Science Matters : Winter 2011 by Syngenta UK Limited

science matters

Keeping abreast of Syngenta R&D

A bright future for chemistry The contribution of our chemists is helping to provide solutions for growers across the world Uncovering the secrets of proteins Getting inspiration from nature The importance of chirality Getting product safety and toxicology right Innovations in IZM and Formula M Making chemistry green An external perspective from the Royal Society of Chemistry

Winter 2011

Contents Science Matters is a magazine supported by the Syngenta Fellows to recognize and communicate the excellent science throughout Syngenta. Here is an overview of the articles in this issue: 03 The importance of chemistry – Sandro Aruffo No branch of science contributes more to the world in which we live than chemistry. In the International Year of Chemistry, Sandro Aruffo, Head of Research and Development, explains why chemistry is vital to sustainable agriculture. 04 The breadth and depth of chemistry at Syngenta – Andrew Plant Andrew highlights the articles in this edition and puts them into the wider context of the challenges we face in agriculture. 06 Uncovering the secrets of proteins – Kathryn Brocklehurst Proteins are essential to life and are the targets of most of our chemistry. Kathryn demonstrates the wide range of modern science used in the Protein Science Group to study proteins, ranging from new molecular techniques to protein production. 08 Following the nature trail to new products – John Clough Nature can be a great source of inspiration to our chemists. John discusses the challenges and successes in using natural products to invent. 10 Getting the chemistry just right or just left – Andrew Plant Chirality is the technical term for the property which, in everyday life, we encounter as left or right ‘handedness’, as in pairs of gloves or shoes. Andrew explains why chirality is important in the search for new agrochemicals.

12 Getting the properties right – physical chemistry and product registration – Torquil Fraser & Kim Travis A new crop-protection product has to pass stringent requirements before it can be marketed. Kim and Torquil explain how the physical properties of molecules are so important for product registration. 14 Surveying the field of toxicology – Richard Peffer Assessing the toxicology of crop protection chemicals is essential to ensure their safe use. Richard explains how different aspects of chemistry are employed in toxicology. 16 Crystal gazing in theory and practice – Daniel Kloer, Russell Viner & Torsten Luksch Computer-aided design and x-ray crystallography have come of age as new technologies enable us to model and visualize ligand-protein interactions. Daniel, Torsten and Russell discuss how Syngenta is using these techniques. 18 IZM: via realizm, optimizm and isomerizm – Harald Walter Isopyrazam (IZM) is a fungicide with a new mode of action. Harald describes the innovative chemistry behind this exciting new product.

Science Matters Keeping abreast of Syngenta R&D Winter 2011

20 Formula M races ahead – Stefan Baum Stefan explains how innovations in seed treatment technologies are providing safer, more environmentally friendly offerings to growers. 22 Making chemistry green – Prashant Potnis A ground-breaking manufacturing process for Thiamethoxam has been implemented at the Santa Monica site in Goa, India. Prashant explains how the team made this happen. 24 Achiever chemist A personal profile of Kikkeri Divakar who is the Director of the Syngenta Research and Technology Centre in Goa, illustrating a life-time in chemistry. 26 External perspective – David Phillips David is President of the Royal Society of Chemistry. In this ‘External perspective’ he reflects on the importance of chemistry to society and the successes of the International Year of Chemistry. 28 Out and About Snippets – Carolyn Riches A selection of short chemistry stories from around the company. 30 Editorial reflections – Stuart John Dunbar This is the last edition of Science Matters Stuart will edit. In his final editorial he reflects on the importance of chemistry science education and sets the scene for the future of the magazine.

The importance of chemistry The United Nations Educational, Scientific and Cultural Organization (UNESCO) has designated this year as the International Year of Chemistry. Syngenta actively took part in the UNESCO launch event and has participated in numerous other events celebrating the International Year of Chemistry around the world. It is therefore fitting that we dedicate the last issue of Science Matters of 2011 to chemistry, recognizing the many contributions that modern chemistry has made, and will continue to make, to agriculture. Chemistry has provided humanity with many very important inventions which have significantly improved peoples’ quality of life; examples include novel pharmaceuticals, agrochemicals, and textiles, among many others. It is clear that as the science of chemistry advances it will continue to have a major positive impact on humanity. Yet the impact of chemistry on modern agriculture needs singling out as a major contributor to improving the human condition. Chemistry has enabled growers to fertilize and protect crops, efficiently improving crop yields and quality. It has allowed growers to protect crops after harvesting, ensuring a safe and reliable food supply. It has permitted farmers to grow more crops per acre than ever before around the globe. These, and other contributions of chemistry to agriculture, have played a very important role improving food security for billions of people around the world. Over the last couple of decades we have witnessed major advances in the application of chemistry to agriculture. This has resulted in the discovery of compounds with greater margins of safety for users, consumers and the environment, superior potency and spectrum of activity, reduced application rates, among many other improvements. Yet today the opportunity for chemistry to make significant contributions to agriculture is as great, or greater, than it has ever been. The development of resistance requires that chemists continue to discover new compounds with novel modes of action. There is a continuing need to discover compounds with even greater safety margins which retain their potency and spectrum of activity. There is also a need to further customize compounds and formulations to better adapt them to both crops and geographies. But what is different today is that major advances in chemistry, as well as related scientific fields such as biology and mathematics, are allowing chemists to design compounds in a very different ways. For example, chemists are now designing and optimizing compounds which work in conjunction with the plant’s genetic potential to further improve a crop’s ability to tolerate both biotic (insects, disease, etc) and abiotic (heat, drought, salinity, etc) stress thereby providing growers with the tools they need to drive a step change in agricultural productivity. Syngenta scientists are taking full advantage of the opportunity to innovate at the interfaces of different scientific disciplines in ways that have not been possible before. This is allowing us to generate novel, value-added products to improve crop yields and quality in a sustainable way. Chemists at Syngenta are now an integral part of multi-disciplinary teams focusing on addressing grower needs by crop. They are discovering novel compounds not only by optimizing parameters such as safety margins, potency and spectrum of activity, but also based on the effects that compounds have on the plants physiology, for example root growth, which is a parameter that correlates with better tolerance to abiotic stress. They are also using the knowledge that their compounds will be included in integrated products to discover compounds that will be used in conjunction with the plants genetic potential, for example native traits, to provide robust control against biotic and abiotic stress. Advances in chemical design specifically for seed treatment, as well as formulation techniques, now allow products to be precisely targeted, minimizing environmental exposure and improving efficacy. These are the types of opportunities that will drive chemical innovation and its continuing positive impact on agriculture in the future. Syngenta’s unique expertise in chemistry, genetics and agronomic practices puts us in a unique position to exploit this new application of chemistry to improve agricultural productivity. In this issue of Science Matters you will learn more about the breadth and depth of our chemistry activities at Syngenta and the very talented chemists on our team. Sandro Aruffo Head of Research & Development

Science Matters Keeping abreast of Syngenta R&D Winter 2011

Syngenta helped celebrate the importance of chemistry in our daily lives at the Basel Festival of Molecules in mid-June

The breadth and depth of chemistry at Syngenta Andrew Plant gives an overview of the articles in this issue, highlighting the breadth and depth of chemistry at Syngenta. This issue of Science Matters has chemistry as its theme, this being the International Year of Chemistry. No branch of science contributes more to the world in which we live than chemistry. It underpins all the key areas of life: food production, water purity, transport fuels, polymers and plastics, and healing drugs. Syngenta of course is concerned with the first of these and so it is fitting that this issue is devoted to chemistry.

The last century saw many milestone achievements for the chemical industry, which produced many of the wonderful materials we now take for granted. Just as important, it produced many other products we hear little about, but on which much of the world now depends for its food. The most complex molecular components of a living organism, such as an insect or a fungal pathogen, are proteins. Find a simple chemical which

Science Matters Keeping abreast of Syngenta R&D Winter 2011

will interfere with them by, for example, blocking an enzyme, and they can be rendered harmless. However, investigating a protein is a complex business but we have the Protein Science Group headed by Kathryn Brocklehurst focusing on producing and analyzing proteins, and within the group there is also the X-ray crystallographic unit headed by Daniel Kloer. This can reveal the three-dimensional structure of a protein, providing valuable information

“Chemistry is key in agribusiness and therefore also at the heart of Syngenta. In this issue we would like to feature the breadth and depth of chemistry at Syngenta and the great scientists behind it.” for the design of new crop protection chemicals. Working alongside and in close cooperation with Daniel are computational chemists like Russell Viner and Torsten Luksch whose skills make it possible to simulate what happens when an active ingredient interacts with its target protein. Inspiring new ideas So where exactly do the ideas for a new crop protection chemical come from? Sometimes the inspiration is nature itself, and the awesome range of chemicals that it produces to protect plants and animals against predators and parasites. However, not all natural products point the way to a commercial product, even when improved by chemical modification, as you will find when you read John Clough’s views on the subject. Of course there are sophistications of molecular structure that appear to be mainly of academic interest, such as chirality, but this particular subject has significant implications for many crop protection agents. I’ve taken it upon myself to explain what chirality means, why it is important, and how chemists meet the challenges and exploit the opportunities this phenomenon brings. In their article Torquil Fraser and Kim Travis talk about the link between physical properties and product registration. They explain why this branch of chemistry is vital when it comes to assessing an active ingredient like isopyrazam (IZM) prior to its selection for development.

Meeting stringent requirements A new crop protection chemical must meet stringent regulatory requirements for human and environmental safety. Our company has some excellent scientists whose work helps to ensure that Syngenta’s new products are cost effective and safe. If you’ve ever wondered how that is achieved, then read the piece about the special techniques that Richard Peffer and the teams in Greensboro and Jealott’s Hill have at their disposal. One article is dedicated to our new fungicide IZM. Its invention, scale-up and production required some state-of-the-art synthetic chemistry as described by Harald Walter. Another success that involves chemistry is Formula M, aka Celest®, which is a seed treatment that solved two problems, namely seeds sticking together, which makes bagging and spreading difficult, and the release of dust from the seed coating. Not only has the research at Muenchwilen, Switzerland solved these problems but Syngenta’s new seed coating offers even more benefits, as Stefan Baum reveals.

