Biographical Essay: A. Jerry Kresge JOHN P. RICHARDa and RORY MORE O’FERRALLb a

Department of Chemistry, University at Buffalo, SUNY, Buffalo, NY 14260-3000, USA b School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland

1

Introduction

Jerry Kresge was born in Kingston, Pennsylvania on July 17, 1926. His parents had arrived as teenagers in Kingston before World War I, with their own parents, as immigrants from Poland. Jerry and his younger sister Rita received good educations and were undergraduates at Cornell University and the University of Pennsylvania, respectively. Jerry’s university education was interrupted by a year in the navy stationed in San Francisco and he graduated with a B.A. degree in 1949. Four years later, he received his Ph.D. degree from the University of Illinois under the direction of Nelson J. Leonard. His Ph.D. training focused on synthetic organic chemistry, and led to three publications in the Journal of the American Chemical Society,1–3 with the first appearing in 1955. The paper was entitled The Influence of Steric Configurations on the Ultraviolet Spectra of ‘‘Fixed’’ Benzils.1 It is interesting to note that a coauthor on this paper, Michinori Oki, moved on to a distinguished career of his own in Japan. Jerry was strongly influenced by a reaction mechanisms course taught at Illinois. His attraction to this subject led to a scholarship to support a 1-year stay at University College London to work with Hughes and Ingold. These two chemists were then at the peak of their careers, but London was recovering from World War II. Meat was scarce, central heating a rare luxury, and University College was still undergoing repair of substantial damage from aerial bombing during the war. Jerry’s year at London did not result in any research publications, but it set a course that would establish him as one of the leading disciples of the Hughes–Ingold school of chemistry. Kresge then moved to a postdoctoral position with H. C. Brown at Purdue University, which in this combative heyday of physical organic chemistry might have been considered a rival camp to the Hughes–Ingold school. Jerry xiii

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claims to have worked nights to reduce the extent of his supervision by Brown. Nevertheless, his studies with Brown on aromatic mercuration helped lay a foundation for later studies on acid-catalyzed exchange reactions of tritiumlabeled aromatic compounds. Kresge then moved to work as a postdoctoral fellow in the laboratory of Gardner Swain at MIT. During this time he developed great respect for his mentor, and an appreciation of the power of integrated kinetic and product studies to provide original insight into reaction mechanisms. Kresge’s first independent position was in the Brookhaven National Laboratory, where he learned to sail on Long Island Sound. Brookhaven provided a ready supply of the hydrogen radioisotope tritium, which Jerry exploited in studies of the loss of a tritium label to monitor reaction kinetics, a method to which he had been introduced while working with Gardner Swain.4 R.M.O.F. recalls the excitement with which his Ph.D. supervisor John Ridd related Kresge’s studies on exchange of tritium from labeled trimethoxybenzene to hydroxylic solvents, and the catalysis of this reaction by relatively weak general acids through the strongly stabilized arenium ion reaction intermediate (Scheme 1).5–8 With the characteristic clarity that is a hallmark of Kresge’s papers, this work dispelled muddled thinking which had invoked p-complexes between the attacking proton and aromatic molecule as reaction intermediates. Jerry moved from Brookhaven to the Illinois Institute of Technology (IIT) in Chicago, where he quickly established an active research group. The Chemistry Department at IIT flourished in the 1960s mainly from the influence of a remarkable Chair, Martin Kilpatrick, who had worked with Brønsted and was therefore well able to appreciate the importance of Kresge’s work and its scope for future development. Jerry was one of several distinguished physical organic chemists who spent the early stages of their careers at IIT. Saul Winstein worked there for a year and Myron Bender was on the faculty for several years before moving across town to Northwestern University. IIT had a small but good undergraduate school in chemistry that benefited from the quality of Kresge’s lectures. These were clear, well-prepared, and delivered with a slight stutter which enhanced rather than detracted from their effect. Lectures at that time were delivered using chalk and blackboard. Students appreciated Kresge’s board work, written in a fine hand and while

