Metolachlor

(S)-Metolachlor

1. Introduction
1.1. Background

The agriculture industry started to developed due to the extensive needs of food in the society. As the technology in agriculture industry developed, new chemicals were created to try to protect crops from external treats, one of this are the so-called Pesticides. These pesticides allow farmers to protect their crops and by this supply goods with increase quality and quantity. These chemicals proved to be beneficial by thus increasing the consumer demand for quality agriculture goods. The pesticides classified in two mainly chemical classes, insecticides and herbicides. Herbicides were introduced in the 19th century, and by the 20th century they had gain wide acceptances as weed killers due to their target specific capacity. This enables them to kill specific plant without harming any others.[1]

Their activities, use, chemical family, mode of action or type of vegetation controlled, are the different ways herbicides can be divided. They are use to clear waste ground, industrial sites, railways and railway embankments, are non-specific, which mean they kill every plan they come in contact with. Smaller quantities are used in forestry, pasture systems, and management of areas set aside as wildlife habitat. They account for the 70% of pesticides used in the United States. In recent years the herbicides have been formulated to decay after a short period of its application. This characteristic allows the farms to use the land for crops that are herbicide sensitive in future seasons.[2]

The way an herbicide is applied is as a water-bases spray, the equipment that is use to spray it varies in design. Some examples are self-propelled, towed, handheld and even horse-drawn sprayers. Other ways to apply them is by air, using helicopters or airplanes with irrigation systems.[3]

In the present time a new term has emerged, the “organic” herbicide, which means that they are used only in organic, farming instead of the correct use of the word that means that they contain carbon as a primary molecular component. Under the new definition an organic herbicide is use only in crops that are classified as organic. They are very expensive and much less effective that the synthetic herbicides (carbon base ones).

There are different names for the type of specification the herbicide has. For instance a control herbicide is the one that destroys or damage the unwanted weeds to the point where they can no longer compete with the crop. Other is suppressive herbicide, and this only reduces the competitiveness of the weed with the crop to the point where it still provides some economical benefit. The last one is crop safety; this is use for selective herbicides and provides very little stress to the crop.[4]

1.2. (S)-Metolachlor

Metolachlor is an organic herbicide, a derivative of aniline and member of the chloroacetanilide herbicides.[5] It is a selective herbicide, and can be use as pre-plant surface-applied, pre-plant incorporated or pre-emerges application; providing long lasting control of most annual grasses and small-seeded broadleaf weeds. Provides weed control, application flexibility and fits all cropping systems.[6]

It was developed by Ciba-Geigy (part of the Novartis Group) in 1972 and produced as a racemic mixture of its four stereoisomers. By the year 1982, it was found that the S-enantiomers provided the most biological activity, and du to concerns of the possible effects of the “inactive” R-enantiomers the company decide to develop a new manufacturing process which will allow them to produce only the active one. An effort to synthesize s-metolachlor via enantioselective catalysis method was made in 1983 that proved to be unsuccessful. In 1985 another attempt was made using rhodium catalyst but this too did not worked. It was until 1987 when the discovery of a Iridium diphosphine catalyst was developed that allow the production of an enantioselective synthesis of s-metolachlor. By 1992 a patent was granted to the company for the production of the racemic mixture of metolachlor with the new process and in 1995-1996 excellent results were achieved in a pilot scale. In 1997 the full-scale plant was launched producing over 10,000 tonnes per year of the new (s)-metolachlor process. A new patent application was submitted in 1998 and granted the next year for the manufacture of the (s)-metolachlor in pure form.[7]

Today it is used in 70 different crops around the world, some examples been corn, soybeans and rice.

This report will cover different ways of manufacturing metolachlor, ones with the final product been (s)-metolachlor and others with a racemic mixture. Base on the analysis of these routes one was selected base on best combination of yield, selectivity, cost and safety. After the selection was made the design of a chemical plant started by taking in consideration the raw materials needed, the manufacturing site, the environmental laws and the market shares.

1.3. Team Picture

Group 6 (from left to right): Darlington Abban, Akshay Rege, Fabiola Segovia, Priyank Patel and Juntao Su.

2. Process Route Evaluation and Selection

Metolachlor is an organic compound and it's a widely used herbicide. It is a derivative of aniline and is a member of chloroacetanilide herbicide. Also it has 4 different isomeric forms, which is governed by arrangement of aliphatic side chain and chiral axis between the phenyl group and nitrogen atom. Consequently, it was found that S-isomer has higher biological activity than the other isomers. Therefore it was crucial for the selection of a manufacturing route, which will favour selectivity for S-enantiomers. In the evaluation of the synthesis of (S)-Metolachlor, we seek a synthesis that can help us produce ten thousand tonnes of (S)-Metolachlor a year with a competitive operating cost. Also we seek a process that will have lesser emission of the toxic gases and hazardous waste also the suitable safety measures will be considered for the development of process for the large scale manufacturing of the product.

2.1. Uses and Application of (S)-Metolachlor

Metolachlor is a widely used herbicide for the effective control of weeds in many agricultural food and feed crops.

2.2. Route Evaluation

In attempts to synthesize (S)-Metolachlor, the problem encountered was the hydrogenation of the imine produced after the condensation of methyl ethyl amine (MEA) and methoxy acetone (MOA) to the chiral amine required.

The Corey-Bakshi-Shibata (Scheme 1) reducing agent was the first catalyst to be tried in the quest to reduce the MEA-imine to the chiral amine. Though overall this synthesis produced a very good yield and enantiomeric excess (ee) it had serious constraints such as the use of p-toluene sulphonic acid in the condensation step. P-toluene sulphonic acid is very expensive and corrosive acid and also the Corey-Bakshi-Shibata reducing agent used was identified to be very expensive and could also not meet the demand of producing the high tonnage required. Also it was realized that to purify the amine after the reduction of the imine chromatography was employed which is difficult for applying at large scale.[8]

Scheme 1. Reduction of imine using Corey-Bakshi-Shibata.

Attempts were made to achieve the chiral amine after condensation by means of enamide hydrogenation, nucleophilic substitution of (R)-Methoxyisopropanol derivatives and catalytic hydrogenation of MEA-imine using iridium based catalyst (Scheme 2).