Also in Goa is the remarkable Research and Technology Centre, a key site for new active ingredient invention, process research and development chemistry and Syngenta’s only Kilolab; this is a particular source of pride for Kikkeri Divakar, and we carry a profile of Divakar (as he prefers to be called). The future of chemistry Finally, since this is the International Year of Chemistry, we have invited the president of the Royal Society of Chemistry, Professor David Phillips, to tell us how he sees the state of chemistry and its future.

Andrew Plant Head of Chemistry Crop Protection R&D Stein Switzerland

Andrew obtained his BSc and PhD in chemistry at the University of Liverpool before embarking on

Going green at Goa Green chemistry has to be the future of our industry. We have got a report from the Syngenta plant at Santa Monica in Goa, India, which shows what can be achieved. The team developed a new, much “greener” production process for our insecticide thiamethoxam (TMX) with much less potentially dangerous chemicals used, less waste and major cost savings.

postdoctoral research at the Technical University (RWTH) in Aachen, Germany. He then joined Bayer AG in 1991 where he held scientific and managerial posts, before moving to Syngenta in 2001 where he is now Head of Chemistry, Crop Protection R&D, and based in Stein, Switzerland. Outside work Andrew likes to relax by reading, listening to music and hiking (preferably from pub-to-pub!).

Contact: andrew.plant@syngenta.com

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Uncovering the secrets of proteins Proteins are essential to life, they are coded by DNA and are important in all aspects of agricultural research from plant breeding to chemical design. Kathryn Brocklehurst, the leader of the Protein Science Group at Jealottâ&#x20AC;&#x2122;s Hill, explains how novel science is being employed to uncover the secrets of Natureâ&#x20AC;&#x2122;s chemistry.

Science Matters Keeping abreast of Syngenta R&D Winter 2011

“Molecular biology tools are often the starting point to working with proteins.” The Protein Science Group consists of 25 scientists covering the areas of molecular biology, protein production, crystallography, and protein analysis and is part of Crop Protection R&D Chemistry. Its members work with researchers across all areas of Syngenta including Crop Protection, Seeds, and Lawn & Garden. They have close contact not only with colleagues at Jealott’s Hill in the UK, but also at Stein in Switzerland, Research Triangle Park (RTP) in the USA and other sites. Indeed, wherever high quality protein or protein analysis is needed they are involved. Kathryn: “Proteins link different aspects of Syngenta’s businesses. For example, crop protection products usually work by binding to a specific protein. Being able to identify, analyze, and produce this protein is therefore essential. The group routinely provides purified target proteins for the biochemists in Biological Sciences so they can generate intrinsic activity data to help guide the design of new compounds.” Proteins are also produced for crystallographic studies. Understanding the interactions between an active chemical and a protein enables rational design of new systems, an example being ACCase, which is a herbicide target. Over the last few years the group has successfully expressed and purified ACCase protein. This is now used in biochemical assays and to generate protein-ligand x-ray structures, data from which are currently used to guide chemical design. Proteins as active ingredients In biotechnology products, such as engineered seeds, the protein is the active ingredient, and it is expressed directly in the crop, for example, amylase in Enogen™, or Vip3A in Agrisure Viptera™. The Protein Science group supports the development of products such as these through analysis of the protein produced by the transgenic plant, and also by large scale production of protein that is identical to that made within the plant. Usually it is necessary to make this in

an alternative system, such as in E.coli, but in some instances it is possible to extract sufficient quantities of the active protein directly from the plant. This protein is required for many product safety studies, sometimes in amounts as large as 100g. Over the last decade there has been rapid progress in technologies such as gene synthesis and DNA sequencing which have revolutionized this area. By using gene synthesis it is now possible to express more genes and to do it more efficiently. This also provides the opportunity to optimize the DNA sequence so it matches that of the organism we are producing it in. This technique is called codon optimization and it results in improved expression of the protein. It also enables more rapid production of multiple variations of the proteins in order to screen for altered protein/enzyme characteristics. Kathryn: “Advances in gene sequencing now allow us to rapidly sequence the genome of whole organisms giving an insight into metabolic pathways and enabling metabolic pathway engineering. There are many examples of how organisms have been genetically modified to produce chemicals of interest. A particularly noteworthy one from the company Amyris, is the creation of microbial strains that produce the precursors for the antimalarial drug artemisinin.”

Protein Science has various tools at its disposal Molecular biology The group uses many DNA techniques including generation of expression constructs for a wide range of different host systems and polymerase chain reaction methodologies. Fermentation There are excellent fermentation facilities for growing biomass used for recombinant protein production, native protein production, production of fungal strains for biochemistry and biotransformation for production of metabolites. Protein expression and purification There is a dedicated in-house protein production facility, producing high quality proteins from 10 mgs to more than 100 g. Proteins are produced from a broad spectrum of sources (plant, insect, yeast, microbial, fungal, engineered etc), in a wide range of expression hosts (including E.coli and yeast). Protein crystallography See page 16 for an article about the work that this section undertakes. Protein analysis Providing analyses ranging from detailed characterization of expressed proteins to quantitative, targeted and large scale proteomics using a combination of biochemical and mass spectroscopy techniques.

Members of Protein Science are also working alongside their synthetic chemistry colleagues and with external collaborators, to see if they can identify biological routes to producing some of our chemical active ingredients, particularly in the natural products area. Proudly supporting others Kathryn is justifiably proud of the way that Protein Science supports others in the company. “We have recently established the Global Protein Network along with our colleagues at RTP, the aim of which is to connect protein producers and end-users across the whole of Syngenta R&D. We hope to increase synergy through sharing of scientific knowledge in order to meet current and future protein related needs and challenges.”

Kathryn Brocklehurst Group Leader Protein Science Group Jealott’s Hill UK

Kathryn studied biological sciences at the University of Birmingham, then did her PhD in molecular biology, followed by four years post-doc at Cardiff University studying the regulation of Zn(II) transport in E. coli. She joined Syngenta in 2000 in Traits Research where she worked on several projects before moving into Bioscience in 2004 as molecular biology team leader in the Protein Science group. Kathryn became group leader in 2007.

Contact: kathryn.brocklehurst@syngenta.com

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Following the nature trail to new products Nature can be a great source of inspiration for our chemists. John Clough, the leader of Syngenta’s Natural Products Team dedicated to finding new crop protection chemicals, is convinced about that. The global market for crop protection chemicals is enormous with annual sales of about $38 billion. Herbicides account for almost half of these sales while fungicides and insecticides account for around a quarter each. However, the work that lies behind developing a new crop protection product is equally huge. John: “A crop protection chemical needs to have potent and selective activity. Moreover, it needs to have physical properties that allow it to reach the enzyme or receptor at which it acts. It must be chemically and metabolically stable so it will survive in sunlight on a leaf surface and then within the target organism, but it must not be so stable that it persists in the environment. And finally it must be cost-effective.”

Providing inspiration Natural products (NPs) can provide the inspiration for new and highly profitable crop protection chemicals. A good example is Syngenta’s fungicide azoxystrobin, launched in 1996, which now has annual sales exceeding US $1 billion. The NPs that inspired it originate from a family of fungi, but they lack potency and appropriate physical properties for a foliar-applied fungicide, so many hundreds of synthetic analogues were prepared in a program that culminated in the discovery of azoxystrobin. Now the scientists in Syngenta are striving to repeat this success – see box. There are lots of issues to be addressed. For example, which structural features of a NP are essential for its activity? Can its structure be simplified and its potency increased?

For a NP to be a useful starting point for synthesis, it should have an appropriate degree of structural complexity and typically should not contain groups associated with reactivity or toxicity, such as phenols and quinones. John: “Syngenta has a collection of assays representing most of the known herbicide, fungicide and insecticide modes of action, and by testing a new NP against these enzymes, we can see whether it has a known or novel mode of action.” A good example of a semi-synthetic compound is Syngenta’s insecticide emamectin, prepared by chemical modification of the NP abamectin which, in turn, is obtained by fermentation of the bacterium Streptomyces avermitilis. Emamectin is a highly potent insecticide, used at rates as low as 5-25 g/ha,

“Natural Products with new modes of action are especially attractive because they lead to resistance-breaking products.”

Major products including azoxystrobin owe their inspiration to nature

Science Matters Keeping abreast of Syngenta R&D Winter 2011

Natural products as leads for novel crop protection chemicals

Pseudomonic Acid A

Stemofoline

Mesotrione

The herbicidal pseudomonic acids Pseudomonic acid A is a major metabolite of the bacterium Pseudomonas fluorescens. Hydrolysis gives monic acid A, which can then be converted into a variety of semi-synthetic esters and amides, many of which were found to be herbicidal, the result of inhibition of isoleucyl-tRNA synthetase (ITRS) in plants. The 2-(vinyloxy)ethyl ester is particularly active, and was taken forward into extensive field trials in cereals. It gave good control of several important weeds at rates of 25-50 g/ha, but its performance was variable and it was not commercialized. Importantly, this research validated ITRS as a herbicide target for the first time.

The insecticidal stemofolines Stemofoline is an insecticidal alkaloid produced in the plant Stemona japonica. It has a good spectrum of activity, with rapid action, and is a potent agonist of the nicotinic acetylcholine receptor in insects. The downside is its highly complex polycyclic structure which poses a challenge for the synthetic chemist. A breakthrough came with the recognition of a tropane substructure embedded within the molecular framework of stemofoline. During the exploration of various tropanes, a series of highly active cyanotropanes was discovered with high potency against aphids and whitefly and rapid action both by contact and stomach routes.

and it is this that justifies its relatively high production costs.

tell which might be developed into high quality lead projects”.

