What Is Glaser Coupling?
The Glaser coupling is a coupling reaction between terminal alkynes, discovered by chemist Carl Glaser in 1869. It is one of the first examples of a C–C bond forming reaction in organic synthesis and the prototypical example of an oxidative homocoupling that produces conjugated 1,3-diynes. This reaction, catalyzed by copper(I) salts in the presence of a base and an oxidant, has evolved from a classical laboratory reaction into a versatile tool with significant applications in natural product synthesis, materials science, and nanotechnology.
Hay improved the Glaser reaction by using a CuCl·TMEDA complex as the copper(I) catalyst. The main difference between Glaser coupling and Hay coupling is the copper salt and the solubility of the metal in organic solvent. Compared to the Glaser coupling, the CuCl·TMEDA complex used in Hay coupling is soluble in many solvents, making it more flexible and versatile.
Eglinton coupling is another well-established variant (using Cu(II) acetate (Cu(OAc)2), in pyridine under anhydrous conditions), which typically used when an oxygen atmosphere is undesirable or for certain substrates.
- Reagents: CuCl or CuI catalyst, a base (e.g., ammonium hydroxide, amine), and an oxidant.
- Reactants: Terminal alkynes.
- Products: Symmetrical 1,3-diynes.
- Reaction Type: Oxidative homocoupling.
- Related Reactions: Hay coupling, Eglinton coupling, Cadiot-Chodkiewicz coupling (synthesis of asymmetrical diynes).
- Experimental Tips:
a) Glaser coupling reactions can be accelerated by microwaves and can also be performed in supercritical carbon dioxide.
b) Intramolecular Glaser couplings, performed via a temporary covalently formed template, can provide macrocyclized products in high yields.
c) Ligands (e.g., TMEDA) and solvent coordinate copper, and can have a profound impact on copper speciation (monomeric vs. dinuclear vs. higher aggregates) and affect rate and selectivity.
d) The reaction is highly tolerant of many functional groups (ethers, esters, protected amines). Functionalities that can be easily reduced (aryl iodides, nitro groups) or are strong coordinators to copper are likely to give poor yields or undergo side reactions. In situ protection of sensitive functionalities may be necessary.
Fig 1. Glaser coupling reaction and its mechanism. [1]
Mechanism of Glaser Coupling
- Formation of copper acetylide: The terminal alkyne is deprotonated (or directly coordinates) to form a copper(I) acetylide complex.
- Oxidative coupling of two metal acetylides: Two copper–acetylide units undergo an oxidative step (formal oxidation at copper) that brings the two alkynyl fragments together to form the 1,3-diyne and a reduced copper species or copper cluster.
- Reoxidation of copper: The copper is reoxidized by the terminal oxidant (O2 in Glaser/Hay; Cu(II) acts as oxidant in Eglinton) to regenerate the active copper species.
Application Examples of Glaser Coupling
- Example 1: Sergii Okorochenkov and colleagues described the use of Glaser–Hay diyne coupling to synthesize conformationally constrained Nα-amino acid amides with varying diyne ring sizes. The smallest rings achieved through this method were twelve-membered. Additionally, it was noted that triethylammonium adducts formed for the smaller rings, specifically those with 10 and 11 members. [2]
- Example 2: Thomas W. T. Muesmann et al. used Glaser coupling to prepare bis(4-sulfophenyl)butadiyne with an overall yield of 30%. Specifically, phenylacetylene derivatives were subjected to copper- and nickel-catalyzed Glaser coupling reactions in air. The obtained dithioester was oxidatively degraded with NCS/HCl, and the bis(sulfonyl) chloride was obtained in moderate yield (55%) after chromatographic separation and crystallization. Finally, it was hydrolyzed with hot water to obtain 1,4-bis(4-sulfophenyl)butadiyne dihydrate. [3]
Fig 2. Synthetic examples via Glaser coupling reaction.
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| 126716-66-3 |  | ETHYNYL-BENZENE | Inquiry |
| 10601-99-7 |  | Benzoic acid,3-ethynyl- | Inquiry |
| 1094679-27-2 |  | 4-Ethynylpyridin-2-amine | Inquiry |
References
- Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 200-205.
- Okorochenkov, Sergii, et al. ACS Combinatorial Science 21.4 (2019): 316-322.
- Muesmann, Thomas WT, et al. Synthesis 2011.17 (2011): 2775-2780.
