Aromatic Heterocycles Reactions PDF | Organic Chemistry

Aromatic heterocycles 1: reactions 29 Connections Building on Arriving at Looking...

Aromatic heterocycles 1: reactions 29 Connections Building on Arriving at Looking forward to Aromaticity ch7 Aromatic systems conceptually derived Synthesis of aromatic heterocycles ch30 Enols and enolates ch20 from benzene: replacing CH with N to Saturated heterocycles ch31 get pyridine Electrophilic aromatic substitution ch21 Biological chemistry ch42 Replacing CH=CH with N to get pyrrole Nucleophilic attack on aromatic rings ch22 How pyridine reacts Reactions of enols and enolates How pyridine derivatives can be used to ch25 & ch26 extend pyridine’s reactivity How pyrrole reacts How furan and thiophene compare with pyrrole Putting more nitrogens in five- and six- membered rings Fused rings: indole, quinoline, isoquinoline, and indolizine Rings with nitrogen and another heteroatom: oxygen or sulfur Introduction The rather precise chemical Benzene is aromatic because it has six electrons in a cyclic conjugated system. We know it is definition of ‘aromatic’ is explained aromatic because it is exceptionally stable, it has a ring current and hence large chemical in Chapter 7. You will find the shifts in the proton NMR spectrum, and it has special chemistry involving substitution rather reactions of benzene and its aromatic derivatives described in than addition with electrophiles. This chapter and the next are about the very large number Chapters 21 and 22: those two of other aromatic systems in which one or more atoms in the benzene ring are replaced by chapters are essential reading heteroatoms such as N, O, and S. There are thousands of these systems with five- and six- before you tackle this one. membered rings, and we will examine just a few. O Me Me O O N S N N N EtO HN N Me H N HO O N H N H2 N sulfapyridine OMe H N NHMe O S N N N O quinine antipyrine Me N N Viagra N CN Me H Tagamet Online support. The icon in the margin indicates that accompanying interactive resources are provided online to help your understanding: just type www.chemtube3d.com/clayden/123 into your browser, replacing 123 with the number of the page where you see the icon. For pages linking to more than one resource, type 123-1, 123-2 etc. (replacing 123 with the page number) for access to successive links. 724 CHAPTER 29 AROMATIC HETEROCYCLES 1: REACTIONS Our subject is aromatic heterocycles and it is important that we treat it seriously because most—probably about two-thirds of—organic compounds belong to this class, and they num- ber among them some of the most significant compounds for human beings. If we think only of drugs we can define the history of medicine by heterocycles. Even in the sixteenth century quinine was used to prevent and treat malaria, although the structure of the drug was not known. The first synthetic drug was antipyrine (1887) for the reduction of fevers. The fi rst effective antibiotic was sulfapyridine (1938). The first multi-million pound drug (1970s) was Tagamet, the anti-ulcer drug, and among the most topical of current drugs is Viagra (1997) for treatment of male impotence. All these compounds have heterocyclic aromatic rings shown in black. Three have single rings, five- or six-membered, two have five- or six-membered rings fused together. The num- ber of nitrogens in the rings varies from one to four. We will start by looking at the simple six-membered ring with one nitrogen atom: pyridine. Aromaticity survives when parts of benzene’s ring are replaced by nitrogen atoms There is no doubt that benzene is aromatic. Now we must ask: how can we insert a heteroatom into the ring and retain aromaticity? What kind of atom is needed? If we want to replace one of the carbon atoms of benzene with a heteroatom, we need an atom that can be trigonal to keep the flat hexagonal ring, and that has a p orbital to keep the six delocalized electrons. Nitrogen fits all of these requirements. This is what happens if we replace a CH group in ben- zene with a nitrogen atom. replace one CH group with a nitrogen atom N benzene pyridine H NOT a chemical reaction! Interactive structure of pyridine H N δH 7.5 H The orbitals in the ring have not changed in position or shape and we still have the six elec- H δH 7.1 trons from the three double bonds. One obvious difference is that nitrogen is trivalent and thus there is no NH bond. Instead, a lone pair of electrons occupies the space of the C–H bond N H δH 8.5 in benzene. 1H NMR spectrum of pyridine In theory then, pyridine is aromatic. But is it in real life? The most important evidence comes from the proton NMR spectrum. The six protons of benzene resonate at 7.27 ppm, some 2 ppm downfield from the alkene region, clear evidence for a ring current (Chapter 13). Nomenclature Pyridine is not as symmetrical as benzene but the three types of proton all resonate in the One of the most annoying same region. As we will see, pyridine is also very stable and, by any reasonable assessment, things about heterocyclic chem- pyridine is aromatic. istry is the mass of what appear We could continue the process of replacing, on paper, more CH groups with nitrogen atoms, to be illogical names. You should not, of course, attempt to learn and would find three new aromatic heterocycles: pyridazine, pyrimidine, and pyrazine: them all, but a basic idea of how replace another CH group N they are designed will help you. N with a nitrogen atom We will give you a guide on N which names to learn shortly. N N N N For the moment accept that NOT a chemical reaction! pyridine pyridazine pyrimidine pyrazine ‘amine’ ends in ‘-ine’ and any heterocyclic compound whose