An almost limitless supply There is an almost limitless supply of different strains of micro-organisms. Extracts of their fermentation broths can be tested for activity against a variety of plants, fungi and insects. But the approach has its disadvantages. For example, re-discovery of known compounds is common, so efficient early ‘de-replication’ of active extracts, based on a large proprietary database of known NPs, is essential.

External collaborations Syngenta collaborates with external partners who have expertise in NPs such as the Hubei Biopesticide Engineering Research Centre (HBERC) and the Central China Normal University (CCNU), both in Wuhan, China. Scientists at HBERC are isolating novel NPs from micro-organisms, while chemists at CCNU are doing early exploratory synthesis based on the best of the leads arising at HBERC, projects that could be followed up in-house if they show promise.

The herbicide mesotrione Mesotrione is related to the NP leptospermone, produced by the red bottle-brush plant, Callistemon citrinus. Leptospermone is only a moderately active herbicide, which gives bleaching symptomology when applied to plants, because it inhibits the enzyme hydroxyphenylpyruvate dioxygenase (HPPD). Mesotrione is an important post-emergence maize-selective herbicide. It contains the triketone toxophore found in leptospermone and also acts by the inhibition of HPPD in plants. It is weakly acidic and water-soluble, ideal properties for uptake and movement in plants.

John Clough Syngenta Fellow & Group Leader

One feature of a discovery program is that the NPs found often have only weak activity and it is difficult to pick out those with the potential to become commercial products. John: “Only by synthesizing and testing carefully designed analogues can we

John: “In the future, we expect to do more NPs research by understanding and exploiting the genetics of micro-organisms.”

Natural Products Team Jealott’s Hill UK

John obtained his PhD in organic chemistry at the University of Nottingham. He is a Syngenta Fellow and Group Leader and a member of the Leadership Team in the Chemistry Department at Jealott’s Hill. Most of the chemists in his group are engaged in synthesis directed towards the discovery of novel herbicides. In addition, he leads a team working on the isolation and structural elucidation of bioactive NPs. Outside work, John likes natural history, walking, cycling, gardening, photography and classical music.

Contact: john.clough@syngenta.com

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Getting the chemistry just right, or sometimes just left! The benefits of chiral molecules require Syngenta chemists to remain at the forefront of technology developments to produce them. Andrew Plant explains. Nature produces chiral molecules in abundance, among which are DNA, amino acids, and carbohydrates. Chirality, derived from the Greek word cheir, meaning hand can be exemplified in everyday life by a pair of gloves (or your hands), which are nonsuperimposable mirror images, otherwise known as enantiomers.

When a molecule docks on to an enzyme or receptor it interacts with a chiral environment composed of amino acids. The response which one molecule can trigger may be very different from that of its mirror image. For example, the (R)-enantiomer of the natural oil carvone smells of spearmint while the (S)-enantiomer smells of caraway. (The R and S notation is derived from the Latin words rectus, meaning right, and sinister, meaning left.)

Andrew: â&#x20AC;&#x153;In many cases the development of modern agrochemicals is accompanied by an increase in molecular complexity. This can include the presence of one or more stereo-chemical centres, giving rise to a number of possible stereo-isomers. Frequently only one of these exhibits the desired biological effect, or at least is significantly more active than the other possible stereoisomers. The rest can often be considered as environmental ballastâ&#x20AC;?.

Your hands are an example of chirality, which occurs in abundance in nature

Science Matters Keeping abreast of Syngenta R&D Winter 2011

Only in a few cases are agrochemicals produced in enantiomerically enriched forms (meaning one isomer is produced in excess over the other). About a third of currently registered pesticides are chiral, but only about 5% of these are manufactured in an enantio-enriched form; the rest are produced as mixtures of stereoisomers. Today, spurred on by the regulatory agencies, the pressure is on manufacturers to produce only (or predominantly) the enantiomer (or stereoisomer) demonstrating a beneficial effect. Andrew: ”Synthesizing compounds enantio-selectively is usually associated with increased costs compared to the isomer mixture, but Syngenta chemists have a good track record of stepping up to the mark and developing methodologies to produce enantioenriched molecules cost-effectively. As long as the cost of a single enantiomer is less than twice the cost of the mixture (or racemate), there is an economic benefit, and a reduced environmental load with potentially fewer off-target toxicity effects”.

“The age of chemical synthesis is far from over – it’s just getting closer to other disciplines such as biology and engineering.” For example, the maize herbicide metolachlor has two chiral elements: a chiral axis and a stereogenic centre leading to four possible stereoisomers. The herbicidal activity resides almost exclusively in the (S)-enantiomers and an enantio-enriched version of this active ingredient is a key component in Syngenta’s Dual product range. In terms of volume, (S)-metolachlor presently constitutes the largest production process of any kind that applies an asymmetric reaction, with an annual capacity measured in tens of thousands of tonnes, a remarkable technical achievement (see box).

Industrial asymmetric hydrogenation for the production of S-Metolachlor

To retain our capability to invent safe and cost-effective products to meet grower needs, Syngenta needs to keep abreast of new technological developments and capitalize on these in the synthesis of new active ingredients. Andrew: “As well as chemical catalysts, biocatalysts such as enzymes and whole organisms have been used in our industry. Fermentation is an example, and is a part of the production process leading to the insecticides abamectin and emamectin.” A dynamic area The field of catalysis is a dynamic one and Syngenta now has a ‘catalyst network’ charged with keeping tabs on new developments (see Snippets section). There are some exciting prospects emerging, including the production of chemicals by metabolic engineering, transplanting enzymatic pathways into other organisms and harnessing the power of nature to produce new molecules in a manner not technically feasible or cost-effective by conventional techniques.

Andrew Plant Head of Chemistry Crop Protection R&D Stein Switzerland

Asymmetric catalysis is the answer Asymmetric catalysis involves the efficient conversion of a non-chiral compound to a chiral one with the predominance of one enantiomer over the other. Syngenta has used this technology to manufacture two of its key active ingredients, the enantio-enriched fungicide (R)-metalaxyl (Ridomil® MZ) and the herbicide (S)-Metolachlor (Dual Magnum®).

This chemical reaction is known as catalytic asymmetric hydrogenation and it required the development of new catalysts and processes, through a deep understanding of the underlying chemical transformation. The efficiency obtained in the synthesis of (S)-metolachlor is remarkable. One single molecule of catalyst has the ability to generate more than one million product molecules, approaching the performance levels of biological catalysis by enzymes.

Andrew obtained his BSc and PhD in chemistry at the University of Liverpool before embarking on postdoctoral research at the Technical University (RWTH) in Aachen, Germany. He then joined Bayer AG in 1991 where he held scientific and managerial posts, before moving to Syngenta in 2001 where he is now Head of Chemistry, Crop Protection R&D, and based in Stein, Switzerland. Outside work Andrew likes to relax by reading, listening to music and hiking (preferably from pub-to-pub!).

Contact: andrew.plant@syngenta.com

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The testing of physical and chemical properties of an active ingredient are essential to determine whether a product can be registered

Getting the properties right – physical chemistry and product registration A new crop protection product has to pass stringent regulatory requirements before it can be marketed. Part of those requirements are its physical chemistry properties, as described by Torquil Fraser and Kim Travis. As well as proving that a product will do what it claims, it is necessary to show that it is safe for humans and the environment and that’s when toxicologists and physical chemists become key witnesses. Stringent regulations ensure that this will happen. In addition, the regulatory authorities sometimes ask for additional testing, invoking the so-called ‘precautionary principle’ as a justification. This increases the pressure on existing products and raises the barriers over which new products must struggle. But why is physical chemistry so important for registration? Torquil: “The physical properties of an active ingredient combine with other factors such as chemical stability, to define how it gets to where it is needed. Equally, they determine where else it might go in the environment, and how

it behaves in non-target organisms, ranging from earthworms to humans.” An example of the importance of physical chemistry is in limiting the transport of active ingredients to ground and surface water. Lipophilic chemicals (see box) can bind to organic matter in soil and be slow to move through this medium, thereby allowing time for them to degrade and avoid contaminating water sources. On the other hand, some active ingredients need to be able to move through the soil if they are to do their job. This applies particularly to preemergence herbicides or to fungicides and insecticides that are given the task of protecting crop root systems. Other molecular properties can be every bit as important as lipophilicity in determining whether a product will be registered, and the challenge is

Science Matters Keeping abreast of Syngenta R&D Winter 2011

always to get the balance right. Active ingredient volatility can improve the effectiveness of many compounds, but release of vapor to the atmosphere must be carefully controlled, or it must persist for only a short time. Photostability limits the persistence of many active ingredients and while this is often a problem it can be beneficial if the photoproducts are environmentally benign. Torquil: “In recent years attention has been focused on rational design of bioactive molecules, making reality what was once just a dream. This is achieved through increased understanding of molecular targets, advances in molecular biology and technologies such as enzyme crystallography and computational chemistry. When we design a new molecule, we need to pay a lot of attention to the properties and interactions which affect its toxicology and environmental fate.”

