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No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise without the prior permission of the author. Published 2008 By University of Lagos Press Unilag P. O. Box 132, University of Lagos, Akoka, Yaba – Lagos, Nigeria. ISSN 1119-4456 i ii SYNTHETIC ORGANIC CHEMISTS: CREATING MOLECULES FOR THE BENEFIT OF MAN An Inaugural Lecture Delivered at the University of Lagos On Wednesday, 4th June 2008 By PROFESSOR OLUWOLE BABAFEMI FAMILONI B. Sc. (Hons.), M. Phil., Ph. D. Chemistry (Lagos) FCSN, FICCON, C. Chem. MRSC, MIPAN, Public Analyst Professor of Chemistry Department of Chemistry Faculty of Science University of Lagos University of Lagos Press, 2008 http://www.pdfonline.com/easypdf/?gad=CLjUiqcCEgjbNejkqKEugRjG27j-AyCw_-AP The Vice-Chancellor, Deputy Vice-Chancellor (Management Services), Deputy Vice-Chancellor (Academic and Research), Registrar, Provost College of Medicine, Dean of Science, other deans present, members of Senate, my colleagues, our students, distinguished ladies and gentlemen. I give thanks to God Almighty, the King of all creation, for allowing this day to materialise. May His name be glorified. Mr. Vice- Chancellor Sir, this is the first inaugural lecture of an alumnus of this University from the Department of Chemistry and the 8th inaugural lecture from the Department; the first being the one delivered forty years ago by the Late Prof. Akitunde Akisanya in 1968 entitled “Old Wines in New Bottles”. The purpose of this lecture is to showcase a little, from my humble contribution to the body of knowledge in Chemistry, as a Synthetic Organic Chemist, which earned me a chair of Chemistry in this great University. Also the lecture will bring to light the contribution of Chemists and Chemistry to the emancipation of mankind. To some, chemistry is a myth, whereas it is not so. I hope by the end of this lecture, I would have been able to convey a message that demystifies chemistry. SYNTHETIC CHEMISTS AND CREATIVITY In Genesis Chapter 2 verses 1-2, the Bible says that “God created the heaven and the earth… and He rested from His works”. Due to his insatiable nature, man has perpetually requested for many more materials that will satisfy his dynamic lifestyle. God having rested from His works, decided to entrust the continuation of the work of creation to chemists. In this lecture I hope to show you that God has given the Synthetic Chemist the power to create. In the Beginning I started my study of Chemistry as a general Chemist in 1981 having obtained a B. Sc. (Hons.) in Chemistry. On the completion of a Master of Philosophy Degree in Organic Chemistry from 1 http://www.pdfonline.com/easypdf/?gad=CLjUiqcCEgjbNejkqKEugRjG27j-AyCw_-AP 3 this great University, God endowed me with the power to create new molecules. I went further to acquire a Ph. D. in Synthetic Organic Chemistry, also at the University of Lagos under the guidance of Prof. B. I. Alo. I have been privileged to accumulate more knowledge in organic synthesis at the Institute National Des Science Appliques, in Rouen, France in 1988, University of Waterloo, Waterloo, Canada 1993-94, University of East Anglia, England 1997, Rhodes University, South Africa 1997 and 2006, Queens University, Kingston, Canada 1999, 2003 and 2007. All these exposures have sharpened the wisdom of God in me to do what He had chosen for me to do. With all the training spells mentioned above, God has endowed me with the power to partner with Him to create molecules previously not known to mankind. I chose to research into the area of compounds with physiological activities or which may have potential physiological activities, i. e. molecules which when used in human body, will effect a biological change in the activity of the cells, positively or negatively. Apart from biological systems, these compounds may also be used for other purposes such as in colours production and other industrial uses providing materials that make life easier, never mind that some synthetic products may also be weapons of mass destruction. WHO IS A CHEMIST? Chemists are the people who understand the behaviour of the constituents of matter - atoms, molecules, and ions which determine everything around us in the world, including how we feel on a given day. They are very well-equipped to tackle many of the problems faced by modern society. Usually a chemist obtains a B.Sc. (Hons.) in Chemistry from a reputable and accredited university like ours. A chemist may chose to study the mechanism of the recombination of DNA molecules, measure the amount of insecticide in drinking water, compare the protein content of meat, develop a new antibiotic, or analyze moon rock. He is capable of designing a synthetic fibre, a life-saving drug, or analyzing a space capsule. To understand why an autumn leaf turns red, or why a diamond is hard, or why soap gets us clean, requires first, a basic understanding of Chemistry.. It may be obvious to us that a chemistry background is important if one plans to teach chemistry or to work in the chemical industry, developing chemical commodities such as polymeric materials, pharmaceuticals, flavourings, preservatives, dyestuffs, or fragrances. You may also be aware that chemists are frequently employed as environmental scientists, chemical oceanographers, chemical information specialists, chemical engineers, and chemical sales persons. However, it may be less obvious to you that a significant knowledge of chemistry is often required in a number of related professions including all aspects of engineering, medicine, pharmacy, medical technology, nuclear medicine, molecular biology, biotechnology, pharmacology, toxicology, paper science, pharmaceutical science, hazardous waste management, art conservation, forensic science and patent law. Thus, a chemistry degree with cognate working experience and possibly possession of an advanced degree either in a business related discipline such as Business Administration or even Law will effectively equip an individual to function effectively in a higher management level in any organisation. It is often observed that today’s graduate, unlike the graduate of a generation ago, should anticipate not a single position with one employer or in one industry, but rather many careers. You will be well-prepared for this future if, in your university years, you take advantage of the opportunity to become broadly educated, to learn to be flexible and to be a creative problem-solver. Knowledge and skills gained in university courses may be directly applicable in your first job, but science and technology change at a rapid pace. Since chemistry provides many of these skills and is a fundamental driver in the business and commerce sector of our society, chemists and biochemists are likely to remain in continual demand. 2 http://www.pdfonline.com/easypdf/?gad=CLjUiqcCEgjbNejkqKEugRjG27j-AyCw_-AP A bachelor’s degree in chemistry is also an ideal pre-medicine degree. Medical schools do not require a particular bachelor degree, but a chemistry background will be helpful in the advanced study of biochemistry, endocrinology, physiology, microbiology, and pharmacology. Chemistry is also an excellent major for students planning careers in other health professions such as pharmacy, dentistry, optometry and veterinary medicine. All of these professional programmes require chemistry for admission. Most require at least one year of general chemistry and one year of organic chemistry, both with laboratory exposures. Many students have found that having a chemistry background gives them a distinct advantage in these professional programmes. From the above definition of a Chemist, you will note that those who sell drugs at patent medicine stores cannot be classified as “Chemists” as commonly and erroneously described. WHY STUDY CHEMISTRY? Chemistry is an incredibly fascinating field of study, because it is so fundamental to our world. It plays a role in everyone’s life and touches almost every aspect of our existence in some way by meeting our essential basic needs of food, clothing, shelter, health, energy, clean air, water, and soil. Chemical technologies enrich quality of life in numerous ways by providing new solutions to problems in health, materials, and energy usage. Thus, studying chemistry is useful in preparing us for the real world. Chemistry is often referred to as the central science because it joins together physics and mathematics, biology and medicine, and the earth and environmental sciences. Knowledge of the nature of chemicals and chemical processes therefore provide insights into a variety of physical and biological phenomena. Knowing chemistry is worthwhile for every human being because it provides an excellent basis for understanding the physical universe we live in. For better or for worse, everything is chemical! 