Introduction to Heterocyclic Chemistry 17 Related Stereoelectronic Effects Further Reading J.Rigaudy and S.P.Klesney (eds.).IUPAC Nomenclature of Organic Chemistry (Sections A to H).Pergamon Press,Oxford.1979. L.A.Paquette,Principles of Modern Heterocyclic Chemistry,Benjamin. nd P.Linda.Aromaticity of Heterocycles Pergamon Press,Oxford,1979. A.R.Katritzky,M.Karelson and N.Malhotra,Heterocyclic Aromaticity,in Heterocycles,1991.32.127. Chich .1994. E.Juaristi and G.Cuev
Introduction to Heterocyclic Chemistry 17 8. J. S. Chickos et al., J. Org. Chem., 1992, 57, 1897. 1 9. A. J. Kirby, The Anomeric Effect and Related Stereoelectronic Effects I ut Oxygen, Springer, New York, 1983. I J. Rigaudy and S. P. Klesney (eds.), IUPAC Nomenclature of Organic Chemistry (Sections A to H), Pergamon Press, Oxford, 1979. L. A. Paquette, Principles of Modern Heterocyclic Chemistry, Benjamin, New York, 1966. A. R. Katritzky, Physical Methods in Heterocyclic Chemistry, Academic Press, New York, 1960-1 972. M. J. Cook, A. R. Katritzky and P. Linda, Aromaticity of Heterocycles, in Adv. Heterocycl. Chem., 1974, 17, 257. D. H. R. Barton and W. D. Ollis (eds.), Comprehensive Organic Chemistry, vol. 4, Heterocyclic Chemistry, ed. P. G. Sammes, Pergamon Press, Oxford, 1979. A. R. Katritzky, M. Karelson and N. Malhotra, Heterocyclic Aromaticity, in Heterocycles, 199 1, 32, 127. B. Ya. Simkin and V. I. Minkin, The Concept of Aromaticity in Heterocyclic Chemistry, in Adv. Heterocycl. Chem., 1993, 56, 303. E. L. Eliel and S. H. Wilen, Stereochemistry of Organic Compounds, Wiley, Chichester, 1994. E. Juaristi and G. Cuevas, The Anomeric Effect, CRC Press, Boca Raton, Florida, 1995
2 Pyridine Aims By the end of this chapter you should understand: The aromaticity and structure of pyridine The nature of its reactions with electrophiles,including acids The reasons why nucleophilic additions occur readily,particu larly in the case of pyridinium salts The reactions of some prominent pyridines and piperidines Ways in which pyridines and Naikylpiperidines are syth sized.The importance of the Hantzsch synthesis of pyridines 2.1 Resonance Description As our first more detailed foray into heterocyclic chemistry we will con- A dipole moment results when a sider pyridine (azabenzene).It is an aromatic compound(see previous chapter).but the replacement of ch by more electronegative n induces a dipole moment of 2.2 D,denoting a shift of electron den sity from the ring towards the nitrogen atom(benzene,which is symmetrical,has no dipole moment).The valence bond (resonance)description indicates that bond m the nitrogen atom of pyridine carries a partial negative charge and the is expressed in debye units (D). carbons 2(6)and 4 bear partial positive charges. The nonical forms shown in Scheme 2.1 may then effectively represent the molecule. moment.but few have dip moments greater than.7 D. ②-p-中- Scheme 2.1 18
Pyridine A dipole moment results when a molecule has a permanent uneven electron density. Individual charge separations in bonds cannot be measured, only the vectorial sum of all individual bond moments. A dipole moment is expressed in debye units (D). Only completely symmetrical molecules fail to have a dipole moment, but few have dipole moments greater than 7 D. 2.1 Resonance Description As our first more detailed foray into heterocyclic chemistry we will consider pyridine (azabenzene). It is an aromatic compound (see previous chapter), but the replacement of CH by more electronegative N induces a dipole moment of 2.2 D, denoting a shift of electron density from the ring towards the nitrogen atom (benzene, which is symmetrical, has no dipole moment). The valence bond (resonance) description indicates that the nitrogen atom of pyridine carries a partial negative charge and the carbons 2(6) and 4 bear partial positive charges. The canonical forms shown in Scheme 2.1 may then effectively represent the molecule. 4 Scheme 2.1 18
