Roadmap for
www.Dial-a-Molecule.org
Transforming synthesis,
Dial-a-MoleculeDial-a-MoleculeAn EPSRC Grand Challenge network
enabling science
synthesis in the 21 Centuryst
Contents Page 2
Contents 1 INTRODUCTION 3
1.1 The Dial-‐a-‐Molecule Network 3
1.2 Definition of the Grand Challenge 3
1.3 Current State of the Art 4
1.4 Impact of the Grand Challenge 6 1.4.1 Economic impact 6 1.4.2 Societal impact 7 1.4.3 Academic impact 8 1.4.4 Impact in government 8
1.5 Purpose of the Roadmap 9
1.6 Guide to the Roadmap 9
2 ROADMAP FOR SYNTHESIS IN THE 21ST CENTURY 10
2.1 Overview 10
2.2 Lab of the Future and Synthetic Route Design 17 2.2.1 Optimum reaction and route design 18 2.2.2 The smart laboratory 23 2.2.3 Next generation reaction platforms 26 2.2.4 Rapid reaction analysis 30
2.3 A Step Change in Molecular Synthesis 35 2.3.1 1000 Click reactions – stepwise perfection 36 2.3.2 Holistic approach to molecular synthesis 39
2.4 Catalytic Paradigms for 100% Efficient Synthesis 42 2.4.1 New reactivity: target-‐driven catalysis 43 2.4.2 Intervention-‐free synthesis by phase-‐distinct, multi-‐dimensional catalysis 46 2.4.3 Engineering control through fundamental mechanistic understanding 48
3 CONCLUSION 50
4 ACKNOWLEDGEMENTS 51
Introduction Page 3
“Dial-‐a-‐Molecule represents a fantastic opportunity for the UK’s scientific community to come together and really understand how synthesis related opportunities can be understood, explored and exploited. The improvement in profile that Dial-‐a-‐Molecule gives the community for its capability, successes and challenge is crucial and as momentum builds this profile will grow. Dial-‐a-‐molecule will give the UK funding bodies confidence to fund in the key areas and equally importantly will improve the UK’s European profile, to allow European funding to be secured by members of the network. The network strongly benefits both academia and industry and will allow strong, collaborative relationships to develop.”
Dr Steve Hillier, Chemistry Innovation KTN
1 Introduction 1.1 The Dial-a-Molecule Network The Dial-‐a-‐Molecule network was funded by the
EPSRC as a result of an extensive consultative and competitive exercise initiated in collaboration with the Chemistry Innovation Knowledge
Transfer Network, The Royal Society of Chemistry and the Institution of Chemical Engineers to identify the next Grand Challenges in Chemistry
and Chemical Engineering. The remit of the network is to define a path to the Grand Challenge (the roadmap) and to establish the
cross-‐disciplinary community needed to tackle it.
The network has employed a highly consultative strategy involving a community and end-‐user driven approach to define the key research
problems. It has built a community of more than 400 researchers with around 38% from industry. Of the academics 56% are drawn from outside
the synthetic chemistry / catalysis community. The steering group, industrial advisory board and launch meeting (200 participating) defined and
structured the challenge. Six themed workshops followed, each attended by around 30 people, to examine separate strands of the problem in
detail and offer possible solutions that form the basis of this roadmap. Wider community involvement and consultation has been through
an interactive website (www.dial-‐a-‐molecule.org), email lists, monthly newsletters and social networking.
Dial-‐a-‐Molecule has broken down barriers
between disciplines and is being strongly
supported by industry. It has created a high profile in the UK, which is already generating
considerable interest in Europe and the USA.
1.2 Definition of the Grand Challenge
Dial-‐a-‐Molecule is a Grand Challenge defined at its conception by the vision:
In 20-‐40 years, scientists will be able to deliver any desired molecule within a timeframe useful to the end-‐user, using safe, economically viable and sustainable processes.
Introduction Page 4
Molecules are collections of atoms connected together in a specific way. Even constrained to
those elements most used (C, N, H, O, P, S) the number of possible molecules, even using small numbers of atoms, is vast (Figure 1), and every
molecule has different properties. It is unsurprising then that much of modern life (and life itself) is based on molecules with specific
structures and properties (e.g. as pharmaceuticals, agrochemicals, plastics, liquid crystals). The task of making molecules is
challenging -‐ an organic molecule containing just a few dozen atoms (e.g. TaxolTM, Figure 2) can take many man-‐years of effort to complete. The
result is that many of the molecules we use
are compromises -‐ the easiest to make that have
acceptable function, rather
than being the best for the job.
The aim of the Dial-‐a-‐Molecule Grand Challenge is to remove synthesis as a constraint to timely
access to a given molecule, thus greatly empowering researchers in many fields. A linked aim is to drive a step-‐change in the efficiency of
synthesis, both in terms of waste produced (which can currently be hundreds of times the mass of product for pharmaceuticals) and the
energy consumed in production.
The importance and difficulty of the challenge can be appreciated by comparison with
oligonucleotide synthesis. Automated oligonucleotide synthesis has had a transformative impact on molecular biology and
enabled the human genome project. The impact of a similar level of efficiency and predictability applied to any desired class of synthetic molecule
would revolutionise problem solving across diverse disciplines such as biology, pharmaceuticals/agrochemicals, effect chemicals,
molecular materials, nanomaterials etc.
The scale of the Grand Challenge becomes clear, however, when one considers that oligonucleotide synthesis:
involves only three basic types of chemistry,
is carried out on a very narrow and
functionally similar set of building blocks, though extremely high yielding, is
massively inefficient in terms of waste
and atom economy, required 20 years of effort to reach this
level of sophistication.
Therefore to be able to make any complex molecular system, with the additional focus on economics / efficiency / sustainability, is going to
require a step-‐change in approach.
1.3 Current State of the Art To contextualise the roadmap that follows, it is helpful to consider the state of the art in
synthesis at the inception of the Grand Challenge.
Synthesis
Gilbert Stork, one of the pioneering chemists of the 20th century, posed the question over 25 years ago “why can’t a 20-‐step synthesis be
completed in 20 days?” to which one might add “and does it need 20 steps!”. The synthesis of many complex molecules has been achieved in
the last 30 years, but even modest target molecules still require many man-‐years to deliver
Figure 1. A molecule
estimated to have more than 3*1011 stable isomers
Figure 2. Structure of TaxolTM
Introduction Page 5
despite dramatic advances in the number, power and scope of available reactions (asymmetric
synthesis and transition metal mediated transformations being most notable). Making even simple molecules with an efficiency and
robustness to allow commercialisation is a considerable challenge. Synthesis is still largely constrained (by thinking, training and equipment)
to step-‐wise manipulations using reactions and work-‐up procedures with ‘accepted’ inefficiencies (be these in respect of yield, by-‐products, poor
catalyst turnover, high cost etc.). An illustration of the limitations is that pharmaceutical development is aimed at the simplest molecule
to achieve the required activity, with cross-‐activity a frequent result.
Synthetic route design
With the exception of the availability of on-‐line reaction databases, little has changed in the way
organic chemists plan synthesis since the introduction of retrosynthetic analysis over 40 years ago. Even the way on-‐line databases are
used has changed little since their widespread introduction 15 -‐ 20 years ago.
The first programs for computer aided design,
Computer Aided Organic Synthesis (CAOS) and its better known successor Logic and Heuristics Applied to Synthetic Analysis (LHASA) are over 40
years old1. Many other attempts have been made, and some are still under active development2,3, but none have made a significant impact in the
design of synthesis.
Increasing computer power and the use of Density Function Theory methods have brought computational chemistry to the point where it is
a very useful tool with predictive value for synthetic chemists developing reactions. 1 M H. Todd, Chem. Soc. Rev., 2005, 34, 247-‐266 2 J. Law, Z. Zsoldos, A. Simon, D. Reid, Y. Liu, S. Y. Khew, A. P. Johnson, S. Major, R. A. Wade, H. Y. Ando, J. Chem. Inf. Model., 2009, 49, 593–602 3 A. Tanaka, H. Okamoto, M. Bersohn, J. Chem. Inf. Model., 2010, 50, 327–338
However, it is still a long way from providing quantitative results on reaction outcomes under
realistic conditions.
However, there are many reasons to think that it is timely for computer-‐based methods to make a big impact on synthetic route design. Electronic
Lab notebooks are becoming the norm in industry, potentially allowing efficient capture of detailed reaction information. Automated
methods for extracting chemical information from text, and ways of embedding chemical information in text in an easily computer
searchable form (for example Chemical Mark-‐up Language -‐ CML) have been developed.
Reaction optimisation and analytical methods
Reaction optimisation is often time consuming. Automated reactors and statistical methods (e.g.
Design of Experiments (DoE), principal component analysis (PCA)) are gaining ground, but are not yet widely used. Capture of data on
reaction conditions and outcomes (i.e. journal papers) is arguably inferior to 30 years ago,
though volume is much greater! Analytical methods, particularly MS techniques (e.g. ionisation of compounds from solution without
fragmentation), have advanced dramatically in the last 10 years to the point at which dynamic reaction monitoring and analysis is viable.
Integration with other analytical techniques such as IR and NMR and their use for real time reaction optimisation are little used. Extraction of
component signals from complex mixtures is a highly refined subject in the area of signal analysis but has seen very limited application in
reaction monitoring.
Catalysis
New modes of reactivity are constantly being
realised (e.g. C−H activation) that approach the
paradigm for atom efficiency but the cost, selectivity and efficiency of these processes is often far removed from the necessary position
(e.g. the levels of efficiency possible in some
Introduction Page 6
enzymatic systems or petrochemical transformations). Additionally, cross-‐
compatibilities between processes are not at a stage where modular telescoped processes are routinely applicable. Correlation between active
catalyst structure and catalytic activity, selectivity, and lifetime are important. Invention and development of catalysts is still predominantly a
trial and error process.
Technology
Synthetic chemistry is still driven to fit available kit and new chemical processes are largely designed and executed without taking into
consideration the best reactor configuration or importantly scalability for pilot or market scale production. Despite the recent surge of interest
in flow reactors they are still very little used at the moment and by a small number of laboratories4. A number of other lab scale reactor
designs have been proposed but their use is still very limited. Furthermore, configurations in current research efforts are largely ad hoc and
focused on specific conditions of, for example, temperature and pressure and therefore do not
easily permit wider access to the chemical space for exploration, optimal route selection and reaction optimisation, without redesign and
assembly. Additional kit is also required for monitoring, probing, measuring, data collection etc. that must be integrated into the reactor.
Finally, replication of reported reactions across laboratories is challenging due to generally poor control and reporting of precise reaction
conditions. Field effects (photochemical, extreme thermal, electrochemical, microwave) are also underused due to limitations of the available
equipment.
1.4 Impact of the Grand Challenge 4 C. Jimenez-‐Gonzalez, P. Poechlauer, Q. B. Broxterman, B.-‐S. Yang, D. am Ende, J. Baird, C. Bertsch, R. E. Hannah, P. Dell’Orco, H. Noorman, S. Yee, R. Reintjens, A. Wells, V. Massonneau and J. Manley, Org. Process Res. Dev., 2011, 15, 900–911
Progress towards Dial-‐a-‐Molecule’s goals will provide the academic and industrial community
with the capability, mind-‐set and networks to deliver new and innovative products and technologies, which both push the boundaries of
academic research and generate strong commercial value. The control of molecular structure and function on a greatly accelerated
time frame, will generate huge benefit for both the established and emerging sectors.
1.4.1 Economic impact The UK is one of the world’s top chemical-‐producing nations, with a high-‐performance industry achieving outstanding levels of growth,
exports, productivity performance and international investment. The chemical industry is also a significant provider of jobs and creator of
wealth for the UK with a turnover in excess of £50 billion and an annual trade surplus of £5 billion5,6.
Dial-‐a-‐Molecule matches a strong industrial drive
towards processes which are as sustainable, efficient and economically viable as possible. The
agrochemical and pharmaceuticals sectors comprise the third most profitable economic activity (after tourism and finance) in the UK and
are immediate beneficiaries of any increase in speed and efficiency of synthesis. For example, a recent pan-‐industry report on synthetic
chemistry in the healthcare environment7 stated that “when synthetic enablement is lacking, we see projects stall, even those with the best
biological or clinical rationale”. Emerging challenges in next-‐generation healthcare pose
5 The Chemistry Innovation Knowledge Transfer Network’s Sustainable technologies roadmap http://www.chemistryinnovation.co.uk/stroadmap/index.htm 6 (a) Oxford Economics, The economic benefits of chemistry research to the UK, September 2010 (b) Chemical Industries Association, Annual Review 2009 7 D. Fox, T. Wood, P. Leeson, D. Lathbury, D. Hollinshead, S. Macdonald, P. Jones, L. Castro, D. Rees, K. Jones, Chemistry World, December 2008, p 39
Introduction Page 7
synthetic problems that are beyond the scope of existing technologies. Examples are:
• expansion of accessible chemical space to
facilitate highly specific small molecule interactions with any genomic protein
(chemical genomics/pharmaceuticals);
• next-‐generation biological drugs
(integrated synthetic chemistry and synthetic biology);
• Personalised medicine (compounds tuned to an individual’s genetic make-‐up).
