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Chapter

Cover Organic Chemistry

Electrophilic Aromatic Substitution  

This chapter focuses on aromaticity - the parent member of a large class of so-called aromatic compounds. It shows that benzene is a conjugated unsaturated compound which has special stability attributed to aromaticity. However, an organic compound does not have to be either aromatic, or not, as a whole: molecules of many compounds, including natural products and biologically important compounds, contain aromatic and non-aromatic residues linked together. The chapter then displays the distinguishing feature of an aromatic compound: its cyclic system of delocalized ? electrons. It looks at electrophilic aromatic substitution and the main reactions of benzene: halogenation, nitration, sulfonation, and Friedel-Crafts alkylation and acylation. Next, the chapter analyzes the regioselectivity of electrophilic substitution directed by substituents and the reactivity of phenol and aniline. It also looks at the preparation of substituted benzenes.

Chapter

Cover Aromatic Chemistry

Reactions of arenes  

This chapter examines the reactions of arenes. If benzene is reacted with a reagent R, it is reasonable to conclude that should R be positively charged (an electrophile), the process will be easier than when R is negative (a nucleophile). For these reasons, electrophilic substitution is commonplace, whereas nucleophilic substitution only occurs under special circumstances. The energy profile of an electrophilic substitution reaction with benzene as the substrate can be represented diagrammatically. In order that the reaction should progress to the final product, another transition state is traversed in which the sigma bond to the proton of the tetrahedral carbon atom weakens and eventually breaks. There is much evidence for the formation of sigma complexes. The chapter then looks at π complexes.

Chapter

Cover Organic Synthesis

Selectivity II: Regioselectivity  

This chapter focuses on regioselectivity. When devising a synthetic route to an organic molecule, substituents and functional groups must be placed in the required positions, i.e. with the correct regiochemistry. The chapter begins by evaluating the regioselectivity of some of the most common methods for the preparation of alkenes. In a regioselective reaction, the formation of one structural (or positional) isomer is favoured. The chapter then describes the control of the reactivity of functional groups which are capable of giving more than one product, with particular reference to: electrophilic addition to a double bond; electrophilic aromatic substitution; electrophilic addition to an enolate; nucleophilic addition to an enone; nucleophilic addition to an epoxide; and oxidation of a ketone to an ester or lactone.

Chapter

Cover Organic Chemistry

Aromatic chemistry  

This chapter explores aromatic chemistry. It begins by looking at electrophilic aromatic substitution (SEAr), where a functional group on an aromatic ring, usually a proton, is replaced by an electrophile. In order to undergo reaction with the electrophile, the aromatic ring must be electron-rich. This is because the mechanism requires the cloud of electrons on the benzene ring to attack the electrophile; if the ring were electron-deficient, it would not be able to do this as readily. The mechanism proceeds via a carbocation intermediate, also known as the Wheland intermediate. The chapter then considers nucleophilic aromatic substitution (SNAr), where a group on an aromatic ring is replaced by a nucleophile. It also discusses azo coupling, which is when an aromatic diazonium-containing compound is joined to another aromatic compound.

Chapter

Cover Aromatic Heterocyclic Chemistry

Pyridines  

This chapter evaluates pyridine, a polar liquid which is miscible with both organic solvents and water. It can formally be derived from benzene by replacement of a CH group by a nitrogen atom. Pyridine is a highly aromatic heterocycle, but the effect of the heteroatom makes its chemistry quite distinct from that of benzene. The aromatic sextet of six π-electrons is complete without invoking participation of the lone pair on the nitrogen. Hence, the lone pair of pyridine is available for bonding without disturbing the aromaticity of the ring. The effect of the heteroatom is to make the pyridine ring very unreactive to normal electrophilic aromatic substitution. Conversely, pyridines are susceptible to nucleophilic attack. The chapter then considers the synthesis, electrophilic substitution, nucleophilic substitution, and anion chemistry of pyridines.

