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Projects / Programmes source: ARIS

Redefinition and revival of copper-free Sonogashira cross-coupling reaction

Research activity

Code Science Field Subfield
1.04.00  Natural sciences and mathematics  Chemistry   

Code Science Field
P395  Natural sciences and mathematics  Organometallic chemistry 

Code Science Field
1.04  Natural Sciences  Chemical sciences 
Keywords
Synthesis; catalysis; Sonogashira cross-coupling reaction; C-C bond formation; organometallic compounds; reaction mechanism; green chemistry
Evaluation (rules)
source: COBISS
Researchers (12)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  08385  PhD Janez Cerkovnik  Chemistry  Researcher  2018 - 2021  178 
2.  31995  PhD Martin Gazvoda  Chemistry  Head  2018 - 2021  189 
3.  52125  Tjaša Gornik  Chemistry  Technical associate  2018 - 2020  25 
4.  12315  PhD Ester Heath  Control and care of the environment  Researcher  2018 - 2021  612 
5.  52320  Anže Ivančič  Chemistry  Researcher  2019 - 2021  14 
6.  19177  PhD Marjan Jereb  Chemistry  Researcher  2018 - 2021  160 
7.  27733  PhD Tina Kosjek  Control and care of the environment  Researcher  2018 - 2021  363 
8.  13822  PhD Janez Košmrlj  Chemistry  Researcher  2018 - 2021  539 
9.  39144  PhD Ana Kovačič  Control and care of the environment  Researcher  2021  62 
10.  50711  PhD Mateja Mihelač  Chemistry  Researcher  2018 - 2021  27 
11.  34347  PhD Luka Rejc  Chemistry  Researcher  2019 - 2021  50 
12.  53159  Žan Testen  Chemistry  Researcher  2019 - 2020 
Organisations (2)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0103  University of Ljubljana, Faculty of Chemistry and Chemical Technology  Ljubljana  1626990  23,426 
2.  0106  Jožef Stefan Institute  Ljubljana  5051606000  91,855 
Abstract
Primary goals of this research project are to provide the chemical community with a revised mechanism of the copper-free Sonogahsira reaction that is substantially different from the currently accepted “textbook” variant and to directly implement the novel understanding of the reaction mechanism for a properly and most efficiently designed copper-free Sonogashira process. For the mechanistic study we will provide a rational design and solid experimental evidences. Modern interdisciplinary techniques for monitoring catalytic processes will allow insight into the reaction mechanism. The experimental results will be compared to those gained from the theoretical DFT studies. As only precise understanding of the reaction mechanism allows the rational design of reaction conditions, improving the scope and the yields of the products, the results of this research project will finally revive the preparative copper-free Sonogashira reaction both in academy and industry. Not only that we expect cutting down on starting materials and pre-catalysts cost, and reducing problematic wastes, the copper-free Sonogashira reaction will become available under considerably more sustainable reaction conditions, including the use of water as a solvent, aryl chlorides as substrates, and no need for heath or air-exclusion protocols. To prove the concept the implementation of the proposed mechanistic considerations will be demonstrated on a range of relevant model substrates on a laboratory scale as well as, in selected examples, on the synthesis of key pharmaceutical intermediates on a multi-gram scale.
Significance for science
More than 90% of industrial processes for preparing various materials for everyday use are based on catalysis. The increased demands of modern world for better technologies and advanced products require unrestrained progress in development of new and advanced catalytic systems. Over recent decades, palladium-catalysed cross-coupling reactions have gained an enormous power in the art of synthetic organic chemistry by providing a fundamental tool for the formation of a carbon–carbon bond, as well as carbon-heteroatom bond, in many relevant academic and industrial applications. In the array of cross-couplings the Sonogashira reaction, the reaction between aryl or vinyl halides and terminal alkynes, has become the most general, reliable, and effective method for preparation of substituted alkynes. The original Sonogashira reaction requires a copper(I) salt as a co-catalyst in combination with the palladium source. Although beneficial for the effectiveness, the usage of copper as a co-catalyst in Pd/Cu catalyzed Sonogashira reaction entails several drawbacks including the application of environmentally unfriendly reagents, the formation of undesirable alkyne homocoupling side products, and the necessity of strict oxygen exclusion in the reaction mixture. Efforts to overcome these unsought circumstances have led to developments in the field of copper-free Sonogashira reaction, also known as the Heck–Cassar coupling or Heck alkynylation. Although the first report on the copper-free Sonogashira reaction dates more than four decades ago, its mechanism remains elusive. Within the framework of this project we aim to provide the chemical community with a revised mechanism of the copper-free Sonogahsira reaction that is substantially different from the currently accepted “textbook” variant. Hence, the results from the mechanistic study will importantly influence the understanding of some other processes in transition-metal catalyzed reactions, which will have a large impact on future development of cross-coupling reactions in general. As only precise understanding of the reaction mechanism allows the rational design of reaction conditions, improving the scope and the yields of the products, the results of this research project will finally revive the preparative copper-free Sonogashira reaction, both, in academy and industry. Not only that we expect cutting down on starting materials and pre-catalysts cost, and reducing problematic wastes, the copper-free Sonogashira reaction will become available under considerably more sustainable reaction conditions, including the use of water as a solvent, aryl chlorides as substrates, and no need for heath or air-exclusion protocols.
Significance for the country
More than 90% of industrial processes for preparing various materials for everyday use are based on catalysis. The increased demands of modern world for better technologies and advanced products require unrestrained progress in development of new and advanced catalytic systems. Over recent decades, palladium-catalysed cross-coupling reactions have gained an enormous power in the art of synthetic organic chemistry by providing a fundamental tool for the formation of a carbon–carbon bond, as well as carbon-heteroatom bond, in many relevant academic and industrial applications. In the array of cross-couplings the Sonogashira reaction, the reaction between aryl or vinyl halides and terminal alkynes, has become the most general, reliable, and effective method for preparation of substituted alkynes. The original Sonogashira reaction requires a copper(I) salt as a co-catalyst in combination with the palladium source. Although beneficial for the effectiveness, the usage of copper as a co-catalyst in Pd/Cu catalyzed Sonogashira reaction entails several drawbacks including the application of environmentally unfriendly reagents, the formation of undesirable alkyne homocoupling side products, and the necessity of strict oxygen exclusion in the reaction mixture. Efforts to overcome these unsought circumstances have led to developments in the field of copper-free Sonogashira reaction, also known as the Heck–Cassar coupling or Heck alkynylation. Although the first report on the copper-free Sonogashira reaction dates more than four decades ago, its mechanism remains elusive. Within the framework of this project we aim to provide the chemical community with a revised mechanism of the copper-free Sonogahsira reaction that is substantially different from the currently accepted “textbook” variant. Hence, the results from the mechanistic study will importantly influence the understanding of some other processes in transition-metal catalyzed reactions, which will have a large impact on future development of cross-coupling reactions in general. As only precise understanding of the reaction mechanism allows the rational design of reaction conditions, improving the scope and the yields of the products, the results of this research project will finally revive the preparative copper-free Sonogashira reaction, both, in academy and industry. Not only that we expect cutting down on starting materials and pre-catalysts cost, and reducing problematic wastes, the copper-free Sonogashira reaction will become available under considerably more sustainable reaction conditions, including the use of water as a solvent, aryl chlorides as substrates, and no need for heath or air-exclusion protocols.
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