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JOHNSON MATTHEY

TECHNOLOGY REVIEW

Johnson Matthey’s international journal of research exploring science and technology in industrial applications

Volume 60, Issue 4, October 2016 Published by Johnson Matthey

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© Copyright 2016 Johnson Matthey

Johnson Matthey Technology Review is published by Johnson Matthey Plc.

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Volume 60, Issue 4, October 2016

JOHNSON MATTHEY TECHNOLOGY REVIEW www.technology.matthey.com

Johnson Matthey’s international journal of research exploring science and technology in industrial applications

Contents

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Guest Editorial: Biocatalysis and PharmaceuticalsBy Bernhard J. Paul Methane Emission Control By Agnes Raj “Catalytic Arylation Methods: From the Academic Lab to Industrial Processes”A book review by Thomas Colacot Optimising Platinum-Rhodium Thermocouple Wire Composition to Minimise Composition Change Due to Evaporation of OxidesBy Jonathan V. Pearce Reduction of Activated Carbon-Carbon Double Bonds using Highly Active and Enantioselective Double Bond Reductases By Beatriz Domínguez, Ursula Schell, Serena Bisagni and Thomas Kalthoff “Handbook of Metathesis”, 2nd Edition A book review by Valerian Dragutan and Ileana Dragutan In the Lab: Bioreaction Engineering for the Implementation of Biocatalysis inIndustryFeaturing Professor John M. Woodley “Heterocycles from Double-Functionalized Arenes: Transition Metal Catalyzed Coupling Reactions”A book review by Thomas Colacot Eighty Years of Steam ReformingBy Chris Murkin and John Brightling Johnson Matthey Highlights “Membrane Technologies for Water Treatment: Removal of Toxic Trace Elements with Emphasis on Arsenic, Fluoride and Uranium”A book review by Nadia Permogorov Palladium Impurity Removal from Active Pharmaceutical Ingredient Process Streams By Stephanie Phillips, Duncan Holdsworth, Pasi Kauppinen and Carl Mac Namara


http://dx.doi.org/10.1595/205651316X692914 Johnson Matthey Technol. Rev., 2016, 60, (4), 226–227


Guest Editorial: Biocatalysis and Pharmaceuticals

Mankind’s ability to harness the power of biocatalysis dates back many thousands of years as evidenced by records that described the production of beer by the Sumerians. Over the next few thousand years many other uses of biocatalysis were discovered, mainly for the production of food and drinks such as cheese and wine. Yet it took until the 20th century for mankind to utilise biocatalytic reactions for the synthesis of chemical intermediates and active ingredients (1).

Biotransformations are chemical reactions that are catalysed by biological systems such as microbial whole cells or isolated enzymes. Most of the early examples of biocatalysis used wild type microorganisms but advances in genetic engineering in the 1970s allowed scientists to clone and express specific enzymes in organisms that are easily handled and grown in a laboratory environment such as Escherichia coli and yeast.

Johnson Matthey has extensive capabilities in terms of enzyme discovery, evolution and manufacture along with a broad range of proprietary enzymes for the effective synthesis of pharmaceuticals and fine chemicals.

Biocatalysts and Chemocatalysts

Biocatalysts – like all catalysts – increase the rate of a reaction by lowering the activation energy and they are not consumed in the reaction they catalyse. Enzymes and whole cell biocatalytic systems display several unique properties. Most importantly, the regio-, chemo- and stereoselectivities of biocatalysts are often much higher than what can be achieved using chemocatalysts as a result of the multiple binding interactions of substrate and catalyst thanks to their complex three-dimensional structure. Biocatalysts are also commonly used in aqueous systems (sometimes with added organic co-solvents to help solubility of

apolar compounds) or in biphasic systems. This results in limited use of organic solvents which leads to a reduced environmental impact.

The industrial use of enzymes encompasses a variety of different market segments such as food and beverage, animal feed, detergents, fine chemicals and pharmaceuticals and the overall size of the market was estimated to be US$4.7 billion in 2013 (2). While the pharmaceutical sector occupies a small portion of the overall enzymes market, the recent technological advances in the area of enzyme engineering have led to a much increased interest in the use of enzymes for the production of active pharmaceutical ingredients (API).

From the point of view of the synthetic chemist, it is important to realise that biocatalysis and chemocatalysis are complementary technologies and neither is inherently superior to the other. As they operate under different reaction conditions and they often display a different substrate scope, it is hard to predict which technology will provide the best performance in a given chemical transformation. For example, when high enantio- or chemoselectivity are required, biocatalysis is often the technique of choice, especially when dealing with complex, multi-functional molecules. On the other hand, chemocatalysis can sometimes be the more cost effective approach as it is easier to achieve very high substrate to catalyst ratios and it is often viewed by organic chemists as inherently more familiar technology.

While chemocatalysis can be highly cost effi cient it sometimes lacks application flexibility, particularly when there is the need for high hydrogen gas pressure or when small amounts of byproducts cannot be avoided. Biocatalysis on the other hand, often offers a superior product purity (and enantiopurity) at the expenses of a narrower scope of reaction conditions and higher catalyst loadings. Therefore, only by having access to bio- and chemocatalytic solutions and considering

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each transformation as a unique case can one unlock the full potential offered by catalysis.

Advances in Technology

Biocatalysis is a field that has benefi ted tremendously from advances in analytical science, genetic engineering and molecular biology technologies. The development of high resolution X-ray single crystal analysis has enabled researchers to understand the structure of the active site of enzymes (Figure 1) which has in turn allowed them to mutate the amino acid sequence of the protein thereby modifying the substrate-enzyme interaction in an effort to increase selectivity or activity. Reduced costs of gene synthesis and gene library synthesis allow for the evaluation of the impact of mutations at target sites more quickly. Additionally, the development of high-throughput material handling and analytics, along with rapid developments in the area of deoxyribonucleic acid (DNA) sequencing has allowed scientists to further optimise enzymes via a process called directed evolution. This way the natural mechanisms of evolution are exploited to artificially evolve an enzyme towards new properties such as substrate scope, thermal stability and solvent stability. The ability to modify the activity, selectivity and stability of enzymes via this approach has resulted in a number of new applications of biocatalysis in organic synthesis and enabled biocatalytic routes to be much more cost competitive with their chemocatalytic counterparts.

Driven by similar advances in genetic engineering and analytical techniques, the field of synthetic biology

Enzyme surfaceEnzyme secondary structure elements

Active site

Acetophenone(substrate)

Entrance to the active site

NADPH (co-substrate)

Fig. 1. X-Ray crystal structure of Lactobacillus brevis (R)-alcohol dehydrogenase © Johnson Matthey

has emerged. Applying modern genetic engineering, molecular biology and microbiology techniques it is nowadays possible to design ‘biological machineries’ that can be utilised for manufacturing complex molecules. From a synthetic chemistry point of view, the ability to combine multiple synthetic steps in a single biological organism as a cascade of reactions is an extremely powerful tool as evidenced by the syntheses of highly complex molecules such as artemisinic acid which is a late stage precursor to the antimalarial drug artemisinin (3) and, more recently, several intermediates in the biosynthesis of morphine and thebaine via this approach (4, 5).

In this issue then, enjoy the range of articles celebrating a selection of ways in which biotechnology and chemical catalysis can be made to benefi t the industry to create new and better processes, products and intermediates. Few other techniques in the toolbox of the synthetic chemist have seen such a rapid evolution over the last few years and with future advances in the areas of genetic engineering, biology and nanotechnology, we can’t even imagine how industrial biotransformation will evolve over the next few decades. Exciting times ahead!

BERNHARD J. PAUL General Manager European Pharma Solutions

Johnson Matthey, 250 Cambridge Science Park, Milton Road, Cambridge, CB4 0WE, UK

Email: [email protected]

References 1. O. Ghisalba, H.-P. Meyer and R. Wohlgemuth,

‘Industrial Biotransformation’, in “Encyclopedia of Industrial Biotechnology: Bioprocess, Bioseparation, and Cell Technology”, ed. M. C. Flickinger, John Wiley & Sons, Inc, New Jersey, USA, 2010, pp. 1–34

2. S. S. Dewan, “Global Markets for Enzymes in Industrial Applications”, BIO030H, BCC Research, Massachusetts, USA, 2014

3. D.-K. Ro, E. M. Paradise, M. Ouellet, K. J. Fisher, K. L. Newman, J. M. Ndungu, K. A. Ho, R. A. Eachus, T. S. Ham, J. Kirby, M. C. Y. Chang, S. T. Withers, Y. Shiba, R. Sarpong and J. D. Keasling, Nature, 2006, 440, (7086), 940

4. K. M. Hawkins and C. D. Smolke, Nat. Chem. Biol., 2008, 4, (9), 564

5. K. Thodey, S. Galanie and C. D. Smolke, Nat. Chem. Biol., 2014, 10, (10), 837


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Methane Emission Control A review of mobile and stationary source emissions abatement technologies for natural gas engines

By Agnes Raj Johnson Matthey Technology Centre, Blount’s Court, Sonning Common, Reading RG4 9NH, UK


Natural gas is of increasing interest as an alternative fuel for vehicles and stationary engines that traditionally use gasoline and diesel fuels. Drivers for the adoption of natural gas include high abundance, lower price and reduced greenhouse gas emissions compared to other fossil fuels. Biogas is an option which could reduce such emissions further. The regulations which cap emissions from these engines currently include Euro VI and the US Environmental Protection Agency (EPA) greenhouse gas legislation. The regulated emissions limits for methane, nitrogen oxides (NOx) and particulate matter (PM) for both stoichiometric and lean burn compressed natural gas engines can be met by the application of either palladium-rhodium three-way catalyst (TWC) or platinum-palladium oxidation catalyst respectively. The drivers, policy and growth of this Pd based catalyst technology and its remaining challenges to be overcome in terms of cost and catalyst deactivation due to sulfur, water and thermal ageing are described in this short review.