It is economically vital that the UK retains a
vibrant presence in this sector in the face of growing pressures from competitors in the emerging economies, and this can only be
achieved by leading in the area of generation of new intellectual property, be that in the form of determining which marketable molecules are
made or how they are made.
Chemistry underpins many other industries, estimated to contribute 21% of the U.K. economy (£258 billion in global sales and employing over 6
million people).5 Examples of challenges in these areas which require the advances proposed by
Dial-‐a-‐Molecule include:
• organic electronics and solar energy capture;
• non-‐invasive monitoring tools (markers, imaging agents);
• security-‐related products (smart-‐dyes
etc).
1.4.2 Societal impact The recent Royal Society of Chemistry roadmap8
“Chemistry for Tomorrow’s World” articulates the role that chemistry can play across seven key areas of societal challenge (Energy, Food, Future
Cities, Human Health, Lifestyle & Recreation,
8 Royal Society of Chemistry roadmap “Chemistry for
Tomorrow’s World”
http://www.rsc.org/scienceandtechnology/roadmap/index.asp
Raw Materials & Feedstocks, Water & Air). A recent report from EuCheMS9 highlighted 8 key
areas in the chemical sciences vital if we are to meet the global challenges facing the society, one of which was synthesis. In these challenge
areas, fields such as (nano)materials, polymers, and chemical biology/medicinal chemistry pose synthetic problems that are limited by the scope
of existing technologies.
The synthesis of new molecules underpins these, yet because of cost and speed constraints, “what is made” is limited by “what can be easily made”.
To deliver the necessary solutions for society in a useful timeframe will require a step-‐change in the efficiency (both speed and resource) of
chemical synthesis. If it was possible to make any molecule on demand at reasonable cost (monetary and environmental) it would lead to
the faster delivery of new medicines and medical technologies, increased yields in food production, sustainable new materials, next generation
electronics, improved forensic determination and security devices etc. Moreover, it underpins
futuristic technologies, being essential to the development of useful nano-‐machines and next generation post-‐silicon super-‐computers. To this
must be added the combined challenges posed by a year-‐on-‐year increase in consumer demand, the world's finite natural resources and a public
ever more conscious of its environmental legacy -‐ it is unsustainable (and unethical) to simply transfer the burden of low-‐cost production and
waste generation to other countries. The outcomes of this Grand Challenge will allow the UK to take a lead in reducing environmental
impact while providing the next generation drugs, materials and products that society demands and requires.
9 EuChem roadmap “Chemistry. Developing solutions in a changing world” http://www.euchems.eu/fileadmin/user_upload/highlights/Euchems_Roadmap_gesamt_final2.pdf
Introduction Page 8
1.4.3 Academic impact The Grand Challenge provides the UK academic community with an opportunity to focus on a truly transformative problem and to be creative
and outward-‐looking in respect of the science that they undertake. It encompasses areas highlighted in the 2009 international (Klein)
review10 as critical to the continued health of UK chemistry and addresses a number of weaknesses identified in the recent EPSRC
landscape review e.g. the potential for more widespread industry-‐academic partnerships in catalysis; the explicit engagement of ECRs; and
the need for synthetic chemists and chemical engineers to engage more in multidisciplinary research.
Alongside the implicit interactions between
synthetic chemists and chemical engineers, the Grand Challenge provides a mechanism for engagement with disciplines as diverse as
computer science, mechanical and electrical engineering, mathematics, analytical science,
physics, surface science, biotechnology, chemical biology, medicine, materials, biochemistry, nano-‐materials and nano-‐science. The opportunities
for academic growth and the development of new research paradigms are immense. It offers UK researchers the chance to engage in agenda-‐
setting collaborative research that will define the way molecules are made worldwide for the foreseeable future. It also offers clearly visible
benefits of global importance (e.g. lower-‐cost healthcare, energy solutions, cleaner/greener processes) that will serve to inspire future
generations of students to take up studies in the chemical sciences, engineering and related disciplines, securing the future supply of experts
to move the discipline forward.
For all scientists involved in the network it provides the opportunity to form new cross 10 2009 International Review of UK Chemistry Research http://www.epsrc.ac.uk/newsevents/pubs/corporate/intrevs/2009ChemistryIR/Pages/default.aspx
disciplinary collaborations to compete for funding in areas which are complementary to
their existing research programs. The collaborations established will also enable scientists outside of chemistry/chemical
engineering to enhance their own science through interactions with the key commercial and intellectual issues in chemistry. The difficulty
and complexity of the problems synthesis poses will drive advancement in these other fields.
For synthetic chemists Dial-‐a-‐Molecule provides a framework to encourage creativity and
adventure in developing synthesis, together with the invigorating effect of input from other disciplines, with a clear, very ambitious, long
term goal. It should also provide routes to the widespread adoption of tools such as automated reaction platforms, real time reaction monitoring,
Electronic Lab Notebooks, theoretical modelling of reactions, and smart computer assisted synthetic planning in academia.
An increase in the speed and efficiency of
synthesis will have a direct and substantial effect on the numerous academics who are users of
molecules whether it be for biological or materials applications, or just to investigate their properties. The provision of molecules is the rate
limiting step in many of these pursuits and removal of this constraint will allow faster progress and much more imagination in selecting
molecules to provide the desired function.
1.4.4 Impact in government As well as the economic benefits outlined above,
Dial-‐a-‐Molecule addresses the ever-‐present dichotomy between wealth creation and environmental impact. The work will allow UK
government to take a lead role in setting international standards to minimize global manufacturing waste and emissions and in
providing low-‐cost healthcare to the third world and emerging economies, etc.
Introduction Page 9
1.5 Purpose of the Roadmap Dial-‐a-‐Molecule has undertaken this technology roadmapping study to develop a strategy for the
research and development of technology aimed at making molecules easily available.
The technology strategy will provide key decision-‐makers in industry, academia and the
UK government with a clear picture of the role that synthetic chemistry can play in developing a vibrant and sustainable chemical industry in the
UK. It will identify the opportunities, the gaps and the key actions that need to be taken to make sure that the potential of synthetic chemical
technology is delivered. The roadmap and technology strategy are documents in need of constant review. In addition to this report a
website has been created to enable all users of molecules to explore and comment on the roadmap and strategy.
1.6 Guide to the Roadmap The challenge was structured into three themes. For each theme several focus areas were
identified:
Lab of the Future and Synthetic Route Selection
Optimum reaction and route design Smart Laboratory (data collection and
automation) Next generation reaction platforms (the
technology of synthesis)
Rapid reaction analysis
A Step Change in Molecular Synthesis. Stepwise perfection (1000 Click Reactions) Holistic approach to molecular synthesis.
Catalytic Paradigms for Efficient Synthesis
New reactivity: target-‐driven catalysis Intervention-‐free synthesis Engineering control through
understanding
Each focus area held a two day meeting to brainstorm the roadmap as well as describe the present state-‐of-‐the-‐art and investigate potential
collaborative areas. The detailed results of each meeting are published on our website. The results for the roadmap were correlated and
after refinement through consultation are presented in this document.
Roadmap -‐ Overview Page 10
2 Roadmap for synthesis in the 21st century 2.1 Overview The process of developing a roadmap for 21st century synthesis was targeted at putting the
network, and its constituent groups and members, in a position to make a meaningful contribution to public debate on issues where
the discipline, in conjunction with others as appropriate, can play a significant role in delivering solutions.
Using a highly consultative process the Dial-‐a-‐
Molecule network has identified a series of key barriers that need to be overcome for the successful delivery of the Grand Challenge. They
are summarised in this document, together with
key recommendations and distinctive research areas in which UK has the strength to be
distinctive and internationally leading in the next five years.
The key challenges and barriers to delivery of the Grand Challenge, shown diagrammatically below,
were identified as: the need to make synthesis predictable, developing smart synthesis by design and providing a sustainable synthesis to answer
the needs for a sustainable future.
To address these issues the network makes a series of key recommendations aimed at defining the path to success. The recommendations
establish how to manage different possible approaches in organic synthesis and how to identify and deliver faster the best results.
Making synthesis predictable
Smart synthesis by design
Sustainable synthesis for a sustainable
future
Key barriers
Key recommendations
Transforming synthesis
Building a mulqdisciplinary community to tackle the Grand Challenge
Maximising economic benefit from tackling the Grand Challenge
Roadmap -‐ Overview Page 11
Making synthesis predictable
The key challenge for Dial-‐a-‐Molecule is to be able to reliably predict the outcome of unknown reactions11. The synthesis of other than trivial
molecules usually requires substantial optimisation of reactions and exploration of alternative routes when proposed steps fail
resulting in slow delivery times. If we could choose the right reactions and conditions first time a huge step would have been taken towards
Dial-‐a-‐Molecule. There are two complementary approaches: use of data and theory to predict reaction outcomes; and developing robust
reactions that ‘always’ work.
11 We use reaction to describe the combination of the transformation carried out, and the particular reagents, conditions, etc used so an unknown reaction can be a well-‐known transformation under unknown conditions, or a novel substrate under known conditions.
Key objectives and actions
(a) Data driven approach
Ø Need better quality (complete) data on reactions. ü Establish a National ELN and means to
access the data. ü Equipment to allow efficient study of
reactions
§ National Service for the Study of Reactions.
§ How to equip departments, groups, individual workers.
§ Develop new reaction platforms
§ Real time analysis in flow and batch
• Develop Low cost MS,
NMR etc.
• Multi-‐technique probe for
batch
• Automatic identification of components.
ü Incorporate statistical methods as routine. ü Automated full re-‐extraction of past data.
Ø Make better use of reaction data. ü Use computed properties to enhance
observational data.
ü Use of statistical and AI methods. ü Virtual centre to bring together chemists,
statisticians, mathematicians, engineers, and computer scientists.
ü Systematic study of substrate structure as a variable.
Ø Computational modelling of reactions under real
conditions.
(b) Better reactions approach. Ø Need fully characterised transformations (toolbox).
Ø Identify which we need, and use high throughput study.
Ø Auto-‐optimisation of reactions. ü Real time analysis in flow and batch (see
above)
Ø Reactions which are ‘Perfect’ by design. ü Understanding of catalysis, particularly
organometallic and surface reactions ü Understanding of reactivity. ü Understanding solvent effects
Roadmap -‐ Overview Page 12
Smart synthesis by design
To deliver complex functional molecules many reactions need to be carried out in sequence.
There are three elements to this challenge: informed selection of the most efficient
route (strategy-‐level); the use of reactions designed for efficient
sequencing (tactical-‐level);
the integration of the reaction sequences to drive up efficiency by minimising external intervention (delivery-‐level).
Key objectives and actions
(a) Develop algorithms for optimum route selection subject to constraints.
(b) Target the invention of transformations identified by objective (data led) means as having most impact on shortening synthetic
routes.
(c) Develop the Holistic (minimum steps) approach
to synthesis.
(d) Efficient sequencing of reactions.
ü ‘Zero emissions’ reactions which produce no interfering by-‐products
ü Phase-‐separable catalysts (solid-‐tagged,
liquid-‐tagged, heterogeneous) with retained catalytic activity
ü Efficient sequencing of reactions with
minimal intervention ü Engineered solutions for phase
separations/compartmentalisation
(membranes, reactor design) ü Integration of chemical and biotechnology
steps. ü Develop flow chemistry for routine
application
ü Integrating flow and batch steps – configurable networks of reactors.
ü In-‐line purification methods.
(e) Synthetic-‐ and Chemical-‐biology for making molecules. ü Integrating the use of biological systems into
routine synthesis ü Designing artificial enzymes and systems to
carry out molecule and site specific
transformations ü Develop artificial systems for multi-‐step
synthetic pathways.
Roadmap -‐ Overview Page 13
Sustainable synthesis for a
sustainable future
Cutting across all of the above is the necessary focus on synthesis that is “sustainable by design” 12. A “perfect” reaction/route eliminates hazards,
minimises human intervention and reduces delivery time. This manifests itself in several ways:
minimising the amount of and hazards from waste streams in reactions
(stoichiometric to catalytic; benign or recyclable outputs from catalytic reactions);
minimising the energy demands of synthesis; developing chemistries to process new (renewable or waste) non-‐
petrochemical feedstocks; ensuring that reagents and catalysts
comprise components that are
themselves abundant and/or recyclable.
