Sonochemically Improved Mannich Reactions
Mannich reaction are important carbon–carbon bond forming reactions, which are widely used in industries such as the pharmaceutical production and the synthesis of natural products. Whilst most of one-pot Mannich reactions are very slow, the positive effects of ultrasonication on Mannich reactions have been quickly implemented in order to improve yield and reaction rate as well as to reduce the traditionally long reaction time down to a short procedure in Mannich reactions.
Sonochemistry and its Benefits in Mannich Reactions
The Mannich reaction is one of the most important carbon–carbon bond forming reactions in organic synthesis, because it affords synthetically and biologically important 𝛽-aminocarbonyl compounds, which are important intermediates for the construction of various nitrogen-containing natural products and pharmaceuticals.
Ultrasonic inline system for sonochemical reactions, e.g. for improved Mannich reactions
Ultrasonic irradiation and the thereby generated sonochemical effects are proven to accelerate the reaction kinetics in Mannich reactions drastically, e.g., with a 13-fold reduction from 20h to 1.5h in reaction time.
Ultrasonication improves the one-pot Mannich reaction of ketones, aldehydes and amines catalyzed by sulfamic acid catalyst.
Scheme adapted from Zeng et al., 2009
- Significantly accelerated reaction time
- Higher yields
- Precisely controllable conditions
- Temperature control
- Batch and in-line
- Green chemistry
Ultrasonic Mannich Reaction of 𝛽-Aminocarbonyl Compounds
Sulfamic acid (NH2SO3H, SA) was used as an efficient, inexpensive, non-toxic and recyclable green catalyst for the ultrasound-assisted one-pot Mannich reaction of aldehydes with ketones and amines. This ultrasound protocol has advantages of high yield, mild condition, no environmental pollution, and simple work-up procedures. Most importantly, beta-aminocarbonyl compounds with ortho-substituted aromatic amines are obtained in acceptable to good yields by this methodology for the first time.
Sulfamic acid as catalyst was examined and 10 mol% sulfamic acid was sufficient to drive the reaction completely to 95% yield in an significantly accelerated reaction time of 1,5h (in comparison to high-speed stirring, which achieved only 85% yield in approx. 20h). This underlines the well-established fact that power ultrasound and sonochemistry accelerate organic reactions. The table below shows the significant advantages of ultrasonication over high-speed stirring for Mannich reactions.
The table shows that ultrasonically catalyzed Mannich reactions are significantly faster and more efficient when compared to high-speed stirring.
Study: © Zeng et al., 2009
High-Performance Sonochemical Equipment for Mannich Reactions
Sonochemical equipment for the synthesis and catalysis of chemical products such as aminocarbonyl compounds and other intermediates is readily available at any size – from compact lab ultrasonicators to fully-industrial ultrasonic reactors. Hielscher Ultrasonics designs, manufactures, and distributes high-power ultrasonicators. All ultrasonic systems are made in the headquarter in Teltow, Germany and distributed from there all around the world.
The sophisticated hardware and smart software of Hielscher ultrasonicators are designed to guarantee reliable operation, reproducible outcomes as well as user-friendliness. The Hielscher ultrasonicators are robust and reliable, which allows to be installed and operated under heavy duty conditions. Operational settings can be easily accessed and dialled via intuitive menu, which can be accessed via digital colour touch-display and browser remote control. Therefore, all processing conditions such as net energy, total energy, amplitude, time, pressure and temperature are automatically recorded on a built-in SD-card. This allows you to revise and compare previous sonication runs and to optimize the synthesis and functionalization of sonochemically improved reactions such as the Mannich reaction, Diels-Alder reaction or Michael addition to highest efficiency.
Hielscher Ultrasonics systems are used worldwide for sonochemical processes (sono-synthesis and sono-catalysis) and are proven to be reliable equipment in batch and continuous in-line mode. Hielscher industrial ultrasonicators can easily run high amplitudes in continuous operation (24/7/365). Amplitudes of up to 200µm can be easily continuously generated with standard sonotrodes (ultrasonic probes / horns). For even higher amplitudes, customized ultrasonic sonotrodes are available. 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 are already installed worldwide on commercial scale. Contact us now to discuss your sonochemically drive synthesis via Mannich reaction! Our well-experienced staff will be glad to share more information on the sonochemical synthesis pathway, ultrasonic systems and pricing!
With the advantage of the ultrasonic synthesis method, your chemical production will excel in efficiency, simplicity and low cost when compared to other catalytic synthesis processes!
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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Hielscher Ultrasonics manufactures high-performance ultrasonic homogenizers for mixing applications, dispersion, emulsification and extraction on lab, pilot and industrial scale.
Literature / References
- Zeng H., Li H., Shao H. (2009): One-pot three-component Mannich-type reactions using sulfamic acid catalyst under ultrasound irradiation. Ultrasonics Sonochemistry16(6), 2009. 758-762.
- Suslick, Kenneth S.; Hyeon, Taeghwan; Fang, Mingming; Cichowlas, Andrzej A. (1995): Sonochemical synthesis of nanostructured catalysts. Materials Science and Engineering: A. Proceedings of the Symposium on Engineering of Nanostructured Materials. ScienceDirect 204 (1–2): 186–192.
- Bravo, José; Lopez, Ignacio; Cintas, Pedro; Silvero, Guadalupe; Arévalo, María (2006): Sonochemical cycloadditions in ionic liquids. Lessons from model cases involving common dienes and carbonyl dienophiles. Ultrasonics Sonochemistry 13, 2006. 408-414.
- Piotr Kwiatkowski, Krzysztof Dudziński, Dawid Łyżwa (2013): “Non-Classical” Activation of Organocatalytic Reaction. In: Peter I. Dalko (Ed.), Comprehensive Enantioselective Organocatalysis: Catalysts, Reactions, and Applications. John Wiley & Sons, 2013.
Facts Worth Knowing
What is the Mannich Reaction?
The Mannich reaction is based on a multi-component condensation of a nonenolizable aldehyde, a primary or secondary amine and an enolizable carbonyl compound, which yields aminomethylated products. The iminium derivative of the aldehyde functions as the acceptor in the Mannich reaction.
The Mannich reaction is used in many areas of organic chemistry. Since the Mannich reaction can be run as a convenient one-pot reaction and also set up as double Mannich reactions, this reaction type is used for the synthesis of fine chemicals, specialty chemicals, pharmaceuticals and natural substances (used in biosynthetic pathways, especially for the synthesis of alkaloids, peptides, and nucleotides).
Common examples for chemicals synthesized via Mannich reaction include:
- alkyl amines
- peptides, nucleotides, antibiotics, and alkaloids (e.g. tropinone)
- agrochemicals, such as plant growth regulators
- paints and polymers
- catalysts
- formaldehyde tissue crosslinking
- medicines and pharmaceutical drugs (e.g. rolitetracycline (the Mannich product of tetracycline and pyrrolidine), fluoxetine (antidepressant), tramadol and tolmetin (anti-inflammatory drug).
- soap and detergents: The Mannich reaction is used to synthesize alkyl amines, converting non-polar hydrocarbons into soap or detergents. These resulting compounds are used in a variety of cleaning applications, automotive fuel treatments, and epoxy coatings
- polyetheramines from substituted branched chain alkyl ethers
- α,β-unsaturated ketones by the thermal degradation of Mannich reaction products (e.g. methyl vinyl ketone from 1-diethylamino-butan-3-one)
Hielscher Ultrasonics manufactures high-performance ultrasonic homogenizers from lab to industrial size.