The use of enamide hydrogenation to achieve the chiral amine required was inspired by Monsanto's successful bid to synthesize L-Dopa by this means. This route was not successful because of the difficulty in the formation of the selective enamide. Hence the use of rhodium diphosphate catalyst did not yield anything, despite the use of different rhodium catalyst under different conditions.[9]

Scheme 2. Enamide Hydrogenation using Rh based catalyst.

For the nucleophilic substitution of (R)-Methoxyisopropanol derivatives, the hydrogenation of methoxy acetone was successful with cinchonidine modified palladium catalyst; the use of this route could not be implemented on the large scale because its ee never went above 12% (Scheme 3).[10]

Scheme 3. Nucleophilic substitution.

The hydrogenation of the imine using iridium catalyst (Scheme 4) resulted the most feasible option in relation to the amount of product that needs to be produced in a year. The inspiration for the use of iridium catalyst came from Crabtree who had described the extra ordinary active Ir/tricyclohexyphosphine/pyridine catalyst that was able to hydrogenate even tetra-substituted double bonds. Because of the activity of iridium described by Crabtree different ligands were screened to optimize the catalytic effect of iridium. When Ir-bdpp was used as the catalyst for the hydrogenation process in the presence of iodide ions ee of 84% was achieved at 0o C, but the activity of the catalyst was disappointing.[11]

Scheme 4. Hydrogenation of imine using Ir catalyst.

In the use of iridium-diphosphine catalyst in the presence of iodine turnover numbers of 10,000 and turnover frequency of 250 per hour at 100 bar and 25o C was observed but the major problem with the use of this catalyst was that its deactivation was irreversible. The activity of this catalyst fell short of the capacity required for production leading to the search and discovery of the iridium-ferrocenyl diphosphine catalyst which proved to be very active and did not deactivated. The use of this catalyst looked very much the better option though it is expensive.[12]

Another synthetic route that was considered to be used on the large-scale synthesis of (S)-Metolachlor employed the use of the enzyme Candida Antarctica lipase B (CAL-B). The process was achieved by the hydrolyse the ester produced from the reaction of methyl ethyl aniline, methyl-2-bromopropionate and sodium bicarbonate to a chiral acid with the stereocentre as required in (S)-Metolachlor (Scheme 5). The problem with this synthesis is that the enzyme used is not very selective for the (S)-Metolachlor enantiomer and its conversion rate of 48.2% was low with respect to demand, though it gave a very good ee of 98% on addition of some organic compound. This route could be very good on large scale considering the health safety and environmental issues and also the mild conditions under which it is done. With this route the unwanted (R)-Metolachlor can be recycled back into the system, which would almost allow a 100% yield.[13]

Scheme 5. Chemoenzymatic synthesis.
2.3. Selection of Route

Considering all the synthetic routes outlined above, the route that will help us achieve our production targets is the use of iridium-ferrocenyl diphosphine catalyst. Despite the high cost of the catalyst, it presented us with the best option aside of the chemoenzymatic one which has not been prove on the large scale. The use of the iridium-ferrocenyl diphosphine catalyst presents us with a high yield of more than 79% and ee of more than 99.5% at 50o C temperature and 80 bar pressure for 4 hours.[14] The catalyst had a turnover frequency of 1,800,000 per hour. Also during the separation of the final product as the iridium metal is recovered and the chiral ligand is lost. This is one of the major advantages of selecting this route as we are recovering a precious and expensive metal. Above all the reactions conditions and safety parameters need to be considered can be efficiently controlled with the application of efficient Distributed Control System. Lastly the manufacturing of (S)-Metolachlor with the use of iridium-ferrocenyl diphosphine catalyst can be very much beneficial for manufacturing 10,000 MT per year. In the optimization of the selected route the synthesis was not smooth running; in the condensation of the MEA and MOA side reactions were observed in an attempt to push the reaction to 100% conversion. Also the catalysed posed a problem in its use, since it was in solid form. In the solid form if new catalyst needed to be added to the reaction it was going to be difficult hence the conversion of the catalyst to the liquid form, which could be easily and safely added to the hydrogenation reactor. Surprisingly the catalyst was found to be more active in the liquid state.

The methoxy acetone was first fed into the reactor followed by the addition of sulphuric acid and methlyethyl aniline simultaneously so that the amount of heat produced by the reaction is reduced. Water was separated from imine product and the product hydrogenated using irridium-xyliphos catalyst at a controlled pressure of 80 bars and temperature of 50 C. The amine product formed (S-NAA) was separated and reacted with chloroacetyl chloride using benzene as the reaction solvent. The final product (S-metolachlor) was extracted and dried.

The manufacturing of S-Metolachlor with the use of iridium-ferrocenyl diphosphine catalyst can be very much beneficial for manufacturing 10,000 MT per year. In the optimization of the selected route the synthesis was not smooth running; in the condensation of the MEA and MOA side reactions were observed in an attempt to push the reaction to 100% conversion. Also the catalysed posed a problem in its use, since it was in solid form. In the solid form if new catalyst needed to be added to the reaction it was going to be difficult hence the conversion of the catalyst to the liquid form, which could be easily and safely added to the hydrogenation reactor. Surprisingly the catalyst was found to be more active in the liquid state.

3. Process Flow Diagram and Evaluation/Selection of Appropriate Unit

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(S)-Metolachlor

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(S)-Metolachlor

4. Sources & Properties of Raw Material Feedstocks (Darlington Abban)

The availability of raw materials, its source sources and cost play an important role in the manufacturing of a product. In the manufacture af agrochemicals, the cost of the end product is very important since it must be fist of all non toxic and cheap to the consumer hence cheaper and non toxic chemicals are the best options.

4.1. 2-Methyl-6 Ethylaniline

It is an aromatic amine of a molecular weight of 135.21g/mol. It is a pale yellow oily liquid with a pungent odour. It has a boiling point of about 2310C/760mmHg and freezes at about -330C. Its vapour pressure it taught to be about 0.06 mmHg/20 C and a vapour density of about 4.66g/cm3. In the liquid form its density is 0.968g/cm3

Chemically, 2-metyl-6ehylaniline is a very stable compound at standard room temperature and pressure, but it is very incompatible with strong oxidizing agents. It undergoes an exothermic reaction when in neutralization with an acid. It is soluble in ethanol, iso-octane, toluene and other organic solvents. This compound is light and air sensitive and hence must be kept away from these sources to prevent it from decomposing before use. This compound on decomposing produces carbon monoxide, carbon dioxide, nitrogen oxides, which are not environmentally friendly, it also produces irritating, toxic fumes and gases such as ammonia o decomposition. It is mostly transported by sea has not been classified as a hazardous material but must not come in contact with anything edible. It is estimated to cost about £100 per tonne.

