HYDROPHOBIC AND ANTIHYDROPHOBIC EFFECTS ON ORGANIC REACTIONS

1. HYDROPHOBIC AND ANTIHYDROPHOBIC EFFECTSON ORGANIC REACTIONS Symposium in Honor of Mike Wasielewski Ronald Breslow Columbia University

2. Some Diels-Alder Reactions in water solution 1. Faster in water than in other solvents. 2. Even in a case in which reaction is faster in isooctane than in methanol. 3. Reaction speeds with additives that increase the hydrophobic effect (LiCl) but slows with an antihydrophobic additive (guanidinium chloride). 4. More selective for endo addition in water, and ON WATER.

3. Selective Diels-Alder Reactions in Aqueous Solutions and SuspensionsR. Breslow, U. Maitra, and D. Rideout Tetrahedron Lett. 1983, 24, 1901-1904Abstract: Diels-Alder reactions show high endo/exo selectivities in aqueous suspensions“Even with a considerable layer of “neat” diene-dienophile solution the selectivities suggest that much of the reaction occurs in or at the water phase. This is consistent with our rough rate measurements.”“Thus water as a medium for Diels-Alder reactions, and other processes, is of practical interest even with poorly soluble substrates.”

4. Hydrophobic Effects on Simple Organic Reactions in WaterR. Breslow, Acts. Chem. Res. 1991, 24, 159-164Interestingly, a high preference for endo addition was found even with suspensions in which the cyclopentadiene was over 90% undissolved.

5. Selectivity Produced by Hydrophobic Packing of Reagents and Substrate in Water

6. Considerations in Choosing a Hydrophobic Oxidant: T.S. Geometry Peracid Dioxirane Hydrophobic packing is permitted in dioxirane transition state. Hydrophobic packing is not permitted in peracid transition state. Houk, K. N.; Liu, J.; DeMello, N. C.; Condroski, K. R. J. Am. Chem. Soc.1997, 119, 10147-10152

7. Considerations in Choosing a Hydrophobic Oxidant: Stability of the Reagent Dioxiranes Oxaziridiniums • Not isolatable -- Formed in situ • Epoxidation by oxone can occur (accelerated in H2O) • Potential for Bayer-Villager oxidation • Isolations are precedented • No Bayer-Villager oxidation • Very similar to dioxiranes in T.S. of epoxidation (spiro and highly synchronous) Biscoe, M.; Breslow, R.. J. Am. Chem. Soc.2005, 127, 10812-10813

8. Hydrophobically-Directed Selective Epoxidations Product ratio of A:B with DDG‡ (kcal/mol) in parentheses Dimethyldioxirane DMDO Oxaziridinium 1 Oxaziridinium 2

9. Hydrophobically Undirected Epoxidations Product ratio of A:B with DDG‡ (kcal/mol) in parentheses Peracetic Acid PAA Mg Monoperoxyphthalate MMPP Perfluoroperoxyphthalate PFPP

10. The Benzoin Condensation

11. Salt Effects on the Rate of the Benzoin Condensation in Water LiCl Relative Rate LiClO4 Concentration

12. Benzoin Condensation 1. LiCl and LiClO4 effects indicate there is Hydrocarbon Overlap in the transition state. How much? What is the exact shape of the transition state? 2. Can we use Quantitative Antihydrophobic Effects to learn? 3. For example, the effect of the addition of small amounts, 3.5 to 7 mole%, of EtOH.

13. Deducing TS Geometries from Solvent Effects • Use antihydrophobic agents, but not salts. • With 20% v/v ethanol, mole fraction is 7.2%,13 waters per ethanol. • Partitioning of the alcohols into the benzaldehyde layer is negligible, < 3%. • Thus the solubility effect is not perturbed by partitioning.

14. A cosolvent lowers the free energy of S, TS, and P

15. Relating TS Geometries to Solvent Effects • From the magnitude of the rate effect of a cosolvent compared with the effect on substrate solubility, we propose that we can say how much of the substrate hydrophobic surface becomes hidden from solvent in the TS. • For example, if the rate effect and the solubility effect are the same in a bimolecular dimerization reaction, we propose that one full hydrophobic substrate surface becomes hidden in the TS, e.g. two half surfaces.

16. Solubilities • From the relative solubility of a compound in water and in water with some added EtOH, we can see how EtOH lowers the free energy of the starting material. • We find that the free energy change G°is proportional to the amount of exposed benzene surface in a solute.