There is another way in which we might transform benzene into a heterocycle. Instead of name ends in ‘-ine’ is a nitrogen heterocycle. The syllable ‘azo-’ using just one electron from N to replace an electron in the π system, we could use nitrogen’s also implies nitrogen and ‘pyr-’ lone pair of electrons to replace two electrons in the π system. We can substitute a CH=CH (usually) implies a six-membered unit in benzene with a nitrogen atom providing that we can use the lone pair in the delocal- ring (except in pyrrole!). ized system. This means putting it into a p orbital. We still have the four electrons from the  P Y R I D I N E I S A V E RY U N R E AC T I V E A R O M AT I C I M I N E 725 remaining double bonds and, with the two electrons of the lone pair on nitrogen, that makes six in all. The nitrogen atom must still be trigonal with the lone pair in a p orbital so the N–H bond is in the plane of the five-membered ring. replace a CH=CH unit with a nitrogen atom N N H H NOT a chemical reaction! H H benzene pyrrole H δH 6.2 The 1H NMR spectrum of pyrrole is slightly less convincing as the two types of proton on the ring resonate at higher field (6.5 and 6.2 ppm) than those of benzene or pyridine but they still H δH 6.5 fall in the aromatic rather than the alkene region. Pyrrole is also more reactive towards electro- N philes than benzene or pyridine, but it does the usual aromatic substitution reactions (Friedel– H Crafts, nitration, halogenation) rather than addition reactions: pyrrole is also aromatic. δH~10 Inventing heterocycles by further replacement of CH groups by nitrogen in pyrrole leads to two compounds, pyrazole and imidazole, after one replacement, to two triazoles after two replacements, and to a single tetrazole after three. pyrazole 1,2,3-triazole replace one replace a second N replace a third CH group N CH group CH group with a with a N with a N N nitrogen atom N nitrogen atom N nitrogen atom N H H N N NOT a NOT a NOT a chemical N chemical N N chemical H H reaction! reaction! reaction! tetrazole N N H H imidazole 1,2,4-triazole All of these compounds are generally accepted as aromatic too as they broadly have the NMR spectra and reactivities expected for aromatic compounds. As you may expect, intro- ducing heteroatoms into the aromatic ring and, even more, changing the ring size actually affect the chemistry a great deal. We must now return to pyridine and work our way more slowly through the chemistry of these important heterocycles to establish the principles that govern their behaviour. More nomenclature The ending ‘-ole’ is systematic and refers to a five-membered heterocyclic ring. All the five-membered aromatic hetero- cycles with nitrogen in the ring are sometimes called ‘the azoles’. Oxazole and thiazole are used for the oxygen and sulfur analogues of imidazole. N N O S oxazole thiazole Pyridine is a very unreactive aromatic imine The nitrogen atom in the pyridine ring is planar and trigonal with the lone pair in the plane of the ring. This makes it an imine. Most of the imines you have met before (in Chapter 11, for example), have been unstable intermediates in carbonyl group reactions, but in pyridine we have a stable imine—stable because of its aromaticity. All imines are more weakly basic than saturated amines and pyridine is a weak base with a pKa (for its conjugate acid) of 5.5. This means that the pyridinium ion is about as strong an acid as a carboxylic acid. 726 CHAPTER 29 AROMATIC HETEROCYCLES 1: REACTIONS Pyridine is also toxic and has a foul smell—so there are disadvantages in using pyridine N pKa 11.2 N N pKa ~9 N N pKa 5.5 N H H H as a solvent. But it is cheap and H H remains a popular solvent in piperidine typical imine pyridine pyridinium ion spite of the problems. Pyridine is a reasonable nucleophile for carbonyl groups and is often used as a nucleophilic catalyst in acylation reactions. Esters are often made in pyridine solution from alcohols and acid chlorides (the full mechanism is on p. 199 of Chapter 10). O O N R2OH O R1 N Interactive mechanism for R1 Cl pyridine as pyridine as R1 OR2 pyridine nucleophilic catalysis nucleophile leaving group acyl pyridinium ion reactive intermediate DMAP One particular amino-pyridine has a special role as a more effective acylation catalyst than pyridine itself. This is DMAP (N,N-dimethylaminopyridine) in which the amino group is placed to reinforce the nucleophilic nature of the nitrogen atom. Whereas acylations ‘catalysed’ by pyridine are normally carried out in solution in pyridine, only small amounts of DMAP in other solvents are needed to do the same job. NMe2 NMe2 NMe2 NMe2 N N N N DMAP O N,N-dimethylaminopyridine O O O O ROH RO Pyridine is nucleophilic at the nitrogen atom because the lone pair of electrons on nitrogen can- not be delocalized around the ring. They are in an sp2 orbital orthogonal to the p orbitals in the ring and there is no interaction between orthogonal orbitals. Try it for yourself, drawing arrows. All attempts to delocalize the electrons lead to impossible results! N lone pair in sp2 orbital at right angles to p orbitals in ring: no interaction between N × N ! orthogonal orbitals attempts to delocalize lone pair lead to absurd structures The lone pair of pyridine’s nitrogen atom is not delocalized. Our main question about the reactivity of pyridine must be this: what does the nitrogen atom do to the rest of the ring? The important orbitals—the p orbitals of the aromatic system— are superficially the same as in benzene, but the more electronegative nitrogen atom will lower the energy of all the orbitals. Lower-energy filled orbitals mean a less reactive nucleophile but a lower-energy LUMO