Scheme 1

BIOGRAPHICAL ESSAY: A. JERRY KRESGE

xv

speaking without hesitation. His ability as a teacher was not confined to the lecture room. R.M.O.F. can testify to personal conversations as a postdoc at IIT on topics as varied as isotope effects, organic reaction mechanisms, and statistical thermodynamics. Jerry relished the exchange of information in these conversations. At the same time, he could be less patient with students falling too far short of his own fairly exacting standards, and he was strict in requesting regular written progress reports from his coworkers. Yvonne Chiang worked with Jerry at Brookhaven Laboratory as a research assistant. They married in 1963 and were together for more than 40 years, until Yvonne’s death in April of 2008. Yvonne and Jerry were full partners in chemistry, at work and at conferences in Canada, the United States, and around the world. Unassuming personally but possessing intelligence and drive, Yvonne provided Jerry’s laboratory with a steady guiding hand. She either carried out or supervised many of the critical experiments in this laboratory and she was responsible for training new personnel in the use and maintenance of laboratory instrumentation. Yvonne’s nearly 50-year collaboration with Jerry resulted in more than 130 jointly authored publications. Of their two children, Nicole has followed in the footsteps of her parents and has taken a Ph.D. in biochemistry from the Scripps Research Institute, but Peter struck an independent path in business and finance. In 1970–1971 Kresge spent a sabbatical year at the University of Toronto. After returning to IIT, he was persuaded to return to Toronto in 1974 where he joined the Chemistry Department of the then new satellite campus of Scarborough College. Jerry was senior among an outstanding group of physical organic chemists at the Scarborough campus, including R. A. McClelland and T. T. Tidwell. The additional presence of Keith Yates and Ronald Kluger at the downtown St. George Campus resulted in a 20-year span, when Toronto was arguably the Americas’ premier center for physical organic chemistry. Jerry worked at Toronto as full professor of chemistry until 1992, at which time he was relieved of his teaching responsibilities by a mandatory ‘‘retirement.’’ His vigorous program of research has continued as an emeritus professor and he has published more that 100 research papers, reviews, and short commentaries since 1993, with the most recent appearing in 2008,9 53 years after his first publication with Nelson Leonard. Several eminent physical organic chemists – E. D. Hughes, C. K. Ingold, H. C. Brown, and C. G. Swain – trained Jerry Kresge. Work by these teachers defined the scope of physical organic chemistry during the 1950s, and Kresge had authored 20 papers by 1963, the year of publication of Volume 1 of Advances in Physical Organic Chemistry edited by Victor Gold. These early publications contain the seeds of ideas that Jerry nurtured and developed into the next millennium. For example, a study of the base-catalyzed reaction of 2alkylaminoethanols with acrylic and methylacrylic esters10 marked the beginning of a lifetime of interest in the mechanism of Brønsted acid–base catalysis and in the meaning of the Brønsted coefficients a and b for these catalyzed

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reactions. An early study of the effect of deuterium and tritium substitution at the a-CH3 group of toluene on the relative rates of electrophilic aromatic mercuration, nitration, and bromination reactions,11 initiated a long-standing interest in kinetic isotope effects. This led to the study on the mechanism of acid-catalyzed aromatic hydrogen exchange of 1,3,5-trimethoxybenzene referred to above (Scheme 1), Kresge’s first examination of a slow proton transfer reaction at carbon.12 He subsequently characterized the general mechanism for slow proton transfers in detail, through the determination of kinetic isotope effects and Brønsted coefficients for catalysis by general bases. Jerry’s early studies have been expanded over the years into the body of work that is being honored in Volume 44 of Advances in Physical Organic Chemistry. Each of seven primary contributors to this volume has been strongly influenced by Jerry’s many contributions to chemistry, and each has published work that in some way represents an extension of earlier results reported by the Kresge laboratories. It is interesting that while Kresge directly supervised none of these contributors, four have coauthored papers with him. The collaborative work described covers a diverse range of topics, and is a testament to Jerry’s wide interests in chemistry and biology. A full description of the results and conclusions from the more that 350 publications from Kresge’s laboratory is beyond the scope of this introductory essay. However, several of Jerry’s seminal contributions will be discussed within the context of their effect on recent work from J.P.R.’s laboratory.

