INTRODUCTION:

The first report about the effect of ultrasound to chemical reactions is from 1927, by Richards and Looms involving rate studies on the hydrolysis of dimethyl sulfate and the iodine “clock” reaction (the reduction of potassium iodate by sulfurous acid).¹ In 1938, Porter and Young reported that ultrasound increased the rate of the Curtius rearrangement². In 1950, Renaud prepared an organometallic compound using ultrasound³. Since 1982 when Han and Boudjouk (Ph.D from UW Madison, 1971) significantly increased the yields and rates of Reformatsky reactions⁴, ultrasound has been investigated intensively in organic synthesis. Enhanced reactivity induced by ultrasonic radiation stems, in many cases, from mechanical and physical effects, namely the dispersion of materials in a finely divided form and the breakage of a passive coating. It is not surprising that most of the synthetic studies have focused on heterogeneous metal reactions, partly owing to the importance of these processes and partly in the search for milder and faster procedures inorganic synthesis^{5, 6}. The driving force for ultrasound developments in organic synthesis has many facets. The increasing requirement for environmentally clean technology that minimizes the production of waste at source⁷.

Ultrasound may offer cleaner reactions by improving product yields and selectivity, enhancing product recovery and quality through application to crystallization and other product recovery and purification processes. Ultrasound enhances the rates of reactions particularly those involving free radical intermediates⁸. Sonication allows the use of non-activated and crude reagents as well as an aqueous solvent system; therefore it is friendly and non-toxic. Ultrasound is widely used for improving the traditional reactions that use expensive reagents, strongly acidic conditions, long reaction times, high temperatures, unsatisfactory yields and incompatibility with other functional groups⁹.

2. Sonochemistry: An explanation:

Ultrasound is the name given to sound waves having frequencies higher than those to which human ears can respond, i.e. greater than 16kHz and with wavelength between 7.0 and 0.015 cm. It is transmitted through any substance – solid, liquid or gas, which possesses elastic properties. Although the range of ultrasonic frequencies can be extended up to 100 MHz, it is customary to divide ultrasound into two distinct regions: conventional power ultrasound, up to 100 kHz, that especially affects chemical reactivity in liquids (although higher frequencies can also do so), and diagnostic ultrasound (above 2 MHz and up to 10 MHz) with applications in both medicine and materials processing. For the sake of comparison it can be mentioned that microwaves lie in a higher frequency range, from 0.3 to 300 GHz, although most devices operate at a single frequency of 2.45 GHz (2450 MHz) to avoid interference with telecommunications. Three classes of sonochemical reactions exist: homogeneous sonochemistry of liquids, heterogeneous sonochemistry of liquid-liquid or solid-liquid systmes, and, overlapping with the aforementioned, sonocatalysis. Sonoluminescence is typically regarded as a special case of homogeneous sonochemistry. The chemical enhancement of reactions by ultrasound has been explored and has beneficial applications in mixed phase synthesis, materials chemistry, and biomedical uses. Because cavitation can only occur in liquids, chemical reactions are not seen in the ultrasonic irradiation of solids or solid-gas systems¹⁰. For example, in chemical kinetics, it has been observed that ultrasound can greatly enhance chemical reactivity in a number of systems by as much as a million-fold; effectively acting as a catalyst by exciting the atomic and molecular modes of the system (such as the vibrational, rotational, and translational modes). In addition, in reactions that use solids, ultrasound breaks up the solid pieces from the energy released from the bubbles created by cavitation collapsing through them. This gives the solid reactant a larger surface area for the reaction to proceed over, increasing the observed rate of reaction¹⁰.