Introduction

There is increased interest in recent years in replacing traditional gasoline and diesel fuels with natural gas for

a number of reasons, such as increasing energy prices, depletion in oil resources and political uncertainty, but mainly due to increasing concern about global warming (1). Natural gas is composed mainly of methane (typically 70–90%) with variable proportions of other hydrocarbons such as ethane, propane and butane (up to 20% in some deposits) and other gases (2, 3). It can be commercially produced from oil or natural gas fields and is widely used as a combustion energy source for power generation, industrial cogeneration and domestic heating. It can also be used as a vehicle fuel. Natural gas has a number of environmental benefits: it is a cleaner burning fuel typically containing few impurities, it contains higher energy (Bti) per carbon than traditional hydrocarbon fuels resulting in low carbon dioxide emissions (25% less greenhouse gas emissions), and it has lower emissions of PM and NOx compared to diesel and gasoline. In the EU there is an aim for more than a 60% reduction in CO2 emissions from transport by 2050 from 1990 levels (4) and using natural gas as a vehicle fuel can contribute to this (1). From the economic point of view, natural gas can be less expensive than diesel and gasoline. For example Table I displays gasoline, diesel and natural gas prices during 2014 and 2015 (5, 6).

The production cost is low and governments worldwide are promoting its usage by providing financial incentives. Political benefits, in countries such as the USA, could include secured national resources for energy, and less dependency on imported oil from other countries. Partly due to these factors, there is a rapid increase in interest in use of natural gas with a


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Table I Comparison between Gasoline, Diesel and Natural Gas prices 2014–2015 (5, 6)

Fuel Price, US$ per GGEa

July 2014 October 2015

Gasoline 3.70 2.35 Diesel 3.51 2.30 Natural Gas 2.17 2.09

aGGE = gasoline gallon equivalent

predicted 30% average annual growth especially in internal combustion engines.

This short review focuses on the demand, policies and growth of natural gas globally and methane abatement via aftertreatment systems for mobile and stationary applications.

Legislation and Challenges

Natural gas engines emit very low PM and NOx (up to 95% and 70% less, respectively) compared to heavy-duty and light-duty diesel engines. Presently, methane is not included in criteria emissions regulations, but the US EPA greenhouse gas legislation caps methane emissions at 0.1 g bhp–1 h–1

for heavy-duty engines and 0.05 g mile–1 for pickup trucks and vans (7). Euro VI natural gas vehicles are required to meet both total hydrocarbon (THC) and methane emissions limits and therefore need methane emission control aftertreatment devices. The current EU emission standards for heavy-duty gas engines are shown in Table II. The methane limits apply for only gas engines and the PM limit is not an issue for CNG vehicles.

The US EPA has also proposed new standards towards meeting the US government’s pledge to reduce the methane emissions mainly from the oil and gas sectors by 40–45% by 2025 from 2012 level (9).

This is further emphasised recently in May 2016 to limit methane emissions from industry leaking compressors, wells and pumps (10).

Natural Gas Resources and the Natural Gas Vehicles Market

Natural gas is available in abundance worldwide. As shown in Figure 1, the worldwide proven reserves of

3natural gas exceed 204.7 × 1012 m and world gas reserves will last for 537 years, another 161 years in Europe (1).

The worldwide natural gas vehicle population increased at an average growth rate of 20% per annum between 1991 and 2007 and some sources predict it to increase further as shown in Figure 2 (11).

Fuel Options

Natural gas can be used as transportation fuel in the form of CNG and liquefied natural gas (LNG). CNG is carried in tanks pressurised to 3600 psi (~248 bar) and has an energy density around 35% of gasoline per unit volume (12). LNG has an energy density 2.5 times that of CNG and is mostly used for heavy-duty vehicles. It is cooled to liquid form at –162ºC and as a result the volume is reduced 600 fold meaning LNG is easier to transport than CNG (2). In general, natural

Table II EU Emission Standards for Heavy-Duty Gas Engines: Transient Testing (8)

Stage Date Test Limit, g kWh–1

CO NMHC CH4 NOx PM

Euro V October 2008 European Transient Cycle (ETC) 4.0 0.55 1.1 2.0 0.03

World Harmonised Euro VI January 2013 Transient Cycle

(WHTC) 4.0 0.16 0.5 0.46 0.01

Courtesy of Dieselnet


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Fig. 1. Worldwide natural gas reserves (units = 109 m3) (1). Source: NGVA Europe

(a)

Num

ber o

f veh

icle

s, th

ousa

nds

600

400

200

0

Light-duty, % Medium- and heavy-duty, %

0.05 0.14

0.5 1.4

Light-duty vehicles Medium- and heavy-duty vehicles

17%

2009

2010

2011

2012

2013

2014

2015

2016

2017

2018

2019

2020

129 135 143 159 171 200

237 282

328 382

448 520

45 938056 6852 91

49 8784

337285

239204176144119 103103 183143124105

2001 1.7 M NGV

2007 7 M NGV

Jan 2011 13 M NGV

163

CAGR 2013–2020

15–20%

12–18%

Num

ber o

f veh

icle

s, m

illio

ns 80 70 60 50 40 30 20 10 0

15% 26% 18% (assumed)

annual growth

2020 65 M NGV (9% market)

1991

1995

1999

2003

2007

2011

2015

2019

2023

7%

(b)

10 years 6 years 13 years

Fig. 2. CNG vehicles in: (a) USA, where CAGR ranges are based on different assumptions regarding CNG vehicle adoption and penetration (in %) is calculated relative to all vehicles currently in use in the USA; and (b) Europe markets as a proportion of worldwide natural gas vehicle with 5% market share for Europe in 2020 and 9% possible for Europe in 2030 (11) (Reproduced with kind permission from Eunseok Kim, Heesung Catalysts, South Korea)

gas vehicles are more expensive than petrol or diesel vehicles mainly due to the cost of the high-pressure or insulated fuel tank which is required to store LNG or CNG.

Alternatively, using gas-to-liquids (GTL) technology (13), the natural gas can be converted to liquid fuels which have ignition characteristics similar to diesel or gasoline fuels and can be used for transportation purposes. Other options include reforming natural gas

to generate hydrogen for hydrogen fuel cell vehicles and generation of electricity for electric vehicles by firing a power plant by natural gas (14).

Bio-LNG could be an alternative to natural (fossil) gas, being produced from biogas, derived by anaerobic digestion from organic matter such as landfill waste or manure (15–17). Its use would further reduce vehicle greenhouse gas emissions (18) and would also be cheaper than diesel, partly because of government


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incentives such as reduced duties in various countries or regions (19).

Emission Aftertreatment Technologies

Based on the combustion conditions, two main operating modes are used for methane fuelled engines: stoichiometric conditions (λ = 1) and lean burn conditions (λ ≥ 1.3). Figure 3 (11) shows the CO2 emission comparison of the various technologies, and it can be seen that natural gas contributes lower emissions than diesel under all conditions.

Methane is the least reactive hydrocarbon and high energy is required to break the primary C–H bond. The

ignition temperature of alkanes generally decreases with increasing fuel to air ratio and increasing hydrocarbon chain length which correlates with the C–H bond strength. Palladium-based catalysts are well known as the most active type of catalyst for methane oxidation.

Figure 4 illustrates how different hydrocarbon species are converted to CO2 and H2O under lean conditions with increasing exhaust temperature over a Pd based catalyst. It is shown that methane has a higher light-off temperature compared to other hydrocarbons, reaching 50% conversion at 550ºC.

