Hielscher – Ultrasound Technology

Ultrasonically Induced and Enhanced Phase Transfer Catalysis

High power ultrasound is well-known for its contribution to various chemical reactions. This is the so-called sonochemistry. Heterogeneous reactions – and especially phase transfer reactions – are highly potential application fields for power ultrasound. Due to the mechanical and sonochemical energy applied to the reagents, reactions can be get initiated, reaction speed can be significantly enhanced, as well as higher conversion rates, higher yields, and better products can be achieved. The linear scalability of ultrasound and the availability of reliable ultrasonic industrial equipment make this technique an interesting solution for chemical production.
Glass reactor for targeted and reliable sonication processes

Ultrasonic Glass Flow Cell

Phase Transfer Catalysis

Phase Transfer Catalysis (PTC) is a special form of heterogeneous catalysis and known as a practical methodology for organic synthesis. By using a phase transfer catalyst, it becomes possible to solubilize ionic reactants, which are often soluble in an aqueous phase but insoluble in an organic phase. This means PTC is an alternative solution to overcome the heterogeneity problem in a reaction in which the interaction between two substances located in different phases of a mixture is inhibited because of the inability of reagents to come together. (Esen et al. 2010) General advantages of phase transfer catalysis are the little efforts for preparation, simple experimental procedures, mild reaction conditions, high-reaction rates, high selectivities, and the use of inexpensive and environmentally benign reagents, such as quaternary ammonium salts, and solvents, and the possibility of conducting large scale preparations (Ooi et al. 2007).
A variety of liquid–liquid and liquid–solid reactions have been intensified and made selective by using simple phase-transfer (PT) catalysts such as quats, polyethylene glycol-400, etc., which allow ionic species to be ferried from aqueous phase to organic phase. Thus, the problems associated with extremely low solubility of the organic reactants in the aqueous phase can be overcome. In the pesticide and pharmaceutical industries, PTC is used extensively and has changed the fundamentals of business. (Sharma 2002)

Power Ultrasound

The application of power ultrasound is a well-known tool to create extremely fine emulsions. In chemistry such extremely fine-size emulsions are used to enhance chemical reactions. This means that the interfacial contact area between two or more immiscible liquids becomes dramatically enlarged and provides thereby a better, more complete and/or faster course of the reaction.
For phase transfer catalysis – the same as for other chemical reactions – enough kinetic energy is needed to start the reaction.
This has various positive effects regarding the chemical reaction:

  • A chemical reaction that will normally not occur because of its low kinetic energy can get started by ultrasonication.
  • Chemical reactions can be accelerated by ultrasonically-assisted PTC.
  • Complete avoidance of phase transfer catalyst.
  • Raw materials can be used more efficient.
  • By-products can be reduced.
  • Replacement of cost-intensive hazardous strong base with inexpensive inorganic base.

By these effects, PTC is an invaluable chemical methodology for organic synthesis from two and more immiscible reactants: Phase transfer catalysis (PTC) enables to use raw material of chemical processes more efficiently and to produce more cost-effectively. The enhancement of chemical reactions by PTC is an important tool for chemical production that can be improved by the use of ultrasound dramatically.

Ultrasonic cavitation in a glass column

Cavitation in liquid

Examples for ultrasonically promoted PTC reactions

  • Synthesis of new N’-(4,6-disubstituted-pyrimidin-2-yl)-N-(5-aryl-2-furoyl)thiourea derivatives using PEG-400 under ultrasonication. (Ken et al. 2005)
  • The ultrasonically assisted synthesis of mandelic acid by PTC in ionic liquid shows a significant enhancement in reaction yields under ambient conditions. (Hua et al. 2011)
  • Kubo et al. (2008) report the ultrasonically assisted C-alkylation of phenylacetonitrile in a solvent-free environment. The effect of the ultrasound to promote the reaction was attributed to the extremely large interfacial area between the two liquid phases. Ultrasonication results in a much faster reaction rate than mechanical mixing.
  • Sonication during the reaction of carbon tetrachloride with magnesium for the generation of dichlorocarbene results in a higher yield of gem-dichlorocyclopropane in the presence of olefins. (Lin et al. 2003)
  • Ultrasound provides the acceleration of the Cannizzaro reaction of p-chlorobenzaldehyde under phase transfer conditions. Of three phase transfer catalysts – benzyltriethylammonium chloride (TEBA), Aliquat and 18-crown-6 -, which have been tested by Polácková et al. (1996) TEBA was found to be the most effective. Ferrocenecarbaldehyde and p-dimethylaminobenzaldehyde gave, under similar conditions, 1,5-diaryl-1,4-pentadien-3-ones as the main product.
  • Lin-Xiao et al. (1987) have shown that the combination of ultrasonication and PTC promotes effectively the generation of dichlorocarbene from chloroform in shorter time with better yield and less amount of catalyst.
  • Yang et al. (2012) have investigated the green, ultrasonically-assisted synthesis of benzyl 4-hydroxybenzoate using 4,4’-bis(tributylammoniomethyl)-1,1’-biphenyl dichloride (QCl2) as catalyst. By the use of QCl2, they have developed a novel dual-site phase-transfer catalysis. This solid-liquid phase-transfer catalysis (SLPTC) has been carried out as batch process with ultrasonication. Under intense sonication, 33% of the added Q2+ containing 45.2% of Q(Ph(OH)COO)2 has transferred into the organic phase to react with benzyl bromide, hence the overall reaction rate was enhanced. This improved reaction rate was obtained 0.106 min-1 under 300W of ultrasonic irradiation, whilst without sonication a rate of 0.0563 min-1 was observed. Thereby, the synergistic effect of dual-site phase-transfer catalyst with ultrasound in phase transfer catalysis has been demonstrated.
The ultrasonic lab device UP200Ht provides powerful sonication in laboratories.