4.2. Methoxy Acetone

It is a clear yellow liquid with molecular weight of 88.106g/mol and a density of 0.95 g/cm3. It has a very low flash point of 250C making the liquid and its vapour very flammable and hence must be kept away from any source of ignition and excess heat. Methoxy acetone is miscible with water and has a boiling point of about 1180C. Under normal conditions, it is stable. It is not compatible with strong oxidizing agents and strong acids and produces carbon monoxide and carbon dioxide on decomposition.

Methoxyacetone is a source of skin and eye irritation and may cause cyanosis of the extremities with exposure to the skin. Inhalation of the vapour causes gastrointestinal irritation and may cause dizziness and sometimes suffocation if exposed to its vapour for along period. Prolonged exposure to methoxy acetone may also cause dermatitis. It also causes irritation to the respiratory tract and depression of the central nervous system. It's estimated to cost about £400 per tonne.

4.3. Sulphuric Acid

It is a highly reactive colourless, odourless, oily liquid with a molecular weight of 98.71g/mol. It has a specific gravity of 1.84g/ccm3 and a vapour density of 3.38g/cm3. Its melting point is known to be about 10.350C and the boiling point 3400C

It combines vigorously with water with the evolution of heat leading to the boiling of liquid mixture sometimes. Explosion can occur if it is mixed with water in a sealed vessel due to the pressure of evolving hydrogen gas. Contact with metals should be avoided since sulphuric acid is known to be a strong corrosive acid. As much as possible, it should not be exposed to excess heat because of it decomposition to give off very toxic fumes and gases such as the oxides sulphur, which are also irritating. Contacts between sulphuric acid and bases should be avoided; it should also not be mixed with dehydrating agents. Cyanide compounds should be far from sulphuric acid since the combination of two will produce hydrogen cyanide that is known to be a very lethal gas. It causes severe burns on contact with the skin.

Its mist is carcinogenic to humans but not the solution. Long term exposure of humans to sulphuric leads to inflammation of the lungs and decay of the teeth. Its cost is estimated to be between £45 and £55 per tonne depending on the purity.

4.4. Benzene

Benzene, sometimes known as benzolene is a colourless liquid with a melting point of about 5.5° C and a boiling point of bout 80° C. It has a specific gravity of about 0.87g/cm3 and a flash point of about -11. Benzene has a vapour pressure of 74.6mmHg/20° C and auto ignites at 561° C.

Normally, benzene is very stable. Benzene should be shielded from strong oxidizing agents, sulphuric acid, nitric acid and halogens. Its contact with any ignition source should be avoided because it is a highly flammable substance.

Before the use of benzene, one must have considered other safer compounds because benzene is a known carcinogen. It is a skin and respiratory irritant. Long-term exposure to benzene causes irreversible effects but in the short term, it causes depression of the central nervous system, nausea, vomiting, dizziness, narcosis and reduction in blood pressure. Contact with the skin leads to dermatitis. Its cost is relatively low at about £230 per tonne.

4.5. Potassium Iodide

It is an odourless white crystal with a molecular weight of 166.0g/mol. It is soluble in water and has a density of 3.1g/mol. It has a melting point at 6800C and a boiling point of about 13300C. It is stable under normal condition of use and storage but when exposed to air for a long period becomes yellow and loses the iodine. Potassium iodide is not compatible with oxidants, metallic salts, tartaric acid, and other salts.

Inhalation of potassium iodide dust causes coughing and shortness of breath. Contact with skin and eyes cause redness and pain. Chronic exposure to potassium iodide causes “iodism” which is made evident through sin rash, running nose, headache, weakness and general depression.

4.6. Hydrogen

It is a colourless odourless gas that boils at -252.80C and freezes at 2590C. It has a density of 0.06g/cm3/ 210C and slightly soluble in water. It stable but react under the conditions of an elevated temperature. Hydrogen is not compatible with oxidizing materials such as oxygen chlorine, bromine and nitrogen triflouride metal oxides, metal salts and halocarbons. Hydrogen is estimated to cost £20 per 100m3.

4.7. Chloroacetyl Chloride

It is a colourless liquid with a strong pungent odour with a molecular weight of 112.95g/mol. It melts at -22° C and boils at 105° C. It has a specific gravity of 1.418g/cm3, and vapour density of 3.9g/cm3.

Though chloroacetyl chloride is stable, it is incompatible with strong bases, alcohols and strong oxidizing agents. It is extremely corrosive and reacts violently with water or moisture.

It is an irritant and corrosive to both the skin and eyes and it is a lachrymator. It is very destructive to the mucus membrane and may cause skin burns when it comes in contact with it. Severe inhalation may cause coughing, choking, or shortness of breathe and may be toxic to the central nervous system.

This compound is not to be released into the environment because it is very toxic to aquatic life. Its cost is also estimated be around £350 per tonne.

4.8. Acetic Acid

Sometimes known as glacial acetic acid, it s a clear colour less liquid with a strong pungent odour like that of vinegar and has a molecular weight of 112.95g/mol. It has a specific gravity of 1.05g/cm3; it has a melting of 16.7° C and a boiling point of about 118° C. Acetic acid is very corrosive and a lachrymator. It causes serious burns when it comes in contact with the skin and very harmful when swallowed. It is miscible with water and also a lachrymator. When using acetic acid, one must avoid heating at high temperatures, ignition source and other substances that are not compatible with it such as; strong oxidizing agents, aldehydes, anhydrides, alcohols, alkali hydroxide, permanganates, peroxides, ethanolamine and carbonates. Its cost is estimated to be about £560 per tonne.

4.9. Iridium Catalyst

The ligand used together with the iridium metal to make the catalyst is xylophone, (ferrocenyl diphosphate). The catalyst itself exist as a solid but make its use easier, its solution was prepared with some additives to maintain the activity of the catalyst.

