22 Heterocyclic Chemistry CI Me I N-Methylpyridinium iodide Scheme 2.7 2.3 Pyridine N-Oxides Pyridine N-oxides are frequently used in place of pyridines to facilitate 2.2 D)and it is important to note. electrophilic substitution.In such reactions there is a balance between however.that because of the o withdrawal,caused by the inductiveec of thxygen atom. and elease throuh resonance from the same atom in the oppo site direction.Here,the resonance effect is more important,and elec- trophiles react at C-2(6)and C-4 (the antithesis of the effect of resonance in pyridine itself). The N-oxide is prepared from pyridine by the action of a peracid(e.g hydrogen peroxide in acetic acid,forming peracetic acid in situ,or m-chloroperbenzoic acid,MCPBA);pyridine is regenerated by de- 0 oxygenation by heating with triphenylphosphine (Ph,PPh,PO) (Scheme 2.8). There is thus a subtlety in the tions of pyridine N-ox es that is not e explained Scheme 2.8 As long as the conditions are selected so that the N-oxygen atom is not irreversibly protonated,reactions with electrophiles give 2-and 4-substituted products.Thionyl chloride,for example,gives a mixture of 2-and 4-chloropyridine N-oxides in which the 4-is spredominant. However,pyridine N-oxide reacts with acetic anhydride first to give 1-acetoxypyridinium acetate and then,on heating,to yield 2- acetoxypyridine through an addition-elimination process(Scheme 2.9a) Whena similar eaction is carried out upo the23-dimethyl the acetoxy group rearranges from N-I to the C-2 methyl group,at 180C,to form 2-acetoxymethyl-3-methylpyridine(possibly as shown in Scheme 2.9b). Nitration at C-4 occurs with conc.sulfuric acid and fuming nitric acid (Scheme 2.10a);very little 2-nitropyridine N-oxide is formed,but in cases where the electrophile binds strongly to the oxygen atom of the N-oxide
22 Heterocyclic Chemistry Scheme 2.7 Pyridine N-oxide exhibits a dipole moment of 4.25 D (cf. pyridine, 2.2 D) and it is important to note, however, that because of the formal positive charge upon the nitrogen atom, pyridine N-oxides are also susceptible to nucleophilic reactions at C-2(6) and C-4. $- 0- 0 OLIrJ - PhCH2C1 N N+ 1 N+ Me I- Ph I c1- N-Benzylpyridinium chloride N-Methylpyridinium iodide 2.3 Pyridine NlOxides Pyridine N-oxides are frequently used in place of pyridines to facilitate electrophilic substitution. In such reactions there is a balance between electron withdrawal, caused by the inductive effect of the oxygen atom, and electron release through resonance from the same atom in the opposite direction. Here, the resonance effect is more important, and electrophiles react at C-2(6) and C-4 (the antithesis of the effect of resonance in pyridine itself). The N-oxide is prepared from pyridine by the action of a peracid (e.g. hydrogen peroxide in acetic acid, forming peracetic acid in situ, or rn-chloroperbenzoic acid, MCPBA); pyridine is regenerated by deoxygenation by heating with triphenylphosphine (Ph,P + Ph,PO) (Scheme 2.8). There is thus a subtlety in the reactions of pyridine N-oxides with both electrophiles and nucleophiles that is not easily explained. Scheme 2.8 As long as the conditions are selected so that the N-oxygen atom is not irreversibly protonated, reactions with electrophiles give 2- and 4-substituted products. Thionyl chloride, for example, gives a mixture of 2- and 4-chloropyridine N-oxides in which the 4-isomer is predominant. However, pyridine N-oxide reacts with acetic anhydride first to give 1-acetoxypyridinium acetate and then, on heating, to yield 2- acetoxypyridine through an addition-elimination process (Scheme 2.9a). When a similar reaction is carried out upon the 2,3-dimethyl analogue, the acetoxy group rearranges from N-1 to the C-2 methyl group, at 180 "C, to form 2-acetoxymethyl-3-methylpyridine (possibly as shown in Scheme 2.9b). Nitration at C-4 occurs with conc. sulfuric acid and fuming nitric acid (Scheme 2.1Oa); very little 2-nitropyridine N-oxide is formed, but in cases where the electrophile binds strongly to the oxygen atom of the N-oxide
Pyridine 品 a (CI “92=0 further attack occurs at C-3.Thus,pyridine N-oxide is brominated at scheme 2.9 70 C by bromine and oleum to form 3-bromopyridine N-oxide,and sulfonated by oleum and mercuric sulfate at 240C to give pyridine-3- sulfonic acid N-oxide(Scheme 2.10b). H NO2 NO HNO 0 b)HO3 OSOH Scheme 2.10 24 Nucleophilic Substitution 2.4.1 The Effects of the Pyridine Resonance and Leaving Groups When pyridine is reacted with nucleophiles the attack occurs pre- ferentially at C-2(6)and/or at C-4,as predicted by the resonance descrip- he ne tion of possible reaction intermediates(Scheme 2.11).The probem shared with the N atom
Pyridine 23 further attack occurs at C-3. Thus, pyridine N-oxide is brominated at 70 "C by bromine and oleum to form 3-bromopyridine N-oxide, and sulfonated by oleum and mercuric sulfate at 240 "C to give pyridine-3- sulfonic acid N-oxide (Scheme 2. lob). Scheme 2.9 (a) H NO2 Possibly the substrate for the last two reactions is the Nsulfonyloxypyridinium cation: 0- 03 0- oleum, 240°C HgS04 0 Br;lp Brm ____c OS03H N+ I N+ I 0- 0- 0- Scheme 2.10 2.4 Nucleophilic Substitution 2.4.1 The Effects of the Pyridine Resonance and Leaving Groups An intermediate formed through attack at c-3(5) the negative charge to be When pyridine is reacted with nucleophiles the attack occurs preferentially at C-2(6) and/or at c-4, as predicted by the resonance descripnot permit tion of possible reaction intermediates (Scheme 2.1 1). The problem, sharedwith the Natom
