the aromatic ring has electron-withdrawing substituents. However, when the R5 substituent is an electron-withdrawing substituent, the yield is increased instead of decreased. Additionally, the efficiency of the reaction is also heavily dependent on the bulkiness of the R6 substituent. The bulkier this group, the less efficient is the reaction. The conditions required for the Madelung synthesis are quite severe. Fortunately, the aforementioned modifications have been since applied to enhance its practicality, working to decrease the required temperature at which the reaction is performed and increase the desired product yield. For example, when electron-donating are placed on the aromatic ring of the N-phenylamide and an electron-withdrawing substituent is substituted at R5, the required temperature for the reaction decreases to approximately 25 °C. Even more impressively, researchers have discovered that the required temperature for the Madelung synthesis decreases to a temperature range of −20 – 25 °C when butyl lithium (BuLi) and lithium diisopropylamide (LDA) bases are used, and when tetrahydrofuran is used as the solvent. This particular modification, the use of either of these metal-mediated bases, is termed the Madelung-Houlihan variation. Synthetic applications The Madelung synthesis has many important applications in chemistry, biochemistry, and industrial chemistry. This reaction served useful in synthesizing, with an 81% yield, the architecturally complex tremorgenic indole alkaloid (-)-penitrem D, a molecule naturally produced by ergot fungus that causes various muscular and neurological diseases in livestock. Because this toxin ultimately causes significant economic problems in the livestock industry, understanding how to synthesize and easily decompose alkaloid (-)-penitrem D is of great importance. Nonetheless, the synthesis of such a complex molecule was, by itself, an incredible feat. Another facet through which the Madelung synthesis has served useful is in the synthesis of 2,6-diphenyl-1,5-diaza-1,5-dihydro-s-indacene, from 2,5-dimethyl-1,4-phenylenediamine. This synthesis was performed without modification to the Madelung synthesis, using sodium ethoxide base at a temperature of 320 – 330 °C. This indacene has shown to be an organic light-emitting diode that may have important applications for low-cost light displays in commercial industry. The Smith-modified Madelung synthesis The Smith-modified Madelung synthesis, also called the Smith indole synthesis, was discovered in 1986 by Amos Smith and his research team. This synthesis employs a condensation reaction of organolithium reagents derived from 2-alkyl-N-trimethylsilyl anilines by esters or carboxylic acids to yield substituted indoles. This synthesis has proven applicable to a wide variety of substituted anilines, including those with alkyl, methoxy, and halide groups, and can