Intelligent use of nmr for synthetic organic chemistry

Improving mechanistic understanding of fast reactions using rapid, reproducible in situ analysis by stop-flow NMR and IR

Nuclear Magnetic Resonance
Mechanistic understanding is essential to control and optimize reactions so that by-products are reduced, yields are increased and reaction selectivities are improved. However, if reactions are very fast, they can be difficult to study and therefore control. In this webinar, Forbes Professor of Organic Chemistry, Guy Lloyd-Jones, will discuss some the stop-flow (SF) techniques he uses to model reaction mechanisms and optimize reaction conditions. As well as welcoming the spectroscopy community in general, this webinar is aimed at any synthetic or process chemist in pharma, other industries and in academia who are interested in reaction understanding and optimization.
This webinar took place on September 12th 2017

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What to expect

A number of reactions will be discussed, including the challenges faced in the trifluoromethylation reaction, which is sensitive and extremely fast, making it difficult to reliably control the reaction and measure the kinetics. Professor Lloyd-Jones will explain how SF-FT-IR and SF-NMR can be used to address this and enable rapid, reproducible monitoring, along with accurate temperature control.

Professor Lloyd-Jones will also introduce InsightXpress, which he has developed in collaboration with TgK Scientific and Bruker and has been critical to understand the mechanisms of the Suzuki-Miyaura protodeboronation side reaction. The InsightXpress SF unit enables fast reactions to be monitored and reaction conditions to be automatically screened by NMR at unprecedented speeds. With the InsightXpress, not only is accurate temperature control possible, but large reagent volumes are not needed and mixing is so efficient that analysis can begin very shortly after the start of the reaction. Importantly, unlike classic SF systems, the concentration of the reagents can be varied rather than it being fixed in the initial set-up, which vastly broadens scope in terms of mapping out the kinetics and screening reaction conditions in process chemistry.

Professor Lloyd-Jones and team have also developed an SF-FT-IR system in collaboration with Bruker and TgK Scientific that will be introduced during the seminar. This device offers the same capabilities as the InsightXpress, but is interfaced with a VERTEX 80 Fourier transform infrared spectrometer instead of an NMR spectrometer.

The protodeboronation reaction will also be covered. This reaction, which is usually undesirable, reduces yields in Suzuki-Miyaura couplings. SF-NMR and SF-FT-IR have enabled mechanistic understanding of protodeboronation by allowing the concentration of reactants to be measured as a function of time when reactions are extremely fast and highly sensitive to pH. Using these techniques, it has been possible to accurately and rapidly initiate these reactions and maintain good control of pH so that they can be accurately monitored. Some of the reagents monitored by SF-IR have half-lives of milliseconds. These are reactions that would otherwise be over almost as soon as the reactants have been mixed.

Key topics

  • Understanding the basic principles of SF and how it can be improved to make a variable ratio SF system
  • How those SF systems have been interfaced with FT-IR and NMR spectrometers and the technical challenges and benefits
  • Example applications of how SF-IR and SF-NMR can be used

Who should attend

As well as welcoming the spectroscopy community in general, this webinar is aimed at any synthetic or process chemist in pharma, other industries and in academia who are interested in reaction understanding and optimization.

Speaker

Guy Lloyd-Jones
Guy Lloyd-Jones
Forbes Professor of Organic Chemistry School of Chemistry University of Edinburgh Scotland
Guy Lloyd-Jones studied Chemical Technology (BSc. 1989) at Huddersfield, and spent a year placement at ICI Pharmaceuticals (now AstraZeneca) in 1987. He obtained his doctorate in organic chemistry (D. Phil. 1992) at Oxford University under John Brown FRS, and conducted postdoctoral research (1993-1995) in asymmetric catalysis at Basel University, with Andreas Pfaltz. In 1996 he returned to the UK, to a lectureship at the University of Bristol and began to build a research group specialising in organic / organometallic stereochemistry, in particular applying NMR and isotopic labelling. He was promoted to Full Professor in 2003, held a Royal Society Wolfson Research Merit Award 2008- 2013, and was Head of Organic and Biological Chemistry at Bristol 2012-2013. In 2013 he moved from Bristol to The Forbes Chair of Organic Chemistry at the University of Edinburgh. In the same year was elected a fellow of the Royal Society (FRS) and and ERC Advanced Investigator. At Edinburgh he and his group continue to build their expertise in the study of reaction mechanism and reactivity relationships in the context of synthetic methodology and catalysis. Intrinsic to this is application and development of physical-organic chemistry methodologies, and associated instrumentation for its analysis.