means a more reactive electrophile. This is a good guide to the chemistry  P Y R I D I N E I S A V E RY U N R E AC T I V E A R O M AT I C I M I N E 727 of pyridine. It is less reactive than benzene in electrophilic aromatic substitution reactions, but Electrophilic substitution nucleophilic substitution, which is difficult for benzene, comes easily to pyridine. in benzene is discussed in Chapter 21. Pyridine is bad at electrophilic aromatic substitution The lower energy of the orbitals of pyridine’s π system means that electrophilic attack on the ring is difficult. Another way to look at this is to see that the nitrogen atom destabi- lizes the cationic would-be intermediate, especially when it can be delocalized onto nitrogen. E H E H E Contrast the unstable H × × E electron-deficient cationic E intermediate with the stable pyridinium ion. The nitrogen N N N N lone pair is used to make the unstable electron- pyridinium ion but is not deficient cation unstable electron-deficient cation involved in the unstable intermediate. Note that reaction An equally serious problem is that the nitrogen lone pair is basic and a reasonably good at the 3-position is the best nucleophile—this is the basis for its role as a nucleophilic catalyst in acylations. The normal option but still doesn’t occur. reagents for electrophilic substitution reactions, such as nitration, are acidic. Treatment of Reaction at the 2- and pyridine with the usual mixture of HNO3 and H2SO4 merely protonates the nitrogen atom. 4-positions is worse. Pyridine itself is not very reactive towards electrophiles: the pyridinium ion is totally unreactive. stable pyridinium ion NO2 × HNO3 HNO3 no reaction H2SO4 N H2SO4 N N H Other reactions, such as Friedel–Crafts acylations, require Lewis acids and these too react at nitrogen. Pyridine is a good ligand for metals such as Al(III) or Sn(IV) and, once again, the complex with its cationic nitrogen is completely unreactive towards electrophiles. stable O pyridine complex × RCOCl RCOCl R no reaction AlCl3 AlCl3 N N N AlX3 Pyridine does not undergo electrophilic substitution Aromatic electrophilic substitution on pyridine is not a useful reaction. The ring is unreactive and the electrophilic reagents attack nitrogen, making the ring even less reactive. Avoid nitration, sulfonation, halogenation, and Friedel–Crafts reactions on simple pyridines. Nucleophilic substitution is easy with pyridines By contrast, the nitrogen atom makes pyridines more reactive towards nucleophilic substitu- Nucleophilic substitution in tion, particularly at the 2- and 4-positions, by lowering the LUMO energy of the π system of benzene is discussed in pyridine. You can see this effect in action in the ease of replacement of halogens in these posi- Chapter 22. tions by nucleophiles. 728 CHAPTER 29 AROMATIC HETEROCYCLES 1: REACTIONS Interactive mechanism for nucleophilic substitution on Nu + Nu Nu pyridines N Cl N Cl N Nu The intermediate anion is stabilized by electronegative nitrogen and by delocalization round the ring. These reactions have some similarity to nucleophilic aromatic substitution (Chapter 22) but are more similar to carbonyl reactions. The intermediate anion is a tetrahedral inter- mediate that loses the best leaving group to regenerate the stable aromatic system. Nucleophiles such as amines or thiolate anions work well in these reactions. Cl Cl Cl SR SR SR Note the similarity to NH3 RSH nucleophilic substitution on the carbonyl group (Chapter 10). N Cl N NH2 N base N N N The leaving group does not have to be as good as chloride in these reactions. Continuing the analogy with carbonyl reactions, 2- and 4-chloropyridines are rather like acid chlorides but we need only use less reactive pyridyl ethers, which react like esters, to make amides. Substitution of a 2-methoxypyridine allows the synthesis of flupirtine. NO2 NO2 H2 MeO N NH2 N N NH2 Raney H Ni + You will see more of this F synthesis later in the chapter. NH2 NH2 NHCO2Et F ClCO2Et N N NH2 N N NH2 H H F F flupirtine (analgesic) The first step is a nucleophilic aromatic substitution. In the second step the nitro group is reduced to an amino group without any effect on the pyridine ring—another piece of evi- dence for its aromaticity. Finally, the one amino group whose lone pair is not delocalized onto the pyridine N is acylated in the presence of two others. Pyridones are good substrates for nucleophilic substitution The starting materials for these nucleophilic substitutions (2- and 4-chloro- or methoxypyri- dines) are themselves made by nucleophilic substitution on pyridones. If you were asked to propose how 2-methoxypyridine might be made, you would probably suggest, by analogy with the corresponding benzene compound, alkylation of a phenol. Let us look at this in detail. ? MeI MeI OH base OMe N OH base N OMe The starting material for this reaction is a 2-hydroxypyridine that can tautomerize to an amide-like structure known as a pyridone by the shift of the acidic proton from oxygen to nitrogen. In the phenol series there is no doubt about which structure will be stable as the ketone is not aromatic; for the pyridine both structures are aromatic. OH × O N OH N O N O N O stable unstable H H H phenol non-aromatic 'phenol' preferred pyridine tautomer tautomer aromatic 2-pyridone  P Y R I D I N E I S A V E RY U N R E AC T I V E A R O M AT I C I M I N E 729 In fact, 2-hydroxypyridine prefers to exist as the ‘amide’ because that has the advantage of Interactive tautomerism a strong C=O bond and is still aromatic. There are two electrons in each of the C=C double between 2-hydroxypyridine and bonds and two also in the lone pair of electrons on the trigonal nitrogen atom