It is not affected by air, acid, and water. It causes irritation to the eye and the digestive tract when it comes into contact with the eye and when it is ingested. It is flammable. It is toxic to aquatic life hence it should not be released into the environment. The catalyst is very expensive but is being used in the chosen synthesis because of its activity and also because it can be recycled.

The reagents, solvents, and catalyst to be used for the process will be purchased from the United States because of its proximity to the chosen site of Brazil and also because of the political stability the country enjoys.

5. Uses and Applications of the Product (Akshay Rege)

Metolachlor is extensively used as an herbicide for weed control for more than 70 crops worldwide. It is one of the most widely used herbicides in United states of America, according to an United states department of agriculture (USDA) survey over 45,000 pounds of metolachlor was used in the year 1996 in which maize and soybeans were the major planted areas. Some of the crops in which metolachlor are used widely are as follows - maize, soya bean, sweet corns, rice, kidney beans, carrots, coffee, cotton, sunflowers, sugarcane, tea, tobacco. Metolachlor is often used in mixture with other herbicides such as atrazine to widen the spectrum of control over weeds.[15] Metolachlor is also used to control broad-leaved weeds and grasses as well. The estimated production of metolachlor is around 30000 tonnes per year worldwide. Metolachlor is a chiral compound and there is presence of two chiral elements, one an asymmetrically substituted carbon and second a chiral axis between the phenyl and the nitrogen atom. Metolachlor mainly consist of four stable isomers of which the most herbicidal activity is shown by the S-isomers i.e. 95 % [2]. In India potato is a major cash crop in north India, which in infected by various species of weeds. Metolachlor has very recently been registered for weed control in India [10]. In Malaysia it was observed that metolachlor caused great reduction in bacterial population. There was approximately 75% reduction in bacterial counts. Thus use of herbicides needs to be careful, as the micro flora is responsible for degradation as their activity affects the accumulation of plant debris on soil surfaces. Organic matter decomposition is an important process.[16]

5.1. Agricultural View

Metolachlor has contributed to the rapid development of conservation of tillage systems. There are many advantages of the system such as reduction in loss of topsoil and water. There is less energy like fuel and labour are required. These reduced tillage systems can prove important for efficient and high production in agriculture technology in future. In areas where (S)-metolachlor is to be used adequate rainfall or efficient irrigation facilities are essential. Rainfall or irrigation is mainly essential in clearing the herbicide from the plant into the soil and moving it into the zone of weed seed germination. Rainfall or irrigation is essential as longer the herbicide remains on the residue higher volatilization, photo degradation and adsorption by the residue is obtained. Metolachlor has a good biological activity. The rate of loss of energy (dissipation) of metolachlor is rapid under normal field conditions to avoid toxic effect of compound on plant growth (phytotoxicity) in case of rotation of crops in during different seasons. Metolachlor can cause some damage to some sensitive crops if they are planted after herbicide application. It has been observed by scientists that rate of degradation of metolachlor was faster in clay loam soils than sandy loam soils. It has also been observed that the rate of degradation of metolachlor is not affected by presence of moisture or carbon dioxide (CO2) in atmosphere. The biological half-life for metolachlor is estimated to be around 13 to 100 days under various temperatures.[17]

5.2. Market for (S)-Metolachlor

Metolachlor and alachlor has similar effects on weed control. Alachlor is a chloroacetanilide herbicide for agricultural crops like corn and soybean. The annual usage of alachlor in United States of America was found to be 6 to 9 million pounds per year in the year 2004 [4]. Alachlor has wide usage in China as well. But certain problems have been faced in use of alachlor. Alachlor is cytotoxic to human hepatoblastoma cells. When tested on rats it is rapidly and extensively metabolized. The liver has been observed as main target organ for toxicity in case of animals like rats and dog.[18] Alachlor is a pre and post - emergent herbicide that was marketed in the year 1969 under the trade name of Lasso. Alachlor showed another problem when tested on animals and when survey of the alachlor manufacturing workers was carried. In animals (rats) alachlor produced thyroid, nasal and stomach cancers by a nongenotoxic, threshold sensitive process. In alachlor manufacturing workers colorectal cancer and leukemia was observed. But, interpretations of these results were difficult as small numbers of cases were observed and lack of safety controls had lead to exposures.[19] Alachlor is also known to be a highly toxic endocrine disrupting chemical.[20] Comparative studies of alachlor and Metolachlor were performed in order to obtain transformation pattern in corn and soil. It was observed that alachlor was more readily absorbed than metolachlor. Alachlor was absorbed 72 % whereas metolachlor was absorbed 55 %. Alachlor and metolachlor were rapidly metabolised in corn. But metabolism rate of metolachlor was higher than that of alachlor. Number of metabolites produced by metolachlor was less than that of alachlor. Another problem faced by alachlor was release of radioactivity. Plants treated with alachlor released more radioactivity than that by plants treated with metolachlor.[21] Acetochlor has similar herbicidal activity as that of alachlor and metolachlor. Acetochlor herbicide is widely used in China. Acetochlor was registered in March 1994. But the main disadvantage of this herbicide is its classification as B -2 carcinogen by the United States environmental protection agency (USEPA). Acetochlor and its metabolites have widely spread in surface, ground waters and soils. High acetochlor concentration effluents are discharged from plants causing severe pollution problems. The toxicity of acetochlor has reported chromatid exchanges in cultured human lymphocytes, mutagenizing germ cell of male rats and altering thyroid hormone- dependent gene expression in xenopus laevis. The presence of acetochlor and its metabolites pollution in water have been a major problem. Treatment of water by processes like ozonation, photo catalysis, etc., has been experimented but no significant result has been observed.[22] Acetochlor is also been reported as a mutagen. It has caused liver carcinomas, carcinomas of the lungs, uterine sarcomas, ovarian tumours, thyroid follicular cell adenomas and nasal papillary adenomas. Rare tumours of femur had also being reported. Basal cell tumours of the stomach were also observed.[23] Similar to alachlor and acetochlor another herbicide having similar action like metolachlor called Butachlor was studied. Butachlor is also reported of consisting of higher cytotoxicity as compared to that of metolachlor. As metolachlor has advantages over alachlor, acetochlor and butachlor it's preferred as an herbicide in its class. The carcinogenicity of (S)-metolachlor has not been reported as compared to its competitors. This herbicide has acquired registration in developing countries like India, Pakistan, and Bangladesh and in developed countries like Belgium, Taiwan where it will be extensively used. As the demand for herbicides is increasing day by day to yield more quality products metolachlor has bright future market as compared to other herbicides.