12 C. Jimenez-‐Gonzalez, P. Poechlauer, Q. B. Broxterman, B.-‐S. Yang, D. am Ende, J. Baird, C. Bertsch, R. E. Hannah, P. Dell’Orco, H. Noorman, S. Yee, R. Reintjens, A. Wells, V. Massonneau and J. Manley, Org. Process Res. Dev., 2011, 15, 900–911
Key objectives and actions
(a) Use of sustainable synthesis. ü ‘Waste-‐free’ reactions (by-‐products
intrinsically or decompose to benign)
ü Catalytic alternatives to current reagents ü Reagentless reactions (field effects –
electro, thermal, photo)
ü Minimal energy requirements.
(b) Sustainable feedstocks, reagents and catalysts
ü Re-‐tooled catalysis for renewable feedstocks
ü Accelerate growth in biotechnological
production of building blocks ü Integrating biosynthesis of ‘complex’
structures with target synthesis
ü Ultra-‐low loading/long lifetime catalysts (homo and heterogenous)
ü Catalysts based on metal-‐free or abundant
metals
Roadmap -‐ Overview Page 14
Transforming Synthesis
Building a multidisciplinary community to tackle the Grand
Challenge
• Synthesis has to change to being a data driven discipline – the information output from carrying out a reaction must be seen as equal in importance to obtaining the product. ⇒ Establish a national ELN. Define a common format for data.
• The equipment used for synthesis must change to that which allows precise repeatable control of reaction conditions, and maximises information output. ⇒ Establish a National Service for the Study of Reactions. Find a way to equip synthetic chemistry laboratories with 21st century equipment, software and methods.
• Statistical and computational methods
need to be integrated with the routine performance of synthesis. ⇒ Build collaborations and enhance education.
• Encourage a focus on developing
methods, “zero-‐emissions” reactions and catalysts identified as having most impact on the pathway to Dial-‐a-‐Molecule. ⇒ Form an industry/academic group to identify specific challenges and establish communities to address them through objective (data-‐led) methods.
Recommendations
• Continue the Dial-‐a-‐Molecule network to ensure transition to a self-‐sustaining community of research clusters addressing the key challenges over a 3-‐4 year period. Provide direct funding to enable critical input from a range of skilled professionals in disciplines not previously engaged with synthesis (e.g. computer science, mathematics, biology, medicine, engineering).
• Engage with government to ensure
sustained and focussed support for the three key research areas: Lab of the future and synthetic route selection, A step change in molecular synthesis, New paradigms in catalysis, as detailed in the roadmap, through responsive mode and other funding mechanisms.
Roadmap -‐ Overview Page 15
Maximising economic benefit from tackling the Grand Challenge.
Distinctive areas
Some areas in which the UK has the strength to be distinctive and internationally leading in the next five years are:
Software / methods for prediction of the outcome of reactions using both data-‐
driven and theoretical approaches (leading to computer aided synthetic route design).
Wide spread use of computer methods for
mechanistic understanding and route design.
The development of flow chemistry and automated methods for laboratory scale
synthesis. Development of low cost, small size
equipment and methods for in situ analysis of reactions.
Development of ‘zero emissions’
transformations (including using phase separated catalysis) suitable for sequencing.
Understanding of complexity and its impact on site specific and holistic reactivity.
Combining appropriate “chemical” and enzymatic/whole organism catalysts to
achieve synthetic goals
• Develop mechanisms to facilitate the rapid translation of important reactions / technologies from academia to industry to maximise impact to the UK.
• Build interactive industry/academia networks/advisory groups to ensure that the types of transformations and molecules of potential future commercial interest are prioritised for investment by key stakeholders to maximise return.
• Ensure that required technologies and
software are developed in association with U.K. companies able to exploit the Intellectual Property.
• Work with industry to shorten the timeframe for the discovery, development and demonstration (“the 3Ds of synthesis”) of new step change reactions.
Roadmap -‐ Overview Page 16
Structure of the roadmap
The roadmap is structured around the theme and focus areas described above. For each area a table is provided summarising the key challenges
and suggested actions along with approximate timescales. The timescales are described as short (0-‐5 years), medium (5-‐10/15 years) and long
(10/15-‐20/30 years).
Dial-‐a-‐Molecule Grand Challenge – key challenges
Lab of the Future/Synthetic Route Selection A Step Change in Molecular Synthesis
Catalytic Paradigms for Efficient Synthesis
Optimum Reaction and Route Design
The Smart Laboratory
Next Generation Reaction Platforms
Rapid Reaction Analysis
Stepwise perfection (1000 Click Reactions)
Holistic approach to molecular synthesis
New reactivity: target-driven
catalysis Intervention-
free synthesis Engineering
control through understanding
Need for high quality reaction data
Electronic Laboratory Notebooks
Reactor Platforms
Equipment development – into the lab.
Establish criteria for ‘perfection’
Tandem & telescoped reactions: generalising the concept
Efficient transformations across chemical space
Phase-separated catalysts
Rapid (self)-optimisation of reactions
New ways to analyse reaction data to predict unknown outcomes
Automated and high throughput equipment for synthesis
Intelligent Feedback Control
Software development – automation of expert tasks.
Establish an inventory of reactions required & with potential for automisation
Rational design & implementation of catalysts for multicompo-nent reactions
Complexity-building reactions
Mutually compatible catalysts
Full elucidation of catalytic mechanisms
Planning of synthetic routes subject to constraints
The intelligent fume cupboard
Microfluidics and Lab-on-a-chip
Equipping academia – overcoming the cost barrier.
Reagentless “zero-emissions” transformations (energy driven & catalytic)
Determining the reactions needed and priorities in targeting new chemical space
Sustainability: feedstocks
Switchable catalysts
Theoretical chemistry: through understanding to prediction
Theoretical prediction of reaction outcomes
Networks of reactors
Automatic identification of components of reactions
Understanding compatibility in complex systems
A framework to design redox-neutral processes
Sustainability: catalysts
Separation technology
Active Study and optimisation of reactions
Purification
Roadmap -‐ Lab of the Future and Synthetic Route Design Page 17
2.2 Lab of the Future and Synthetic Route Design
The number and power of reactions developed in
synthetic chemistry over the past 30 years are staggering, particularly in the area of asymmetric synthesis and the use of transition metals.
Despite that, the time and effort required to make complex molecules has not dramatically fallen. The key reason must be that the selection
of which reactions to use in a synthesis has fallen behind. Typically for reasonably complex molecules the ratio between the number of steps
in a successful total synthesis, and the number of reactions performed to achieve that synthesis may be less than 1:100. Both the need to re-‐
optimise reactions and to find alternative routes when proposed steps fail contributes to the poor ratio. If we could choose the right reactions and
conditions first time a huge step would have been taken towards Dial-‐a-‐Molecule. The use of data on reaction conditions and outputs is thus
central to Dial-‐a-‐Molecule.
Synthesis, particularly in academia, is still largely carried out manually, and documented in a paper laboratory notebook. Analytical data is still
mostly collected ‘offline’ after work-‐up of reactions. Automated and high throughput
equipment is not generally available.
To achieve the Dial-‐a-‐Molecule goals synthesis needs to become a data driven discipline that makes full use of the revolution in computing and
automation that has taken place in the past 20 years.
Lab of the Future is about how synthesis should
be performed, and Synthetic Route Selection is about the prediction of which reactions to use. The two are so closely linked that they are dealt
with as one theme. The theme was divided into four areas to allow focused discussion, but all are strongly interdependent and indeed many of the
same ideas came to the fore in each group although below they are generally discussed in one. Smart Laboratory is principally about
collecting and making available data; Optimum Reaction and Route Design (ORRD) is about how to use data to predict the outcome of reactions
and hence allow optimum synthetic route selection as well as the data analysis side of reaction optimisation; Next Generation Reactor
Platforms (NGRP) looked at how the technology used to carry out synthesis should change to achieve the Dial-‐a-‐Molecule goals and Rapid
Reaction Analysis (RRA) at the challenge of collecting full analytical data on reactions.
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2.2.1 Optimum reaction and route design
Focus area definition
The aims of this focus area were to examine state of the art and make recommendations in three
areas: 1. prediction of the outcome of unknown
reactions under particular conditions enabling both selection of the best reaction and optimum conditions;
2. selection of the optimum synthetic route to a target molecule;
3. statistical and mathematical methods for
the active optimisation of reactions and multi-‐step routes.
The principle reason for the length of time taken for molecular synthesis, and hence the initial
target for Dial-‐a-‐Molecule, is that reactions that would be expected to work based on precedents from the literature, do not, so requiring
optimisation or route change. The problem is the infinite variety of potential substrate structures, and the complex and unpredictable way that the
entire structure affects reactions at particular sites, as well as inadequacy in the ways in which experimental procedures are reported.
Overview of main challenges
Need for high quality reaction data. The lack of complete experimental data was identified as a
key barrier to the Dial-‐a-‐Molecule goals. Currently the available databases of reaction outcomes have been largely manually abstracted
from the primary literature. Only selected (positive) data is published, and more is
discarded in the abstraction step. Only the most successful examples of particular reactions get
published, and failed reactions are very rarely reported.
There is a huge amount of data available in journals, patents and theses, and the only
practical way for the full content to be made available for reaction planning is for data mining to be entirely automated. The development of
software to allow fully automated extraction of complete data from text and images is thus identified as an important goal.
Much more useful data is potentially available by
collecting at source (in the laboratory). The Smart Laboratory focus area is promoting the adoption of, and data sharing from, Electronic Laboratory
Notebooks (ELNs). The use of automated and high throughput equipment to carry out reactions will provide a valuable source of data
and is highlighted in both the Smart Laboratory and Next Generation Reaction Platform focus areas.
An action identified by this focus area is to develop software to harvest ELNs and related experimental data.
New ways to analyse reaction data. The
challenge is to use data on known reactions to predict the outcome of unknown ones reliably, and as a consequence the optimum conditions to
use.
Reaction substructure searching of existing databases and manual examination of the hitset produced for close analogues of the desired
transformation is currently the main approach, but does not make use of much relevant information. Ways of visualising the results from
a much larger dataset, perhaps in combination with computationally derived information, would allow the chemist to make better choices, and is
a near-‐term target.
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Optimum Reaction and Route Design State-‐of-‐the-‐
art Short term Medium term Long term Goal
Need for high quality
reaction data
Commercial databases
Develop programs to harvest
relevant data from ELNs
A million high quality
reactions/year
Systems to automatically extract information from text sources (Thesis, patents, papers, lab books)
10 million records including as much reaction detail as
available.
New ways to analyse
reaction data to predict unknown outcomes
Reaction substructure searching with human interpretation.
Improved ways to present data from reaction databases to chemists
Reliable prediction of the
outcome of unknown reactions.
Develop ways to deal with high dimensional (many parameters) complex geometry reaction space.
Combine theoretical calculation of molecular properties with reaction data – Substrate variability as a continuous variable
Planning of synthetic routes
subject to constraints
Human generated routes checked using manual reaction substructure search of steps.
Develop way to deal with complex topology of reaction space (many routes)
Computational prediction of optimum
synthetic route (subject to
constraints such as feedstocks, scale, available equipment, cost, time) which works
1st time. A universal synthesiser
Interactive computer-‐aided route finding
Computational generated routes essential as aid to chemist
Use of computer generated routes routine.
Develop measures for how good a route is.
Theoretical prediction of reaction outcomes
DFT useful for predicting trends. Continuum solvent models generally used
Embed as routine tool in synthesis planning.
Multi-‐scale models produce useful data on relative rates of reactions under real conditions.
In silico prediction of reaction
outcomes and design of new reactions.
Mechanism used by chemists, but not efficiently computerised yet
Develop automated mechanism or modelling based algorithms for predicting all reasonable products from a reaction – exploring potential energy surfaces
Enables automatic structure
assignment from analytical data
Active Study and
optimisation of reactions
Virtually no auto-‐optimisation. Off-‐line statistical methods available, if little used.
Statistical methods for reaction optimisation in routine use
Optimisation over multi-‐step routes
Optimisation of reactions within
allowed parameters carried out
transparently
Closed loop auto-‐optimisation of reactions
Only narrow studies in reaction scope have been reported
Study selected reactions in sufficient detail that optimum conditions and outcome can be predicted for any substrate(s).
A toolbox of reactions for
which outcome can be predicted for any substrate
Roadmap -‐ Lab of the Future and Synthetic Route Design Page 20
The challenge is to develop ways to deal with high dimensional (many parameters) complex
geometry reaction space. The data is also sparse, subject to error, and noisy. The problem is one that will challenge the most advanced data
analysis methods and we suspect require the invention of new ones. In the longer term, due to continually increasing computational power and
refinements in theoretical methodologies, quantum chemical methods may play a role in predicting reaction outcomes in silico where
experimental data is unavailable (as described below).
Whereas methods to map a reaction space in terms of continuous variables (temperature,
concentration etc) are well developed, those for discrete variables (substrate, solvent, catalyst, and reagent) are not. The substrates are the
ultimate discrete variable – there are countless of them, all different.
The way in which solvents can be dealt with is informative. By characterising solvents in terms
of continuous molecular descriptors (molecular weight, molecular volume, dipole, polarisability
etc) screening a small number of solvents and use of a statistical model of solvent diversity (e.g. principal component analysis – developed using a
large set of solvents) allows the optimum to be picked from a much larger set.