Lipophilicity Lipophilicity describes the tendency of a molecule to prefer a lipid environment such as an oil, fat, wax or even an organic liquid. It is the opposite of hydrophilicity which relates to materials that prefer an aqueous environment. Lipophilicity can dominate the behavior of active ingredients in complex biosystems. Lipophilicity can be modeled by descriptors such as Kow, which is the partition coefficient between 1-octanol and water. The higher this is, the more a compound prefers the organic phase. The lipophilic/hydrophilic balance of an active ingredient affects important processes. For example, it determines movement through barriers into target organisms, as

in the case of penetrating leaf waxes. It is relevant to its mobility in xylem and phloem which are the two types of tissue that distribute water and nutrients around plants. Kim: “Lipophilicity is important when observing the interaction of the active ingredient with target enzymes, and in determining how it moves in soil through interaction with soil organic matter, and of course it affects its bioaccumulation in non-target organisms.” While Kow is a ‘whole-molecule’ property, it can also be treated as a sum of various parts. Most bioactive molecules consist of lipophilic and hydrophilic regions, and logKow can be can be calculated as a sum of these different parts, making it an important parameter in chemical design. Quantitative structure-activity

relationships (QSAR) can define the optimal range of logKow values for a chemical series, and calculation during the design process can ensure that new analogues have the desired properties. Syngenta’s fungicides isopyrazam and sedaxane nicely illustrate the importance of lipophilicity. Isopyrazam’s value of 4.4 allows it to partition into leaf waxes, and subsequently into fungi, there to target the succinate dehydrogenase enzyme. The value for sedaxane is 3.3, giving it more freedom to move in hydrophilic environments, so it can be used in seed applications and move better from soil to plant. These two molecules are very similar in structure, and the logKow difference arises from just one lipophilic section of the molecule.

Torquil Fraser

In France where does the rainfall go: ground-water or surface-water?

Syngenta Fellow Chemistry Department Jealott’s Hill UK

Torquil obtained his degree in Chemistry at Edinburgh University in 1977 and shortly afterwards joined ICI Agrochemicals at Jealott’s Hill. He has influenced the chemical design of many projects using his wide knowledge of physical chemistry. Torquil is also a Syngenta Fellow in the Chemistry Department at Jealott’s Hill.

Contact: torquil.fraser@syngenta.com

Kim Travis Syngenta Fellow Product Safety Jealott’s Hill UK

Kim obtained his first degree in Applied Biology at Cambridge University and stayed to do an MSc by research in crop biometry with Bill Ridgman. After working for Rothamsted Research he joined Syngenta in 1988 as an environmental fate modeller. Physicochemical properties affect the potential movement of pesticides to ground- and surface-water. The map shows where rainwater goes mainly to groundwater (reds) or to rivers (green)

Today he is a Syngenta Fellow in Product Safety. Outside work, Kim likes running, cycling and golf.

Contact: kim.travis@syngenta.com

Science Matters Keeping abreast of Syngenta R&D Winter 2011

Surveying the field of toxicology When it comes to assessing the safety of a crop protection chemical then it falls to Syngentaâ&#x20AC;&#x2122;s toxicologists at Greensboro and Jealottâ&#x20AC;&#x2122;s Hill to investigate. Richard Peffer explains how, even in the case of water, it is the dose that makes the poison.

Science Matters Keeping abreast of Syngenta R&D Winter 2011

Richard: “Many different aspects of chemistry are employed in the practice of toxicology. As one example, we utilize analytical chemistry to be certain that the concentration of the test item in the dose vehicle is accurate and homogenous. Only then can we be certain that our studies are well founded.” In an ideal world a crop protection chemical will destroy only the target organism and have no effect whatsoever on any other living being. As this is never entirely the case in the real world, companies like Syngenta have to prove that their crop protection products don’t harm species other than the targeted pest, especially not humans. This requires the skills of toxicologists. It is their job to assess the effects of agricultural chemicals, primarily to establish levels of use that are safe. Richard: “As toxicologists we are aware of the dictum of Paracelsus (1493–1541) who said that it is the dose which makes the poison. In other words every substance can have adverse effects on living systems at some level.” Of course readers may be saying to themselves that this dictum does not apply to water, but in fact it does, as witness the bizarre death of 28-year-old Jennifer Strange in January 2007. She took part in a contest at a California radio station to see who could drink the most water. She drank more than 240 fluid oz of water (7 litres) before passing out and dying the next day.

Baseline toxicology studies of an agricultural chemical in various species are required by regulatory authorities in every region where Syngenta seeks to sell its products. Such studies investigate effects on reproduction, fetal development, carcinogenicity, neurotoxicity, and general toxic effects after short-term to lifetime exposure. For each study, a NOAEL is established based on a dose that produced no differences between treated animals and an untreated control group. Higher doses produce adverse effects, which may include lower body weights or microscopic changes in certain organs, and from this it is possible to determine a ‘Lowest Observed Adverse Effect Level’ (aka LOAEL). The type and severity of effects that are produced, as well as the dose level that causes them, are weighed by regulators in determining whether a product can be registered for use.

Richard Peffer Senior Toxicologist

1. Structure-activity relationships can be approached using the DEREK software (Deductive Estimation of Risk from Existing Knowledge). With this it is possible to predict the toxicology of a new metabolite based on its structure and chemical components. DEREK can predict if a substance will be a skin sensitizer, whether it is likely to be mutagenic or carcinogenic, or if it has other potential toxicities. 2. Clinical chemistry measurements will reveal how a substance affects the body. They rely on biochemical markers, namely endogenous compounds in the blood which change in concentration. For example if alanine aminotransferase levels increase in plasma then this is a likely sign of liver damage, causing leakage of this enzyme out of damaged cells. Another indicator of potential toxicity is increasing levels of creatinine and blood urea nitrogen, which are signs of kidney damage. A compromised kidney cannot clear these chemicals into the urine out of the blood with normal efficiency. 3. Biochemistry measurements are employed when delving deeper into a substance’s Mode of Action for toxic effects. For example, a toxicologist may measure enzyme activities within a tissue of interest. Various cytochrome P450 (CYP) enzymes exist in the liver, and the pattern of those whose activity increases when a new substance is administered can reveal which class of liver toxicant it is.

Toxicology & Health Sciences group Greensboro USA

Establishing NOAELs Assessing the dose which makes a particular substance a poison, and what types of effects it produces, allows a toxicologist to establish a ‘No Observed Adverse Effect Level’ (aka NOAEL). The science of risk assessment then uses this NOAEL value to establish a hazard endpoint that is the maximum amount to which a human can be exposed with a reasonable certainty of them coming to no harm.

The chemical tools of today’s toxicologists

Richard has a PhD in toxicology and pharmacology from the University of Pittsburgh. He is a Senior Toxicologist in Syngenta’s Toxicology & Health Sciences group at Greensboro, North Carolina, and has explored and published the toxicological Mode of Action for numerous Syngenta products.

4. Metabolomics is a new technique which uses mass spectrometry or NMR spectroscopy to observe a wide range of biochemicals in control samples and treated samples, looking to see changes in biochemical substances in blood and urine. Hundreds of endogenous substances can be tracked at the same time, and reveal metabolic pathways affected by a foreign substance.

Contact: richard.peffer@syngenta.com

Science Matters Keeping abreast of Syngenta R&D Winter 2011

Crystal gazing in theory and practice Daniel Kloer is an X-ray crystallographer, while Russell Viner and Torsten Luksch are two computational chemists. It falls to them (and others) to reveal exactly how a crop protection molecule targets a protein and to suggest other chemicals which might work.

The image shows the IZM molecule bound to a specific target

Science Matters Keeping abreast of Syngenta R&D Winter 2011

An agrochemical is similar to a pharmaceutical drug in that it will bind to a specific protein target and thereby interfere with its essential function. In the case of crop protection chemicals it does this in order to kill some unwanted invader such as a weed, insect pest, or fungal pathogen. To succeed in its attack, the molecule (or ligand) needs to have the right three dimensional shape to bind to the protein target and, ultimately, kill the pest. There is another way of gaining an insight into the mechanism of interaction and that is by means of computer-aided design methods like homology modeling and ligand ‘docking’. Homology modeling builds a model of the protein target using the three dimensional structure of equivalent proteins from other species. These structures are often available in online databases because crystallographers must also publish the coordinates of their proteins when they publish their work in scientific journals. Ligand docking is a computational method which tries to fit a molecule into a protein target cavity in such a way that attractive interactions are maximized, and repulsive interactions minimized. While this may not have the finesse of crystallography it is nevertheless a valid research tool. What it lacks in exactness it compensates for by enabling a high throughput of ligand/target information. An understanding of the three dimensional shape of the target cavity, and the molecular features required to bind into it, allows the computational chemists to construct a pharmacophore – a set of three-dimensional

X-ray crystallography has brought new insights to how crop protection chemicals bind to proteins at the molecular level. This information is not always easy to obtain. requirements that must be satisfied by a new crop protection molecule with this mode of action. The kinds of feature that are of interest in pharmacophore modeling are aromatic rings, hydrogen bonds, polarity, cationic and anionic centers, and hydrophobicity (i.e. water repellency). Armed with this pharmacophore, vast databases of real or potential new molecules can be searched to find those that might also inhibit the target protein. Typically, Russell and Torsten will have a specific question to answer about how a molecule binds to the active site of a protein – most of the time, computational methods such as docking will give them a good idea of what the interaction looks like and they don’t need a new crystal structure. New impetus from insights In some cases the binding mode is hard to predict and an experimental structure is required. It is then up to Daniel to crystallize the protein together with the ligand, solve the structure by singlecrystal x-ray analysis, and then report the results back to the modelers – see box. Insights from the crystal structure will often give new impetus to synthesis. If exactly the same result is obtained as predicted by modeling, then the modelers know the methods they use are sound.

Protein crystallography This uses single crystals and X-ray radiation to determine protein and protein-ligand structures and multiprotein complexes in their native conformation. It is by far the most important way of delivering such structural information but far from routine because proteins are notorious for not forming the crystals essential for X-ray analysis. Nevertheless it can be done with care, and crystals as tiny as 50 microns are suitable for study. Once obtained, they are suspended in glycerol to protect the protein and subjected to the X-ray generator at Jealott’s Hill. Obtaining a successful X-ray crystallographic image starts with the production of a pure sample of material. Crystallization itself involves the screening of usually thousands of conditions, varying such parameters as crystallization method, temperature, buffers, salts, and alcohols, before a successful combination might be found – and even when the crystal looks perfect it might be of no use due to internal disorder. However, once well-diffracting crystals have been grown, it may take as little as five minutes to collect data and only a few days to produce a structure.