24 Heterocyclic Chemistry 一◇一÷◇ 3-的d Scheme 2.11 however,is that for unsubstituted pyridines the leaving group is the high ly reactive hydride ion.So,although the first step in the reaction is favoured,the second step is not.Oxygen in the air,or an added oxidant, may ease the situation and serve to oxidize the intermediate to an aro- matic pyridine. 2.4.2 Chichibabin Reaction A classic reaction of this type is Chichibabin amination.leading mainly to 2-aminopyridine(Scheme 2.12a).This takes place when a pyridine is heated at 140 C with sodamide (NH,is a very strong nucleophile) Although hydrogen gas is certainly evolved during the reaction,the ini- tial proton donor is not known.However,once some 2-aminopyridin is formed this product could function as the donor(Scheme 2.12b),and the process may then become a form of chain reaction. (a H2N(N b HX (X) Scheme2.12
24 Heterocyclic Chemistry 0 N Nu Nu H Nu H N N N N Scheme 2.11 Scheme 2.12 however, is that for unsubstituted pyridines the leaving group is the highly reactive hydride ion. So, although the first step in the reaction is favoured, the second step is not. Oxygen in the air, or an added oxidant, may ease the situation and serve to oxidize the intermediate to an aromatic pyridine. 2.4.2 Chichibabin Reaction A classic reaction of this type is Chichibabin amination, leading mainly to 2-aminopyridine (Scheme 2.12a). This takes place when a pyridine is heated at 140 "C with sodamide (NH, is a very strong nucleophile). Although hydrogen gas is certainly evolved during the reaction, the initial proton donor is not known. However, once some 2-aminopyridine is formed this product could function as the donor (Scheme 2.12b), and the process may then become a form of chain reaction. 0 N
Pyridine 25 2.4.3 Nucleophilic Reactions of Halopyridines Halide lon versus Hydride lon Normally,nucleophilic attack occurs preferentially at C-2(6);this selec- tivity is the result of the enhancedinductive effect experienced by the carbon atoms immediately adjacent to the more electronegative nitroger (Scheme 2.13).If both C and C are occupied,then attack at takes place.However,it is possible to influence the site and rate of the reaction if a potential leaving group replaces hydrogen.After addition. the oss of the leaving groupfrom the-intemediate will be easier than if it were the very reactive hydride ion.Halopyridines are often used. although not exclusively,and this normally ensures preferential nucle- ophilic substitution at the site of the halogen atom. CI、Nu 个N Scheme 2.13 'Addition-substitution'easily occurs with a variety of nucleophilic reagents,including NaOMe,PhSH,PhNHMe and NH,.Thus,with 2. ropyridine a range of 2-substituted pyridines is formed (Scheme 2.14)
Pyridine 25 2.4.3 Nucleophilic Reactions of Halopyridines Halide Ion versus Hydride Ion Normally, nucleophilic attack occurs preferentially at C-2(6); this selectivity is the result of the enhancedinductive effect experienced by the carbon atoms immediately adjacent to the more electronegative nitrogen (Scheme 2.13). If both C-2 and C-6 are occupied, then attack at C-4 takes place. However, it is possible to influence the site and rate of the reaction if a potential leaving group replaces hydrogen. After addition, the loss of the leaving group from the o-intermediate will be easier than if it were the very reactive hydride ion. Halopyridines are often used, although not exclusively, and this normally ensures preferential nucleophilic substitution at the site of the halogen atom. c1 very strongly favoured c1 I Scheme 2.13 ‘Addition-substitution’ easily occurs with a variety of nucleophilic reagents, including NaOMe, PhSH, PhNHMe and NH,. Thus, with 2- chloropyridine a range of 2-substituted pyridines is formed (Scheme 2.14)
26 Heterocyclic Chemistry PhNHMe 20 H2N Me Scheme2.14 Worked Problem 2.1 Q Outline a synthesis of 2-acetoxy-4-methoxypyridine from pyridine. AThis synthesis requres several steps,and illustrates the way pyri- dine N-oxides can be used in the electrophilic substitution of pyridines.It also indicates selectivity in the reactions of nucle- ophiles with pyridinium salts.The first step is to convert pyridine into its N-oxide,and to react this with c.nitric acid and con. sufuri acid(Scheme 2.15).This provides the -ntr derivative in which the nitro group directs the position of attack by sodium methoxide in methanol,by providing a good leaving xypyridine N. causes O-acetylation and the formation of an intermediate O-ace- toxypyridinium salt.This adds acetate anion at C-2 and,without isolation,the adduct 1,2-diacetoxy-4-methyl-1.2-diydropyridine which is produced eliminates acetic acid,thus rearomatizing the heterocycle and forming the required pyridine
26 Heterocyclic Chemistry Scheme 2.14 phNHMY heat I I Me