Picture 1: The UP200Ht is a 200 watts powerful ultrasonic homogenizer

Ultrasonic Enhancement of Asymmetric Phase Transfer Reaction

With the aim of establishing a practical method for the asymmetric synthesis of a-amino acids and their derivatives Maruoka and Ooi (2007) investigated “whether the reactivity of N-spiro chiral quaternary ammonium salts could be enhanced and their structures simplified. Since ultrasonic irradiation produces homogenization, that is, very fine emulsions, it greatly increases the interfacial area over which the reaction can occur, which could deliver substantial rate acceleration in the liquid–liquid phase-transfer reactions. Indeed, sonication of the reaction mixture of 2, methyl iodide, and (S,S)-naphtyl subunit (1 mol%) in toluene/50% aqueous KOH at 0 degC for 1 h gave rise to the corresponding alkylation product in 63% yield with 88%ee; the chemical yield and enantioselectivity were comparable with those from a reaction carried out by simple stirring of the mixture for eight hours (0 degC, 64%, 90%ee).” (Maruoka et al. 2007; p. 4229)

Improved phase transfer reactions by sonication

Scheme 1: Ultrasonication enhances the reaction rate during the asymmetric synthesis of α-amino acids [Maruoka et al. 2007]

Another reaction type of an asymmetric catalysis is the Michael reaction. The Michael addition of diethyl N-acetyl-aminomalonate to chalcone is positively influenced by ultrasonication which results in an increase of 12% of the yield (from 72% obtained during the silent reaction up to 82% under ultrasonication). The reaction time is six times faster under power ultrasound compared to the reaction without ultrasound. The enantiomeric excess (ee) has not changed and was for both reactions – with and without ultrasound – at 40%ee. (Mirza-Aghayan et al. 1995)
Li et al. (2003) demonstrated that the Michael reaction of chalcones as acceptors with various active methylene compounds such as diethyl malonate, nitromethane, cyclohexanone, ethyl acetoacetate and acetylacetone as donors catalyzed by KF/basic alumina results in adducts in high yield within a shorter time under ultrasound irradiation. In another study, Li et al. (2002) have shown the successful ultrasonically-assisted synthesis of chalcones catalyzed by KF-Al2O3.
These PTC reactions above show only a small range of the potential and possibilities of ultrasonic irradiation.
The testing and evaluation of ultrasound concerning possible enhancements in PTC is very simple. Ultrasonic lab devices such as Hielscher’s UP200Ht (200 watts) and bench-top systems such as Hielscher’s UIP1000hd (1000 watts) allow first trials. (see picture 1 and 2)
Ultrasonic improved asymmetric Michael addition (Click to enlarge!)

Scheme 2: Ultrasonically assisted asymmetric Michael addition of diethyl N-acetyl-aminomalonate to chalcone [Török et al. 2001]

Efficient Production Competing on the Chemical Market

Using ultrasonic phase transfer catalysis you will profit from one or more various beneficial advantages:

  • initialization of reactions that are otherwise not feasible
  • increase of yield
  • cut back of expensive, anhydrous, aprotic solvents
  • reduction of reaction time
  • lower reaction temperatures
  • simplified preparation
  • use of aqueous alkali metal instead of alkali metal alkoxides, sodium amide, sodium hydride or metallic sodium
  • use of cheaper raw materials, especially oxidants
  • shift of the selectivity
  • change of product ratios (e.g. O-/C-alkylation)
  • simplified isolation and purification
  • increase of the yield by suppressing side reactions
  • simple, linear scale-up to industrial production level, even with very high throughput
UIP1000hd Bench-Top Ultrasonic Homogenizer

Setup with 1000W ultrasonic processor, flow cell, tank and pump

Simple and risk-free testing of Ultrasonic Effects in Chemistry

To see how ultrasound influences specific materials and reactions, first feasibility tests can be conducted in small scale. Hand-held or stand-mounted laboratory devices in the range of 50 to 400 watts allow for sonication of small- and mid-size samples in the beaker. If the first results show potential achievements, the process can developed and optimized in the bench-top with an industrial ultrasonic processor, e.g. UIP1000hd (1000W, 20kHz). Hielscher’s ultrasonic bench-top systems with 500 watts to 2000 watts are the ideal devices for R&D and optimization. These ultrasonic systems – designed for beaker and inline sonication – give full control over the most important process parameter: Amplitude, Pressure, Temperature, Viscosity, and Concentration.
The accurate control over the parameters allows for the exact reproducibility and linear scalability of the obtained results. After testing various setups, the configuration found to be best can be used to run continuously (24h/7d) under production conditions. The optional PC-Control (software interface) also facilitates the recording of the individual trials. For the sonication of flammable liquids or solvents in hazardous environments (ATEX, FM) the UIP1000hd is available in an ATEX-certified version: UIP1000-Exd.