of the amide. pyridone Delocalization of the lone pair in typical amide style makes the point clearer. Pyridones are easy to prepare (see Chapter 30) and can be alkylated on oxygen as predicted by their structure. A more important reaction is the direct conversion to chloropyridines with POCl3. The reaction starts by attack of the oxygen atom at phosphorus to create a leaving group, followed by aromatic nucleophilic substitution. The overall effect is very similar to acyl chloride formation from a carboxylic acid (Chapter 10). O O P P N O Cl Cl N O Cl N Cl H Cl H Cl Cl The same reaction occurs with 4-pyridone, which is also delocalized in the same way and exists in the ‘amide’ form, but not with 3-hydroxypyridine, which exists in the ‘phenol’ form. Its only tautomer is a zwitterion but the pyridine nitrogen is too weak to remove a proton from the hydroxyl group. O Cl O OH 4-pyridone POCl3 3-hydroxy- pyridine N × N N N H H Pyridines undergo nucleophilic substitution Pyridines can undergo electrophilic substitution only if they are activated by electron-donating substituents (see next section) but they readily undergo nucleophilic substitution without any activation other than the ring nitrogen atom. Activated pyridines will do electrophilic aromatic substitution Useful electrophilic substitutions occur only on pyridines having electron-donating substit- uents such as NH2 or OMe. These activate benzene rings too (Chapter 21) but here their help is vital. They supply a non-bonding pair of electrons that raises the energy of the HOMO and carries out the reaction. Simple amino- or methoxypyridines react reasonably well ortho and para to the activating group. These reactions happen in spite of the molecule being a pyridine, not because of it. E H E E MeO N MeO N MeO N A practical example occurs in the manufacture of the analgesic flupirtine where a doubly activated pyridine having both MeO and NH2 groups is nitrated just as if it were a benzene ring. The nitro group goes in ortho to the amino group and para to the methoxy group. The activation is evidently enough to compensate for the molecule being almost entirely proton- ated under the conditions of the reaction. NO2 HNO3 This is the starting material for H2SO4 the flupirtine synthesis on p. 728. MeO N NH2 MeO N NH2 730 CHAPTER 29 AROMATIC HETEROCYCLES 1: REACTIONS Pyridine N-oxides are reactive towards both electrophilic and nucleophilic substitution This is all very well if the molecule has such activating groups, but supposing it doesn’t? How pyridine are we to nitrate pyridine itself? The answer involves an ingenious trick. We need to activate N the ring with an electron-rich substituent that can later be removed and we also need to stop RCO3H the nitrogen atom reacting with the electrophile. All of this can be done with a single atom! Because the nitrogen atom is nucleophilic, pyridine can be oxidized to pyridine N-oxide with reagents such as m-CPBA or just H2O2 in acetic acid. These N-oxides are stable dipolar pyridine species with the electrons on oxygen delocalized round the pyridine ring, raising the HOMO N-oxide N of the molecule. Reaction with electrophiles occurs at the 2- (ortho) and 4- (para) positions, O chiefly at the 4-position to keep away from positively charged nitrogen. Interactive structure of pyridine O N O H NO2 NO2 NO2 N-oxide HNO3 PX3 N H2SO4 N N N N O O O O O PX3 NO2 Now the oxide must be removed and this is best done with trivalent phosphorus com- pounds such as (MeO)3P or PCl3. The phosphorus atom detaches the oxygen atom in a single step to form the very stable P=O double bond. In this reaction the phosphorus atom is acting as both a nucleophile and an electrophile, but mainly as an electrophile since PCl3 is more N reactive here than (MeO)3P. O The same activation that allowed simple electrophilic substitution—oxidation to the PX3 N-oxide—can also allow a useful nucleophilic substitution. The positive nitrogen atom encour- phosphorus donates ages nucleophilic attack and the oxygen atom can be turned into a leaving group with PCl3. its lone pair while accepting electrons Our example is nicotinic acid, whose biological importance we will discuss in Chapter 42. into its d orbitals CO2H CO2H COCl CO2H H2O2 PCl3 H2O N N N Cl N Cl nicotinic acid O The N-oxide reacts with PCl3 through oxygen and the chloride ion released in this reaction adds to the most electrophilic position between the two electron-withdrawing groups. Now a simple elimination restores aromaticity and gives a product looking as though it results from chlorination rather than nucleophilic attack. CO2H CO2H CO2H CO2H H N N Cl N Cl N Cl Interactive mechanism for O P O Cl O Cl nucleophilic substitution on Cl Cl P P pyridine N-oxide Cl Cl Cl The reagent PCl3 also converts the carboxylic acid to the acyl chloride, which is hydrolysed back again in the last step. This is a useful sequence because the chlorine atom has been intro- duced into the 2-position, from which it may in turn be displaced by, for example, amines. CO2H CO2H + nifluminic acid (an analgesic) N Cl H2N CF3 N N CF3 H  P Y R I D I N E I S A V E RY U N R E AC T I V E A R O M AT I C I M I N E 731 Pyridine N-oxides Pyridine N-oxides are useful for both electrophilic and nucleophilic substitutions on the same carbon atoms (2-, 4-, and 6-) in the ring. Nucleophilic addition at an even more distant site is possible on reaction with acid anhyd- rides if there is an alkyl group in the 2-position. Acylation occurs on oxygen as in the last reaction but then a proton is lost from the side chain to give an uncharged intermediate. O N N O O O N O O O O OAc H This compound rearranges with migration of the acetate