2

Solvent deuterium isotope effects

Jerry Kresge has published a wide range of studies of primary and secondary isotope effects on organic reactions.6,13–20 However, his seminal contributions have been to the study of solvent deuterium isotope effects, and subsequent work in this area by many different investigators has been built upon the foundations laid down by Kresge. Solvent deuterium isotope effects were first examined in the 1930s, but the number of significant applications of this work to organic chemistry remained small for more than 20 years and there were essentially no applications to biochemistry. This is partly because the field was mired in complex notation and vocabulary that few people understood well enough to undertake studies in D2O or mixed H2O/D2O solvents. When Jerry entered this field, he set about simplifying the mathematical treatment to reduce terms, such as fractionation factor, to readily understood concepts with concrete underlying physical bases. He then illustrated the use of solvent isotope effects in the solution of mechanistic problems, such as the separation of contributions from primary and secondary isotope effects to the observed solvent deuterium isotope effects on Brønsted general acid–base catalysis by lyonium and lyoxide ions. Dick Showen has credited Kresge’s review in Pure and Applied Chemistry21 with providing critical insight that

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allowed his own group to develop mixed-solvent isotope effects as a probe for the mechanisms of enzyme-catalyzed reaction.22,23 1 ½SH  ðxÞ ¼ ðPIEÞAL ¼ FTS ½SD  ð1  xÞ

ð1Þ

1 ½AHðxÞ ¼ FAL ½ADð1  xÞ

ð2Þ

ðKIEÞAL ¼



kAH kAD



¼



K  KAD



¼

FAL ¼ FAL ðPIE Þ AL FTS

ð3Þ

Kresge’s systematic interpretation of solvent isotope effects laid the ground work for J.P.R.’s recent study of the effect of changing reactions driving force on the product deuterium isotope effects on protonation of ring-substituted aryl vinyl ethers by substituted acetic acids in 50/50 (v/v) HOH/DOD ([HOH]/ [DOD] = 1.0, Scheme 2).24,25 The ratio of the yields of the hydrogen- and deuterium-labeled products from reactions in this solvent [(PIE)AL] is equal to the fractionation factor 1/FTS for partitioning of H and D between the solvent and the reaction transition state [Equation (1)]. Combining 1/FTS with the fractionation factor 1/FAL [Equation (2)] for the acid catalyst gives the isotope effect on protonation of carbon by the Brønsted acid [Equation (3)]. The interpretation of the ratio of second-order rate constants for the lyonium ion-catalyzed reactions in pure HOH (kH) and in DOD (kD) is more difficult, because of the large secondary solvent deuterium isotope effects on the acidity of L3Oþ.26 However this can be dealt with using the framework developed in other laboratories and clarified by Kresge’s writings.27

Scheme 2

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3

J.P. RICHARD AND R.M. O’FERRALL

Brønsted coefficients

Logarithmic plots of rate constants for general acid- and base-catalyzed reactions against the pKa for the acidic form of the catalyst are generally linear with slopes of –a and b for acid and base catalysis, respectively. The values of these Brønsted coefficients depend upon the overall reaction driving force, and reflect the extent of proton transfer from the catalyst to the substrate at the reaction transition state.28 Strongly favorable Brønsted acid-catalyzed reactions (DG > 0) are characterized by large Brønsted coefficients a and product-like transition states (Scheme 3c).  2 DG  !r þ !p DG{ ¼ !r þ L 1 þ 4L

