Paul R. Rablen
Research in my laboratory focuses on fundamental questions about the relationship between structure, stability, and reactivity in organic compounds, and on the mechanistic pathways of organic reactions. These questions are pursued primarily through the use of ab initio molecular orbital calculations. These approximate quantum mechanical calculations yield highly accurate predictions for the energies, geometries, and other properties of stable compounds, intermediates, and even transition states.
For instance, a recently completed project concerned the roles of resonance and electrostatics in determining the acidity and basicity of acetic acid and related compounds. Systematic comparisons between related molecules demonstrated that the acidity of carboxylic acids results more from electrostatic (or inductive) effects than from resonance, in contradiction with the explanation given in most introductory textbooks. However, the situation is reversed with the nitrogen analogs.
These conclusions were drawn from a careful analysis of the acidities and basicities of a series of structures designed specifically to elucidate the separate effects of electrostatics and resonance. The acidities and basicities, on the other hand, were derived from the energy differences between the neutral, protonated (cationic), and deprotonated (anionic) forms of the molecules -- energies that can be obtained from the quantum mechanical calculations described above.
Currently, the most active project is a collaboration with Professor Maitland Jones at Princeton University. Professor Jones' group, and also other groups, have observed an unusual sort of reaction of singlet carbenes with highly strained bicyclic ring systems. A generalized example appears below:
This reaction, in which a s bond and a Ļ bond are formed simultaneously, defies the usual categories of carbene reactions -- simple insertion into either a s or a Ļ bond. There is some controversy about how this reaction takes place. One group of researchers insists that the reaction takes place through a polar intermediate, as shown below.
Another group of researchers claims that the reaction takes place in a concerted fashion, with no intermediates:
One line of experimental evidence concerns the regiochemistry that results if the bicyclobutane starting material is substituted in certain ways. The observed products of the reaction are well explained by the mechanism involving an intermediate. However, there is nothing to preclude the concerted mechanism from favoring the same regiochemistry. Consequently, the mechanistic question remains unsolved.
We are attempting to resolve the controversy by calculating the complete pathway for the reaction, exploring both of the two proposed mechanisms. Fully addressing the issue will require more than just computing whether or not an intermediate of the purported structure is stable. All transition state structures relevant to the pathway must be found, and then the effects of various perturbations must be explored. What happens if one varies the nature of the carbene, say, from CH2 to CCl2 to CF2 to C(OCH3)2? What happens if the bicyclobutane ring is substituted -- does the predicted regiochemistry of the reaction agree with experiment? What happens if one changes the "level" at which the quantum mechanical calculations are carried out? This step is important in order to demonstrate that the findings are likely to correspond to experimental reality, and are not just an artifact of the inherently approximate nature of the calculations. What happens if one simulates the presence of a solvent? After all, the reaction is carried out experimentally in solution, and the solution environment would be expected to help stabilize a polar intermediate.
There are lots of questions to ask and to answer . . . .
1. Rablen, P. R.; Deuber, M. A.; Lim, A. C.; Dickson, R. M.; Wintner, C. E. "Cyclic Ketals of 9-Fluorenone: Advanced Organic Laboratory Exercise in Synthesis and Stereochemical Analysis Using C-13 NMR " J. Chem. Ed. 1991, 68, 796-797.
2. Wiberg, K. B.; Rosenberg, R. E.; Rablen, P. R. "Butadiene. 2. Examination of the Energetic Preference for Coplanarity of Double Bonds. Comparison of Butadiene, Acrolein, and Vinylamine" J. Am. Chem. Soc. 1991, 113, 2890-2898.
3. Wiberg, K. B.; Hadad, C. M.; Rablen, P. R.; Cioslowski, J. "Substituent Effects. 4. Nature of Substituent Effects at Carbonyl Groups" J. Am. Chem. Soc. 1992, 114, 8644-8654.
4. Wiberg, K. B.; Rablen, P. R.; Marquez, M. "Resonance Interactions in Acyclic Systems. 5. Structures, Charge Distributions, and Energies of Some Heterobutadiene Rotamers" J. Am. Chem. Soc. 1992, 114, 8654-8668.
5. Wiberg, K. B.; Rablen, P. R. "Origin of the Stability of Carbon Tetrafluoride: Negative Hyperconjugation Reexamined" J. Am. Chem. Soc. 1993, 115, 614-625.
6. Wiberg, K. B.; Rablen, P. R. "Substituent Effects. 5. Vinyl and Ethynyl Derivatives. An Examination of the Interaction of Amino and Hydroxy Groups with C-C Double and Triple Bonds" J. Am. Chem. Soc. 1993, 115, 9234-9242.
7. Wiberg, K. B.; Rablen, P. R. "A Comparison of Atomic Charges Derived via Different Procedures" J. Comp. Chem. 1993, 14, 1504-1518.
8. Hartwig, J. F.; Bhandari, S.; Rablen, P. R. "Addition of Catecholborane to a Ruthenium-Alkyl: Evidence for a s-Bond Metathesis with a Low Valent, Late Transition Metal" J. Am. Chem. Soc. 1994, 116, 1839-1844.
9. Rablen, P. R.; Hartwig, J. F.; Nolan, S. P. "The First Transition Metal-Boryl Bond Energy and Quantitation of Large Differences in Sequential BDEs of Boranes" J. Am. Chem. Soc. 1994, 116, 4121-4122.
10. Wiberg, K. B.; Rablen, P. R. "Why Does Thioformamide Have a Larger Rotational Barrier Than Formamide?" J. Am. Chem. Soc. 1995, 117, 2201-2209.
