Heterocyclic Compounds

Chapter 31

Heterocyclic Compounds

Heterocyclic systems

• A heterocyclic compound is one that contains a ring made up of more than one kind of atom. In most of the cyclic compounds that we have studied so far benzene, naphthalene, cyclohexanol, cyclopentadiene the rings are made up only of carbon atoms; such compounds are called homocyclic, or alley die

• compounds. But there are also rings containing, in addition to carbon, other kinds of atoms, most commonly nitrogen, oxygen, or sulfur. For example:

• In the biological world, as we shall see in the final chapters of this book, heterocyclic compounds are everywhere. Carbohydrates are heterocyclic; so are chlorophyll and hemin, which make leaves green and blood red and bring life to plants and animals. Heterocycles form the sites of reaction in many enzymes and coenzymes. Heredity comes down, ultimately, to the particular sequence of attachment of a half-dozen heterocyclic rings to the long chains of nucleic acids. In this chapter we can take up only a very few of the many different heterocyclic systems and look only briefly at them. Among the most important and most interesting heterocycles are the ones that possess aromatic properties; we shall focus our attention on a few of these, and in particular upon their aromatic proper tic.

Structure of pyrrole, furan, and thiophene

• The simplest of the five-membered heterocyclic compounds are pyrrole, furan, and thiophene, each of which contains a single hetero atom. Judging from the commonly used structures I, II, and JH, we might expect each of these compounds to have the properties of a conjugated diene and of an amine, an ether, or a sulfide (thioether). Except for a certain tendency to undergo Addi.

• Tion reactions, however, these heterocycles do not have the expected properties: thiophene does not undergo the oxidation typical of a sulfide, for example, pyrrole does not possess the basic properties typical of amins.

• Instead, these heterocycles and their derivatives most commonly undergo electrophilic substitution: nitration, sulfonation, halogenation, Friedel-Crafts acylation, even the Reimer-Tiemann reaction and coupling with diazonium salts. Heats of combustion indicate resonance stabilization to t mole; somewhat less than the resonance energy of benzeneJ36 kcal/moje),^but much greater than that of most conjugated! dienes (about JetCell/mole). On the basis of these properties, pyrrole, furan, and thiophene must be considered aromatic. Clearly, formulas I, II, and III do not adequately represent the structures of these compounds. 

• Let us look at the orbital picture of one of these molecules, pyrrole. Each atom of the ring, whether carbon or nitrogen, is held by a cry bond to three other atoms. In forming these bonds, the atom uses three spa 2 orbitals, Whicher in a plane and are 120 apart. After contributing one electron to each a bond, each carbon atom of the ring has left one electron and the nitrogen atom has left two electrons; these electrons occupy p orbitals. Overlap of the/? orbitals gives rise to TT clouds, one above and one below the plane of the ring; the -n clouds contain a total of six electrons, the aromatic.

Source of pyrrole, furan, and thiophene

• Pyrrole and thiophene are found in small amounts in coal tar. During the fractional distillation of coal tar, thiophene (B.Pd. 84) is collected along with the benzene (bop, 80); as a result, ordinary benzene contains about 0.5% of thiophene and must be specially treated if thiophene-free benzene is desired. Thiophene can be synthesized on an industrial scale by the high-temperature reaction between w-butane and surfer.

• The pyrrole ring is the basic unit of the porphyrin system, which occurs, for example, in chlorophyll (p. 1004) and in hemoglobin (p. 1152). Furan is most readily prepared by decarbonization (elimination of carbon monoxide) of furfural (furfuraldehyde), which in turn is made by the treatment of, oat hulls, corncobs, or rice hulls with hot hydrochloric acid. In the latter reaction pentosans (polypeptide's) are hydrolyzed to pentoses, which then undergo dehydration and cyclization to form furfural.

Electrophilic substitution in pyrrole, furan, and thiophene. Reactivity an orientation

• Like other aromatic compounds, these five-membered heterocycles undergo nitration, halogenation, sulfonation, and Friedel-Crafts acylation. They are Muc more reactive than benzene and resemble the most reactive benzene derivatives (amines and phenols) in undergoing such reactions as the Reimer-Tiemann reaction, nitration, and coupling with diazonium salt.

• In some of the examples we notice modifications in the usual electrophilic reagents. The high reactivity of these rings makes it possible to use milder reagents in many cases, as, for example, the weak Lewis acid stannic chloride in the Friedel Crafts acylation of thiophene. The sensitivity to protic acids of furan (which undergoes ring opening) and pyrrole (which undergoes polymerization) makes it necessary to modify the usual sulfonating agent.

