Organocatalytic Reactions Promoted by Sonication

In organic chemistry, organocatalysis is a form of catalysis in which the rate of a chemical reaction is increased by an organic catalyst. This “organocatalyst” consists of carbon, hydrogen, sulfur and other nonmetal elements found in organic compounds. The application of high-power ultrasound to chemical systems is known as sonochemistry and a well established technique to increase yields, improve reaction rates and to accelerate reaction speed. Under sonication, it becomes often possible to switch chemical pathways avoiding unwanted by-products. Sonochemistry can promote organocatalytic reactions making them more efficient and environmental-friendly.

Asymmetric Organocatalysis – Improved by Sonication

Sonochemistry, the application of high-performance ultrasound into chemical systems, can improve organocatalytic reactions significantly. Asymmetric organocatalysis combined with ultrasonication often allows to transform organocatalysis to an environmental-friendlier route, thereby falling under the terminology of green chemistry. Sonication accelerates (asymmetric) organocatlytic reaction and lead to higher yields, faster conversion rates, easier product isolation/purification, and improved selectivity and reactivity. Beside contributing to the improvement of the reaction kinetics and yield, ultrasonication can be often combined with sustainable reaction solvents, such as ionic liquids, deep eutectic solvents, mild, non-toxic solvents, and water. Thereby, sonochemistry not only improves the (asymmetric) organocatlytic reaction itself, but also assists the sustainability of organocatalytic reactions.

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Ultrasonic probe for sonochemical initiation and acceleration of organocatalytic reaction with higher yields

Ultrasonication promotes organocatalytic reactions resulting in improved conversion rates, higher yields and selectivity.

Research has shown manifold examples for sonochemically intensified oragnocatalytic reactions. For instance, double stranded DNA molecules as a chiral scaffold are used in order to assemble metal-biomacromolecule hybrid catalysts for asymmetric synthesis reactions. G-quadruplex DNA-based catalysts have been applied in asymmetric Michael addition, Diels-Alder and Friedel-Crafts reactions. (cf. Zhao and Shen, 2018)
For inidium-promoted reaction, sonication shows beneficial effects since the sonochemically driven reaction runs under milder conditions, thereby preserving high levels of diasteroselection. Using the sonochemical route, good results on the organocatalytic synthesis of β-lactam carbohydrates, β-amino acid and spirodiketopiperazines from sugar lactones as well as allylation and Reformatsky reactions on oxime ethers were achieved.

Ultrasonically Promoted Organocatalytic Drug Synthesis

Rogozińska-Szymczak and Mlynarski (2014) report the asymmetric Michael addition of 4-hydroxycoumarin to α,β-unsaturated ketones on water without organic co-solvents – catalysed by organic primary amines and sonication. The application of enantiomerically pure (S,S)-diphenylethylenediamine affords a series of important pharmaceutically active compounds in good to excellent yields (73–98%) and with good enantioselectivities (up to 76% ee) via reactions accelerated by ultrasound. The researchers present an efficient sonochemical protocol for the ‘solids on water’ formation of the anticoagulant warfarin in both enantiomeric forms. This environmentally friendly organocatalytic reaction is not only scalable, but also yields the target drug molecule in enantiomerically pure form.

Ultrasonically promoted asymmetric Michael addition of 4-hydroxycoumarin to α,β-unsaturated ketones

Sonication promotes the asymmetric Michael addition of 4-hydroxycoumarin to α,β-unsaturated ketones on water without organic co-solvents.
Picture and study: ©Rogozińska-Szymczak and Mlynarski; 2014.

Sonochemical Epoxidation of Terpenes

Charbonneau et al. (2018) demostrated the successful epoxidation of terpenes under sonication. The conventional epoxidation requires the use of a catalyst, but with sonication the epoxidation runs as catalyst-free reaction.
Limonene dioxide is a key intermediate molecule for the development of biobased polycarbonates or nonisocyanate polyurethanes. Sonication allows the catalyst free epoxidation of terpenes within a very short reaction time – at the same time giving very good yields. In order to demonstrate the effectivenes of ultrasonic epoxidation, the research team compared the epoxidation of limonene to limonene dioxide using in-situ-generated dimethyl dioxirane as the oxidizing agent under both conventional agitation and ultrasonication. For all sonication trials the Hielscher UP50H (50W, 30kHz) lab ultrasonicator was used.

