Research Philosophy

My pleasures and satisfactions from carrying on organic chemical research are legion. Organic compounds are architectural in character, subject to rational design. I estimate that over the years my research group has designed, prepared, and characterized over 10,000 new compounds. The structures of many of these compounds have been designed for specific purposes to answer specific questions. Their syntheses had to be designed, and consisted of anywhere from two to thirty steps. The test systems to which the new compounds were subjected were also designed. Overcoming obstacles was subject to a blend of trial and error, reasoning by analogy, and the interplay between intuition derived from experience and the character of the challenge. Thus research is an art form, highly individualistic, and involving at least four kinds of creativity - the design of molecules - the design of syntheses - design of test systems - discovery of paths around obstacles.

The evolutionary character of the development of a research problem is illustrated by the carcerand project. The principle of preorganization was already being used in my research group as a guide to both strong host-guest binding and guest specificity. The binding properties of spherand 8 clearly demonstrated the central importance of preorganization. This concept, coupled with the knowledge that the active sites of enzymes contain preorganized lipophilic pockets, led to the cavitand concept of designing and preparing hosts with substantially rigid structural frameworks. The thought that these were container compounds for guests led to the extreme type of closed-surface container compounds capable of fully imprisoning guests. Molecular model examination led us to prototype structure 28 for carcerands, which is composed of potential building blocks such as 29 and 30. In these structures, O, S, NH, CH2CH2, CH2CCH2, CH2SCH2, OCH2O, and many other groups could be substituted for the CH2 groups. [37]

I proposed the syntheses of compounds such as 28 to my research group co-workers, but they were pessimistic about our finding ways of preparing carcerands. However, when a literature search revealed that derivatives of 29 and 36 were already known and easily made, they warmly endorsed the carcerand concept. The interesting questions posed by potential carceplexes occurred to several members of my group, as did potential synthetic routes leading to them [37]. Over a period of time the concept of carcerands and carceplexes became commonplace among my co-workers, and led to the design of new cavitands as well. The discussions and arguments between the different members of my group have proved to be my most stimulating source of new research ideas. I strongly encourage my graduate students and postdocs to discuss and argue about the research problems, and to propose alternate approaches to their goals, as well as alternate goals.

I start a new research program by posing general questions. It was by chance that I discovered the first phenonium ion [38]. This research led me to ask and answer many questions about the mechanisms of organic reactions using a blend of kinetic and stereochemical probes in noncyclic systems [39]. Cram's rules about asymmetric induction emerged from a need to design target molecules of particular configurations for our mechanistic studies [40]. The ion pair phenomena encountered in carbocation stereochemistry [41] led me to pose the general question: What are the stereochemical capabilities of carbanions? The answer to this question led to the discovery of phenomena such as isoinversion, conducted tour mechanism, and ion-pair reorganization phenomena [42]. I invented and named the cyclophanes as a result of our desire to study transannular electronic and steric effects [43]. Our contribution to the host-guest complexation chemical field grew out of the general question. How can the organic chemist design and prepare compounds that mimic features of the natural evolutionary system of organic compounds responsible for life? [11,12] The answer to this question led to the Nobel Prize.

Future Prospects for Organic Chemistry

By the end of 1988, my contact with organic chemistry will have spanned half a century. My early hopes of working in a profession that challenged my creative and organizational capacities have been fulfilled beyond expectations. The opportunities for being creative in organic chemistry research are limited only by the imaginations and skills of the investigators. The design and preparation of new compounds, reactions, synthetic sequences, and test systems, and the discovery of new principles, correlations, and uses will go on for as many years as the spirit of inquiry is alive in society. I know of no other profession as rich in diverse phenomena, scientific enterprise, and practical rewards as that of the organic research chemist. No other scientists engage in such a variety of types of reasoning, is putting predictions to test with such speed, and in extracting such gratification of combining the pursuit of personal goals with sociological relevance. The amalgams of certainty and uncertainty, of the approximate with the exact, and of speculation and observed result are the daily companions of the investigator in this field.

Among its many rewarding aspects, organic chemical research has a vast literature, each article of which represents a piece of some scientist's biography. This "keeping track" is very satisfying. I like to know what has and what has not been done, and how well something has been done. Any scientist by reading my papers can see in some detail how I have spent most of my mature life. They can judge the quality of my mind and imagination, and my research abilities. They can see how thoroughly my claims have been documented by experimental results published in full-length papers. Any investigator can repeat my experiments - and many have! Only in the sciences can the history of a discovery be so thoroughly validated. I know of no other profession in which contributions to world culture are so clearly on exhibit, so cumulative, and so subject to verification.

Organic Chemical Contributions to the Twenty-First Century

Since discoveries and the testing of concepts feeds on itself, no one can perceive in other than a fanciful way what the next hundred years will bring. Certainly it will be an exciting time in scientific history. I believe that in the twenty-first century, essentially all biological phenomena will be described in physical organic terms. Many infectious and genetic diseases will disappear, or be corrected. I suspect that most organic reactions will be run in water as solvent with synthetic catalysts. Discrete compounds in the 1,000-20,000 molecular weight range will be invented and thoroughly investigated, particularly with respect to their utility in material science. Hundreds of new reactions will be discovered. Most of the elements of the periodic table will be integrated into organic compounds. Instrumentation will, in effect, make small molecules photographable. Computers will be designed in which information storage and retrieval depends on complexation-decomplexation of organic compounds. Many metals will be replaced by organic-inorganic polymers. Gas to polymer reactions will be commonplace. Complete stereospecificity in organic reactions will be realized when needed.

If I had a son or daughter of college age who was intelligent, hard working, enterprising, creative, and liked excitement and intellectual fulfillment, I would strongly recommend that he or she become a research chemist.