Daniel Kloer

Russell Viner

Torsten Luksch

Protein

Senior Consultant

Computational

crystallographer

Chemistry Design

Chemist

Jealott’s Hill

Stein

Switzerland

Daniel obtained his PhD in Chemistry from Freiburg,

Russell did his PhD in computational chemistry at

Torsten did his PhD in computational chemistry at

Germany. After a postdoc at the National Institutes

Bath. He joined Syngenta legacy company ICI in

Marburg University, Germany, following which he

of Health, USA, he joined Syngenta in 2010 as a

1989. He is now a senior consultant in Chemistry

worked at the Drug Discovery Unit at Dundee

protein crystallographer. He is based at Jealott’s Hill

Design based at Jealott’s Hill and his speciality is

University, Scotland. He joined Syngenta in 2009

where he now leads the X-ray crystallography

the modeling of herbicides.

and is based at Stein. His specialty is data analysis

section as part of the Protein Science group.

Contact: daniel.kloer@syngenta.com

and the modeling of fungicides and insecticides.

Contact: russell.viner@syngenta.com

Contact: torsten.luksch@syngenta.com

Science Matters Keeping abreast of Syngenta R&D Winter 2011

IZM: via Idealizm, Realizm, Optimizm, and Isomerizm Isopyrazam (IZM) has a new mode of action and is the first active ingredient from Syngenta’s pipeline of next generation fungicides. The invention, scale-up and production of IZM is a tribute to the creativity of Syngenta’s synthetic chemists, as Harald Walter explains.

Isopyrazam (IZM) is Syngenta’s newest foliar fungicide, launched last year under the label Bontima® in the UK for use in barley and as Seguris Flexi® in New Zealand. It delivers broad-spectrum fungicidal activity against major cereal diseases by inhibiting the succinate dehydrogenase enzyme. IZM demonstrates excellent efficacy at a rate of only 125 grams per hectare on cereals, with long lasting activity against two fungi which afflict these crops, namely Septoria tritici which causes leaf blotch and Puccinia recondita which causes leaf rust. IZM can also be used against leaf spots and powdery mildews in fruits and vegetables. Harald: “A great deal of research lies behind this product, not only in constructing the IZM molecule in the laboratory (first accomplished by Hans Tobler, now retired). An equally big challenge was to find a way of manufacturing it on a large scale, but we managed to develop a successful process protected by many patents.”

The chemistry of IZM synthesis IZM contains a unique structural feature, the benzonorbornene ring system, a three-dimensional molecular architecture hitherto not found in commercial succinate dehydrogenase inhibitors (SDHIs), or indeed in any commercial agrochemical. The design employed in the conception of IZM required a detailed understanding of the structure-activity relationships within the broader pyrazole carboxamide chemical class. For that, a thorough search in the patent literature was undertaken, to which a good dose of chemical inspiration was added. IZM has a unique chemical structure for which several innovative synthetic routes have been developed involving the following key steps: (i) Unprecedented [4+2] cycloaddition of benzynes with dimethylfulvene to afford the benzonorbornene architecture. (ii) Selective Pd-catalysed hydrogenation to afford predominantly the syn-isomer. (iii) Pd-catalysed Buchwald-Hartwig amination.

Science Matters Keeping abreast of Syngenta R&D Winter 2011

The key benzonorbornene ring system is produced from the unprecedented reaction of a highly energetic benzyne with dimethyfulvene (step 1). This reaction has to be carefully controlled in order to produce high yields of the desired product and is very challenging on a manufacturing scale. The benzyne intermediate is generated from bromo-dichlorobenzene on treatment with a Grignard reagent and trapped in situ with the cyclic diene (prepared from reaction of cyclopentadiene with acetone). Step (2) involves an amination with benzylamine under palladium catalysis. Step (3) also employs palladium catalysis, this time to effect hydrogenation of three different functional groups in a one-pot reaction. These are deprotecting the amine functionality, reducing the endocyclic carbon-carbon double bond and, very importantly, reducing the exocyclic carbon-carbon double bond in a highly selective fashion to afford predominantly the syn-isomer, in a highly selective fashion to afford predominantly the syn isomer (syn/anti ratio ca. 9:1).

IZM protects cereals from major diseases leading to cleaner crops for growers

An alternative sequence was developed whereby palladium-catalysed amination with ammonia was accomplished. This had the advantage of eliminating the need for an amine protecting group, but required an additional step as the carbon-carbon double bonds had to be reduced first.

Acylation of the aniline with the requisite pyrazole acid chloride affords IZM in very good overall yield. The pyrazole acid chloride was prepared in six steps from dichloroacetyl chloride. A highly efficient route This synthetic route is highly efficient and has overcome some significant

challenges on scale-up, both in terms of technical feasibility and achieving the required costing. In addition to intellectual property generated for the active ingredient, several patent applications have been filed based on the process chemistry developed in bringing IZM to market.

Harald Walter

A reaction scheme for the synthesis of IZM

Research Portfolio Manager for Fungicides and New Technologies

Harald obtained his first degree in chemistry and mathematics at T端bingen University and then went on to do a PhD in chemistry. After working for Ciba and Novartis, he joined Syngenta in 2000 as a senior project leader. Today he is Research Portfolio Manager for Fungicides and New Technologies in the Global R&D Portfolio Organization. He is also a Syngenta Fellow. Outside work, Harald likes good Italian wines and going to the mountains.

Contact: herald.walter@syngenta.com

Science Matters Keeping abreast of Syngenta R&D Winter 2011

Formula M races ahead When it comes to innovation in cereal seed treatments, Syngentaâ&#x20AC;&#x2122;s Formula M offers clear advantages over other formulation technologies, as Stefan Baum explains.

The presence of water can slow things down in the use of seed treatments as well as in Formula One racing

Science Matters Keeping abreast of Syngenta R&D Winter 2011

The use of seed treatments for cereals ensures control of diseases and pests which cause damage during the early growing stage. However, things have changed in recent years. Crop seed treatments no longer use organic solvents, preferring instead more environmentally friendly water-based suspensions. The downside of these formulations is a reduced flow of the treated seeds through the treatment device including bagging and a poor distribution of the product on the seeds. In addition they can result in the release of dust during handling and sowing, which can affect operator safety, with potential losses of active ingredient to the environment. This so-called ‘dust-off’ is being legislated against in many countries. To address these issues, Syngenta now offers Formula M technology in several existing cereal brands like Celest®, Landor®, or Dividend®.

Stefan: “The initial target of Formula M technology was to overcome weaknesses in the water-based seed treatment formulations. An improved rate of bagging the seed after treatment, and easier cleaning of equipment, were just two real benefits. These have been confirmed at a number of German seed treatment facilities and in large scale tests.”

Celestial science

Treated seed was tested immediately after application to identify the impact of different formulation recipes on the flowability. In general water-based formulations show an increase of flowability over the full length of the test during the drying process of the seed coating. In addition to this general effect Formula M products, due to its lubricant effect, reach their final speed of flow much quicker with a 5-10% higher rate.

Syngenta’s goal was to find a product that was better than the water-based seed formulations which were introduced when organicsolvents were phased out. Moreover, it had to overcome the drawbacks of reduced seed flow and greater dust-off. A wide range of chemistries was tested using oils, polymers, surfactants, waxes, and carriers. The targets set were for there to be better coverage and appearance of the seeds, better flowability of the treated seeds so bagging time was quicker, improved adherence of the product to the seeds so there was less dust-off, and for there to be easier cleaning of the treating equipment. Formula M Technology meets all of them. Seed Flow solution A specific funnel with a pneumatic closable lid connected to a timer was used to measure the flow of treated seeds relative to untreated seeds. The seeds are placed in the funnel, the lid opens for a given time (e.g. 2 seconds at 20 second intervals) and the weight of seeds that flow out is measured.

Stefan Baum Group Leader Seed Care,

Reducing dust-off is another aim and seeds treated with Formula M based products show a much reduced dust-off during the treatment process, bagging, transportation and sowing. At the user stage Formula M technology offers yet another bonus. Stefan: “Formula M results in a more uniform seed distribution and it reduces the risk of single seeds being treated with too little or too much of the crop protection chemicals. The fact that Celest® treated seeds are colored an intense red reminds users that these are high quality and this boosts customer confidence.”

These tests showed that the research was on the right lines and this was confirmed by application tests at five commercial seed plants in Germany. Compared to competitor seed treatments, they reported an increase of seed treatment efficiency of 10 to 35% with an average of about 15%. For a treatment facility with a capacity of 12 tonnes per hour capacity this means the additional filling of 30 bags per hour, equivalent to one and a half pallets. Dust-off dimension There are various ways to measure the amount of dust associated with various processes. The one Syngenta uses is known as the Heubach dustmeter. The treated seeds are mechanically stressed in a rotating chamber for a given time which

Insecticides and Lawn & Garden Formulation Group Muenchwilen Switzerland Stefan obtained his first degree in chemistry (Diploma) and his PhD at the University of Giessen, Germany. He joined one of the predecessors of Syngenta in 1989 as formulation chemist. Currently he is leading the Seed Care, Insecticides and Lawn & Garden formulation group in Formulation Europe.