5.3. Method of Application

Metolachlor is a selective pre- emergence herbicide of chloroacetanilide group. S-metolachlor is used for control of Echinocloa crusgalli, Digitaria bifociculata, Amaranthus Viridis, Cyperus esculentus, Setaria viridis, Striga asiatica, Eleucine indica, Portulaca oleracea and trianthema monogyna. The roots and shoots of seedlings that help in inhibition of root elongation absorb the herbicide. The inhibition of cell development, cell enlargement with cell expansion and mitotic activity restricts growth of early seedlings. Biochemically and physiologically metolachlor affects protein synthesis, lipid synthesis, gibberallic acid induced reactions, respiration and photosynthesis.[24]

5.4. Technical Obsolescence

The term obsolescence refers to change of equipment done due discovery of a new equipment performing the same functions. Due to advancement in science and technology there has been a tremendous boom in the discovery of new equipments. The equipments used in process of metolachlor such as pumps, storage tanks, reactors, distillation columns, dryers, transfer pipes consist wide range of inventions.

To summarize, metolachlor has a wide application and potential market in the field of agriculture. It scores a number of advantages over its competitors in main applications like health and safety making it fore runner in its class. The presences of two chiral elements enhance the herbicide activity.

6. Site Selection (Priyank S. Patel)

The geographical location of the manufacturing facility or a plant site plays a vital role for any chemical business venture. Therefore utmost care and judgment should be taken for the selection of the plant site. The ideal location for a plant site would be the place where the cost of manufacturing is comparatively low and the potential market is not very far. Moreover the government policy for chemical industries, availability and cost of labour along with the infrastructure development & support from surrounding community is very much crucial for future development of the industry.[25]

6.1. Critical aspects of site selection

There are several more factors, which need careful consideration for site selection of a chemical plant. Below mentioned are some of the important considerations to be made however the list should not be considered exhaustive.[26]

6.1.1. Raw materials availability

The source or the availability of the raw material is very much important factor influencing the site selection. This is particularly true for our project as the production capacity is in thousands of tones. Attention should be given to the price of raw material, transportation expenses, availability and reliability of the supplier and lastly the specific storage requirements of the raw materials.

6.1.2. Energy Requirement

For the continuous and large-scale production of (S)-Metolachlor it is very much important to consider the cost of energy for operating of the plant, as the electricity consumption will be significantly high. Therefore the local cost of electricity can help to determine whether electricity is to be purchased or self generated, if it has to be self generated the availability of large quantities of coal or oil in the nearby areas would be preferable.

6.1.3. Water Supply

For the production of (S)-Metolachlor in large quantity, amount of water used in different unit operations will be very much high, therefore plant site must be located where sufficient water supply is available i.e. site near a river, lake or huge quantity of water in deep well is preferable. Moreover the quality of water needs to be assured and if required the purification cost should be considered.

6.1.4. Waste treatment and disposal

Due to increase in awareness in respect to environmental damage done by chemical industries and many legal restrictions imposes, it is very much important for developing efficient Effluent Treatment Plant for treating huge quantity of waste generated for manufacturing of (S)-Metolachlor. Therefore care should be taken for proper disposal of waste left after treatment and controlling the permissible limits of waste disposal set out by the local government.

6.1.5. Transportation facilities

Water, Railway, and Roadways comprise the common means of transportation for various chemicals. Since the quantity of raw materials and production of (S)-Metolachlor is very much it is will be very much beneficial for having access to all the three major means of transportation in the nearer to the plant site. Lastly the existing and future developments of infrastructure for railways and roadways should be carefully considered.

6.1.6. Climatic conditions

If the plant is located in a colder region, it may have significant influence on the capital as well as operating cost of the plant as the necessity for constructing protective shelter around the process equipments and a special cooling or heating equipment may be required depending upon the behaviour of the S-Metolachlor at different temperature conditions. Also the effect of humidity and extreme temperatures fluctuations observed over the period of day and night observed at some place should be carefully considered before the final selection of the site.

6.1.7. Market proximity

The availability of a potential market nearer to the manufacturing facility is the most important factor for consideration of site selection. As the location of markets has the significant effect on marketing distribution and shipping of the product, moreover a buyer usually prefers to purchase from the nearer source. It has also to be noted that along with the potential market of desired product, market for the side or by products should also be given importance.

6.1.8. Labour supply

The type and availability of labourers in vicinity of the plant site must be carefully examined. Also considerations should be given to prevailing pay scale, restrictions on working hours per week, presence of other industries in the nearby location and the wages paid by those industries can also affect the availability of work force for our industry and variations in skills and productivity of workers should be carefully examined.

6.1.9. Local community

The nature and facilities provided by the government or the industry can have an effect on the selection of plant site. If minimum number of facilities for satisfactory living plant personnel is not provided, it can become a burden or a source of many difficulties for smooth operation of manufacturing facility on the continuous scale. Availability for cultural facilities like religious centres, libraries, grocery markets, civic theatres and many more should be considered. In this context the efficiency of state and national level government should be carefully evaluated. The existence of low taxes is not a favourable situation unless the community is well developed.

6.1.10. Taxation and Legal Restrictions

Tax collected by state and National governments on property, income and other forms of government duties should be carefully studied as they vary from nation to nation and final choice of site should be made considering the long term effects and any increase in taxation structure by the government in future. Also the different type of insurance required for operating the manufacturing facility guided by the local government policies needs a critical consideration.

6.2. Potential Site for S-Metolachlor

For manufacturing 10,000 MT of S-Metolachlor per year it was very much essential to have a potential market in the proximity of the manufacturing facility, along with the suitability of the factors discussed above. The factors discussed above were channelized for the selection of suitable plant site and Brazil was selected to be the potential manufacturing site over The United States of America, Canada, China and India.