group to the side chain and the restoration of aromaticity. This may be an ionic reaction or a type of rearrangement that you will learn to call a [3,3]-sigmatropic rearrangement (Chapter 35). [3,3]-sigmatropic rearrangement N N O OAc O O N OAc O Pyridine as a catalyst and reagent Since pyridine is abundant and cheap and has an extremely rich chemistry, it is not surprising that it has many applications. One of the simplest ways to brominate benzenes is not to bother with the Lewis acid catalysts recommended in Chapter 21 but just to add liquid bromine to catalytic the aromatic compound in the presence of a small amount of pyridine. Only about one mole Br2 pyridine per cent is needed and even then the reaction has to be cooled to stop it getting out of hand. As we have seen, pyridine attacks electrophiles through its nitrogen atom. This produces the reactive species, the N-bromo-pyridinium ion, which is attacked by the benzene. Pyridine Br is a better nucleophile than benzene and a better leaving group than bromide. This is another example of nucleophilic catalysis. pyridine recycled N Nucleophilic catalysis is N H discussed on p. 200. Br Br Br Br Br Another way to use pyridine in brominations is to make a stable crystalline compound to replace the dangerous liquid bromine. This compound, known by names such as pyridinium tribromide, is simply a salt of pyridine with the anion Br3−. It can be used to brominate reactive compounds such as alkenes (Chapter 19). Br N Br Br H Br Ph PyH Br3 Ph Ph Ph pyridinium tribromide HOAc Br Both of these methods depend on the lack of reactivity of pyridine’s π system towards electrophiles such as bromine. Notice that, in the fi rst case, both benzene and pyridine are present together. The pyridine attacks bromine only through nitrogen (and reversibly at that) and never through carbon. Oxidation of alcohols is normally carried out with Cr(VI) reagents (Chapter 23) but these, like the Jones’ reagent (Na 2Cr2O7 in sulfuric acid), are usually acidic. Some pyridine complexes 732 CHAPTER 29 AROMATIC HETEROCYCLES 1: REACTIONS of Cr(VI) compounds solve this problem by having the pyridinium ion (pKa 5) as the only acid. The two most famous are PDC (pyridinium dichromate) and PCC (pyridinium chloro- chromate). Pyridine forms a complex with CrO3 but this is liable to burst into flames. Treatment with HCl gives PCC, which is much less dangerous. PCC is particularly useful in the oxidation of primary alcohols to aldehydes as over-oxidation is avoided in the only slightly acidic conditions (Chapter 23). Cl CrO3 HCl H Cr PCC N N N O O O R OH R O Cr H O O O PCC Bipyridyl (bipy) The ability of pyridine to form metal complexes is greatly enhanced in a dimer—the famous ligand ‘bipy’ or 2,2′-bipyridyl. It is bidentate and because of its ‘bite’ it is a good ligand for many transition metals, with a partiality for Fe(II). FeCl2 N N N N Fe 'bipy' or 2,2 ′-bipyridyl Cl Cl It looks like a rather difficult job to persuade two pyridine rings to join together in this way to form bipy. It is indeed very difficult unless you make things easier by using a reagent that favours the product. And what better than Fe(II) to do the job? Bipy is manufactured by treating pyridine with FeCl2⋅4H2O at high temperatures and high pressures. Only a small proportion of the pyridine is converted to the Fe(II) complex of bipy (about 5%) but the remaining pyridine goes back in the next reaction. This is probably a radical process (Chapter 37) within the coordination sphere of Fe(II). heat, FeCl2 pressure N N N N N Fe Fe Cl Cl Cl Cl Six-membered aromatic heterocycles can have oxygen in the ring Although pyridine is overwhelmingly the most important of the six-membered aromatic het- erocycles, there are oxygen heterocycles, pyrones, that resemble the pyridones. The pyrones are aromatic, although α-pyrone is rather unstable. O O O O O O 2-pyrone or α-pyrone O 4-pyrone or γ-pyrone O The pyrylium salts are stable aromatic cations and are responsible as metal complexes for some flower colours. Heterocycles with six-membered rings based on other elements (for example, P) do exist but they are outside the scope of this book. OH OH a red pyrilium flower pigment O HO O the pyrilium cation OH  F I V E - M E M B E R E D A R O M AT I C H E T E R O C Y C L E S A R E G O O D AT E L E C T R O P H I L I C S U B S T I T U T I O N 733 Five-membered aromatic heterocycles are good at electrophilic substitution Just about everything is the other way round with pyrrole. Electrophilic substitution is much 1.43 Å easier than it is with benzene—almost too easy in fact—while nucleophilic substitution is 1.37 Å H δH 6.2 more difficult. Pyrrole is not a base nor can it be converted to an N-oxide. We need to find out why this is. The big difference is that the nitrogen lone pair is delocalized round the ring. The H δH 6.5 N NMR spectrum suggests that all the positions in the ring are about equally electron-rich with chemical shifts about 1 ppm smaller than those of benzene. The ring is flat and the bond 1.38 Å H δH~10 lengths are very similar, although the bond opposite the nitrogen atom is a bit longer than the others. N N N N Interactive structure of pyrrole H H H H The delocalization of the lone pair can be drawn equally well to any ring atom because of the five-membered ring and we shall soon see the consequences of this. All the delocalization pushes electrons from the nitrogen atom into the ring and we expect the ring to be electron- rich at the expense of the nitrogen atom. The HOMO should go up in energy and the ring become more nucleophilic. An obvious consequence of this delocalization is the decreased basicity of the nitrogen atom and