Pyridine 19 2.2 Electrophilic Substitution 2.2.1 Attack at Nitrogen and at Carbon From the resonance description you might conclude that although the primary site for electrophilic attack is at N-1,reactions at carbon C-3(5) might be possible,even if not as likely.However,an important point to remember is that the N atom of pyridine carries a lone pair of electrons; these electrons are NOT part of the n-system.As a result,pyridine is a base(pK.5.2).reacting with acids,Lewis acids and other electrophiles me2.2 Direct attack at a ring carbon,even C-3,is normally slow (a)because the concentration of free pyridine in equilibrium with the pyridinium salt is extremely low,and(b)attack upon the salt would also require the pos- Pyndinesulfonic acids are strongly itive pyridinium cation to bond to a positively charged reactant Indeed,where reactions at a ring carbon take place under relatively mild conditions,special circumstances are at work.For example,2,6-tert- butylpyndine N-protonaton is butylpyridine combines with sulfur trioxide in liquid sulfur dioxide at -10C to give the corresponding 3-sulfonic acid(Scheme 2.3).An expla nation is that the bulky tert-butyl groups prevent access of the 'large' electrophile to N-1.Steric hindrance is much less at C-3 and sulfonation ectrophlc attacks strongly is diverted to this site using the 'free'pyridine as the substrate. SO3H S03 Me Me M Me Me Scheme 2.3
Pyridine I9 2.2 Electrophilic Substitution 2.2.1 Attack at Nitrogen and at Carbon From the resonance description you might conclude that although the primary site for electrophilic attack is at N-1, reactions at carbon C-3(5) might be possible, even if not as likely. However, an important point to remember is that the N atom of pyridine carries a lone pair of electrons; these electrons are NOT part of the n;-system. As a result, pyridine is a base (pKa 5.2), reacting with acids, Lewis acids and other electrophiles (E') to form stable pyridinium salts (Scheme 2.2), in which the heterocycle retains aromatic character. 0 0 -,o N - 0 N - o+ N Y+ I I I N E E E E Direct attack at a ring carbon, even C-3, is normally slow (a) because the concentration of free pyridine in equilibrium with the pyridinium salt is extremely low, and (b) attack upon the salt would also require the positive pyridinium cation to bond to a positively charged reactant. Indeed, where reactions at a ring carbon take place under relatively mild conditions, special circumstances are at work. For example, 2,6-tertbutylpyridine combines with sulfur trioxide in liquid sulfur dioxide at -10 "C to give the corresponding 3-sulfonic acid (Scheme 2.3). An explanation is that the bulky tert-butyl groups prevent access of the 'large' electrophile to N- 1. Steric hindrance is much less at C-3 and sulfonation is diverted to this site using the 'free' pyridine as the substrate. Scheme 2.2 Pyridinesulfonic acids are strongly acidic, so that the 3-sulfonic acid that forms then protonates a second molecule of 2,6-tertbutylpyridine (N-protonation is permitted because of the small size of the proton). Once protonated, however, further electrophilic attack is strongly disfavoured, and so the overall conversion is limited to 50%. Scheme 2.3
20 Heterocyclic Chemistry 2.2.2 Addition-Elimination Another feature that is clear from the resonance description of the pyri- dinium cation is that attack by nucleophiles is favoured at C-2(6)and C-4.This has importance in some reactions where at first sight it may appear that electrophilic reagents combine quite easily with pyridine These reactions are more subtle in nature! For example,3-bromopyridine is formed when pyridine is reacted with bromine in the presence of oleum(sulfur trioxide in conc.sulfuric acid) at 13C(Scheme).Direct electrophilic however,aszwitterionic (dipolar)pyridinium-N-sulfonate is the substrate for an addition of bromide ion.Subsequently,the dihydropyridine that that no bromination occurs under similar conditions when oleum is replaced by conc.sulfuric acid alone;instead,pyridinium hydrogensul- fate is produced. Br CB 29 Br 30 SO 0 B Na:COaq SO Scheme 2.4 Similarly,pyridine can be 3-sulfonated with hot sulfuric acid,or oleum if mercuric [mercury(ID)]sulfate is present as a catalyst(Scheme 2.5).Th process is not straightforward and may involve a C-mecuriated pyridine intermediate [it is known,for example,that pyridine reacts with mer- curic acetate at room temperature to form a pyridinium salt that decom- sary;even then,the yield of pyridine-3-sulfonic acid is poor. 2.2.3 Acylation and Alkylation Pyridine reacts with acyl chlorides,or acid anhydrides,to form N- acylpyridinium salts,which are readily hydrolysed (Scheme 2.6a)