Similarities between sonochemistry and radiation chemistry were explored by numerous investigators from the early 1950s. Cavitational implosion (vide infra) generates solvent radicals; in the case of water these are H⁺ and OH^- that can combine to give hydrogen and hydrogen peroxide. They can also react with other substances to induce secondary reduction and oxidation reactions¹¹. For example, iodide can be sonochemically oxidized to triiodide by OH^- radicals or by H₂O₂ produced during cavitations. This so-called Weissler reaction constitutes a standard dosimetric method in sonochemistry since the rate of triiodide formation can be determined spectrophotometrically. If aqueous solutions contain chlorocarbons (e.g. CCl4), Cl^- and Cl₂ are also generated in high yields, which increases the rate of iodide oxidation. Molecular oxygen, if present, can also be broken down, and the subsequent radical pathways parallel those found in flame chemistry, particularly those leading to oxygen production. Yields of these short-lived species are less than those found in radiolysis experiments; moreover, a certain skepticism persisted about the existence of some intermediates. Only recently has electrochemical evidence provided confirmation for ultrasound- generated hydrogen radicals¹². Schultes and Gohr were the first to outline a possible mechanism for the fixation of atmospheric nitrogen when they showed that ultrasonic irradiation at 540 kHz produced hydrogen peroxide in water saturated with oxygen. When air was present instead, nitrous acid was also formed. If enough oxygen was available, further oxidation took place and nitric acid was produced ¹³. Interestingly, some reactions caused by sonication of aqueous solutions may have relevance to prebiotic chemistry. Thus, ultrasonic irradiation of a mixture of gases such as N2, H2, CH4 and CO dissolved in water resulted in formation of formaldehyde, hydrogen cyanide, imidazole and amino acids¹⁴.

3. Cavitation:

Ultrasound waves can be transmitted through any material possessing elastic character. The movement of the sound source is transmitted to the particles of the medium, which oscillate in the direction of the wave and produce longitudinal waves as well as transverse waves. As the molecules of the medium vibrate, the average distance between the molecules decreases in the compression cycle and increases during rarefaction. When the average distance between the molecules exceeds the critical molecular distance necessary to hold the liquid intact, the liquid breaks down; cavities (cavitation) and bubbles are formed. This process, known as cavitation, refers to the formation and the subsequent dynamic life of bubbles in liquids. These bubbles can be filled with gas or vapour and occur in water, organic solvents, biological fluids, liquid helium, molten metals or other fluids. Bubble collapse results in high temperature (as much as 4700^oC) and pressure changes (10Pa). The solvent/reagent vapour suffers fragmentation to generate reactive species, such as free radicals or carbenes. These high-energy species are concentrated at the interface and lead to intermolecular reactions. However, if there are in volatile solutes, they would also collect at the interface and react with the high energy species. Besides this, the shock wave produced by a bubble collapse can influence the reactivity by altering the solvation of the reactive species¹⁵.

3.1 Stable and transient Cavitation:

Theoretical sonochemists distinguish between two types of cavitation: stable and transient^16,17. Stable cavitation takes place when microbubbles mainly contain a gas (e.g. air) and their mean life is very much longer than a cycle of the ultrasound. During their growth, as long as their resonance frequency is higher than that of the ultrasound, they are driven into pressure antinodes, where they induce chemical reactions. Conversely, transient cavitation is a phenomenon of shorter duration: a cavity is rapidly formed which contains mainly vapor of the liquid and vigorously collapses after a few cycles. At ultrasound intensities of a few W cm^-2, probably both kinds of cavitation take place. As most theoretical work has been devoted to transient cavitation, this is often considered the most efficient way of producing chemical reactions, which is probably true for experiments conducted with high ultrasound intensities and avoiding the formation of standing waves. Nevertheless, at low intensities, when standing waves must occur if high bubble numbers and significant yields are to be achieved, most chemical reactions are induced through stable cavitation.