the increased acidity of the NH group. In fact, the pKa of pyrrole acting as a base is about –4, and protonation occurs at carbon below pH –4. By contrast, the NH proton (pKa 16.5) can be removed by much weaker bases than those that can remove protons on normal secondary amines. The nucleophilic nature of the ring means that pyrrole is attacked readily by electrophiles. Reaction with bromine requires no Lewis acid and leads to substitution (con- firming the aromaticity of pyrrole) at all four free positions. Contrast pyridine’s reactivity with bromine (p. 731): it reacts just once, at nitrogen. Br Br Br2 Br2 N Br Br N EtOH, 0 °C N N EtOH, 0 °C H Br H This is a fine reaction in its way, but we don’t usually want four bromine atoms in a molecule so one problem with pyrrole is to control the reaction to give only monosubstitution. Another problem is that strong acids cannot be used. Although protonation does not occur at nitrogen, it does occur at carbon and the protonated pyrrole then adds another molecule like this. H H etc. H reaction N H N N H N N continues H H H H H to give polymer Pyrrole polymerizes! Strong acids, those such as H2SO4 with a pKa of less than –4, cannot be used without polymerization of pyrrole. Some reactions can be controlled to give good yields of monosubstituted products. One is the Vilsmeier reaction, in which a combination of an N,N-dimethylamide and POCl3 is used to make a carbon electrophile in the absence of strong acid or Lewis acid. It is a substitute for the Friedel–Crafts acylation, and works with aromatic compounds at the more reactive end of the scale (where pyrrole is). 734 CHAPTER 29 AROMATIC HETEROCYCLES 1: REACTIONS O 1. POCl3 R N + N R NMe2 2. Na2CO3, H2O H O H In the first step, the amide reacts with POCl3, which makes off with the amide oxygen atom and replaces it with chlorine. This process would be very unfavourable but for the formation of the strong P–O bond, and is the direct analogy of the chloropyridine-forming reaction you have just seen. O O P Cl P O Cl O Cl Cl Cl Cl Cl R NMe2 R NMe2 R NMe2 The product from this fi rst step is an iminium cation that reacts with pyrrole to give a more stable iminium salt. The extra stability comes from the conjugation between the pyrrole nitrogen and the iminium group. The work-up with aqueous Na2CO3 hydrolyses the imine salt and removes any acid formed. This method is particularly useful because it works well with Me2NCHO (DMF) to add a formyl (CHO) group. This is difficult to do with a conven- tional Friedel–Crafts reaction. Cl H R R Interactive mechanism for N N N R NMe2 Vilsmeier reaction of pyrrole NMe2 H NMe2 H H You may have noticed that the reaction occurred only at the 2-position on pyrrole. Although all positions react with reagents like bromine, most reagents go for the 2- (or 5-) position and attack the 3- (or 4-) position only if the 2- and 5-positions are blocked. A good example is the Remind yourself of the Mannich reaction. In these two examples N-methylpyrrole reacts cleanly at the 2-position Mannich reaction on p. 621 of while the other pyrrole with both 2- and 5-positions blocked by methyl groups reacts cleanly Chapter 26. at the 3-position. These reactions are used in the manufacture of the non-steroidal anti- inflammatory compounds tolmetin and clopirac. Mannich Me2NH NMe2 CO2H N N N CH2=O Me AcOH Me O Me tolmetin NMe2 CO2H Mannich N Me2NH N N clopirac CH2=O AcOH Interactive mechanism for the Mannich reaction on pyrrole Cl Cl Cl Now we need an explanation. The mechanisms for both 2- and 3-substitutions look good and we will draw both, using a generalized E + as the electrophile. Both mechanisms can occur very readily. Reaction in the 2-position is somewhat better than in the 3-position but the dif- ference is small. Substitution is favoured at all positions. Calculations show that the HOMO of pyrrole does indeed have a larger coefficient in the 2-position, and one way to explain this result is to look at the structure of the intermediates. The intermediate from attack at the  F U R A N A N D T H I O P H E N E A R E OX Y G E N A N D S U L F U R A N A L O G U E S O F P Y R R O L E 735 2-position has a linear conjugated system. In both intermediates the two double bonds are, of E H course, conjugated with each other, but only in the fi rst intermediate are both double bonds conjugated with N+. The second intermediate is ‘cross-conjugated’, while the fi rst has a more E stable linear conjugated system. N H N H H reaction with electrophiles in the 2-position reaction with electrophiles in the 3-position E more stable less stable E E H H E E E N N N N N N H H H H H H Since electrophilic substitution on pyrroles occurs so easily, it can be useful to block substi- tution with a removable substituent. This is usually done with an ester group. Hydrolysis of the ester (this is particularly easy with t-butyl esters—see Chapter 23) releases the carboxylic acid, which decarboxylates on heating. There is no doubt that the fi nal electrophilic substitu- tion must occur at C2. R2 R3 R2 R3 R2 R3 R2 R3 CO2 E R1 OR R1 OH R1 H R1 E N N N N H H H H O O The decarboxylation is a general reaction of pyrroles: it’s a kind of reverse Friedel–Crafts reaction in which the electrophile is a proton (provided by the carboxylic acid itself) and the leaving group is carbon dioxide. The protonation may occur anywhere but it leads to reaction only if it occurs where there is a CO2H group. H CO2 H H OH OH O N N N N H H H H H O O O Furan and thiophene are oxygen and sulfur analogues of pyrrole The other simple five-membered heterocycles are furan, with an oxygen atom instead of pyrrole furan thiophene nitrogen, and thiophene, with a