Contact: stefan.baum@syngenta.com

generates dust-off. The dust is carried out by a defined airflow and finally collected on a filter and weighed. Under the internally defined testing parameters, dust levels in wheat of Formula M treated seed are in the range of 0.5–1 g/100 kg seeds. This is a significant improvement over non-Formula M internal or competitor products which result in dust off values between 2–5g/100kg seeds or even higher. The reduced dust-off means practically all product remains on the seed, but equally important there is a lower risk of exposure for workers during the seed treatment process and bagging, but also users in the field when emptying bags into the driller. Formula M technology does not increase stickiness to the seed treatment equipment, or impact on its cleaning, because it adheres better to the seeds than to the machines. Personnel The researchers involved in developing the Formula M technology were Frédérique Guyon, René Bircher, Simon Leuenberger and their teams based at Münchwilen, Switzerland.

Science Matters Keeping abreast of Syngenta R&D Winter 2011

Members of the team who are going green in Goa through their invention of the ground breaking new production process

Making chemistry green Plants are green, emeralds are green, but have you ever thought about chemistry being green? The implementation of a ground breaking new production process at the Santa Monica plant in Goa, India, has proven that chemistry can indeed be green. The innovations in manufacture were recognized with a Syngenta Award for Health in 2008. Prashant Potnis explains the work behind making this happen and the progress made over the past three years. It has been recognized in recent years that the science of chemistry is a focal point for addressing the problems pertaining to the environment. As an industry leader, Syngenta takes its ethical, social, scientific and environmental responsibilities seriously. The development of a new, much “greener” production process for thiamethoxam (TMX) at our Santa Monica plant is a nice example of Syngenta’s commitment

for Green Chemistry and the global warming cause. Why were improvements needed? Syngenta Production and Supply has an important facility in Santa Monica, Goa – which is different but located very closely to the R&D Research & Technology Centre. In 2008 to meet the rising demand for the insecticide active ingredient TMX, the Santa Monica facility needed to increase the production of CCT (2-chloro-5

Science Matters Keeping abreast of Syngenta R&D Winter 2011

chloromethyl thiazole), which is a major intermediate in TMX production. However, this process used concentrated HCl (hydrochloric acid), producing large quantities of highly acidic organic and aqueous waste that occupied a large incineration capacity. A further challenge was that the HCl was only available from one supplier, which meant a high dependency on a single vendor and the consequent need to establish an assurance The orang-utan has become a symbol of of supply. in the forests of Indonesia conservation

The non-tangible benefits include both the logistics and the effect on the environment. Less transportation of chemicals means less fuel consumption, less risk of chemical hazards on the road and better utilization of storage facilities. Recognizing the gravity of the problem, two areas were explored to find an alternative to this production process. The first area was to establish a smooth thermal oxidizer operation and the second area was to work on an innovative solution to either reduce or eliminate the waste streams mainly responsible for adding to the thermal oxidizer capacities. At the laboratory scale The Technology & Engineering Process Chemistry Group at Santa Monica extensively researched how to best utilise the HCl remains in the reaction mass to hydrolyze the key bi-products. The aim was to use the remains instead of externally adding concentrated HCl and chlorinated solvent. The breakthrough alternative process for the CCT extraction was achieved by adding a small amount of de-mineralized water to generate in-situ concentrated HCl in the reaction mass by utilizing trapped HCl. This new process eliminated the concentrated HCl and chlorinated solvent additions and consequently, the waste generation. The next stage was to evaluate the proposed change for process safety. The local team started networking with the Process Hazards groups in Huddersfield, UK and MĂźnchwilen, Switzerland. Together, they delivered a protocol for safe plant production operating conditions. At the plant scale The new process was soon well established in the lab. However, commercialization to a large tonnage was a key challenge and trials were needed to make sure this could happen. It required a high level of co-ordination

and dedication from all employees at the facility. Additionally due to the high demand for TMX, it was impossible to cease production completely for the trials. This challenge was addressed by intense cross-functional interactions and experience sharing across site. Luckily, the Santa Monica facility has two TMX production plants, with one plant (TMX 2) already established. So it was decided to use this plant for the trials. The team worked around the clock on a rota basis to test 10 batch trials in two phases, without any loss in CCT production. The collected data was analyzed and the results validated. The TMX produced out of these batches was validated in all major formulations. The benefits There are many tangible and nontangible benefits associated with the new process. It has eliminated the use of concentrated HCl and reduced the quantity of chlorinated solvent, which means less handling of hazardous chemicals whilst reducing the chance of exposure. This also reduces the variable cost which needs to be evaluated once the process is stabilized. The new process gives energy savings, as it reduces the batch cycle time from 19 hours to 9 hours. This contribution has been key in light of increasing crude oil prices in recent times.

Switzerland. Throughout the continuous production, there have only been a few challenges in terms of waste storage and these are currently being addressed. The highlight, however, is that significant amounts of TMX have already been produced using the new greener chemistry. It is well validated in seed and crop protection applications across the globe. â&#x20AC;&#x153;This is a landmark achievement for the Santa Monica plant. It is not only a technology receiver, but also a technology contributor,â&#x20AC;? says Paul Gordon, Head of Technology and Engineering, Switzerland.

Prashant Potnis Head of Technology and Engineering (Production Technologies) Goa India

Prashant holds both a PhD in Organic Chemistry and a Bachelor of Law degree. He joined Syngenta

For the environment, there has been a reduced loading of the greenhouse gas, CO2, in terms of post incineration of gases.

in 2005, based at the Goa facility in India. He is now the Head of Technology and Engineering. Prashant has more than 15 years industrial research and development experience with companies such as BASF and Clariant in India.

Three years on Three years after its invention, the new process has been running commercially at the Goa facility and has also been implemented at the Monthey plant,

Prashant is married with two daughters and enjoys watching and playing cricket.

Contact: prashant.potnis@syngenta.com

Science Matters Keeping abreast of Syngenta R&D Winter 2011

Our best-in-class chemistry center in Goa The R&T Center in Goa is one of the three major Syngenta chemistry research centers and one of the company’s newest additions. Its director Dr Kikkeri Divakar, an accomplished chemist with a lifetime’s experience, talks about it.

Divakar: “We want to build a strong brand for ourselves through our contributions to Syngenta’s innovation.”

Divakar, as he prefers to be known, played a key role in setting up the Research and Technology (R&T) Center in Goa, on the South West coast of India. The project started in May 2005 and by June 2006 the center was up and running, which he says was a tribute to a remarkable team effort led by Robert Nyfeler (now retired). Thanks to support from Syngenta India, the team not only delivered the

Head of R&D Sandro Aruffo inaugurating the new Process Chemistry and Technology building at Goa in February 2010

Science Matters Keeping abreast of Syngenta R&D Winter 2011

project in time but also preserved the pristine natural environment around the site. This achievement was recognized by a Syngenta Intensity Award in 2007. Today, the Goa R&T Center is widely acknowledged in Syngenta – and in India – as a best-in-class institution. Chemistry is its backbone science and with the recent addition of Process Research, every chemistry-intensive activity of crop protection R&D is represented.

To create the right atmosphere for research, the center has a seminar program, a literature corner and hosts regular lectures by visiting speakers. There is a vibrant scientist exchange program between Syngenta’s major chemistry sites Goa, Stein and Jealott’s Hill; a unique PhD program for selected chemists is also in place. What has really made an impact at Goa is the Kilolab which, as its name implies, is the next step in producing a promising chemical by scaling it up. Kilolab teams have already delivered on some really tough projects, the most notable of which was their production of 50 kg of a single enantiomer. There will be more successes to come as the research chemists are making excellent progress, witness the 15 patents which have Goa scientists as co-authors. Field trials on compounds made in Goa are all indications of this. Researchers are particularly thrilled that one of the compounds they first synthesized has made it to the development stage.

Divakar: “We have some excellent chemists in leadership roles and great talent down the line. I believe we have the right people and culture to stimulate and encourage innovation.”

Above: Divakar holds up the Syngenta Awards Intensity trophy which was awarded to the team from Goa at the Global Finalist event Left: Divakar is pictured presenting the work of the Goa site at the Syngenta Awards global final

Divakar’s life in chemistry Divakar’s life-long career in chemistry started at Mysore University before going to do his PhD at the National Chemical Laboratory in Pune, India where he worked with some of the most well known chemists in India. After his PhD, Divakar moved to the UK to do a post-doc at King’s College, University of London, with Professor Colin Reese FRS, working on modified nucleosides supported by the UK Cancer Research Campaign. The research was focused on new approaches to leukemia. On his return to India in 1982, Divakar took a position as a medicinal chemist in the R&D section of Hindustan Ciba-Geigy where he worked on drug discovery. “Very similar to what we now do at the Goa Research & Technology Center” he says. The research was focused on agents to treat human filariasis, a parasitic disease.

By1994, Divakar was Senior Manager R&D of Ciba Specialty Chemicals India, still focused on specialty organic chemicals and cooperating with colleagues in Basel, Switzerland. In 1998 Divakar moved to become Vice-President of the R&D Chemicals Division of Indian Organic Chemicals of Mumbai (now Innovassynth Technologies). There he teamed up again with a Dr Yogesh Sanghvi who he’d known at NCL and at King’s College, and together they scaled up the process of triazolation-mediated conversion of U nucleosides to C nucleosides. This was a process which Divakar had developed while at King’s College, but which had never been done on such a scale before. Then in 2003 Divakar moved to become Vice-President R&D with Indofil Chemicals in Mumbai, focusing on crop protection chemicals. Finally he joined Syngenta in August 2005, where he says he found the atmosphere inspiring and

the enthusiasm of his young colleagues truly energizing. It’s to this wonderful combination that he attributes his achievements. Divakar is also a visiting professor at the Mangalore University and professor at the Institute of Chemical Technology in Mumbai. Outside of work Divakar is a keen follower of cricket, being a passionate supporter of the Indian cricket team. The current team is rebuilding after being number one in the world for many years, a baton passed to England in summer 2011, much to the delight of his English colleagues but not to the millions of Indian cricket fans, including Divakar! Divakar is married to to Suman, who is a trained vocalist in the North Indian musical tradition. Their son Nikhil has a PhD in IT and now works for Oracle in the US and is married to Priya, a Masters in Dentistry. As well as cricket, Divakar’s outside interests include Indian classical music, reading and tennis.