Brazil is selected as the potential plant site as it has vast agricultural resources and the climatic conditions are semi-temperate, higher rainfall, good compositions of minerals in soil, experienced farmers and well developed farming technology and infrastructure. These factors suggest that the potential market for S-Metolachlor is very high in Brazil, although other countries like USA, Canada, China and India are definitely potential market for S-Metolachlor, the key factor for selecting Brazil in this context is the presence of lesser competitive S-Metolachlor manufacturing companies. Despite the availability of raw materials is much higher in India and China at cheaper rate because of huge competitive market, this can often lead to compromise in raw materials quality and thereby may affect the continuous and smooth operation of plant for manufacturing S-Metolachlor in large quantities. Therefore it is advisable to import raw materials from USA if not available from Brazil itself. Moreover Brazil is a promising and emerging economies in the world and therefore the government policies can be quite flexible in terms of taxation and future expansion of the industry as compared to countries like USA, Canada, China and India, also the geographical location and infrastructure development in terms of Road, Rail and Water Transport are easily accessible in brazil as compared to the other countries being considered. Also the labour cost in Brazil much lesser than USA and Canada and a bit higher as compared to China and India, this is because of availability of more skilled personnel in this region as compared to China and India. As the consumption of electricity will be very much higher for the continuous production of S-Metolachlor it is advisable to generate electric power on our own and the availability of coal is large quantity in Brazil itself makes Brazil a stronger candidate.[27] Furthermore with the efficient use of technology waste generated will be recycled and water obtained after tertiary treatment can also be used for farming.

These are some of the major aspects, which clearly present Brazil to be a potential site for manufacturing of S-Metolachlor on large scale as compared to other potential sites being considered. Therefore higher profitability is expected for manufacturing S-Metolachlor in Brazil.

7. Process Economics[28] (Juntao Su)

To scale up a chemical plant, there are many factors can affect the amount of the capitals; sufficient capital investment is one of the most important factors. The capital investment includes the direct fixed cost and the indirect cost, operation cost, and others such as the source of the equipment, the operating time and the rate of the production, the company policy and the government policy. For the metolachlor, it is a typically solid-fluid based chemical plant and a totally new plant being setup at a new site. Thus, compare to a new plant at an existing site, the metolachlor plant is to include everything such as the cost of service facilities, land and utilities which a new plant at the existing site just takes and uses instead of building them. Therefore, the cost of metolachlor plant at a new site can be estimated from items below.

7.1. Cost of Equipment and Installation

The price of the equipment varies. It depends on the manufacturer, the brand, and the area where the manufacturer is. And also depends on the quantity of the equipment you are going to buy. For metolachlor, the 3 main reactors with stirs and 2 distillers are the key equipments, which will be the large part of the cost of all the equipments. The price of the equipments may also include the delivery charge. Normally, the delivery charge is base on the equipment weight, size, the distance from the source to plant and the method of transport. It is about 10% of the cost of the equipment usually.

Installation of equipment involves costs for labour, foundations, supports, platforms, construction expenses, and other factors related to the erection of the equipment. The cost of the installation also depends on the type and the complexity of the equipments. The cost of installation is expected to be 25-55% of the delivered equipment.

7.1.1. Cost of Instrumentation

Instrument costs, installation labour costs, and expenses for auxiliary equipment and materials comprise the cost of instrumentation. For the (s)- metolachlor plant, the cost of instrumentation and control is estimated around 26% of delivered equipment cost.

7.1.2. Cost of Piping

The cost of piping covers labour, valves, fittings, pipe, supports, and other items involved. This includes raw material, intermediate-product, finished-product, steam, water, air, sewer, and other process piping. For a solid-fluid type of plant, the cost of piping is considered to be 31% of the equipment. And, labour for installation is about 40-50% of the total installed cost of piping, material and labour for pipe insulation are 15-25% of the total installed cost of piping, and for the (s)-metolachlor process, the required temperature of one stage is 50℃ where the insulation of the pipes is required, so the cost of piping is considered to be at 16%.

7.2. Land and Buildings

This part will be decided by the site where the plant is to be built up. Different countries or regions, the price of land is different. As in this case, our plant will most probably be setup in Brazil. The land price in Brazil in 2008 is typical at 2000 US dollar per acre with extra 0.2-3.5% of tax. Typically, the cost of land is 4-8% of the equipment. The cost of the building includes the labor, materials and heating, lighting, ventilation. This part cost about 47% of the equipment cost for the newly build up solid-fluid plant such as the metolachlor plant.

7.3. Service facilities

Utilities include supplying steam, water, power, and fuel. The first aid, cafeteria, the storage of the raw materials and the finished product are part of the service facilities. The waste disposal system also needs to be considered. For metolachlor plant, as a single product plant, the cost of the service facilities is about 30% of the cost of the equipments.

7.3.1. Electrical

The electrical systems consist of power wiring, lighting, transformation and service, and instrument and control wiring. Cost of installation is about 15-30% of the delivered equipment.

7.4. S.H.E Function

As the environment is concern more, to build up the metolachlor as a environment friendly plant, S.H.E will be more responsible. Explosion and fire hazards, personal safety, noise control and waste disposal system (gas, liquid and solid) are part of the safety, pollution prevention or pollution minimization. For metolachlor, Hydrogenation is the major step, the investment to prevent explosion is seriously required. The waste water/solvent handling system is also required before released to the environment.

7.5. Indirect Fixed Capital Cost
7.5.1. Engineering and supervision

The construction design and engineering, including accounting, purchasing, travelling, communications, the computer-based drawing such as P.I.D and the home office expense plus overhead comprise the engineering and supervision cost. It normally takes about 30% of the cost of delivered equipments.

7.5.2. Legal expenses

The legal expenses are mainly from land purchase, equipment purchase and construction contracts. For metolachlor to be setup in Brazil, certain law firms are involved to settle the law issues, such as understanding and providing compliance with government, environmental and safety requirements. The legal expenses are about 4% of the cost of the equipments. The patent on the metolachlor is expired, so the cost of patents and royalties is not considerable.

7.5.3. Construction expenses

Except the cost of the plant construction, the service buildings discussed in the cost of building section, the temporary construction and operation, tools and rentals, Brazil government personnel located at the construction site, construction payroll, travel and living, taxes and insurance. This cost can be included under equipment installation, engineering and supervision, and construction. While separately, the construction expenses normally cost 34% of the cost of the equipments.