4 5 Chemistry: The Central Science WHO IS A SYNTHETIC ORGANIC CHEMIST? So far, I have only defined a general chemist. Now, synthetic chemists are those who specialize in the area of chemistry combining small chemicals together to make bigger and more complex compounds for the benefit of mankind. They also synthesize compounds which can be used for killing or inconveniencing, which ever may be necessary. For example, tear gas is used to disperse a riotous crowd or to kill; to deter a disturbing rat in your house a rodenticide like warferin (an anticoagulant) is used. The synthetic chemist synthesizes compounds ranging from nylon, teregal to rayon; and polyester of all kinds are products of chemists providing clothing for the populace including Poly Vinyl Chloride (PVC), all kinds of plastic for different uses, numerous drugs in use now and the ones that are obsolete. Drugs play a significant role in our lives, ranging from relieving pains, preventing diseases, curing diseases to generally making life better (Figure 1). Synthetic Chemists also make available those condiments that make our sauce and food more palatable such as sodium glutamate popularly called MSG. http://www.pdfonline.com/easypdf/?gad=CLjUiqcCEgjbNejkqKEugRjG27j-AyCw_-AP 6 7 N N Cl H CH3 N Et Et HN OH O CH3 4-Aminoquinoline (e.g. Nivaquine) Paracetamol Figure 1: Some Physiologically Active Compounds Figure 1 shows some examples of products of synthetic organic chemists and shortly I will elaborate on the works that show out chemist as partners with God in further creation of materials of all kinds. EXAMPLES OF ORGANIC COMPOUNDS IN OUR LIVES1 Chemistry has a unique place in our pattern of understanding of the universe. It is the science of molecules. Organic Chemistry, however, is something more. It literally creates itself as it grows. Of course we need to create and study the molecules of nature because they are interesting in their own right and that their functions are important to our lives. Organic chemistry adds value to life by creating new molecules that give information which are not available in the molecules actually present in living things. The creation of new molecules has given us new material such as plastics, new dyes to colour our clothes, new perfumes to wear, and new drugs to cure diseases. Some people think that these activities are unnatural and their products dangerous or unwholesome. But these new molecules are built by humans from other molecules found on earth using the skills inherent in our natural brains. There are toxic compounds and there are nutritious ones, stable compounds and reactive ones, but there is only one type of chemistry: it goes on both inside our brains and bodies and also in our flasks and reactors, born from the ideas in our minds and the skill in our hands. We are not going to set ourselves up as moral judges in any way. We believe it is right to try to understand the world about us as best as we can and to use that understanding creatively. This is what I want to share with you. Dyes Dyes are responsible for the colours that beautify our lives. The colours produced are determined by the structure of the dyes. Some of their structures and the colours produced are shown in Figure 2 below. Figure 2: Structure of Dyes in Use in Everyday Life Edible and Other Dyes The fast Green FCF and Quinoline Yellow are colours permitted to be used in foods and cosmetics and have structures shown here. Quinoline Yellow is a mixture of isomeric sulphonic acids in the two rings shown below (Figure 3). Figure 3: Structure of Two Edible Colours N Et N Et OH SO2O - SO2O--OO2S + 2Na+ N O OH SO2OHHOO2S Fast Green FCT Quinoline yellow O O O O H3C H CH3 H H O H3C 13 4 5 6 8 10 11 12 13 14 15 9 sodium glutamate Na+ Na+ NH2 O -O O O- Atemisinin MeO O N NH2C N NO + -- Azulene9-nitroso julolidineDiazomethanedichloro dicyanoquinoline3-methoxybenzocyclo heptatriene-2-one bluegreenyelloworangered http://www.pdfonline.com/easypdf/?gad=CLjUiqcCEgjbNejkqKEugRjG27j-AyCw_-AP 8 9 There is a big market for intense colours for dyeing cloth, colouring plastic and paper, painting walls, and so on. This is the dyestuff and pigment industry and leaders in the United States of America are companies like ICI and Akzo Nobel. ICI has a target stake in this aspect of the business, their paints turnover alone being £2,003,000,000 in 1995. The most famous dyestuff is probably indigo, an ancient dye that used to be isolated from plants but is now made chemically. Figure 4: Structure of Blue Jeans Colour It is the colour of the world famous and popular blue jeans. More modern dyestuffs can be represented by ICI’s benzodifuranones, which give fashionable red colours to synthetic fabrics like polyesters. Colour photography Colour photography starts with inorganic silver halide but they are carried on an organic gelatin. Light acts on silver halides to give silver atoms that form the black and white photographic image. The colour in the films like Kodakchrome then comes from the coupling of two colourless organic compounds. One, usually an aromatic amine, is oxidized and couples with the other to give a coloured compound. Figure 5: Structure of Compound Responsible for Colour in a Photographic Film Colour is not the only characteristic by which we can recognize compounds. All too often it is their odour that lets us know they are around. There are some quite foul smelling organic compounds too, for example the smell of the skunk (a small animal) is a mixture of two thiols (a sulfur compound containing SH groups) shown below (Figure 6). Skunk spray Figure 6: Structure of the Factor Responsible for Smell of Skunk Spray COMPOUNDS WITH PHYSIOLOGICAL EFFECTS Humans are not the only creatures with a strong sense of smell. We can find mates in insects. They are usually small in a crowded world and they find others of their own species and the opposite sex by smell. Most insects produce volatile compounds called pheromones that can be picked up by a potential mate in incredibly weak concentrations. Only 1.5 mg of serricomin, the sex pheromone of the cigarette beetle, could be isolated from 65,000 female beetles—so there isn’t much in each beetle. Nevertheless, the slightest whiff of it causes the males to gather and attempt a frenzied copulation. Indigo the colour of blue Jeans http://www.pdfonline.com/easypdf/?gad=CLjUiqcCEgjbNejkqKEugRjG27j-AyCw_-AP 10 11 The sex pheromone of the Japanese beetle, also given off by the females, has been synthesized by chemists. As little as 5 µg (micrograms) was more effective than four virgin females in attracting the males. Figure 7: Structure of Two Insect Pheromones The pheromone of the gypsy moth, disparlure, was identified from a few µg isolated from the moths and only 10 µg of synthetic material. As little as 2 x 10-12 g is active as a lure for the males in field tests. The three pheromones we have mentioned are available commercially for the specific trapping of these destructive insects. Mr. Vice-Chancellor Sir, we should not suppose that the females always do all the work; both male and female olive flies produce pheromones that attract the other sex. The remarkable thing is that one mirror image of the molecule shown in figure 8 attracts the males while the other attracts the females! Figure 8: Male and Female Pheromone of Olive Flies What about taste? Take the grapefruit as an example; the main flavour (Figure 9) comes from another sulfur compound. Human beings can detect 2 x 10-5 parts per billion of this compound. This is an almost unimaginably small amount equal to 10-4 mg per tonne or a drop, not in a bucket, but in a good-sized lake. Why evolution should have left us abnormally sensitive to grapefruit?, we leave you to imagine. Figure 9: Structure of Grapefruit Flavour Other organic compounds have strange effects on humans. Various ‘drugs’ such as alcohol and cocaine (figure 10) are taken in various ways to make people temporarily happy. They have their dangers. Too much alcohol leads to a lot of misery and any cocaine at all may make you a slave for life. Figure 10: Structure of Cocaine Again, let us not forget other creatures. Cats seem to be able to go to sleep at any time and recently a compound was isolated from the cerebrospinal fluid of cats that makes them, or rats or even humans go off to sleep quickly. It is a surprisingly simple compound – cis-9, 10-octadecenoamide. cis-9,10-octadecenoamide. Figure 11: Sleep Principle in Cats http://www.pdfonline.com/easypdf/?gad=CLjUiqcCEgjbNejkqKEugRjG27j-AyCw_-AP 12 13 Another fashionable molecule is resveratrole, which may be responsible for the beneficial effects of red wine in preventing heart disease. Resveratrole shown below is from the skin of grapes. Figure 12: Resveratrole From a long list of edible organic molecules, I choose vitamin C (figure 13). This is an essential factor in our diets. Indeed, that is why it is called a vitamin. The disease scurvy, a degeneration of soft tissues, particularly in the mouth, from which sailors on long voyages like those of Columbus’ expedition suffered results, if we lack vitamin C. It is also a universal antioxidant, scavenging for rogue free radicals and so protecting us against cancer. Some people think an extra large intake protects us against the common cold, but that is not yet fully proved. Vitamin C (ascorbic acid) is a vitamin for primates, guinea-pigs and fruit bats, but other mammals can produce it for themselves. Figure 13: Structure of Vitamin C Flavours and Fragrances and Sweeteners That brings us to flavours and fragrances. Companies like International Flavours and Fragrances (USA) or Gtvaudan-Roure (Swiss) produce very wide ranges of fine chemicals