11. Wiberg, K. B.; Rablen, P. R.; Rush, D. J.; Keith, T. A. "Amides. 3. Experimental and Theoretical Studies of the Effect of the Medium on the Rotational Barriers for N,N-Dimethylformamide and N,N-Dimethylacetamide" J. Am. Chem. Soc. 1995, 117, 4261-4270.
12. Jorgensen, W. L.; McDonald, N. A.; Selmi, M.; Rablen, P. R. "The Importance of Polarization for Dipolar Solutes in Low-Dielectric Media: 1,2-Dichloroethane and Water in Cyclohexane" J. Am. Chem. Soc. 1995, 117, 11809-11810.
13. Rablen, P. R.; Hartwig, J. F. "Accurate Borane Sequential Bond Dissociation Energies by High-Level ab Initio Computational Methods" J. Am. Chem. Soc. 1996, 118, 4648-4653.
14. Rablen, P. R. "Large Effect on Borane Bond Dissociation Energies Resulting from Coordination by Lewis Bases" J. Am. Chem. Soc. 1997, 119, 8350-8360.
15. Rablen, P. R.; Lockman, J. W.; Jorgensen, W. L. "Ab Initio Study of Hydrogen-Bonded Complexes of Small Organic Molecules with Water" J. Phys. Chem. A 1998, 102, 3782-3797.
16. Richardson, A. D.; Hedberg, K.; Wiberg, K. B.; Rablen, P. R. "Internal hydrogen bonding in gaseous 3-aminoacrolein: an electron-diffraction investigation augmented by ab initio calculations of its molecular structure and conformational composition" J. Mol. Struct. 1998, 445, 1-11.
17. Wiberg, K. B.; Rablen, P. R. "Substituent Effects. 7. Phenyl Derivatives. When is Fluorine a Ļ-Donor?" J. Org. Chem. 1998, 63, 3722-3730.
18. Hadad, C. M.; Rablen, P. R.; Wiberg, K. B. "C-O and C-S Bonds: Stability, Bond Dissociation Energies, and Resonance Stabilization" J. Org. Chem. 1998, 63, 8668-8681.
19. Rablen, P. R.; Miller, D. A.; Bullock, V. R.; Hutchinson, P. H.; Gorman, J. A. "Solvent Effects on the Barrier to C-N Bond Rotation in N,N-Dimethylaminoacrylonitrile" J. Am. Chem. Soc. 1999, 121, 218-226.
20. Rablen, P. R.; Pearlman, S. A.; Miller, D. A. "Solvent Effects on the Barrier to C-N Bond Rotation in N,N-Dimethylaminoacrylonitrile: Modeling by Reaction Field Theory and by Monte Carlo Simulations" J. Am. Chem. Soc. 1999, 121, 227-237.
21. Rablen, P. R.; Hoffmann, R. W.; Hrovat, D. A.; Borden, W. T. "Is hyperconjugation responsible for the ‘gauche effect’ in 1-fluoropropane and other 2-substituted-1-fluoroethanes?" J. Chem. Soc. Perkin Trans. 2 1999, 1719-1726.
22. Rablen, P. R.; Pearlman, S. A.; Finkbiner, J. "A Comparison of Density Functional Methods for the Estimation of Proton Chemical Shifts with Chemical Accuracy" J. Phys. Chem. 1999, in press.
23. DerHovanessian, A.; Doyon, J. B.; Jain, A.; Rablen, P. R.; Sapse, A.-M. "Models of Fl H Contacts Relevant to the Binding of Fluoroaromatic Inhibitors to Carbonic Anhydrase II" manuscript submitted.
24. Rablen, P. R. “Is the Acetate Anion Stabilized by Resonance or Electrostatics? A Systematic Structural Comparison” J. Am. Chem. Soc. 2000, 122, 357-368.
25. DerHovanessian, A.; Rablen, P. R.; Jain, A. “Ab Initio and Density Functional Calculations of 19F NMR Chemical Shifts for Models of Carbonic Anhydrase Inhibitors” J. Phys. Chem. A 2000, 104, 6056-6061.
26. Rablen, P. R. “Computational Analysis of the Solvent Effect on the Barrier to Rotation in Methyl N,N‑Dimethylcarbamate” J. Org. Chem. 2000, 65, 7930-7937.
27. Rablen, P. R.; Paquette, L. A.; Borden, W. T. "Why Doesn’t All-trans-1,2,3,4,5,6-hexaspiro(THF)cyclohexane Complex Metal Ions?" J. Org. Chem. 2000, 65, 9180-9185.
28. Taboada, R.; Ordonio, G. G.; Ndakala, A. J.; Howell, A. R.; Rablen, P. R. "Directed Ring-opening of 1,5-Dioxaspiro[3.2]hexanes: Selective Formation of 2,2-Disubstituted Oxetanes" J. Org. Chem. 2003, 68, 1480-1488.
29. Paley, R. S.; Liu, J. M.; Lichtenstein, B. R.; Knoedler, V. L.; Sanan, T. T.; Adams, D. J.; Fernández, J.; Rablen, P. R. "Simultaneous and Stereoselective Formation of Planar and Axial Chiralities in Enantiopure Sulfinyl Iron Diene Complexes" Organic Letters 2003, 5, 309-312.
30. Rablen, P. R.; Bentrup, K. H. "Are the Enolate Anions of Amides and Esters Stabilized by Electrostatics?" J. Am. Chem. Soc. 2003, 125, 2142-2147.
31. Merrer, D. C.; Rablen, Paul R. “Dichlorocarbene Addition to Cyclopropenes: A Computational Study” J. Org. Chem. 2005, 70, 1630-1635.