The challenge is thus to find computationally derived molecular descriptors of substrates as
well as reagents, catalysts, ligands, etc to use in statistical analysis of known reaction outcomes in order to provide a suitable model of reactivity
and thus reliable prediction of outcomes in unknown cases and the precise definition of the limits of the model. Enhancement of existing
reaction databases through the addition of calculated molecular descriptors is the first objective.
A close collaboration between synthetic and
computational chemists and statisticians (and
others) is required and we recommend that these are brought together in a virtual National
Centre for the Study of Reactions. It would be closely associated with the proposed National Service for the Study of Reactions described in
the Smart Laboratory focus area providing expert advice to users of the service, and a proportion of service time would be used to generate the data
needed to develop the ideas above.
Planning of synthetic routes subject to constraints The challenge is to select the best synthetic route to a target from the myriad
possibilities subject to various constraints which may be applied in different situations, for example minimum cost, fastest delivery, scale,
available equipment, particular feedstocks etc. Currently a chemist will typically design a route using their knowledge and experience, and then
check each proposed step manually by carrying out reaction substructure searches of existing databases and examining the dataset produced.
If potential problems are found, an alternative route may be investigated. Computers are
intrinsically much better than humans at such exhaustive searches, but current synthesis design programs perform poorly. One reason is the
difficulty in rating the probability of a particular reaction working that is tackled above. Prediction of side reactions will also be important in
assessing the suitability of proposed steps. The second requirement is to be able to rank how good a proposed synthesis is and developing such
a measure is an initial aim. With both individual step and overall route ranking available ways to deal efficiently with the complex topology of
reaction space (many routes) should allow effective route prediction. Current synthesis design programs are expert systems using rules
derived from known reaction outcomes and thus use directly only a tiny proportion of the information in even current reaction databases.
Developing methods that use the totality of information available thus avoiding the rule
Roadmap -‐ Lab of the Future and Synthetic Route Design Page 21
extraction step is an ideal, but probably impossibly slow.
Early stage objectives should produce tools to aid
interactive route finding with a chemist. The ultimate aim, when coupled with suitable hardware, is the universal synthesiser that
realises the Dial-‐a-‐Molecule Grand Challenge. The synthetic route design software and techniques developed can also be used to inform
other aspects of Dial-‐a-‐Molecule, for example what impact a proposed new transformation would have, or indeed to identify novel
transforms which would have maximum effect on shortening synthetic routes. The prediction of all reasonable products from a reaction is another
application of the techniques described above. Even if relative amounts cannot be predicted accurately the outcome would make the
automatic identification of reaction components using spectroscopic and analytic methods possible (see Rapid Reaction Analysis focus area).
Theoretical and mechanism based prediction of
reaction outcomes. Theoretical modelling of molecules, and even transition states, has
recently developed into a practical tool for guiding the investigation of reactions and should be a routine tool for synthetic chemists. However,
simplifications of the system are nearly always required for such studies. The detailed effects of solvents, for example, are usually treated using
approximations. As a consequence of this as well as the inherent approximations made, calculation of absolute activation energies for reactions
under real conditions with an accuracy that would allow reliable prediction of reaction outcomes is a distant dream. Most chemically
useful information comes from the comparison of relative activation energies that, due to error cancellation, are often much more reliable than
absolute energies. It is possible for example to accurately model the stereoselectivity of some catalytic reactions where competing pathways
are only separated by a few kJ mol-‐1. Perhaps a bigger problem is the enormous complexity of
the possible potential energy surfaces for realistic reaction systems. How we go about mapping a
sufficient proportion of these to make predictions, in particular by automating the process, is a challenge we should start to tackle
now.
Active development of multi-‐scale models of reaction kinetics is an important part of the Dial-‐a-‐Molecule roadmap as even partial success
could have a huge impact on in silico screening of possible reactions, including the prediction of currently unknown transformations.
Another important outcome would be to predict
all reasonable products from a reaction – needed for the Rapid Reaction Analysis focus area as described above.
Active study and optimisation of reactions and
multi-‐step routes. Distinct from the above areas is the active interaction between experiment and theory. The use of ‘Design of Experiments’ and
other statistical methods for reaction optimisation is well established in process
chemistry, but little used in small scale ‘discovery’ chemistry due to the overhead imposed by its use, together with unfamiliarity. In the short
term a priority should be to increase the familiarity of synthetic chemists with the techniques used in process chemistry and
process engineering. Embedding Design of Experiments and other statistical methods into postgraduate training is important to develop the
generation of chemists who will be responsible for developing the Dial-‐a-‐Molecule idea.
The challenge is to develop methods that are easy to use, and indeed which can be used with
automated equipment in ‘closed loop’ auto-‐optimisation without intervention.
The aim is to develop and apply statistical modelling and mathematical optimisation
approaches to identify optimised conditions for single and multi-‐step reactions, subject to constraints. This is challenging due to:
Roadmap -‐ Lab of the Future and Synthetic Route Design Page 22
the complex nature of the relationship between reaction outputs (yield,
impurities, …) and inputs (temperature, pressure, time, catalysts, solvents, …);
the high-‐dimensionality of the input
space (large number of input variables); the discrete nature of the input space,
with large numbers of discrete solvents,
catalysts etc. (where we need to develop quantitative descriptors as described above);
a potentially large number of constraints (e.g. on impurities or on inputs) that may result in complex, non-‐regular, input
spaces with many infeasible regions; the lack of mechanistic or theoretical
models to describe the entire process for
some variables.
An extension of the above would be to select an important transformation and study it so
thoroughly using high throughput techniques that the optimum conditions and outcome can then be predicted for any substrate(s). The
National Service for the Study of Reactions described elsewhere would provide the ideal environment for these studies, with data being
provided through a Virtual Centre for the Study of Reactions to statisticians, computational chemists, cheminformaticians, etc. The data
analysis techniques described in ‘New ways to analyse data’ above, particularly the use of calculated molecular descriptors, will be
important to achieving the goal with minimum experiments. A toolbox of reactions that have been characterised in this way enable part of the
‘Stepwise Perfection’ approach of A Step Change in Molecular Synthesis theme.
Roadmap -‐ Lab of the Future and Synthetic Route Design Page 23
2.2.2 The smart laboratory
Focus area definition
The aim of the area is to examine how the Lab of
the Future could make the acquisition and sharing of high quality complete reaction and process data a low-‐overhead part of the
synthesis workflow. It also looks at how intelligent automation can allow the chemist to be more productive.
Overview of main challenges
At the launch meeting of Dial-‐a-‐Molecule an often repeated theme was that a key enabling
step would be to collect and make available information on all reactions carried out (including ‘failed’ reactions), not just those that make it into
publications, or even theses. The necessity for more complete information was also identified as a contributory factor in the common difficulty to
repeat (or at least to require substantial re-‐optimisation) of literature reactions. Data is thus at the heart of tackling the Dial-‐a-‐Molecule Grand
Challenge, and collecting it ‘at source’ is crucial. As there is little direct benefit to the individual researcher of making such data available it is
essential that the collection and (controlled) distribution requires as little human input as possible.
Electronic Laboratory Notebooks (ELNs)
potentially provide an excellent means of collecting reaction data at source, but although
now well established in industry, are little used in academia. We recommend that moving academic
laboratories to the use of ELNs should be a high priority. Apart from the relevance to Dial-‐a-‐
Molecule there are many other benefits such as data archiving and accessibility, as well as improved productivity of users.
Unfortunately although modern ELNs are good at
collecting data, making it available in a suitable form for computerised harvesting of reaction data is less well developed. We propose that
standards for data exchange between laboratories (and between different ELNs) to enable automated processing of data across
platforms are developed, and implementation encouraged.
For the Dial-‐a-‐Molecule Grand Challenge data from many laboratories needs to be combined.
We propose that a national framework (which should eventually extend worldwide) for the sharing of experimental data is established.
Protection of Intellectual Property is of course essential, but there needs to be a change in culture, perhaps driven by publishers and funders,
to one where sharing of all data is expected.
To maximise the benefit of ELNs for collecting reaction processes and outcomes, without
increasing the users workload, automatic reaction data collection from sensors in the equipment (e.g. temperature, stir rate, opacity,
colour, viscosity) is needed. Simple changes to basic laboratory equipment, or cheap stand-‐alone units would allow this and should be
developed and adoption encouraged.
Automated and High throughput equipment for synthesis. A drawback of reactions carried out manually is that capture and repeatability of the
precise process is limited. A necessary step, for both the provision of high quality reaction information, and eventually for carrying out
predicted optimum methods, is the use of automated equipment (flow and batch). When these are married to automated analysis of
reaction mixtures (see Rapid Reaction Analysis
Roadmap -‐ Lab of the Future and Synthetic Route Design Page 24
focus area) a flood of information results which will enable full realisation of the Optimum
Reaction and Route Design focus area aims. Furthermore the delivery of the Dial-‐a-‐Molecule will require multi-‐step synthesis to be carried out
entirely by automated systems so developing chemistry well suited to such equipment is a necessary preparation. Even in the short and
medium term such equipment should allow a step change in the time taken to synthesise novel targets. Our aspiration for a Smart Laboratory
must be that automated equipment becomes standard, but unfortunately, although available it is currently too expensive to appear in many
laboratories, and as a result the skills to make best use of it are not well developed in academia. The development and prospects for much
reduced cost of such equipment are considered in the Next Generation Reaction Platforms and Rapid Reaction Analysis focus areas.
We propose the following steps:
1. Establish a National Service for the Study of Reactions to provide access to state of
the art equipment and skills for the high throughput study of reactions to all U.K. academics as well as industry
(particularly SME’s). 2. Aim for basic automated batch and flow
equipment to be available on a group
basis, and high throughput equipment on a departmental basis over the next 5 years. This will require special funding
from government and requires the case to be made that it is essential to the competitiveness of UK synthesis on the
international stage, and will provide a substantial benefit to the UK economy via industrial users of synthesis and
producers of said equipment.
As an interim step developing methods to maximise the use of such equipment as is available, perhaps via the EPSRC equipment
The Smart Laboratory
State-‐of-‐the-‐art
Short term Medium term Long term Goal
Electronic Laboratory Notebooks
Widely used in large companies. Little used in academia
Establish a nationwide ELN
A million high quality reaction descriptions/year
Define and get adopted a common data format for ELNs
Establish a national Framework for data sharing
Establish worldwide framework for data sharing
Automated and high
throughput equipment
for synthesis
Is available, but too expensive for routine use in academia
Establish and maintain a National Service for the Study of Reactions
Step change in productivity of
synthesis research, and of speed of
complex molecule synthesis.
Shared equipment database
Departmental services for high throughput study of reactions expected
Widespread adoption of basic automated flow and batch equipment by individuals/groups.
Automated high throughput equipment standard.
The intelligent
fume cupboard.
‘AMI project’ Computer audio and vision to automatically log procedures and observations
Automatic
recording of all experiments.
Roadmap -‐ Lab of the Future and Synthetic Route Design Page 25
database 13 , is encouraged. We expect that advances in technology mean that in 10-‐20 years
the cost will be such that automated equipment will be the standard way to carry out reactions.
The Intelligent Fume Cupboard. Reducing the mundane chore of writing up experiments, while
increasing the quantity and quality of data recorded while using current (non automated) laboratory equipment is likely to be beneficial for
at least the next 10 years. Tracking of actions and experiments via suitable computer vision system so that operations (e.g. adding a reagent) and
observable changes (e.g. colour, precipitation) can be automatically logged is one approach. Voice recognition and intelligent interpretation
to allow the option of "literate experimentation" (from literate programming) where humans annotate the experiment while it is executed, is
also attractive. Semi-‐automated analysis of collected data using various pattern recognition, data mining and machine learning techniques,
supported by human annotation, to provide summaries of important information should
reduce much of the routine part of experiment documentation whilst increasing the quality of data collected.
13 http://equipment.epsrc.ac.uk/
National Service for the Study of Reactions
Mission: To provide access to state-‐of-‐the-‐art equipment and skills for the study of reactions to academia and industry.
The service would contain state-‐of-‐the art automated equipment for the high-‐throughput study of reactions (batch and
flow), and a staff to manage, run and maintain them. It would also provide access to expert statistical help in interpretation of
results.
Uses might include the optimisation of a particular reaction, or the high throughput
screening of a wide number of substrates against a reaction to establish scope.
The service would encourage users to visit to
carry out the work, and might operate a loan scheme for equipment.
