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Cram, Donald J.

CRAM, DONALD J.

(b. Chester, Vermont, 22 April 1919;

d. Palm Desert, California, 17 June 2001), physical organic chemistry.

As a young adult, Cram became enamored of research in chemistry. In the aftermath of World War II, he thrived in the new style of American science: he led a large group of graduate students and postdoctoral associates at the University of California at Los Angeles (UCLA); applied successfully for grants from funding agencies such as the National Science Foundation; and mastered the new instrumentation, such as nuclear magnetic resonance and mass spectrometry. He saw chemistry as an artistic endeavor, heeding the structural lessons offered by natural products in order to improve upon nature. His devising of inclusion complexes for both ground states (equilibrium) and transition states (catalysis) won him the Nobel Prize in Chemistry for 1987 jointly with Charles J. Pedersen and Jean-Marie Lehn. He had successfully joined the powerful new host-guest chemistry which his colaureates had pioneered a few years earlier.

Early Life . Cram was the youngest of four children. At the age of just four, he lost his father to pneumonia, yet he nevertheless enjoyed a bucolic and idyllic childhood, immersed in books. Cram’s mother, with Victorian upper-class English values, taught him to read at four and a half. Cram was a precocious child, curious, self-assured, and troublesome, whose self-education was very American, that of a latter-day Benjamin Franklin. This rawboned New Englander was already fully grown by the age of sixteen: he was six feet tall, weighed 195 pounds, and excelled in competitive sports such as tennis, football, and ice hockey. He also had had eighteen different employers by the age of sixteen, at which time his family dispersed.

Cram became a drifter, first in Florida, then in Massachusetts and New York. He completed his secondary schooling while supporting himself as a manual worker. Having won a four-year scholarship, he returned to Florida for study at Rollins College in Winter Park. Still unfocused, Cram read widely, studying chemistry and philosophy, but he also invested time and energy in extracurricular activities, such as learning to fly an airplane, singing in a choir and a barbershop quartet, acting in plays, and producing-announcing a radio program. During the summers from 1938 through 1941, Cram earned money, first as a salesman in some of the worst neighborhoods of New York City, then as a laboratory analyst for the National Biscuit Company.

Cram’s first college chemistry professor, Guy Waddington, told him he had the stuff of a good industrial investigator, not an academic one. Thus prodded, Cram, with his contrarian spirit, ultimately became a professor of chemistry. He entered the University of Nebraska and obtained his master’s degree in 1942 under the supervision of Norman O. Cromwell.

After Pearl Harbor, Cram (C) went to work for Merck and Co., eventually in its penicillin project. Max Tishler, (T), who became a father figure, recruited him. Their first meeting proceeded in this manner : “T: So you are interested in doing research? What can you do?/C: In my master’s work at Nebraska, I worked on rearrangements of…/T: What is the base-catalyzed condensation of benzaldehyde and acetophenone?/C: Benzalacetophenone—I made a ton …/T: Why are you here without your Ph.D.?/C : My draft board told me to leave school and get a job to aid the war effort. I fully intend to return to …/T: As far as I am concerned, you are hired.”

Immediately after the war ended, Tishler arranged for Cram (C) to enter Louis F. Fieser’s laboratory at Harvard University; eighteen months later, Cram had obtained his PhD. After a short, three-month stint as a postdoctoral fellow in John D. (Jack) Roberts’ laboratory at the Massachusetts Institute of Technology, he went in 1947 to UCLA, again as a postdoctoral fellow, with Saul Winstein, who became a mentor to Cram. Cram remained at UCLA, rising through the ranks to become a full professor in 1956.

Researcher and Educator . Winstein, Roberts, Paul D. Bartlett, and a few others brought American physical organic chemistry to a level of excellence that eventually surpassed that of the pioneering British school of Christopher K. Ingold and Edward Hughes. The mainstay of this American accent was the synthesis of novel molecules tailor-made for testing working hypotheses or new principles. The sheer number of molecules that Cram’s group synthesized over the duration of his career is very impressive, more than ten thousand by his own count.

Winstein became not only a colleague of Cram’s, but a trusted friend and a competitor. Their joint evening seminar became legendary. It lasted for hours and the presenter would be submitted to a harsh and relentless stream of questions and comments. The aggressivity was not personal; its only aim was to ascertain the reliability of the results and their importance. Those seminars brought to the fore Cramo’s qualities as a pedagogue, a critical and quick thinker who had an encyclopedic knowledge of organic chemistry. They also expressed a playfulness that was as basic to his personality as was his extreme competitiveness.

