The Engineering of Chemical Synthesis: Humans and Machines Working in Harmony

Words and phrases such as Artificial Intelligence, Machine Learning, Neural Networks, Robotics, the Cloud, Big Data and the Internet of Things are typically associated with many modern technological and scientific developments. Until recently, however, they have not been applied systematically to the chemical assembly of society’s functional molecules. Indeed, due to the lack of suitable tools, chemical synthesis in the past has tended to rely heavily on robust labour intensive batch processes that were often developed decades ago. This situation is changing rapidly owing to many reasons and, in particular, to the continuing need to discover new reactivity and new reactions, especially more sustainable processes. Smart, self-optimising platforms for continuous compound production along with a vast range of new analytical, monitoring and control devices for improved management of research experimentation and for accelerating the synthesis process are now available.support from the Woolf Fisher Trust (DEF), ECH2020 Future and Emerging Technologies (SVL. Sponsor reference 206410) and the Engineering and Physical Sciences Research Council (SVL. Grant codes: EP/K009494/1, EP/M004120/1)

Professor Steven V Ley CBE FRS FMedSci

Professor Steven Ley is currently Professor of Chemistry and Director of Research at at the University of Cambridge. He is also a Fellow of Trinity College and was BP 1702 Professor of Chemistry for 21 years. Steve obtained his PhD from Loughborough University with Professor Harry Heaney and afterwards carried out postdoctoral research with Professor Leo Paquette (Ohio State University) and then Professor Derek Barton (Imperial College). He was appointed as a lecturer at Imperial College in 1975, promoted to Professor in 1983, and became Head of Department there in 1989. In 1990 he was elected to the Royal Society (London) and was President of The Royal Society of Chemistry from 2000-2002. Steve’s research interests are varied and span many disciplines including new synthetic methodologies, the total synthesis of natural products and the development of enabling technologies for chemical synthesis - especially in the area of flow chemistry technologies. Four spin-out companies have emerged from these research interests. Steve has published over 860 papers and has been honoured with 50 major awards including recently (since 2009): the Tetrahedron Prize for Creativity in Organic Chemistry (Elsevier); Heinrich Wieland Prize (Boehringer Ingelheim, Germany); The Paracelsus Prize (Swiss Chemical Society); The Royal Medal (The Royal Society, London); The Longstaff Prize (The Royal Society of Chemistry); the Franco-Britannique Prize (Société Chimique de France); and the IUPAC-Thales Nano Prize in Flow Chemistry. Professor Ley is also recipient of the 2018 Arthur C. Cope Award

Studies in the chemistry of benzobicyclo systems

Reactions of tetrahalogenobenzynes with certain tertiary arylamines afford products which are derived by both 1,2- and 1,4-cyclo-addition as well as from a betaine. The tetrahalogenobenzynes and benzyne react with eneamines to give benzocyclobutene-derivatives via betaines; the tetrahalogenobenzyne derivatives are readily hydrolysed to 2-tetrahalogenophenyl cycloalkanones. 1-N-alkylamino derivatives of 5,6,7,8-tetrahalogeno-1,4-dihydronaphthalene also undergo cleavage reactions in protic media. Thus, for example, 1-N, N-dimethylamino-tetrafluorobenzobarrelene gives 2,3,4,5- tetrafluoro-k'-N, N-dimethylaminobiphenyl in high yield and 1,2,3,1- tetrafluoro-5,8-dihydro-5,8-N-(-methyl)-iminonaphthalene affords 2'- (2,3,4,5-tetrafluorophenyl)-N-methyl. pyrrole. Apparent similarities between mass spectral and thermal processes have been investigated in connection with retro-Diels-Alder reactions leading to k, 5,6,7-tetrahalogeno-isobenzofurans and 1,5,6,7-tetrafluoro- 2-methylisoindole. These derivatives are more stable than the nonhalogenated compounds. The rearrangement reactions of 1-methoxybenzobarrelene derivatives in strong acids have been studied. Various possible mechanistic pathways have been investigated by deuterium labelling methods. Benzobicyclo[3.2.1] derivatives arise via a 2-carbonium ion while a 3-carbonium ion leads to benzobicyclo[2.2.2)dien-2-one derivatives. The solvolyses of certain toluene-p-sulphonates have been used to check mechanistic predictions. The position of protonation and the extent of the rearrangement can be controlled by the use of alkyl substituents. Thus 2,6-dimethyl-l-methoxytetrafluorobenzobarrelene affords only derivatives of benzobicyclo[3.2.1]- octadiene while 3,5-dimethyl-l-methoxy-tetrafluorobenzobarrelene gives products derived by rearrangement to the benzobicyclo[2.2.2] system

The Evolution of Flow Chemistry: An Opinion on Factors Driving Innovation

This article seeks to provide an overview of the environmental factors within the pharmaceutical industry that have contributed to the emergence of flow chemistry over the past two decades. It highlights some of the challenges facing the industry and describes how they are being overcome by the exponential trajectory of scientific progress in the area. We identify current trends and offer a speculative glimpse into the future of drug development and manufacturing with some examples of progress being made at CARBOGEN AMCIS

A multistep continuous flow synthesis machine for the preparation of pyrazoles via a metal-free amine-redox process.

