V. Tamara Perchyonok is currently a Research Fellow at the School of Chemistry Centre for Green Chemistry at Monash University. Her research interests cover Analytical, Nano and Organic Chemistry with a specialization in free radical chemistry, green analytical chemistry, molecular recognition and polymer chemistry. She also lectures on heterocyclic chemistry and drug synthesis. Previous research appointments include: Marie Curie Senior Research Fellow at ISOF, CNR (Bologna, Italy); Senior Researcher (Chirogen PTY. Ltd., The University of Melbourne), and DFG Post Doctoral Fellow (LMU, Munich, Germany). Her research there covered both academic and commercial aspects of bio-compatible free radical chemistry via experimental and computational approaches. Her current research includes three broad areas of the development and commercialization of novel aspects of green analytical chemistry, synthesis and applications of novel nano-materials and bio-compatible free radical chemistry. The overall aim is to develop alternative and recyclable technology to facilitate the conversion of bio-actives from waste materials into value added and specialty chemicals, as well as the development of novel areas of green bio-compatible free radical chemistry.

Radical Reactions in Aqueous Media

By V. Tamara Perchyonok

The Royal Society of Chemistry

Copyright © 2010 V. Tamara Perchyonok
All rights reserved.
ISBN: 978-1-84973-000-6

Contents

Chapter 1 Free Radical Chemistry and Green Chemistry: The Historical Perspective, 1,
Chapter 2 Basic Radical Chemistry: General Aspects of Synthesis with Radicals, 15,
Chapter 3 Why Water as a Solvent? Reasons and Advantages, 29,
Chapter 4 Reducing Agents Based on Group 4 and Aqueous Media, 34,
Chapter 5 On the Use of Phosphorus Hydrides as Efficient Hydrogen Donors, 51,
Chapter 6 Organoboron Compounds as Radical Reducing Agents, 63,
Chapter 7 Carbon-Carbon Bond Formation through Radical Addition Chemistry, 71,
Chapter 8 Redox Processes and Electron Transfer: Free Radicals Are a Central Player, 91,
Chapter 9 Chain versus Non-chain Free Radical Processes in Aqueous Media, 106,
Chapter 10 Future Directions and Practical Considerations, 113,
Subject Index, 121,

CHAPTER 1

Free Radical Chemistry and Green Chemistry: The Historical Perspective

Green chemistry means environmentally friendly organic synthesis. The essential aims are to reduce the amounts of dangerous, toxic starting materials and by-products (waste disposal) and to reduce damage to the natural environment. Most processes that involve the use of chemicals have the potential to cause a negative impact on the environment. It is therefore essential that the risks involved be eliminated or at least reduced to an acceptable level. Traditionally, the risks posed by chemical processes have been minimized by limiting exposure by controlling so-called circumstantial factors, such as the use, handling, treatment and disposal of chemicals. The existing legislative and regulatory framework that governs these processes focuses almost exclusively on this issue. By contrast, green chemistry seeks to minimize risks by minimizing hazards. It thereby shifts control from circumstantial to intrinsic factors, such as the design or selection of chemicals with reduced toxicity and of reaction pathway that eliminate by-products or ensure that they are benign. Such design reduces the ability to manifest hazards (and therefore risks), providing inherent safety from accidents or acts of terrorism.

The most widely accepted definition of green chemistry is ‘the design, development and implementation of chemical processes and products to reduce or eliminate substances hazardous to human health and the environment’. This definition has been expanded into 12 ‘Principles of Green Chemistry’:

• Prevent waste: Design chemical syntheses to prevent waste, leaving no waste to be treated or cleaned up.

• Design safer chemicals and products: Design chemical products to be fully effective, yet have little or no toxicity.

• Design less hazardous chemical syntheses: Design syntheses to use and generate substances with little or no toxicity to humans and the environment.