Cram took very seriously his responsibilities as an educator. He would disseminate in classrooms the new knowledge he was acquiring in the laboratory. Something of an iconoclast, Cram would challenge established wisdom whenever he felt it was mistaken. When both he and George S. Hammond were postdoctoral fellows at UCLA, they resolved to reform and update the teaching of organic chemistry. Instead of cataloging reactions in the traditional manner in terms of reactants, reaction conditions, and products, they emphasized mechanisms, based on recently established knowledge. Rationality would supersede empiricism.

Their joint textbook, titled simply Organic Chemistry, like the manual by Fieser it was intended to replace, appeared in 1959. Its very organization set it apart from its predecessors. It started with the structure of organic compounds, their nomenclature, and their grouping into major classes. Proceeding logically, its ensuing chapters presented a modern treatment of chemical bonding, stereochemical definitions, and graphical representations, followed by correlations between structure and equilibrium properties or chemical reactivity. These early chapters served to introduce reaction mechanisms. Moreover, the “Cram and Hammond” (as it became known among chemists) did not shy away from topics earlier deemed difficult or too specialized, such as molecular rearrangements, heterocyclic chemistry, polymers, and spectroscopy.

This text won a large measure of peer respect for its authors and it did well in sales. But its lasting value was not commensurate. It failed to make as durable, as deep an impact as, say, Linus C. Pauling’s General Chemistry(1944), to which it can validly be compared. The underlying reason was, in retrospect, that the predominant audience for organic chemistry was found in service courses rather than in classes intended for chemistry majors. Starting in the 1960s, American undergraduate students took organic chemistry during their sophomore year. For a great number, it was an inescapable prerequisite for application to medical school.

To many among these premedical students, Cram and Hammond was too confusing, packed as it was with, to them, bewildering information. They needed lighter fare. Accordingly, their instructors favored a competing manual, Organic Chemistry (1959), by Robert Thornton Morrison and Robert Neilson Boyd, surely less hearty and less sapid, but an easier read and much easier to ingest by rote memorization—its authors had seen to it by building in systematic repetition. “Morrison and Boyd” became the standard. Nonetheless, with his usual energy, that of the apostle intent on spreading the faith, Cram would go on to write a few other textbooks in subsequent years.

Cram’s Rule . If innovative in teaching and textbooks, following Pauling’s lead, Cram ambitioned to become a research leader in physical organic chemistry. Winstein, his mentor and colleague, privileged the topic of reaction mechanisms and the tool of kinetics. Cram had thus to find another niche for himself. He chose to devise new molecular structures, with a stereochemical outlook. Paul-ing’;s influence was again blatant.

Crams entry into academic research was marked by his serendipitous discovery of the phenonium ion rearrangement. Upon loss of a leaving group from a reactant dissolved in a highly polar solvent, assistance could be provided by an adjacent benzene ring within the reactant molecule, which would provide some of its mobile (electrons to compensate in part for the electronic deficiency at the carbon losing the departing group. This aromatic ring would thus bridge the two adjacent carbons, the one it was originally bonded to and that which had borne the departing group, forming a so-called phenonium ion:

Cram had analyzed for this purpose the products from solvent-induced ionization of the isomeric L- threo and erythro-3-phenyl-2-butyl tosylate. He proposed a phenonium ion intermediate of the type described above. Winstein came to his support with kinetic data for this reaction, demonstrating rate acceleration from participation of the neighboring benzene ring.

A controversy ensued. Herbert C. Brown questioned the intermediacy of a nonclassical, bridged phenonium ion in these processes. Both rate enhancement and product stereospecificity had to be explained. While Cram proposed a bridged structure that prevented nucleophilic attack from one side, Brown countered that the same result could come from a “windshield wiper” effect caused by rapid 1,2-phenyl shifts. The difference between the two models is mostly a matter of language. Even Browns classical cations are stabilized through hyperconjugation.

The ion-pair phenomena encountered in carbocation stereochemistry led Cram to pose the general question of the stereochemical capabilities of carbanions. This led him to discover phenomena that, with his taste for lexical invention he termed isoinversion, conducted tour mechanism, and ion-pair reorganization. It also allowed him take advantage of stabilization of a carbanionic center by an adjacent sulfur atom.

Chemists use the term asymmetric induction to describe the transfer of molecular asymmetry, with its attendant physical property of rotatory power, from a preexisting chiral molecule or chiral center to a newly forming chiral molecule or center. In 1951 Vladimir Prelog of the Eidgenössische Technische Hochschule in Zürich proposed a rule for predicting the stereochemical outcome of addition of nucleophiles, Nu: (that is, an atom or a group of atoms Nu bearing an electronic lone pair) to (-keto esters. Prelogs rule predicted the stereoselectivity in this addition from an intuitively satisfactory arrangement of the alkyl substituents and the trans-coplanar carbonyl C=O groups.

