Dissection of Elementary Steps in Nucleophilic Vinylic Substitution Reactions
  • Background
  • Current and Future Projects
  • References

    Background

    A nucleophilic vinylic substitution (SNV) is a reaction of the general type shown in eq 1 where Nu- is a nucleophile and LG is a leaving group.

    Depending on the specific structure of the vinylic substrate, LG, Nu, solvent, etc. the reaction may proceed by a variety of mechanisms. The most common one is the two-step mechanism of eq 2 which prevails when X and/or Y are moderately to strongly electron withdrawing groups.

    Until about 10 years ago all the evidence for the two-step nature of these reactions was circumstantial but in 1989 we were able to devise a system (eq 3) which allowed us to directly observe the intermediate by UV spectroscopy (Ref. 1).

    This was not only a breakthrough in terms of having found the most compelling evidence for the two-step mechanism, it also made it possible to determine all the rate constants (k1, k-1, k2) of the reaction. This study opened up a new direction in the investigation of SNV reactions because it led to the discovery of other similar reactions for which k1, k-1, and k2 in eq 2 could be measured directly. This is important because there are so many factors that affect the reactivity in SNV reactions that only a systematic investigation of each step can provide insights into the complex interplay of these factors. These factors include the basicity of nucleophile, the leaving group ability of LG, steric effects, anomeric effects, pi-donor effects of the leaving group and of the nucleophile in the product, solvation effects, polarizability effects, and possibly others.

    Current and Future Projects

    Most of our work on SNV reactions is done in collaboration with Professor Zvi Rappoport at the Hebrew University in Jerusalem. Examples of systems that are under current investigation or planned for the future include the reactions of thiolate ions, alkoxide ions, amines and amide ions with vinylic substrates such as 1 (R = Me, Et, i-Pr), 2-4.

    The emphasis is on determining intrinsic barriers (see The Big Picture) of the individual elementary steps. This will allow us to evaluate how the various factors listed above affect the reactivity in these reactions because for many of these factors we now know whether they tend to develop early or late at the transition state (e.g. resonance and solvation effects develop late/are lost early; steric and polarizability effects develop early). Based on this knowledge and applying the rules of the PNS (see The Big Picture) we can assess the relative importance of these factors (see, e.g., ref.10). Additional insights, especially about the role played by the leaving group, can be gained by making comparisons with reactions involving substrates of the type 1-4 but where the leaving group is replaced by hydrogen; for a review of such reactions, see reference 1.