When operating in stoichiometric conditions (λ = 1), a TWC is used as an effective and cost effi cient aftertreatment system to combust methane. Mostly bimetallic Pd-Rh catalysts with high total platinum

Spe

cifi c

CO

2 em

issi

ons,

g k

Wh–

1 800

700

600

500

400

300

200 Diesel Natural gas Natural gas Natural gas

lean stoichiometric stoichiometric with EGR

Displacement ≈ 7 l, 1200 rpm Full load 30% load

Fig. 3. CO2 emission dependence on technologies in HDD CNG engines (11). EGR = exhaust gas recirculation (Reproduced with kind permission from Eunseok Kim,

group metal (pgm) loadings of >200 g ft–3 are needed for high levels of methane conversion to meet end of life THC regulations due to the very low reactivity of

Con

vers

ion,

%

Ethene Propene Butane Propane Ethane Methane

100 90 80 70 60 50 40 30 20 10 0

0 100 200 300 400 500 600 Temperature, ºC

Increasing alkane chain length

Fig. 4. Hydrocarbon species conversion of Pd basedHeesung Catalysts, South Korea) catalyst as a function of temperature under lean conditions

(a) (b)

110 110

cie

ncy,

%

100

90 CO, %

cie

ncy,

%

100

90

80 HC, % NOx, %

80

Con

vers

ion

effi

Con

vers

ion

effi

70

60

50

40 0.97 0.98 0.99 1.00 1.01 1.02 1.03 0.97 0.98 0.99 1.00 1.01 1.02 1.03

Lambda Lambda

Fig. 5. Comparison of the performance of an aged Pd:Rh (120/0:11:1) TWC as a function of lambda at 450ºC on: (a) a gasoline engine; (b) a stoichiometric CNG engine


70

60

50

40

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this hydrocarbon and catalyst deactivation via thermal and chemical effects. Figure 5 shows the performance of a typical Pd-Rh TWC as a function of engine lambda on a standard gasoline engine compared to a stoichiometric CNG engine (a gasoline engine fuelled by CNG). Stoichiometric operation is chosen for CNG because it is easier to reduce both methane and NOx emissions under stoichiometric conditions than under lean conditions. It is evident that in the gasoline engine going from rich to lean operation, carbon monoxide combustion improves and reaches 100% above λ = 0.995 and remains the same during lean operation. 100% HC conversion is seen on rich operation, but starts dropping slightly when going lean; NOx shows a dramatic drop with increase in λ value. On the stoichiometric CNG engine, the CO and NOx conversion follow a similar trend to the gasoline engine, but HC conversion is much lower especially lean of stoichiometry. Use of high pgm loadings will improve the overall HC conversion in stoichiometric CNG engines. However, high methane conversions can be achieved with relatively low pgm based on engine calibration, i.e. controlling air to fuel ratio so as to operate near stoichiometric or rich of stoichiometric; the pgm loading can also be varied corresponding to the regional legislation requirement with regards to methane and non-methane conversions.

Figure 6 shows the difference in light-off combustion temperatures of a series of catalysts used in both gasoline and stoichiometric CNG applications. The need for high pgm loadings for CNG applications in order to attain similar light off combustion temperatures as for gasoline applications is clearly evident. The explanation lies in the fact that hydrocarbon emissions from natural gas vehicles consist mostly of methane which is much more difficult to oxidise than the alkenes,

100

aromatics and longer chain alkanes which are present in gasoline engine exhausts.

One of the advantages of using lean burn engines is high fuel economy. However, unlike with stoichiometric engines, a reductant needs to be injected into the exhaust stream in order to be able to reduce NOx in the presence of excess oxygen. This is normally in the form of ammonia (NH3), and thus lean burn applications require a completely different catalyst system to those that are stoichiometric, where effi cient NOx reduction can be achieved with the use of CO or HC at slightly rich or stoichiometric conditions. Other technical problems with lean burn engines include the possibility of misfiring at high air-to-fuel ratios resulting in higher emissions. The reduction of NOx and oxidation of methane is also more difficult under very oxidising conditions. For lean burn CNG applications, Pd-Pt at high total pgm loadings (>200 g ft–3) are needed for methane combustion at lower temperatures.

Due to the unreactive (or poorly reactive) nature of methane at lower temperatures, increased methane emissions result during cold start and idle situations, mainly for lean burn where the exhaust temperatures are lower than stoichiometric. In order to improve the reactivity of methane at lower temperatures, one of the options is to use high pgm loadings. Figure 7 shows the signifi cant benefit in methane conversion with increase in pgm loading from 100 to 200 g ft–3 of Pd, however the benefit diminishes above 200 g ft–3 .

Other Challenges

CNG catalysts, especially Pd-based catalysts, suffer from poisoning by water (5–12%) and sulfur (


deactivation due to water is significant due to the formation of hydroxyl, carbonates, formates and other intermediates on the catalyst surface (20). The activity is reversible, and can be recovered completely if water is removed (Figure 8). However, this is impractical as methane combustion feed always contains a high level of water due to the high content of H in methane. H2O can be either an inhibitor or a promoter depending on the air-to-fuel ratio, i.e. lambda. Under stoichiometric and reducing conditions, lambda 1, H2O can act as a promoter for the oxidation of hydrocarbons through the steam reforming reaction in both CNG and gasoline engines. However for lean burn CNG operating at lambdas >1, H2O acts as an inhibitor for methane oxidation. It is critical to understand the water inhibition effect and design catalysts which are more tolerant to the presence of H2O. This would allow for improvement when trying to control methane emissions from lean burn CNG.

Though the sulfur level is very low in the engine exhaust, Pd-based catalysts deactivate significantly upon sulfur exposure due to the formation of stable sulfates (21, 22). Regeneration of the catalyst in order to restore the activity following sulfur poisoning is challenging and will usually require high temperatures, rich operation or both. This is easily achievable in stoichiometric operation but more difficult in lean burn. A lean burn vehicle operates with a much higher air-to-fuel ratio than a stoichiometric vehicle and will need injection of a much higher concentration of reductant to switch to rich operation. Thermal deactivation resulting from a high level of misfire events due to poor engine transient control and ignition systems destroys the

CH

4 co

nver

sion

, %

100

80

60

40

20

0

Pd catalyst

0 50 100 150 Time, min

H2O on H2O off H2O on H2O off

Fig. 8. Effect of water on methane conversion of Pd catalyst

catalyst and correspondingly leads to a high level of exhaust emissions. This problem is common to all types of engine, but some catalysts are more resistant to the thermal deactivation. This leads to a high demand for catalyst efficiency and durability.

Figure 9 shows the effect of high-temperature thermal ageing and sulfur exposure on the methane conversion of a Pd-based oxidation catalyst. It is evident that the catalyst deactivates under both conditions, but sulfur poisoning has a more dramatic impact than thermal ageing. Both the thermal durability and sulfur poisoning can be improved by the addition of small amounts of Pt to the Pd catalyst (23, 24), as shown in Figures 10 and 11. Figure 11 shows that the sulfur inhibition due

Con

vers

ion,

%

100 90 80 70 60 50 40 30 20 10 0 100 200 300 400 500

Temperature, ºC

Fresh 700ºC 850ºC 1st SO2 2nd SO2

Fig. 9. Effect of thermal ageing and sulfur poisoning on a Pd-based methane oxidation catalyst. ‘1st SO2’ and ‘2nd SO2’ show successive sulfation

CH

4 co

nver

sion

, %

100

80

60

40

20

0 460ºC 520ºC

Pd (fresh) Pt/Pd (fresh) Pt/Pd (aged)

Fig. 10. Role of Pt in methane conversion (11) (Reproduced with kind permission from Eunseok Kim, Heesung Catalysts, South Korea)

at 450ºC


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100


methane emissions control aftertreatment. The obvious path for natural gas is via methane for stationary and

CH

4 co

nver

sion

, %

Fig. 11. Impact of Pt addition to reduce the impact of sulfur poisoning on Pd-based oxidation catalysts (25)

to formation of palladium sulfates can be reduced significantly on addition of Pt (25).

Abbreviations

CH4 methane CNG compressed natural gas CO carbon monoxide CO2 carbon dioxide EGR exhaust gas recirculation ETC European Transient Cycle GTL gas-to-liquids HC hydrocarbons HDD heavy duty diesel LNG liquified natural gas NMHC non-methane hydrocarbons NOx nitrogen oxides pgm platinum group metal PM particulate matter THC total hydrocarbons TWC three way catalyst WHTC World Harmonised Transient Cycle

Conclusions

An increased interest in the use of natural gas as an alternative fuel in mobile and stationary applications is apparent. Some of the main reasons are its relative high abundance, lower cost compared to other fuels and most importantly the urge to meet targets for the reduction of greenhouse gas emissions. Methane emissions and total hydrocarbons (including methane) are capped by regulations globally including the US EPA greenhouse gas legislation and Euro VI, requiring vehicles to use

80

60

40 Pt:Pd 20 Pd

Reference 0

0 25 50 75 100 125 150 175 200 Engine running time (approx.), h

mobile applications, where it can be used in the form of either CNG or LNG. With further improvement in natural gas fuelling infrastructure and an increase in the number of natural gas engines, the rate of uptake of natural gas vehicles can be enhanced to a greater extent. Pd-Rh TWC under stoichiometric conditions, while Pd-Pt catalyst under lean conditions are used to deal with methane combustion. High methane combustion can be achieved at lower temperatures by altering the pgm loading and through engine calibration depending on the regional legislation requirements. However, these might make the technology rather expensive. Further challenges include the issues with catalyst deactivation due to sulfur (from lubricant), water, thermal ageing and methane slip at low temperatures. These need to be addressed quickly so that this technology is readily available to meet the current and upcoming stricter legislation and challenges.

Acknowledgements

The author would like to gratefully acknowledge Lee Gilbert, Andy Walker, Gudmund Smedler, Raj Rajaram, Dave Thompsett and Joseph McCarney, all of Johnson Matthey Plc, for their contributions towards writing the report.

