Since this is a performance based proposal, the proposed research of the Perrin Laboratory perforce covers a wide range of topics, including symmetry of hydrogen bonds (H-bonds), conformational analysis, anomeric effects, steric hindrance to ionic solvation, isotope effects (IEs) on acidity, NMR coupling constants, and the chemical reactivity of para-benzynes and malonic anhydrides. Techniques include multinuclear NMR, NMR titration, calorimetry, and computation. A frequent theme of these projects is solvation, which (1) affects H-bonds by breaking the symmetry of the local environment, (2) becomes less effective for sterically hindered ionic groups, (3) affects IEs by H-bonding to lone pairs, and (4) reduces the reactivity of nucleophiles toward para-benzynes. Examples of specific projects include the study of anomeric effects on stabilizations of anions that arise from properly positioned electron pairs in certain small organic molecules, NMR titration studies on deuterium IEs on acidity and their conformational dependence, and calculations of the conformational dependence of NMR coupling constants in ethers, amines, thioethers and their derivatives. The broader impact of these studies for advancing discovery remains quite long-range, since the studies are not aimed at practical application but at developing a thorough understanding of some fundamental chemistry, to guide further research in physical organic chemistry. The broader educational impact of these studies is far-reaching. Students learn to ask and answer questions, to solve problems, and to think critically. In recent years many of them have been inspired to enter academia. In addition, Prof. Perrin was elected chair of the 2006 Gordon Conference on Isotopes, where he made special efforts to encourage participation by graduate students and postdoctoral researchers, and provided financial support to them.
Our studies address fundamental questions about the relation between molecular structure and chemical reactivity. Areas include hydrogen-bond (H-bond) symmetry, isotope effects (IEs), and reactivities of a p-benzyne diradical and malonic anhydrides. Such basic research has no immediate practical applications, but it furnishes lasting answers to important questions. These studies have provided students with excellent opportunities to develop problem-solving skills while using modern instrumentation to elucidate principles of chemistry. Most of my co-workers have chosen to enter academia, where they can continue such intellectual pursuits. Hydrogen-Bond Symmetry. H-bonding is one of the most widely studied topics in chemistry. H-Bonds are a key determinant of molecular structure and intermolecular interactions. They are responsible for the folding of proteins, the functioning of nucleic acids, and the unique properties of water. Our interest has been in "symmetric" H-bonds, with a centered hydrogen. Such H-bonds are thought to possess enhanced stability. However, our search for them did not find any. Instead, each of the examples thought to have a symmetric H-bond is asymmetric in solution. There is no reason to impute special stabilization to such H-bonds. Instead, relief of strain accounts for their apparent strength. We have attributed the asymmetry of H-bonds to the inherent disorder of the local solvation environment. As solvent molecules reorient, the instantaneous solvation varies, in contrast to the organized environment in crystals. The disorder of instantaneous solvation is a fundamental feature of solutions. We have further proposed that the H-bond exists in an equilibrium multitude of solvation environments, which we have called "solvatomers", a new concept clarifying the impact of solvation on molecular structure. Recently Bogle and Singleton have reinterpreted some of our results. According to their calculations, isotopic substitution is intrinsically desymmetrizing. It is imperative to resolve this issue. Difluoromaleate is pertinent. We find that its monoanion too is asymmetric in solution, even though it is symmetric in the crystal. Most telling is that this monoanion is a symmetric structure in the more ordered medium of an isotropic liquid crystal. These results support our earlier conclusion that the symmetry of H-bonds can be determined by disorder of the local environment. Isotope effects. IEs are sensitive probes of molecular structure and reactivity because they represent a minimum perturbation. We used our highly accurate NMR titration method to measure deuterium IEs on the basicity of pyridine. The data resolve a discrepancy between two published IEs for pyridine-d5. We also verified that a-deuteration increases the basicity of amines. Attribution of the IEs to changes of vibrational frequencies implies that IEs of successive deuteriums are nonadditive, as confirmed experimentally. For 50 years an additional inductive contribution to IEs has been accepted. The key to testing this is that inductive effects are manifested in entropy. We therefore measured the temperature dependence of deuterium IEs on the acidities of formic acid, acetic acid, and 3,5-difluorophenol. The IEs appear solely in enthalpy, with no detectable entropic or inductive contribution. Parker and coworkers reinterpreted the mechanisms of some fundamental reactions of organic chemistry. By analyzing their kinetic data, unusually large kinetic IEs (KIEs) were deduced for several reactions, including hydride transfer from 1-d2 to 2. We were skeptical. As a test, we measured the KIE of 1-d and found it to be inconsistent with the large KIEs proposed. We therefore rejected the two-step mechanism and Parker's reinterpretations. insert Image1 Nucleophilic Addition to a p-Benzyne. Enediynes have aroused much interest because of their toxicity. They act by cyclizing to a p-benzyne diradical, which abstracts hydrogens from DNA. We discovered a new reaction of p-benzynes, nucleophilic addition. The rate-limiting step is cyclization of 3 to 4. We measure relative reactivities of nucleophiles by assaying the product ratio and thereby define the reactivity of this unusual species. Insert Image2 Malonic Anhydrides. Malonic anhydrides (5) had been sought for 70 years until we succeeded in synthesizing them. They decompose below room temperature, which is why they had eluded synthesis. Rate constants for this unusually facile decomposition were measured and modeled by computations, which reveal no intermediates. Indeed, this reaction may be the most unambiguous example of a concerted cycloreversion. Insert Image3 Outreach. In teaching 400 undergraduate students Introductory Organic Chemistry, I have tried to communicate my enthusiasm for science and my encouragement that every student can learn the material. In graduate courses I have included examples from my own research. I have long been active with the International Union of Pure & Applied Chemistry (IUPAC). One of our accomplishments was the Glossary of Terms Used in Physical Organic Chemistry. Currently I chair an IUPAC task force charged with revising this Glossary, which provides a major service to students and researchers worldwide.
