL2 complex is formed in a reductive process known as a σ-complexation-dehydropalladation-reductive reaction. During this process, palladium is reduced to form a complex with electron donors as they act either as solvents or ligands during the reaction.

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σ-Complexation-Dehydropalladation-Reductive Reaction With Amide

The Pd0 complex is subjected to oxidative addition of R1-X forming a coordinated palladium complex. At this point, the palladium cycle is intersected with the copper cycle. For a co-catalyzed reaction, amide shall be used due to its low basicity. As a result, a π-alkyne-copper complex is formed to increase the acidity of the alkyne to undergo the process of deprotonation. Following the deprotonation step, copper acetylide is formed. The formation of the palladium acetylide from copper acetylide and palladium complex is the rate-determining step in this cycle, known as transmetalation. In this step, Trans/cis isomerization happens to arrive at the final product. 

Copper-free Catalytic Cycle

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For copper-free Sonogashira coupling, the first step is an oxidative addition to form palladium complexes. The basicity of amine is not sufficient for the process of deprotonation. In such cases, the dissociation of the neutral ligand and the formation of the π-alkyne-palladium complex occurs. After the formation of the complex, the deprotonation of the alkyne occurs for the formation of palladium acetylide. The trans/cis isomerization, along with reductive elimination occurs to generate the Pd0L2 catalyst and the final product. 

Sonogashira Cross-Coupling Reaction Mechanistic Studies

Without no knowledge of the exact mechanism, it is difficult to characterize and isolate palladium intermediates. However, some transient species are identified when used with a multinuclear NMR spectroscopy. Many alternative methods have considered using heterogeneous catalysts to analyze the transient organometallic intermediates using gas chromatography to corroborate with the mechanisms. The real catalysts that are involved in the cycle are still debatable. 

Mono-ligated palladium is seen when the neutral ligand is bulky, suggesting that the catalyst is subjected to dissociation before oxidative addition. It has also been shown that Pd0L2 will form an anionic palladium complex if the solution contains halides in the place of anions. For example, [L2Pd0Cl] can be formed from the Pd0L2 in the presence of chloride ions. It is possible for anionic palladium to act as a real-time catalyst in the cycle.

Example of Sonogashira Cross-Coupling Reaction

A basic example of the reaction is the synthesis of Tazarotene in the treatment of psoriasis and acne. It is also mostly known as Altinicline. 

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FAQ (Frequently Asked Questions)

1. What is the best procedure for Sonogashira coupling?

The procedure for Songashira coupling varies from the substrate to the substrate. The reaction condition is highly based on the substrate that we are using. In earlier days, we only used palladium as a catalyst with the combination of CuI and TEA. But with a lot of advancements in the industry, heterogeneous catalysts can also be used. The literature has too many options that can be tried where you can look for examples that are similar to your system. Coupling aryl bromide with triisopropyl silyl acetylene in the presence of alcohol using 20 mol% CuI, 10 mol% of Pd(PPh3)2Cl2 and six eq. of Et2N at room temperature for 2-3 days is recommended. In case if your compound is soluble, you can use pure Et3N as well. 

2. What would be the end product of a reaction between carbon tetrachloride and acetylene through Sonogashira coupling?

If you take a poly-haloalkane and acetylene together, it will lead to the formation of a network polymer because the R group which participates in two couplings, is known for forming a linear polymer. The two halo substituents in the compounds are available for further coupling creating a new type of plastic.