sulfur atom. They also undergo electrophilic aromatic substi- tution very readily, although not so readily as pyrrole. Nitrogen is the most powerful electron N O S donor of the three, oxygen the next, and sulfur the least. Thiophene is very similar to benzene H in reactivity. Thiophene is the least reactive of the three because the p orbital of the lone pair of electrons on sulfur that conjugates with the ring is a 3p orbital rather than the 2p orbital of N or O, so overlap with the 2p orbitals on carbon is less good. Both furan and thiophene undergo more or less normal Friedel–Crafts reactions, although the less reactive anhydrides (here acetic anhydride, Ac2O) are used instead of acid chlorides, and weaker Lewis acids than AlCl3 are preferred. Ac2O Ac2O ZnCl2 ZnCl2 O S O 0 °C S 100 °C O O Notice that the regioselectivity is the same as it was with pyrrole—the 2-position is more reactive than the 3-position in both cases. The product ketones are less reactive towards electrophiles than the starting heterocycles and deactivated furans can even be nitrated 736 CHAPTER 29 AROMATIC HETEROCYCLES 1: REACTIONS with the reagents used for benzene derivatives. Notice that reaction has occurred at the 5-position in spite of the presence of the ketone. The preference for 2- and 5-substitution is quite marked. HNO3 O2N O H2SO4 O O O Electrophilic addition may be preferred to substitution with furan So far, thiophenes and furans look much the same as pyrrole but there are other reactions in which they behave quite differently and we shall now concentrate on those. Furan is less aro- matic than pyrrole, and if there is the prospect of forming stable bonds such as C–O single bonds by addition, this may be preferred to substitution. A famous example is the reaction of furan with bromine in methanol. In non-hydroxylic solvents, polybromination occurs as expected, but in MeOH no bromine is added at all! Br Br and other Br2 Br2 H H products Br Br other solvents O MeOH MeO O OMe O Bromination must start in the usual way, but a molecule of methanol captures the fi rst formed cation in a 1,4-addition to furan. Br Br H H H MeOH MeO O Br O O Br The bromine atom that was originally added is now pushed out by the furan oxygen atom to make a relatively stable conjugated oxonium ion, which adds a second molecule of methanol. H H H H H MeO O Br MeO O HOMe OMe MeO O This product conceals an interesting molecule. At each side of the ring we have an acetal, and if we were to hydrolyse the acetals, we would have ‘maleic dialdehyde’ (cis-butenedial)—a molecule that is too unstable to be isolated. The furan derivative may be used in its place. H H hydrolysis of acetals MeO OMe OHC CHO O cis-butenedial acetal acetal (very unstable) The same 1,4-dialdehyde can be made by oxidizing furan with the mild oxidizing agent dimethyldioxirane, which you met on p. 432. In this sequence, it is trapped in a Wittig reac- tion to give an E,Z-diene, which is easily isomerized to E,E. OHC Ph3P CHO O O dimethyl OHC CHO OHC O dioxirane CHO CHO We can extend this idea of furan being the origin of 1,4-dicarbonyl compounds if we con- sider that furan is, in fact, an enol ether on both sides of the ring. If these enol ethers were hydrolysed we would get a 1,4-diketone.  F U R A N A N D T H I O P H E N E A R E OX Y G E N A N D S U L F U R A N A L O G U E S O F P Y R R O L E 737 enol enol ether ether H , H2 O 1 4 R R 1,4-diketone R R hydrolysis of enol ethers O O O This time the arrow is solid, not dotted, because this reaction really happens. You will dis- cover in the next chapter that furans can also be made from 1,4-diketones so this whole pro- cess is reversible. The example we are choosing has other features worth noting. The cheapest starting material containing a furan is furan-2-aldehyde or ‘furfural’, a by-product of break- fast cereal manufacture. Here it reacts in a typical Wittig process with a stabilized ylid. Ph3P CO2Me CHO + O O CO2Me furfural stabilized phosphorus ylid E-alkene from stabilised ylid Now comes the interesting step: treatment of this furan with acidic methanol gives a white We explained some of the crystalline compound having two 1,4-dicarbonyl relationships. You might like to try and challenges in making draw a mechanism for this reaction. 1,4-difunctionalized compounds in O Chapter 28. H O CO2Me MeOH MeO2C 3 1 3 CO2Me 4 2 2 4 The thiophene ring can also be opened up, but in a very different way. Reductive removal of Raney nickel was introduced the sulfur atom with Raney nickel reduces not only the C–S bonds but also the double bonds in Chapter 23, p. 537. in the ring and the four carbons in the ring form a saturated alkyl chain. If the reduction fol- lows two Friedel–Crafts reactions on thiophene the product is a 1,6-diketone instead of the 1,4-diketones from furan. Thiophene is well behaved in Friedel–Crafts acylations, and reac- tion occurs at the 2- and 5-positions unless these are blocked. 1. R1COCl, 3 4 Raney Ni R1 R2 SnCl4 R 1 R 2 1 2 5 6 S 2. R2COCl, S O O SnCl4 O O Lithiation of thiophenes and furans A reaction that furans and thiophenes do particularly well and that fits well with these last two reactions is metallation, particularly lithiation, of a C–H group next to the heteroatom. Metallation of benzene rings (Chapter 24) is carried out by lithium–halogen (Br or I) exchange—a method that works well for heterocycles too as we will see later with pyridine— or by directed (ortho) lithiation of a C–H group next to an activating group such as OMe. With thiophene and furan, the heteroatom in the ring provides the necessary activation. BuLi BuLi O H O Li S H S Li Activation is by coordination of O or S to Li followed by proton removal by the butyl group—the by-product is gaseous butane. These lithium compounds have a carbon–lithium σ bond and are soluble in organic solvents. We shall represent them very simply, but in fact they are typically dimers or more complex aggregates, with the coordination sphere of Li completed by THF molecules. simpified structure: O H O H true structure is a O Li solvated aggregate Li BuH Li Bu Bu 738 CHAPTER 29 AROMATIC HETEROCYCLES 1: REACTIONS These lithium compounds are very reactive and will combine with most electrophiles—in this example the organolithium is alkylated by a benzylic halide. Treatment with aqueous acid gives the 1,4-diketone by hydrolysis of the two enol ethers. 