Chapter

Cover Aromatic Heterocyclic Chemistry

Oxazoles, imidazoles, and thiazoles  

This chapter examines oxazoles, imidazoles, and thiazoles. Oxazole, imidazole, and thiazole are the parent structures of a related series of 1,3-azoles containing a nitrogen atom plus a second heteroatom in a five-membered ring. They are isomeric with the 1,2-azoles isoxazole, pyrazole, and isothiazole, and their aromaticity derives from delocalization of a lone pair from the second heteroatom. Oxazole, imidazole, and thiazole can be formally derived from furan, pyrrole, and thiophene respectively by replacement of a CH group by a nitrogen atom at the 3 position. The presence of this pyridine-like nitrogen deactivates the 1,3-azoles towards electrophilic attack and increases their susceptibility towards nucleophilic attack. The chapter then looks at the synthesis, electrophilic substitution reactions, anion chemistry, and nucleophilic aromatic substitution of oxazoles, imidazoles, and thiazoles.

Chapter

Cover Aromatic Heterocyclic Chemistry

Five-membered ring heterocycles with three or four heteroatoms  

This chapter addresses the broad category of five-membered ring heterocycles containing three or four heteroatoms, which encompasses many heterocyclic systems. Obviously, there is considerable variation in the physical and chemical properties of such a large group of heterocycles. For instance, with regard to aromaticity, oxadiazole is considered to be less aromatic than triazole or tetrazole. Nevertheless, this collection of heterocycles does share certain characteristics. The trend of decreasing tendency towards electrophilic substitution on going from furan, pyrrole, and thiophene to the azoles is continued into these series. The presence of additional ‘pyridine-like’ nitrogen atoms renders these systems particularly ‘electron-deficient’, and electrophilic substitution is of little importance. Conversely, nucleophilic substitution does occur in these systems. The chapter then considers the synthesis of 1,2,4-ozadiazoles; 1,2,3-triazoles; and tetrazoles.

Chapter

Cover Stereoelectronic Effects

Substitutions at saturated centres  

This chapter focuses on substitutions at saturated centres. Substitution, or displacement, reactions are the commonest of all organic reactions, and substitutions at sp3-carbon were the first to be studied in depth. We know that two, conceptually quite different, mechanisms may be involved. The reaction can be concerted, with the new bond forming as the old bond breaks, or stepwise, with separate bond-breaking and bond-making steps. It can be a cation, as in the SN1 mechanism for nucleophilic substitution; an anion, in which case the reaction is electrophilic substitution; or a radical. The chapter then looks at concerted nucleophilic substitution; stereoelectronic barriers to intramolecular alkyl-group transfer; and the stabilization of the SN2 transition state by delocalization.

Chapter

Cover Chemical Structure and Reactivity

Organic chemistry 3: reactions of π systems  

This chapter evaluates reactions in which C=C double bonds are formed and the reactions which such molecules undergo, including elimination reactions. Given that C=C double bonds are electron rich, their most characteristic reactions are with electrophiles. The chapter looks at typical examples of these reactions and the factors that control which carbon is attacked in an unsymmetrical double bond. It then turns to the enols and enolates, which are formed from aldehydes and ketones under acidic and basic conditions. The chapter also considers aromatic systems, exemplified by benzene. The special stability of the π system in a benzene ring means that the molecule tends to react in such a way that the aromatic ring is preserved. As a result, the reactions of benzene are quite different to those of simple π systems, being mainly electrophilic substitution rather than addition.

Chapter

Cover Organic Chemistry

Reactions of Nucleophiles with Alkenes and Aromatic Compounds  

This chapter explores the reactions of nucleophiles with ?, ?-unsaturated carbonyl compounds and related electrophilic alkenes as well as with aromatic compounds carrying a nucleofuge - usually haloarenes. It looks at the kinetic and thermodynamic control of carbonyl and conjugate additions, then reviews the nucleophilic addition to other electrophilic alkenes. The chapter then investigates the substitution reactions of highly electrophilic arenediazonium ions (which have an excellent nucleofuge, N2) by the SN1 and other mechanisms. It then looks at Michael reactions (or Michael addition) and Robinson annulation. Finally, the chapter considers nucleophilic aromatic substitution by addition-elimination and elimination-addition mechanisms.