for the perfume, cosmetic, and food industries. Many of these will come from crude oil but others come from plant sources. A typical perfume will contain 5-10% fragrances in an ethanol/water (about 90:10) mixture. So, the perfumery industry needs a very large amount of ethanol and very little perfumery material. In fact, important fragrances like jasmine are produced on a > 10,000 tonnes per annum scale. The cost of a pure perfume ingredient like cis-jasmone, the main ingredient of jasmine, may be several hundred pounds, dollars, or euros per gram because of the high cost of its complex synthesis. Figure 14: Structure of Jasmine Perfume Some flavouring compounds are also perfumes and may also be used as an intermediate in making other compounds. Two such large scale flavouring compounds are vanillin (vanilla flavour as in ice cream) and menthol (mint flavour) both synthesized on a large scale and with many uses. Figure 15: Structure of Two Food Flavours Food chemistry includes much larger scale items than flavours. Sweeteners such as sugar itself are isolated from plants on an enormous scale. Other sweeteners such as saccharin (discovered in 1879) and aspartame (1965) are however synthesized on a sizeable scale. Aspartame is a compound of two of the natural ammo acids present in all living things and is made by Mosanto (a chemical company) on a large scale (over 10,000 tonnes per annum). http://www.pdfonline.com/easypdf/?gad=CLjUiqcCEgjbNejkqKEugRjG27j-AyCw_-AP 14 15 Figure 16: Structure of Aspartame and its Precursors Adhesives and Sealants Another oil-derived class of organic chemicals in business includes adhesives, sealants, coatings, and so on, with companies like Ciba- Geigy, Dow, Monsanto, and Laporte in the lead. Nowadays aircrafts are glued together with epoxy-resinsand you can glue almost anything with ‘Superglue’, a polymer of methyl cyanoacrylate. Methyl cyanoacrylate Figure 17: Structure of Super Glue Superglue bonds materials together when this small molecule joins up in a quick reaction with hundreds of its fellows in a polymerization reaction. Antibiotics The treatment of infectious diseases relies on antibiotics such as the penicillins to prevent bacteria from multiplying. One of the most successful of these is SmithKline Beecham’s amoxycillin. The four- membered ring at the heart of the molecule is the ‘-lactam’ (figure 18). Figure 18: Structure of Some Antibiotics AGROCHEMICALS We cannot maintain our present high density population in the developed world, nor deal with malnutrition in the developing world unless we preserve our food supply from attacks by insects and fungi and from competition by weeds. The world market for agrochemicals is over £10,000,000,000 per annum divided roughly equally between herbicides, fungicides, (figure 19a) and insecticides, Figure 19a: Benomyl - A Fungicide which Controls Many Plant Diseases One fungus (potato blight) caused the Irish potato famine of the Nineteenth Century and the Various blights, blotches, rots, rusts, smuts, and mildews, can overwhelm any crop in a short time. Especially now that so much is grown in Western Europe in winter, fungal diseases are a real threat. Pesticides2 Just as we create compounds, as synthetic chemists that preserve and make life easier for us human beings, so do we make compounds that terminate life. The life of pests which trouble us at home and on the field must be terminated to make our produce available, prevent diseases and remove disturbances. Some of the compounds created are DichloroDiphenyl-Trichloroethane (DDT), isolan, pirimicarb, baygon, zectram, dinitrophenol herbicides, chlorodane, and organophosphorous compounds, etc. http://www.pdfonline.com/easypdf/?gad=CLjUiqcCEgjbNejkqKEugRjG27j-AyCw_-AP 16 17 DDT is synthesised by condensation of chlorate with mono chloro benzene agitated with three times their combined weight of sulphuric acid (concentrated H2SO4). Chlorate DDT Baygon (or propoxur) Isolan Figure 19b: Structure of Some Pesticides Figure 20: Primicarb Isolan is a water soluble, effective aphidcide but highly toxic to mammals. Primicarb was made by ICI. Baygon is made from catechol and stepwise alkylation with 2-chloropropane and methylisothiocyanate. Baygon has a moderate toxicity of 150 mg/ kg. It shows a rapid knock-down action particularly against cockroaches. H Cl Cl Cl Cl ClCl + H Cl Cl Cl O H2SO4 + H2O ON H H3C O CH3 H CH3 N N H3C O N CH3 CH3 H3C H CH3 O N N CH3 H3C N H3C CH3 O O N R2 R1 Propham is a cabamate that is highly selective against grasses without harming crop plant while Barban is a variation of the herbicide (figure 21). Propham Barban Figure 21: Structure of Herbicidal Carbamate The above illustrations are just to let you know the chemistry behind most of what we use and see in our daily lives. NATURAL PRODUCTS CHEMISTS AND HUMAN NEEDS There is another group of chemists referred to as natural product chemists. They are trained to investigate products that are naturally occurring in plants and marine substances for the purpose of understanding their nature, uses and their modification. Their functions include isolating the compounds present in the plant, synthesizing the compounds to make them more available for use without recourse to nature. The drive to synthesized naturally occurring organic compounds is because sometimes the quantity at which they are present in nature may not satisfy the purpose for which they are required and synthesis makes them available at a greater quantum all year round unlike from plant that could be seasonal. Natural Product Chemists add value to natural products by removing some of the side effects of the drugs or by modifying them to make them more potent for whatever they are used for. They usually work with herbs, bark, leaves, shoots and different parts and sizes of plants, for use in herbal medicine. Do not confuse Natural Product Chemists with herbalists (babalawo) because they do their own work with a procedure different from the herbalists. A Natural Product Chemist extracts leaves, roots, stems or flowers of a plant like other herbalists do, but will not extract ten different plants together like H N O O CH3 Cl H CH3 H N O O CH3 Cl H CH3 http://www.pdfonline.com/easypdf/?gad=CLjUiqcCEgjbNejkqKEugRjG27j-AyCw_-AP 18 19 they (herbalists) do. A Natural Product Chemist will rather identify the active ingredients in the plant by knowing the compounds present in the extracts, their structures and isolate them one from the other. For example, the quantity of camphor available naturally cannot satisfy the volume that is used in the world. Hence camphor is synthesized and made available at the right quantity without destroying a lot of plants. There is one thing we must know about natural products. They are formed by ‘untrained’ trees without any one giving them the starting chemicals, they don’t require a Power Holding Company of Nigeria (PHCN) to provide power to stir their reactions, yet they form compounds that take chemists sometimes up to thirty years before they can fully understand what the plant has formed. It only shows that God who created them is a great God who can do anything He wishes to do with or without us. Human wisdom is nothing compared to God’s wisdom, we should be humbled by this understanding. The machine below can synthesize (±) oxomaritidine but it will require the starting materials as well as many other gadgets like electricity and computer controls3. Even with that the plant makes up to ten compounds simultaneously. This function is carried out by plants easily without much assistance. Figure 22: Picture of an Automatic Reactor for the Synthesis of Oxomaritidine The need to understand natural products and also produce them on the bench is the meeting point of a Synthetic Chemist and a Natural Product Chemist. HETEROCYCLES AS NATURAL PRODUCTS Heterocycles are compounds with circular shapes that contain other elements apart from carbon. For example, nicotine, purine and penicillin are all obtainable from natural sources. from tobacco from coffee Penicillin from algae Figure 23: Some Naturally Occurring Heterocyclic Compounds All heterocycles are all useful in one manner or the other. The challenge is to find the use for which it can be deployed. The work of a Synthetic Chemist is to make the heterocycles available. A lot of work must be done to identify the structure using various instruments like Fourier Transform Infra Red spectrometer (FT- IR), Nuclear Magnetic Resonance Spectrometer (NMR), Gas Chromatography coupled with Mass Spectrometer (GC/MS), X- Ray Crystallography to be able to confirm the structure of the compound produced fully. The organic compounds available to us today are those present in living things and those already formed over millions of years from dead things, for example, crude petroleum. In earlier times, the organic compounds known from nature were those in the ‘essential oils’ that could be distilled from plants and the alkaloids. These could be extracted from crushed plants with acid. Menthol is a famous example of a flavouring compound from the essential oil of spearmint and cis-jasmone, an example of a perfume distilled from jasmine flowers. N N CH3 Nicotine HN N H N H N O O 3,4,5,7-Tetrahydro-purine-2,6-dione N S O R O H N CH3 