In 1952 Cram and his coworker, Fathy Ahmed Abd Elhafez, published a paper, “Studies in Sterochemistry,” that presented their rule of “steric control of asymmetric induction in the synthesis of acyclic systems.” They based it on much earlier work, dating to the beginning of the twentieth century by a Frenchman, Marc Tiffeneau, and a Scot, Alexander McKenzie. Whereas Prelog had investigated a similar problem, he had concerned himself with systems in which the chiral centers, inducing and induced, bore a 1,4 relationship to one another. Cram’s Rule had premises and made predictions similar to Prelog’s.

Cram and Elhafez examined nucleophilic addition to the carbon atom of a carbonyl group adjacent to (1,2 relationship) a chiral center that consisted of a carbon atom bearing three different substituents, ranked small, medium, and large according to their relative bulk. Cram’s rule was “that diastereoisomer will predominate which would be formed by the approach of the entering group [Nu:] from the least hindered side of the double bond when the rotational conformation of the C-C bond is such that the double bond is flanked by the two least bulky groups attached to the adjacent asymmetric center.” (See Figure 1.)

Cram’s rule predicted the major stereoisomers produced in more than two dozen reactions. It was a convenient and a rather empirical mnemonic. In Cram’s own words (written in December 1977), “the explanation offered is reasonable, arbitrary, unprovable, and provocative.”

This last adjective, nicely consonant with Cram’s personality, was indeed well chosen. Among the numerous organic and theoretical chemists who rose to the challenge posed by this conjecture, predicting the stereochemical outcome of C=O addition reactions, were John Corn-forth, Hugh Felkin, Nguyen Trong Anh, Odile Eisenstein, Piotr Cieplak, and Shuji Tomoda.

Cram’s rule expressed its author’s familiarity with molecular models, the inferences he made from a close examination of their features, and his erudition about the major reactions of organic chemistry showing asymmetric induction. Which brings up a key issue: the role of molecular models in Cram’s thinking about organic molecules and their reactivities—in this case the stereochemical bias responsible for an observed stereoselectivity.

CPK Models as Inspiration . Some of Cram’s former coworkers, when queried about his singularity as a scientist, gave pride of place to his reliance on CPK molecular models. Cram himself emphasized how important they had been to his thinking during the planning stages in his research. Those models were made initially of hard wood (1 inch per angstrom) and plastic (0.5 inch per angstrom). Individual atoms were shaped as spheres or portions thereof, with a radius proportional to van der Waals radius. Wooden atoms were connected by steel rods and clamps, plastic atoms with snap fasteners. CPK models embodied the detailed structural knowledge that Pauling had accumulated, by the end of the 1930s, from his numerous determinations of molecular structures using x-ray crystallography and electron diffraction.

CPK models had originated in 1960 within the U.S. National Institutes of Health’s biophysics and biophysical chemistry study section. Its members had given their principal consultant, Walter L. Koltun, the responsibility of convening an ad hoc committee to design and develop new models for biological molecules and macromolecules based on the earlier ones devised by Robert B. Corey and Pauling. Hence, the newer variety became known as CPK models. By comparison with the earlier CP models, they were not only lighter, but more accurate in their bond angles because of their increased rigidity and better connectors, which Koltun had devised.

These space-filling (or compact) CPK models contrasted with the skeletal, ball-and-stick models. The former aim at realism with respect to the overall molecular shape, the latter are a three-dimensional rendition of the molecular formula. These representations complement one another. In the 1960s, every organic chemist used skeletal models. The version devised by André S. Dreiding from the University of Zürich was ubiquitous and to be seen in many offices. Conversely, only the best-funded research groups could afford a set of the considerably more expensive CPK models.

Crams recourse to the latter is instructive in two ways. His imagination was highly visual. He handwrote more than four hundred manuscripts for scientific publications and also handsomely illustrated them. The figures Cram devised for his articles and communications would usually be quite eloquent, telling the story independently of the text.

On the other hand, CPK models originated in molecular biology. Cram’s forte was to borrow an idea from the album of nature and run with it until he scored. For example, he would scrutinize the structural details of an enzymatic binding site and then design biomimetic synthetic analogues to explore all the consequences of a given arrangement.