A versatile multistep continuous flow setup is reported for the four-step conversion of anilines into pyrazole products. The synthesis machine incorporates the use of amine-redox chemistry through diazotization and a metal-free vitamin C mediated reduction. The machine can be used for the synthesis of an array of analogues or the scale up of an individual target.We are grateful to the Cambridge Home and European Scholarship Scheme (JSP) and EPSRC (DLB and SVL, grant numbers EP/K0099494/1 and EP/K039520/1) for financial support.This is the final version of the article. It first appeared from the Royal Society of Chemistry via http://dx.doi.org/10.1039/C5RE00082

A Practical Method for Continuous Production of sp3-Rich Compounds from (Hetero)Aryl Halides and Redox-Active Esters.

A practically useful coupling reaction between aromatic halides and redox-active esters was realized by nickel catalysis through the use of a packed zinc bed column in continuous flow. Multiple reuse of the column showed a negligible decrease in efficiency, affording high space/time yields. A wide range of substrates, including a number of heteroaryl halides and polyfunctional materials were coupled in generally good yields. Longer-time and larger-scale experiments further demonstrates the robustness of the system

A Photoredox Coupling Reaction of Benzylboronic Esters and Carbonyl Compounds in Batch and Flow.

Mild cross-coupling reaction between benzylboronic esters with carbonyl compounds and some imines was achieved under visible-light-induced iridium-catalyzed photoredox conditions. Functional group tolerance was demonstrated by 51 examples, including 13 heterocyclic compounds. Gram-scale reaction was realized through the use of computer-controlled continuous flow photoreactors.Uniqsis Ltd and Mark Ladlow for the generous loan 236 of a Photosyn reactor. Y.C. thanks Pfizer for funding the 237 postdoctoral fellowship. The authors also gratefully acknowl- 238 edge financial support from H2020-FETOPEN-2016-2017 239 program of European commission (S.V.L.; grant agreement 240 no.: 737266-ONE FLOW)

In silico rationalisation of selectivity and reactivity in Pd-catalysed C-H activation reactions.

A computational approach has been developed to automatically generate and analyse the structures of the intermediates of palladium-catalysed carbon-hydrogen (C-H) activation reactions as well as to predict the final products. Implemented as a high-performance computing cluster tool, it has been shown to correctly choose the mechanism and rationalise regioselectivity of chosen examples from open literature reports. The developed methodology is capable of predicting reactivity of various substrates by differentiation between two major mechanisms - proton abstraction and electrophilic aromatic substitution. An attempt has been made to predict new C-H activation reactions. This methodology can also be used for the automated reaction planning, as well as a starting point for microkinetic modelling.EPSRC grant EP/K009494/1 (MK and SL) and the National Research Foundation, Prime Minister’s Office, Singapore under its CREATE programme, project “Cambridge Centre for Carbon Reduction in Chemical Technology” (LC and AL)

Mimicking the surface and prebiotic chemistry of early Earth using flow chemistry.

When considering life's aetiology, the first questions that must be addressed are "how?" and "where?" were ostensibly complex molecules, considered necessary for life's beginning, constructed from simpler, more abundant feedstock molecules on primitive Earth. Previously, we have used multiple clues from the prebiotic synthetic requirements of (proto)biomolecules to pinpoint a set of closely related geochemical scenarios that are suggestive of flow and semi-batch chemistries. We now wish to report a multistep, uninterrupted synthesis of a key heterocycle (2-aminooxazole) en route to activated nucleotides starting from highly plausible, prebiotic feedstock molecules under conditions which mimic this scenario. Further consideration of the scenario has uncovered additional pertinent and novel aspects of prebiotic chemistry, which greatly enhance the efficiency and plausibility of the synthesis

Visible-Light-Mediated Annulation of Electron-Rich Alkenes and Nitrogen-Centered Radicals from N-Sulfonylallylamines: Construction of Chloromethylated Pyrrolidine Derivatives.

A visible-light-mediated annulation of N-sulfonylallylamines and olefins is reported. Rapid access to highly functionalized chloromethylated pyrrolidines can be achieved using mild conditions for the generation of nitrogen-centered radicals. Both a transition-metal-based catalyst and an organic dye can be used as photosensitizers with 0.5 mol % loading. The reaction was found to be applicable to a large variety of electron-rich and electron-neutral olefins.This work was supported by a postdoctoral fellowship from Pfizer (L.C. and A.G.) and the EPSRC Grants EP/K009494/1 and EP/M004120/1 (S.V.L.)