Terpene epoxidation is significantly faster and highly efficient when sonication is applied. Using ultrasound enables to runthe epoxidation reaction of terpenes as catalyst-free reaction.

Highly efficient sonochemical epoxidation of terpenes (e.g., limonene dioxide, α-pinene oxide, β-pinene oxide, triepoxide etc.) with the ultrasonicator UP50H
picture and study: © Charbonneau et al., 2018

The time required to completely convert limonene to limonene dioxide with 100% yield under sonication was only 4.5 min at room temperature. In comparison, when conventional agitation using a magnetic stirrer is used, the required time to reach a 97% yield of limonene dioxide was 1.5 h. The epoxidation of α-pinene has also been studied using both agitation techniques. Epoxidation of α-pinene to α-pinene oxide under sonication required only 4 min with an obtained yield of 100%, while in comparison with the conventional method the reaction time was 60 min. As for other terpenes, β-pinene was converted to β-pinene oxide in only 4 min whereas farnesol yielded 100% of the triepoxide in 8 min. Carveol, a limonene derivative, was converted to carveol dioxide with a yield of 98%. In the epoxidation reaction of carvone using dimethyl dioxirane the conversion was 100% in 5 min producing 7,8-carvone oxide.
The main advantages of the sonochemical terpene epoxidation are the environmental-friendly nature of the oxidizing agent (green chemistry) as well as the significantly reduced reaction time performing this oxidation under ultrasonic agitation. This epoxidation method allowed reaching 100% conversion of limonene with a 100% yield of limonene dioxide in only 4.5 min compared to 90 min when traditional agitation is used. Furthermore, no oxidation products of limonene, such as carvone, carveol, and perrilyl alcohol, were found in the reaction medium. The epoxidation of α-pinene under ultrasound required only 4 min, yielding 100% of α-pinene oxide without oxidation of the ring. Other terpenes such as β-pinene, farnesol, and carveol have also been oxidized, leading to very high epoxide yields.

Ultrasonically stirred reactor for sonochemical applications including organocatalysis, asymmetric reactions and many other.

Ultrasonically agitated reactor with the ultrasonicator UP200St for intensified organocatalytic reactions.

Sonochemical Effects

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.As an alternative to classical methods, sonochemical-based protocols have been used to increase the rates of a wide variety of reactions, resulting in products generated under milder conditions with a significant reduction in reaction times. These methods have been described as more environmentally friendly and sustainable and are associated with greater selectivity and lower energy consumption for the desired transformations. The mechanism of such methods is based on the phenomenon of acoustic cavitation, which induces unique conditions of pressure and temperature through the formation, growth, and adiabatic collapse of bubbles in the liquid medium. This effect improves mass transfer and increases turbulent flow in the liquid, facilitating the chemical transformations. In our studies, the use of ultrasound has led to the production of compounds in reduced reaction times with high yields and purity. Such characteristics have increased the number of compounds evaluated in pharmacological models, contributing to accelerating the hit to lead optimization process.
Not only can this high-energy input enhance mechanical effects in heterogeneous processes, but it is also known to induce new reactivities leading to the formation of unexpected chemical species. What makes sonochemistry unique is the remarkable phenomenon of cavitation, which generates in a locally confined space of the micro-bubble environment extraordinary effects due to alternating high-pressure / low-pressure cycles, very high temperature differentials, high-shear forces, and liquid streaming.

Examples of asymmetric reactions involving organocatalysts are:

  • Asymmetric Diels-Alder reactions
  • Asymmetric Michael reactions
  • Asymmetric Mannich reactions
  • Shi epoxidation
  • Organocatalytic transfer hydrogenation

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Ultrasonic reactors can significantly improve organocatalytic reactions such as the Mannich reaction.