3.2 Cavitation and chemistry:

The fundamentals of cavitation outlined above highlight the uniqueness of sonochemistry and show that factors affecting cavitation, such as the nature of solvents or the volatility of substrates,may be crucial to understanding how this high-energy chemistry can be performed in a simple flask. What is more important, solvent effects in sonochemistry should not be reckoned in terms of such parameters as acidity, basicity, dipole moments etc., but rather taking into account volatility, viscosity, surface tension and dissolved gas, all of them directly involved in bubble formation and energy¹⁸. Two physical parameters, ultrasonic frequency and intensity, are often poorly understood from a chemical perspective. Unlike electromagnetic radiation, sound is not quantized, therefore a direct relationship between its energy and frequency cannot be established. As frequency is increased, it is necessary to increase the amplitude (or the power) of irradiation to maintain the same amount of cavitational energy. This is why it becomes more difficult to produce cavitation at higher frequencies, especially in the MHz region. Intuitively, this can be explained in terms of shorter cycles of compression and rarefaction at very high frequencies: since the creation of cavities requires enough time for molecules to be pulled apart, cavitation can be extremely difficult to achieve with very short cycles. If predictions are to be made, it must be borne in mind that reactions induced by cavitation will depend on the lifetimes of primary radicals relative to bubble lifetime. Frequency will influence the time taken by a bubble to collapse, although studies on this aspect are few. At high frequencies, say 500 kHz, collapse occurs in 4 6 1027 s, less than the lifetime of most radicals. These will then diffuse into the liquid phase and interact with other species. At a frequency of 20 kHz, however, bubble collapse occurs in approximately 1025 s, a time long enough for ^.OH radicals to undergo recombination reactions (yielding hydrogen peroxide, superoxides, excited water molecules) or other reactions in which dissolved gases may also participate. This suggests that ‘‘primary’’ sonochemistry will be observed only at high frequencies, while the chemistry of low frequencies will be determined by sequential transformations of radicals.

To test the above predictions, the sono-oxidation of 2,2,6,6- tetramethylpiperidin-4-one was investigated at 520 and 20 kHz and the formation of its stable nitroxide was monitored by ESR (Scheme 1)¹⁹. The reaction requires the presence of ^.OH and either molecular oxygen or superoxide radical anion. At 520 kHz a higher rate of nitroxide formation was observed with an oxygen-saturated solution, while it was not under argon. In contrast, the same reaction run at 20 kHz proceeded more slowly under oxygen than under argon. As it requires oxygen, at low frequency under argon this must be produced by reaction pathways involving ^.OH recombination (vide supra, Scheme 1). The next important parameter is acoustic intensity, or the amplitude of the pressure wave which is linked to our perception of sound strength.

4. Ultrasound sources:

A variety of devices have been used for ultrasonic irradiation of solutions. For common laboratory use, there are three main designs (a) ultrasonic cleaning bath (b) cup horn sonicator, and (c) direct immersion ultrasonic horn. The source of the ultrasound is a piezoelectric material (lead-zirconate-titanate ceramic (PZT) or quartz) which is subjected to high voltage alternating current with an ultrasonic frequency (15 kHz – 10MHz).

Scheme 1: Sonochemical oxidation of 2,2,6,6-tetramethylpiperidin-4-one.

The piezoelectric material expands and contracts in this electric field and is attached to the walls of the cleaning bath (or amplifying horn) and converts electrical energy into sound energy. In most applications the sonicators operate at a fixed frequency in the range of 20 – 35 kHz. In cleaning baths the acoustic field is continuous whereas it is in the pulsed form in probes. In the ultrasonic cleaning bath (Figure 1, left) a liquid (H2O) is present for transferring the ultrasound from the generators to the reaction vessel. The reaction vessel (conical or R B flask) is submerged in the water at a level where the liquid in the flask is just above the surface of the water. After sonication is started, the flask is adjusted to the point where cavitation (bubbles) is maximum. The temperature of the water is kept constant by cooling. Results obtained by using a cleaning bath are not always reproducible and therefore at times the use of sonic probes (Figure 2, right) is preferred.

