Key Steps and Applications of the 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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FAQs on Sonogashira Coupling Reaction Mechanism Made Simple
1. What is the Sonogashira coupling reaction?
The Sonogashira coupling is a powerful cross-coupling reaction in organic chemistry used to form a carbon-carbon bond between a terminal alkyne and an aryl or vinyl halide. It is highly valued for synthesising complex molecules, particularly conjugated enynes and arylalkynes, using a palladium catalyst and a copper co-catalyst.
2. What is the basic mechanism of the Sonogashira coupling reaction?
The mechanism involves two interconnected catalytic cycles:
- Palladium Cycle: A palladium(0) catalyst undergoes oxidative addition with the aryl/vinyl halide. This is followed by a transmetallation step where the acetylide group is transferred from copper. The final step is reductive elimination, which forms the final product and regenerates the palladium(0) catalyst.
- Copper Cycle: A copper(I) salt reacts with the terminal alkyne in the presence of a base to form a copper(I) acetylide intermediate. This intermediate is crucial for transferring the alkyne group to the palladium centre.
3. What are the key components required for a Sonogashira coupling?
A typical Sonogashira coupling reaction requires four main components:
- Terminal Alkyne: One of the coupling partners, which has a hydrogen atom on a triple-bonded carbon (R-C≡C-H).
- Aryl or Vinyl Halide: The second coupling partner (Ar-X, where X is typically I, Br, or a triflate).
- Palladium Catalyst: Usually a palladium(0) complex, like Pd(PPh₃)₄, which drives the main catalytic cycle.
- Copper(I) Co-catalyst: A salt like copper(I) iodide (CuI), which activates the alkyne.
- Base: An amine base, such as triethylamine (Et₃N) or diisopropylamine (DIPA), is used to deprotonate the alkyne.
4. What is the specific role of the copper(I) co-catalyst in the Sonogashira reaction?
The copper(I) co-catalyst plays a crucial role in activating the alkyne. Its primary function is to react with the terminal alkyne (in the presence of a base) to form a copper(I) acetylide intermediate. This intermediate is more reactive than the alkyne itself and readily participates in the transmetallation step of the palladium cycle, efficiently transferring the acetylide group to the palladium complex. This significantly accelerates the overall reaction rate.
5. What is the difference between the classic Sonogashira coupling and a copper-free Sonogashira coupling?
The main difference lies in the use of the co-catalyst.
- Classic Sonogashira Coupling: Employs both a palladium catalyst and a copper(I) co-catalyst. The copper is essential for forming the copper acetylide intermediate, which facilitates the reaction. However, the presence of copper can sometimes lead to undesirable side reactions, like the homocoupling of alkynes (Glaser coupling).
- Copper-Free Sonogashira Coupling: This modified version avoids the use of a copper co-catalyst to prevent side reactions and simplify product purification. It typically requires a more reactive palladium catalyst system and a stronger base to proceed efficiently, but it offers a "greener" and often more reliable alternative for sensitive substrates.
6. Can you provide a simple example of a Sonogashira coupling reaction?
A classic example is the reaction between iodobenzene (an aryl halide) and phenylacetylene (a terminal alkyne). In the presence of a palladium catalyst like Pd(PPh₃)₂Cl₂, a copper(I) iodide (CuI) co-catalyst, and a base like triethylamine (Et₃N), they couple to form diphenylacetylene, a molecule where the two phenyl rings are connected by a carbon-carbon triple bond.
7. What is the importance of the Sonogashira coupling in modern organic synthesis?
The Sonogashira coupling is extremely important because it provides a reliable and versatile method to construct sp-sp² carbon-carbon bonds. This structure is a fundamental part of many complex organic molecules. Its applications are widespread, including:
- Pharmaceuticals: Synthesis of biologically active compounds and potential drug candidates.
- Materials Science: Creation of conjugated polymers, molecular wires, and organic light-emitting diodes (OLEDs).
- Agrochemicals: Development of new pesticides and herbicides.
- Natural Product Synthesis: A key step in the total synthesis of complex natural products.
