Click Chemistry – How to Enhance Click Reactions with Sonication
Click chemistry reactions such as copper-catalyzed azide-alkyne cycloaddition (CuAAC) reactions can greatly benefit from the application of power ultrasound. Sonochemical effects increase yield and conversion rate. Additionally, the overall efficiency of click chemistry reactions is improved. As a technique of green chemistry, ultrasonication contributes to more efficient and environmental-friendlier chemical reactions.
Ultrasonically Promoted Copper-Catalyzed Azide-Alkyne Cycloaddition
The copper-catalyzed azide-alkyne cycloaddition (CuAAC) is renown as the most important and prominent example of click chemistry reactions. Cravotto and colleagues from the Univerisity of Turin (Italy) have developed a protocol for an ultrasound-assisted 1,3-dipolar cycloaddition reaction of azides and alkynes using metallic copper (Cu) as catalyst. The azido group is a willing participant in this kind of organic reaction. The coupling capacity of the azido group with alkynes is substantially improved in the presence of Cu(I) and sonication promotes the click reaction.
- improved coupling capacity
- higher yields
- faster reaction
- improved reaction kinetics
- green chemistry
- simple & safe operation
Advantages of Sonochemical Reactions
Ultrasonic synthesis (sono-synthesis) has emerged as one of the most appreciated intensifying techniques in chemistry due to multiple advantages. Sonochemically promoted reactions excel conventional agitated or thermal-based methods with respects to reaction rate, yield, operational simplicity, purity of the products, energy efficiency etc. It is scientifically demonstrated that the use of power ultrasound can promote chemical reactions, and can decrease reaction time as well as unwanted side reactions. As an alternative green source of energy, sonication makes many chemical reactions environmental-friendlier as less reactants, milder solvents, and less energy are required.
Sonochemical Copper-Catalyzed Organic Reactions
The beneficial effects of ultrasound and sonochemistry to reactions involving metals are well-known. Sonication promotes mechanical removal of passivating layers and enhances both mass transfer and electron transfer from the metal to the organic acceptor.
The ultrasound-assisted click synthesis has been applied for the preparation of a wide range of 1,4-disubstituted 1,2,3-triazole derivatives starting both from small molecules and oligomers such as cyclodextrins (CDs). Using this efficient and greener protocol, all the adducts can be synthesized in 2-4 h (including work-up and excluding characterization). Click chemistry has been shown to be able to directly link chemistry to biology, thus becoming a true interdisciplinary reaction with extremely wide applicability.
(cf. Cintas et al., 2010)
Time-Saving Click Chemistry due to Ultrasonically Accelerated Reaction Kinetics
The implementation of ultrasound can accelerate slow chemical reactions, which take normally several hours in batch mode. Due to significantly improved reaction kinetics, the reaction time can be reduced to several minutes. Using an ultrasonic flow reactor can considerably improve the yields, obtain time savings and thereby resulting in great efficacy of conventionally slow syntheses.
High-Performance Ultrasonicators for Sonochemically Enhanced Click Reactions
Hielscher Ultrasonics designs, manufactures and distributes high-performance probe-type ultrasonicators, sonochemical reactors and accessories for sophisticated sonochemical processes. With ultrasonic processors ranging from 50 watts to 16,000 watts per probe (sonotrode / horn), Hielscher is able to offer you the most suitable sonochemical setup for your chemical reaction.
Hielscher ultrasonicators are recognized for their quality, reliability and robustness. Hielscher Ultrasonics is an ISO certified company and put special emphasis on high-performance ultrasonicators featuring state-of-the-art technology and user-friendliness. Of course, Hielscher ultrasonicators are CE compliant and meet the requirements of UL, CSA and RoHs.
The table below gives you an indication of the approximate processing capacity of our ultrasonicators:
|Batch Volume||Flow Rate||Recommended Devices|
|1 to 500mL||10 to 200mL/min||UP100H|
|10 to 2000mL||20 to 400mL/min||UP200Ht, UP400St|
|0.1 to 20L||0.2 to 4L/min||UIP2000hdT|
|10 to 100L||2 to 10L/min||UIP4000hdT|
|15 to 150L||3 to 15L/min||UIP6000hdT|
|n.a.||10 to 100L/min||UIP16000|
|n.a.||larger||cluster of UIP16000|
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Literature / References
- Cintas, Pedro; Barge, Alessandro; Tagliapietra, Silvia; Boffa, Luisa; Cravotto, Giancarlo (2010): Alkyne-azide click reaction catalyzed by metallic copper under ultrasound. Nature Protocols 5, 2010. 607-16.
- El-bendary, M.M.; Saleh, T.S.; Al-Bogami, A.S. (2018): Ultrasound Assisted High-Throughput Synthesis of 1,2,3-Triazoles Libraries: A New Strategy for “Click” Copper-Catalyzed Azide-Alkyne Cycloaddition Using Copper(I/II) as a Catalyst. Catalysis Letters 148, 2018. 3797–3810.
- Nobel Prize Committee: The click reaction that changed chemistry.
- Andrijana Mescic; Anita Salic; Tomislav Gregoric; Bruno Zelic; Silvana Raic- Malic (2017): Continuous flow-ultrasonic synergy in click reactions for the synthesis of novel 1,2,3-triazolyl appended 4,5-unsaturated l-ascorbic acid derivatives. RSC Advances 7, 2017. 791-800.
- Salvatore Marullo, Francesca D’Anna, Carla Rizzo, Renato Noto, (2015): The ultrasounds–ionic liquids synergy on the copper catalyzed azide–alkyne cycloaddition between phenylacetylene and 4-azidoquinoline. Ultrasonics Sonochemistry, Vol. 23, 2015. 317-323.
- Arafa, Wael & Nayl, A.A. (2019): Water as a solvent for Ru‐catalyzed click reaction: Highly efficient recyclable catalytic system for triazolocoumarins synthesis. Applied Organometallic Chemistry 2019.
Facts Worth Knowing
Click Chemistry Awarded with Nobel Prize for Chemistry 2022
Click chemistry, coined by Sharpless and co-workers in 2001, is a concept proposed for a class of almost perfect reactions that are highly effective with high atom economy, wide in scope, and stereospecific (but not necessarily enantioselective), generate only inoffensive by-products that can be easily removed, and require only simple reaction conditions as well as readily available reactants and simple product isolation procedures.