Contact: kikkeri.divakar@syngenta.com

Science Matters Keeping abreast of Syngenta R&D Winter 2011

Young people across the world were encouraged to measure water quality as part of the activities during the International Year of Chemistry

International Year of Chemistry 2011 In this ‘External Perspectives’ article the President of the Royal Society of Chemistry Professor David Phillips gives his views on the International Year of Chemistry 2011 and how the world relies on chemistry. Can we feed nine billion? The title of a book written by John Emsley, and recently published by the Royal Society of Chemistry, asked this question of its readers. An expanding population on a finite amount of land means we need more efficient ways to grow and harvest food. Without new ideas about how to best use the land we have, the world faces a major food security problem. We as chemists know the central importance of crop science and innovative chemistry in tackling this global challenge, and indeed other challenges like sustainable clean water, clean energy,

and new treatments and cures for diseases. Governments and civil servants know this too, probably. But what about the general public? Ask a passer-by to explain if they might need a lithium electrochemical cell to push electrons through an indium-tin-oxide layer on liquid crystals, and you will likely get a quizzical look: these things are just science, what uses have I for that? Ask if they need the vibrant colour screen and excellent battery life on their smartphone and you’ll get an equally quizzical look: of course I need these things, they’ll say; it’s part of my life.

Science Matters Keeping abreast of Syngenta R&D Winter 2011

Chemistry is essential to the economy It’s not just the personal items, either: chemistry is essential to the UK economy. A study by Oxford Economics for EPSRC and RSC found that over 20% of the country’s GDP is reliant on chemical science research – that’s £258 billion – and it supports over six million jobs. Other developed economies are likely just as dependent on chemical science. The world’s population is reliant on chemistry, but few know just how reliant they are. Still fewer know how much more dependent we will be in the future, when the challenges ofasustainable The orang-utan has become symbol of sources ofinfood, water and energy will conservation the forests of Indonesia

British students helped measure global water quality as part of the IYC

be all the more acute. Chemistry can solve these problems, and we need a scientifically literate, engaged society to accept and welcome those solutions. Inspiring young people The primary aims of the International Year of Chemistry (IYC) have been to inspire young people to continue studying chemistry, and to raise awareness of the importance of chemistry in everyday life. The former will help the latter; a healthy education in science gives people the tools to participate in an informed debate about contentious issues like genetic modification. Inspiring young people to study chemistry has been the Royal Society of Chemistry’s main focus during IYC. We helped British students lead the world in the IYC Global Experiment – a worldwide collaboration by school pupils to measure global water quality – with nearly half of the 15,000 participants coming from UK schools. The spirit of IYC will live on through other RSC education programs including Faces of Chemistry, a set of short online videos for schools that show the real people behind chemistry research and innovation, and how they apply their chemistry knowledge to real problems. Syngenta’s own Mell Morris stars in one of the first sets of videos, talking personably and with enthusiasm about the importance of crop protection products.

So we hope that, as they learn the importance of chemistry in their daily lives, today’s young people will grow up with an appreciation for the chemical science research that goes into making life comfortable. When they’re asked to make decisions as an electorate that will impact food security, they’ll be equipped with the knowledge to make an informed decision. It will take time to know if we’ve been truly successful, but the signs that the public are warming further to science are starting to show. This matters because it touches on most of the key questions facing society. A recent survey suggested public attitudes towards nuclear power have become more positive, despite the tragic events in Fukushima and the resulting scare-mongering news coverage. It appears that the public are becoming more aware that we face stark challenges and that we must rationally decide how to overcome them, after weighing all of the risks involved. In educating the public about science, we hope to equip them to make informed, rational decisions about all the challenges the world faces. The International Year of Chemistry is bringing the chemical science community together to highlight the vital role we must play in finding solutions to these challenges. Let’s make sure that this continues beyond 2011.

We hope that the legacy of the International Year of Chemistry will be a profoundly positive one. It has brought the global chemistry community together in a concerted effort to raise the profile of the chemical sciences’ role in everyday life.

Professor David Phillips OBE BSc PhD CSci CChem FRSC Professor Emeritus, Imperial College London President, Royal Society of Chemistry David Phillips was born in 1939 and educated in the north east of England at South Shields Grammar-Technical School (Boys) and at the University of Birmingham (BSc and PhD). He enjoyed postdoctoral experience in Austin, Texas, USA, and in Moscow, USSR, before joining the University of Southampton as a Lecturer in Physical Chemistry in 1967. He left as Reader in 1980 to become Wolfson Professor of Natural Philosophy, at The Royal Institution, subsequently becoming Acting Director 1986 and the Deputy Director 1987-89. He then moved to become Professor of Physical Chemistry of Imperial College of Science, Technology and Medicine, University of London (now Imperial College London) in 1989, Head of Department of Chemistry 19922002 and Hofmann Professor of Chemistry 1999-2006. He was Dean of the Faculties of Life Sciences and Physical Sciences 20022005 and Senior Dean 2005-2006. He is currently Senior Science Ambassador, Schools, Professor Emeritus and Senior Research Investigator. David gave the Christmas Lectures (jointly with John Meurig Thomas) on BBC TV in 1986-87 and many series abroad. He has broadcast for TV and radio on his research interests, popular science and the state of British science. He regularly gives 20-30 popular lectures per annum to schools and lay audiences and e-masterclasses to groups of schools in the UK and abroad. He was awarded the RSC Nyholm Lectureship and Medal in 1994-95 for services to Chemical Education, the Michael Faraday Award of the Royal Society, London for public understanding of science. He received the OBE in The Queen’s Birthday Honours in June 1999 for services to science education. He is the author of many books and research papers (some 585 in all) in the field of photochemistry and laser research. He is currently President of the Royal Society of Chemistry.

Science Matters Keeping abreast of Syngenta R&D Winter 2011

Out and About

Carolyn Riches has been tracking down scientific snippets from across the world on a chemistry theme. Thanks go to everyone who has contributed to ideas, text and images for this edition of Out and About.

Festival of Molecules

Periodic Table make-over

Syngenta was one of the many companies celebrating the importance of chemistry in our daily lives at the Basel Festival of Molecules in mid-June. Employees from our sites in Basel and Stein took part in this International Year of Chemistry event by hosting stands and giving presentations themed on ‘innovative molecules for healthy food’. During the two-day event, some 4,000 visitors passed through the science village. The audience ranged from school children through to representatives from political, scientific, and economic circles. The Syngenta interactive displays were brought to life with crops such as grape, cotton and peanut, and focused on our integrated crop protection solutions. Gerardo Ramos, Head of Syngenta Crop Protection R&D, also presented a talk on ‘Innovative Solutions for Agriculture’.

There are many ‘R&D Networks’ within Syngenta but only one is truly dedicated to chemistry: the Global Catalysis Network. Established in December 2008, the network is now recognized across Syngenta as a dependable resource for the collection, exchange of knowledge and practical support on aspects of catalysis.

Syngenta’s Periodic Table has videos of key reactions

Syngenta has taken the Periodic Table and given it a make-over of color, energy and interactivity. Launched in January 2011, it has since been endorsed by IUPAC* and the global external IYC* Committee. “Based on feedback from teachers and students, we have built on its success to include more films of chemical reactions and added supporting information,” says Jim Morton. This exciting and educational online version of the Periodic Table is designed to encourage young people to take an active interest in chemistry. Found in the newly updated Learning Zone section of the Syngenta UK website, the resource is aimed at students aged 13-18 and their teachers.

Chemistry comes to life for children at the Festival of Molecules

Children had the opportunity to take part in hands-on activities, such as building a mandipropamid molecule, the active ingredient in REVUS®, and use a silicate garden to understand how crystals grow. “It was exciting to share our science and highlight the role chemistry plays. It was also great to see the popularity of our activities, our booth was constantly full of eager children building mandipropamid models!” says Fred Cederbaum, Head Fungicide Chemistry & Chemistry Operations Manager, based at Stein in Switzerland. Contact: eugenio.garcia@syngenta.com

Global Catalysis Network

A virtual lab in the ‘Reaction Zone’ allows students to mix elements with reactors and watch whilst the equations and pre-recorded videos play out in front of them. In addition, a ‘Compounds’ section helps put chemistry into context with 3D models of our products’ active ingredients. “These come to life on screen when you wear 3D glasses,” says Jim.

Catalysis – a process that speeds up a chemical reaction due to the participation of a substance called a catalyst – is a very important aspect of chemistry; all chemists across Syngenta use catalysts. Research in this area moves at a breathtaking speed and many of the catalytic methods now considered to be standard by organic chemists were almost unthinkable just 10 years ago. “Syngenta needs rapid access to breakthroughs in these catalysis technologies,” says Paul Worthington. “The purpose of the network is to evaluate the potential of new opportunities for catalysis in Crop Protection R&D,” says Paul. “It has over 50 members from Switzerland, UK, USA and India and we keep in touch by monthly conference calls and newsletters.” One key goal of the network is to evaluate external collaborations with leading academic institutions. Syngenta is currently engaged in over 20 collaborations in the area of catalysis, notably with the Scripps Research Institute and the Engineer School of Fribourg. Paul Worthington is a Syngenta Fellow and leader of the Catalysis Network.

