Chemical Science Blog

US scientists have found a way to stop solid byproducts clogging channels in continuous flow reactors, a problem that has hampered their progress for use in manufacturing pharmaceuticals.

Klavs Jensen, Stephen Buchwald and their team at the Massachusetts Institute of Technology believe that flow methods will become increasingly important in the future of pharmaceuticals and chemical manufacturing. ‘One of the biggest hurdles is handling solids,’ says group member Timothy Noël. ‘Precipitates can form during the reactions, which usually lead to irreversible clogging of microchannels in the reactors.’ Previous methods suggested to overcome this problem include introducing another solvent to dissolve the solids, but this can reduce the overall efficiency of the reactions. Now, the team have used an ultrasound bath to break up the byproducts to prevent clogging.

Traditionally, pharmaceutical manufacture is done in a batch-based system, but the process suffers from interruptions and the need to transport material between batch reactors. Performing these reactions in a continuous flow system would speed up the process and reduce chemical waste.

The team tested the method on palladium-catalysed C-N cross-coupling reactions, making amines that are common in biologically active molecules. The reactions couple aryl halides to nitrogen nucleophiles and form byproducts – inorganic salts – that are insoluble in the solvents used.

As a result, says Noël, they were able to obtain diarylamine products with reaction times ranging from 20 seconds to 10 minutes. At very short residence times (time in the reactor under reaction conditions) they observed a significantly higher rate for the reaction in flow compared to the equivalent batch experiments. With high conversions in short reaction times, they were able to reduce the catalyst loading in flow to just 0.1 mol per cent. ‘Extremely low catalyst loadings such as these are of particular interest to the pharmaceutical industry,’ says Noël.

Noël believes that in the future microfluidics will be used to construct increasingly complex molecules. Different devices will automate and integrate many synthetic steps that are currently performed using the more traditional and time-consuming batch-based practices.

Oliver Kappe, from the Christian Doppler Laboratory for Microwave Chemistry, Institute of Chemistry, Karl-Franzens-University Graz says: ‘Jensen and Buchwald clearly demonstrate that immersing a flow device into an ultrasound bath can prevent clogging problems that unfortunately are all too familiar to the flow/microreactor community.’

Sarah Corcoran

Find out more by downloading the Chemical Science Edge article.

Stephen Buchwald is Associate Editor for Chemical Science. Submit your exceptional organic research to him today to be seen with the best.

Also of interest: 
Continuous flow multi-step organic synthesis 
Damien Webb and Timothy F. Jamison 
Chem. Sci., 2010, 1, 675-680, DOI: 10.1039/C0SC00381F, Minireview

US chemists have developed a new highly stereoselective route to a natural product with potent anticancer properties.

David MacMillan and colleagues at Princeton University made the structurally challenging diazonamide A by exploiting three different types of catalysis – Lewis acid, transition metal and organocatalysis – in the key steps.

The principal challenge was stereoselectively installing the C(10) quaternary carbon stereocentre, explains MacMillan, as this aspect of the structure had not been successfully addressed in any of the three completed total syntheses. Using asymmetric iminium catalysis, the team efficiently synthesised the furanindoline core and C(10) centre with high stereoselectivity, which they believe is the most complex and challenging setting in which organocatalysis has been employed to date.

Find out more by downloading MacMillan’s Chemical Science Edge article.

Researchers from the Biophotonics Research Unit of  Gloucestershire Hospitals NHS Foundation Trust, in collaboration with scientists from the University of Strathclyde and the Rutherford Appleton Laboratory, have published results of their exploration into surface enhanced spatially offset Raman spectroscopy (SESORS) imaging, a new technique combining surface enhanced Raman scattering (SERS) with spatially offset Raman spectroscopy (SORS).

They achieved, for the first time, imaging of SERS signals recovered from a depth of 20 mm in tissues, opening the way for sampling a number of disease conditions in the same organ at the same time. This could potentially lead to a new methodology for enhanced personalised treatment plans to be developed in realtime.

The Chemical Science Edge article has been highlighted in the following RSC press release:

“UK scientists have explored surface enhanced spatially offset Raman spectroscopy (SESORS) imaging and found that multiplexed surface enhanced Raman scattering (SERS) signals have been recovered non-invasively from a depth of 20 mm in tissues for the first time and reconstructed to produce a false colour image. This approach could be adapted into a clinical setting for disease diagnosis, say the researchers.

The team injected four unique ‘flavours’ of SERS nanoparticles (NPs) into a 20 x 50 x 50 mm porcine tissue block at the corners of a 10 mm square. A transmission Raman data cube was acquired over an 11 x 11 pixel grid made up of 2 mm steps. The signals were reconstructed using the unique peak intensities of each nanoparticle. A false colour image of the relative signal levels was produced, demonstrating the capability of multiplexed imaging of SERS nanoparticles using deep Raman spectroscopy.

A secondary but no less significant achievement was to demonstrate that Raman signals from SERS nanoparticles can be recovered non-invasively from samples 45–50 mm thick. This is a significant step forward in the ability to detect and identify vibrational fingerprints within tissue, say the team.

The prospects for SESORS as a medical tool are significant, say the researchers. There are numerous applications where this approach could have a major impact on rapid specific diagnosis, patient specific treatment selection and treatment monitoring. However, the greatest hurdle will be introducing nanoparticles into the body without fully understanding their excretion mechanism or long term accumulation sites and whether this is likely to have detrimental effects.”

Reference:

N Stone, M Kerssens, G R Lloyd, K Faulds, D Graham and P Matousek, Chem. Sci., 2011, DOI: 10.1039/c0sc00570c



Here in the UK we’ve been enduring the coldest start to winter since 1976. Thankfully, we published a great selection of hot Edge articles last month. As per all Chemical Science articles, they are free to access until the end of 2011.

Enjoy!

A ‘hole’ lot of mobility: Chi-Ming Che and colleagues report single crystal organoplatinum complexes with high charge mobility

Fingerprinting red wine: Eric Anslyn and colleagues have developed a sensor that can discriminate between different tannins and fingerprint a wide variety of red wines

Dinitrogen complexation with main group radicals: Spectroscopic evidence for weak but distinct interactions between several main group element radicals and physically dissolved dinitrogen in solution

New class of organic acceptors: A family of push–pull chromophores with a [4]dendralene backbone and a remarkably high propensity for reversible electron uptake

Carbene catalysts for group transfer: Gregory Hillhouse discusses the synthesis and carbene transfer reactivity of dimeric nickel bridging-carbene complexes

Building complex oxides layer-by-layer: Matthew Rosseinsky and colleagues exploit the capabilities of modern thin film deposition to grow an artificial metastable oxide

Carbenoids’ role in silver catalysis: Silver(I)-catalysed reactions of vinyldiazoacetates involve the intermediacy of silver-carbenoid species

Submit your own hot research to Chemical Science today.

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