Ultrasonic inline system with UIP2000hdT (2000W, 20kHz) for sonochemical reactions, e.g. for improved organocatalytic reactions

The Advantages of Sonochemically Promoted Organocatalytic Reactions

Sonication is increasingly used in organic synthesis and catalysis since sonochemical effects show a substantial intensification of chemical reactions. Especially when compared with traditional methods (e.g., heating, stirring), sonochemistry is more efficient, convenient, and precisely controllable. Sonication and sonochemistry offer several major advantages such as higher yields, increased purity of the compounds and selectivity, shorter reaction times, lower costs, as well as the simplicity in operating and handling the sonochemical procedure. These beneficial factors make ultrasonically-assisted chemical reactions not only more efficacious and saver, but also environmental-friendlier.
Numerous organic reactions have been proven to give higher yields in shorter reaction time and / or under milder conditions when performed using sonication.

Ultrasonication Allows for Simple One-Pot Reactions

Sonication allows to initiate multicomponent reactions as one-pot reactions that provide the synthesis of structurally diverse compounds. Such one-pot reactions are valued for a high overall efficiency and their simplicity since isolation and purification of intermediates is not required.

The effects of ultrasound waves on asymmetric organocatalytic reactions have been successfully applied in various reaction types including phase transfer catalyses, Heck reactions, hydrogenation, Mannich reactions, Barbier and Barbier-like reactions, Diels-Alder reactions, Suzuki coupling reaction, and Micheal addition.

Find the Ideal Ultrasonicator for Your Organocatalytic Reaction!

Hielscher Ultrasonics is your trusted partner when it comes to high-performance, high-quality ultrasonic equipment. Hielscher designs, manufactures and distributes state-of-the-art ultrasonic probes, reactors and cup-horns for sonochemical applications. All equipment is manufactured under ISO certified procedures and with German precision for superior quality in our headquarter in Teltow (near Berlin), Germany.
The portfolio of Hielscher ultrasonicators ranges from compact lab ultrasonicators to fully industrial ultrasonic reactors for large scale chemical manufacturing. Probes (also known as sonotrodes, ultrasonic horns or tips), booster horns, and reactors are readily available in numerous sizes and geometries. Customized versions can be manufactured for your requirements, too.
Since Hielscher Ultrasonics’ ultrasonic processors are available at any size from small lab devices to large industrial processors for batch and flow chemistry applications, high-performance sonication can be easily implemented into any reaction setup. Precise adjustment of the ultrasonic amplitude – the most important parameter for sonochemical applications – allows to operate Hielscher ultrasonicators at low to very high amplitudes and to fine-tune the amplitude exactly to the required ultrasonic process conditions of the specific chemical reaction system.
Hielscher’s ultrasonic generator feature a smart software with automatic data protocolling. All important processing parameters such as ultrasonic energy, temperature, pressure and time are automatically stored onto a built-in SD-card as soon as the device is switched on.
Process monitoring and data recording are important for continuous process standardization and product quality. By accessing the automatically recorded process data, you can revise previous sonication runs and evaluate the outcome.
Another user-friendly feature is the browser remote control of our digital ultrasonic systems. Via remote browser control you can start, stop, adjust and monitor your ultrasonic processor remotely from anywhere.
Contact us now to learn more about our high-performance ultrasonic homogenizers can improve your oragnocatalytic synthesis reaction!

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)
  • high user-friendliness and comfort
  • 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

Facts Worth Knowing

What is Organocatalysis?

Organocatalysis is a type of catalysis in which the rate of a chemical reaction is increased by the use of an organic catalyst. This organocatalyst can consist of carbon, hydrogen, sulfur and other nonmetal elements found in organic compounds. Organocatalysis offers several advantages. Since organocatalytic reactions do not require metal-based catalysts, they are environmental-friendlier and contribute thereby to green chemistry. Organocatalysts can be often cheaply and easily produced, and allow for greener synthetic routes.

Asymmetric Organocatalysis

Asymmetric organocatalysis is the asymmetric or enantioselective reaction, which produces only enantiomer of handed molecules. Enantiomers are pairs of stereoisomers that are chiral. A chiral molecule is non-superimposable on its mirror image, so that the mirror image is actually a different molecule. For instance, the production of specific enantiomers is particularly important in the production of pharmaceuticals, where often only one enantiomer of a drug molecule offers a certain positive effect, whereas the other enantiomer shows no effect or is even harmful.

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.