Jim: “It’s great to hear that teachers are finding the resource a useful and welcoming teaching aid.” Jim Morton is Visits and Education Officer based at Jealott’s Hill in the UK. * IUPAC: International Union of Pure and Applied Chemistry * IYC: International Year of Chemistry Microencapsulated palladium catalysts developed

Visit: www.syngenta.co.uk/periodictable

through a Syngenta collaboration

Contact: paul.worthington@syngenta.com

Contact: james.morton@syngenta.com

Science Matters Keeping abreast of Syngenta R&D Winter 2011

Carolyn Riches Carolyn is a Communications Associate at Jealott’s Hill in the UK. Her degree is in soil and plant science, with an emphasis on the agricultural environment. Carolyn joined Syngenta in R&D nine years ago as part of the Discovery Biology Group, before moving into Communications.

Make a Molecule

Novel Molecules

Dial a Molecule

Jealott’s Hill chemists are turning an almost impossible challenge into a reality. They have invited non-chemistry colleagues into their labs to ‘make a molecule’ and in the process are helping them understand Syngenta’s chemical discovery process. “Our aim is to make chemistry accessible to all – some staff have never been in a lab before. Others know something about chemical synthesis, but have never practiced it,” explains Steve Wailes.

“The novel molecule challenges (NMCs) enable us to tap into the capabilities of global synthetic chemists and to extend our network of contacts for future projects,” says Phil Wege. Traditionally in Syngenta, scientists have selected the target areas they wish to work on and then either bought a ready-made library of compounds from existing suppliers or synthesized them in our labs. However, sometimes our scientists wish to explore specific chemistry which is not available through these routes or would necessarily show up in published papers. This is where the NMCs come into play. “We post a chemistry request for material online at www.innocentive.com, specifying the structural and physical chemical requirements. Potential partners post their solutions and we select the option that best suits us,” explains Phil. Only the desired compounds are purchased and the solver receives a monetary reward for structures if they meet purity requirements.

Everybody makes a molecule. From left to right: Don Moseley, Domingo Salazar, Linda Curley and Julia Hill

Participants are given a brief introduction to chemical synthesis and then taken into the lab where they choose a reaction aiming to produce a target compound from a current herbicide project. If the reaction works, the compound is registered in the Syngenta collection and goes for further testing. “The participant receives analytical data on their molecule and will be invited to view its activity in the glasshouse,” says Steve. The selection for Spring/Summer 2012 field trials will take place in November. “I’m looking forward to seeing if any of the ‘make-a-molecules’ will be selected,” says Steve. “It’s been really enjoyable so far and worth the investment of our time... especially when people find out that their molecule has never existed before!”

“NMCs provide our scientists with an increased opportunity to explore speculative areas. We extend our innovation base without compromising our synthetic chemistry resources,” says My Nguyen. “Put simply, we are able to do more with less!” Phil Wege is Head of Biology Support at Jealott’s Hill in the UK. My Nguyen is Technology and Strategy Integration Projects Manager based at Slater in the USA.

Imagine if it was as easy to make any target molecule as it is to dial a phone number! This vision attracted scientists from industry and academia to an EPSRC* ‘Dial a Molecule’ meeting at Jealott’s Hill in July, focusing on the themes of predicting reaction outcomes and developing perfect reactions. “We discussed areas of research that might help us take steps towards achieving this vision,” explains John Clough. “You can usually write down many routes to a target compound, so where do you begin? We would like to be able to select the best route and reaction conditions with much less experimentation.” The participants were from a range of disciplines – not only organic synthesis – and included computer scientists, statisticians and chemical engineers. Making better use of experimental data to predict the outcome of novel reactions was one discussion topic. “This is something we are already doing with our new Electronic Lab Notebooks,” says Caroline Winn. “Chemists are able to share their research, including the failures, with their colleagues, and this can save a lot of time when similar areas are revisited.” John Clough is a Chemistry Group Leader and Syngenta Fellow. Caroline Winn is a Senior Research Chemist. Both are based at Jealott’s Hill in the UK.

Steve Wailes is a Chemistry Team Leader based at Jealott’s Hill in the UK.

A Syngenta Novel Molecule Challenge

*EPSRC: Engineering and Physical Sciences Research Council

Contact: steve.wailes@syngenta.com

Contact: philip.wege@syngenta.com or chris.godfrey@syngenta.com

Contact: john.clough@syngenta.com or caroline.winn@syngenta.com

Science Matters Keeping abreast of Syngenta R&D Winter 2011

Editor’s comments The editor of Science Matters, Stuart John Dunbar, reflects on the importance of chemistry in education and the future of the magazine as it enters a new era.

The International Year of Chemistry 2011 is nearly over, this edition of the magazine not only celebrates Syngenta’s excellence in chemistry but it also illustrates how chemistry touches our world from new crop protection products to innovative teaching tools, like the interactive periodic table. I have personal experience of the impact of the interactive periodic table showing it to my partner’s god-daughter, who is 10 years old. The elements that explode in air were of particular interest! It simply illustrated the power of science education and how Syngenta has an important part to play in this. The power of chemistry As part of the International Year of Chemistry the Chemistry Department started a program called ‘Make a Molecule’. You can read more about this in one of the snippets, but I was delighted to see a group of biochemists outside my office laughing and enthusing about how they had spent the morning in Chemistry making potential new herbicides. They were giggling because they were wondering what would happen if the compounds they had made became the next blockbuster chemical. Somehow I think the odds are against this, but the enthusiasm perfectly illustrated the power of chemistry, even for non-chemists! In this edition you will have read articles on a wide range of chemical subjects. Unfortunately however it was not possible to cover the breadth of everything we do. One notable omission is analytical chemistry, which touches almost every part of R&D and crosses all of our businesses. This will be rectified in future editions as we illustrate

the power of analytical chemistry in our new integrated, cropfocused strategy. Since we finished drafts of the articles we also learned that thiamethoxam became the world’s best selling insecticide. A notable landmark, and one which the company can be justifiably proud. The future This is my last editorial as editor of Science Matters. Future editions will be edited by Alan Raybould, who is a Syngenta Fellow in Product Safety at Jealott’s Hill. Let me tell you a bit about Alan. He has a PhD in genetics from the University of Birmingham in the UK and is a visiting Professor in Biological Sciences at the University of Southampton. He worked for the Centre for Ecology and Hydrology for 12 years, before joining Syngenta in November 2001. Alan is an expert in environmental risk assessment of GM crops. He is also leading an initiative in understanding the social science and ethical aspects of new scientific opportunities such as Systems and Synthetic Biology.

Stuart John Dunbar Senior Syngenta Fellow and Editor of Science Matters Jealott’s Hill UK

For me, though, he is best remembered for an article called ‘There is a better way of assessing risk’ in the Spring 2009 edition of the magazine. The article is one of the most memorable I edited, due to the image of a black swan we used to illustrate the text. The two black pages with white text perfectly illustrated the challenge of risk assessment; looking for the black swan. I know Alan and the team will do a great job and he will stamp his character on the magazine as it moves into this new era. I wish Alan and everyone associated with the magazine good luck for the future.

Science Matters Keeping abreast of Syngenta R&D Winter 2011

Stuart’s degree is in Zoology from Nottingham University and he did a PhD in insect neurobiology. After a couple of post-docs, Stuart joined the company in 1985 as an insect electrophysiologist. He currently heads the Mode of Biological Action Group which is part of Biological Sciences at Jealott’s Hill and is project leader of the University Innovation Center on Systems Biology at Imperial College London. Stuart is also an Adjunct Professor of Cellular and Molecular Sciences at Imperial College London

Contact: stuart.dunbar@syngenta.com

Crops like potatoes are benefiting greatly from Syngenta chemistry

Syngenta Fellows – supporting Syngenta Science Science Matters is a magazine supported by the Syngenta Fellows to recognize and communicate the excellent science throughout Syngenta. The Syngenta Fellows are a leading community of Syngenta scientists with a role to promote Syngenta’s excellence in science. The contact for comment on this issue is Stuart J. Dunbar who can be contacted at Syngenta Limited, Jealott’s Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, United Kingdom or by email at stuart.dunbar@syngenta.com. For future content the main contact for comment on this issue is Alan Raybould who can be contacted at Syngenta Limited, Jealott’s Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, United Kingdom or by email at alan.raybould@syngenta.com. Editor: Stuart John Dunbar Editorial Team: Isabelle Baumann and Carolyn Riches The Editors would like to acknowledge the valuable contributions of John Emsley and the authors and other persons named in each article. The views expressed in this magazine are the views of the authors and may not necessarily always reflect the views or policies of Syngenta. Design & Production: Kre8tive Communications Limited. Print: Geerings Print Limited Unless otherwise indicated, trademarks indicated thus ® or TM are the property of a Syngenta Group Company. The Syngenta wordmark and ‘Bringing plant potential to life’ are trademarks of Syngenta International AG. © Syngenta International AG, 2011. All rights reserved. Editorial completion November 2011. Science Matters is printed using water reduction processes, including a completely chemical and water free printing plate making process. In addition, all water used in the actual printing process is re-circulated and new water is only added to replace that lost by evaporation. Science Matters is printed on 9lives80 which is produced with 80% recovered fibre comprising 10% packaging waste, 10% best white waste, 60% de-inked waste fibre and only 20% virgin totally chlorine free fiber sourced from sustainable forests. Cautionary statement regarding forward-looking statements This document contains forward-looking statements, which can be identified by terminology such as “expect”, “would”, “will”, “potential”, “plans”, “prospects”, “estimated”, “aiming”, “on track”, and similar expressions. Such statements may be subject to risks and uncertainties that could cause actual results to differ materially from these statements. We refer you to Syngenta’s publicly available filings with the US Securities and Exchange Commission for information about these and other risks and uncertainties. Syngenta assumes no obligation to update forward looking statements to reflect actual results, changed assumptions or other factors. This document does not constitute, or form part of, any offer or invitation to sell or issue, or any solicitation of any offer, to purchase or subscribe for any ordinary shares in Syngenta AG, or Syngenta ADSs, nor shall it form the basis of, or be relied on in connection with, any contract therefore.

Science Matters Keeping abreast of Syngenta R&D Winter 2011