ð4Þ

  @DG{ @log kHA ðDG Þobsd  !r þ !p ¼  ¼ a ¼ 0:5 þ @DG @pKHA 8L

ð5Þ

@a @ 2 log kHA 2:303RT ¼ ¼ @pKCH 8L @pKHA @pKCH

ð6Þ

Kresge recognized that the first derivative of the simple Marcus equation [Equation (4)] is equal to the Brønsted coefficient a for a general acidcatalyzed reaction so that a depends on both the reaction driving force DG and the intrinsic barrier L [Equation (5)], which is often taken to be DG{ for the appropriate thermoneutral proton transfer reaction (DG = 0).29,30 The change in a with changing basicity of the reacting Brønsted base is the second derivative of the Marcus equation [Equation (6)]. Equation (6) shows that there is a simple relationship between the magnitude of the change in the

(b)

(a)

ΔG° > 0

BIOGRAPHICAL ESSAY: A. JERRY KRESGE (a) − Large Λ

(b) − Small Λ

BH:C

Λ1 BH :+C

xix

B + HC

BH + :C

ωr

Λ2

B HC ωp B + HC

Scheme 4

Brønsted coefficient a with changing driving force and the intrinsic barrier L. Jerry has used this relatively simple Marcus treatment of Brønsted coefficients, and a related treatment of primary kinetic isotope effects, extensively in analysis of kinetic data for proton transfer reactions in aqueous solution and at enzyme active sites.17,31–33 The change in the Brønsted coefficient a with changing driving force is small when the intrinsic barrier L is large (Scheme 4a), but this coefficient will change sharply with changing driving force when L is small (Scheme 4b). Conversely, it is possible to determinine the value of L as the slope of a correlation of Brønsted a against reaction driving force. J.P.R. has expanded upon this analysis and partitioned the observed barrier DG{ for thermoneutral protonation of aryl vinyl ethers by carboxylic acids into the intrinsic reaction barrier L and the work terms wR and wP, respectively, for formation of the complex between reactants and breakdown of the complex between products.34,35

4

Generation of reactive intermediates by laser flash photolysis

Until the late 1970s there were few experiments to directly characterize the lifetimes of carbocations, enols, enolates, ynols, ketenes, and other reactive intermediates. The stability of these intermediates could be inferred by making the assumption that the kinetic activation barrier for generation of the intermediate is similar to the thermodynamic reaction barrier. This assumption fails badly when there is a significant kinetic barrier to the reverse reaction of the intermediate to reform the reactant. For example, the barrier to exchange of a-hydrogen of ethyl thioacetate for deuterium from the solvent by ratedetermining formation of the thioester enolate (Scheme 5)36 will be substantially larger than the thermodynamic reaction barrier, if there is a substantial barrier to protonation of the enolate for reaction in the microscopic reverse

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J.P. RICHARD AND R.M. O’FERRALL

