[B 2 ] G TS2 - G TS1 t [B 1 ] t = ( (G TS2 - G TS1 ) ) e RT ΔG 1 ΔG 21 ΔG 2 So, relative reaction rates depend only on relative transition-state energies, and not on starting-material ground-state energies. k 1 B 1 A 1 A 2 B 2 k 2
Example: Dynamic Kinetic Resolution Question: How can enantioselective chemistry convert a racemic mixture into exclusively one diastereomer? (R) CH 3 (S) CH 3 (S) to (S,S) makes sense just incorporate new chiral center by enantioselective reduction. H 2 enantioselective reduction of ketone But how to convert (R) to (S,S)? H H CH 3 (S,S) Ryoji Noyori, Nagoya University (Nobel Prize, 2001)
Example: Dynamic Kinetic Resolution CH 3 (S)-BINAP-Ru 2 H 2 H H CH 3 (R) is converted to (R,S) much more slowly than (S) to (S,S) with this catalyst. (S) (S,S) Diastereospecific yield of reaction on racemic mixture could not exceed 50%. Ph Ph P Ru P Ph (S)-BINAP-Ru 2 Ph (S)-BINAP BINAP ligand creates two sterically hindered quadrants. Tokunaga, M.; Kitamura, M.; Noyori, R. J. Am. Chem. Soc. 1993, 115, 144-152. Noyori, R.; et al. J. Am. Chem. Soc. 1989, 111, 9134-9135.
Example: Dynamic Kinetic Resolution CH 3 (S)-BINAP-Ru 2 H 2 H H CH 3 (R) is converted to (R,S) much more slowly than (S) to (S,S) with this catalyst. (S) (S,S) lower-energy (rate-determining) transition state steric congestion higher-energy (rate-determining) transition state (S)-BINAP (S)-ketoester (S)-BINAP (R)-ketoester
Example: Dynamic Kinetic Resolution H (S)-BINAP-Ru 2 (S) CH 3 H 2 (S,S) CH 3? CH 3 (R) So, how to convert (R)-ketoester to (S,S)-β-hydroxyester?
Example: Dynamic Kinetic Resolution H (S)-BINAP-Ru 2 (S) CH 3 CH 3 H H 2 (S,S) CH 3 (S)-BINAP-Ru 2 achiral ester enolate (R) CH 3 H 2 (R,S) CH 3 Equilibrate two enantiomeric starting materials through achiral enolate, by tuning Lewis acidity in solvent. Curtin-Hammett ensures that all racemate goes to (S,S), as long as equilibration is faster than catalysis.
Example: Dynamic Kinetic Resolution (S)-BINAP-Ru (S)-ketoester (S)-BINAP-Ru (R)-ketoester CH 3 H H CH 3 CH 3 CH 3 CH 3 (S,S) (S) (R) (R,S) (not observed)
Kinetic vs. Thermodynamic Control E increase frequency of going over reaction barriers (e.g., by lowering TS energy w/ catalyst, or by increasing T) B 1 A 1 A 2 B 2 B 1 A 1 A 2 B 2 Under kinetic control, make product with lowest-energy transition state Under thermodynamic control, make product with lowest ground-state energy
Kinetic vs. Thermodynamic Control δ δ more δ on 2 o carbon H δ δ δ δ -80 C 40 C δ δ kinetic product thermodynamic product
Principle of Microscopic Reversibility The lowest-energy pathway from reactant to product must also be the lowest-energy pathway from product to reactant. Pathway I Pathway II A P and P A choose this path. If I were hiking, I d take Pathway I from A P, and Pathway II from P A. But molecules aren t hikers. They d always take Pathway II.
Principle of Microscopic Reversibility An interesting corollary: Catalysts activate both forward and reverse reactions. N H H 2 subtilisin, trypsin, papain H H 2 N subtilisin, trypsin, papain Enzymes that catalyze protein cleavage also catalyze protein synthesis! So, how does our body selectively degrade the proteins it wants to eat, and synthesize the proteins it wants to use?
Principle of Microscopic Reversibility Answer: Isolate different reactions in different places. In the gut Inside cells N H H 2 N H H 2 ADP Pi subtilisin, trypsin, papain ribosome H H 2 N H H 2 N ATP proteolysis is driven by water. protein synthesis is driven by energy (ATP). Enzymes work both ways, but thermodynamics drives reactions in desired directions.