References 1 M. Maedge, ‘Methane as a Vehicle Fuel in Europe’,

in: Gaseous Fuels for Road Vehicles, Institution of Mechanical Engineers, London, UK, 11th September, 2014

2 NaturalGas.org: http://naturalgas.org/ (Accessed on 4th July 2016)

3 A. Demirbas, “Methane Gas Hydrate”, Springer-Verlag, London, UK, 2010

4 ‘Communication From the Commission to the European Parliament, the Council, the European Economic and Social Committee and the Committee of the Regions: A Roadmap for Moving to a Competitive Low Carbon Economy in 2050’, Brussels, Belgium, 8th March, 2011

5 E. Bourbon, ‘Clean Cities Alternative Fuel Price Report, July 2014’, Energy Efficiency and Renewable Energy, US Department of Energy, Washington, DC, USA, 31st July, 2014


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6 E. Bourbon, ‘Clean Cities Alternative Fuel Price Report, October 2015’, Energy Efficiency and Renewable Energy, US Department of Energy, Washington, DC, USA, 10th December, 2015

7 Heavy-Duty Vehicles: GHG Emissions & Fuel Economy, Other Standards and Provisions, Diesel net: https://www.dieselnet.com/standards/us/fe_hd.php (Accessed on 5th July 2016)

8 EU Emission Standards for Heavy-Duty Diesel and Gas Engines: Transient Testing, Heavy-Duty Truck and Bus Engines, Diesel net: https://www. dieselnet.com/standards/eu/hd.php (Accessed on 4th July 2016)

9 ‘FACT SHEET: Administration Takes Steps Forward on Climate Action Plan by Announcing Actions to Cut Methane Emissions’, The White House, Office of the Press Secretary, Washington, DC, USA, 14th January, 2015

10 E. Jones, ‘EPA Releases First-Ever Standards to Cut Methane Emissions from the Oil and Gas Sector’, US EPA Press Office, Washington, DC, USA, 12th May, 2016

11 E. Kim, H. Han, I. Im and N. Choi, ‘Development of Durable Pd-based Catalyst System for Lean-CNG Application’, in SAE 2014 Light Duty Emissions Control Symposium, Troy, Michigan, USA, 9th–10th December, 2014

12 ‘Few Transportation Fuels Surpass the Energy Densities of Gasoline and Diesel’, US Energy Information Administration, US Department of Energy, Washington, DC, USA, 14th February, 2013

13 E. F. Sousa-Aguiar, F. B. Noronha and A. Faro Jr, Catal. Sci. Technol., 2011, 1, (5), 698

14 S. J. Curran, R. M. Wagner, R. L. Graves, M. Keller

and J. B. Green, Energy, 2014, 75, 194

15 P. van der Gaag, ‘Analysing Challenges of Producing Bio-LNG and Building the Infra for It’, in: Brussels Global Biomethane Congress, Brussels, Belgium, 10th October, 2012

16 D. J. van Kasteren, ‘Upgrading Biogas to Bio LNG’, BioenNW, European Bioenergy Research Institute, Eindhoven, Netherlands, 31st October, 2014

17 H. P. van Kemenade, R. J. van Benthum and J. J. H. Brouwers, Energy Technol., 2014, 2, (11), 874

18 ‘Detailed carbon intensity data year 7 version 7.0’, in “Renewable Transport Fuel Obligation (RTFO) guidance: year 7”, Department for Transport, London, UK, 8th April, 2014

19 T. Rydberg, M. Belhaj, L. Bolin, M. Lindblad, Å. Sjödin and C. Wolf, ‘Market conditions for biogas vehicles’, IVL Report B1947, Swedish Environmental Research Institute, Göteborg, Sweden, 2010

20 D. Ciuparu, E. Perkins and L. Pfefferle, Appl. Catal. A: Gen., 2004, 263, (2), 145

21 P. Gélin and M. Primet, Appl. Catal. B: Environ., 2002, 39, (1), 1

22 M. Honkanen, M. Kärkkäinen, T. Kolli, O. Heikkinen, V. Viitanen, L. Zeng, H. Jiang, K. Kallinen, M. Huuhtanen, R. L. Keiski, J. Lahtinen, E. Olsson and M. Vippola, Appl. Catal. B: Environ., 2016, 182, 439

23 K. Narui, H. Yata, K. Furuta, A. Nishida, Y. Kohtoku and T. Matsuzaki, Appl. Catal. A: Gen., 1999, 179, (1–2), 165

24 A. Ersson, H. Kušar, R. Carroni, T. Griffin and S. Järås, Catal. Today, 2003, 83, (1–4), 265

25 G. Corro, C. Cano and J. L. G. Fierro, J. Mol. Catal. A: Chem., 2010, 315, (1), 35

The Author

Agnes Raj is a Senior Scientist, compressed natural gas (CNG) project leader and global coordinator at Johnson Matthey Emission Control Technologies, Sonning Common, UK. She obtained her MSc and MPhil in Chemistry from the University of Madras, India, and PhD in Material Science from Imperial College London, UK. Since joining Johnson Matthey in 2007, her research activities have been focused on pgm-based catalysts for diesel and CNG aftertreatment systems.


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“Catalytic Arylation Methods: From the Academic Lab to Industrial Processes” By Anthony J. Burke and Carolina Silva Marques (University of Évora, Portugal), Wiley-VCH, Weinheim, Germany, 2015, 400 pages, ISBN: 978-3-527-67285-1, £134.00, €180.90, US$222.00

Reviewed by Thomas Colacot Johnson Matthey Inc, 2001 Nolte Drive, West Deptford, New Jersey, 08066-1727, USA


Introduction The book describes an overview of the various arylation methods under metal-catalysed conditions. There are nine chapters covering about 500 pages which are:

1. ‘Cross-Coupling Arylations: Precedents and

Rapid Historical Review of the Field’

2. ‘Amine, Phenol, Alcohol, and Thiol Arylation’ 3. ‘Decarboxylative Coupling Techniques’ 4. ‘C–H Bond Activation for Arylations’ 5. ‘Conjugate Additions’ 6. ‘Imine Arylations – Synthesis of Arylamines’ 7. ‘Carbonyl Group Arylation’ 8. ‘-Arylation Processes’ 9. ‘Catalytic Cycloaddition Aromatization

Processes’.

A Modern Approach

This book came after Lutz Ackermann’s (Georg-August-Universität Institut für Organische und Biomolekulare

Chemie, Germany) 2009 book (1) by the same publisher. It is interesting to note that Marko Hapke wrote reviews on these two books (2, 3) in which he compared how this book is different, hence we don’t intend to make any comparisons to avoid duplication.

We are delighted to observe that in Chapter 1, the authors copied the chart (Figure 1.1) from our review (4) to include the already existing information, rather than replicating the efforts. I am particularly impressed by Chapters 3, 6 and 9 which are on subject matter not usually featured in many of the recent books on related topics.

Each chapter opens with a quote from famous scientists such as the Nobel Laureate Physicist, Richard Feynman (1918–1988):

“It doesn’t matter how beautiful your theory is, it doesn’t matter how smart you are. If it doesn’t agree with experiment, it’s wrong.”

Although these quotes increase the readability, for some reason, personally I am not able to relate the quote fully to the contents of the respective chapters. In addition, each chapter ends with a conclusion, for example, in Chapter 1 the authors quoted Didier Astruc (Groupe Nanosciences Moléculaires et Catalyse Université Bordeaux, France):

“In conclusion, the field of palladium-catalyzed cross-coupling reactions for their work in which


mailto:[email protected]:US$222.00http:www.technology.matthey.comhttp://dx.doi.org/10.1595/205651316X692671


Heck, Negishi and Suzuki were awarded the 2010 Nobel Prize in chemistry is extremely rich and productive and will continue to grow with major synthetic applications and ‘green’ implications in the future.” (5)

Although palladium is the ‘king’ of arylations (6), the authors did include other metals such as ruthenium, rhodium, iridium and even base metals such as copper, iron and nickel. This will be useful for chemists from academia and industry to look ‘out of the box’. The authors also tried to incorporate some model experimental reactions from the literature at the end of each chapter, which will be very useful for those who practice organic and organometallic chemistry.

If I have to be critical the chapters are not comprehensive. Some systematic approach also seems to be missing. The reason for that is that each chapter can be developed into a book; therefore I am amazed to see the quantum (amount) of work by these two authors to produce this book.

Conclusion

Overall this book complements other books such as the above mentioned book by Ackermann (1) and other works by Colacot (7), and by Javier Magano and Joshua Dunetz (Pfizer Inc, USA) (8). I recommend chemists buy this for their libraries.

References 1. “Modern Arylation Methods”, ed. L. Ackermann, Wiley-

VCH, Weinheim, Germany, 2009

2. M. Hapke, Angew. Chem. Int. Ed., 2009, 48,

(37), 6768

3. M. Hapke, Angew. Chem. Int. Ed., 2015, 54, (49), 14618

4. C. C. C. Johansson Seechurn, M. O. Kitching, T. J. Colacot and V. Snieckus, Angew. Chem. Int. Ed., 2012, 51, (12), 5062

5. D. Astruc, Anal. Bioanal. Chem., 2011, 399, 1811 6. S. K. Ritter, Chem. Eng. News, 2016, 94, (18), 20 7. “New Trends in Cross Coupling: Theory and

Applications”, ed. T. Colacot, RSC, Cambridge, UK, 2014

8. “Transition Metal-Catalyzed Couplings in Process Chemistry: Case Studies from the Pharmaceutical Industry”, eds. J. Magano and J. R. Dunetz, Wiley-VCH, Weinheim, Germany, 2013

“Catalytic Arylation Methods: From the Academic Lab to Industrial Processes”

The Reviewer

Thomas Colacot is a Johnson Matthey Technical Fellow/Global Research and Development (R&D) Manager in Homogeneous Catalysis (Fine Chemicals Division) managing new catalyst development, catalytic organic chemistry processes, ligands, scale-up and technology transfers. He is a co-author of about 100 articles and several patents and a Royal Society of Chemistry (RSC) book, “New Trends in Cross-Coupling: Theory and Applications” (2014). He has received the 2015 American Chemical Society (ACS) Industry Chemistry Award, 2015 International Precious Metals Institute (IPMI) Henry Alfred Award, 2016 Chemical Research Society of India (CRSI) Medal by the Chemical Research Society of India and the Indian Institute of Technology (IIT) Madras Distinguished Alumnus Award (2016) and the 2012 RSC Applied Catalysis Award.