Scheme 5

direction. While it is possible to draw inferences about the barrier for protonation of reactive carbanions from the results of studies of the deuterium exchange reactions of their precursor carbon acids,37,38 these are a poor substitute for barriers determined by direct measurement of reaction rate constants. In the early 1980s, Jerry Kresge established a fruitful collaboration with Jakob Wirz at the University of Basel. This collaboration combined Wirz’s expertise in photochemistry and his mastery of the methods for generation of reactive intermediate by flash photolyis with Kresge’s knowledge of the protocols for determining complex kinetic mechanisms for acid- and basecatalyzed reactions in aqueous solution and his insight into the intermediates that would prove of greatest interest to the communities of organic chemists and biochemists. Kresge and Wirz were the first to use laser flash photolysis to generate the enol of acetone in water by the Norrish type II process shown in Scheme 6a, and to monitor protonation of this enol by solvent and other Brønsted acids.39 Their thorough characterization of the kinetic parameters for acid- and basecatalyzed protonation of the enol of acetophenone in water is worthy of close examination by anyone who aspires to use kinetics as a probe for organic and biochemical reaction mechanisms.40 In time, Kresge, Tidwell, and McClelland acquired flash photolysis instrumentation for their laboratories in Toronto. This led to a remarkably creative period of research punctuated by the characterization of intermediates of fundamental importance to organic chemistry and biochemistry. Kresge’s work focused on enols of ketones (Scheme 6a)39,40 and carboxylic acid derivatives (Scheme 6b),41,42 ynols (Scheme 6c),43 ketenes (Scheme 6c),44 and quinone methides.45,46 While Jerry Kresge was an extremely hard worker, he knew how to relax. A good raconteur, he enjoyed dining with friends, especially like-minded chemists. He and Yvonne both dressed in memorably stylish manner. Jerry lived close to work when he first moved to Chicago and did not own a car there until 1964, when a graduating Ph.D. student (John Jones, subsequently a lecturer in the University of Ulster in Northern Ireland) offered to sell him a 15-year-old Mercury saloon for $25. Jerry beat down this offer to $17.50 and drove the car for several years before purchasing the then new Mercedes Pagoda Roadster while on sabbatical in Oxford in 1967. In later years, he reverted to a saloon style better suited to family use but kept his loyalty to the Mercedes or Lexus brand.

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Scheme 6

Jerry appreciated good wine and was disadvantaged by the restrictive nature of Canada’s liquor laws and the dismal selection of wines provided by the Ontario Liquor Board. He would typically bring back with him from his trips to the United States several bottles of French or Californian wines. The custom officials were either blind, or willing to turn a blind eye, until one day they insisted on confiscating an entire case of bottles. Unable to bear the thought of this wine being enjoyed by anyone other than himself or friends, Jerry poured the contents of these bottles down the nearest drain. In compensation, he enjoyed taking advantage of the availability of Cuban cigars in Canada. Jerry liked to quote Mae West: ‘‘Too much of a good thing can be wonderful’’! In truth, his commitment as a bon viveur was limited, perhaps because of Yvonne’s wise guidance and gentle hand (‘‘enough is enough’’). He retains today the slim and scholarly aspect of his youth. Lunch with Yvonne usually consisted of an apple and cheese and crackers consumed in the office and accompanied by discussions to devise the key experiment for the afternoon’s work. While at Scarborough, they both worked a garden allotment close to the campus, which at first was close to the city limits. Apart from their own vegetables, they made good use of asparagus growing as a weed from a previous occupant’s overplanting. Notwithstanding his commitment to teaching and research, Jerry was and is a family man first. At home in Toronto he is closely engaged with family and, as befits a scholar, he reads widely from the best works of contemporary nonfiction and fiction.

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In 2007 the Canadian Institute of Chemistry marked Kresge’s 80th birthday with a symposium at which many friends and collaborators presented lectures. At last, following Yvonne’s death, Jerry closed his lab in 2008 and has since lived in more conventional retirement, visiting the Chemistry Department only occasionally, spending time with his grandchildren and being visited, occasionally too, by old friends from around the world. Long may this continue.

Acknowledgments We thank Nicole Kresge, the daughter of Yvonne and Jerry, for reading this chapter and sharing with us several memories of her parents. J.P.R. acknowledges the National Institutes of Health (GM 39754) for generous support of the work from his laboratory described in this essay.

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28.