Fig. 2. Left: Apparatus for carrying out reaction in an ultrasonic cleaning bath. Right: Suslick cell apparatus attached to a sonic probe for use in small scale reactions in an inert atmosphere.

5. Sonochemical reactions:

The analysis of numerous experiments revealed that ultrasound had no effect on chemical pathways and reaction rates were often comparable to those of non-irradiated (or silent) processes. Thus, in many heterogeneous reactions the application of ultrasound, whether by bath or probe, has the same effect as a high-speed agitator or a homogenizer in which fluids do not cavitate²⁰. Enhanced yields and rates can be observed owing to the mechanical effects of shock waves. Chemical effects of ultrasound (‘‘true sonochemistry’’) will occur only if an elemental reaction is the sonication-sensitive step or when the high-energy species released after cavitational collapse do indeed participate as reaction intermediates. Then changes in product distribution upon irradiation, switching of mechanisms, and in some instances changes of regio- and diastereoselectivity²⁰ suggest, although do not explicitly prove, that a true activation is occurring. A set of empirical rules (a–c) have been established to distinguish between true and false sonochemistry;²¹ they represent a first rational approach to sonochemical reactions and can provide clues for future work. The following are examples of general reaction situations possible in sonochemistry.

a) Type I: In homogeneous reactions chemical effects can be rationalized by assuming that sequential electron transfers are favored by ultrasonic irradiation. Transition metal complexes will undergo ligand–metal bond cleavage producing coordinatively unsaturated species. In general, homogeneous ionic reactions will not be affected by sonication.

b) Type II: In heterogeneous liquid–liquid or liquid–solid ionic reactions, mechanical effects associated with sound waves can affect both rates and yields to an extent depending on surface tension, density, temperature and nature of participant solids. These are in fact cases of false sonochemistry.

c) Type III: In heterogeneous reactions which can follow either an ionic or an electron-transfer path, the latter will be preferentially induced by ultrasound. These biphasic systems will also be sensitive to the mechanical component of shock waves in addition to chemical activation.

6. CONCLUSIONS:

Sonochemistry has certainly moved a long way from its beginnings in the late 1920s through its renaissance in the 1980s to where it stands as a valuable store of knowledge, especially within the community of synthetic chemists. It is however still far from being ripe science. Ultrasound can increase yields, change harsh reaction conditions to milder ones, improve selectivities, and most of all it can make the reactions that do not proceed under normal conditions occur smoothly. However, sonicated reactions are quite solvent sensitive and these solvent sensitivities are still quite poorly understood. Since it is an upcoming and a recent field of interest, there is a great deal more to explore in ultrasonics as an important tool in order to tap its full potential for the discovery of new reactions utilising highly energetic sound waves. Both sonosynthesis and sonocrystallization will be very useful in drug discovery. The sonochemical boom is turning out to be a real boon for synthetic chemistry. Although sonochemistry may offer simple solutions to synthetic problems, from a theoretical viewpoint it is really a complex topic. Even if the overall picture of cavitation is still incomplete, it is now possible to rationalize sonochemical reactivities. Practically unexplored, ultrasound-induced cavitation at increased pressures may open up new vistas in high-pressure chemistry. Sonication has largely been limited to atmospheric conditions, as an increased static pressure hinders the formation of bubbles in a liquid. However, cavitation does occur in liquid CO₂, where the vapor pressure in the bubble is considerably higher than in ordinary liquids. Finally, the challenges of scale-up represent a current concern of non-conventional technologies. A series of commercially available ultrasonic rectors can be readily adapted for scale-up,^3,4 even operating below the ultrasonic threshold. Interestingly, a giant probe system using a large bar of steel as horn and operating with audible sound has found a variety of applications in processing and catalysis²².

