It’s Time for Chemists to Go with the Flow

January 2013
REUTERS/Brian Snyder

The techniques of chemical synthesis are undergoing a revolution, as revealed by the fast-growing number of continuous-flow microreactor papers in the literature. From its origins a dozen or so years ago, the technology is currently being embraced in a big way by increasing numbers of chemists. Therefore, ScienceWatch now turns its attention to a selection of notable papers and players in the field.

Such has been the advance of this method of organic synthesis that working with liquids in large round-bottom flasks now seems somewhat antiquated. Indeed, so rapid has been the advance that there are now commercially available systems with numerous add-ons, including some that researchers can control via their cell phones and observe via their webcams.

Continuous-flow offers economy of scale, efficiency of yield, and especially safety, all of which appeal to chemists both in universities, institutes, and industrial research laboratories. Making new molecules this way, albeit in tiny amounts, still means they can be analyzed and tested because of the ultra-sensitivity of analytical techniques that are now available, and these can be built into the flow system.

Table 1Selected, key reports on continuous-flow chemistry published since 2001 are featured in the accompanying table, listed by citations.

MICROREACTORS, MAXIMUM YIELDS

One of the first chemists to suggest using microreactors to synthesize organic molecules was Paul Watts of Hull University, UK, and this he did in paper #5, published in 2001. Since then, he has published other highly cited works, including two others collected here, at #1 and #6; together, this trio of papers has attracted more than 670 citations. A summary of Watts’ work can be accessed at www.rscspecialitychemicals.org.uk/downloads/20-8%20Paul%20Watts.pdf , which was his contribution to a symposium on continuous-flow technology organized by the Royal Society of Chemistry and held at York, UK, in March 2012.

Watts says that when microreactors were first introduced they were seen as research tools, but their potential for small-scale production was soon noted. The chemical company DSM now uses microreactors to generate more than 4,000 tons of an agrochemical in Austria, using the Ritter reaction to produce N-alkyl amides.

As Watts tells ScienceWatch: “There is now a plethora of commercial reactors on the market, and most companies are using continuous-flow technology to screen reactions rapidly. Moreover, the inherent safety associated with small reactors enables users to employ reaction conditions previously thought to be too hazardous or which produced hazardous compounds.”

Microreactor technology offers obvious advantages where the product is intrinsically dangerous such as in making nitro-glycerine, and this is how it is now produced by one company in China.

SEVEN-STEP PROGRAM

One of the first chemists to make microreactors a part of continuous-flow chemistry, and to realize its potential, was Steve Ley of Cambridge, UK, and his research has led to groundbreaking papers. The one reporting the preparation of oxomaritidine in a seven-step program (#9) shows just what can be achieved. In another influential paper (#12) he describes the preparation of grossamide, a phenolic amide, using an immobilized enzyme in one of the key steps. Ley’s other innovations have included incorporating infrared spectrometers to measure and identify intermediates, and the use of ultrasonification to prevent in-line blockages.

Continuous-flow offers economy of scale, efficiency of yield, and especially safety, all of which appeal to chemists both in universities, institutes, and industrial research laboratories.

As Ley notes, “When we started using these methods many years ago, little did we realize how quickly they would be taken on by other scientists. We now have a lab dedicated solely to flow chemistry and we are particularly proud of our multi-step syntheses.”

So what advantages does continuous-flow offer the organic chemist? The answer is rapid heating of reagents, less solvent use, little waste, and faster reaction times. Yields are of necessity small in weight terms—although high in percentage terms—but it is possible to run a micro-processor continuously and accumulate products, or to have several working at the same time, a system referred to as “numbering up.” There are, of course, drawbacks to flow synthesis such as blockages of small bore tube lines, and there can be teething problems when setting a system up, as Ley admits.

A paper garnering lots citations is a review by D. Tyler McQuade of Cornell University (#2). In this he explains the design and operation of a microreactor and extols its many virtues over conventional methods of synthesis. He lists two kinds of synthesis for which this method is particularly advantageous. The first kind consists of stoichiometric reactions such as carbon-carbon bond formation, oxidation, heterocyclic formation, fluorination, and even polymerization. The second kind involves catalytic reactions of various types.

One of the more prolific publishers of papers in continuous-flow synthesis is Klavs F. Jensen of MIT, whose most heavily cited paper (#8) is about the synthesis of carbamates from sodium azide and benzoyl chloride using the Curtius rearrangement reaction. This process involves three reaction steps and two separation steps, one gas-liquid, the other liquid-liquid.

PHARMACEUTICAL IMPLICATIONS

Other highly cited papers of Jensen’s are his review articles #11 and #16, but it is his research papers #23 and #24 that are particularly noteworthy. In the first of these he describes the synthesis of β-amino alcohols, a process that has implications for making pharmaceutical compounds, while the second reports the formation of diarylamines using palladium-catalyzed reactions which involve sonication to manipulate solids in the system and with reaction times as fast as 20 seconds.