7.5.4. Contractor's fee

The contractor's include the contractor of the buildings, the contractor of the equipment and instrumentation installation, the contractor of road construction, and also include the certain cleaning companies or may be the pest control companies. The contractor's fee is about 19% of the cost of equipment typically for a solid-fluid plant.

7.5.5. Contingency

The contingency cost is amount of money to treat the emergency situation such as flood, hurricane, earthquake, strikes, design change, and the government policy changes including the tax rate. The capital investment of contingency is about 37% of the equipment cost for a solid-fluid plant.

7.5.6. The working capital

The working capital cost for the metolachlor process includes the raw material inventory and finished product inventory, which will supply sufficiently for one month. And the amount of the working capital depends on the throughput of the metolachlor.

7.6. Operating Cost

The cost of raw materials is one of the major costs of the process. Raw materials are that directly consumed in making the final product, in this case, is Metolachlor. The raw materials using are methoxy acetone (MEA), methyl ethylamine (MOA), potassium iodide, N(CH3)3, hydrogen, Benzene, ClCOCH2Cl, (C2H5)2O and xyliphos. The cost of raw materials may also include any transportation charges that normally are around 10% of the cost of the materials.

7.6.1. Cost of Utilities

Utilities costs include the cost of stream, electricity, process and cooling water, fuel oil, and waste treatment and disposal. As for metolachlor, the electricity power supplies the lighting, motors, and pumps. The condensation reaction of the metolachlor process is a heat generation reaction; to remove the heat is required by using the cooling water. Stream is used to heat the water that is used to maintain the reaction temperature at 50 ℃ through the jacket as well as using at the distillation stages.

7.6.2. Cost of Distribution, Marketing and Packaging

This part mainly depends on the market size of the metolachlor, the competition and the main selling destination. The cost includes the salaries, supplies for the sales offices, the salaries, commission, travelling expenses for sales representatives and other expenses such as shipping costs, cost of containers, advertising and technical supporting services. Packaging cost includes cost of the packaging materials likely are the containers, the labels. The containers and labels may be patented which requires extra expenses.

7.6.3. Operating labour and Supervision costs

As the metolachlor plant will run 24/7 with 3 shifts, the direct supervision of the process operation is always required. The complexity of the process, of the equipments, and the number of the batches per month and the throughput will affect the operating labour involved.

7.6.4. Depreciation

The equipments, buildings, and other material objects of the metolachlor plant need to be paid back by charging the depreciation as a manufacture expense. The depreciation is difference year by year and will affect the amount of the incoming tax.

7.6.5. Local taxes and insurance

The local property taxes depend on the location of the plant and the regional law on the tax. As the (s)-metolachlor is going to setup at less populated area, industry park, so the local taxes can consider being lower. The insurance for the plant depends on what type of product is manufactured and the total capital investment.

7.6.6. Maintenance

Once the plant is erected with the proper equipments, the maintenance starts. Maintenance and repairs of the equipments are normally based on annually.

7.6.7. Laboratory charges

The laboratory charges are the cost of the tests that carry out to check the raw materials, control the quality of the product, or to investigate the product out of specification or to precede investigation on complaints about the products by customers.

The investment of the (s)-metolachlor is mainly sitting in those items discuss above.

8. Health, Safety and Environment Aspects of the Process (Fabiola Segovia)
8.1. Health and Safety
8.1.1. Hazards from Equipments
8.1.2. Hazards from Materials
8.1.3. Occupational Safety
8.2. Environmental Aspects
8.2.1. Day-to-day Operating Conditions
8.2.2. Worst Case Scenario Management
8.2.3. Waste Treatment

http://www.syngentacropprotection.com/prodrender/index.aspx?nav=environimpact&CGID=5&ProdID=716&ProdNM=Dual%20Magnum

9. Conclusions

This report has given overall view about an exercise to setup a new manufacturing plant of S- metolachlor in Brazil to produce 10,000 mt/yr. It describes about every aspects that can affect the scale up of the plant. In all five process routes were evaluated covering the synthesis of the metolachlor, the route with enzyme catalyst and chiral catalyst was selected. The selected route with chiral catalyst, which was of an advantage of xyliphos ligand, is due to its safety, less process time, less complexity of the equipments, the less overall cost, and its potential market.

The main raw materials used for the process are: xyliphos, 2- ethyl- 6- methyl imine (MEA), methoxyacetone (MOA), sulphuric acid (H2SO4), hydrogen gas (H2), 1,2-dichloroacetone (ClCOCH2cl). These raw materials are available on large scale at cheaper cost except for xyliphos, which are expensive. The reaction conditions for the process of hydrogenation can be controlled and maintained at a pressure of 80 bars and 500C temperature. The raw materials used are less corrosive thus proving an advantage on safety and health issues. Due to low corrosive nature of the compounds the maintenance of equipments is cost efficient.

The major use of S- metolachlor is its herbicidal activity, which helps in controlling growth of weeds. S- metolachlor is a major herbicide, which has a wide market in developed and developing countries. It has acquired new registrations in countries in which agriculture is backbone of the economy. The use of the herbicide has increased as compared to its competitors due to advantages in health issues such as carcinogenicity.

The suitable sites for the S- metolachlor production plant were United States of America, India, China, Brazil, and Taiwan. The selected site for production in this exercise is Brazil due to availability of large potential market in whole of South America and the welcome of local government to the foreign investment. The raw materials for production are available at economic cost. The transportation facilities are cheaply available with quality labour and favourable government policies.

The investment of the plant involves the cost of the land, equipments, buildings, piping, the service facilities and long term cost of the legal expenses, raw materials, maintenance and the labours, etc. The capital investment is estimated base on the cost of the equipments as with the specific equipments the cost of scale up of the other aspects as mentioned above could be decided as well.