CH3 COOH http://www.pdfonline.com/easypdf/?gad=CLjUiqcCEgjbNejkqKEugRjG27j-AyCw_-AP 20 21 Figure 24: Naturally Occuring Organic Compounds Even in the Sixteenth Century one alkaloid was famous — quinine was extracted from the bark of the South American cinchona tree and used to treat fevers, especially malaria. The Jesuits who did this work (the remedy was known as “Jesuits’ bark’) did not of course know what the structure of quinine was, but now we do. The main reservoir of chemicals available to the Nineteenth Century Chemist was coal. Distillation of coal to give gas for lighting and heating (mainly hydrogen and carbon monoxide) also gave a brown tar, rich in aromatic compounds such as benzene, pyridine, phenol, aniline, and thiophene. Figure 25: Early Known Naturally Occurring Compounds Phenol was used by Lister (a scientist) as an antiseptic in surgery and aniline became the basis for the dyestuffs industry. It was this that really started the search for new organic compounds made by chemists rather than by nature. A dyestuff of this kind — still available — is Bismarck Brown, (figure 26) which should tell us that much of this early work was done in Germany. To make more complex compounds available is the work of chemists, creating more compounds. Figure 26: Early Known Complex Organic Compound HOW DO SYNTHETIC CHEMISTS CHOOSE THEIR TARGET COMPOUNDS? Having gone through some structures of compounds that are in daily use we can see that most of these compounds are not naturally available or where they are, they are not available in the quantum at which they are needed. They therefore have to be produced in a larger quantity to match demand. Chemists partner with God to make these compounds available for the comfort or delight of mankind. Another objective of the synthetic chemist may be to improve the quality or activity of the available compounds. Modification of some parts of the compounds may improve them dramatically. A classical example of this is phenothiazine which has the function –S- in its structure; the sulphur (-S-) can be replaced by vinylene group -C=C- because they are isosteres4. Phenothiazine dibenzoazepine (More active than Phenothiazine) Figure 27: Structures of Tranquilisers Phenothiazines by themselves are good tranquilisers: when the -S- is replaced by -C=C- (vinyl group) bond it gives S N H N H C C http://www.pdfonline.com/easypdf/?gad=CLjUiqcCEgjbNejkqKEugRjG27j-AyCw_-AP 22 23 dibenzoazepine. The isosteric replacement of -S- in phenothiazine with -C=C- group led to a more active drug used in treatment of mental depression. After the development of the dibenzoazepine, the -C=C- was hydrogenated to become - CH2CH2- to give a saturated dibenzoazepine which is even more active than dibenzoazepine. This has developed into the real drug impramine (a substituted saturated dibenzoazepine) which is used in the treatment of mental illness. The example above is a typical end to a challenge to a synthetic chemist. Figure 28: Structure of Impramine Tranquiliser WHAT HAS THIS SYNTHETIC CHEMIST CREATED? Mr. Vice-Chancellor Sir, as a worker with God, He has allowed me to do some work for mankind. Some of them are enumerated below as simple as possible. My contribution to knowledge has three components: * Creating new heterocycles for the benefit of mankind. * Discovering new methods of making precursors for useful heterocycles and not necessarily making the heterocycles. * Natural Product Chemistry.  MAKING NEW HETEROCYCLES AVAILABLE TO MANKIND FOR POTENTIAL USE The use of organic compounds for the treatment of diseases was introduced by Paul Ehrlich in 1907. These organic substances other than antibodies which inhibit pathogenic micro organisms, without affecting to any material extent, the tissues N H H2 C H2 C N H2 C H2 C CH2 CH2 CH2 N HCl CH3 CH3 + Impramine of the host. The first compounds used by Ehrlich were organic dyes, e.g., gentian violet, acriflavine and other azo dyes. Organic compounds of diverse chemical structures have been used in chemotherapy. These compounds could be of biological origin or synthesized compound. The useful chemotherapeutic compound can either be a natural product, e.g., salicylic acid, quinine, penicillin, etc., or a synthetic compound e.g., chloramphenicol. Substances which simply improve natural body defences such as vitamins and hormones are not considered as being chemotherapeutic. An example is oestrogen pills for controlling natural cycles. Oestrogen is a hormone, but when used in the treatment of gonococcus vulvovaginitis it is a chemotherapeutic compound. Many of these compounds have been used in the treatment of diseases and there has been increasing drugs resistance brought about by mutation and abuse of the drugs. This has brought about the need to continuously make available new drugs. The emergence of new diseases also makes it imperative for constant development of new compounds that can be used for treatment of diseases and for other uses. Creating these molecules can only be when God allows it. It is not all those who work and want to create these compounds succeed. Psalm 127 verse 2 states: “it is in vain you wake up early to sleep late, to eat the bread of sorrow because God gives all these things to his beloved even while they are sleeping” (Amplified Bible). The revelation of what to do and the direction to go about it is given by God as in Isaiah 45 verse 3  “And I will give thee the treasures of darkness, and hidden riches of secret places, that thou mayest know that I, the Lord, which call thee by thy name, am the God of Israel”. http://www.pdfonline.com/easypdf/?gad=CLjUiqcCEgjbNejkqKEugRjG27j-AyCw_-AP 24 25 HETEROCYCLIC COMPOUNDS THAT I HAVE CREATED Synthesis of Tricyclic Thiazoloquinazolines My first series of compound were the 4H-3,3a-dihydrothiazolo [4,3-b]quinazolines derivatives5 which have been well identified as antimalarials, antihypotensive agents and as possessing blood platelet aggregation inhibiting activity6,7 were under the direction of my supervisors, Professors Alo and Adegoke. This group of compounds was formed via iminium salts generated from phosphorous oxychloride treatment of tertiary amino acids at about 105oC (figure 29). The method gave the expected products in good yield. Figure 29: Synthesis of Thiazoloquinazolines Synthesis of New Benzo-substituted Angular Tricyclic Quinoxalines Quinoxalinones and their derivatives have been found to be useful for their antimicrobial activities,8 potent antithrombotic agents9 and as non-nucleoside HIV-1 reverse transcriptase inhibitors.10 This made them to become a valuable synthetic target. The compounds were synthesized as result is shown below.11 CH2Cl NO2 R + S N COOH H NO2 R SN COOH H2 C NO2 R SN NH2 H2 C N H R SN H2 C POCl3 DCM Fe/AcOH Reflux X NO2 R1 + H N (CH2)n COOH N (CH2)n COOH NO2 R1 N (CH2)n C NH R1 O Na2CO3 EtOH/H2O Reflux R1 = H, CF3, NO2, Cl, X = F, Cl R1 = H, CF3,NH2, Cl, R R R R = H, OH Fe/AcOH n = 1, 2 Figure 30: Synthesis of Tricyclic Quinoxalinones The synthesized compounds were tested at the Shell Agrochemical facility in England and it was found that they prevented rice blast (a disease) in field test. This activity is in addition to the ones mentioned earlier. SYNTHESIS OF BENZOTHIADIAZINES AS POTENTIAL DIURETICS Diuretic compounds are chemical compounds that increase the flow of urine in patients having fluid retention problem, for example, oedema, common in pregnant women. This usually leads to serious diabetes, and hypertension. The medical problem associated with fluid or electrolyte retention in the body often leads to such conditions that result in heart failure, hypertension, high blood pressure and sometimes chronic diabetes. Fluid retention is usually due to primary retention of sodium ion in the body and therefore one of the most effective ways of reducing oedema is to increase sodium excretion by the kidneys. It is necessary in such a state to induce a negative sodium balance in which the quantity of sodium loss by the body is in excess of that taken in. Such a state has hitherto been treated with 6 major types of medicinal compounds12. http://www.pdfonline.com/easypdf/?gad=CLjUiqcCEgjbNejkqKEugRjG27j-AyCw_-AP 26 27 H N O2 S R H2N N-substituted-4-aminobenzenesulphonamide Figure 31: Structure of a Monocyclic Diuretic The compounds of interest are the bicyclic benzothiadiazines like the one below (figure 32) have found good use as a diuretic and shows several fold better activity when compared to the monocyclic ones. Figure 32: Structure of a Bicyclic diuretics The logical way forward in the search for new diuretics was therefore to synthesize tricyclic analogues as shown in our work of 199013. The compound was synthesized using a new method involving iminium salts that was then just discovered by Adesogan and Alo14. The compound in figure 33 was requested for by NIH in USA for testing; but due to financial constraints, I could not oblige the request. N H N O2 S RH2NO2S Cl 2-Substituted-6-chloro-7-sulphonamidobenzothiadiazine-1,1-dioxide O2 S N COOHNO2R O2 S N NH2NO2R N H N O2 S R SO2Cl NO2R N H COOH + Base R = H, CH3, OCH3, -OCH2CH3, CF3, Cl Fe/AcOH/ Ref lux 1. SOCl2 2. CF3SO3Ag 3. NH3 N SO2NH N SO2NH Li N SO2NH Ph Ph OH N SO2 Ph Ph NH LDA, DEE -78oC Ph2CO 50% HCl Reflux Figure 