HOMO-LUMO approach to Electrophilic reactivity in Heterocyclic Rings

The site of electrophilic substitution in heterocyclic aromatic rings can be modelled by inspecting the calculated form of the HOMO molecular orbital. The following are the HOMO orbitals for a selection of heterocyclic rings. Notice how the larger contribution to the HOMO for furan, pyrrole, thiophene and benzothiophene all come from the C-2 carbon, whereas with benzofuran and indole it is at C-3. This all accords with the known reactivity of these systems. The origins of these effects can be traced to the nodal characteristics of the HOMO, and where the best position to place an electronegative atom is in relation to these nodes. It also relates to the size of the overlap between the adjacent p-p orbitals.

For comparison, the relative energies of the Wheland intermediate resulting from protonation (the model electrophile) are shown, 3-substituent first, 2-substituent second, calculated using the AM1 method.

furan (3:182.2/2:174.1) pyrrole (3:199.7/2:200.4) thiophene (3:199.7/2:200.5)
benzofuran (3:192.4/2:189.3) indole (3:206.7/2:218.2) benzothiophene (3:205.5/2:214.3)

To demonstrate the 3D nature of these orbitals, each thumbnail image below is linked to a 3DMF file. To view these orbital models, you will need a 3DMF viewer such as the Quick3D or 3DMFPlugin (both browser plugins), 3DMF Optimizer (a Macintosh application), Geo3D (for Mac) or 3DMF Viewer for Windows. Windows users must also install the QuickDraw3D libraries from Apple.