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Optimising Platinum-Rhodium Thermocouple Wire Composition to Minimise Composition Change Due to Evaporation of Oxides Determining the optimal composition as a function of temperature

Jonathan V. Pearce National Physical Laboratory, Hampton Road, Teddington, TW11 0LW, UK


Barring the presence of significant amounts of impurities, an important cause of thermoelectric inhomogeneity and therefore calibration drift of platinum-rhodium thermocouples at high temperatures is the vaporisation and transport of the oxides of Pt and Rh, which causes local changes in wire composition. By examining the vapour pressures of Pt and Rh oxides and their temperature dependence, it is shown that at a given temperature there is an optimal wire composition at which evaporation of the oxides has no effect on the wire composition, provided the vapour does not leave the vicinity of the wire. This may also have applications for Pt-Rh heater elements.

Introduction

Noble metal thermocouples based on Pt and Rh are widely used in industry for applications requiring high accuracy and good long-term stability. Thermocouples consist of two dissimilar metal wires joined together at one end (the measurement junction). Usually the other end of each wire is connected to a copper wire which is connected in turn to a high accuracy voltmeter to enable

measurement of the voltage across the two wires. The two junctions between the thermocouple wires and the copper wires are held at a known temperature; this comprises the reference junction. Thermocouples rely on the thermoelectric principle (1–4) to generate an electromotive force (emf) in response to a temperature gradient along the metal wires, which, since the wires are dissimilar, manifests itself as a measurable voltage across the wires. As the temperature at the reference junction of the wires is known and the thermocouple provides a measure of the temperature gradient from the measurement junction to the reference junction, the thermocouple can be used as a temperature sensor. Thermocouples are calibrated by exposing the measurement junction to known temperatures; this enables the relationship between emf and temperature to be established.

However, above about 1300ºC, where many high-value manufacturing processes operate, most conventional Pt-Rh thermocouples exhibit thermoelectric instability (1, 5–7) which causes a progressive loss of information about the relationship between emf and temperature. This results in reduced process effi ciency, increased environmental footprint and increased product rejection rates. The general trend of process control towards higher temperatures to increase efficiency places increasing demands on thermocouple stability. Furthermore, above about 1300ºC only thermocouples with Pt-Rh alloy thermoelements of substantial Rh content are recommended, due to the high sensitivity

© 2016 Crown Copyright 238



of alloys of low Rh content to changing composition arising from the significant vapour pressure of Pt and Rh oxides (6, 8–10) and the resulting vapour transport (1, 5, 6, 8–14). For this temperature range, Pt-30%Rh/Pt-6%Rh (designated Type B) (15, 16) and Pt-40%Rh/Pt-20%Rh (Land-Jewell thermocouple) (17) are in widespread use. Above about 1500ºC the Land-Jewell thermocouple is preferred for long term use. In this report, it is shown how to optimise the Pt-Rh wire composition to minimise local composition changes at high temperature due to vapour transport and thereby maximise thermoelectric homogeneity (and therefore stability). This is also applicable to heater elements, where it is desirable to minimise the change in resistance associated with changing composition.

Local changes in composition of Pt-Rh wires are due to evaporation of the oxides of Pt and Rh. Only saturation vapour pressures are considered in this analysis. The vapour pressures of the pure metals Pt and Rh are several orders of magnitude smaller than those of their oxides; only the oxide vapours are considered in this analysis. The vapour pressure of platinum oxide (PtO2) and rhodium oxide (RhO2) have been well characterised and are well known as a function of temperature (8). If the vapour pressures of the two oxides PtO2 and RhO2 are in the same proportion as the molar amount of the two elements Pt and Rh, and there is no significant vapour transport away from the evaporation site, the amount of composition change should be minimised. As the temperature dependence of the oxide vapour pressure is monotonic, at a given temperature there is a unique Pt-Rh alloy which corresponds to the case where the oxide vapour pressures are in the same proportion as the molar ratio of the species in the

into solid metal. The high-temperature end will become depleted and the temperature gradient region enriched (1, 6). These limitations should be borne in mind when considering the analysis.

The Model

The vapour pressures of PtO2 and RhO2 are directly proportional to the partial pressure of oxygen in the atmosphere (8), so the following argument applies to Pt and Rh in air. In pure oxygen gas with partial pressure 100,000 Pa, it has been shown by Alcock and Hooper (8) that the vapour pressure (P) of PtO2 is given by Equation (i):

(8585 ± 74)log PPt = – + (0.204 ± 0.047) + 5 (i)T

For RhO2 it is given by Equation (ii):

(9866 ± 126)

log PRh = – T + (1.079 ± 0.079) + 5 (ii)

The temperature range of validity is from 1000ºC to 1600ºC. Here, P has units of Pa and T has units of K. It is assumed that the uncertainties given in (8) represent expanded uncertainties (coverage factor k = 2) associated with a normal probability distribution. The vapour pressures are plotted in Figure 1 together with their corresponding uncertainties. Also shown in

10

1wire. Thus, in this study the optimal composition is determined as a function of temperature.

This study is concerned with an isothermal wire in stagnant conditions. It should be pointed out that, P

ress

ure,

Pa

0.1

in the case of a thermocouple in typical usage, only Pt oxide Rh oxide

those parts of the wires in the temperature gradient generate the emf. Hence, for application to a real-world system, it is more plausible to base calculations on an intermediate location within the gradient, where the temperature gradient is large and where oxide vapour pressure is signifi cant. Stagnant conditions are assumed: when a temperature gradient is present vapour pumping action occurs within the temperature gradient region. The oxide vapour will naturally diffuse to the low-temperature regions and either condense back to a solid form or disassociate

0.01 Pt oxide – Selman Rh oxide – Selman

1100 1200 1300 1400 1500 1600 1700 Temperature, ºC

Fig. 1. Vapour pressure as a function of temperature for each oxide in isolation (1). Note the crossover where the Rh oxide vapour pressure exceeds that of the Pt oxide above about 1200ºC. Short dashed lines represent uncertainty arising from the parameters given in (8). Grey lines indicate data of Selman (6)


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Figure 1 are the vapour pressure values of Selman (6) which extend to 1500ºC, though the values of Alcock and Hooper are used in preference in this study because Selman does not describe how the vapour pressures were derived.

It is assumed that the thermocouple wire is in a stagnant environment, i.e. vapour does not leave the system. In Figure 2, the molar ratio of Rh and Pt, fRh/fPt, in the wire is plotted as a function of Rh content in wt%. The ratio of vapour pressures of Rh and Pt, PRh/PPt at two temperatures are used to calculate the optimum Pt-Rh composition where the vaporisation leaves it unchanged. When the two curves intersect, the ratios are the same, i.e. Pt and Rh atoms leave the wire in the same proportion as their population in the wire. This means that vaporisation of the oxides leave the wire composition unchanged. It can be seen in Figure 2 that this optimum composition, expressed in terms of wt% Rh, is dependent on temperature.

Rather than using graphical methods, it is of interest to develop an algorithm to locate the optimum fRh at a given temperature. It occurs when the ratio of oxide vapour pressures is equal to the ratio of molar amount of species in the wire (Equation (iii)):

PRh fRh fRh = = (iii)PPt fPt 1 – fRh

2.0

1.5

1.0

0.5

0.0

Rh/

Pt m

olar

ratio

0 10 20 30 40 50 Rh content, wt% Optimal Rh

content at 1100ºC

Optimal Rh content at 1600ºC

Rh:Pt molar ratio in wire Rh:Pt oxide vapour pressure ratio, 1100ºC Rh:Pt oxide vapour pressure ratio, 1600ºC

Fig. 2. Variation of the molar ratio of Rh and Pt in the wire and the ratio of Rh and Pt oxide vapour pressures, with wire Rh composition. Two temperatures are considered: 1100ºC (blue vapour pressure ratio) and 1600ºC (red vapour pressure ratio). At each temperature, the ratios are equal at the intersection of the two curves; at this point, there is no preferential volatilisation of Rh or Pt oxides. The Rh content of the wire corresponding to this point is optimal

Setting Equation (iv): PRh

= (iv)PPt

It follows that the optimum fRh(opt) takes the value (Equation (v)):

fRh (opt) = (v)1 +

It is then possible to plot the optimal wire composition (in terms of the more familiar wt% rather than molar fraction); this is done in Figure 3.

It can be shown with Monte Carlo techniques that the uncertainty of fRh is approximately represented by a normal distribution, regardless of the initial distribution of uncertainties in the original expressions for the vapour pressures (P) (8). The uncertainties of the parameters in (8) were propagated to estimate the resulting uncertainty in fRh using the Monte Carlo method (dashed lines in Figure 3).