Saturated five-membered heterocycles

• Catalytic hydrogenation converts pyrrole and furan into the corresponding saturated heterocycles, pyrrolidine and tetrahydrofuran. Since thiophene poisons most catalysts, tetrahydrothiophene is synthesized instead from open chain compounds.

• Saturation of these rings destroys the aromatic structure and, with it, the aromatic properties. Each of the saturated heterocycles has the properties we would expect of it: the properties of a secondary aliphatic amine, an aliphatic ether, or an aliphatic sulfide. With nitrogen's extra pair of electrons now available for sharing with acids, pyrrolidine (KKB ~ 10~ 3) has the normal basicity of an aliphatic amine. Hydrogenation of pyrrole increases the base strength by a factor of 10 11 (100 billion); clearly a fundamental change in structure has taken place.

• Hygric (C8 H 15ON) is insoluble in aqueous NaOH but soluble in aqueous JHC1 It does not react with benzenesulfonic chloride. It reacts with phenylhydraxine to yield a phenyl hydra/one. It reacts with Nao to yield a yellow precipitate and a carboxylic acid (C7 H 13 O-N). Vigorous oxidation by CrO3 converts hygrine into hygrine acid (C6 Hn 2 N).

Structure of pyridine

• Of the six-membered aromatic heterocycles, we shall take up only one, pyridine. Pyridinic is classified as aromatic on the basis of its properties. It is flat, with bond angles of 120; the four carbon-carbon bonds are of the same length, and so are the two carbon-nitrogen bonds. It resists addition and undergoes electrophilic substitution. It heals of combustion indicates a resonance energy of 23 kcal/mole.

• Pyridine can be considered a hybrid of the Kakul structures I and M. We shall represent it as structure III, in which the circle represents the aromatic sextet. In electronic configuration, the nitrogen of pyridine is considerably different from the nitrogen of pyrrole. In pyridine the nitrogen atom, like each of the carbon atoms, is bonded to other members of the ring by the use of sp 2 orbitals and provides one electron for Jhe^7rj: loud. The third sp 2 orbital of each carbon atom is used to form a bond to hydrogerTfthe third spa 2 orbitals of nitrogen simply contains a pair of electrons, which are available for sharing with acids.

• Because of this electronic configuration, the nitrogen atom makes pyridine a much stronger base than pyrrole and affects the reactivity of the ring in a quite different way, as we shall see.

Source of pyridine compounds

• Pyridine is found in coal tar. Along with it are found a number of methylpyridines, the most important of which are the monomethyl compounds, known as picolines. Oxidation of the picolines yields the pyridine carboxylic. 

• The 3-isomer (nicotinic acid or niaciri) is a vitamin. The 4-isomer (Isonicotinic acid) has been used, in the form of its hydrazide, in the treatment of tuberculosis.

Reactions of pyridine

• The chemical properties of pyridine are those we would expect on the basis of its structure. The ring undergoes the substitution, both electrophilic and nucleophilic, typical of aromatic rings; our interest will lie chiefly in the way the nitrogen atom affects these reactions. There is another set of reactions in which pyridine acts as a base or nucleophile; these reactions involve nitrogen directly and arc due to its unshared pair of electrons.

Electrophilic substitution in pyridine

• Toward electrophilic substitution pyridine resembles a highly deactivated benzene derivative. It undergoes nitration, sulfonation, and halogenation only under very vigorous conditions, and does not Jandro the Friedel-Crafts reaction at all.

• It is important to see the difference between substitution in pyridine and substitution in pyrrole. In the case of pyrrole, a structure in which nitrogen bears a positive charge (see Sec. 31.4) is especially stable since every atom has an octet of electrons; nitrogen accommodates the positive charge simply by sharing four pairs of electrons. In the case of pyridine, a structure in which nitrogen bears a positive charge (III) is especially unstable since nitrogen has only a sextet of electrons; nitrogen shares electrons readily, but as an electronegative atom it resists the removal of electrons.

