Organic Synthesis: A Plea for Pure Science

Abstract

In 1883, Henry A. Rowland, the first President of the American Physical Society and Professor of Physics at Johns Hopkins University, published an essay entitled “A Plea for Pure Science” in Popular Science Monthly. He took the development of gunpowder as an example to emphasize that SCIENCE itself must be sought in the applications of science. “They (Chinese) have known the application of gunpowder for centuries; and yet the reasons for its peculiar action, if sought in the proper manner, would have developed the science of chemistry, and even of physics, with all their numerous applications.” This paper includes some questionable viewpoints, but the one mentioned here is worthy of our reflection on its implications. Over the years, merely the application of science (often in terms of Technology) has been regarded as decisive for civilization, while the role of science itself has been considered to be recessive and has not been deliberated carefully. Herein, organic synthesis, a subject containing abundant applied aspects, will be employed as an example to illustrate the course to plead for pure science. To implant the element of pure science into organic synthesis, it is essential to establish organic synthesis first and foremost as a science, whose Latin origin scientia means “knowledge.” Accordingly, science is the form of testable explanations and predictions about the universe. It goes without saying that organic synthesis could build naturally occurring complex and intriguing molecules or their variants to facilitate biological, pharmaceutical, and medical applications, because these natural molecules and their derivatives are often useful as drug leads and biological tools. By its virtue as a creative science involving the construction of molecules through chemical procedures, organic synthesis is able to provide novel molecules that are properly designed and synthesized via carefully planned routes for possible uses in everyday life such as food, medicine, clothes, fuels, polymers, dyes, paints, cosmetics, perfumes, engineering materials, and many more. To elevate organic synthesis from a seemingly rather applied category to the genre of pure science, we have to express our gratitude to two masters of organic synthesis. The most notable case in point is concerned with the Woodward-Hoffmann rules, which are used to rationalize or predict certain aspects of the stereochemistry and activation energy of pericyclic reactions, an important class of reactions in organic chemistry. During the course of his total synthesis of vitamin B12 (Figure 1A), 1 Professor Robert B. Woodward (1917–1979) of Harvard University came across a puzzling set of reactions (Figure 1B) that would not be easily explained by alluding to ordinary organic reactions. 2 , 3 Professor Woodward then sought collaboration from Professor Roald Hoffmann (born 1937), a theoretician and at that time a Junior Fellow of Harvard University, to attempt to unravel these challenges. The Woodward-Hoffmann rules were ultimately formulated. These rules are a consequence of changes in electronic structure that occur during a pericyclic reaction and are predicated on the phasing of the interacting molecular orbitals. Professor Hoffmann was awarded the Nobel Prize in Chemistry in 1981 for conceiving the Woodward-Hoffmann rules, which he shared with Professor Kenichi Fukui (1918–1998) of Kyoto University, who developed a similar set of rules within the context of frontier molecular orbital theory. Due to the fact that Professor Woodward had died 2 years before the announcement of the 1981 Nobel Prize, he did not share the Prize with Professors Hoffmann and Fukui. The formulation of the Woodward-Hoffmann rules is an excellent example to reveal how pure science is thought to have originated through the necessity to clarify experimental impasse. These rules can also put all classes of pericyclic reactions as well as their microscopic “retro” processes into practical operation, which include electrocyclizations, cycloadditions, sigmatropic reactions, ene reactions, cheletropic reactions, and dyotropic reactions. Because of their simple and general nature, the Woodward-Hoffmann rules have prodigiously taught generations of synthetic organic chemists in their comprehension of molecular orbital theory as well as their creation of new organic reactions. 4 Figure 1 Organic synthesis: arts of science (A) Vitamin B12 (left) and erythromycin (right). (B) Magic ring-opening/ring-closing reactions. (C) Retrosynthetic analysis of beninine as target molecule. The second example is the development of retrosynthetic analysis, proposed by Professor Elias J. Corey (born 1928), also of Harvard University. Retrosynthetic analysis is a technique to solve problems in the planning of synthesis by disconnection of the target molecule (TM) into simpler precursors regardless of reagents (Figure 1C). 5 The disconnection is repeated until very simple or commercially available compounds are obtained. Since an organic synthesis will usually have more than one possible synthetic route, these repeated disconnections would offer plenty of available routes for the TM. As a result, a retrosynthetic tree with many branches would be generated, leading to different routes and different synthetic precursors. Consequently, a synthetic tree is a graph of several potential synthetic routes to the TM, which can be subject to design, comparison, and evaluation, from which the most efficient method is chosen according to a rational analysis. After the most efficient route is chosen, reagents and reaction conditions would then be taken into consideration. Due to the fact that databases can be employed during the retrosynthetic analysis in order to verify whether a compound already exists in the literature, the use of computers is apparent. Professor Corey was the first organic chemist to explore the possibility of using computational methods to simplify organic synthesis, more than two decades before the recent advocacy of deploying artificial intelligence to aid organic synthesis. In 1990, Professor Corey was awarded the Nobel Prize in Chemistry for his development of the theory and methodology of organic synthesis, specifically retrosynthetic analysis. It is noteworthy that Professors Woodward and Corey, who are world-renowned for their advancement of the science of organic synthesis, did step outside their comfort zone to embrace new concepts such as molecular orbital theory, analysis of synthetic steps, and computer application. They are maestros because they contributed profoundly in their launch of an element of pure science into organic synthesis. To have progress in pure science, we should educate ourselves for never questioning the commercial and monetary benefits of a research program. Useless as it might appear, research results can only be adjudicated by the passing of time. We should bear in mind that fuzzy logic began as a pure mathematical theory in the 1920s, but has been nowadays applied to many fields, from control theory to artificial intelligence, as well as even to kitchenware. As exemplified by the aforementioned achievements of Professors Woodward and Corey, the notion that pure science can bring about great science, influential discoveries, and major breakthroughs is by all means emphatic. The quest for pure science must be advocated repeatedly. By doing so, our society aspires to strive for scientific excellence. To achieve this target, it is paramount to train our next generation of youngsters to acquire an attitude of being inquisitive, and to be ready to always ask “why?” Above all, they should not be afraid to challenge authority; they should possess the ability of independent and critical thinking; and they should have a speculative, imaginative, creative, and innovative mindset. Last but not least, they should also show determination to achieve a particular goal despite difficulties. It is my sincere hope that one day these ingredients, in the form of Key Performance Indicators, could be integrated into the framework of our primary, secondary, and tertiary education.