Having found the optimum wire composition at a particular temperature (Figure 3), the remaining question is then what the composition of the other wire should be. It might be suggested that the other

55

50

45

40

35

30

25 1100 1200 1300 1400 1500 1600 1700

Temperature, ºC

Opt

imal

Rh

cont

ent,

wt%

Fig. 3. Variation of optimal Rh composition (wt%), fRh(opt) with temperature. This is the point of intersection of the two curves shown in Figure 2, determined at all temperatures. Dashed lines represent the propagated uncertainty, coverage factor k = 2

wire should have lower Rh content to avoid influencing the optimum wire with excess RhO2 vapour. How much lower this should be depends on the acceptable sensitivity (μV ºC–1).

However, given the magnitude of the uncertainties (Figure 3), it is proposed that the optimum strategy is to use a thermocouple having wires of compositions at


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the extremes of the uncertainty limits applicable to the envisaged temperature range of use. For example, if the thermocouple is expected to be used up to 1500ºC, the upper bound on the optimum Rh composition is 50 wt%, while the lower bound is 35 wt%. In this case one may choose the Pt-50%Rh vs. Pt-35%Rh thermocouple, provided the sensitivity (about 1.5 μV ºC–1) is high enough for useful measurements. Note that the above analysis suggests that the Land-Jewell (Pt-40%Rh vs. Pt-20%Rh) thermocouple is not a bad all-round choice for temperature measurements above 1100ºC.

This analysis ignores the fact that in use, the length of the thermocouple will experience the whole range of temperatures from that considered down to the temperature at the reference junction. This approximation is partly justified by the fact that the vapour pressures of both oxides and therefore the effect considered here, decrease exponentially with temperature, with correspondingly diminishing influence of oxide evaporation. The study is based on one set of measurements of the vapour pressure of Pt and Rh oxides which to the author’s knowledge represents the only sufficiently complete data set; should further data come to light it may of course be necessary to review the findings.

Conclusion

By considering transport of Pt and Rh oxide vapour, it has been shown that there is an optimum Pt-Rh wire composition at a given temperature of use for which the evaporation of oxides has no effect on the wire composition, provided the vapour does not leave the vicinity of the wire. This analysis offers a range of suitable wire compositions to study in long-term thermocouple drift tests. The findings may also be of interest for heating applications, where changing Pt-Rh composition results in changing resistance; here the composition of the heating element could be tailored to minimise compositional change.

Acknowledgments

The author is grateful to Richard Rusby (National Physical Laboratory (NPL), UK) for helpful comments on the manuscript. This work was carried out as part of a European Metrology Programme for Innovation and Research (EMPIR) project to enhance process efficiency through improved temperature control (EMPRESS). The EMPIR is jointly funded by the EMPIR

participating countries within the European Association of National Metrology Institutes (EURAMET) and the European Union. © Crown Copyright 2016. Reproduced by permission of the Controller of Her Majesty’s Stationery Office (HMSO) and the Queen’s printer for Scotland.

References 1. T. J. Quinn, ‘Thermocouples’, in “Temperature”,

Academic Press, London, UK, 1983

2. R. D. Barnard, “Thermoelectricity in Metals and Alloys”, Taylor & Francis Group, London, UK, 1972

3. F. J. Blatt, P. A. Schroeder, C. L. Foiles and D. Greig, “Thermoelectric Power of Metals”, Plenum Press, New York, USA, 1976

4. D. D. Pollock, “Thermoelectricity: Theory, Thermometry, Tool”, ASTM Special Technical Publication 852, American Society for Testing and Materials, Philadelphia, Pennsylvania, USA, 1985

5. A. S. Darling and G. L. Selman, “Some Effects of Environment on the Performance of Noble Metal Thermocouples”, Vol. 4, Part 3, TMCSI, 1972, pp. 1633–1644

6. G. L. Selman, “On the Stability of Metal Sheathed Noble Metal Thermocouples”, Vol. 4, Part 3, Section 8C, STSI, 1972, pp. 1883–1840

7. I. L. Rogel’berg and V. M. Beilin, “Alloys for Thermocouples: Handbook”, Metallurgiya, Moscow, Russia, 1983

8. C. B. Alcock and G. W. Hooper, Proc. Roy. Soc. A, 1960, 254, (1279), 551

9. F. Edler and P. Ederer, AIP Conf. Proc., 2013, 1552, 532

10. J. C. Chaston, Platinum Metals Rev., 1975, 19, (4), 135

11. J. Sojka, V. Vodárek, J. Sobotka and M. Dubský, J. Less Common Metals, 1991, 171, (1), 41

12. M. Rubel, M. Pszonicka, M. F. Ebel, A. Jabłoński and W. Palczewska, J. Less Common Metals, 1986, 125, 7

13. H. Jehn, J. Less Common Metals, 1984, 100, 321 14. C. A. Krier and R. I. Jaffee, J. Less Common Metals,

1963, 5, (5), 411 15. British Standards Institution, Thermocouples – Part 1:

E.M.F. Specifications and Tolerances, BS EN 605841: 2013, BSI, London, UK

16. G. W. Burns and J. S. Gallagher, J. Res. Nat. Bur. Stds., 1966, 70C, (2), 89

17. R. E. Bedford, Rev. Sci. Instrum., 1965, 36, (11), 1571


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The Author

Jonathan Pearce, a fellow of the Institute of Physics (FInstP), is a Principal Research Scientist at NPL, where he is responsible for contact thermometry, mainly comprising metrology associated with thermocouples and platinum resistance thermometers. His focus is on solving temperature measurement problems across government, industry and academia. His main interests are improving process control in high-value manufacturing and harsh environments, reducing measurement uncertainty in the realisation and dissemination of the International System of Units (abbreviated SI from the French: Système international dʹunités) unit of temperature, the kelvin and its approximation by the International Temperature Scale of 1990. He joined NPL in 2006 following appointments in the USA and France, and represents the UK on two task groups of the Consultative Committee for Thermometry at the Bureau International des Poids et Mesures (BIPM).


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Reduction of Activated Carbon-Carbon Double Bonds using Highly Active and Enantioselective Double Bond Reductases ENEs from Johnson Matthey’s enzyme collection provide a suitable alternative to metal-catalysed hydrogenation

By Beatriz Domínguez*, Ursula Schell, Serena Bisagni and Thomas Kalthoff Johnson Matthey Catalysis and Chiral Technologies,

260 Cambridge Science Park, Milton Road, Cambridge, CB4 0WE, UK

*Email: [email protected]

The use of enzymes for the asymmetric reduction of activated C=C double bonds is a viable and straightforward alternative to chiral hydrogenation. The number of isolated and characterised double bond reductases (ENEs) has grown significantly over the past fifteen years and the use of this enzyme class in organic synthesis has increased accordingly. In this article we examine the ENE-catalysed reduction of a number of activated alkenes using enzymes from Johnson Matthey’s collection. These reductions proved to be scalable: they can be run at high substrate concentration, delivering the reduced product in high yield and high chemical purity.

1. Introduction

The use of enzymes in organic synthesis offers an alternative to the use of metal catalysts and allows a high degree of chemo-, regio- and enantioselectivity.

Among the redox enzymes commonly employed in organic synthesis there is the group known as ene-reductases (ENEs) that is used for the reduction of activated C=C double bonds. Traditionally, whole cell microorganisms were used for this purpose but a recent increase in the number of isolated and characterised ENEs means that recombinantly expressed enzyme preparations are now generally favoured over whole cells, as a number of recent publications show (1–5).

One well characterised type of ENEs is old yellow enzyme (OYE). Although OYE was first isolated from Saccharomyces pastorianus back in 1932 (6), it was not until 1993 that the reduction of activated alkenes by this enzyme class was reported (7, 8). Since then, OYE family members have been found widely distributed in fungi, bacteria and plants (9).

The enzymatic reduction of alkene derivatives using isolated ENEs has been broadly reported in the literature (1–5, 10–17). Examples of reductions carried out at large, preparative scale are however scarce. To the best of our knowledge, the first reported example of an ENE-catalysed enantiospecific reduction at large scale (70 g) was published in 2012 (18). An initial enzyme screening programme followed by further optimisation of the reaction conditions allowed the authors to achieve acceptable conversion (53% after 20 h, 73% after 44 h) on the reduction of an ester-activated olefin at volume efficiency of 200 mM. Previously to that, low




productivities have been overcome by implementing an in situ substrate feeding product removal (SFPR) strategy (19). This strategy proved very successful, allowing the substrate loading to be increased from 15 to 30 g l–1 and achieving productivities of 59.4 g l–1 day–1 in the reduction of an α,β-unsaturated aldehyde, a chiral intermediate in the synthesis of antidiabetic drug ethyl (S)-2-ethoxy-3-(p-methoxyphenyl)propanoate (EEHP). The reaction was demonstrated at preparative scale (1 g substrate) in the presence of AmberliteTM XAD 1180 ion-exchange resin (1 g, Xr/s = 1).

Alternative strategies to increase the productivity of ENEs in order to make them more attractive for transformations at commercial scale have resorted to protein engineering, including generation of chimeric enzymes. These efforts have led to increased enzyme thermostability, solvent stability or both, resulting in up to ten-fold improvements in conversion rates compared to the naturally occurring enzymes (20). These engineered enzymes have been used at substrate concentrations up to 300 g l–1 .