1. BuLi, Et2O H O H 2. Br Ar H2O O Ar = p-tolyl O O Treatment of this diketone with anhydrous acid would cause recyclization to the same furan (see Chapter 30) but it can alternatively be cyclized in base by an intramolecular aldol reac- tion (Chapter 26) to give a cyclopentenone. O O base O This completes our exploration of chemistry special to thiophene and furan, and we now return to all three heterocycles (pyrrole in particular) and look at nucleophilic substitution. More reactions of five-membered heterocycles Nucleophilic substitution requires an activating group Nucleophilic substitution is a relatively rare reaction with pyrrole, thiophene, or furan and requires an activating group such as nitro, carbonyl, or sulfonyl, just as it does with benzene (Chapter 22). This intramolecular example is used to make the painkiller ketorolac. Ph N SO2Me CO2Me NaOEt Ph Ph N N CO2H O CO2Me O O ketorolac MeO2C CO2Me The nucleophile is a stable enolate and the leaving group is a sulfi nate anion. An intermedi- ate must be formed in which the negative charge is delocalized onto the carbonyl group on the ring, just as you saw in the benzene ring examples in Chapter 22. Attack occurs at the 2-position because the leaving group is there and because the negative charge can be delocal- ized onto the ketone from that position. Ph Ph SO2Me SO2Me N N SO2Me Ph CO2Me Ph CO2Me O N CO2Me N CO2Me O O O OMe MeO2C MeO2C CO2Me O Five-membered heterocycles act as dienes in Diels–Alder reactions All of the reactions of pyrrole, furan, and thiophene we have discussed so far have been vari- ations on reactions of benzene. But heterocycles also do reactions totally unlike those of benzene and we are now going to explore two of them.  M O R E R E AC T I O N S O F F I V E - M E M B E R E D H E T E R O C Y C L E S 739 The first is a reaction you will meet in detail in Chapter 34. It is known as the Diels–Alder reaction, and although it has a number of subtleties we will not discuss here, it has a simple cyclic mechanism in which six electrons (three curly arrows) move around to form a new six- membered ring. Here is an example with the Boc derivative of pyrrole. The electron-deficient Boc group makes pyrrole less nucleophilic and promotes the Diels–Alder reaction with an alkynyl sul- The Boc protecting group is discussed in Chapter 23, p. 558. fone. Benzene, and even many other heterocycles, will not do this sort of reaction. Boc O Diels–Alder N N = N Boc N Boc reaction Ot-Bu SO2Ar SO2Ar Epibatidine was discovered in The product is a useful intermediate in the synthesis of the analgesic epibatidine. the skin of Ecuadoran frogs in Selective reduction of the non-conjugated double bond is followed by addition of a pyri- 1992. It is an exceptionally dine nucleophile (a lithium derivative can be prepared from a bromopyridine) to the vinyl powerful analgesic and works by sulfone. a different mechanism from that of morphine so there is hope Boc Boc that it will not be addictive. The compound can now be synthe- N H2, Pd/C N Boc OMe sized so there is no need to kill N the frogs to get it—indeed, they N are a protected species. SO2Ar H Cl SO2Ar N OMe OMe SO2Ar N BuLi N N epibatidine Br Li Furan is particularly good at Diels–Alder reactions but it gives the thermodynamic product, the exo adduct, because with this aromatic diene the reaction is reversible. O O H H O H O O O O thermo- Endo and exo Diels–Alder O kinetically O dynamically adducts are explained in O H H preferred preferred endo adduct O H exo adduct Chapter 34. O Aromaticity prevents thiophene taking part in Diels–Alder reactions, but oxidation to the thiophene sulfone destroys the aromaticity because both lone pairs become involved in bonds to oxy- [O] gen. The sulfone is unstable and reacts with itself but will also do Diels–Alder reactions. With S an alkyne, loss of SO2 gives a substituted benzene derivative. thiophene thiophene sulfoxide sulfone O O [O] Diels–Alder S O reaction S S S O O O O X X SO2 X Similar reactions occur with α-pyrones. These are also rather unstable and barely aromatic and they react with alkynes by Diels–Alder reactions followed by reverse Diels–Alder reac- tions to give benzene derivatives with the loss of CO2. 740 CHAPTER 29 AROMATIC HETEROCYCLES 1: REACTIONS O reverse R Diels–Alder Diels–Alder R O reaction O reaction R O R R CO2 R Nitrogen anions can be easily made from pyrrole Pyrrole is much more acidic than comparable saturated amines. The pKa of pyrrolidine is N about 35, but pyrrole has a pKa of 16.5, making it some 1023 times more acidic! Pyrrole is N about as acidic as a typical alcohol so bases stronger than alkoxides will convert it to its H H H H anion. We should not be too surprised at this as the corresponding hydrocarbon, cyclopenta- pKa pKa pKa ca. 35 16.5 ca. 35 diene, is also extremely acidic, with a pKa of 15. The reason is that the anions are aromatic with six delocalized π electrons. The effect is much greater for cyclopentadiene because the base