REFERENCES:

1. Rechards, W. T.; Loomis, A. L. J. Am. Chem. Soc. 1927, 49, 3086. “The Chemical Effects of High Frequency Sound Waves I. A Preliminary Survey”

2. Porter, C. W.; Young, L. J. Am. Chem. Soc. 1938, 60, 1497. “A Molecular Rearrangement Induced by Ultrasonic Waves”

3. Renaud, P. Bull. Soc. Chim. Fr. 1950, 1044. “Note de laboratoire sur L’application des ultra-sons a la preparation de compose organo-metalliques”.

4. Han, B. H.; Boudjouk, P. J. Org. Chem. 1982, 47, 5030. “Organic Sonochemistry. Sonic Acceleration of the Reformatsky Reaction”.

5. Synthetic Organic Sonochemistry, ed. J.-L. Luche, Plenum Press,New York, 1998.

6. J.-L. Luche and P. Cintas, Active Metals. Preparation, Characterization, Applications, ed. A. Furstner, VCH, Weinheim, 1996, pp. 133–190.

7. Cains, P. W; Martin, P. D.; Price, C. J. Organic Process Research & Development 1998, 2, 34. “The Use of Ultrasound in Industrial Chemical Synthesis and Crystallization 1. Applications to Synthetic Chemistry”.

8. Singh, J., Kaur; J., Nayyar, S.; Bhandari, M.; Kad G. L. Indian J of Chem. 2001, 40B,386. “Ultrasound Mediated Synthesis of a few Naturally Occurring Compounds”.

9. Yadav, S. J.; Reddy, B. V. S.; Reddy, K. B. Raj, K. R.; Prasad, A. R. J. Chem. Soc., Perkin Trans. 1, 2001, 1939. “Ultrasound-accelerated Synthesis of 3,4-Dihydropyrimidin-2(H1)-ones with Ceric Ammonium Nitrate”.

10. .Sonication 101, UPS. Diagnostics, 672, Rt 202-206, North Building 3, Lower Level, Bridge water, NJ 08807 USA.

11. For a historical perspective: D. Bremner, Advances in Sonochemistry, ed. T. J. Mason, JAI Press, London, 1990, Vol. 1, pp. 1–37.

12. P. R. Birkin, J. F. Power and T. G. Leighton, Chem. Commun.,2001, 2230.\

13. H. Schultes and H. Gohr, Angew. Chem., 1936, 49, 420.

14. A. Negro´n-Mendoza and G. Albarra´n, Chemical Evolution: Origin of Life, ed. C. Ponnamperuma and J. Chela-Flores, A. Deepak Publishing, Hampton, 1993, pp. 235–247.

15. C. O. Kappe, Angew. Chem., Int. Ed., 2004, 43, 6250 and references therein.

16. T. G. Leighton, The Acoustic Bubble, Academic Press, London, 1994.

17. T. Lepoint and F. Lepoint-Mullie, Synthetic Organic Sonochemistry, ed. J.-L. Luche, Plenum Press, New York, 1998, pp. 1–49.

18. T. J. Mason, Practical Sonochemistry. User’s Guide to Applications in Chemistry and Chemical Engineering, Ellis Horwood, Chichester, 1991, pp. 17–51.

19. C. Petrier, A. Jeunet, J.-L. Luche and G. Reverdy, J. Am. Chem. Soc., 1992, 114, 3148.

20. For a survey of stereochemical effects of ultrasounds: J.-L. Luche and P. Cintas, Advances in Sonochemistry, ed. T. J. Mason, JAI Press, London, 1999, Vol. 5, pp. 147–174.

21. J.-L. Luche, Advances in Sonochemistry, ed. T. J. Mason, JAI Press, London, 1993, Vol. 3, pp. 85–124 and references therein.

22. J. P. Russell and M. Smith, Advances in Sonochemistry, ed. T. J. Mason, JAI Press, London, 1999, Vol. 5, pp. 279–302.

Received on 04.06.2009 Modified on 14.10.2009

Research J. Pharm. and Tech. 3(1): Jan. - Mar. 2010; Page 13-16