The Chemistry of the Aromatic Heterocycles

Home , Benzothiophene, Furan, Heterocyclic compound

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25 25 The Chemistry of the Aromatic Heterocycles

Heterocyclic compounds are compounds with rings that contain more than one element. The heterocyclic compounds of greatest interest to organic chemists have rings containing carbon and one or more heteroatoms—atoms other than carbon. Although the chemistry of many saturated heterocyclic compounds is analogous to that of their noncyclic counterparts, a sig- niﬁcant number of unsaturated heterocyclic compounds exhibit aromatic behavior. The re- mainder of this chapter focuses primarily on the unique chemistry of a few of these aromatic heterocycles. The principles that emerge should enable you to understand the chemistry and properties of other heterocyclic compounds that you may encounter.

NOMENCLATURE AND STRUCTURE OF 25.1 THE AROMATIC HETEROCYCLES

A. Nomenclature The names and structures of some important aromatic heterocyclic compounds are given in Fig. 25.1. This ﬁgure also shows how the rings are numbered in substitutive nomenclature. In all but a few cases, a heteroatom is given the number 1. (Isoquinoline is an exception.) As illustrated by thiazole and oxazole, the convention is that oxygen and sulfur are given a lower number than nitrogen. Substituent groups are given the lowest number consistent with the ring numbering. (These are the same rules used in numbering and naming saturated heterocyclic

compounds; see Secs. 8.1C and 23.1B.) "

C" 2H5 4 CO2H 3 3 3 CH3O 5 3 2 2 % 2 2 NO2 N 1 N 1 O L S H H 1 1 3-ethylpyrrole 5-methoxyindole 2-nitrofuran 3-thiophenecarboxylic acid

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25.1 NOMENCLATURE AND STRUCTURE OF THE AROMATIC HETEROCYCLES 1221

4 4 5 445 3 9 3 N 4 N 3 5 N 66332 8 2 6 227 7 N N N N N 2 1 5 N 7 1 118 8 1 6 H pyridine pyrimidine quinoline isoquinoline purine

4 3 3 4 3 4 3 4 3 N NN5 2 552225 2 N S N 6 1 111O N 1 H H 7 H pyrrole thiazole oxazole imidazole indole

4433 3 3 55 22 2266 O11S O 11S 7 7 furan thiophene benzofuran benzothiophene

Figure 25.1 Common aromatic heterocyclic compounds. The numbers (red) are used in substitutive nomenclature.

PROBLEMS 25.1 Draw the structure of (a) 4-(dimethylamino)pyridine (b) 4-ethyl-2-nitroimidazole

25.2 Name the following compounds. (a) (b) " (c) (d) N NO2 CH O

Br CH3 L S L N Br N L N "OCH3 "H

B. Structure and Aromaticity The aromatic heterocyclic compounds furan, thiophene, and pyrrole can be written as

resonance hybrids, illustrated here for furan. 1 _ _ 4 5 (25.1) _ _ O O 3 O O 3 O 1 1 1 1 1 | | | | Because separation of charge is present in all but the ﬁrst structure, the ﬁrst structure is considerably more important than the others. Nevertheless, the importance of the other structures is evident in a comparison of the dipole moments of furan and tetrahydrofuran, a saturated heterocyclic ether. 25_BRCLoudon_pgs5-0.qxd 12/5/08 11:48 AM Page 1222

1222 CHAPTER 25 • THE CHEMISTRY OF THE AROMATIC HETEROCYCLES

O O tetrahydrofuran furan dipole moment: 1.7 D 0.7 D boiling point: 67 °C 31.4 °C

The dipole moment of tetrahydrofuran is attributable mostly to the bond dipoles of its polar C O single bonds. That is, electrons in the s bonds are pulled toward the oxygen because of itsL electronegativity. This same effect is present in furan, but in addition there is a second effect: the resonance delocalization of the oxygen unshared electrons into the ring shown in Eq. 25.1.

This tends to push electrons away from oxygen into the p-electron system of the ring. 1 _ 4 etc. (25.2) O O _3 O 1 1 1 | |

dipole moment +=dipole moment net dipole contribution of contribution of moment of C O s bonds p-electron furan L delocalization

Because these two effects in furan nearly cancel, furan has a very small dipole moment. The relative boiling points of tetrahydrofuran and furan reﬂect the difference in their dipole moments. Pyridine, like benzene, can be represented by two equivalent neutral resonance structures. Three additional pyridine structures of less importance reﬂect the relative electronegativities of nitrogen and carbon.

| (25.3) N N | N N N | _2 _2 _2 2 2 2 minor contributors2 2

The aromaticity of some heterocyclic compounds was considered in the discussion of the Hückel 4n 2rule(Sec.15.7D).Itisimportanttounderstandwhichunsharedelectronpairs in a heterocyclic+ compound are part of the 4n 2aromaticp-electron system, and which are not (Fig. 25.2). Vinylic heteroatoms, such as the+ nitrogen of pyridine, contribute one p electron to the six p-electron aromatic system, just like each of the carbon atoms in the p system. The orbital containing the unshared electron pair of the pyridine nitrogen is perpendicular to the 2p orbitals of the ring and is therefore not involved in p bonding. In contrast, allylic heteroatoms, such as the nitrogen of pyrrole, contribute two electrons (an unshared pair) to the 25_BRCLoudon_pgs5-0.qxd 12/5/08 11:48 AM Page 1223

25.1 NOMENCLATURE AND STRUCTURE OF THE AROMATIC HETEROCYCLES 1223

4n + 2 p-electron system 4n + 2 p-electron system 4n + 2 p-electron system

2p orbital 2p orbital 2p orbital . .

