Physical-Organic Chemistry: A Swiss Army Knife

“Physical-organic chemistry” is not really about physical chemistry, organic chemistry, or even chemistry. It is a strategy for the design of programs in experimental scientific research – admittedly, a strategy most highly developed for research involving organic molecules as components – that offers a general, and remarkably versatile, method for tackling complex problems. The idea underlying “physical-organic” design is simple: it requires a system that enables one to carry out similar physical measurements on a set of structurally related compounds, to change the structures of these compounds systematically and by design, and to infer the nature of processes of interest from changes in these physical measurements with structure. (It thus differs from physical chemistry, in which one might make a series of measurements at different temperatures, or focus on detailed spectroscopic measurements, but on a single compound.) There is, of course, no sharp line between examining how the variation in an observable correlates with changes in structure, and focusing on the detailed examination of that observable in a single structure (or small group of structures). The physical-organic approach is most useful when sets of structurally related compounds are available through synthesis or isolation (thus its particular utility in studies of organic, organometallic, and biological molecules). It does not exclude programs that include variations in environment (temperature, pH, solvent character), but its emphasis is on the relationships between the structures of molecules of interest and the properties of those molecules. Its beauty is that – within in the constraints of certain assumptions – it provides a simple and conceptually transparent way to isolate the influence of molecular structure on a property or function of interest. Assume that one is interested in a problem in which available – and relevant – physical tools are either limited or cumbersome. Examples of such problems in which we have been interested include the mechanism of formation of Grignard reagents; the wetting of (and adhesion to) the surfaces of organic solids presenting complex functional groups by water, cells, or other organic molecules; the mechanism of tunneling of electrical charge through nanometer-thick organic films; and the role of water in biology. These, and in fact most, scientific problems dealing with complex reality are almost always too complicated to understand using only the information generated by a single, simple approach. As an experimentalist, then, one has a choice: one can take a specific system, and study it in great detail, hoping that “depth” will yield understanding; or one can take a series of related compounds, and look for trends. Physical-organic chemistry is based on the latter strategy. (By analogy, when exploring a new continent, one generally wants to know first where the rivers and mountains are, and only then the details of the local terrain.) It may, for example, be impossibly difficult to understand entirely how cyanide ion, dissolved in a complex solvent containing salts, reacts with methyl chloride; it is, however, practical to ask how the reaction(s) of organic chlorides – whatever its (or their) mechanism(s) – respond(s) to a broad range of changes in the structure of the reactants. What happens when one changes methyl chloride to ethyl-, propyl-, isoAbstract : “Physical-organic chemistry” is the name given to a subfield of chemistry that applies physical-chemical techniques to problems in organic chemistry (especially problems involving reaction mechanisms). “Physical-organic” is, however, also a short-hand term that describes a strategy for exploratory experimental research in a wide range of fields (organic, organometallic, and biological chemistry; surface and materials science; catalysis; and others) in which the key element is the correlation of systematic changes in molecular structure with changes in properties and functions of interest (reactivity, mechanism, physical or biological characteristics). This perspective gives a personal view of the historical development, and of possible future applications, of the physical-organic strategy.