20 Heterocyclic Chemistry 2.2.2 Addition-Elimination Another feature that is clear from the resonance description of the pyridinium cation is that attack by nucleophiles is favoured at C-2(6) and C-4. This has importance in some reactions where at first sight it may appear that electrophilic reagents combine quite easily with pyridine. These reactions are more subtle in nature! For example, 3-bromopyridine is formed when pyridine is reacted with bromine in the presence of oleum (sulfur trioxide in conc. sulfuric acid) at 130 "C (Scheme 2.4). Direct electrophilic substitution is not involved, however, aszwitterionic (dipolar) pyridinium-N-sulfonate is the substrate for an addition of bromide ion. Subsequently, the dihydropyridine that is formed reacts, possibly as a dienamine, with bromine to generate a dibromide, which then eliminates bromide ion from C-2. It is notable that no bromination occurs under similar conditions when oleum is replaced by conc. sulfuric acid alone; instead, pyridinium hydrogensulfate is produced. 0 N 0- +yJ 0-Br so,- n c&rBr H I S0,- Br soy- I -H+ I s0,- Scheme 2.4 Similarly, pyridine can be 3-sulfonated with hot sulfuric acid, or oleum, if mercuric [mercury(II)] sulfate is present as a catalyst (Scheme 2.5). The process is not straightforward and may involve a C-mecuriated pyridine intermediate [it is known, for example, that pyridine reacts with mercuric acetate at room temperature to form a pyridinium salt that decomposes at 180 "C into 3-(acetoxymercuri)pyridine (X = OAc)]. Without the catalyst, long reaction times and a temperature of 350 "C are necessary; even then, the yield of pyridine-3-sulfonic acid is poor. 2.2.3 Acylation and Alkylation Pyridine reacts with acyl chlorides, or acid anhydrides, to form Nacylpyridinium salts, which are readily hydrolysed (Scheme 2.6a)
Pyridine 21 HgX: Scheme 2.5 However,the salts can be used as valuable transacylating agents,par- ticularly for alcohols,and in this application the salt is not isolated but reacted in situ with the alcohol.An excess of pyridine is needed and such tel riine s o rmofrom thepdt were carried out in pyridine both as reagent and as solvent use has been superseded by DMAP [4-(N,N-dimethylamino)pyridine] Now,after N-acylation the 4-N,N-dimethylamino group reinforces the of the responding acylpyridinium salt(). and this promotes the transfer of the acyl group from the salt to the alco hol in the next step.Only a catalytic amount of DMAP is used. RCOX -OH R=alkyl or aryl (b) NMe NMe. DMAP Me. Scheme 2.6 Alkyl halides and related alkylating agents react with pyridines to form N-alkylpyridinium salts(Scheme 2.7).These compounds are much more stable than their N-acylpyridinium equivalents and can often be isolat- ed as crystalline solids,particularly if the halide ion is exchanged for r per chlorate,tetrafluoroborate or another less polarizable counter anion
Pyridine 21 HgX Scheme 2.5 However, the salts can be used as valuable transacylating agents, particularly for alcohols, and in this application the salt is not isolated but reacted in situ with the alcohol. An excess of pyridine is needed and such reactions were carried out in pyridine both as reagent and as solvent. Unfortunately, pyridine is difficult to remove from the products, and its use has been superseded by DMAP [4-(N, N-dimethy1amino)pyridinel. Now, after N-acylation the 4-N, N-dimethylamino group reinforces the nucleophilicity of the corresponding acylpyridinium salt (Scheme 2.6b), and this promotes the transfer of the acyl group from the salt to the alcohol in the next step. Only a catalytic amount of DMAP is used. R = alkyl or aryl + R,oYMe 0 Scheme 2.6 Alkyl halides and related alkylating agents react with pyridines to form N-alkylpyridinium salts (Scheme 2.7). These compounds are much more stable than their N-acylpyridinium equivalents and can often be isolated as crystalline solids, particularly if the halide ion is exchanged for perchlorate, tetrafluoroborate or another less polarizable counter anion