...... N N H O ..

2 sp sp2 orbital orbital

(a) pyridine (b) pyrrole (c) furan The unshared pair is vinylic The unshared pair is allylic One unshared pair is allylic and is and thus is not part of the and thus is part of the part of the 4n + 2p-electron system; 4n + 2 p-electron system. 4n + 2 p-electron system. the other unshared pair is vinylic and is not.

Figure 25.2 The orbital conﬁgurations in pyridine, pyrrole, and furan.(a) In pyridine, the nitrogen 2p orbital, like the carbon 2p orbitals,contributes one electron to the 4n 2 p-electron system,and the nitrogen unshared electron pair occupies an sp2 orbital (blue), which is not part of+ the p system. (b) In pyrrole, the unshared electron pair occupies a 2p orbital on nitrogen (blue),and it contributes two electrons to the 4n 2 p-electron system.(c) Furan has two unshared electron pairs (red). One unshared pair occupies a 2p orbital and+ contributes two electrons to the 4n 2 p-electron system,as in pyrrole.The other unshared pair occupies an sp2 orbital.Like the unshared pair in pyridine,+ it does not contribute to the 4n 2 p-electron system. +

aromatic p-electron system. This nitrogen adopts sp2 hybridization and trigonal planar geometry so that its unshared electron pair can occupy a 2p orbital, which has the optimum shape and orientation to overlap with the carbon 2p orbitals and thus to be part of the aromatic p-electron system. Consequently, the hydrogen of pyrrole lies in the plane of the ring. The oxygen of furan contributes one unshared electron pair to the aromatic p-electron system, and the other unshared electron pair occupies a position analogous to the carbon– hydrogen bond of pyrrole—in the ring plane, perpendicular to the 2p orbitals of the ring. The empirical resonance energy can be used to estimate the additional stability of a heterocyclic compound due to its aromaticity. (This concept was introduced in the discussion of the aromaticity of benzene in Sec. 15.7C.) The empirical resonance energies of benzene and some heterocyclic compounds are given in Table 25.1. To the extent that resonance energy is a measure of aromatic character, furan has the least aromatic character of the heterocyclic compounds in the table. The modest resonance energy of furan has signiﬁcant consequences for its reactivity, as we’ll learn in Sec. 25.3B.

TABLE 25.1 Empirical Resonance Energies of Some Aromatic Compounds

Resonance energy Resonance energy

1 1 1 1 Compound kJ mol _ kcal mol _ Compound kJ mol _ kcal mol _ benzene 138–151 33–36 thiophene 121 29 pyridine 96–117 23–28 pyrrole 89–92 21–22

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1224 CHAPTER 25 • THE CHEMISTRY OF THE AROMATIC HETEROCYCLES

PROBLEMS 25.3 Draw the important resonance structures for pyrrole. 25.4 (a) The dipole moments of pyrrole and pyrrolidine are similar in magnitude but have opposite directions. Explain, indicating the direction of the dipole moment in each compound. (Hint: Use the result in Problem 25.3.)

N N 2 2 "H "H m 1.80 D m 1.57 D = = (b) Explain why the dipole moments of furan and pyrrole have opposite directions. (c) Should the dipole moment of 3,4-dichloropyrrole be greater than or less than that of pyrrole? Explain. 25.5 Each of the following NMR chemical shifts goes with a proton at carbon-2 of either pyridine, pyrrolidine, or pyrrole. Match each chemical shift with the appropriate heterocyclic compound, and explain your answer: d 8.51; d 6.41; and d 2.82.

25.2 BASICITY AND ACIDITY OF THE NITROGEN HETEROCYCLES

A. Basicity of the Nitrogen Heterocycles Pyridine and quinoline act as ordinary amine bases.

(25.4) H3O| H2O N + N + | 2 "H pKa 5.2 =

(25.5) H3O| H2O N + N + | 2 "H pKa 4.9 = Pyridine and quinoline are much less basic than aliphatic tertiary amines (Sec. 23.5A) because of the sp2 hybridization of their nitrogen unshared electron pairs. (Recall from Sec. 14.7A that the basicity of an unshared electron pair decreases with increasing s character. Because pyrrole and indole look like amines, it may come as a surprise that neither of these two heterocycles has appreciable basicity. These compounds are protonated only in strong acid, and protonation occurs on carbon, not nitrogen.