"The late historian and philosopher Thomas Kuhn in his book The Structure of Scientific Revolutions discusses the nature of dramatic changes or revolutions in science by saying: "Science does not develop by the orderly accumulation of facts and theories, but by dramatic revolutions" and that "Scientific revolutions need creative thinking of a kind that cannot grow out of the old order."
This is sometimes referred to as a paradigm shift and for it to occur in science, scientists need to step out of their box and explore the unknown territory around them. For the many traditionalists this is nothing short of heresy but for those who choose it, it is the road to excitement and discovery. In chemistry the combining of electronic, material and IT technology with chemical physical and biological processes is well out of the box stuff and for those of us working in the field of Lab-on-a-chip every day brings unexpected thrills and challenges. And why shouldn’t science be one big thrill?
In very simplistic terms, a chemical reaction proceeds when one molecule comes into close enough proximity with another for a favourable exchange of electron energy to occur. In general, this is a bimolecular event where component A reacts with component B to form a quantity of product C or a combination of products. Whilst the energy exchange in such a process is extremely fast, its initiation and control at the right time and place (often in multi step reactions), underpins the practical nature of reaction chemistry.
In practical terms the way we perform a chemical reaction in the laboratory has changed little over the past 300 years with the familiar test tube simply becoming more complex but remaining essentially a hand held process. The scale of laboratory reactions and indeed industrial plants therefore rely heavily upon experimental techniques and methods that mix many millilitres or litres of reactants together in a common solvent at a suitable concentration for a given period of time. Reaction processes may also include the addition of a catalyst, variation in temperature and the addition of specific reagents, which favour a desired molecular interaction.
In order to achieve the required reaction and generate the desired product a whole range of techniques such as stirring, refluxing, distillation, crystallization and chromatographic separations are used. However, in an ideal chemical environment, the chemist would like the ability to select and control (in spatial and temporal terms) a chemical reaction, such that they can synthesize the product in a preferred quantity and location. In short, do what cells have been doing as small chemical reactors for millennia and if we care to learn from nature then we will realize that it is telling us that chemical reactors should be less than 100 microns in cross-sectional size.
Building a micro reactor
To construct a chemical reactor on the scale of a biological cell in a material that is chemically and thermally compatible and in which flow and mixing control can be achieved is not trivial, not least because it is necessary to access a range of complimentary scientific disciplines and technologies.
Currently micro reactors can be made out of glass, metal and a range of polymeric materials. The typical channel dimensions are in the range 10-100 microns. A number of techniques are used to create the required network of channels and these range from photolithography through molding and embossing to milling processes. Liquids and suspended solids can be moved around the channels from one reservoir to another using either electrical field (electrokinetic) or hydrodynamic (pressure) pumping. Optimization of the flow and mixing processes can be monitored by a number of electrochemical and spectroscopic techniques, which also serve to detect chemical products.
The chemical benefits of going small
So what are the real attributes miniaturisation can offer reaction chemistry that cannot be realized using current methodology? Perhaps the most important properties of micro reactors which make them unique are the presence of diffusive mixing under laminar flow conditions and their efficient heat dissipation property arising from their low mass reaction volume compared to the very large heat sink properties of the effective container.
Diffusion can be considered as the last stage of any mixing process, which traditionally uses mechanical stirring to overcome the mass transfer difficulties of getting two reactant molecules sufficiently close enough to react. Thus mixing without mass in a micro system allows the rapid generation of products as reactants can be positioned in close proximity to each other for efficient diffusion to occur. In practical terms, reaction products can be produced in a matter of seconds/minutes compared with laboratory scale taking hours or even days.
However, the fundamental properties of the chemistry performed in a micro reactor are no different to that performed in the laboratory but the real chemical advantage lies with the fact that a larger number of reactions can be carried out in a given unit of time with minimal reagent consumption. Thus for the first time, statistical design of experiments and optimization models have been successfully applied in a robust way to well established chemical reactions. The important message here is that we have not fundamentally altered the underlying chemistry so the realization of kinetic data etc for a reaction is transferable to bulk systems, given that the mass diffusion issues can be addressed. The capacity however for massive scale synthesis offers a richness of chemical information not attainable through conventional methodology.
In chemical terms the diffusive reaction environment within a micro reactor leads to the generation of localized concentration and thermal gradients which will have a direct bearing on the equilibrium distribution of both the starting materials and products. Whilst the ability to manipulate the equilibrium of a reaction is not a new concept in chemistry, the ease and selectivity with which it can be achieved is a unique feature of the micro reactor environment."
Sources of further information
The Lab on a Chip Journal (LOC) publishes work relating to miniaturisation across a wide range of disciplines, including chemistry, biology, physics, engineering, electronics, and medicine.
General references relating to chemical reaction in micro reactors
Microreactors, W. Ehrfeld, V. Hessel and H. Lowe, Wiley-VCH, (2000)
The application of micro reactors to synthetic chemistry, Haswell, S.J., Middleton, R.J., O’sullivan,B., Skelton, V., Watts, P. and Styring, P., Chem. Commun., (2001), 391
The synthesis of peptides using micro reactors, Watts, P., Wiles, C., S.J. Haswell, Pombo-Villar, E. and Styring, P, Chem. Commun., (2001), 990-991
The preparation of a series of nitrostilbene ester compounds using micro reactor technology, Skelton, V., Greenway, G.M., Haswell, S.J, Styring, P., Morgan, D.O., Warrington, B.H. and Wong, S., Analyst, (2001), 126, 7-10
The generation of concentration gradients using electroosmotic flow in micro reactors allowing stereo selectivity in chemical synthesis, Skelton, V., Greenway, G.M., Haswell, S.J, Styring, P., Morgan, D.O., Warrington, B.H. and Wong, S., Analyst, (2001), 126, 11-13
Chemical and Biochemical Microreactors, Haswell, S.J. and Skelton, V., Trends in Anal. Chem. (2000), 19, 389-395
Downsizing Synthesis, Fletcher, P.D.I. and Haswell, S.J., Chemistry in Britain, November (1999), 38- 41
Theoretical investigation into the rates of chemical reactions in micro-total analytical systems (µTAS) operating under electroosmotic and electrophoretic control, Fletcher, P.D.I., Haswell, S.J. and Paunov, V.N., Analyst, (1999), 124, 1273-1282
First broadcast: Friday 11 May 2001 on BBC TWO