As he wrote in his Nobel lecture (and note his nautical metaphor),

from the beginning, we used Corey-Pauling-Koltun (CPK) molecular models, which served as a compass on an otherwise uncharted sea full of synthesizable target complexes. We have spent hundreds of hours building CPK models of potential complexes, and grading them for desirability as research targets. Hosts were then prepared by my co-workers to see if they possessed the anticipated guest-binding properties. Crystal structures of the hosts and their complexes were then determined to compare what was anticipated by model examination with what was experimentally observed. (Cram, 1992, p. 420)

One may add here, in a more speculative but nevertheless equally relevant vein, that Cram’s playfulness was very much in evidence when he put together a mole

cule from the CPK building blocks. This highly time-consuming activity resembles that of a child with tinker-toys such as Lego, or an Erector set (Meccano). In doing this activity, Cram behaved as a genuine molecular architect, relying, as is the wont of architects, on three-dimensional mock-ups built to scale. To Cram, the CPK models not only bridged biochemistry and organic chemistry, the natural and the artificial, they also bridged his mental imagining of molecules and their actualization, first in laboratory flasks, second as crystal structures obtained from x-ray diffractometry.

It is no accident that Cram opted for a career in chemistry. This science had a Promethean, transgressive appeal for him. To be able to circumvent natural rules and obstacles, to impose one’s will upon matter, to sculpt it into one’s own imaginings, was the type of undertaking he relished. Forcing molecules into his preconceptions gave him the utmost satisfaction.

Cyclophanes and Inclusion Complexants . Thus, Cram’s next big research topics was cyclophanes—significantly, he coined that name. These are molecules in which two or more aromatic rings are bridged in such a manner as to bring them into close contact and interaction. For instance, [2.2]paracyclophane is a molecule in which two benzene rings are held face-to-face by opposite bridges consisting each of two methylene CH2 units. Such close contact brings together the clouds of φ electrons associated with each benzene ring; then, φ-φ complexes can be shown to occur. If, to give an example, a molecule of tetracyanoethylene withdraws φ electrons from one of the benzene rings, the electronic deficiency is partly compensated by donation of φ electrons from the second benzene ring:

After Charles J. Pedersen had published his serendipitous production of crown ethers, reporting on their cation-complexing abilities (1967), after Jean-Marie Lehn had synthesized his cryptands and publicized their uncanny aptitude at selectively encapsulating metallic ions (1969), Cram decided around 1970 to enter this new field. To Cram, this supramolecular chemistry, as Lehn had named it, was immensely engaging. It was challenging, broke new ground, and required big resources, both human and material. It upstaged nature and promised to rival enzymatic processes in their speed and efficiency. In brief, Cram saw the opportunity for a culmination to his career. He entered the new area with characteristic determination and vitality, and by 1980, he had already published around fifty papers on it. An early accomplishment was chiral catalysis of the Michael addition, achieving 99 percent stereospecificity.

Cram’s style of supramolecular research started with biomolecules: “The biotic world is such a wonderful world; it shows what can be done,” he said. He would put together, for instance, a molecule with the same kinds of functional groups and in the same arrangements as in the enzyme αchymotrypsin, with a view to seeing if it would catalyze trans-acylation. As always, he relied on CPK models when designing these new molecular types.

For this host-guest chemistry, Cram defined topologically a host (guest) as having convergent (divergent) binding sites. Another principle of his, arguably his main contribution to this field, was preorganization, that is, hosts already showing holes of various sizes, held open within a rigid framework, typically one containing rigid and planar benzene rings. This ensured that binding of guests was less energy-demanding. But creating them was not an easy task. As Cram remarked, “holes don’t like to exist,” a twentieth-century variant of the ancient adage, “nature abhors a vacuum.” He had not only to contend with sometimes lengthy and sophisticated syntheses, and with van der Waals forces both attractive and repulsive; he also had to convince his sometimes skeptical coworkers of the feasibility of some revolutionary-looking molecular construct. In Crams words, “they were pessimistic about our finding ways of preparing carcerands. However, when a literature search revealed that (some) derivatives were already known and easily made, they warmly endorsed the carcerand concept” (Cram, 2001).

Cram’s contribution was a numerous manifold of increasingly complex host systems capable of binding molecules, not only ions, that emulated enzymatic sites. The carcerand concept was a generalization of his initial devising of “spherands,” that is, guests with cation-binding oxygen atoms preset in an octahedral array (see Figure 2). Some of Cram’s hosts were capable of enantiomeric recognition and were thus applicable to resolution of racemic mixtures.