Chapter

Cover Aromatic Chemistry

Orientation of electrophilic substitution reactions  

This chapter evaluates the orientation of electrophilic substitution reactions. When an arene C6H5X is substituted by an electrophile R+, there are three principal sites for bonding: C-2 (ortho, o), C-3 (meta, m), and C-4 (para, p). Halogen atoms and most of the commonly encountered substituent groups, apart from alkyl units, are more electronegative than the sp 2 hybridized carbon atoms which constitute the benzene ring. As a result, a dipole is created and charge is withdrawn from the ring. The chapter then looks at resonance effects within sigma intermediaries. While resonance normally has the dominant role in determining the site adopted by the entering electrophile (the electromeric effect), the rate of the reaction is also influenced by the electron withdrawing power of the original substituent (the inductive effect). The chapter also considers ipso substitution, kinetic and thermodynamic control, and Birch reduction.

Chapter

Cover Aromatic Heterocyclic Chemistry

Quinolines and isoquinolines  

This chapter assesses quinolines and isoquinolines. Quinoline and isoquinoline are two isomeric heterocyclic systems, which can be envisaged as being constructed from the fusion of a benzene ring at the C2/C3 and C3/C4 positions of pyridine respectively. They are both ten π-electron aromatic heterocycles. Like pyridine, they are moderately basic. Indeed, quinoline is sometimes used as a high boiling-point basic solvent. As with pyridine, the nitrogen atoms of quinoline and isoquinoline each bear a lone pair of electrons not involved in aromatic bonding which can be protonated, alkylated, or complexed to Lewis acids. The chapter then considers the synthesis, electrophilic substitution, nucleophilic substitution, and anion chemistry of quinoline and isoquinoline.

Chapter

Cover Making the Transition to University Chemistry

Hydrocarbons: Arenes  

This chapter discusses arenes, a type of hydrocarbon. Benzene is known to be the archetypal arene as it features the original Kekulé structure with alternating double and single bonds. The electrophilic substitution reactions of benzene go in line with the high electron density above and below the benzene ring. Nitration is a particularly vital reaction undergone by benzene. This involves a nitrating mixture of concentrated nitric acid and sulfuric acid. Additionally, the electrophilic substitution of Friedel–Crafts acylation involves reagents of acyl chloride and aluminium chloride , the latter which acts as a Lewis acid. On the other hand, the electrophilic substitution of halogenation pertains to how benzene needs a catalyst for halogenation.

Chapter

Cover Organic Chemistry

Regioselectivity  

This chapter explores regioselectivity. Chemoselectivity means that there are two separate functional groups and that a reagent must choose between them. By contrast, regioselectivity implies that there is one functional group that can react in two different places and a reagent must choose where to react. Simple examples include addition of HX to an alkene and nucleophilic attack on the epoxide derived from that alkene. It might also mean that two functional groups are combined in a single conjugated system that can again react in two (or more) places. The choice between ortho/para and meta substitution when an electrophile attacks a benzene ring is also a matter of regioselectivity. The chapter considers regioselectivity in electrophilic aromatic substitution and in radical reactions.

Chapter

Cover Organic Chemistry

Electrophilic aromatic substitution  

This chapter assesses electrophilic aromatic substitution. Formation of the enol tautomer is catalysed by acid or by base, and because the ketone and enol are in equilibrium, enolization in the presence of D2O can lead to replacement of the protons in the α positions of ketones by deuterium atoms. Because the enolization and deuteration process can be repeated, eventually all of the α-protons are replaced by deuterium. The way this ketone is deuterated provides evidence that its enol form exists, even though the keto/enol equilibrium greatly favours the ketone form at equilibrium. The chapter discusses similar reactions of a compound that exists entirely in its enol form. That very stable enol is phenol and its stability is a consequence of the aromaticity of its benzene ring. The chapter then looks at alkyl benzenes, halogens, and the Friedel–Crafts chemistry.