• Use renewable feedstocks: Use raw materials and feedstocks that are renewable rather than depleting. Renewable feedstocks are often made from agricultural products or are the wastes of other processes; depleting feedstocks are made from fossil fuels (petroleum, natural gas or coal) or are mined.

• Use catalysts, not stoichiometric reagents: Minimise waste by using catalytic reactions. Catalysts are used in small amounts and can carry out a single reaction many times. They are preferable to stoichiometric reagents, which are used in excess and work only once.

• Avoid chemical derivatives: Avoid using blocking or protecting groups or any temporary modifications if possible. Derivatives use additional reagents and generate waste.

• Maximize atom economy: Design syntheses so that the final product contains the maximum proportion of the starting materials. There should be few, if any, wasted atoms.

• Use safer solvents and reaction conditions: Avoid using solvents, separation agents or other auxiliary chemicals. If these chemicals are necessary, use innocuous compounds.

• Increase energy efficiency: Run chemical reactions at ambient temperature and pressure whenever possible.

• Design chemicals and products to degrade after use: Design chemical products to break down to innocuous substances after use so that they do not accumulate in the environment.

• Analyse in real time to prevent pollution: Include in-process real-time monitoring and control during syntheses to minimise or eliminate the formation of by-products.

• Minimize the potential for accidents: Design chemicals and their forms (solid, liquid or gas) to minimize the potential for chemical accidents, including explosions, fires and releases to the environment.

Thus, green chemistry involves the study of the removal of these risks fundamentally during the preparation and isolation of chemical materials, based on molecular chemistry; it is not, therefore, the treatment of symptoms. What it does do is replace solvents and reagents with safer ones.

The areas for the development of green chemistry have been identified as follows:

• Use of alternative feedstocks: The use of feedstocks that are both renewable rather than depleting and less toxic to human health and the environment.

• Use of innocuous reagents: The use of reagents that are inherently less hazardous and are catalytic whenever feasible.

In later chapters, we will see the evolution of free radical chemistry, starting from the typical Bu3SnH radical hydrogen donor in benzene to the use of broad-range non-toxic and effective hydrogen donors in water and/or aqueous media. Generally, radical reactions with Bu3SnH initiated by azobisisobutyronitrile (AIBN) proceed effectively in benzene, which bears a conjugated p-system. It is proposed that the radicals formed are stabilised somewhat through the SOMO–LUMO or SOMO–HOMO interaction between the radical and benzene.

Occasionally, it may be required to study the fundamental radical reactions with organotin and benzene. However, the use of radical reactions with such toxic reagents and solvents cannot be considered in the chemical and pharmaceutical industries, even if the results in terms of organic synthesis are excellent and effective. Hence free radical chemists should develop ways to conduct new and less toxic radical reactions in ways that address the 12 principles of green chemistry. Therefore, by creating a new direction in free radical chemistry, green free radical chemistry brings the environmentally benign aspects of free radical chemistry into the spotlight.

Fortunately, radicals are a neutral species in general. Hence they are not generally affected by the various kinds of solvents (reaction media), i.e. protic polar solvents such as ethanol and water, aprotic polar solvents such as acetonitrile and dimethyl sulfoxide and non-polar solvents such as hexane and benzene. Moreover, radicals are not affected fundamentally by basic species or acidic species. Radical reactions should take place not only in benzene, but also in water and proceed not only in 1 M aqueous HCl solution, but also in 1 M aqueous NaOH solution. This is the fundamental character of radicals and radical reactions and is a great advantage – an advantage that should be reflected in green chemistry.

Let us look at the history of the development of radical and green chemistry as both of these branches of chemistry were created through a significant paradigm shift of ideas, thoughts and people who trusted in intuition and wanted to be at the frontier of development of knowledge.