33: Synthesis of Hexahydro(1,2)(1,2,4) Benzothiadiazine-6, 6- dioxides (Potential Tricyclic diuretic) Synthesis of Pyridine-fused Heterocycles Pyridine ring fused with sulphur containing heterocycles possesses interesting pharmacological and other activities15. Synthesis of such compounds makes a ready target. The pyridine containing heterocycles were prepared using an emerging technique at the time called Directed ortho Metalation (DoM). This reaction was carried out with a strong base called Lithium Diisopropyl Amide (LDA)16 as mediating agent. Figure 34: Synthesis of Isothiazolo[5,4-c]pyridine-3-one-1,1-dioxide N-substituted-4-aminobenzenesulphonamide http://www.pdfonline.com/easypdf/?gad=CLjUiqcCEgjbNejkqKEugRjG27j-AyCw_-AP 28 29 Other compounds that were similarly prepared by using this novel metalating method included the following: A Isothiazolo[5,4-c]pyridine-3-one-1,1-dioxide B N-t-butylisothazolo[5,4-c]pyridine-3-one-1,1-dioxide C 3,3-diphenyl-1,2-oxathiolo[3,4-b]pyridine-1,1-dioxide D 3,3- diphenyl-1,2-oxathiolo[4,3-c]pyridine-1,1-dioxide Figure 35: Structures of Pyridine-Fused Heterocycles Synthesis of 1, 2-Benzothiazines We then turned our attention to the synthesis of 1,2- Benzothiazines which are useful in the treatment of diseases in which products of lipoxygenase enzyme activity or the action of leukotrienes contribute to the pathological condition.17 This is in addition to its anticancer activities and other physiological activities18. Our emerging strategy19 for creating heterocycles called Directed ortho metalation method (DoM) was therefore extended to benzothiazine synthesis and a sample of the representative result is shown in the scheme below (figures 36 and 37). R = -CH 2 CH 3 , -CH 2 (CH 2 ) 2 CH 3 , -CH 2 Ph, -Ph % Yield 40 41 35 35 Figure 36: Synthesis of Precursors to Benzothiazines N SO2 O NH N SO2 O N N SO2 Ph O Ph N SO2 Ph O Ph A B C D S N H O O S N H O O 2 eq. n-BuLi 0oC S N H O O R OH R H3O+ Figure 37: Synthesis of Benzothiazines using POCl 3 Apart from the using POCl 3 in the cyclisation, we also showed that hydrochloric acid could also be used in the ring closure giving two types of products- substituted and unsubstituted benzothiazinones. Figure 38: Synthesis of Benzothiazines Using HCl Synthesis of Tricyclic Benzothiazinones 20,21. Our forays into synthesis of novel heterocyclic compounds led us to tricyclic 1,2-benzothiazinones and related compounds. These compounds are used as anti-inflammatory, antihypnotic and anticonvulsant agents. Other known properties are antispasmodic, diuretic and hypotensive activities22. With all these significant activities, benzothiazinones therefore present a desirable synthetic target. Tricyclic benzothiazinones was specially attempted in this work because of the dearth of information on these types of heterocycles. Snieckus and his group in 1994 pioneered the use of Friedel- Craft Anionic Equivalents (FCAE) strategy in the formation of S O N H OH H R O S O N R O POCl3 R= a - CH2CH3, b - CH2(CH2)2CH3, c - CH2OPh S O N H OH Ph Ph O S O N Ph Ph O S O NH Ph Ph O +HCl / 48h 33% HCl 50% HCl Product A B A B % Yield 48 25 52 75 http://www.pdfonline.com/easypdf/?gad=CLjUiqcCEgjbNejkqKEugRjG27j-AyCw_-AP 30 31 ketones from carboxamides for the preparation of phenanthroviridin thioxanthon-9-one-6,6-dioxides, xanthones and phosphoro-oxanthones. This method removed the problem associated with classical Friedel-Craft reactions especially for rings substituted with sulfonamides. The regiospecificity is also predictable. Sulfonamides in classical reactions direct to meta position, but with FCAE the ketone is formed at the ortho position. We extended the use of FCAE strategy to the synthesis of benzenesulphonamides in the preparation of tricyclic benzothiazinones-1,1-dioxide in moderate yields (figures 39 and 40). A previous method of preparation of these types of compounds was achieved by the side-chain cyclization of bicyclic benzothiazinones. The metalation was carried out at 0°C and allowed to warm to room temperature for one hour to give the expected product. Scheme for the Synthesis of 1,2,3,4-Tetrahadropyrido benzothiazin-5-one 10,10-dioxide Figure 39: Synthesis of Tricyclic Benzothiazines. S N CONEt2 OO S N COOH OO S N H COOH OO Cl + NaOH SOCl2 Et2NH LDA 0oC to rtN S O O O Figure 40: Synthesis of Substituted Benzothiazine-1, 1-dioxides Figure 41: Some of The Products Obtained Using FCAE Strategy Synthesis of Xanthen-9-ones Xanthones and xanthone derivatives have been known to have beneficial effects on some cardiovascular diseases, including ischemic heart disease, atherosclerosis, hypertension and thrombosis. The protective effects of xanthones in the cardiovascular system may be due to their antioxidant, anti- inflammatory, platelet aggregation inhibitory, anti-thrombotic and/ or vasorelaxant activities. In particular, the antagonism of endogenous nitric oxide synthase inhibitors by xanthones may represent the basis for improved endothelial function and for reduction of events associated with atherosclerosis. Xanthones may also have anti-tumour activity23. S O2 NH NEt2 O R1 R2 S O2 NH O R1 R2 R1 = H, R2 = Me; R1 = Me, R2 = Me, R1 = H, R2 = S S O2 N O NEt2 S S O2 N O LDA/THF 0oC to rt LDA/THF 0oC to rt NS O O O H3C CH3 NS O O O H3C CH3 S H N O O O N S O O O N S O O O N S O O O S S N C O O N S O O O O H3C H3C MeO http://www.pdfonline.com/easypdf/?gad=CLjUiqcCEgjbNejkqKEugRjG27j-AyCw_-AP 32 33 The new method of using Friedel-Craft Anionic Equivalent (FCAE)24 for the synthesis of heterocycles that we just discovered was applied to the synthesis of xanthen-9-one and derivatives (figures 42 and 43). Figure 42: Pathway to Synthesis of Xanthones Some of the products obtained in this research are as follows: Figure 43: Xanthones obtained from FCAE Strategy Synthesis of Dibenzooxapinone 24 We introduced a variation in the FCAE strategy by placing a methyl group at the ortho position. This places a methyl group in position for a detrotonation and attack by the amide giving rise to a seven-membered-ring rather than the six in xanthon-9-ones to give dibenzooxapinones. Benzo[b,f]oxapinones have anti-inflammatory properties that are superior to dibenzoxazocine and fenclofenac25. When we discovered that our method can make available these O NEt2 O +s_BuLi/TMEDA O O NEt2 Li O O NEt2 O o O O O OMe OMeO O OMe ClO O OMe O OiPr 63%70%84% 93% benzoxapin-ones we capitalised on that by making many compounds available. The yields of the products were very good. Figure 44: Synthesis of Benzoxapinones and benzothiapinones via Friedel Craft Anionic Equivalents (FCAE) Preparation of 6-Deoxyjacareubin (A Natural Product) Using the above method 6-deoxyjacareubin, a natural product was synthesized according to the scheme below using the FCAE cyclisation strategy24 (figures 45 and 46). Figure 45: Synthesis of Precursor to 6-deoxyjacareubin X O O O O O X CONEt2 Me O CONEt2 Me Me Me Me Me + Starting Benzamide Dibenzoxapinone its its analogues LDA 0oC rt LDA 0oC rt X = S, O ONa OMe + OiPr OiPrI O NEt2 CuCl/ TDA Py/150oC 5h, (96%) O OMe OiPr OiPrNEt2 O LDA (2.5 Eq) THF/ 0oC to rt 1h (75%) O OMe OiPr OiPrO http://www.pdfonline.com/easypdf/?gad=CLjUiqcCEgjbNejkqKEugRjG27j-AyCw_-AP 34 35 O OMe OiPr OiPrO 1. BCl3 (10 eq.) 0oC to rt 2. H O PhB(OH)2 / HOAc O OMe OHO O O OH OHO O BBr3 (5 Eq.) CH2Cl2 / -78oC to rt 72% Figure 46: Synthesis of 6-deoxyjacareubin The Synthesis of 2-Aryl-3-Hydroxy Benzo[b]thiophenes 26-28 Thiophene compounds are useful as antianxiety drugs, hypnotics and antiepileptic drugs. There is continuous interest in benzo[b]thiophene derivatives because of their many varied uses. Besides the manifold uses of this class of compounds, it has been reported that benzo[b]thiophene derivatives carrying side- chains have shown anticancer activities. Uses of benzo[b]thiophene derivatives as excitatory amino acid antagonists, in the treatment of myocardial eschemia, hypertension, fungal infection, or as oral contraceptives and as hypoglycemic agents are also known. More recently there have been reports on the anti-inflammatory, antiexudative, analgesic and antipsychotic activities of benzo[b]thiophene derivatives as well as their inhibitory action on protein tyrosin phosphatase and 5-lypoxygenase. This heterocycles therefore becomes a ready target for synthesis. We therefore used our metalation strategy in the synthesis of the benzothiophene skeleton as delineated below29 (figures 47,48). Figure 47: Synthesis of Some Precursor to Benzothiophenes CONEt2 1. s-BuLi/TMEDA -78oC, 1h 2. (PhCH2S)2 CONEt2 S CONEt2 CONEt2 OMe1 2 CONEt2 S Ph CONEt2 S Ph OMe 66% 68% CONEt2 S S Ph OH LDA/ 0oC to rt R R S OH Ph S OH Ph S OH Ph S OH Ph OMe MeO MeO 68% 68% 64% 65% Figure 48: Synthesis of substituted Benzothiophenes Synthesis of Substituted 2-Phenyl-3-Hydroxybenzofurans Many natural products incorporating the benzofuran skeleton30 have been isolated. These include formannoxin from Fomes annosus,31 anodendroic acid32 from Anodendon affine, Euarium from Eupatorium,33, 34 pterofuran from Pterocarpus indicus35,36. Others included feranoeremorphine isolated from aerial parts of South African composite Ehryops herecarpus. The versatility of our FCAE strategy was again exploited in the synthesis of benzofurans. Figure 49: Synthesis