The Ion-Dipole Effect is a Force for Molecular Recognition and Biomimetic Catalysis Thesis by David Alan Stauffer In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy California Institute of Technology Pasadena, California 1989 (Submitted May 25, 1989) ii © 1989 David Alan Stauffer All rights reserved 111 Two Moms Too Dads Tu Holmes To those who Bum iv Acknowledgement My experiences at Caltech have been enriched by many special friends. I wish I had time and space to put into words my appreciation for your support and affection. Here is a flavor of what I take with me. ... I thank Dennis Dougherty for his encouragement, enthusiasm, support, and advice about science and my career objectives. His patience and tolerance during difficult times are most appreciated. His relentless, often subtle, advocacy of scientific truth continues to grow with me. (There is one word to describe Dennis that cannot be found in this thesis; those who know him well know that this word is not unremarkable.) I have been fortunate to stand upon the shoulders of two brilliant scientists. Drs. Michael Petti and Timothy Shepodd laid the foundation and put up most of the structural framework for the evolving work described in this thesis. I am grateful for Tim's "Ah!" contagious enthusiasm for our project in particular and for life in general; Mike's brainstorming ability during "rhea sessions" and "work with similar compounds" are part of the growing legend of The Babe. (l apologize for the exaggerated images I've helped to create for these two gentleman; however, I am both confident and fearful that future generations will make "Spud" filled with schmaltz.) I am also grateful to Rich Barrans for his invaluable assistance with data reduction. "Mr. Metabolism's" computational and programming appetite can devour all the experimental results we feed him. I am happy to "pass the torch" into the increasingly capable hands of Rich, Pat, Alison, Laura, and Liz. v On the hardware side of things, I thank Dave Wheeler and Dom McGrath for helpful discussions and consideration for my countless time consuming nmr experiments. I had 'lots of fun apart from the lab, too. Summer smog was much easier to digest with the comical athleticism of the Chicken Boy Mutant Killer Pig Potato Smeggies. Whether it was football, softball, or basketball, I'm happy that Frank Coms was a late-afternoon co-conspirator. (I sometimes wonder if Dennis ever went outside when we weren't conspiring?) Thanks to Gary Snyder and his U nc1e Roy for teaching Brian Masek and myself how to sail without a keel. Thanks to Josh The Boy and Dave Mack for letting me hack with them Brookside. Also thanks to Rakesh Jain, and expecially David Kaisaki, for helping me survive the Last Road Trip of Our Lives (yeah, right!). I warmly thank Ernie Harrison and Phil DeShong for spar~ng my interest in chemistry a long time ago in a galaxy called Penn State. I also thank the NSF for a Predoctoral Fellowship and BioDesign and Caltech Housing for financial assistance. Finally, I acknowledge the incredible love and support of my mother, without whom I could not have come so far, and still have so far to go .... vi Random thoughts I remember: A nanogram is a ton of iron This is what happens when God gives you infinite computer time--you stop thinking This is an important point It's kind of subtle And it really doesn't matter I have worked with similar compounds Tuesday Ah!!! Speed bah Please don't be a lazy boo-boo head Never mind This may be a stupid question, but. .. 12:13 Nothing ever lasts I know anudder X word: Xcape Get back to work! 8040-2 Oh, definitely!! Myahm! Where's the beef?! Brunie and ChlOe ... Didn't anyone ever tell you. .. ? The permutational approach to dynamic stereochemistry vii Syncomposition Well, how did I get here? One step And down the hall we fall ... To catch my breath. .. Said the woman give him Courage and Strength In the long run. .. One pebble snatched The fortune hunt continues I'll be back ibidibidi viii "I think that enzymes are molecules that are complementary in structure to the activated complexes of the reactions. they catalyse, that is, to the molecular configuration that is intermdeiate between the reacting substances and the products of reaction for these catalysed processes. The attraction of the enzyme moleucle for the activated complex would thus lead to a decrease in its energy, and hence to a decrease in the energy of activation of the reaction, and to an increase in the rate of the reaction. Although convincing evidence is not yet at hand, I believe that it will be found that the highly specific powers of self-duplication shown by genes and viruses are due to the same intermolecular forces, dependent upon atomic contact, and the same processes of replica formation through complementariness in structure as are operative in the formation of antibodies under the influence of an antigen. I believe that it is molecular size and shape, on the atomic scale, that are of primary importance in these phenomena, rather than the ordinary chemical properties of the substances, involving their power of entering into reactions in which ordinary chemical bonds are broken and formed." Linus Pauling, 1948 ix Abstracts Chapterl In aqueous and organic media, electron-rich synthetic macro cycles serve as hosts for positively-charged guests. Binding studies in different solvents have quantified hydrophobic, donor/acceptor, and ion-dipole interactions as forces for molecular recognition. We have found clear evidence for substantial host-guest donor/acceptor x-stacking interactions (ca. 1.5 kcallmol) in aqueous media only. The ion-dipole effect is an appreciable driving force (worth up to 3.5 kcallmol) for molecular recognition in both aqueous and organic media. Cbapter2 Variable-t~mperature binding studies were performed to assess enthalpic (dHO) and entropic (dSO) contributions to free energies (dGO) of host-guest complexation. The van't Hoff plots (RlnKa vs T-l), which are clearly non-linear, have revealed significant values for the heat capacities (dCp) of complexation in both organic and aqueous media. The dCp values reflect a phenomenon generally overlooked in molecular recognition studies: both dHO and dSo are strongly temperature-dependent. Hydrophobic, donor/acceptor, and ion-dipole interactions are tentatively partitioned into dHO and dSo contributions at 298K. "Classic" hydrophobic binding is characterized by a large, positive dSo and a near zero dHO term. Strong donor/acceptor x-stacking interactions are typically balanced between large, favorable enthalpic and unfavorable entropic contributions. The ion-dipole effect is primarily an enthalpically-driven binding force. x Chapter 3 Electron-rich synthetic macrocyclic host 1 accelerates a class of alkylation reactions in aqueous media. Specifically, host 1 catalyzes the reactions of pyridine-type nucleophiles with alkyl halides in an aqueous pD-9 borate buffer. The rate constants of catalyzed versus uncatalyzed reactions and the binding affinities for substrates and products demand that host 1 binds transition states more tightly than ground states. This extension of molecular recognition through ion-dipole interactions to biomimetic catalysis provides compelling evidence for transition-state stabilization via favorable dipole-dipole interactions in aqueous media. Chapter 4 A new class of high-symmetry, water soluble, hydrophobic binding sites is described that feature 1,5-substituents on a rigid ethenoanthracene (DEA) framework. These new 1,5-hosts are compared to the analogous 2,6- hosts described in the Ph.D. theses of Petti and Shepodd. Because of more favorable solvation (by water) of amide linker groups that line the cavity, the 1,5-hosts exhibit significantly reduced affinities for all guests considered: only positively-charged guests are bound to any appreciable extent. While the binding sites designed herein are composed of topographically well-defined, rigid units to give a chiral host (with a "greater sense of twist"), the disposition of the 1,5-substituents allows the collapse of hosts into a "bowl" conformation. We therefore suggest that the more successful high-symmetry, hydrophobic binding sites are to be found with 2,6-DEA-constructed hosts rather than with 1,5-DEA-constructed hosts.