1.1 Radicals: Historical and Practical Importance

1.1.1 What Are Free Radicals

Radicals have an impact on all of our lives. We make them in our bodies, they are produced when we light a fire or drive a car and we use plastics as part of our daily living that are produced on a large scale using radical reactions. Radicals affect our health and vitality and govern our ageing through the formation of various harmful radicals. Destructive radicals also affect our environment and radicals generated from chlorofluorocarbons (CFCs) are responsible for the destruction of the Earth’s protective ozone layer. So what are free radicals?

We can define radicals as atoms or compounds that contain an unpaired electron. They all contain an odd number of electrons. The single unpaired electron for each atom is represented in formulae by a dot. Almost all radicals can be described as ‘free radicals’ as they exist independently, free of any support from other species. They are generally very unstable and are regarded as reactive intermediates, together with carbocations, carbanions and carbenes. The high reactivity of radical species is due to the unpaired electron, which would like to pair with a second electron to produce a filled outer shell. The driving force in each case is the formation of a two-electron covalent bond. If we want to prepare the original radicals from the newly formed molecule, we could consider the reverse processes and attempt to break the covalent bond by applying energy (e.g. heat or light). This type of bond cleavage, to give each atom one electron, is known as homolysis or homolytic bond cleavage.

There are various pathways by which radicals can react to form stable molecules. They can be combined with themselves or other radicals, but they can also be oxidized to a cation (by loss of an electron) or reduced to an anion (by addition of an electron). These ions could then react with nucleophiles or electrophiles, respectively, to produce neutral and stable products. This is illustrated for a carbon–centred radical in Scheme 1.1. These radicals contain seven valence electrons, which is one electron more than in carbocations and one electron less than in carbanions. We can see that both the radical and cations are electron defficient as they require the addition of one and two electrons, respectively, to produce a filled (eight-electron) outer shell.

Not all radicals are highly reactive. Notably, naturally occurring exceptions include oxygen (O2) and nitrogen monoxide (NOx). Molecular oxygen (O2) can be thought of as a di- or biradical as it contains two unpaired electrons. Whereas (mono/uni)radicals have an odd number of electrons, biradicals have an even number and O2 has 12 electrons. The following sections outline the brief history of evolution of free radical chemistry and green chemistry and subsequently discuss a variety of biologically and industrially important radical reactions with a particular focus on the green chemistry aspects of transformations.

1.1.2 Brief History and Development of Free Radical Chemistry and Evolution of Green Chemistry

In chemistry, as in any other branch of science, experiments often precede theory. Accidental discoveries bring fresh light and reveal aspects hitherto unsuspected of the subject. Neither radical chemistry nor green chemistry is an exception. It is therefore useful, perhaps, to outline, in a very broad manner, the way in which the field developed over the past century or so, viewed from the perspective of the synthetic organic chemist.

In the early days of organic chemistry, when structural and mechanistic concepts were still elusive, it was noted that reactions that could in principle lead to a trivalent carbon species produced dimers instead.

• 1789: Lavoisier first used the term ‘radical’ when he described acids as being composed of oxygen and an entity called a radical. The meaning of the name has changed since then but the word ‘radical’ has remained.

• 1849: Kolbe described the product derived from the electrolysis of potassium acetate (ethanoate) as a ‘methyl radical’ with the formula xC2H3. We now know that the product is ethane (C2H6), which is actually a product of dimerization of two methyl radicals (xCH3).

• 1847: Faraday first demonstrated that oxygen is drawn into a magnetic field and hence is strongly paramagnetic, whereas nitrogen monoxide is weakly paramagnetic. We now associate paramagnetism with molecules (or ions) that contain unpaired electrons, as the spinning electrons behave like tiny magnets and the molecules are drawn into a magnetic field.

• 1900: Victor Meyer showed that an iodine molecule (Ix) could dissociate into iodine atoms or radicals (Id). However, the key breakthrough came in 1900, when Gomberg investigated the reaction of triphenylmethyl bromide with silver. In the absence of oxygen, the reaction yielded a highly reactive white solid which, when dissolved, gave a yellow solution. Gomberg proposed that the product was hexaphenylethane, which, when in solution, existed in equilibrium with coloured triphenylmethyl radical. The presence of a radical helped to explain why other radicals, including oxygen, react rapidly with the product. This was a major discovery and chemists started to accept radicals as a novel chemical entity separate from cations or anions.