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2.2.3 Next generation reaction platforms
Focus area definition
Synthetic chemistry is still driven to fit available kit and new chemical processes are largely
designed and executed without taking into consideration the best reactor configuration or importantly scalability for pilot or market scale
production. Flow reactors are used very little at the moment. A number of other lab scale reactor designs have been proposed but their use is also
very limited. Furthermore, configurations in current research efforts are largely ad hoc and focused on specific conditions of for example
temperature and pressure and therefore do not easily permit wider access to the chemical space for exploration, optimal route selection and
reaction optimisation, without redesign and assembly. Additional kit is also required for monitoring, probing, measuring, data collection
etc. that must be integrated into the reactor, which is typically of high cost and requires additional effort for integration and calibration.
Finally, replication of reported reactions across laboratories is not easy as it requires
considerable effort and trial and error.
This focus area is seeking to advance and redefine technology that is used in chemical synthesis. In particular, the aim is to define the
near-‐, medium-‐ and long-‐term prospects and
impact of new innovative and integrated technology.
During consultation14 there was a consensus by both industry and the academic research
community on the future requirements for next generation reaction platforms. It has been recognised that today a chemist spends a
disproportionate amount of time on less value adding activities such as handling, preparation and data collection and not on value adding
activities such as the actual reaction and the subsequent analysis and interpretation of results. A key requirement therefore for the next
generation platforms is to automate non value adding activities to the greatest extent possible. Furthermore, several other challenges were
identified and are summarised in the figure which should be addressed in the short to medium term. In the figure the specific
challenges for flow and batch type synthesis are distinguished, while those that are common to both are highlighted.
The consultation led to the main challenges for
the next 20-‐40 years given below.
Overview of main challenges
New Modular Reactor Platforms. The design requirements for reactors that are applicable to flow, batch, stirred tank or microfluidic chemistry,
including models for selection of the best configuration need to be defined. The development of standard modular components
with standard hardware interfaces so that the
14 The focus area champions acknowledge the contributions of all the delegates who attended the NGRP meeting in August 11th-‐12th at GSK, Stevenage.
“Can we develop a universal reactor system that is modular, flexible, automated and can
synthesise a range of complex products from a given range of feedstocks under a wide
range of conditions?”
Roadmap -‐ Lab of the Future and Synthetic Route Design Page 27
best configuration for particular applications can be used. The modules should have heat and mass
transfer models that are well defined and understood and can therefore enable repeatability of reaction schemes. Furthermore,
the modules should allow control of reaction conditions that can be routinely (and programmatically via software) adjusted on
demand or by algorithms enabling access to a larger chemical space. Ensuring that the reactor platforms are scalable, meaning that processes
developed are well documented and understood and can thus be replicable and transferable to
market scale production with minimal effort, is important. The reaction platforms should allow deployment of multiphase (gas/liquid,
gas/liquid/solid, liquid/solid) with a similar ease as liquid phase reactions. Of special interest is handling of solids in flow as it would enable the
technique for much wider application. Developing modules with wide operational envelopes (e.g. High Pressure, High Temperature)
would allow more of reaction space to be accessed. Modules that allow parallel reactions to enable high throughput studies are important,
as is the ability of reactors to self-‐clean. Finally it is important that the modules are affordable and easy to use.
Microfluidics, Lab-‐on-‐a-‐chip. Microfluidic
platforms are currently costly, particularly if they
are custom made. Their inherent low volume characteristics make them suitable for discovery
applications, and information generation such as kinetic investigations. Hydrodynamics are well-‐characterised for single phase flow. Multiphase
microfluidics contains pockets of intense current investigation (e.g. droplet microfluidics), but in general they are challenging to employ and
understand. Application of alternative energy forms (light, microwaves, ultrasound) are at their infancy. To harness the information generation
potential of microfluidics, devices need to be multiplexed with intermediate purification,
separation devices (e.g. gas from liquid) with capability of multiple addition/withdrawal, in-‐line analysis, on-‐line control, on-‐line optimisation.
Strategies for seamless evolution from microscale, information generation, discovery systems, to mesoscale, g-‐scale synthesis, development
systems are required.
Intelligent Feedback Control. As feedback into high level controllers can direct reactions into more desirable or optimal regions of the
chemical space, definition and specification of feedback architectures and standard interfaces to measuring and probing devices is essential. A
challenge here is for measurements and probing in flow chemistry by means of suitable flow cells that are interchangeable, reusable and
standardised. For batch chemistry the
Figure: Challenges identified at Next Generation Reaction Platform
focus group meeting
Roadmap -‐ Lab of the Future and Synthetic Route Design Page 28
development of a small multi-‐technique probe was identified as an important objective. This
area links strongly with Optimum Reaction and Route Design focus area where development of software to allow automated exploration of
reaction space and optimisation of reactions is an aim.
Networks of reactors. Linking reactors in dynamically reconfigurable networks can provide
a step change in capability. What are the characteristics of networked reactors? What could be the key modules in the network? What
can be the standard interfaces to link such reactors together?
Purification. Design requirements and specification for integrated and modular
purification systems are needed. What are the most important purification methods? Advances in purification approaches/devices need to be
developed to move from single to multiple transformations (e.g. microdistillation, microextraction). The challenge here also
includes green chemistry/sustainability considerations such as rapid solvent (and catalyst)
switching, reuse and recycling.
Data collection and On-‐Line Reaction Analytics. Specifying standards and standard interfaces between the reactor and sensors and collection
and manipulation of reaction information feeding a higher level system are important. The area is developed more fully in the Reaction Analysis
focus area.
Information-‐rich experimentation. Reaction platforms must maximise the quality and quantity of information from the experiments.
The area is developed more fully in Optimum Reaction and Route Design focus area.
Widespread adoption of new reactor technology would require on-‐going research support that is
sustainable. Therefore, one additional consideration has been included in the Next Generation Reaction Platform area.
Centre of Excellence. Establishing a collaborative, virtual centre of excellence for the development,
extension, prototyping, training and promotion of next generation Reactor Platform Technology, within academia and industry, nationally and
internationally.
One concern that has been expressed by equipment vendors engaging with the Dial-‐a-‐Molecule network relates to the different
timescales between academic outputs and commercial exploitation which seem somewhat incompatible. There is the concern that research
outputs are either not relevant to immediate commercial needs or are too far away from commercial exploitation while in some cases are
obsolete as commercial offerings are already at advanced stages of development. Furthermore, sometimes equipment developed by chemical
groups which lack engineering expertise or market knowledge is either too narrowly focused or even inferior to commercial offerings already
in existence. This could be translated into inefficient use of public funding. It has been
therefore highlighted by equipment suppliers that this gap between academic research output and commercial exploitation must be bridged as
this can potentially lead to commercially exploitable ideas and products as well as efficiency in public funding allocation. It is such
challenges that the proposed Centre of Excellence will be addressing.
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2.2.4 Rapid reaction analysis
Focus area definition
The problem considered is the rapid generation
of both qualitative and quantitative data on the products from experiments designed to explore and/or optimise reactions. It is envisaged that
the generation, validation and reporting of such data does not cause any perturbations, give rise to unnecessary experimental delays or otherwise
compromise the experiments. It is further envisaged that the data can be used as the basis of an automatic feedback system whereby the
experimental conditions and/or the reagents used are tuned. The time taken to perform the measurements (i.e. from "sampling" to reporting)
is in the range of seconds to minutes with this time generally decreasing in the longer term. The required fidelity of the measurement (i.e.
limit of detection, limit of quantitation, degree of structural/conformational proof) is an important consideration that affects the viability of the
various Rapid Reaction Analysis approaches. Although the ultimate aim is clear -‐ full automatic identification and quantification of all
components in a reaction mixture – it is important this does not detract from work directed towards immensely important advances
that can be made with much reduced requirements (e.g. for reaction optimisation identification of components may not be needed).
Overview of the main challenges
Modern experimental practices can incorporate close coupled analytics, for example open access UPLC/MS or NMR instruments and in-‐situ
spectroscopy for reaction monitoring. Therefore, several aspects of this particular challenge are commercially available. However, the following
elements are cause for general concern:
Method Development Time. For measurement approaches that are
dependent upon an initial chromatographic separation then definition of the method conditions should be minimised or generic
methodologies put in place. Response Time. This is defined as the time
delay between “sampling” (i.e. the taking of a
physical sample or the illumination of the chemistry stream by an optical method for example and the reporting of the data).
Generally, the response time should be minimised and any method through which this can be reduced are considered to be in
scope for this challenge. Dynamic Range. Of particular interest to this
challenge are analytical methods that can
analyse samples that contain components which span a very large dynamic range e.g. from 10’s of percent to ppm of an individual
sample. Costs. Currently, the (capital and
maintenance) costs associated with RRA can
be prohibitively large. This is a significant concern and is the likely to be limiting implementation.
Integration / Physical Size. There are some examples of technique integration / hyphenation but they tend to be bespoke
and generic / multi-‐vendor capabilities offer advantages. Also, the footprints of sophisticated analytical techniques are very
large compared to the size of the experimental equipment generally used for synthesis. A significant reduction in the size
of the analytical equipment would help with
Roadmap -‐ Lab of the Future and Synthetic Route Design Page 31
its integration with the experimental equipment required for the chemistry.
Sample Heterogeneity. Analytical techniques that are able to cope with mixed phase (e.g. solid/liquid and liquid/liquid) samples, and
are able to analyse each phase are required for some chemistries.
Equipment development.
Mass spectrometry. Many new ionisation techniques have been developed over the past
10 years providing wide application. ‘Lab on a chip’ HPLC/MS and GC/MS are already available (with U.K. companies leading the field) <
www.microsaic.com> and although currently too expensive for routine deployment there seem no technical barriers to low cost, very small size
instruments being developed and this should be a high priority. Perhaps a bigger challenge is automating the interpretation of data.
Nuclear Magnetic Resonance. Costs and
capabilities of high field solution NMR have been relatively stable for the past 20 years. Recently
there has been a breakthrough in the development of small lower field, lower resolution benchtop instruments using non-‐
cryogenically cooled, and even permanent magnets 15 that seem ideal for monitoring reactions, particularly under flow conditions.
One challenge is making the technology routinely available – cost, and demonstrated applications are key. Development to provide higher
resolution, other nuclei (13C, 31P, 19F) and particularly the capability to perform 2D NMR is needed. The use of diffusional techniques for
resolving mixtures is another important research area. Lab-‐on-‐a-‐chip detection using integrated NMR, or by spatially resolved NMR (Magnetic
resonance imaging techniques) is another
15 (a) www.picospin.com. (b) Kustner, S. K.; Danieli, E.; Blumich, B.; Casanova, F. Phys. Chem. Chem. Phys., 2011, 13, 13172
important way forward 16 . Software for automated analysis of results is likely to be
important.
IR, Raman and UV. Small instruments, relatively small probes, and flow cells are available. For Raman non-‐invasive monitoring is possible. The
main application is likely to be in reaction optimisation rather than compound identification. The challenge is to reduce the cost and develop
software for routine multicomponent analysis of changing mixtures. Fairly advanced multivariate analysis software for extraction of qualitative
and/or quantitative information from overlapping signals is available, the key challenge is to make it easier to use by non-‐experts.
Separation techniques. HPLC, UHPLC, and GC are
effective, but large, relatively expensive, and run-‐times are minutes. Chip based methods integrated with analytical techniques seem the
most promising ways forward.
Sampling. (1) Flow. A great advantage of flow is that it is ideally suited to in situ reaction
monitoring, and a variety of techniques (Raman, IR, UV, NMR, MS) are already used. The challenge is to reduce the cost and footprint of the
equipment. Combining multiple techniques into one ‘box’ is important.
(2) Batch. Since the challenge is to apply methods to routine (i.e. small scale) synthesis the
development of small multi-‐technique probes is needed. Another approach is to use an extractive sampling system which uses flow to transfer
samples of the reaction mixture to analytical tools, and perhaps even returns them.
Standard data and interfaces. Needs a common format (already close), but also ideally a standard
interface (hardware and software) to connect a variety of analytical tools to computers.
16 Harel, E. Prog. Nucl. Magn. Reson. Spect. 2010, 57, 293.
Roadmap -‐ Lab of the Future and Synthetic Route Design Page 32
Rapid Reaction Analysis State-‐of-‐the-‐
art Short term Medium term Long term Goal
Equipment Development
Needed equipment is generally available, but too expensive and often too large.
Benchtop (chip based) MS for reaction monitoring
Multi-‐technique (MS, NMR, IR etc) routine for
reaction development
Integrate MS, NMR in lab-‐on-‐a-‐chip systems
Small multi-‐techniquesprobes and
extractive sampling systems for monitoring batch reactions
Scanning Probe microscopy for
compound identification and
quantification
Small low cost, low resolution NMR for reaction monitoring
Multi-‐dimensional, multi-‐nuclear, high resolution bench/flow NMR
Software Development
Software for non-‐expert use lags a long way behind equipment.
Auto-‐assignment of spectra to given compound(s)
Automatic Identification, quantification, and assignment of compounds.
Auto-‐identification of compounds
Combining data from multiple techniques
Establish centre with all techniques for shared use by groups developing methods
Equipping academia
with analytical equipment needed for reaction analysis.