Chapter

Cover Aromatic Heterocyclic Chemistry

Pyrimidines  

This chapter explores pyrimidines. Formal replacement of a CH unit in pyridine by a nitrogen atom leads to the series of three possible diazines: pyridazine, pyrimidine, and pyrazine. Like pyridine, they are fully aromatic heterocycles. The effect of an additional nitrogen atom as compared to pyridine accentuates the essential features of pyridine chemistry. Electrophilic substitution is difficult in simple unactivated diazines because of both extensive protonation under strongly acidic conditions and the inherent lack of reactivity of the free base. Nucleophilic displacements are comparatively easier. The most important of the diazines is pyrimidine. The actual biosynthesis of purines involves construction of a pyrimidine ring onto a pre-formed imidazole. The chapter then considers the synthesis and chemistry of the pyrimidine ring system.

Chapter

Cover Aromatic Heterocyclic Chemistry

Isoxazoles, pyrazoles, and isothiazoles  

This chapter investigates isoxazoles, pyrazoles, and isothiazoles. Isoxazole, pyrazole, and isothiazole are the parent structures of the 1,2-azole family of heterocycles, having a nitrogen atom plus one other heteroatom in a 1,2-relationship in a five-membered ring. The aromatic sextet is completed by delocalization of the lone pair from the second heteroatom. Consequently, as in pyridine, the nitrogen atoms of the 1,2-azoles have a lone pair available for protonation. However, the 1,2-azoles are significantly less basic than the 1,3-azoles because of the electron-withdrawing effect of the adjacent heteroatom. Isoxazole and isothiazole are essentially non-basic heterocycles, and even pyrazole is a much weaker base than the corresponding 1,3-azole imidazole. As with substituted imidazoles, substituted pyrazoles may exist as a mixture of tautomers. The chapter then looks at the synthesis, electrophilic substitution, and anion chemistry of isoxazoles, pyrazoles, and isothiazoles.

Chapter

Cover Aromatic Heterocyclic Chemistry

Pyrroles, thiophenes, and furans  

This chapter discusses pyrroles, thiophenes, and furans. Pyrrole, thiophene, and furan are five-membered ring heteroaromatic compounds containing one heteroatom. They derive their aromaticity from delocalization of a lone pair of electrons from the heteroatom. Consequently, the lone pair is not available for protonation and hence these heterocycles are not basic. Furan is the least aromatic of the trio because oxygen has the greatest electronegativity. The chapter then considers how this variation in aromaticity affects the reactivities of these three related heterocycles. It also looks at the synthesis of pyrroles, thiophenes, and furans, using the Paal–Knorr synthesis. Finally, the chapter reviews the electrophilic substitution and anion chemistry of pyrroles, thiophenes, and furans.

Chapter

Cover Foundations of Organic Chemistry: Worked Examples

Reactions with electrophiles  

This chapter reviews the addition of HX to C=C, the mechanisms of the reactions of HCI HBr, H2O addition to ethene and propene, carbocations, and cationic polymerization. It discusses the mechanism and stereochemistry of the addition of X2 and XY to C=C and addition to ethene and propene. It also examines the electrophilic aromatic substitution reactions, which includes aromatic compounds, halogenation, nitration, and acylation. The chapter highlights the crowding around the central carbon atom, wherein the larger C-C-C angle in the secondary carbocation keeps the other two carbon atoms further apart than they are in the primary carbocation. It talks about the electron-releasing inducive effect of two alkyl groups on the C+ that favours the secondary C+.

Chapter

Cover Foundations of Organic Chemistry

Reactions with electrophiles  

This chapter assesses organic reactions with electrophiles. Electrophiles have centres of low electron density, which will accept an electron pair to make a covalent bond. There are three types: positively charged cations, neutral molecules, and radicals. We could also include as electrophiles all the organic molecules which react with the nucleophilic reagents in the previous chapter, e.g. the polarized haloalkanes and carbonyl compounds. The chapter then looks at the addition of hydrogen halides to alkenes; the reactions of alkenes with sulfuric acid; the addition of halogens to alkenes; the cationic polymerization of alkenes; and the oxidation of alkenes. It also considers benzene and related compounds, studying the electrophilic substitution of benzene; the oxidation of benzene and related compounds; and the comparison between benzene and alkenes.