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.

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Ultrasonically stirred reactor for sonochemical applications including click chemistry reactions.

Ultrasonically agitated reactor with the ultrasonicator UP200St for intensified chemical reactions in click chemistry.

Advantages of Sonochemically Enhanced Click Chemistry

  • improved coupling capacity
  • higher yields
  • faster reaction
  • improved reaction kinetics
  • green chemistry
  • simple & safe operation
Click chemistry reactions greatly benefit from sonochemical treatment. Sonication enhances the yield of cycloaddition reactions and accelerates reaction speed.

Sonochemically enhanced click chemistry: The copper-catalyzed cycloaddition with phenylacetylene is improved by ultrasonication.
(Study and graphic: © Cintas et al., 2010)

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.

In this video, a Hielscher 200 Watts ultrasonic homogenizer UP200St with a 7mm sonotrode is mounted to a standard glass fitting at the bottom of a glass reactor. The mounting can be horizontal, vertical or any in other direction. Multiple ultrasonic probes can be mounted to one reactor vessel - for example at different heights. Often, the installation from the side or from the bottom is preferred, because it works better with varying liquid levels. You can combine the ultrasonic agitation with conventional overhead stirrers.

Ultrasonically Agitated Stirred Batch Reactor - UP200St Hielscher Ultrasonics

Sonochemical Copper-Catalyzed Organic Reactions

Ultrasonication promotes Fenton reactions resulting in higher radical formation. Thereby, higher oxidation and improved conversion rates are obtained.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)

Closed batch reactor for Hielscher ultrasonicators: This reactor is ideal for sonochemical reactions, including click chemistry, cycloaddition, organochemical, and other reaction types.

A closed ultrasound reactor for sonochemical reactions, e.g. in click chemistry.

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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Ultrasonic high-shear homogenizers are used in lab, bench-top, pilot and industrial processing.

Hielscher Ultrasonics manufactures high-performance ultrasonic homogenizers for mixing applications, dispersion, emulsification and extraction on lab, pilot and industrial scale.



Literature / References

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.


High performance ultrasonics! Hielscher's product range covers the full spectrum from the compact lab ultrasonicator over bench-top units to full-industrial ultrasonic systems.

Hielscher Ultrasonics manufactures high-performance ultrasonic homogenizers from lab to industrial size.