Essentials of Organic Chemistry: For students of pharmacy, medicinal chemistry and biological chemistry
For more years than I care to remember, I have been teaching the new intake of students to the Nottingham pharmacy course, instructing them in those elements of basic organic chemistry necessary for their future studies. During that time, I have also referred them to various organic chemistry textbooks for additional reading. These texts, excellent though they are, contain far too much material that is of no immediate use to pharmacy students, yet they fail to develop suf?ciently areas of biological and medicinal interest we would wish to study in more detail. The organic chemistry needs of pharmacy students are not the same as the needs of chemistry students, and the textbooks available have been specially written for the latter group. What I really wanted was an organic chemistry textbook, considerably smaller than the 1000–1500-page tomes that seem the norm, which had been designed for the requirements of pharmacy students. Such a book would also serve the needs of those students on chemistry-based courses, but who are not specializing in chemistry, e.g. students taking medicinal chemistry and biological chemistry. I have wanted to write such a book for a long time now, and this is the result of my endeavours. I hope it proves as useful as I intended it.
Whilst the content is not in any way unique, the selection of topics and their application to biological systems should make the book quite different from others available, and of especial value to the intended readership. It is a combination of carefully chosen material designed to provide a thorough grounding in fundamental chemical principles, but presenting only material most relevant to the target group and omitting that which is outside their requirements. How these principles and concepts are relevant to the study of pharmaceutical and biochemical molecules is then illustrated through a wide range of examples.
I have assumed that readers will have some knowledge of organic chemistry and are familiar with the basic philosophy of bonding and reactivity as covered in pre-university courses. The book then presents material appropriate for the ?rst 2 years of a university pharmacy course, and also provides the fundamental chemical groundwork for courses in medicinal chemistry, biological chemistry, etc. Through selectivity, I have generated a textbook of more modest size, whilst still providing a suf?ciently detailed treatment for those topics that are included.
I have adopted a mechanism-based layout for the majority of the book, an approach that best enables the level of detail and selection of topics to be restricted in line with requirements. There is a strong emphasis on understanding and predicting chemical reactivity, rather than developing synthetic methodology. With extensive use of pharmaceutical and biochemical examples, it has been possible to show that the same simple chemistry can be applied to real-life complex molecules. Many of these examples are in self-contained boxes, so that the main theme need not be interrupted. Lots of cross-referencing is included to establish links and similarities; these do not mean you have to look elsewhere to understand the current material, but they are used to stress that we have seen this concept before, or that other uses are coming along in due course.
I have endeavoured to provide a friendly informal approach in the text, with a clear layout and easy-to-?nd sections. Reaction schemes are annotated to keep material together and reduce the need for textual explanations. Where alternative rationalizations exist, I have chosen to use only the simpler explanation to keep the reasoning as straightforward as possible. Throughout, I have tried to convince the reader that, by applying principles and deductive reasoning, we can reduce to a minimal level the amount of material that needs be committed to memory. Worked problems showing typical examination questions and how to approach them are used to encourage this way of thinking.
Four chapters towards the end of the book diverge from the other mechanism-oriented chapters. They have a strong biochemical theme and will undoubt-edly overlap with what may be taught separately by biochemists. These topics are approached here from a chemical viewpoint, using the same structural and mechanistic principles developed earlier, and should provide an alternative perspective. It is probable that some of the material described will not be required during the ?rst 2 years of study, but it could sow the seeds for more detailed work later in the course.
There is a measure of intended repetition; the same material may appear in more than one place. This is an important ploy to stress that we might want to look at a particular aspect from more than one viewpoint. I have also used similar molecules in different chapters as illustrations of chemical structure or reactivity. Again, this is an intentional strategy to illustrate the multiple facets of real-life complex molecules.
I am particularly grateful to some of my colleagues at Nottingham (Barrie Kellam, Cristina De Matteis, Nick Shaw) for their comments and opinions. I would also like to record the unknowing contribution made by Nottingham pharmacy students over the years. It is from their questions, problems and dif?culties that I have shaped this book. I hope future generations of students may bene?t from it.
Finally, a word of advice to students, advice that has been offered by organic chemistry teachers many times previously. Organic chemistry is not learnt by reading: paper and pencil are essential at all times. It is only through drawing structures and mechanisms that true understanding is attained.
Molecular representations and nomenclature
From the beginnings of chemistry, scientists have devised means of representing the materials they are discussing, and have gradually developed a compre-hensive range of shorthand notations. These cover the elements themselves, bonding between atoms, the arrangement of atoms in molecules, and, of course, a systematic way of naming compounds that is accepted and understood throughout the scien-ti?c world.
The study of carbon compounds provides us with the subdivision ‘organic chemistry’, and a few simple organic compounds can exemplify this shorthand approach to molecular representations. The primary alcohol propanol (systematically propan-1-ol or 1-propanol, formerly n-propanol, n signifying normal or unbranched) can be represented by a structure showing all atoms, bonds, and lone pair or non-bonding electrons.