The present article reports the use of wild-type ENEs from Johnson Matthey’s enzyme collections, which are particularly promising and economically viable for industrial applications owing to their tolerance to high substrate concentrations, up to 1.5 M (equivalent to 257 g l–1).

2. Results and Discussion 2.1 Substrate Scope Characterisation

ENE-101TM , ENE-102TM and ENE-103TM OYEs have been tested for the reduction of a number of electron-deficient double bonds, conjugated to acyl, carboxy, acyloxy, nitro and acylamino groups

(Figure 1). This initial test helped us to defi ne the substrate scope of these enzymes. Results from these reactions are described in Table I.

Reduction of substrates 1 and 2 proved slow and only partial conversion was obtained with ENE-101TM and ENE-102TM (Table I). The formation of side products was not detected for these reactions and enantioselectivity was excellent for both substrates. Substrate 3 was rapidly reduced by ENE-101TM , ENE-102TM and ENE-103TM . Racemisation of the corresponding reduction product, 2-methylcyclopentanone, under the reaction conditions resulted in disappointing enantioselectivity values. The fact that OYEs are better at reducing α-substituted than β-substituted enones has been extensively reported in the literature (21– 23). Good to excellent conversions were observed for substrates 4, 5, 6, 7, 8 and 9 and, again, we did not detect any side product formation.

Substrates 3, 4, 5, 6 and 7 were subsequently tested at higher concentrations: 50, 100 and 300 mM (Table II). The amount of enzyme and other reagents were scaled up accordingly, so the number of equivalents remained constant. The reactions were run in 250 mM phosphate buffer pH 7.0. It should be noted that gluconic acid is generated as the reaction takes place, therefore the buffer strength may not be suffi cient for the more concentrated reactions and the pH of the media may turn too acidic for the enzymes to remain active. Although the evolution of the pH of the reaction media with conversion was not specifi cally measured for these experiments, we observed that, at 100 mM substrate concentration, the media pH had decreased from 7 to ca. 5 when 40% conversion was reached and to ca. pH 4 at 75% conversion.

OO O O CO2Me NO2

CO2Me 1 2 3 4 5 6

NO2NO2 CHO

CO2MeAcHN

7 8 9 10

Fig. 1. Activated alkenes tested in this study


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3

4

3

3

3


Table I Conversion Percentagea and Enantiomeric Excess Percentageb at 20 mM Substrate Concentration, pH 7, 35°C, 18 h

Substrate ENE-101TM ENE-102TM ENE-103TM

1 010.2 (>99.9 S) 37.3 (>99.9 S)

2 018.7 (>99.9 S) 41.6 (>99.9 S)

100 (34.6) c, d 100 (49.2) c, e 100 (75.4) c, d

91.1 (>99.9 R) 100 (>99.9 R)c 85.2 (>99.9 R)

5 97.7 100 100

6 80.2 97.6 100

7 72.7f 88.8f 35.9f

8 100 100 97.4

9 91.6f 80.5f 80.9f

10 33.0f 97.7f 40.1f

a Integration of the product peak in the GC (uncorrected AUC), values below 100% indicate that unreacted starting material was

detected; no side products were detected for these reactions b Stereo. refers to the assigned stereochemistry of the product c Erosion of the product ee in the reaction media has been observed; this erosion is not enzymatically-catalysed d Full conversion was achieved in 6 h e Full conversion was achieved in 3 h f ee has not been determined

Table II Conversion Percentagea and Enantiomeric Excess Percentageb at 50, 100 and 300 mM Substrate Concentration, pH 7, 35C, 18 h

Substrate Enzyme 50 mM 100 mM 300 mM

ENE-101TM 70.1 (14.9)c 67.2 (26.8)c 36.4 (16.0)c

ENE-102TM 68.8 (38.1)c 44.1 (31.8)c 43.9 (31.8)c

ENE-103TM 74.5 (55.2)c 87.3 (48.7)c 51.5 (67.8)c

4 ENE-101TM – 46.3 (>99.9 R) 17.6 (>99.9 R)

4 ENE-102TM – – 37.3 (>99.9 R)

4 ENE-103TM – 69.7 (>99.9 R) 47.1 (>99.9 R)

5 ENE-101TM 52.8 68.5 39.4

5 ENE-102TM 61.9 49.8 39.5

5 ENE-103TM 96.8 83.1 47.0

6 ENE-101TM 7.3 49.9 23.0

6 ENE-102TM 3.4 5.9 11.3

6 ENE-103TM 94.9 95.0 56.2

ENE-101TM 92.4d 81.2d 52.3d

ENE-102TM 85.9d 75.0d 46.8d

ENE-103TM 14.2d 21.6d 21.8d

a Integration of the product peak in the GC (uncorrected AUC), values below 100% indicate that unreacted starting material was

detected; no side products were detected for these reactions b Stereo. refers to the assigned stereochemistry of the product c Erosion of the product ee in the reaction media has been observed; this erosion is not enzymatically-catalysed d ee has not been determined


7

7

7

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These results encouraged us to repeat these reactions at higher than 300 mM substrate concentration introducing strict external pH control of the reaction media.

2.2 Scale-up Experiments

Con

vers

ion,

%

100

80

60

40

20

0 0 12 24 36 48 60 72 84 96

Time, h

The reduction of electron-deficient alkenes by ENE-101TM , ENE-102TM and ENE-103TM , so far demonstrated only at screening scale in Tables I and II, was successfully repeated at preparative scale for substrates 4 (5.9 g) and 6 (4.7 g) at relatively high substrate concentration (from 0.73 to 1.5 M).

The reduction of 4 (5.9 g) at 0.73 M was especially fast with ENE-102TM and full conversion was achieved in 7 h (Figure 2). Additionally, ENE-101TM and ENE-103TM could convert more than 90% of substrate, although over a longer time period (Figure 2). The enantioselectivity of the reaction, 99.9% towards the (S) enantiomer, remained unchanged during the reaction time.

The reduction of 6 was demonstrated at 0.75 M at similar scale (4.7 g). In this case ENE-101TM was the most active enzyme towards the substrate, while ENE-102TM achieved less than 50% conversion (Figure 3). In order to challenge further this enzymatic process, the reduction of 6 was attempted with ENE-101TM at 1.5 M concentration, reaching more than 90% conversion in 96 h (Figure 3).

3. Experimental 3.1 General

All reagents were purchased from Sigma-Aldrich or Alfa Aesar and were of the highest available purity.

0 12 24 36 48 Time, h

Con

vers

ion,

%

100

80

60

40

20

0

Fig. 2. Conversion profiles based on the integration of the

Fig. 3. Conversion profiles based on the integration of the product peak in the GC (uncorrected AUC) for the reduction of 6 (0.75 M substrate concentration) by: ENE-101TM (blue triangles), ENE-102TM (red squares) and ENE-103TM

(green circles) and for the reduction of 6 (1.5 M substrate concentration) by ENE-101TM (purple diamonds). No side products were detected for these reactions

3.2 Enzyme Preparations Genes coding for Johnson Matthey ENEs (ENE-101TM , ENE-102TM and ENE-103TM) were ordered codonoptimised from GeneArt® (Thermo Fisher Scientifi c Inc) and cloned into T5 vector pJEx401 (DNA2.0). Enzymes were expressed recombinantly in Escherichia coli BL21 in both shake flasks and fed batch fermentations, whereby induction was carried out with isopropyl β-D-thiogalactopyranoside (IPTG) at 30C. Harvested biomass was resuspended in 100 mM potassium phosphate buffer (pH 7) and cells were broken up either by sonication or homogenisation. The so-obtained cell lysate was clarified by centrifugation and filtrated prior to lyophilisation. Protein expression was assessed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and chromatographic activity assays.

3.3 Small Scale Reactions for Substrate Scope Characterisation

50 μl of substrates 1–10 solution in toluene (400 mM) followed by 50 μl of a solution of ENE-101TM , ENE-102TM or ENE-103TM enzymes in water (100 mg ml–1; 5 mg enzyme per test) were added to reaction vials containing 900 μl of aqueous media at pH 7 (250 mM potassium phosphate buffer pH 7, 1.1 mM nicotinamide adenine dinucleotide (NAD+), 30 mM

product peak in the GC (uncorrected AUC) for the reduction of 4 (0.73 M substrate concentration) by: ENE-101TM (blue

D-glucose, 10 U ml–1 glucose dehydrogenase (GDH)) to give a final concentration of substrate of 20 mM.

triangles), ENE-102TM (red squares) and ENE-103TM (green circles). No side products were detected for these reactions

The vials were shaken at 35C for 18 h. After adding 1 ml of ethyl acetate the reaction vials were vortexed


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and centrifuged. Samples of the organic phase were analysed by gas chromatography (GC) to measure conversion and enantiomeric excess (ee). When higher concentrations of substrate were added to the reaction (50, 100 and 300 mM) the substrate was added neat without co-solvents and 1.1 equivalents of co-substrate D-glucose were added.

