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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

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

“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

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

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

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

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

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

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

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


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


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).


(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.


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


(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


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.


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.


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

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.


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.


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


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


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:


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.


2.2.2 The smart laboratory


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.


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


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.


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.


2.2.3 Next generation reaction platforms


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.


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?”


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


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.


2.2.4 Rapid reaction analysis


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


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.


Rapid Reaction Analysis State-‐of-‐the-‐


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


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.


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

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


2.3.1 1000 Click reactions – stepwise perfection


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.


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


1000 Click Reactions – Stepwise Perfection State-‐of-‐the-‐


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


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.


2.3.2 Holistic approach to molecular synthesis


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.


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


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


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).

Roadmap -‐ Catalytic Paradigms for 100% Efficient Synthesis

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.


2.4.1 New reactivity: target-driven catalysis


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.


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)


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


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.


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.


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.


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


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.


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


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

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

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

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