Equipment available but expensive IR/Raman/UV (£10-‐20k), MS (£40k-‐), NMR (£100k).
National Service for the Study of Reactions. Loan pool of equipment. More sharing.
Provide access to equipment to allow efficient and effective investigation of
reactions.
Promote ‘bulk order’ deals.
Establish as expected departmental service.
Equipment standard in synthetic laboratories
Support industry to produce cheap but good solutions (see Equip. dev.)
Multiplexing equipment to reactors to allow shared use
Automatic identification
of components of reactions
O.K. for known compounds by MS. Little for unknown
Combined data / calculation of molecular properties (spectra and chromatography)
Automatic
identification, quantification, and assignment of complex reaction mixtures.
Software for predicting all reasonable products from a reaction
Auto-‐assignment of composition of reaction mixtures
Roadmap -‐ Lab of the Future and Synthetic Route Design Page 33
Equipment for rapid analysis for reaction optimisation. There are two distinct advantages
with a focus on reaction optimisation (1) identification of components is probably not needed (2) the relative ratio of components will
vary as conditions are changed allowing multi-‐component analysis techniques to be used. It is likely that lower resolution / lower sensitivity
instruments will produce the answers required so low cost solutions should be possible and should be a priority to develop. Another option to
reduce cost is the use of higher resolution instrumentation but with a limited spectral coverage. Small size of probe (particularly for
batch), or the use of non-‐invasive methods (e.g. Raman) to avoid perturbing the reaction, and small footprint of instrument as it will need to be
located close to the reaction vessel, are also important.
Software development.
In general software development for analysis lags a long way behind the equipment. Companies
generally sell equipment not solutions, and traditionally have sold to experts in the
respective fields. For the applications envisioned herein the users will be synthetic chemists without expert support. For MS and NMR
(particularly 2D) there is a need for a much higher degree of automation of interpretation of the data. The amount of data produced, and the
wide range of experiments which can be performed imposes an excessive peripheral workload on someone whose expertise is
synthesis. The problem is particularly severe when multi-‐dimension data is involved (2D NMR, MS-‐MS, multi-‐technique). There is active
commercial development in the area but there is a continuing need for academic research.
The software for correlating multiple techniques to identify components and / or assign structures
needs development. The data needed to allow development of such methods might be best obtained by establishing a centre where all the
needed techniques can be simultaneously be applied to samples or system. The expectation is
that within 10-‐15 years the cost of equipment would be such that the techniques developed would be central to a chemist’s workflow.
Even modest steps towards the aim described
above are important – the user of synthesis wants answers (which compound, how much) not data to analyse.
Reaction optimisation. The key developments
needed are in the software used to correlate the various spectroscopic / analytical data to extract components, and in more distant future (see
below) identify them. The chemist just wants to see the relative amounts of components in the mixture and how they change with conditions.
The eventual aim is to remove the chemist from the loop altogether (closed loop optimisation – see Next Generation Reaction Platforms (NGRP)
and Optimum Reaction and Route Design (ORRD). Software for reaction optimisation is described in ORRD.
Equipping academia and SME’s to use state-‐of-‐the art analytical equipment for reaction monitoring/investigation/optimisation –
overcoming the cost and acceptance barrier.
The main barrier to using analytical instruments for rapid reaction analysis is cost, with size, lack of familiarity and training in use also significant.
For most instruments the main reason for the
high cost is the small market. The possibility of initiatives to overcome this through planned large-‐scale implementation should be considered.
Investing in academic or commercial instrument development with the promise to drastically reduce costs is important. The U.K. is strong in
the area so strategic investment, including promoting industry-‐academic partnerships is worthwhile. It does need to be establishing if
there is a sufficient market for cheap, lower resolution and sensitivity instruments specifically for study/optimisation of reactions.
Roadmap -‐ Lab of the Future and Synthetic Route Design Page 34
In the short term a national service to allow access to a pool of equipment and expertise is
the best way to provide U.K. academia and SME’s with access to state-‐of-‐the-‐art equipment for reaction study. It would have an important role in
increasing the familiarity of synthetic chemists with rapid reaction analysis techniques. It may also help to build stronger links between
synthesis and chemical engineering if both were involved. It is likely that this would be the same as the National Service for the Study of Reactions
described in the Smart Laboratory focus area although there are slight differences in mission. We feel that a loan service (similar to the laser
loan pool) should also be established. A means for more efficient use of equipment already extant should be developed.
Techniques for efficiently multiplexing
instruments so that they can serve multiple reactions in close to real time are an important medium term step. In the long term the
expectation is that size and cost of equipment will have fallen so far that it will be standard in
synthetic laboratories.
Automatic identification of components in a reaction mixture.
Although identification of known compounds is possible, often using mass spectrometry, for
unknown compounds the only significant success is using MS-‐MS techniques, or when a range of 2D NMR techniques are used requiring
substantial sample and time. The challenge is for identification and quantification of components to be entirely automated – the chemist should be
able to concentrate on the synthesis.
We propose that the following steps could lead to the challenge:
(1) Develop methods for the prediction of all reasonable products from a reaction.
(2) Much better prediction of molecular properties.
(3) Use of a combination of separation and
spectroscopic methods to obtain data on components of a reaction.
Combination of (1) and (2) with (3) should allow the problem to be solved.
Point (1) is dealt with in the Optimum Reaction
and Route Design (ORRD) focus area.
For point (2) theoretical calculation of molecular properties has taken great strides, but currently the best prediction methods use databases of
properties from known compounds and use substructure matching algorithms. We suggest that the best route forward is to improve the
latter method by correlating observed data with a range of calculated molecular properties rather than just substructures. Calculations on
suggested structures combined with the correlations derived above should allow
substantial progress on point (2). A similar approach has been proposed for the enhancement of reaction databases in the
Optimum Reaction and Route Design focus area.
The technology of acquiring data for point (3) is largely dealt with elsewhere. For identification of compounds in a reaction mixture, given the
dynamic range of quantities of components involved, a separation step of some sort is likely to be necessary and the ability to predict
chromatographic retention times with a range of stationary and mobile phases is particularly important.
Roadmap -‐ A Step Change in Molecular Synthesis Page 35
2.3 A Step Change in Molecular Synthesis It is recognised that a step change in our ability to make molecules is necessary if we are to meet the aims of the Grand Challenge. Though we
have reached a stage where it is possible to make most molecules if given sufficient time and resource, synthesis remains as a perennial
bottleneck in key disciplines such as healthcare, agrochemisty, molecular electronics and other emerging fields. Two contrastive approaches to
the problem of tackling the synthesis of any given molecule have emerged. The first, with the working title ‘1000 Click Reactions – Stepwise
Perfection’, is based on a simple hypothesis that with sufficient ‘perfect’ and utterly reliable
reactions, we would be able to build even the most complex molecules predictably in a stepwise fashion. The second draws on past
experience in recognising that the first synthesis of a complex target is seldom the best -‐ then poses the question ‘why can’t we identify the
best approach to a synthetic problem from the outset?’ Thus, the ‘Holistic Approach to Molecular Synthesis’ seeks the most direct way
of moving from a starting material to the end product by regarding both as parts of a well-‐defined whole.
The societal and economic benefits that follow from addressing the main bottleneck holding back the development of next generation
medicines, smart materials, pesticides, next generation electronics, sensors etc. are legion. In addition, an ability to make any molecule at will,
inexpensively and on a meaningful timescale will unlock hitherto unimagined opportunities for future scientific advance.
Within these focus areas, several themes
emerged. In addition to those highlighted below, it was recognised that advances in catalysis, as well as computational and technological methods,
will have a huge part to play. If mention of these appears scant below, it is solely because they
have emerged as Grand Challenge themes in their own right and given fuller consideration elsewhere.
Stepwise Perfection and Holistic Approach:
The two extremes of synthesis
Roadmap -‐ A Step Change in Molecular Synthesis Page 36
2.3.1 1000 Click reactions – stepwise perfection
Focus area definition
As noted above, the stepwise perfection approach is based on the hypothesis that with sufficient ‘perfect’ and utterly reliable reactions,
we would be able to build even the most complex molecules predictably in a stepwise fashion. The high yield associated with these
reactions greatly reduces the effect of the ‘arithmetic demon’ allowing, if necessary, longer linear sequences than is usual. In essence, we
need to emulate the success of peptide and nucleic acids synthesis for ‘non-‐polymeric’ molecular structures. Implicit in this approach is
that such reactions should be clean with the aspiration of zero waste or, at worst, facile recycling of minimal waste. Achievement of this
fundamental goal will greatly ease sequencing of reactions during a synthesis and facilitate automation. Low purification requirements will
allow processes to run 24/7, with intermediates in a synthetic sequence passing directly from one processing phase to the next. Thus, a second
strand of this focus area is to develop automation. It will demand significant synergy with Lab of the Future. Progress in this area would make a
substantial contribution toward achieving the overall goal of the Grand Challenge.
Overview of main challenges
The associated challenges are legion and some immediate objectives are outlined below. First
and foremost we need to:
Define ‘Perfection’ and Identify the Reactions Inventory needed to address the Dial-‐a-‐Molecule
Grand Challenge. The latter will doubtless include i) tried and trusted reactions; ii) reactions with
some precedent that are underdeveloped; iii) reactions as yet unknown with the potential to be transformative and iv) niche reactions needed
to tackle specific problems yet are unlikely to be transformative. Tried and trusted reactions would need to be assessed against emerging
criteria for ‘perfection’ with failings widely communicated to encourage further development. We envision a distinct role for
informatics in helping to identify transformative reactions, whether they are precedented or not. In the medium to long term we envision the need
for the development of niche reactions. In respect to the above all the three phases, discovery, development and demonstration (the
3D approach to chemistry) are required and need to be given equal merit. Implicit within the inventory is a need for diversity, as the Grand
Challenge will not be solved with myriad ‘perfect’ reactions giving the same outcome.
In parallel we need to establish criteria against
which ‘perfection’ can be judged and these need to become guiding principles for practitioners of chemical synthesis. Examples include chemical
yield, solvent compatibility, by-‐product management, functional-‐group tolerance, selectivity (chemo-‐, regio-‐, stereo-‐, enantio-‐ and
torquo-‐selectivity), waste stream management (e.g. Sheldon’s E factor), suitability for sequencing, and compatibility with flow. It is
recognised that priorities will change as we move towards greater automatisation in the medium and longer term. Whether automatisation is best
achieved through mobilisation or immobilisation of the substrate remains unclear at this time. To increase the impact of each reaction we need to
identify a range of useful ‘first-‐step’ conversions from each product e.g. the utility of the Sharpless asymmetric epoxidation was greatly enhanced
following publication of a series of papers transforming the hydroxy-‐epoxide into other functional groups.
Total Synthesis of Sceptrin
Roadmap -‐ A Step Change in Molecular Synthesis Page 37
1000 Click Reactions – Stepwise Perfection State-‐of-‐the-‐
art Short term Medium term Long term Goal
Define ‘Perfection’ and Identify the Reactions Inventory
Many reactions work in narrow chemical space with an unacceptable waste stream (<100% efficient and giving byproducts etc.)
Establish ideals for ‘perfection’ and criteria against which any reaction can be judged
Widespread adoption of these ideals and a change of working practice/culture to acknowledge failings
Critical evaluation of new chemical reactions or advances within complex systems
Robust reactions that can be relied upon in a
wide area of chemical space
Ability to prepare any molecule predictably and reliably, including those in hitherto
unexplored areas of chemical space
Define and refine list of reactions needed for GC
A Chemical Inventory of
Perfect Reactions that Deal with Complexity
Current inventory of reactions is insufficient to address the Grand Challenge
Assess known reactions -‐ ‘perfection’ & ‘merit’
Combining perfect reactions to achieve complex target oriented synthesis
For ‘known’ transformations deemed essential, develop low/no waste protocols or alternatives. For ‘unknown’ transformations deemed essential, develop protocols to achieve them
Develop low/no waste protocols for emerging transformative reactions
Many reactions are fickle – sensitive to modest changes in substrate or reaction conditions
Development of new low/no waste chemical reactions that are broad in scope and robust
Establish robustness and practicability as other important ideals
Routine scoping of reactions for compatibility (in respect of: other functional groups, solvents, trace water, pH, temperature etc.)
Reagentless Transformations
Many methods lack practicability and have failed to enter the mainstream
Development of cheap, robust and easy-‐to-‐use instruments for photo-‐, sono-‐, electro-‐ and high pressure chemistry & potential for automisation
Integrated instruments offering ‘all-‐in-‐one' sequencing
Development of no-‐waste
stock reactions that are reliable, robust and easy to
sequence.
