Aromatic Heterocycles Pyridine and Pyrrole

Look back once again at the definition of aromaticity in Section 15.4 . a 

Note that nitrogen atoms have different roles depending on the structure of the molecule. The nitrogen atoms in pyridine and pyrimidine are both in double bonds and contribute only one tt electron to the aromatic sextet, just as a carbon atom in benzene does. The nitrogen atom in pyrrole, however, is not in a double bond and contributes two tt electrons (its lone pair) to the aromatic sextet. In imidazole, both kinds of nitrogen are present in the same molecule— a double-bonded pyridine-like nitrogen that contributes one v electron and a pyrrole-like nitrogen that contributes two. 

Pyrimidine and imidazole rings are particularly important in biological chemistry. Pyrimidine, for instance, is the parent ring system in cytosine, thymine, and uracil, three of the five heterocyclic amine bases found in nucleic acids An aromatic imidazole ring is present in histidine, one of the twenty amino acids found in proteins. 

Thiophene, a sulfur-containing heterocycle, undergoes typical aromatic substitution reactions rather than addition reactions. Why is thiophene aromatic  

Test your knowledge of Key Ideas by using resources in ThomsonNOVV or by answering end-of-chapter problems marked with A. 

Strategy Recall the requirements for aromaticity—a planar, cyclic, conjugated molecule with 4/ + 2 7T electrons—and see how these requirements apply to thiophene. 

Solution Thiophene is the sulfur analog of pyrrole. The sulfur atom is. v/Ahybridized and has a lone pair of electrons in a p orbital perpendicular to the plane of the ring. Sulfur also has a second lone pair of electrons in the ring plane. 

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Our study of heterocyclic compounds is directed primarily to an understanding of their reactivity and importance in biochemistry and medicine. The synthesis of aromatic heterocycles is not, therefore, a main theme, but it is useful to consider just a few examples to underline the application of reactions we have considered in earlier chapters. From the beginning, we should appreciate that the synthesis of substituted heterocycles is probably not best achieved by carrying out substitution reactions on the simple heterocycle. It is often much easier and more convenient to design the synthesis so that the heterocycle already carries the required substituents, or has easily modified functions. We can consider two main approaches for heterocycle synthesis, here using pyridine and pyrrole as targets. 

The circulating electrons in the 7t-system of aromatic hydrocarbons and heterocycles generate a ring current and this in turn affects the chemical shifts of protons bonded to the periphery of the ring. This shift is usually greater (downfield from TMS) than that expected for the proton resonances of alkenes thus NMR spectroscopy can be used as a test for aromaticity . The chemical shift for the proton resonance of benzene is 7.2 ppm, whereas that of the C-1 proton of cyclohexene is 5.7 ppm, and the resonances of the protons of pyridine and pyrrole exhibit the chemical shifts shown in Box 1.12. 

Heterocyclic These are compounds having at least one hetero atom (any other atom but carbon, e.g. O, N and S) within the ring, and conforming to Hiickel s rule. The aromaticity of heterocyclic compounds, e.g. pyridine and pyrrole, can be explained as follows. 

Substitution in aromatic hydrocarbon naturally shifts the wavelength of fluorescence in agreement with the effect of the same substitution on the absorption spectrum. Alkyl substitution has little effect. Chlorine and bromine weaken the florescence and iodine completely inhibits it. The simplest aromatic heterocyclics, pyridine, pyrrole, furan and thiophene do not show fluorescence. 

Aromatic heterocycles such as thiophene, pyridine, and pyrrole are also able to form arene complexes, for example (7j5-C4H4N)(7j5-CsHs)Fe (azaferrocene), (7j5-C4H4S)Cr(CO)3, and (tj6-CsH5N)W(CO)3. 

Heterocycles containing oxygen, nitrogen, or sulfur—atoms that also have at least one lone pair of electrons—can also be aromatic. With heteroatoms, we must always determine whether the lone pair is localized on the heteroatom or part of the delocalized ji system. Two examples, pyridine and pyrrole, illustrate these different possibilities. 

The MM3 force field has been extended by Allinger and co-workers to cover aromatic heterocycles of the pyridine and pyrrole types <93JA11906>. Structures (32 compounds), dipole moments (35 compounds), heats of formation (35 compounds), and vibrational spectra (11 compounds) were examined. The results are good for structure and fair for the other items resonance energies were reported for the series benzene (17.79 kcal mol ), pyridine (17.02 kcal mol ), pyridazine (14.35 kcal mol ), pyrazine (17.01 kcal mol ), pyrimidine (15.60 kcal mol ), 1,3,5-triazine (13.51 kcal mol ), and 1,2,4,5-tetrazine (17.72 kcal mol ). Finally, ab initio studies of the dipole polarizabilities of conjugated molecules have been reported in which monocyclic azines (pyridine, pyridazine, pyrimidine, pyrazine, 5-triazine, and 5-tetrazine) are compared <94JST(304)109>. 