    References

    1. C. F. Bernasconi, "Nucleophilic Addition to Olefins. Kinetics and Mechanism," Tetrahedron, 45, 4017-4090 (1989).
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    2. C. F. Bernasconi, R. B. Killion, Jr., J. Fassberg, Z. Rappoport, "Kinetics of Reaction of b-Methoxy-a-nitrostilbene with Thiolate Ions. First Direct Observation of the Intermediate in a Nucleophilic Vinylic Substitution," J. Am. Chem. Soc. 111, 6862-6864 (1989).
    3. C. F. Bernasconi, J. Fassberg, R. B. Killion, Z. Rappoport, "Kinetics of the Reactions of Thiolate Ions with a-Nitro-b-Substituted Stilbenes in 50% Me2SO-50% Water. Observation of the Intermediate in Nucleophilic Vinylic Substitution Reactions," J. Am. Chem. Soc. 112, 3169-3177 (1990).
    4. C. F. Bernasconi, J. Fassberg, R. B. Killion, Z. Rappoport, "Kinetics of Reactions of Amines with a-Nitro-b-Substituted Stilbenes in 50% Me2SO-50% Water. Search for the Intermediate in Nucleophilic Vinylic Substitution," J. Org. Chem. 55, 4568-4575 (1990).
    5. C. F. Bernasconi, J. Fassberg, R. B. Killion, D. F. Schuck and Z. Rappoport, "Kinetics of Reactions of Hydroxide Ion and Water with b-X-Substituted a-Nitrostilbenes (X = Cl, I, SEt, OMe, SCH2CH2OH) in 50% Me2SO-50% Water. Search for the Intermediate in Nucleophilic Vinylic Substitution," J. Am. Chem. Soc. 113, 4937-4946 (1991).
    6. C. F. Bernasconi, A. E. Leyes, Z. Rappoport and I. Eventova, "Reaction of N-Methylmethoxyamine with b-Methoxy-a-nitrostilbene. First Direct Observation of the Intermediate in a Nucleophilic Vinylic Substitution with an Amine Nucleophile," J. Am. Chem. Soc. 115, 7513-7514 (1993).
    7. C. F. Bernasconi, D. F. Schuck, R. J. Ketner, M. Weiss and Z. Rappoport, "Kinetic Analysis of Elementary Steps in Nucleophilic Vinylic Substitution Reactions of a-Nitro-b-X-stilbenes (X = OCH2CF3, OCH3, NO2) with Various Nucleophiles. Detection of the Intermediate in the Reaction of a-Nitro-b-(2,2,2-trifluoroethoxy)stilbene with HOCH2CH2S— and of b-Methoxy-a-nitrostilbene with CF3CH2O—," J. Am. Chem. Soc., 116, 11764-11774 (1994).
    8. C. F. Bernasconi, A. Leyes, I. Eventova and Z. Rappoport, "Kinetics of the Reaction of b-Methoxy-a-nitrostilbene with Methoxyamine and N-Methylmethoxyamine. Direct Observation of the Intermediate in Nucleophilic Vinylic Substitution," J. Am. Chem. Soc., 117, 1703-1711 (1995).
    9. C. F. Bernasconi, D. F. Schuck, R. J. Ketner, I. Eventova and Z. Rappoport, "The CF3CH2O— Adducts of a-Nitro-b-(2,2,2-trifluoroethoxy)stilbene and b-Methoxy-a-nitrostilbene, and the MeO— Adduct of b-Methoxy-a-nitrostilbene. Kinetics of Competition between Protonation and Acid Catalyzed Alkoxide Ion Departure," J. Am. Chem. Soc., 117, 2719-2725 (1995).
    10. C. F. Bernasconi, R. J. Ketner, X. Chen, and Z. Rappoport, "Kinetics of the Reactions of Methoxybenzylidene Meldrum’s Acid with Thiolate Ions, Alkoxide Ions, OH— and Water in Aqueous DMSO. Detection and Kinetic Characterization of the SNV Intermediates," J. Am. Chem. Soc., 120, 7461-7468 (1998).
    11. C. F. Bernasconi and R. J. Ketner, "Kinetics of the Reactions of Benzylidene Meldrum’s Acid with Thiolate and Alkoxide Ions in Aqueous Dimethylsulfoxide," J. Org. Chem., 63, 6266-6272 (1998).
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    12. C. F. Bernasconi, A. E. Leyes, and Z. Rappoport, "Kinetics of the Reaction of b-Methoxy-a-nitrostilbene with Cyanamide in 50% DMSO-50% Water. Failure to Detect the SNV Intermediate," J. Org. Chem. 64, 2897-2902 (1999).
    13. C. F. Bernasconi, R. J. Ketner, X. Chen, and Z. Rappoport, "Detection and Kinetic Characterization of SNV Intermediates. Reactions of Thiomethoxybenzylidene Meldrum's Acid with Thiolate Ions, Alkoxide Ions, and OH- and Water in Aqueous DMSO," Can. J. Chem. 77, 584-594 (1999).
    14. C. F. Bernasconi, R. J. Ketner, S. D. Brown, X. Chen and Z. Rappoport, "Acid Catalyzed Breakdown of Alkoxide and Thiolate Ion Adducts of Benzylidene Meldrum's Acid, Methoxybenzylidene Meldrum's Acid and Thiomethoxybenzylidene Meldrum's Acid," J. Org. Chem. 64, 8829-8839 (1999).