New reactions leading to new understanding
Avenues to new areas of chemical space – towards complete predictability
Adding practicable procedures to the chemical inventory
Addressing compatibility issues between these techniques and extending this to include key catalytic procedures
Integration of practice and theory – towards in silico optimisation Better training in computational methods and automisation techniques – access to state of the art equipment
Roadmap -‐ A Step Change in Molecular Synthesis Page 38
A Chemical Inventory that Deals with Complexity is one of the greatest challenges
facing the stepwise perfection approach. The emerging reactions and paradigms must be able to perform well under a diverse range of
conditions and within molecules with diverse functionality and structural features. Thus, as chemists develop the chemical inventory they
also need to address scoping and compatibility issues in a systematic way while seeking to gain a fuller understanding of key reaction parameters.
We can predict with some certainty that in the longer term, only reactions that cope with complexity and give reliable access to new
chemical space will be considered transformative and find widespread adoption. Attention should therefore be focussed on these ideals with
researchers encouraged to do both the invention of new chemical reactions and the associated scoping studies.
Reagentless Transformations (field effects: light,
heat, pressure, ultra sound, electricity, etc.) are ideally suited to automatisation and sequencing.
They produce no chemical waste stream if achieved with 100% efficiency so, in conjunction with transformative catalytic processes and lab of
the future technologies, they are likely to play an increasingly significant role moving forward. These processes also lend themselves particularly
suitable for in silico modelling, a potential quick win for the Grand Challenge. To achieve this goal we need to develop a full understanding of
existing processes to make them utterly predictable in complex systems. In addition, more needs to be done to identify new
reagentless transformations and understand the underpinning characteristics of each. It should then be possible to use in silico methods to
predict new and useful chemical reactivity for development into ‘perfect zero-‐emission’ reactions in the laboratory. Thus, a framework
needs to be established to facilitate greater understanding of compatibility issues and the complementarity of processes to enable
sequencing with other perfect reactions in an automated fashion.
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2.3.2 Holistic approach to molecular synthesis
Focus area definition
The holistic approach to molecular synthesis seeks to change the way synthesis chemists
assemble molecules. The intention is to develop a new paradigm for the construction of organic structures in which the feedstock (starting-‐point)
and end product are regarded as parts of a well-‐defined whole, rather than separate entities as present. Complex molecular syntheses typically
have a small number of critical staging posts, signposted by reactions that build complexity. These are linked by sequences of reactions that
achieve little other than to prime the molecule to trigger the complexity-‐generating step. The goal of the holistic approach to synthesis is to reduce
the number of priming steps to a minimum so that targets can be made using a small number of complexity-‐generating reactions. In this way the
time taken to accomplish a target-‐synthesis will be greatly reduced and our ability to access useful new chemical space greatly enhanced.
Overview of main challenges
Knowing where to start – New Feedstocks. A classical idea when planning a target-‐oriented
synthesis is to start from ‘something simple’. This usually means a commercially available
substance of relatively low molecular weight, purchased from a fine chemicals supplier. But the hegemony of petrochemicals in defining
feedstocks is being challenged by the emergence of biotransformations, biomass and
bioengineering as rich sources of highly functional starting materials, which are often
stereochemically defined.
Telescoping transformations. When planning the chemical synthesis of a molecule, it is usual to
employ the principles of retrosynthetic analysis. However, by its very nature this leads to a step-‐intensive synthesis as the method usually
considers each C−C bond in isolation and defines
the problem in terms of a series of ‘logical’ bond disconnections. Each disconnection requires the appropriate functional groups (FGs) to be in place.
When they are not, they must be introduced by manipulation of other FGs (FG interconversions). At each juncture, every FG within the molecule
must be considered as they may need to be rendered benign (protecting group strategies), to prevent unwanted side reactions. These priming
steps serve no purpose other than to facilitate the ‘complexity-‐generating’ reaction. The recent emergence of new ‘no-‐waste’/clean catalytic and
reagentless transformations offers immediate potential for the telescoping of such transformations – i.e. using the output of one
chemical reaction directly in the next. Though the idea is not new, if telescoping is to become routine a step change in current practice is
required. We will need to establish a series of operating parameters for every clean transformation in order to know when they can
and can’t be telescoped. In addition, new complexity-‐generating clean reactions will need to be invented and linked to other telescopic
transformations. It will change the synthesis paradigm from relying solely on precedent to embracing the unknown with confidence.
Understanding and exploring reactivity. Despite longstanding global activity in organic synthesis, only recently have the scientists involved
embraced the more quantitative aspects of the discipline and, for the most part, this has been in the context of catalysis. Frequently, considerable
synthetic effort is expended to overcome a lack of selectivity. This makes product isolation more
Roadmap -‐ A Step Change in Molecular Synthesis Page 40
difficult, adds by-‐products to the waste-‐stream and in some cases makes it necessary to use protecting groups and/or auxiliary groups, which
are inherently wasteful. With a fuller understanding of key processes (e.g. nucleophilic versus basic behaviour; steric effects;
regioselectivity; effect of solvent on reactivity) many of these issues could be foreseen and
resolved at the planning stage. In turn, this will enable the development of improved predictive tools and lead to higher synthetic efficiency.
Realising a wish list of new reactions. Many desirable chemical transformations have yet to be discovered. Although most transformations
are achievable if constraints such as the number of manipulations, overall yield and available
Holistic Approach to Synthesis State-‐of-‐the-‐
art Short term
Medium term
Long term Goal
New Feedstocks
Heavy reliance on simple petrochemicals. Limited by catalogue of fine chemicals available – few opportunities to exploit other sources
Better awareness and exploitation of biotransformations
Widespread appreciation of ‘state of the art’ biotransformations – moving away from catalogue suppliers as a first resort
Escaping the petrochemical straightjacket towards more appropriate starting materials.
Improved understanding of biotechnologists capabilities and their understanding of our needs
Telescoping transformations
Known but application limited by issues of compatibility and poor understanding of physical parameters
Better understanding of operating parameters e.g. solvent, trace H2O tolerance, temperature
Design of new ‘no waste’/clean reactions with good tolerance of other functionality and capable of working in diverse situations
Ability to sequence complexity generating reactions
predictably and without human intervention
Integration of practice and theory – towards in silico optimisation
Routine establishment of key parameters for new reactions. Moving away from case-‐by-‐case development towards a holistic approach
Understanding and exploring reactivity
We’re getting better but under-‐developed as a topic. Opportunities are legion.
Profound understanding of solvent effects
Routine sequencing of reactive intermediates to trigger the controlled manipulation of several chemical bonds in a single step to introduce only required complexity.
Rapid access to target
molecular architectures
Realising a wish list of new reactions
Many reactions are available yet few have found widespread use. We need to be better at identifying the transformative reactions.
Development of in silico techniques to identify reactions with transformative potential
Understanding the new capabilities
Development of an armoury of complexity-‐generating chemical
transformations capable of
addressing any target without unnecessary manipulation
Development of new reactions with transformative potential. Reactions needed are wide-‐ranging
Towards a needs driven approach and away from a perceived needs driven approach
Guidance from industry to achieve quick impact. Also to help identify future wealth-‐generating reactions and molecular/generic targets
Venturing into new chemical space
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resource are removed, there is a growing realisation that, with a relatively small set of new
bond-‐forming reactions, target-‐oriented synthesis would be transformed. The new reactions would need to be complexity-‐building,
using functionality in newer and smarter ways. As indicated above, they would need to be clean, atom efficient and selective so as to be used in
sequence with other catalytic and reagentless transformations without need for protection.
Examples include reductive conversion of a secondary alcohol into a carbon nucleophile with
retention of configuration; oxidative coupling of unfunctionalised sp3-‐hybridised carbon atoms; internal redox reactions that relay reactive
centres around a molecule as desired, etc. New ideas for identifying transformative reactions need development (e.g. examining impact by
adding ‘unknown’ reactions in computational retrosynthetic analysis programmes).
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2.4 Catalytic Paradigms for 100% Efficient Synthesis
Catalysis will clearly be central to any efforts to address the Grand Challenge. Recent years have
seen phenomenal advances in the application of catalysis to complex molecules, with recent Nobel prizes recognising contributions in
asymmetric catalysis (Knowles, Noyori and Sharpless, 2001), olefin metathesis (Chauvin, Grubbs and Schrock, 2005) and cross-‐coupling
reactions (Heck, Negishi and Suzuki, 2010). In the last 5-‐10 years, enormous advances have been made in the long-‐held goal of selective C-‐H
functionalization (mainly of aromatic molecules), but there remain significant challenges before these key 21st-‐century transformative methods
can be regarded as robust or mature. Contemporaneously, the field of organocatalysis has been clearly established as a new paradigm
for non-‐metal catalysis, offering complementary methods with advantages for sustainability and environmental agendas. The issue of
sustainability itself presents both a key challenge and opportunity for the development of modern catalysis. Enormous strides have been made in
commercial biotechnology (e.g. directed evolution of enzymes, re-‐engineered biosynthetic
pathways) but there remain (and will likely always remain) key constructs and transformations which are beyond the scope of
biocatalysis, especially when considering formation of carbon-‐carbon bonds: selecting and developing the most appropriate catalyst
whether man-‐made or biological, for each task, and dovetailing these catalytic technologies is key. Shifting landscapes in terms of the economics
and acceptability of petroleum-‐based versus alternative feedstocks will drive new
developments, while the long-‐term security of precious metal supplies creates a further
challenge. We have defined three broad challenge-‐led focus
areas for the catalysis theme.
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2.4.1 New reactivity: target-driven catalysis
Focus area definition
This focus area addresses the issues of WHICH strategic new catalytic processes will enable delivery of the Dial-‐a-‐Molecule goals, and WHAT
the key catalysts/technologies to ensure this delivery would be. It is clear that prioritisation of the highest-‐impact strategic new catalytic
reactions overlaps with the ‘holistic synthesis’ focus area.
Overview of main challenges
Efficient transformations across chemical space: A significant barrier to translation of new technologies to GDP-‐generating products of the
end-‐user community is the lack of predictability of extrapolating reactions optimised for one area of ‘chemical space’ to others of value: for
instance, a reaction that is successful with polar substrates, products and reaction media does not necessarily transfer to a non-‐polar paradigm, and
vice versa. Understanding and agreeing metrics that define success for a reaction in broadened areas of chemical space will provide an objective
assessment of the current state of the art, accelerate the translation of new methods and also a rationale and impetus to address areas
currently lacking robust/general solutions. A predictivity rubric will also clearly identify high-‐
impact but ‘difficult’ transformations (e.g.
selective C−F bond formation) for immediate
prioritisation.
Complexity-‐building reactions: A productive strategy to augment overall synthetic efficiency
would consider the ‘functionality balance’ of the reaction. Even robust and widely-‐used reactions such as the Suzuki coupling are clearly far from
perfect by such an analysis, since the reaction consumes two functional groups (an organic halide and an organoboron reagent) to form an
unreactive (‘dead’) carbon-‐carbon bond; thus this Nobel-‐winning reaction inexorably leads to an overall loss of two functional groups. Step-‐
changes in efficiency will only be possible by focusing on reactions that at least maintain but preferably engender functionality rather than
consume it; exemplar processes of this type
include C−H activation and functional group
transfer reactions. Although significant advances have been made in these areas recently, many
further advances are required. The scope (types of functionalisations) and especially the efficiency (catalyst loading, burden of expensive/wasteful
co-‐reagents) of (hetero)aromatic functionalisation still remain far from optimal and should be optimised in the next 5-‐10 years.
A longer-‐term specific challenge is the selective generation and functionalisation of 3D structures: the pharmaceutical industry in particular urgently
needs to explore this space more completely since current molecular portfolios (often containing high proportions of aromatic subunits)
clearly have an unsustainable attrition rate in the drug discovery process.
Sustainability: feedstocks While the availability of petrochemical starting materials will doubtless
continue, there is no agreement about how availability will be maintained and there are accordingly diverse economic and consumer-‐
market driven pressures to adapt to alternative feedstocks. For instance, such pressures are already manifesting themselves in the design and
implementation of engineered biocatalytic approaches to polymer monomers. The engineering of biocatalysts to deliver new
functional building blocks will continue to be
tetrakis(triphenylphosphine) palladium(0)
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important across the entire period of the challenge.. The chemocatalysis community has a
vital role to play in adapting or developing new catalytic methods to process renewable (biomass or engineered) feedstocks (e.g. selective
functionalisation of polyoxygenated products such as carbohydrates or natural hydrocarbon-‐rich products such as fatty acids). The
combination of sunlight (photocatalysis) with
biomass to give renewable feedstocks approaches perfection. The integration of
chemocatalysis with biocatalysis pathways to deliver products (either providing access to feedstocks for biocatalytic processes or
functionalising key building blocks delivered by biotechnology) will be a crucial enabling interface, recognising that certain reaction
types/functionalities are unlikely ever to be
New reactivity: target-‐driven catalysis State-‐of-‐the-‐art Short term Medium term Long term Goal
Efficient transformations across chemical
space
Many reactions work in narrow chemical space
Understand & agree metrics for ‘broadened’ chemical space
Robust catalytic
technologies for ‘any bond, any substrate’
Development of more robust catalysts across chemical space
Incomplete catalytic toolbox
Define key ‘high value’ missing transformations
Development of ‘difficult’ transformations (e.g. selective C−H to C−F)
Complexity-‐building reactions
Reactions consume not generate functionality
Optimise (hetero)aromatic functionalisation
Molecular properties
drive synthesis,
not available technologies
C−H functionalisation as emerging field
Selective generation and functionalisation of 3D structures
Sustainability: feedstocks
Fine chemicals etc mostly from petrochemicals
New catalytic methods to process biomass or engineered feedstocks
Use of diverse,
sustainable range of feedstocks
Engineered pathways to ‘advanced’ materials
Engineered biocatalysts to deliver new functional building blocks Integration of chemo/biocatalytic pathways to deliver products
Sustainability: catalysts
Many processes use ‘at risk’ precious metals
Ultra low-‐loading precious-‐metal homo-‐ and heterogeneous catalysts
Catalysis using
economical, sustainable components
Non-‐precious metal catalysts for ‘traditional’ transformations
Organocatalysis as a developing field
Continued evolution of reaction scope/efficiency of organocatalysis
Biocatalysis highly successful for limited substrate scope
Further broadening of functional scope of biocatalysis
Roadmap -‐ Catalytic Paradigms for 100% Efficient Synthesis Page 45
achievable using biocatalysis alone.
