Minggu, 11 Oktober 2009

Heteroaromatic Compounds


The conept of aromaticity extends beyond simple hydrocarbons such as benzene, naphthalene, and anthracene. We have seen that MO theory treats the pi system of aromatic molecules independently of the sigma-bonded framework. This means that the identity of the the atoms that comprise that framework is not important. They may be carbons, but they might also be nitrogen or oxygen or sulfur, or other, less common, atoms. In this topic we will take a brief look at aromatic molecules where the sigma-bonded framework includes nitrogen, oxygen, and sulfur atoms. We will consider two situations, electron rich systems and electron poor systems.

Electron Rich Systems

In benzene there are 6 pi electrons distributed over a sigma bonded framework of 6 carbon atoms. From this perspective there is one pi electron per nucleus. In electron rich systems that ratio is larger. Consider the heterocyclic compounds shown in Figure 1.

Figure 1

These Cups All Runneth Over

All of the compounds in the figure are considered aromatic. In each case, the lone pair of electrons shown in red on the heteroatom constitutes part of the pi system as indicated in the orbital drawings of furan, pyrrole, and imidazole. Each of the molecules in this figure has a pi system that contains 6 electrons. In furan those 6 pi electrons are attracted to four carbon nuclei and one oxygen nucleus; a total of 32 protons. The electron/proton ratio is 6:32 = 0.1875 electrons/proton. Since this is higher than the 0.167 electrons/proton in benzene, furan is considered electron rich. Another way to look at this is to ask the hypothetical question "What would the electron density be in an "imaginary benzene molecule" if the electron/proton ratio were 0.1875 electrons/proton rather than 0.167 electrons/proton?" Since a carbon atom has 6 protons, the electron/proton ratio of 0.1875 for the heterocyclic system is equivalent to 6 x 0.1875 = 1.125 electrons per nucleus in such an "imaginary benzene".

In the case of pyrrole the electron/proton ratio is 6/31 = 0.1935. If the electron density on each carbon atom in benzene were 0.1935 electrons/proton, then there would be 1.161 electrons per nucleus for each carbon nucleus in this "imaginary benzene molecule".

Exercise 1 Which compound would you expect to react fastest with an electrophilic reagent such as Br2/FeBr3, benzene, furan, or pyrrole?

Exercise 2 Which compound would you expect to react faster with an electrophilic reagent such as Br2/FeBr3, pyrrole or imidazole?

Exercise 3 Which compound would you expect to react slowest with an electrophilic reagent such as Br2/FeBr3, pyrrole, oxazole, or imidazole?

Many heterocyclic molecules are play important roles in biological systems. Pyrrole, for example, is a building block for porphyrins, macrocyclic ring systems found in hemoglobin and chlorophyll a. The heme portion of hemoglobin, which is a protein, is shown in Figure 2 where the four pyrrole rings are highlighted in blue.

Figure 2

Hey, Look, It's a Bloody Heme!

Imidazole is a substituent on the side chain of the amino acid histidine. It is found at the active site of many enzymes, where it is involved in proton transfer reactions. Imidazole is often thought of as the biological equivalent of hydroxide ion.

Electron Poor Systems

If electron rich systems are those in which there are more than one electron/nucleus, then electron poor systems are those in which there are less than 1. Figure 3 shows three common examples.

Figure 3

The 3 Ps

The electron/proton ratio in pyridine is 6:37 = 1:6.17 which is equivalent to 0.973 electrons/nucleus. It is electron poor. While molecules like pyridine and pyrimidine do undergo electrophilic aromatic substitution reactions, they require much harsher conditions than their electron rich counterparts.

Figure 4 compares the reactivities of benzene, pyrrole, and pyridine towards nitric acid. Note how seemingly small changes in the electron/nucleus value- 0.973 to 1.000 to 1.161- result in very large changes in reactivity.

Figure 4

Different Strokes for Different Folks


Finally, we will take a brief look at an important class of heterocyclic aromatic compounds known as nucleosides. These molecules are important because they are components of the nucleic acids RNA and DNA. There are 5 different nucleosides that occur in RNA and DNA; adenine, guanine, cytosine, thymine, and uracil. Structures of these compounds are shown in Figure 5.

Figure 5

Meet the Nucelosides

Adenine and guanine are purines. Cytosine, uracil, and thymine are pyrimidines. Adenine, guanine, and cytosine occur in both RNA and DNA. Thymine occurs only in DNA, while uracil is found in RNA. Note that with the exception of adenine, all of the nucleosides are shown as keto tautomers of their enol forms which are redrawn in Figure 6.

Figure 6

Meet the Nucleosides (in disguise)

In their book The Double Helix, Watson and Crick, who first described the double helical structure of DNA, confess that they were unaware of the possibility of keto-enol tautomerization and that their ignorance of this phenomenon delayed their insight into the structure of DNA for a significant length of time.

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