Electrophilic substitution in the azoles is intermediate in facility between pyridine and pyrroles, thiophene and furans the presence of the electron-with-drawing azomethine unit has an effect on the five-membered aromatic heterocycles just as it does when incorporated into a six-membered aromatic framework, i.e. the comparison is like that between benzene and pyridine (chapter 4). The order of reactivity - pyrrole > furan > thiophene - is echoed in the azoles, though the presence of the basic nitrogen complicates such comparisons. The regiochemistry of electrophilic attack can be seen nicely by comparing the character of the various ring positions - those that are activated in being five-membered in character and those that are deactivated by their similarity to a-and y-positions in pyridine. 

Heterocyclic aromatic compounds contain C and H atoms other than carbon and hydrogen (Fig. 6). For the monocyclic molecules Hiickel s rule is applicable. For example both pyridine and pyrrole contain six ti electrons. Unlike the former the lone pair of the latter is delocalized. Armit and Robinson have shown a connection between the electronic sextet and the heteroaromaticity. Due to the electronegativity difference between carbon and nitrogen the bonds in pyridine are not of equal length and the delocalization is not perfect. Five membered heteroaromatics with oxygen and sulfur are furan and thiophene respectively. Pyrazole/imidazole, triazoles and tetrazoles are five membered heteroaromatics with two, three and four nitrogen atoms respectively. Three important aromatic six membered heterocyclic molecules are pyrimidine, pyrazine and pyridazine. Benzofused... 

In aqueous solution, aromatic heterocyclic amines such as pyridine, pyrimidine, and pyrrole are much weaker bases than nonaromatic amines or ammonia. (In the gas phase, however, pyridine and pyrrole are more basic than ammonia, indicating that solvation has a very important effect on their relative basicities see Section 20.3.)... 

Look back again at the definition of aromaticity in the previous section "... a cyclic, conjugated molecule containing 4n + 2 tt electrons. Nothing in this definition says that the number of tt electrons mnst he the same as the number of atoms in the ring or that all the atoms in the ring mnst he carbon. In fact, both ions and heterocyclic compounds, which contain atoms of different elements in their ring, can also he aromatic. The cyclopentadienyl anion and the cycloheptatrienyl cation are perhaps the best known aromatic ions, while pyridine and pyrrole are common aromatic heterocycles. 

Other kinds of molecules besides benzene-like compounds can also be aromatic. The cyclopentadienyl anion and cycloheptatrienyl cation, for instance, are aromatic ions. Pyridine and pyrimidine are srx-memhered, nitrogen-containing, aromatic heterocycles. Pyrrole and imidazole are five-membered, nitrogen-containing heterocycles. Naphthalene, quinoline, indole, and many others are polycyclic aromatic compounds. 

Cyclic compounds that contain at least one atom other than carbon within their ring are called heterocyclic compounds, and those that possess aromatic stability are called het erocyclic aromatic compounds Some representative heterocyclic aromatic compounds are pyridine pyrrole furan and thiophene The structures and the lUPAC numbering system used m naming their derivatives are shown In their stability and chemical behav lor all these compounds resemble benzene more than they resemble alkenes... 

Other kinds of substances besides benzene-like compounds can also be aromatic. For example, the cyclopentadienyl anion and the cycloheptatrienyl cation are aromatic ions. Pyridine, a six-membered, nitrogen-containing heterocycle, is aromatic and resembles benzene electronically. Pyrrole, a hve-membered heterocycle, resembles the cyclopentadienyl anion. 

Heterocyclic amines are compounds that contain one or more nitrogen atoms as part of a ring. Saturated heterocyclic amines usually have the same chemistry as their open-chain analogs, but unsaturated heterocycles such as pyrrole, imidazole, pyridine, and pyrimidine are aromatic. All four are unusually stable, and all undergo aromatic substitution on reaction with electrophiles. Pyrrole is nonbasic because its nitrogen lone-pair electrons are part of the aromatic it system. Fused-ring heterocycles such as quinoline, isoquinoline, indole, and purine are also commonly found in biological molecules. 

Heterocycles with conjugated jr-systems have a propensity to react by substitution, similarly to saturated hydrocarbons, rather than by addition, which is characteristic of most unsaturated hydrocarbons. This reflects the strong tendency to return to the initial electronic structure after a reaction. Electrophilic substitutions of heteroaromatic systems are the most common qualitative expression of their aromaticity. However, the presence of one or more electronegative heteroatoms disturbs the symmetry of aromatic rings pyridine-like heteroatoms (=N—, =N+R—, =0+—, and =S+—) decrease the availability of jr-electrons and the tendency toward electrophilic substitution, allowing for addition and/or nucleophilic substitution in yr-deficient heteroatoms , as classified by Albert.63 By contrast, pyrrole-like heteroatoms (—NR—, —O—, and — S—) in the jr-excessive heteroatoms induce the tendency toward electrophilic substitution (see Scheme 19). The quantitative expression of aromaticity in terms of chemical reactivity is difficult and is especially complicated by the interplay of thermodynamic and kinetic factors. Nevertheless, a number of chemical techniques have been applied which are discussed elsewhere.66... 

Important aromatic heterocycles that contain a single hetero-atom include pyridine, quinoline, isoquinoline, pyrrole, thiophene, furan and indole. 

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