An earlier highly cited paper, which also involved a palladium catalyst, was the work of Ley’s group (#10) and was innovative in another way in that he used microwave heating in combination with an external cooling source. This enabled a lower temperature to be maintained throughout the reaction and gave much improved yields and purity of products for Suzuki reactions. Moreover, the catalysts could be used many times.

Stephen Buchwald at MIT also found palladium a useful catalyst in his preparation of 3,3-disubstituted oxindoles, see #27. These substitutions occur on the heterocyclic ring of this naturally occurring alkaloid, derivatives of which are being sought as potential anticancer agents. His work on C-N bond formation, also using palladium catalyst, (#26), is noteworthy, particularly for his efforts to overcome clogging of the system (#22).

Another chemist making his name in continuous-flow synthesis is Andreas Kirschning of Leipzig University, Germany, whose paper #14 highlights 10 essentials to be contemplated when considering flow synthesis. These are flow rate, residence time, scale, high pressure, high temperature, reactivity of intermediates, support reagents, support catalysts, complexity of stages, and photochemistry. Kirschning’s paper #4 is devoted to hetero catalysis.

Takahide Fukuyama of Osaka Prefecture University, Japan, is also a leading light in this area, as papers #7 (review article) and #3 reveal. He introduced ionic liquids into the new technology, and paper #3’s high level of citations clearly indicates its importance. Fukuyama used the ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate, aka [BMIM][PF6], with PdCl2(PPh3)2 as a catalyst, to perform the Sonogashira coupling reaction which forms carbon-carbon bonds. Yields were good and he was able to recycle the catalyst successfully.

Along with these advanced forms of synthesis, very basic chemical reactions also get their due when it comes to flow-chemistry. Paper #25 describes potassium permanganate oxidation of alcohols, aldehydes, and nitroalkanes to their corresponding carboxylic acids, processes which of necessity produce insoluble slurries of manganese dioxide. The disruption that might be caused by this by-product blocking the reactor was prevented by means of ultrasound pulses.

FAVORABLE FLUORINATION

Fluorination has become a key process for modifying molecules in a way that dramatically changes their biological behavior—see this recent story in ScienceWatch. Simply substituting a hydrogen with a fluorine can transform an innocuous compound into one which can cure disease. In the last century, fluorination invariably involved dangerous and vicious chemicals, whereas today there are methods of achieving this with much safer reagents. Could these reagents be used in continuous-flow microreactors?

The answer was given in #18 which reports safe and reliable continuous-flow fluorinations of the various types. These are nucleophilic fluorination using diethylaminosulfur trifluoride (aka DAST), electrophilic fluorination using 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (aka Slectfluor), and trifluoromethylation using trifluorotrimethylsilane (aka Rupper’s reagent). What is special about this paper is the way in which clean products were produced without the need for purification, and this was achieved by in-line scavenging.

RECENT WORK

So what about more recent work in continuous-flow chemistry? Limiting the choice to papers published in the past two years, and whose citations place them on the top 20 list of continuous-flow synthesis, gave the following ones.

The highest-cited such paper is #15 by Oliver Kappe of the Karl Franzens University, Graz, Austria, and this demonstrates that many conditions not generally considered suitable for flow synthesis, such as those requiring high temperatures and pressures, can be operated at production-scale quantities.

Also highly cited is paper #19, which is about a three-component coupling involving an optically active butyloxazole performed either in a one-pot reaction at -78 oC, or with a flow microreactor at 0 oC. This originated from the group of Seiji Suga, now at Okayama University.

The potential for continuous-flow technology in the field of pharmaceutical chemistry is demonstrated with #20 which concerns the clean synthesis of the drug imatinib. This is prescribed for the treatment of chronic myeloid leukemia, and it was generated via flow through a system consisting entirely of tubular coils or cartridges packed with reagents and which resulted in minimum manual handling of intermediates.

And so it goes on, with more and more processes in organic chemistry being shown to be feasible within continuous-flow technology, such as ozonolysis (#17), or which involve several steps, such as in paper #13. This last one is devoted to two reactions. The first is the formation of alkynes via multistep syntheses involving the reaction of a ketone with dimethyl (diazomethyl)phosphonate (aka the Seyferth-Gilbert reagent). The second is the formation of triazoles from an alcohols via copper(I) catalyzed azide-alkyne cycloaddtion and without the intermediate compounds being isolated.

Organic synthesis techniques are moving forward in a way that would have been unthinkable ten years ago, and are continuing to attract adherents in chemistry labs around the world. It seems likely that by the end of this decade there will be a practitioner in every university chemistry department and industrial research laboratory. Its benefits are truly enormous.


Dr. John Emsley is based at the Department of Chemistry, Cambridge University, UK.

Keywords: 
chemistry, continuous-flow chemistry, organic synthesis, microreactors, fluorination, Steve Ley, Stephen L. Buchwald

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