3.4 Scale-up Reactions

In a magnetically stirred 50 ml round bottom flask, equipped with a pH controlled dosing pump, were introduced deionised water (36.3 ml), dipotassium hydrogen phosphate (K2HPO4) (597 mg) and potassium dihydrogen phosphate (KH2PO4) (27 mg), D-glucose monohydrate (1.1 equiv.), sodium chloride (1.68 g) (24), ENE (ENE-101TM, ENE-102TM or ENE-103TM, 1.0 g), GDH (103 mg; 4.88 U mg–1; 500 U), NAD+ (166 mg) and substrate (4 5.9 g; 37.3 mmol; 6 4.67 g, 37.6 mmol or 9.34 g, 75.2 mmol). By default we add NaCl to the reaction media, according to Chaplin and Bucke:

“In general, proteins are stabilised by increasing their concentration and the ionic strength of their environment. Neutral salts compete with proteins for water and bind to charged groups or dipoles. This may result in the interactions between an enzyme’s hydrophobic areas being strengthened causing the enzyme molecules to compress and making them more resistant to thermal unfolding reactions” (24).

The reaction was stirred at 40C until full conversion was observed by GC analysis. In order to maintain a constant pH at 7.0 the reaction was dosed with a 45% sodium hydroxide solution.

3.5 Gas Chromatography Methods

GC analysis of conversion and ee was performed on a Varian CP-3800 using γ-DEXTM 225 capillary column (30 m × 0.25 mm × 0.25 μm) and using helium as carrier gas. The conversion percentage was measured by integration of the product peak in the GC (uncorrected area under curve (AUC)), values below 100% indicate that unreacted starting material was detected. No side products were detected in any of the reported reactions. GC program parameters: injector 250C, flame ionisation detector (FID) 250C, constant flow 5 ml min–1 unless specifi ed otherwise.

1: 60C for 5 min then 5C min–1 up to 110C, then 20C min–1 up to 180C, hold 0.5 min (total time 19 min). tR 7.8 min (R-3-methylcyclopentanone), 7.9 min (S-3-methylcyclopentanone) and 14.0 min (substrate 1)

2: 80C for 5 min then 10C min–1 up to 130C, then 15C min–1 up to 180C, hold 1.67 min (total time 15 min). tR 6.8 min (S-3-methylcyclohexanone), 7.0 min (R-3-methylcyclohexanone) and 10.0 min (substrate 2)

3: 60C for 5 min then 5C min–1 up to 90C, then 20C min–1 up to 180C, hold 0.5 min (total time 16 min). tR 7.0 min, 7.2 min (R- and S-2-methylcyclopentanone) and 9.6 min (substrate 3)

4: 90C for 5 min then 0.5C min–1 up to 94C, then 20C min–1 up to 180C, hold 0.7 min (total time 17 min). tR 6.9 min (dimethyl R-2-methylsuccinate), 7.2 min (dimethyl S-2-methylsuccinate), 10.1 min (substrate 4)

5: 120C for 2 min then 10C min–1 up to 190C, hold 1 min (total time 10 min). tR 4.7 min (nitrocyclohexane) and 5.8 min (substrate 5)

6: 110C for 1 min then 15C min–1 up to 160C, hold 1.67 min; flow 2.5 ml min–1 . tR 3.1 min (1-cyclohexylethanone) and 3.7 min (substrate 6)

7: 100C then 5C min–1 up to 135C, then 15C min–1

up to 170C, hold 1.67 min. tR 5.8 min (citronellal), 6.1 min and 6.5 min (substrate Z/E-7)

8: 80C then 30C min–1 up to 145C, then 0.5C min– 1

up to 150C, then 15C min–1 up to 180C (total time 14.16 min). tR 5.7 min (2-nitropropyl benzene) and 8.11 min (substrate 8)

9: as in 8. tR 5.6 min (2-nitroethylbenzene) and 7.53 min (substrate 9)

10: 120C for 2 min then 1C min–1 up to 140C, then 20C min–1 up to 180C hold 0.7 min (total time 24.7 min). tR 8.14 min (methyl 2-acetamidopropanoate) and 4.8 min (substrate 10).

4. Conclusions

The substrate scope of Johnson Matthey’s ENE-101TM , ENE-102TM and ENE-103TM for the reduction of electron-deficient double bonds has been defined. In addition, the scalability of these reactions has been demonstrated: dimethyl itaconate 4 (5.9 g, 0.73 M) was reduced with excellent enantioselectivity by ENE-102TM to achieve full conversion in 7 h, while the reduction of 1-cyclohexenylethanone 6 (9.34 g, 1.5 M) with ENE-101TM reached more than 90% conversion in 96 h.


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These examples demonstrate the synthetic potential of ENE-101TM, ENE-102TM and ENE-103TM for the synthesis of chiral and achiral intermediates.

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The Authors

Beatriz Domínguez gained her PhD in Synthetic Organic Chemistry from the University of Vigo, Spain, and then moved to the UK where she worked with Professor Tom Brown at the University of Southampton, UK, and with Professor Guy Lloyd-Jones at the University of Bristol, UK. In 2002 she joined Synetix, soon to become Johnson Matthey Catalysts and Chiral Technologies and has worked at the company’s facilities in Cambridge since. For the last fifteen years Beatriz has gained broad experience in the application of metal catalysis, particularly hydrogenation and cross-coupling, working closely with pharmaceutical companies to deliver optimal catalysts for chemical processes. Her interests have more recently expanded to the area of biocatalysis.


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Ursula Schell completed her PhD in Molecular Microbiology in 1998 from the University of Stuttgart, Germany, and then focused on engineering gene clusters for polyketide biosynthesis in streptomycetes. Between 2004 and 2007 she was involved as a postdoctoral fellow in the Engineering and Physical Sciences Research Council (EPSRC) funded Bioconversion – Chemistry – Engineering Interface (BiCE) programme at University College London (UCL), UK, where she recruited transaminases for chiral aminodiol synthesis. She later gained experience at GlaxoSmithKline, UK, where her team improved a microbial expression platform and contributed to the early process development of microbially derived drug candidates. Ursula joined Johnson Matthey’s catalysis team in 2012 and supervises both enzyme engineering and bioproduction projects.

Serena Bisagni completed her MSc in Industrial Biotechnology from the University of Pavia, Italy, in 2010 and then moved to Lund University, Sweden, for her postgraduate studies. In 2014 she obtained her PhD in Biotechnology in which she focused on the identification of new Baeyer-Villiger monooxygenases for fine chemicals synthesis within the Marie Curie Innovative Training Networks (ITN) ‘Biotrains’. In 2015 Serena joined Johnson Matthey Catalysts and Chiral Technologies where she is a Research Chemist. Her main interests are enzyme screening for synthesis of active pharmaceutical ingredients and fine chemicals and identification of new biocatalysts to add to Johnson Matthey’s enzyme portfolio.

Thomas Kalthoff graduated in Chemical Engineering from Niederrhein University, Germany. He co-founded Jülich Fine Chemicals GmbH, Germany, while working on process development in biocatalysis. After the acquisition by Codexis Inc in 2005, Thomas was involved in technology integration and scale-up projects for the production of chiral intermediates before he joined Johnson Matthey Catalysis and Chiral Technologies in 2010 as Senior Process Engineer.


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“Handbook of Metathesis” 2nd Edition Edited by Robert H. Grubbs (California Institute of Technology, USA), Anna G. Wenzel (W. M. Keck Science Center, USA), Daniel J. O’Leary (Pomona College, USA) and Ezat Khosravi (University of Durham, UK), Volumes 1–3, ISBN: 978-3-527-33424-7, 1608 pages, Wiley-VCH, Weinheim, Germany, 2015, £365.00, €492.80, US$605.00

Reviewed by Valerian Dragutan* and Ileana Dragutan** Romanian Academy, Institute of Organic Chemistry 202B Spl. Independentei, POB 35-108, Bucharest 060023, Romania

Email: *[email protected], **[email protected]

Published more than ten years after the fi rst edition of “Handbook of Metathesis” (1) which enjoyed tremendous success, the new edition is a milestone in the development of metathesis chemistry. The three volumes are edited by the Nobel laureate Professor Robert H. Grubbs (California Institute of Technology, USA) in collaboration with an impressive panel of co-editors, all famous experts in the field. 41 comprehensive chapters, superbly written by 86 internationally well-recognised contributors, cover to date the most significant advances in metathesis chemistry and its industrial applications based on more than 2200 literature references. Since the fi rst edition several books, thematic issues and extensive reviews on metathesis reactions have appeared (2–8) and this new edition enormously adds to the present knowledge, representing the most important compendium of the

state-of-the-art of alkene, alkane and alkyne metathesis and metathesis polymerisation, with a strong focus on the present research in this fascinating fi eld of chemistry. Metathesis has real potential for large scale valorisation in many industrial areas in the near future.

Volume 1: “Catalyst Development and Mechanism”

The first volume, “Catalyst Development and Mechanism” (423 pp.), edited by Robert Grubbs and Anna Wenzel covers the most recent developments in metathesis catalysts and reaction mechanism.

High Oxidation State Molybdenum and Tungsten Catalysts

In Chapter 1 the Nobel laureate Professor Richard R. Schrock (Massachusetts Institute of Technology, USA) authoritatively and attractively surveys high oxidation state molybdenum and tungsten complexes relevant to olefin metathesis. Special attention is paid to the synthesis of novel imido ligands, bispyrrolide and related complexes, and to the appealing applications of monoalkoxide pyrrolide (MAP) complexes which are highly effi cient in Z-selective olefin metathesis reactions (homocoupling, cross-coupling, ethenolysis and ring-opening metathesis polymerisation (ROMP)). Th

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