Leonard NJ, Kresge AJ, Oki M. J Am Chem Soc 1955;77:5078–83. Leonard NJ, Little JC, Kresge AJ. J Am Chem Soc 1957;79:6436–42. Leonard NJ, Little JC, Kresge AJ. J Am Chem Soc 1957;79:2642–6. Swain CG, Kresge AJ. J Am Chem Soc 1958;80:5281–3. Kresge AJ, Chiang Y. J Am Chem Soc 1959;81:5509–10. Kresge AJ, Satchell DPN. Tetrahedron Lett 1959;13:20–3. Kresge AJ, Chiang Y. J Chem Soc 1961;81–2. Kresge AJ, Chiang Y. J Am Chem Soc 1961;83:2877–85. Kolmakov KA, Kresge AJ. Can J Chem 2008;86:119–23. Sims HJ, de Benneville PL, Kresge AJ. J Org Chem 1957;22:787–9. Swain CG, Knee TEC, Kresge AJ. J Am Chem Soc 1957;79:505. Kresge AJ. Acc Chem Res 1975;8:354–460. Kresge AJ, Rao KN, Lichtin NN. Chem Ind (London, UK) 1961;53. Kresge AJ, Sagatys DS, Chen HL. J Am Chem Soc 1968;90:4174–5. Kresge AJ, Chiang Y. J Am Chem Soc 1969;91:1025–6. Kresge AJ, Nowlan V. Tetrahedron Lett 1971;12:4297–300. Kresge AJ. J Am Chem Soc 1980;102:7797–98. Arrowsmith CH, Baltzer L, Kresge AJ, Powell MF, Tang YS. J Am Chem Soc 1986;108:1356–7. Perrin CL, Thoburn JD, Kresge AJ. J Am Chem Soc 1992;114:8800–7. Chang TK, Chiang Y, Guo HX, Kresge AJ, Mathew L, Powell MF, et al. J Am Chem Soc 1997;119:3848. Kresge AJ. Pure Appl Chem 1964;8:243–58. Schowen RL. Prog Phys Org Chem 1972;9:275–332. Schowen KB, Schowen RL. Meth Enzymol 1982;87:551–606. Tsang W-Y, Richard JP. J Am Chem Soc 2007;129:10330–1. Tsang W-Y, Richard JP. J Am Chem Soc 2009;131:13952–62. More O’Ferrall RA, Koeppl GW, Kresge AJ. J Am Chem Soc 1971;93:9–20. Kreevoy MM, Steinwand PJ, Kayser WV. J Am Chem Soc 1966;88:124–31. Kresge AJ. In: Caldin EF, Gold V, editors. Proton-transfer reactions: London: Chapman Hall; 1975. pp. 179–99.

BIOGRAPHICAL ESSAY: A. JERRY KRESGE 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46.

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Marcus RA. J Phys Chem 1968;72:891–9. Kresge AJ. Chem Soc Rev 1974;2:475–503. Kresge AJ, Silverman DN. Meth Enzymol 1999;308:276–97. Albery WJ, Bernasconi CF, Kresge AJ. J Phys Org Chem 1988;1:29–31. Koeppl GW, Kresge AJ. J Chem Soc Chem Commun 1973;371–3. Richard JP, Williams KB. J Am Chem Soc 2007;129:6952–61. Richard JP, Amyes TL, Williams KB. Pure Appl Chem 1998;70:2007–14. Amyes TL, Richard JP. J Am Chem Soc 1992;114:10297–302. Richard JP, Williams G, Gao JL. J Am Chem Soc 1999;121:715–26. Richard JP, Williams G, O’Donoghue AC, Amyes TL. J Am Chem Soc 2002;124:2957–68. Chiang Y, Kresge AJ, Tang YS, Wirz, J. J Am Chem Soc 1984;106:460–2. Chiang Y, Kresge AJ, Santaballa JA, Wirz J. J Am Chem Soc 1988;110:5506–10. Chiang Y, Guo HX, Kresge AJ, Richard JP, Toth K. J Am Chem Soc 2003;125:187–94. Chiang Y, Kresge AJ, Popik VV, Schepp NP. J Am Chem Soc 1997;119:10203–12. Chiang Y, Kresge AJ, Popik VV. J Am Chem Soc 1995;117:9165–71. Allen AD, Andraos J, Kresge AJ, McAllister MA, Tidwell TT. J Am Chem Soc 1992;114:1878–9. Chiang Y, Kresge AJ, Zhu Y. J Am Chem Soc 2001;123:8089–94. Chiang Y, Kresge AJ, Zhu Y. J Am Chem Soc 2002;124:6349–56.