General benefits from ultrasonication in chemistry:

  • A reaction may be accelerated or less forcing conditions may be required if sonication is applied.
  • Induction periods are often significantly reduced as are the exotherms normally associated with such reactions.
  • Sonochemical reactions are often initiated by ultrasound without the need for additives.
  • The number of steps that are normally required in a synthetic route can sometimes be reduced.
  • In some situations a reaction can be directed to an alternative pathway.

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Literature/References

  1. Esen, Ilker et al. (2010): Long Chain Dicationic Phase Transfer Catalysts in the Condensation Reactions of Aromatic Aldehydes in Water Under Ultrasonic Effect. Bulletin of the Korean Chemical Society 31/8, 2010; pp. 2289-2292.
  2. Hua, Q. et al. (2011): Ultrasonically-promoted synthesis of mandelic acid by phase transfer catalysis in an ionic liquid. In: Ultrasonics Sonochemistry Vol. 18/5, 2011; pp. 1035-1037.
  3. Li, J.-T. et al. (2003): The Michael reaction catalyzed by KF/basic alumina under ultrasound irradiation. Ultrasonics Sonochemistry 10, 2003. pp. 115-118.
  4. Lin, Haixa et al. (2003): A Facile Procedure for the Generation of Dichlorocarbene from the Reaction of Carbon Tetrachloride and Magnesium using Ultrasonic Irradiation. In: Molecules 8, 2003; pp. 608 -613.
  5. Lin-Xiao, Xu et al. (1987): A novel practical method for the generation of dichlorocebene by ultrasonic irradiation and phase transfer catalysis. In: Acta Chimica Sinica, Vol. 5/4, 1987; pp. 294-298.
  6. Ken, Shao-Yong et al. (2005): Phase transfer catalyzed synthesis under ultrasonic irradiation and bioactivity of N’-(4,6-disubstituted-pyrimidin-2-yl)-N-(5-aryl-2-furoyl)thiourea derivatives. In: Indian Journal of Chemistry Vol. 44B, 2005; pp. 1957-1960.
  7. Kubo, Masaki et al. (2008): Kinetics of Solvent-Free C-Alkylation of Phenylacetonitrile Using Ultrasonic Irradiation. Chemical Engineering Journal Japan, Vol. 41, 2008; pp. 1031-1036.
  8. Maruoka, Keiji et al. (2007): Recent Advances in Asymmetric Phase-Transfer Catalysis. In: Angew. Chem. Int. Ed., Vol. 46, Wiley-VCH, Weinheim, 2007; pp. 4222-4266.
  9. Mason, Timothy et al. (2002): Applied sonochemistry: the uses of power ultrasound in chemistry and processing. Wiley-VCH, Weinheim, 2002.
  10. Mirza-Aghayan, M. et al (1995): Ultrasound Irradiation Effects on the Asymmetric Michael Reaction. Tetrahedron: Asymmetry 6/11, 1995; pp. 2643-2646.
  11. Polácková, Viera et al. (1996): Ultrasound-promoted Cannizzaro reaction under phase-transfer conditions. In: Ultrasonics Sonochemistry Vol. 3/1, 1996; pp. 15-17.
  12. Sharma, M. M. (2002): Strategies of conducting reactions on a small scale. Selectivity engineering and process intensification. In: Pure and Applied Chemistry, Vol. 74/12, 2002; pp. 2265-2269.
  13. Török, B. et al. (2001): Asymmetric reactions in sonochemistry. Ultrasonics Sonochemistry 8, 2001; pp. 191-200.
  14. Wang, Maw-Ling et al. (2007): Ultrasound assisted phase-transfer catalytic epoxidation of 1,7-octadiene – A kinetic study. In: Ultrasonics Sonochemistry Vol. 14/1, 2007; pp. 46-54.
  15. Yang, H.-M.; Chu, W.-M. (2012): Ultrasound-Assisted Phase-Transfer Catalysis: Green Synthesis of Substituted Benzoate with Novel Dual-Site Phase-Transfer Catalyst in Solid-Liquid System. In: Proceeding s of 14th Asia Pacific Confederation of Chemical Engineering Congress APCChE 2012.


Facts Worth Knowing

Ultrasonic tissue homogenizers are often referred to as probe sonicator, sonic lyser, ultrasound disruptor, ultrasonic grinder, sono-ruptor, sonifier, sonic dismembrator, cell disrupter, ultrasonic disperser or dissolver. The different terms result from the various applications that can be fulfilled by sonication.