of Substituted 2- Phenyl-3-Hydroxy Benzofurans The substituted benzofurans were obtained in good yield by this our strategy and therefore was a milestone contribution to the OH OCONEt2 ClCONEt2 OH s-BuLi -78oC 0oC Cl OMe CONEt2 OMe O CONEt2 OMeO OH LDA 0oC rt http://www.pdfonline.com/easypdf/?gad=CLjUiqcCEgjbNejkqKEugRjG27j-AyCw_-AP 36 37 synthesis of these useful compounds which are also important natural product analogues37. Figure 50: Synthesized Substituted Benzofurans An important natural product that contains this benzofuran as the core of its skeleton is Anigiopresin. We synthesised this compound as shown in the scheme below using our novel strategy38. Figure 51: Anigiopressin A - A Natural Occuring Benzofuran The Baylis-Hillman Approach to Quinoline Derivatives The quinoline nucleus features prominently in compounds which exhibit medicinal properties.39 Notable amongst these are synthetic antimalarials40 such as chloroquine and primaquine, fungicides such as halacrinate,41 antibacterial 4-quinolones such as ciprofloxacin and norfloxacin,42 the HIV-1 protease inhibitor saquinavir,43 and styrylquinolines as potential HIV-1 integrase inhibitors.44 Not surprisingly, an array of synthetic methods have been developed to access quinoline derivatives, including the O H3CO OH OCH3 O H3CO OH O H3CO OH OCH3 O H3CO OH O H3C OH O OH H3CO H3CO OCH3 O OMe OMe MeO OMe MeO BCl3 O OH OH HO OH HO Anigiopressin A classic Skraup, Doebner-von Miller, Conrad-Limpachand Knorr syntheses45. We therefore investigated the Baylis-Hillman46 reaction as a route to provide an additional method for the synthesis of quinolines. Our reaction followed the scheme below. The synthesis pioneers a new method for quinoline synthesis and it has enjoyed numerous citations47, 48. Figure 52: Synthesis of Substituted Quinolines from Baylis Hillman Reaction Products Combined Directed ortho Metalation (DoM) – C-N, C-O Cross Coupling Route to Dibenzo[b,f]oxathiazepines and Dibenzo[b,f]oxazepines - A New Synthetic Strategy for the Synthesis of Biologically Active Heterocyclic Molecules49. Dibenzo[b,f]oxazepines and dibenzo[b,f]oxathiazepines ring systems are prevalent in bioactive molecules and pharmaceuticals50. We discovered a new general one-step synthesis of the reaction involving the copper-catalyzed cross- coupling of ortho-halo benzamides and sulfonamides, prepared by the versatile Directed ortho Metalation (DoM) strategy51, with phenols in sequential intermolecular C- O and intramolecular C- R3 R2 R4 R1 R O NO2 OH R = -COR, -CO 2R R3 R2 R4 R1 R O N H OH N R R4 R3 R2 R1 N R R4 R3 R2 R1 H R =COR R =COR R =CO 2R Baylis H illman reaction product http://www.pdfonline.com/easypdf/?gad=CLjUiqcCEgjbNejkqKEugRjG27j-AyCw_-AP N coupling processes. The reliance on DoM, the ready availability of both starting materials from commercial sources, and the potential to obtain derivatives of these drug-like tricyclics that are (including analogues of nevirapine, an anti-AIDS drug)52 that are not available by other routes augurs well for the broad utility of our new synthetic method especially in medicinal chemistry programs of pharmaceutical companies. Mr Vice Chancellor Sir a strategy for the practical syntheses of bioactive dibenzo[b,f]oxazepines and dibenzo[b,f]oxathiazepines by a combined one-pot Cu-catalyzed C-N and C-O bond forming sequence from readily available substituted ortho iodo benzenesulphonamides and substituted ortho bromophenols was developed by us. Such double cross coupling reactions53 are, to the best of our knowledge, unknown. The discovery has further progressed to rapid generalization for the synthesis of dibenzo-condensed 7-membered ring systems represented as dibenzo-1,2,5-oxathiazepine and dibenzo[b,f] oxazepinone which are respectively useful as key intermediates for the synthesis of dibenz[b,f][1,4]oxazepines and thiazepine-11(10H)-one HIV-1 reverse transcriptase inhibitor 50b and antidepressant agents 52b figure 53, 54, 55 . Yield = 30 – 80% R1 = H, -OMe, R2 = H, Cl, Br. R3 = H, Me, Hal1 = I; Hal2 = Br, l; X = O, S. Figure 53: Synthesis of Dibenzo[b,f]oxazepines S Hal1 N H O O + Hal2 HX S O O X N CH3 Cs2CO3 MePh CuPF6(MeCN)4 S O O X N H CH3 Hal2 R3 R2 +R1R1 R1R3 R3 S I N H R1 O O + Hal2 HO S O O O N R1 MePh CuPF6(MeCN)4 S O O X N H R1 Br Cl Me Me Cl Cl Me + Figure 54: Synthesis of Dibenzo[b,f]oxathiazepines Yield = 40 – 60% R1 = H, -OMe, R2 = H, Cl, Br. R3 = H, Me, Hal1 = I; Hal2 = Br, l; X = O, S. Figure 55: Synthesis of Dibenzo[b,f]oxazepines Synthesis of Pyridine substituted analogues of Dibenzo- oxazepine and Oxathioazepines We have also developed new synthesis of dibenzo[b,f]oxa- thiazepine, dibenzo[b,f]oxazepine and some of their pyridine analogues using sequential intermolecular copper–catalyzed C- O and intramolecular C-N arylation of N- alkyl-2- iodobenzenesulfonamides coupling with substituted 2- halogenophenol and N- alkyl-2-halogenobenzamides with substituted 2-halogenophenols respectively. These compounds exhibit ring systems of several classes of pharmaceutical agents (figure 56). Figure 56: Synthesized Various Substituted Heterocycles using Sequential Double Cross Coupling Strategy O O N N CH3MeO 70% S O O O N N CH3 68% N S O O O N N CH3 71% N S O O O N CH3 Cl 62% N S O O S N CH3 45% 38 39 O N H Hal1 R4 HX Hal2 R2 R3 + X N O R R4 R 2 R3 O N H R O R4CuPF6(MeCN)4 Cs2CO3 MeCN + R2 R3 http://www.pdfonline.com/easypdf/?gad=CLjUiqcCEgjbNejkqKEugRjG27j-AyCw_-AP Microwave Assisted Organic Synthesis (MAOS) Mr. Vice Chancellor Sir, in the present age, everything including reactions must be done quickly and the products must be ready within a short time, for us to keep pace with our dynamic world. We all know that microwave ovens make hot food available within a short time due to its ability to heat very quickly. This has recently been employed as a tool in the preparation of chemical compounds54. To be at the cutting edge of chemistry I have joined fellow chemists in using this source of heat in my work55. Microwave heating apart from providing rapid heat, it also provides some products that are not conventionally possible. This makes the Microwave Assisted Organic Synthesis (MAOS) very useful. Another good reason for using MAOS is that it provides a solvent free reaction condition giving us a chance for green chemistry. This is due to the elimination of organic solvents that often pollute the environment in this procedure. It must be said also that due to this rapid heating, explosions are also possible and therefore the reactions must be monitored carefully. To avoid this type of explosions, special microwave ovens designed to safeguard all parameters that could lead to explosion are available on the market, but unfortunately this is still out of reach to our laboratory which is not well endowed yet we are struggling to keep up with this cutting edge chemistry. Figure 57: Differences in Microwave Heating Compared With Convectional Heating While we have only recently forayed into this burgeoning technique of chemical synthesis, my only contribution to this method so far was in the synthesis of angular nitrogen quinoxalinones. The classical method to synthesize such quinoxalines which normally should take up to 6 hours of heating and cooling (reflux) is now completed in about 30 minutes without the use of organic solvents. The advantage of not using any organic solvent emphasises the new concern for the environment referred to as Green Chemistry. The acid adducts were obtained in 30 minutes of microwave heating. The quinoxalines were also obtained in one and a half hours compared to six to twelve hours by convectional heating. Figure 58: Synthesis of Acid Adducts And Angular Nitrogen Fused Tricyclic Quinoxaline via Microwave Heating Figure 59: Acid Adducts Obtained With MAOS The heterocycles: Quinazolines were obtained by Microwave assisted heating in just about one and a half hour are as follows: Figure 60: Tricyclic Quinoxalines Obtained With MAOS More contributions are anticipated in no distant future in this area. X NO2 R1 + H N (CH2)n COOH N (CH2)n COOH NO2 R1 N (CH2)n C NH R1 O K2CO3 KF Al2O3 MW R1 = H, CF3, NO2, Cl, X = F, Cl R = H, CF3, NH2, Cl, 1 2 3 4 R R R R = H, OH Fe/AcOH n = 1, 2 No organic solvent was used in this reaction 30 min MW 1.5h NO2 N COOH NO2 NO2 N COOH N NO2 N COOH NO2 N COOH NO2 NO2 N COOH NH N O NH NH2 N O NH N O N H N N O NH N O NH NH2 N O 40 41 http://www.pdfonline.com/easypdf/?gad=CLjUiqcCEgjbNejkqKEugRjG27j-AyCw_-AP * DISCOVERING NEW METHODS OF MAKING PRECURSOR TO HETEROCYCLES In order to record success in the synthesis of new compounds and efficiently making old ones, I have been involved in developing and improving upon methods of synthesis over the years. One of them is lithiation of ortho alkylarene sulphonate which was carried out to make a variety of functional groups ortho to the sulphonate available. These precursors are used in making new heterocycles available as shown below56. E = EtCH(OH), Me 2 C(OH), PhCH(OH), Ph 2 C(OH), EtO 2 C, -COOH, -SO 2 Ph, PhCH(OH), Ph 2 C(OH), -COOH. Figure 61: Preparation of 2- β-Substituted Benzenesulphonates Figure 62: Preparation of 4- Methyl 2- β-Substituted Benzenesulphonates New Cross Coupling Method One of the best method of constructing carbon-carbon bond (C- C), Carbon Oxygen bond (C-O) and Carbon Nitrogen (C-N) bond is cross coupling reactions. Several methods are available using different reagents. We made our own contribution by making new reagents available for this burgeoning method. In addition to this new reagent which is the use of nickel (0) we connected it with our well established directed ortho metalation strategy to make new library of precursors as shown below. The nickel (0) was derived from nickel acac57. SO3Et CH3R SO3Et CH2Li R SO3Et R E E+ Reagents = i = BuLi, MeI, NH4Cl; ii BuLi, -78oC SO3Et CH3R i ii Reagents = i = BuLi, MeI, NH4Cl; ii BuLi, -78oC, E+; H3O+ i ii SO3Et CH3H3C SO3Et H3C SO3Et H3C R Figure 63: Biphenyls Obtained From New Cross-Coupling Reaction Kinetic and Thermodynamic Stabilities of the Sulphonamide Lithio Species Lithio species of sulphonamides are stable between -78°C and 25°C, but as Hellwinkel58 and Closson59 have reported, they could undergo rearrangement with a secondary N-phenyl group. The temperature dependence of the kinetic and thermodynamic stabilities of sulphonamide anions has been reported. Figure 64: Previous Methods of Rearrangements in Substituted Benzene Tertiary toluene sulphonamide was metalated at 0°C to give the 2-lithio species. When the reaction was warmed to room temperature, the ortho anion rearranged to the 4-position before the addition of electrophiles60 (Figure 65). In tertiary p-toluamide, these two products were obtained by using two different types of bases as shown in Figure 64. OTf G Ni(acac) G ArZnBr R2 R1 R1= H, 2-OMe, 3-OMe,4-OMe, R2 = -OMOM, -CONEt2, OCONEt2,-OMe, G = H, -CONEt2 = H, -CONEt2, SO3Et CH3 n-BuLi/0oC n-BuLi/RT CONiPr2 CH3 n-BuLi/TMEDA/-78oC LDA/0oC 42 43 http://www.pdfonline.com/easypdf/?gad=CLjUiqcCEgjbNejkqKEugRjG27j-AyCw_-AP H3C S N O O R R n-BuLi -78oC RT H3C S N O O R R H2C S N O O R R EH2C S N O O R R E+ 0 o C E = D, TMS, -COOH, -CH 3 , -C(OH)Ph 2 , -CH(OH)Ph, -C(OH)CH 3 , Figure 65: 2 to 4- Rearranged Substituted Benzenesulphonamides The rearrangement, shown in Scheme 65, was exploited in the functionalization of sulphonamides by trapping the 4-lithio species with electrophiles, giving easy access to such products. * NATURAL PRODUCT CHEMISTRY My first work in natural products was in 1997 when I was approached by my colleague Dr Joy Okpuzor Associate Professor in Cell Biology and Genetics Department who requested that we work together on the plant Buchholzia coriacea (Engl. Bot. Jahrb.) Buchholzia coriacea also known as musk tree is a member of the family Capparidaceae. It is an evergreen understorey tree of lowland rain forest, up to 20 metres high occurring in West Africa, from Guinea to west and east of Cameroon and in Gabon. The tree can be found in the southern part of Nigeria, Ghana and Liberia61. The bark can be made into a pulp for inhalation or into a snuff to relieve headache, sinusitis, and nasal congestion in Ivory Coast; small pox or skin itching in Gabon. The pulped bark is applied to the chest to treat chest pains and also to boils. In Liberia, the seeds are used on skin eruption and internally for worms. In Ivory Coast, the crushed up seeds, are pasted over the stomach for difficult childbirth. It is also considered anthelmintic. It is used as cough medicine, and in the treatment of ulcer. It is also used in the treatment of hypertension by drinking the fluid squeezed out of the leaves with pea leaves and small salt. It is envisaged that studying this plant and obtaining more information on the active ingredients of Buchholzia coriacea will put all these speculations into their proper perspective. Our study was therefore directed to a preliminary investigation into some chemical components of Buchholzia coriacea. The seeds of Buchholzia coriacea (Capparidaceae) were found to contain three aliphatic acids. The structures of the purified samples were determined on the basis of spectroscopic data. Figure 66: Structure of Naturally Occurring Acid from Buchholzia Spp Natural Products Containing Antioxidant Properties In continuation of my interest in natural products chemistry, we engaged in another collaboration with my colleagues from the Department of Pharmacognosy with Associate Professor Kemi Odukoya and Mrs. Toyin Sofidiya on natural products with antioxidant properties. HO O HO O HO O Tetradecanoic acid Hexadecanoic acid 9,12-Octadecadienoic acid 44 45 http://www.pdfonline.com/easypdf/?gad=CLjUiqcCEgjbNejkqKEugRjG27j-AyCw_-AP It is known that oxygen centred free radicals and other reactive oxygen species are by-products of numerous physiological and biochemical processes in the human body. Overproduction of such free radicals cause oxidative damage to biomolecules such as lipids, proteins and DNA, eventually leading to many chronic diseases, such as atherosclerosis, cancer, diabetes, aging and other degenerative diseases in humans. These oxygen radicals must be eliminated or removed from the body. Most known antioxidants are also known to be phenolics. Herbs that can carry out this function are most desirable. It has been found that many Nigerian plants have been speculated to have antioxidant activities from folklores. To back this up scientifically five Nigerian medicinal plants (Dalbergia saxatilis Hook (Papilionaceae), Ekebergia senegalensis A Juss (Meliaceae), Hymenocardia acida Tul. (Hymenocariaceae), Icacina tricantha Oliv. (Icacinaceae) and alacia pallescens Oliv. (Celastraceae) were tested scientifically. It was found from this work that some of these plants especially Hymenocardia acida Tul. has antioxidant activity similar to vitamin C and close to queretin. In this study a good linear correlation was found between reducing power and the total phenolic content from the extract. The chemical component that was isolated was homorentin. Figure 67: Structure of Homorentin Lecaniodiscus cupanioides is a medicinal plant widely used in Nigeria folk medicine for the treatment of inflammatory conditions, hepatomegaly, and bacterial infections. In this context, we investigated the antioxidant and antibacterial activity of the O O OH OH O O HO OH OH HO OH OH HO methanol extracts from Lecaniodiscus cupanioides leaves towards selected antibacterial as well as different antioxidant activity models. The extract exhibited strong activity comparable to ascorbic acid used as reference in the assays. The strongest activity was found on Bacillus cereus, Staphylococcus aureus, Micrococcus kristine and Streptococcus pyrogens at 1.0 mg/ ml. The data obtained clearly establishes the antioxidant potential of the extract and justify its ethnomedical uses for the treatment of bacterial infections61-63. Conclusion Mr Vice Chancellor Sir, I hope I have shown in this lecture the various compounds that were previously unknown, that God has allowed me to create for the potential use by man for different kinds of purposes. These compounds were created out of what God Almighty had previously created. We just worked with Him to make new ones. Recommendations Mr. Vice Chancellor Sir, based on my experiences as a research Chemist and as it is traditional, I wish to make the following recommendations. a. For Chemists to be able to put themselves forward as Synthetic Chemists they need extensive training up to the Ph. D and postdoctoral levels. Postdoctoral training is not available in Nigeria due to lack of funds and its absent in Nigerian universities’ master plan. I therefore recommend compulsory postdoctoral training and the creation of postdoctoral training facilities in Nigerian universities. This will enable quality work to be done in Nigeria rather than all our bright promising young academics helping foreign countries to develop at our expense. It will enable newly certified Ph. D. holders to carry out quality work that would assist them generate quality published works before they get bogged down with teaching. Nigeria by this may become a hub of scientific activities. 