• 1911: The experimental evidence for the formation of the triphenylmethyl radical was so overwhelming that the case for free radicals was firmly established. So why was Gomberg able to observe this particular radical? Part of the reason for the stability of the triphenylmethyl radical can be attributed to the presence of three bulky benzene rings that effectively shield the central carbon atom bearing the radical and slow any reactions.

• 1929: Paneth showed that tetramethyllead (PbMe4) produces a metallic lead mirror when heated to high temperature (around 200 °C) in a glass tube containing a stream of unreactive carrier gas.

• 1939: Radicals are postulated to be important intermediates in a variety of chemical reactions, e.g. the Kharasch reaction and mechanism, anti-Markovnikov addition of HBr to alkenes and the first demonstration of radical chain reaction – initiation, propagation and termination nomenclature were introduced. Radical polymerization was introduced, investigated and adapted for industrial use. All these investigations led to the same conclusion that not all carbon-centred radicals are the same: they have a different character and as a result can react differently. This is an important concept, as it allows us to explain and also predict selective radical reactions.

• 1950–70: Physical organic chemists began to measure and characterise free radicals in order to quantify radical reactions and determine absolute rates of reaction in solution. This was revolutionised by the development of a new technique, known as electron spin resonance (ESR) spectroscopy, which offered a sensitive method for the detection and identification of radical species. The important structural and reactivity features of free radicals have been uncovered through this technique. It was around this time that the synthetic utility of Bu3SnH as a powerful reducing agent came to light and established the important role of free radical chemistry. It was also around that time that researchers began to investigate and propose mechanisms for the deterioration of fats, oils and other foodstuffs in the presence of oxygen (early examples of in vitro models of biologically and environmentally important processes). Radical intermediates were shown to be involved and the term autoxidation was introduced to describe these processes. This prompted the design of molecules, called antioxidants or inhibitors, which could slow or even prevent undesired reactions.

Armed with the knowledge of reaction rates, chemists were now at the point of beginning to explore the use of radicals in the preparation not only of polymers but also of small molecules. Since 1970, a number of important radical reactions have been developed and numerous target molecules have been prepared using these methods. Today, when planning the synthesis of even very complex molecules, the arsenal of chemists is rich with a broad range of free radical reaction classes and also solvents suitable for all kinds of transformations with a great degree of stereo- and even enantio-control that can have a number of advantages over traditional ionic methods (involving anions and cations). It should also be highlighted that radical reactions do not occur only in laboratories. The process by which benzaldehyde is oxidized in air to benzoic acid on a laboratory bench is the same type of radical reaction as that which leads to the deterioration of foods, the ageing of unprocessed natural rubber and the drying of paints and varnishes. The following sections aim to show the important developments and highlight the origins of free radical chemistry while dispelling the myth and ill-deserved reputation that such molecules are unruly and are likely to produce tar.

The period 1960–70 was an exciting time and also very challenging as environmental concerns became an integral part of public perception of the chemical industry and chemical science in general and the effects that chemicals have on the environment. The foundation of green chemistry was established. Below some important historical dates relating to green chemistry being established as an independent but not mutually exclusive branch of chemistry are outlined.

From the late 1960s to 1970, the environment received a great deal of attention, including formation of the US Environmental Protection Agency (EPA) and the celebration of the first Earth Day, both of which occurred in 1970. In the intervening years, in excess of 100 environmental laws have been passed. These include several major laws listed below:

1. 1970 Clean Air Act, to regulate air emissions.

2. 1972 National Environmental Policy Act, which requires in part that the EPA reviews environmental impact statements for proposed major federal projects (such as highways, buildings, airports, parks and military complexes).

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