11. References

Blaser, H-U., Buser, H-P., Coers, K., Hanreich, R., Jalett, H-P., Jelsch, E., Pugin, B.,

Schneider, H-D., Spindler, F., Wegmann, A. (1999). The Chiral Switch of Metolachlor: The Development of a Large-Scale Enantioselective Catalytic Process. Chimia, 53(6), 275-280. Retrieved from:http://www.ingentaconnect.com/content/scs/chimia/1999/00000053/00000006/art00005

Zheng, L., Zhang, S., Wang, F., Gao, G., Cao, S. (2006). Chemoenzymatic synthesis of the chiral herbicide: (s)-metolachlor. Canadian Journal of Chemistry, 84(8), 1058. Retrieved from: http://www.encyclopedia.com/doc/1G1-155476134.html

O'Connell, P.J., Harms, C.T., Allen, J.R. (1998). Metolachlor, S-metolachlor and their role within sustainable weed-management. Crop Protection, 17(3), 207-242. Retrieved from: http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T5T-3TGN8R8-2&_user=7523285&_coverDate=05%2F31%2F1998&_rdoc=2&_fmt=high&_orig=browse&_srch=doc-info%28%23toc%235011%231998%23999829996%2317745%23FLP%23display%23Volume%29&_cdi=5011&_sort=d&_docanchor=&_ct=11&_acct=C000005458&_version=1&_urlVersion=0&_userid=7523285&md5=79533690fff9994de7eca4066e245fb8

Cho, B.T., Chun, Y.S. (1992). Enantioselective synthesis of optically active metolachlor via asymmetric reduction. Tetrahedron: Asymmetry, 3(3), 337-340. Retrieved from: http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6THT-42K6FGR-2V&_user=7523285&_coverDate=12%2F31%2F1992&_rdoc=3&_fmt=high&_orig=browse&_srch=doc-info%28%23toc%235291%231992%23999969996%23237579%23FLP%23display%23Volume%29&_cdi=5291&_sort=d&_docanchor=&_ct=25&_acct=C000005458&_version=1&_urlVersion=0&_userid=7523285&md5=3c1aa0f7e9624c33a4088546c7390ec1

Turton, R., Bailie, R.C., Whiting, W.B., Shaeiwitz, J.A. (2003). Analysis, Synthesis, and Design of Chemical Processes. New Jersey, NJ: Pearson Education, Inc.

12. Appendix A

Ø CV Darlington ABBAN

Ø CV Priyank S. PATEL

Ø CV Akshay REGE

Ø CV Fabiola SEGOVIA TORRES

Ø CV Juntao SU

13. Appendix B

Minutes of meeting

13

[1] Agriculture, Pesticides. In Wikipedia. Retrieved 6th December, 2009 from: http://en.wikipedia.org/wiki/Agriculture#Pesticides

[2] Agriculture, Herbicides. In Wikipedia. Retrieved 6th December, 2009 from: http://en.wikipedia.org/wiki/Herbicide

[3] Agriculture, Herbicides. In Wikipedia. Retrieved 6th December, 2009 from: http://en.wikipedia.org/wiki/Herbicide

[4] Agriculture, Herbicides. In Wikipedia. Retrieved 6th December, 2009 from: http://en.wikipedia.org/wiki/Herbicide

[5] Metolachlor. In Wikipedia. Retrieved 30th October, 2009 from: http://en.wikipedia.org/wiki/Metolachlor

[6] Syngenta. (6th December, 2009). Dual Magnum. Retrieved from: http://www.syngentacropprotection.com/prodrender/index.aspx?prodid=716&ProdNM=Dual%20Magnum

[7] Baiker, A. (1997). Heterogeneous catalysis and fine chemicals IV. USA: Roelof Prins.

[8] [1]

[9] [2]

[10] [2]

[11] [2]

[12] [2]

[13] [3]

[14] [2]

[15] O'Connell, P.J., Harms, C.T., Allen, J.R.F. (1998). Metolachlor, (S)-Metolachlor and their within sustainable weed-management role. Crop Protection vol.17.

[16] Ismail, B.S., Shamsuddin, N. (2005). Effects of alachlor and metolachlor on microbial population in the soil. Malaysian Journal of Microbiology, vol. 1, pp 36.

[17] Kearney, P.C., Kaufman, D.D. (1998). Herbicides chemistry, degradation and mode of action. New York, NY.

[18] Miranda, S.R., Meyer, S.A. (2006). Cytotoxicity of chloroacetanilide herbicide alachlor in HepG2 cells independent of CYP3A4 and CYP3A7. Food and Chemical Toxicology, 45 pp 871.

[19] Lee, W.J., Hoppin, J.A., Blair, A., Lubin, J.H., Dosemeci, M., Sandler, D.P., Alavanja. M. (2003). Cancer Incidence among Pesticide Applicators Exposed to Alachlor in the Agricultural Health Study. American Journal of Epidemiology vol. 159, pp 373.

[20] Da Silva, M.P., Vieira, E.M. (2009). Degradation of alachlor herbicide by gamma radiation from cobalt-60 in aqueous and alcohol solution. Journal of Rational Nucl Chem, pp 323.

[21] Kassim Al-Khatib, Jolene Baumgartner Unland, Brian L. S. Olson, and David W. Graham. (September 2002). Alachlor and Metolachlor transformation pattern in corn and soil. Weed science society of America, pp 581-586.

[22] Liu, S.Y., Chen, Y.P., Yu, H.Q., Zhang, S.J. (2004). Kinetics and mechanisms of radiation-induced degradation of acetochlor. Chemosphere vol 59, pp 13-19.

[23] Ankita, B. (2002). Appendix III: Biocides and Health. Treasure of Japan, pp 386.

[24] Singh, S.B., Yaduraju, N.T., Kulshrestha, G. (1997). Residues of Metolachlor Herbicide in Soil and Potato Tubers Under Indian Tropical Conditions. Bulletin of Environmental Contamination and Toxicology, pp 216.

[25] Global-Production. (4th December, 2009). The Scoreboard Indicators. Retrieved from: http://www.global-production.com/scoreboard/indicators/index.htm

[26] Ray, M.S., Johnston, D.W. (1983). Chemical Engineering Design Project: A case study Approach, vol. 6. USA: Gordan and Breach.

[27] Reuters. (12th October, 2009). Riversdale sees Zambeze coal resources at 1.7 billion. Reuters. Retrieved from: http://www.reuters.com/article/idUSLC35593120091012

[28] Peters, M.S., Timmerhaus, K.D., West, R.E. (2003). Plant Design and Economics for Chemical Engineers. New York, NY: McGraw-Hill.

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