Hemicarcerands have a small gap in the wall of the carcerand. Molecules can travel through this gap only if the temperature is high enough. Once inside, however, the molecules cannot escape if the temperature has been lowered. The ultimate test of hemicarcerands came when Cram allowed a molecule of αpyrone to enter the carcerand cage. Inside, the αpyrone was photochemically

converted into cyclobutadiene and carbon dioxide, which escaped (see Figure 3). Cyclobutadiene is normally so highly reactive that it can neither be isolated nor studied. Cram’s carceplex, however, kept it from reacting for quite long periods and allowed the molecule to be observed spectroscopically for the first time. This was possibly, Cram’s finest result.

In 1979 Orville L. Chapman, a fellow professor of Cram in the UCLA Department of Chemistry, revealed privately that he was lobbying the Nobel Committee on behalf of a Cram-Lehn ticket. The lobbying would bear fruit in 1987.

A hard worker, Cram enjoyed life to the full. As a transplant to Southern California, he loved to take advantage of the sunny, seasonless climate. He played a mean game of tennis, having trained with the top tennis coach at UCLA. His zest for challenges of any kind caused him to embrace other sports in which he would set ambitious goals for himself and then proceed to meet them. He went downhill skiing in the Sierras, swam numerous laps in the UCLA pool, and sailed as well. Perhaps his favorite sport was surfing on the nearby beaches. It was a passion that he related to his other passion—chemistry. In both those avocations he yearned to be or feel “on the crest of a wave.”

BIBLIOGRAPHY

WORKS BY CRAM

With Fathy Ahmed Abd Elhafez. “Studies in Stereochemistry.’ 10. The Rule of ‘Steric Control of Asymmetric Induction’ in the Synthesis of Acyclic Systems.” Journal of the American Chemical Society 74 (1952): 5825–5835.

With George S. Hammond. Organic Chemistry. New York:McGraw-Hill, 1959.

Fundamentals of Carbanion Chemistry. New York: Academic Press, 1965.

Letter to Citation Classics, no. 11 (13 March 1978): 248. Available from http://www.garfield.library.upenn.edu/classics1978/A1978EM93500002.pdf.

Interview by Leon Gortler. 14 January 1981. Transcript, Chemical Hertitage Foundation, Philadelphia, PA.

“Preorganization—From Solvents to Spherands.” Angewandte Chemie International Edition in English 25 (1986): 1039–1134.

From Design to Discovery. Profiles, Pathways and Dreams: Autobiographies of Eminent Chemists series, edited by Jeffrey I. Seeman, Washington, DC: American Chemical Society, 1990.

“The Design of Molecular Hosts, Guests, and Their Complexes.” In Nobel Lectures, Chemistry 1981–1990, edited by Bo G. Malmström. Singapore: World Scientific Publishing, 1992. Contains his 1988 Nobel lecture.

With Martin E. Tanner and Robert Thomas. “The Taming of Cyclobutadiene.” Angewandte Chemie International Edition in English 30 (1991): 1024–1027.

With Siavash K. Kurdistani and Roger C. Helgeson. “Stepwise Shell Closures Provide Hosts that Expose or Protect Guest from Outer-phase Reactants.” Journal of the American Chemical Society 117 (1995): 1659–1660.

With T. A. Robbins. “Comparisons of Activation Energies for Guest Escapes from the Inner Phases of Hemicarcerands with Varying Numbers of Bowl-Linking Groups.” Journal of the Chemical Society, Chemical Communications (1995): 1515–1516.

With Roger C. Helgeson, Kyungsoo Paek, Carolyn B. Knobler, et al. “Guest-Assisted and Guest-Inhibited Shell Closures Provide Differently Shaped Carceplexes and Hemicarceplexes.” Journal of the American Chemical Society118 (1996): 5590–5604.

With Juyoung Yoon. “The First Water-Soluble Hemicarceplexes.” Journal of the Chemical Society. Chemical Communications (1997): 497–498.

With Roger C. Helgeson and Carolyn B. Knobler. “Correlations of Structure with Binding Ability Involving Nine Hemicarcerand Hosts and Twenty-four Guests.” Journal of the American Chemical Society 119 (1997): 3229–3244.

“Donald Cram Speaks on His Research Philosophy.” (2001). Available from http://www.chem.ucla.edu/research/org/CRAM/Cram_RschPhil.html.

OTHER SOURCES

Franklin, James. “Diagrammatic Reasoning and Modelling in the Imagination: The Secret Weapons of the Scientific Revolution.” In 1543 and All That, edited by Guy Freeland and Anthony Corones. Dordrecht, Netherlands, and Boston: Kluwer, 2000. While Cram is not mentioned, this is an excellent paper on the seminal role of models for scientists.

Hawthorne, M. Frederick. “Obituary: Donald J. Cram (1919–2001).” Nature 412 (2001): 696.

Pierre Laszlo

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