- Also called:
- heterocycle
- Related Topics:
- azetidine
- propylene oxide
- benzimidazole
- benzopyrylium
- aziridine
Aromaticity denotes the significant stabilization of a ring compound by a system of alternating single and double bonds—called a cyclic conjugated system—in which six π electrons generally participate. A nitrogen atom in a ring can carry a positive or a negative charge, or it can be in the neutral form. An oxygen or sulfur atom in a ring can either be in the neutral form or carry a positive charge. A fundamental distinction is usually made between (1) those heteroatoms that participate in a cyclic conjugated system by means of a lone, or unshared, pair of electrons that are in an orbital perpendicular to the plane of the ring and (2) those heteroatoms that do so because they are connected to another atom by means of a double bond.
An example of an atom of the first type is the nitrogen atom in pyrrole, which is linked by single covalent bonds to two carbon atoms and one hydrogen atom. Nitrogen has an outermost shell of five electrons, three of which can enter into three covalent bonds with other atoms. After the bonds are formed, as in the case of pyrrole, there remains an unshared electron pair that can engage in cyclic conjugation. The aromatic sextet in pyrrole is made up of two electrons from each of the two carbon-carbon double bonds and the two electrons that compose the unshared electron pair of the nitrogen atom. As a consequence, there tends to be a net flow of electron density from the nitrogen atom to the carbon atoms as the nitrogen’s electrons are drawn into the aromatic sextet. Alternatively, the pyrrole molecule may be described as a resonance hybrid—that is, a molecule whose true structure can only be approximated by two or more different forms, called resonance forms.
An example of a heteroatom of the second type is the nitrogen atom in pyridine, which is linked by covalent bonds to only two carbon atoms. Pyridine also has a π-electron sextet, but the nitrogen atom contributes only one electron to it, one additional electron being contributed by each of the five carbon atoms in the ring. In particular, the unshared electron pair of the nitrogen atom is not involved. Moreover, because nitrogen’s attraction for electrons (its electronegativity) is greater than that of carbon, electrons tend to move toward the nitrogen atom rather than away from it, as in pyrrole.
Quite generally, heteroatoms may be referred to as pyrrolelike or pyridine-like, depending on whether they fall into the first or second class described above. The pyrrolelike heteroatoms ―NR― (R being hydrogen or a hydrocarbon group), ―N−―, ―O―, and ―S― tend to donate electrons into the π-electron system, whereas the pyridine-like heteroatoms ―N=, ―N+R=, ―O+=, and ―S+= tend to attract the π electrons of a double bond.
In six-membered heteroaromatic rings, the heteroatoms (usually nitrogen) are pyridine-like—for example, the compounds pyrimidine, which contains two nitrogen atoms, and 1,2,4-triazine, which contains three nitrogen atoms.
Six-membered heteroaromatic compounds cannot normally contain pyrrolelike heteroatoms. Five-membered heteroaromatic rings, however, always contain one pyrrolelike nitrogen, oxygen, or sulfur atom, and they may also contain up to four pyridine-like heteroatoms, as in the compounds thiophene (with one sulfur atom), 1,2,4-oxadiazole (with one oxygen atom and two nitrogen atoms), and pentazole (with five nitrogen atoms).
The quantitative measurement of aromaticity—and even its precise definition—has challenged chemists since German chemist August Kekule formulated the ring structure for benzene in the mid-19th century. Various methods based on energetic, structural, and magnetic criteria have been widely used to measure the aromaticity of carbocyclic compounds. All of them, however, are difficult to apply quantitatively to heteroaromatic systems because of complications arising from the presence of heteroatoms.
Chemical reactivity can provide a certain qualitative insight into aromaticity. The reactivity of an aromatic compound is affected by the extra stability of the conjugated system that it contains; the extra stability in turn determines the tendency of the compound to react by substitution of hydrogen—i.e., replacement of a singly bonded hydrogen atom with another singly bonded atom or group—rather than by addition of one or more atoms to the molecule via the breaking of a double bond (see substitution reaction; addition reaction). In terms of reactivity, therefore, the degree of aromaticity is measured by the relative tendency toward substitution rather than addition. By this criterion, pyridine is more aromatic than furan, but it is difficult to say just how much more aromatic.
Physical properties of heterocyclic compounds
Physical properties are important as criteria for judging the purity of heterocycles just as for other organic compounds. Organic compounds generally show great regularity in their physical properties, and heterocycles are no exception.
