Ultrasonically Promoted Michael Addition Reaction

Asymmetric Michael reactions are a type of organocatalytic reactions, which can benefit heavily from sonication. The Michael reaction or Michael addition is widely used for chemical syntheses, where carbon-carbon bonds are formed under mild conditions. Ultrasonication and its sonochemical effects are highly efficacious in driving and promoting Michael reactions resulting in higher yields, significantly reduced reaction time and at the same time contributing to environmental-friendly green chemistry.

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The ultrasonicator UP200St in a sonochemical reactor

Continuously stirred reactor with ultrasonicator UP200St for improved chemical reactions, e.g., Michael addition

Sonochemistry and the Michael Addition

Acoustic cavitation as shown here at the Hielscher ultrasonicator UIP1500hdT is used to initiate and promote chemical reactions. Ultrasonic cavitation at Hielscher's UIP1500hdT (1500W) ultrasonicator for sonochemical reactions.Sonochemistry is well established for its benefical effects on chemical reactions – often resulting in higher yields, accelerated reaction speed, milder, environmental-friendly conditions as well as save and simple operation. This means sonochemistry is an efficient and innocuous method to activate, promote and drive synthetic and catalytic chemical reactions. The mechanism of ultrasonic processing and sonochemistry is based on the phenomenon of acoustic cavitation, which induces unique conditions of very high pressures and temperatures through the violent collapse of bubbles in a liquid medium. The effects of ultrasonic or acoustic cavitation initiate reactions by the introduction of high energy, improve mass transfer, thereby facilitating chemical transformations.
The Michael reaction or Michael addition is the nucleophilic addition of a carbanion or another nucleophile to an α,β-unsaturated carbonyl compound that contains an electron-withdrawing group. The Michael reaction is grouped into the larger class of conjugate additions. Valued as one of the most useful methods for the mild formation of carbon–carbon bonds, the Michael addition is widely used for the organic synthesis of manifold substances. Many asymmetric variants of the Michael addition exist, which are a type of organocatalytic reactions.

Advantages of Sonochemical Michael Addition

  • Rapid reaction speed
  • Higher yields
  • Environmental-friendly, green chemistry
  • Save and simple handling

Sonocatalysis and Basic Clay Catalysed Michael Addition of Imidazole

Martin-Aranda et al. (2002) took the advantage of ultrasonication and its sonochemical effects in order to develop a novel synthesis route of N-substituted imidazole derivatives 21 by the Michael addition of imidazole to ethylacrylate catalysed by basic clays, namely Li+ and Cs+ montmorillonites. Using ultrasonic activation, imidazole was condensed with ethyl acrylate using the two basic clays – Li+ and Cs+ montmorillonites. Alkaline clays such as Li+ and Cs+ montmorillonites are active and very selective catalysts under sonication, thereby showing positive effects on the Michael addition of imidazole to ethyl acrylate. Sonochemically promoted catalysis promotes and improves the formation of N-substituted imidazole derivatives when compared to other conventional thermal heating reactions. The conversion increases with the basicity of clays and the time to ultrasonication. The yield was higher when Cs+ montmorillonites was used in comparison to Li+, which might be explained due to the higher basicity. (See reaction scheme below)

Ultrasonication and its sonochemical effects promote asymmetric organocatalytic reaction such as the Michael addition of imidazole to ethyl acrylate.

Sonocatalytic reaction: Michael addition of imidazole to ethyl acrylate
(scheme adapted from Mohapatra et al, 2018.)

Another ultrasound-assisted Michael addition is the silica sulfuric acid promoted catalysis of indole. Li et al. (2006) reacted silica sulfuric acid and α,β-unsaturated ketones under ultrasonication in order to obtain the β-indolylketones yields of 50–85% at room temperature.

The video shows the ultrasonic disperser UP400ST for the production of hydrogels. Sonication is an efficient technique to produce nano-dispersions and to promote the synthesis of high-performance hydrogels.

Ultrasonic nano-dispersion with the ultrasonicator UP400ST


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Solvent-Free and Catalyst-Free Aza-Michael Reactions

The conjugate addition of amines to conjugated alkenes – known as aza-Michael reaction – is a chemical key step for the synthesis of various complex natural products, antibiotics, a-amino alcohols and chiral auxiliaries. Ultrasonication has been shown capable to promote such aza-Michael addition reaction in a solvent-free and catalyst-free setting.

Ultrasonically promoted aza-Michael reaction in aqueous medium gives very high yields and is environmental-friendly.

The ultrasound-induced aza-Michael reaction in water has been tested with several amines and unsaturated ketones, unsaturated nitrile and unsaturated ester. The sonochemically promoted reaction gave high yields in a rapid and simple procedure.
study and table: © Bandyopadhyay et al., 2012

A facile Michael addition of ferrocenylenones with aliphatic amines can be run in a sonochemically promoted reaction without the use of solvents and catalysts at room temperature. This sonochemical Michael addition can afford 1-ferrocenyl-3-amino carbonyl compounds in a a rapid process giving high yields, which is also efficient in the aza-Michael reaction of other α,β-unsaturated carbonyl compounds such as chalcone, carboxylic ester etc. This sonochemical reaction is not only very simple and easy to handle, it is also a rapid, environmental-friendly and inexpensive process, which are attributes of green chemistry. (Yang et al., 2005)
The research group of Banik developed another simple, straightforward, rapid, aqueous-mediated catalyst-free protocol for the aza-Michael addition reaction of several amines to α,β-unsaturated carbonyl compounds applying ultrasonication. The sonochemically-induced addition of several amines to α,β-unsaturated ketones, esters and nitriles has been carried out very efficiently in water as well as under solvent-free conditions. No catalysts or solid supports have been used in this method. Remarkable enhancement of reaction rate has been observed in water under ultrasound-induced method. This environmentally benign procedure has provided clean formation of the products with enhanced selectivity. (Bandyopadhyay et al., 2012)

Sonication and various solvents have beneficial effects on the sonochemical treatment on the aza-Michael reaction of piperidine and methyl acrylate

Effects of solvents and sonochemical treatment on aza-Michael reaction of piperidine (1 mL) and methyl acrylate (1 mL) in 1 mL solvent.
study and table: © Bandyopadhyay et al., 2012

Ultrasonic Probes and Reactors for Sonochemical Reactions

Hielscher ultrasonicators can be remotely controlled via browser control. Sonication parameters can be monitored and adjusted precisely to the process requirements.The sophisticated hardware and smart software of Hielscher ultrasonicators are designed to guarantee reliable sonochemical processing, e.g. performing organic synthesis and catalysis reactions with reproducible outcomes and in user-friendly manner.
Hielscher Ultrasonics systems are used worldwide for sonochemical processes including organic synthetic reactions such as the Michael additions, Mannich reaction, Diels-Alder reaction and many other coupling reactions. Proven to be reliable for the synthesis of high yields of high-quality chemical products, Hielscher ultrasonicators are not only used in laboratory settings but also in industrial production. Due to their robustness and low maintenance, our ultrasonicators are commonly installed for heavy duty applications and in demanding environments.
Hielscher ultrasonic processors for sonochemical syntheses, catalyses, crystallization and other reactions are already installed worldwide on commercial scale. Contact us now to discuss your sonochemical manufacturing process! Our well-experienced staff will be glad to share more information on the sonochemical synthesis pathway, ultrasonic systems and pricing!

Why Hielscher Ultrasonics?

  • high efficiency
  • state-of-the-art technology
  • reliability & robustness
  • batch & inline
  • for any volume
  • intelligent software
  • smart features (e.g., data protocolling)
  • CIP (clean-in-place)

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
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

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.