17. Some Relationships 1. Solubilities are equilibrium constants. Therefore changes in solubilities with added antihydrophobic agents can be described as G°s. 2. We find that (S/So) for a solute with two exposed phenyl groups is (S/So)2 that for a solute with one exposed phenyl group. [So is the solubility in water, S is the solubility with added cosolvent] 3. Therefore the G°s are proportional to the amount of exposed phenyl surface.

18. Relative water solubility G°s with a few mol% EtOH

19. Some Relationships • 1. G°(2) = •G°(1) • therefore • 2. log(S/S0)2 = •log(S/S0)1 • 3. log(k0/k) = h•log(S/S0) • where his the fraction of the original hydrophobic surface that becomes inaccessible to solvent in the transition state (assuming no other effects).

20. Diels-Alder Dimerization of Cyclopentadiene In the transition state, about one face of each cyclopentadiene (Cp) is covered, not in contact with the solvent, Therefore added EtOH will lower the transition state energy about as much as it lowers the energy of ONE Cp, so the rate will be lowered about as much as the solubility of one Cp is increased. Finding: 92% of a Cp surface is covered in the TS.

21. Cp dimerization in water and 5, 10, 15 v/v% EtOH, 25°C

22. Anthracenecarbinol with N-Methylmaleimide 1. Effect of EtOH additive: in the t.s. the maleimide covers ca. 27% of the anthracene surface. 2. In the product (from solubility change) only 10% is still covered.

25. Cosolvent Effects on Nucleophilic Reactions in Water Sorting out effects on hydrophobic character from effects on ionic character

29. How to Sort out the Many Effects? 1. Phenoxide ion nucleophile becomes MORE hydrophobic in the transition state. 2. Benzyl chloride electrophile becomes LESS hydrophobic in the transition state. 3. Chloride ion is less well solvated when EtOH is added. 4. Does the phenoxide ion stack with the benzyl chloride? R. Breslow, Accts. Chem. Res. 3, 471 (2004)

30. DMSO as Cosolvent 1. In water (v/v) it is 50% more antihydrophobic than EtOH, judged by solubility increases. 2. It is more polar than EtOH. Dielectric constant: Water, 78.5; 20% v/v DMSO, 77.1; 20% v/v EtOH, 72.1. 3. Therefore the contrast in results with DMSO vs. EtOH can be used to sort out solvent polarity and hydrophobic effects.

31. Two Competing Displacement Reactions with the Same Reactants and Same Leaving Groups The contrast in cosolvent and substituent effects supports our conclusions on the geometry of the phenoxide reactions.

32. Displacements by Phenoxide and 2,6-Dimethylphenoxide Ions

33. O vs. C Alkylation of Phenoxide Ions by a Benzyl Chloride in Water

35. O vs. C Alkylation of Phenoxide Ions by a Benzyl Chloride in Water

36. isoPropyl Groups Block the Face of the Benzene Ring More than they Block the Oxygen

37. Hydrophobic Overlap is More Important than Steric Hindrance

38. Alkylation of p-Substituted Phenoxide Ions in Water with p-Carboxybenzyl Chloride

39. DMSO vs. EtOHp-carboxybenzyl chloriderate effect of cosolvents in water Nucleophile 20% EtOH 20% DMSO • PhNHMe 0.75 0.60 • PhO - 0.97 1.0 • 2,6diMePhO- (O) 1.06 1.25 • “ (para-alk) 0.65 0.56

40. The Effects of Substituents and of Cosolvents Show that C-Alkylation By a Benzyl Halide Involves Packing of Hydrophobic Surfaces, but O-Alkylation Does NOT!This Confirms our Previous Picture for Phenoxide O-Alkylation

41. With EtOH vs. DMSO and MeSMe vs. Cl- Leaving Groups, and p-Nitrobenzyl vs. p-Carboxybenzyl, we also Confirm that Benzylation of N-Methylaniline DOES Involve Hydrophobic Stacking of the Phenyl Groups

42. Coworkers Transition State Geometries Kevin Groves Uljana Mayer Zhaoning Zhu Richard Connors Tao Guo Atom Transfers Sherin Halfon Mark Biscoe Eric Kool Chris Uyeda Carmelo Rizzo Uday Maitra Darryl Rideout Support: NIH, NSF, ONR