The melting point was once a widely used criterion for purity, but it has been increasingly superseded by optical spectra, based on light absorption; mass spectra, based on relative masses of molecular fragments; and magnetic resonance spectra, based on nuclear properties (see spectroscopy). Nevertheless, knowledge of melting and boiling points is still helpful for judging the purity of a compound.
Melting and boiling points
The boiling points of certain saturated heterocycles are listed in the first table and are compared with those of the corresponding cycloalkanes (rightmost column of the table). The melting points or boiling points of common heteroaromatic compounds and their substituted derivatives are compared with those of benzene and its derivatives in the second table.
ring system (with position of substituent) | substituent | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
H | CH3 | C2H5 | CO2H | CO2C2H5 | CONH2 | NH2 | OH | OCH3 | Cl | Br | |
*In °C. Boldface indicates the melting points. A dash indicates that a compound is unstable or unknown or that data are not readily available. | |||||||||||
**Calculated using the experimentally obtained boiling point at reduced pressure. | |||||||||||
***Compound melts with decomposition. | |||||||||||
benzene | 80 | 111 | 136 | 122 | 212 | 129 | 184 | 41 | 154 | 132 | 156 |
pyridine (2) | 115 | 129 | 148 | 137 | 243 | 107 | 57 | 107 | 140 | 170 | 193 |
pyridine (3) | 115 | 144 | 165 | 237 | 224 | 130 | 65 | 127 | 179 | 148 | 173 |
pyridine (4) | 115 | 145 | 168 | 315 | 219 | 156 | 158 | 148 | 190 | 147 | 174 |
pyrrole (1) | 130 | 113 | 129 | 95 | 178 | 166 | 175 | 185** | — | — | — |
pyrrole (2) | 130 | 148 | 164 | 208 | 39 | 174 | 285** | — | — | — | — |
pyrrole (3) | 130 | 143 | 179 | 148 | 40 | 152 | — | — | — | — | — |
furan (2) | 31 | 65 | 92 | 133 | 34 | 142 | — | — | 110 | 78 | 103 |
furan (3) | 31 | 66 | 92 | 122 | 175 | 168 | — | — | 110 | 80 | 103 |
thiophene (2) | 84 | 113 | 134 | 129 | 218 | 180 | — | 218 | 151 | 128 | 150 |
thiophene (3) | 84 | 115 | 136 | 138 | 208 | 178 | 146 | 270** | 156** | 136 | 159 |
pyrazole (1) | 68 | 127 | 136 | 102 | 213 | 141 | 185** | 72 | — | — | — |
pyrazole (3) | 68 | 204 | 209 | 214 | 158 | 159 | 38 | — | — | 40 | 70 |
pyrazole (4) | 68 | 206 | 247** | 275 | 78 | — | 81 | 118 | 60 | 77 | 97 |
isoxazole (3) | 95 | 118 | 138 | 149 | — | 134 | — | 98 | — | — | — |
isoxazole (5) | 95 | 122 | 138** | 146 | — | 174 | 77 | — | 200** | — | — |
imidazole (1) | 90 | 196 | 208 | — | 218 | — | 315** | 93 | 252** | — | — |
imidazole (2) | 90 | 144 | 80 | 164 | 178 | 312 | — | 251 | 71 | 165 | 207 |
imidazole (4) | 90 | 56 | 76 | 281 | 157 | 215 | — | — | — | 117 | 130 |
pyrimidine (2) | 124 | 138 | 152 | 197 | 64 | 166 | 127 | 180 | 175** | 65 | 56 |
pyrimidine (4) | 124 | 141 | 140 | 240 | 39 | 194 | 151 | 164 | 152 | — | — |
pyrimidine (5) | 124 | 153 | 175 | 270 | 38 | 212 | 170 | 210 | 47 | 37 | 75 |
pyrazine (2) | 55 | 137 | 155 | 225*** | 50 | 189 | 118 | 188 | 187 | 152 | 180 |
ring size | number (and position) of heteroatoms | type of heteroatom | saturated cycloalkane | ||
---|---|---|---|---|---|
N (as NH) | O | S | |||
*Calculated using the experimentally obtained point at reduced pressure. | |||||
3 | one | 56 | 11 | 55 | −33 |
4 | one | 63 | 48 | 94 | 13 |
5 | one | 87 | 65 | 121 | 49 |
6 | one | 106 | 88 | 141 | 80 |
6 | two (1,2) | 150 | 116 | 190* | 80 |
6 | two (1,3) | 150 | 106 | 207 | 80 |
6 | two (1,4) | 145 | 101 | 200 | 80 |
7 | one | 138 | 120 | 174 | 119 |
Replacement of a two-carbon unit (two carbon and two hydrogen atoms, molecular weight equal to 26) by a single sulfur atom (atomic weight 32) has little effect on the melting or boiling point. On the other hand, replacement of a two-carbon unit by an oxygen atom (atomic weight 16) lowers the boiling point by about 40 °C (72 °F), which is to be expected because of the decreased molecular weight of the furan compounds (lighter compounds being more volatile). Introduction of nitrogen atoms into the benzene ring is accompanied by less-regular changes. Replacement of a two-carbon unit by an imino (NH) group, or of a single carbon by a nitrogen atom, increases the boiling point. Furthermore, making these two changes simultaneously increases the boiling point even more, probably as the result of intermolecular association by hydrogen bonding (a weak form of attachment via certain types of hydrogen atoms; see chemical bonding) between the pyridine-like nitrogen atom and the imino group.