46 47 http://www.pdfonline.com/easypdf/?gad=CLjUiqcCEgjbNejkqKEugRjG27j-AyCw_-AP b. The University or the Federal Government through the NUC must provide the state of the art analytical spectrometers and facilities for the proper identification of the compounds that are synthesized and those obtained from natural products. The Spectrometers required are Nuclear Magnetic Resonance (NMR), Fourier Transform Infra Red (FT-IR) spectrometers, Recordable Double Beam Ultra Violent spectrometer, Gas Chromatography/ Mass Spectrometers (GCMS). Lack of these instruments is a major reason for the annual flight of the researcher to overseas laboratories where these instruments are available. Unfortunately there is a limit to what can be achieved through such travels. If these equipment are too expensive for each university (which should not be) the NUC can pull resources together and establish regional facilities to which users, with the help of their research grant, can pay to use in order to ensure sustainability. The research grants must therefore allow for such cost of analysis. c. Ample laboratory space is of paramount importance for research to grow in the sciences. The ideal situation is for a professor to have a laboratory where he carries out his research with his students. A situation where a professor in science does not have a laboratory dedicated to him is abnormal. I therefore recommend that immediate effort be made to remedy the situation by building more laboratories for research work and teaching for the Faculty of Science. By so doing we will have more research output that will elevate the University of Lagos to higher ranking institution in research. d. The development of new and/or resuscitation of a petrochemical company that will make available FINE chemicals (fine chemicals are chemicals reagents that can be converted from one form to the other to provide drugs or starting materials for them). The availability of fine chemicals (the Synthetic Chemists’ tool) will improve the Synthetic Chemists contributions to the nation and make them to be appreciated and Nigeria will be better for it. The employment that could be generated from the ability of several chemists being able to work will be enormous. If you imagine the quantity of analgesics that are used in Nigeria and all of them are imported when these can be produced in about three to four steps in Nigeria if fine chemicals were available in Nigeria. When I finished my Ph. D. Prof. Fola Tayo of the Faculty of Pharmacy, University of Lagos, was commissioned to raise a team to make paracetamol in Nigeria in view of the large quantities of it that are used in Nigeria. He invited me then to be the Synthetic Chemist in the team. To our amazement there was only toluene of all the chemicals required for the synthetic programme. If we therefore ventured into it the cost of our paracetamol will be several times more expensive than that of foreign competitors who readily have fine chemicals to use. 48 49 http://www.pdfonline.com/easypdf/?gad=CLjUiqcCEgjbNejkqKEugRjG27j-AyCw_-AP Acknowledgments I thank the Almighty God, the creator, who has graciously made me one of His friends and Partner, by giving me the power to create new things from the things He had created. Without Him we can do nothing but with Him we can do all things. Praise be to His name, Amen. I thank God for my father Mr. Gabriel Ibitoye Familoni who did not marry more than one wife, and therefore prevented problems after his death in 1966. I thank my Mother, Madam Alice Opeloye Familoni for her love who after the death of my father 42 years ago, as a young woman did not remarry but chose to bring her Children up properly. May God bless you Mama. May God bless Mrs. Julianah Daramola, my Aunt and her husband Venerable Daramola (of blessed memory) for training me in the way of the Lord. The training shaped my life permanently. I can categorically state that I may not be who I am today but for the huge contribution of Chief Jonathan Mayowa Akinola (of blessed memory) popularly called JM who single-handedly sponsored my secondary education up to Higher School Certificate Level when there was no hope of going to a secondary school. May God continue to raise help for his children and children’s children, Amen. I acknowledge the wonderful work God did through my brother Dr. Kayode Adegbola Familoni of the Department of Economics who brought me to Unilag after my secondary school. My life changed direction for good and this is probably why I am able to become a professor of this wonderful University rather than any other. May the good God bless him in retirement, Amen. The contributions from my siblings, five of them, led by the eldest and my only sister, Mrs. Olufunmilayo Olaleye, Matron of the Health Centre, University of Lagos, who kept us together through the difficult period of struggling is greatly acknowledged. The others are Mr. Rufus Familoni, Gbenga Familoni, Commander Susi Familoni and Reverend Femi Familoni, as well as their husbands and wives. During my Postgraduate days, my Father in-Law Chief Christopher Mackson Akinyelu virtually purchased all the chemicals which the Chemistry Department could not provide from England. This helped me immensely; I therefore thank Chief and Mrs. C. M. Akinyelu for their support for my career. I am blessed to be associated during my B. Sc., M. Phil. and Ph.D with my supervisor and my brother, Professor Babajide Alo. He directed my path into the area of synthetic chemistry when I knew nothing about it and I have received encouragement from his lovely wife Mrs. Funmi Alo who was also my HSC teacher in Government College, Ibadan. Our association has moved far beyond chemistry to a family relationship. I also acknowledge my M. Phil. co-supervisor, Prof. Emmanuel Adegoke. I thank my teachers in the Chemistry Department, the Technical staff who analyzed most of the compounds being reported today. The contributions of my students both present and past are gratefully acknowledged. My “Twin brother” in academics, Professor Oluwatoyin Ogundipe, we have been running mates in many good things, as well as Professor Tokunbo Sofoluwe (DVC-MS), who was my Dean when I was Sub Dean in the Faculty of Science. The prayers and diverse supports from the Chapel of Christ Our Light, Unilag has been tremendous. These prayers led by my brother and Pastor, Rev. Azuka Ogbolumani and his wife, Lola, other Pastors and the entire congregation, are wonderful. I pray that God will continue to bless them all. Amen. My Foreign collaborators have been very instrumental to my success. Starting from Professors Guy Queguiner and Francis Marsais in INSA Rouen, France, they were the ones who gave 50 51 http://www.pdfonline.com/easypdf/?gad=CLjUiqcCEgjbNejkqKEugRjG27j-AyCw_-AP me my first international exposure. It was with them that a wonderful encourager Professor Victor Snieckus met me and carried me on his shoulders to the point that I am today, he is a multi medal winner and chemist of international repute. Professor Perry Kaye of Rhodes University in South Africa has been wonderful in supporting me. I also acknowledge the assistance of Professor McKillop of University of East Anglia, United Kingdom. Funding for my work has been graciously provided by the following: * The University of Lagos has given me the opportunity to achieve my dream of becoming an academic and has allowed me to go for several study leaves and has sometimes provided air fares. * Royal Society of Chemistry London, Research Award 1999, 2003, 2006, JWT Traveling Fellowship, 1997 and 2007 * CIDA/NSERC of Canada, University of Waterloo, Canada. 1993-1994 * Dutch Academy of Science 1991, * Federal Ministry of Science and Technology 1991, * Alfred Bader Chair, Queen’s University, Kingston, Ontario, Canada, 1999, 2007. * South African Foundation for Research Development 1997, 2006 Finally I cannot but thank my nuclear family for enduring the life of having an academic as father resulting in absence from home many times. For making the home front conducive for study and thinking. They are the lovely gifts God gave us: Mr. Babajide Familoni, Olumuyiwa Familoni, the previous last born Miss Omolabake Familoni and the real last born Miss Olubukola Familoni. The success of this Inaugural Lecture can be attributed to my darling wonderful gift of God for me, my lovely, beautiful wife, Mrs. Bosede Familoni. There was an occasion when I was in South Africa in 1997, I informed the only lady professor in my group that my wife was expecting a baby and would give birth while I was away from home and she bluntly said she could never agree to such absenteeism, but here we are, Bosede did it for me. I say thank you my Bosede for your wonderful complementary role in the home. I thank all of you wonderful people who are too numerous to mention individually, professional Colleagues in Chemistry Department, Faculty of Science, Chemical Society, Institute of Chartered Chemists and Institute of Public Analysts of Nigeria who have come from far and near to grace the occasion, I thank you very much and I pray that God will bless you all richly, Amen. 52 53 http://www.pdfonline.com/easypdf/?gad=CLjUiqcCEgjbNejkqKEugRjG27j-AyCw_-AP References 1. J. Clayden, N. Greeves, S. Warren and P. Wothers,; Organic Chemistry- Oxford University Press. 2004 2. R. Kumar, Insect Pest Control, Arnold Publications 1984 3. P. Kundig; Science 2006, 314, 430-431 4. O.B. Familoni and B.I. Alo, Bioactive Organic Compounds, Published by Panaf Press, Lagos, Nigeria 1995 pp. 82, ISBN #978-32843-4-7 5. E. A. Adegoke,; B. I. Alo; and O. B. Familoni, J. Heterocyclic Chem. 1987, 27, 107-110 6. F. Alexandre, A. Berecibar, R Wriggleworth and T. Besson.; Tetrahedron Lett. 2003, 44, 4455-4458 7. F. 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D.Closson, J. Org. Chem.1975, 40, 889. 60. Familoni, O.B. Kinetic and Thermodynamic Stability of Lithio-Anions In The Synthesis of Substituted Arylsulphonamides J. Sci.. Res. And Dev. 1999, 4, 231-242 61. O. Familoni and J. Okpuzor, J. Sci. Res. Dev. 2000, 5, 113-116. 62. M. O. Sofidiya, O. A. Odukoya, O. B. Familoni, S. I. Inya- Agha Pakistan Journal of Biological Sciences 2006, 9, 1438 – 1441. 63. M. O. Sofidiya, O. A. Odukoya, A. J. Afolayan and O. B. Familoni, International Journal of Botany, 2007, 3, 302- 306. 64. M. O. Sofidiya, F. O. Jimoh, A. A. Aliero, A. J. A. Afolayan, O. A. Odukoya and O. B. Familoni; Research J. of Microbiology 2008, 3, 91-98. 58 59 View publication statsView publication stats http://www.pdfonline.com/easypdf/?gad=CLjUiqcCEgjbNejkqKEugRjG27j-AyCw_-AP https://www.researchgate.net/publication/272082430