Nucleophilic substitution in pyridine

• Here, as in electrophilic substitution, the pyridine ring resembles a benzene ring that contains strongly electron-withdrawing groups. Nucleophilic substitution takes place readily, particularly at the 2- and 4-positions. For example:

•  As we have seen nucleophilic aromatic substitution can take place by a mechanism that is quite analogous to the mechanism for electrophilic substitution. Reaction proceeds by two steps; the rate of the first step, formation of a charged particle, determines the rate of the overall reaction. In electrophilic substitution, the intermediate is positively charged; in nucleophilic substitution, the intermediate is negatively charged. The ability of the ring to accommodate the charge determines the stability of the intermediate and of the transition state leading to it, and hence determines the rate of the reaction.

Basicity of pyridine

• Pyridine is a base with KKB = 2.3 x 10 ~ 9. It is thus much stronger than pyrrole (KKB ~ 2.5 x 10" 14) but much weaker than aliphatic amines (KKB ~ 10~ 4). Pyridine has a pair of electrons (in a spa 2 orbital) that is available for sharing with acids; pyrrole has not and can accept an acid only at the expense of the aromatic character of the ring. The fact that pyridine is a weaker base than aliphatic amines is more difficult to account for, but at least it fits into a pattern. Let us turn for a moment to the basicity of the carbon analogs of amines, the carbanions, and use the approach of Sec. 8.10. Benzene is a stronger acid than an alkane, as shown by its ability to displace an Alkire from its salts; this, of course, means that the phenyl anion, C6 H5 ~, is a weaker base than an alkyl anion, R~

• A possible explanation for these sequences can be found in the electronic configuration of the carbanions. In the alkyl, phenyl, and acetylide anions, the unshared pair of electrons occupies respectively a spa 3, a spa 2, and a spa orbital. The availability of this pair for sharing with acids determines the basicity of the particular anion. As we proceed along the series spa 3, spa 2, spa, the p character of the orbital decreases and the 5-character increases. Now, an electron in a p orbital is at some distance from the nucleus and is held relatively loosely; an electron in an s orbital, on the other hand, is close to the nucleus and is held more tightly. Of the three anions, the alkyl ion is the strongest base since its pair of electrons is held most loosely, in a spa 3 orbital. The acetylide ion is the weakest base since its pair of electrons is held most tightly, in a spa orbital.

Quinoline. The Straup synthesis

• Quinoline, CQ H 7 N, contains a benzene ring and a pyridine ring fused as shown in fused as show

• In general, its properties are the ones we would expect from what we have learned about pyridine and naphthalene.

• Quinoline is found in coal tar. Although certain derivatives of quinoline can be made from quinoline itself by substitution, most are prepared from benzene derivatives by ring closure. Perhaps the most generally useful method for preparing substituted quinolines is the Straup synthesis. In the simplest example, quinoline itself is obtained from the reaction of aniline with glycerol, concentrated sulfuric acid, nitrobenzene, and ferrous sulfate.

• Ferrous sulfate in some way moderates the otherwise very vigorous reaction. Thus, we see thali what at first appears to be a complicated reaction i actually a sequence of simple steps involving familiar, fundamental types of reactions: acid-catalyzed dehydration, nucleophilic addition to an a, j3-unsaturated carbonyl compound, electrophilic aromatic substitution, and oxidation. The components of the basic synthesis can be modified to yield a wide variety of quinoline derivatives. For example:

Iso quinoline. The Bichler-Napieralski synthesis

• Iso quinoline, C9H7 N, contains a benzene ring and a pyridinic ring fused as shown in I

• Iso quinoline, like quinoline, has the properties we would expect from what we know about pyridine and naphthalene.

• Account for the following properties of isoquant incline. (Hint: Review orientation in /^-substituted naphthalene's, Sec. 30.13.) (a) Nitration gives 5-nitroisoquinoline. (b) Treatment with potassium amide, KNH2, Ives 1-aminoisoquinoline, and treatment with alkyl lithium compounds gives l-alkylisoquinoline; the 3-substituted products are not obtained. (c) 1-Methylisoquinoline reacts with benzaldehyde to vied compound II, whereas 3-methylisoquinoline undergoes no reaction. (Hint: See Problem 21.22 (c), p. 

• An important method for making derivatives of Iso quinoline is the BischlerNapieralski synthesis. Acyl derivatives of ^-phenylethylamine arc cyclized by treatment with acids (often P2O5) to yield dihydroisoquinolines, which can then be aromatized.

•  To what general class of reactions does the ring closure belong? What is the function of the acid? (Check your answers in Sec. 32.7.) Problem 31.29 Outline the synthesis of N-(2-phenylethyl) acetamide from toluene and aliphatic and inorganic reagents.