Sustainability: catalysts Much catalysis for fine chemical synthesis relies upon precious metals
which are nearing depletion (potentially creating excessively-‐high cost-‐of-‐goods for existing processes, rendering them uneconomical or
commercially unfeasible). This will drive moves towards (a) ultra-‐low loading/long-‐lifetime catalysts, including the development of ‘next-‐
generation’ heterogeneous catalysts capable of operation for fine chemical transformations; (b) the development of catalytic methods using
more abundant non-‐precious metals e.g. for ‘traditional’ transformations that use ‘at risk’ metals; (c) the continuing evolution and
broadening of the scope and efficiency of reactions possible through organocatalysis; and (d) further broadening of the functional scope of
biocatalysis for fine chemical applications.
Roadmap -‐ Catalytic Paradigms for 100% Efficient Synthesis Page 46
2.4.2 Intervention-free synthesis by phase-distinct, multi-dimensional catalysis
Focus Area Definition
This area addresses the long-‐term goal of driving
up process efficiency (maximum speed, minimum waste) by sequencing catalytic reactions with minimal human intervention (work-‐ups,
separations etc). Inspiration can be taken from biosynthesis, where highly efficient and specific sequential reactions are programmed to deliver
complex molecules: in these cases the synthetic efficiency is engendered by precise and predictive control of the operational timing of
different catalytic reactions, coupled with the inherent high selectivity of biocatalysts. Engineering such control in chemocatalysis
systems will be fundamental to achieving this goal.
Overview of main challenges
Phase-‐separated catalysts: The spatial and temporal separation of catalysts with different activities is an essential component of reaction
sequencing in biosynthesis. The current state of the art for (catalytic) synthetic reaction sequencing involves flow reactor technology with
solution-‐phase reactants and solid-‐phase immobilised catalysts. However, current
methodology brings undesirable compromises (for instance, catalyst immobilisation frequently results in lower activity) and the evolution of
diverse new phase-‐tagging methods that address
this (such as phase-‐switchable catalysts) will be important. The development of next-‐generation
heterogeneous catalysts (e.g. nanofabricated integration of catalyst function within support structures) for complex molecule applications
could play a strong role. There is a critical role for selection of support materials in terms of synergistic effects. Liquid-‐liquid phase tagging is
used for catalyst separation in some bulk chemical processes, and if integrated with engineering solutions/new reactor designs for
efficient phase separation could facilitate sequenced synthesis.
Mutually compatible catalysts: A second approach is to have several mutually compatible
catalysts in ‘one-‐pot’, each of which performs a single (or multiple repetitive) task(s) with exquisite selectivity. Many examples where
‘tandem’ (ie two sequential processes) are carried out are known, and a short to medium-‐term goal will be to extend this to elongated
sequences. The full integration of selective chemocatalysts and of bio-‐/chemocatalysts will
be a powerful technique.
Switchable catalysts: A third approach to the issue of selectivity is to develop ‘switchable’ catalysts which can be turned on/off in response
to an external physical or chemical stimulus (e.g. light, temperature, pH) to allow externally programmable sequences to take place within a
single unit vessel. The switch could operate by one of several mechanisms – e.g. by chemical activation/deactivation, or by control of access to
a catalyst active site (coordination events or encapsulation). In the short to medium term, research to develop suites of technologies for
catalyst switching by a range of stimuli will be important, leading to the longer term integration into programmable sequences of catalytic
reactions.
Roadmap -‐ Catalytic Paradigms for 100% Efficient Synthesis Page 47
Separation technology: Crucial to the
achievement of these will be the development of improved separation technologies, both in terms of reactor design (e.g. for high performance
liquid-‐liquid phase separation) and membrane technologies for compartmentalisation. Improved reactor design to enable the routine
integration of membrane separations into standard synthetic sequences will deliver immediate benefits. The development of a
broadened range of selective membrane technologies for control of adduct/educt ingress/egress to reactors will enable novel
strategic approaches to reaction sequencing and processing. This encompasses both ‘hard’ polymeric membranes and ‘soft’ membrane
assemblies (e.g. micellar environments similar to
biological cells).
Intervention-‐free Synthesis by Phase-‐Distinct Multi-‐Dimensional Catalysis
State-‐of-‐the-‐art Short term Medium term
Long term Goal
Phase-‐separated catalysts
Flow synthesis using solid-‐supported catalysts
Improved activity of solid-‐supported catalysts
Readily
integrated and configurable reactions and reactor units for efficient continuous multi-‐step synthesis
Engineering solutions and tools for efficient phase-‐separation
Evolution of diverse phase-‐tagging approaches
Next-‐generation heterogeneous catalysis (inc. nanofabricated): bulk chemical levels of performance on fine chemical structures
Mutually compatible catalysts
Tandem metal-‐metal catalysis or metal-‐organocatalysis
Move beyond ‘tandem’ to multi-‐step approaches
One-‐pot, multi-‐step sequencing as standard
Full integration of chemo-‐ and biocatalysis
Switchable catalysts
Catalysts can be programmed to switch on (activation) or off (poisoned) but not reversibly
Develop suite of technologies for catalyst switching to range of stimuli
Externally
programmable and
controllable multi-‐step synthesis
Integration into programmable sequences
Separation technology
Size or pH-‐selective polymeric membranes
Broadened range of selective membranes
Intervention-‐free
separations;
Towards ‘chemical cell’ manufacturing
Reactor design for routine integration of membrane separations
Soft membrane (cell-‐like) reactors with selective ingress/egress profiles
Roadmap -‐ Catalytic Paradigms for 100% Efficient Synthesis Page 48
2.4.3 Engineering control through fundamental mechanistic understanding
Focus Area Definition
This area addresses both the acceleration of catalyst discovery/optimisation and the improvement in catalyst performance (selectivity,
turnover rates and numbers) by knowledge-‐based approaches combining data gathering/mining, experimental determination of
mechanism, and theoretical approaches. In the early phases, this will deliver predictability and robustness to catalytic processes, but longer
term will move towards predictive science, with an ultimate goal being the ability to design a priori novel and selective catalyst species for
specific transformations. There are clear links to the requirements outlined in the focus area Rapid Reaction Analysis and the goal of
establishing a National Centre for the Study of Reactions.
Overview of main challenges
Rapid (self)-‐optimisation of reactions: The use of statistical methods (e.g. Design of Experiment (DoE) analyses) to efficiently optimise reactions,
coupled with improvements in automation, have led to rapid improvements in the development of
robust reaction systems. This will continue to be
a key driver in the short to medium term, leading to the (development of robust
protocols/catalysts for standard reactions in well-‐defined “compound space”. In silico prediction of ‘best guess’ starting points for reaction
optimisation by DoE through efficient database searching will greatly accelerate this process. Self-‐optimisation of catalytic reactions using in
situ feedback loops has been demonstrated in some exemplar cases by international research groupings and such self-‐learning approaches will
experience a step-‐change in application if coupled with improved analytical instrumentation and intelligent learning
(integration with reaction database).
Full elucidation of catalytic mechanisms: The need for improved ‘on the fly’ and in situ/operando analytical methods has been
clearly articulated in the focus area of Rapid Complete Reaction Analysis and wider adoption of such ‘alternative’ analysis tools (ie beyond
standard linked chromatographies and spectroscopies) will accelerate developments in
the short to medium term. This will comprise both improvements in relatively low-‐cost ‘local’ analytical equipment (e.g. MS, benchtop
spectroscopic) but also driving the increased use by workers in complex molecule catalysis of larger national facilities e.g. Diamond. The
proposed National Centre for the Study of Reactions, described in the Smart Laboratory focus area, has a role to play in coordinating this
activity and potentially hosting large-‐scale equipment.
Theoretical chemistry: through understanding to prediction: Advances in theoretical methods
coupled with improvements in computational power will ultimately bring the rapid analysis of transition states and comparisons of multiple
possible pathways (important both for issues of selectivity and catalyst deactivation) for a much broader range of reactions into scope. The
ultimate goal will be the in silico prediction a priori of new catalyst species to achieve
Novel Palladium-‐Platinum catalyst
Source: Sandia National Laboratory
Roadmap -‐ Catalytic Paradigms for 100% Efficient Synthesis Page 49
particular transformations (e.g. unprecedented
transformations, selective transformations on complex molecules, development of new
reactions on sustainable metals). Development
of automated theoretical approaches offers the possibility of integrating computational methods into experimental mechanistic analyses and
reaction optimisation.
Engineering control through fundamental mechanistic understanding State-‐of-‐the-‐art Short term Medium term Long term Goal
Rapid (self)-‐optimisation of reactions
Self-‐learning based on single reactions and limited reaction output data
Improved analytical instrumentation drives step-‐change in self-‐learning approaches
Self-‐learning approach
becomes widely available standard technique
DoE techniques available but need well-‐defined ‘starting point’
In silico prediction of ‘best guess’ starting point
Standardisation of conditions for key reactions
Full elucidation of
catalytic mechanisms
Limited techniques for probing low-‐level components
Wider adoption of ‘alternative’ analysis tools e.g. development of real-‐time/operando methods
Analytical
techniques no longer a
limitation to understanding
In line and in situ techniques limited in scope
Improved scope and use of analytical instrumentation (local and larger scale)
Theoretical chemistry: through
understanding to prediction
Complex calculations possible but slow, computationally expensive
Advances in theoretical methods for complex (esp. metal-‐containing) transition state analysis
Theoretical
chemistry moves from
rationalisation to prediction as standard
In silico prediction of reaction selectivity/new reactivity/new catalyst species
High-‐level calculations only possible on small atom number reactions
Roadmap -‐ Conclusion Page 50
3 Conclusion We have outlined in the roadmap document challenges and areas of foreseeable direct relevance to achieving Dial-‐a-‐Molecule. However, transformative discoveries are often unforeseen and success in
achieving the challenge relies as much on the strength of the fundamental science that underlies it. For example design and development of the catalysts with the properties required above needs a much deeper understanding than currently exists, particularly in respect of mechanism and the
effect of catalyst structure and environment. The work described in other roadmaps (e.g. the RSC “Chemistry for Tomorrows World”7 and Landscapes11 documents, Chemistry Innovations KTN’s Sustainable technologies roadmap4) is important in maintaining a healthy U.K. scientific community
without which no ‘directed research’ can hope to flourish.
Roadmap -‐ Acknowledgements Page 51
4 Acknowledgements We thank the hundreds of people who took part in the various Dial-‐a-‐Molecule meetings and workshops that provided basis for the roadmap.
We would also like to extend all our thanks to EPSRC for the all the financial support provided.
We are particularly grateful to the people who championed the various focus areas and were
directly involved in constructing the roadmap. Stephen Hillier (Chemistry Innovation KTN), David Hollinshead (AstraZeneca), Andrew Russell (University of Reading), Joe Sweeney (University of Huddersfield), Harris Makatsoris (Brunel University), Sean Bew (University of East Anglia), David
Woods (University of Southampton), Frank Langbein (Cardiff University), Sophie Schirmer (Swansea University), Donald Craig (Imperial College), Asterios Gavriilidis (UCL), Rebecca Goss (University of East Anglia), Robin Bedford (University of Bristol), Alison Nordon (University of StrathClyde), and Ian
Clegg (Pfizer).
However, final responsibility for errors and omissions from the roadmap rests with principle authors of this document: Richard Whitby, David Harrowven, and Bogdan Ibanescu (University of Southampton) and Steve Marsden (University of Leeds).
Roadmap -‐ Acknowledgements Page 52
www.Dial-a-Molecule.org
Dial-a-MoleculeDial-a-MoleculeAn EPSRC Grand Challenge network