Lines are used to show what we call single bonds, indicating the sharing of one pair of electrons. In writing structures, we have to remember the number of bonds that can be made to a particular atom, i.e. the valency of the atom. In most structures, carbon is tetravalent, nitrogen trivalent, oxygen divalent, and hydrogen and halogens are univalent. These valencies arise from the number of electrons available for bonding. More often, we trim this type of representation to one that shows the layout of the carbon skeleton with attached hydrogens or other atoms.
Atomic structure and bonding
Atoms are composed of protons, neutrons and electrons. Protons are positively charged, electrons carry a negative charge, and neutrons are uncharged. In a neutral atom, the nucleus of protons and neutrons is surrounded by electrons, the number of which is equal to the number of protons. This number is also thesameasthe atomic number of the atom. If the number of electrons and protons is not equal, the atom or molecule containing the atom will necessarily carry a charge, and is called an ion. A negatively charged atom or molecule is termed an anion,and a positively charged species is called a cation.
The inert or noble gases, such as helium, neon, and argon, are particularly unreactive, and this has been related to the characteristic number of electrons they contain, 2 for helium, 10 for neon (2 + 8), and 18 for argon (2 + 8 + 8). They are described as possessing ‘?lled shells’ of electrons, which, except for helium, contain eight electrons, an octet. Acquiring a noble gas-like complement of electrons governs the bonding together of atoms to produce molecules. This is achieved by losing electrons, by gaining electrons, or by sharing electrons associated with the un?lled shell, and leads to what we term ionic bonds or covalent bonds. The un?lled shell involved in bonding is termed the valence shell,and the electrons in it are termed valence electrons.
Stereochemistry
From our discussions of bonding, we have learnt something about the arrangement of bonds around various atoms (see Chapter 2). These concepts are fundamental to our appreciation of the shape of molecules, i.e. stereochemistry.Beforewedelve into these matters, let us recap a little on the disposition of bonds around carbon.
Bonding at four-valent carbon is tetrahedral, with four sp3-hybridized orbitals mutually inclined at 109.5?. Remember that the tetrahedral array is demon-strated by experimental measurements, and that hybridization is the mathematical model put forward to explain this observation (see Section 2.6.2). We can conveniently represent the tetrahedral arrangement in two dimensions by using a wedge–dot convention.In this convention, single bonds written as normal lines are considered to be in the plane of the paper. Bonds in front of this plane, i.e. coming out from the paper, are then drawn as a wedge, whilst bonds behind the plane, i.e. going into the paper.
Acids and bases
A particularly important concept in chemistry is that associated with proton loss and gain, i.e. acidity and basicity. Acids produce positively charged hydrogen ions H+ (protons) in aqueous solution; the more acidic a compound is, the greater the concentration of protons it produces. In water, protons do not have an independent existence, but become strongly attached to a water molecule to give the stable hydronium ion H3O+.Inthe Brønsted–Lowry de?nition:
Reaction mechanisms
A reaction mechanism is a detailed step-by-step description of a chemical process in which reactants are converted into products. It consists of a sequence of bond-making and bond-breaking steps involving the movement of electrons, and provides a rationalization for chemical reactions. Above all, by following a few basic principles, it allows one to predict the likely outcome of a reaction. On the other hand, it must be appreciated that there will be times when it can be rather dif?cult to actually ‘prove’ the mechanism proposed, and in such instances we are suggesting a reasonable mechanism that is consistent with experimental data.
The basic layout of this book classi?es chemical reactions according to the type of reaction mechanism involved, not by the reactions undergone within any speci?c group of compounds. As we proceed, we shall meet several types of general reaction mechanism. Initially, however, reactions can be classi?ed as ionic or radical, according to whether bond-making and bond-breaking processes involve two electrons or one electron respectively.
Nucleophilic reactions: nucleophilic substitution
As the term suggests, a substitution reaction is one in which one group is substituted for another. For nucleophilic substitution, the reagent is a suitable nucleophile and it displaces a leaving group. As we study the reactions further, we shall see that mech-anistically related competing reactions, eliminations and rearrangements, also need to be considered.
Nucleophilic reactions of carbonyl groups
The carbon–oxygen double bond C=Oistermed a carbonyl group, and represents one of the most important reactive functional groups in chemistry and biochemistry. Since oxygen is more electronegative than carbon, the electrons in the double bond are not shared equally and the carbon–oxygen bond is polar-ized, with the oxygen atom attracting more of the electron density (see Section 2.7). This polarization may be represented via the resonance structures A and B, where A is uncharged and B has full charge separation (see Section 2.10).
Electrophilic reactions
In the preceding chapters we have seen how new bonds may be formed between nucleophilic reagents and various substrates that have electrophilic centres, the latter typically arising as a result of uneven elec-tron distribution in the molecule. The nucleophile was considered to be the reactive species. In this chapter we shall consider reactions in which elec-trophilic reagents become bonded to substrates that are electron rich, especially those that contain multi-ple bonds, i.e. alkenes, alkynes, and aromatics. The p electrons in these systems provide regions of high electron density, and electrophilic reactions feature as the principal reactivity in these classes of compounds. We term the reactions electrophilic rather than nucle-ophilic, since it is the electrophile that provides the reactive species.