The effects of substituent groups in heteroaromatic rings show considerable regularity. Methyl (CH3) and ethyl (C2H5) groups attached to ring carbon atoms usually increase the boiling point by about 20–30 °C (36–54 °F) and 50–60 °C (90–108 °F), respectively, whereas a similar attachment to a ring nitrogen atom (e.g., pyrrole → 1-methylpyrrole) significantly decreases the boiling point because of decreased ease of intermolecular association by hydrogen bonding (the active hydrogen having been replaced by a hydrocarbon group). Heterocyclic carboxylic acids and amides are all solids at room temperature. Carboxylic acids of heterocycles containing a ring nitrogen atom usually melt at higher temperatures than those containing ring oxygen or sulfur atoms, because of hydrogen bonding. Compounds containing both a ring nitrogen atom and a hydroxyl (OH) or amino (NH2) group are usually relatively high-melting solids. Compounds containing chlorine (Cl) usually have boiling points similar to those of the corresponding ethyl-substituted compounds.
Ultraviolet, infrared, nuclear magnetic resonance, and mass spectra
Spectroscopic studies of heterocyclic compounds, like those of other organic compounds, have became of great importance as means of identification of unknown materials, as criteria for purity, and as probes for investigating the electronic structures of molecules, thereby explaining and helping to predict their reactions. The ultraviolet spectrum of an organic compound (the pattern of its light absorption in the ultraviolet region of the spectrum) is characteristic of the π-electron system of the molecule—i.e., of the arrangement of double bonds within the structure. The ultraviolet spectra of heteroaromatic compounds show general similarity to those of benzenoid compounds (compounds with one or more benzene rings), and the effects of substituents can usually be rationalized in a similar way.
The infrared spectrum of an organic compound, with its complexity of bands, provides an excellent “fingerprint” of the compound—far more characteristic than a melting point. It also can be used to identify certain common groups, such as carbonyl (C=O) and imino, as well as various heterocyclic ring systems.
Magnetic resonance spectra are indispensable today for studies in heterocyclic chemistry. Proton resonance spectra, the most common type, yield information regarding the number of hydrogen atoms in the molecule, their chemical environment, and their relative orientation in space. Mass spectra are used to determine not only the complete molecular formula of the compound but also the molecular structure from the way the molecule fragments.
Synthesis and modification of heterocyclic rings
The important methods for synthesizing heterocyclic compounds can be classified under five headings. Three are ways of forming new heterocyclic rings from precursors containing either no rings (acyclic precursors) or one fewer ring than the desired product; one is a way of obtaining a heterocyclic ring from another heterocyclic ring or from a carbocyclic ring; and one involves the modification of substituents on an existing heterocyclic ring.
In the formation of rings from acyclic precursors, the key step is frequently the formation of a carbon-heteroatom linkage (C―Z, in which Z represents an atom of nitrogen, oxygen, sulfur, or a more unusual element). The actual ring closure, or cyclization, however, may involve the formation of a carbon-carbon bond. In any case, ring formation reactions are divided into three general categories according to whether the cyclization reaction occurs primarily as a result of nucleophilic or electrophilic attack or by way of a cyclic transition state.