1. Structure-Activity Relationships in Enantioselective Oxidations of Alcohols by Pd II Complexes Smith (Robert J.) Nielsen Jason M. Keith, William A. Goddard III Materials and Process Simulation Center, Beckman Institute (139-74), Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125

2. (-)-Sparteine stands out among chiral ligands (Ferreira and Stoltz, J. Am. Chem. Soc., 123, 7725 (2001); Sigman, et al., J. Am. Chem. Soc. 123, 7475 (2001)) /background

3. /background/experimental_observations Enantioselectivities (s) range from below 10 to 40+ Dichloride complexes are faster and more selective than diacetate complexes Reactions in chloroform are faster and more selective (by ~50%) Drawbacks –Sparteine is naturally available in only the (-) enantiomer –As a natural product, it’s not amenable to optimization –Primary and saturated alcohols show low reactivity

4. /methods Gas phase energies: B3LYP/6-31G** Los Alamos core-valence pseudopotential for Pd Solvation energies: Poisson-Boltzmann polarizable continuum solvent model dielectric  r p (Å) toluene 2.382.76 chloroform 4.802.51 1,2-DCE 10.652.51

5. As reference, take Non-viable pathways: Oxidative addition Concerted pericyclic mechanism Noyori, et al. J. Am. Chem. Soc. 122, 1466, 2000 /sparteine/mechanism 0.0 kcal Unstable 61 kcal ~30 kcal

6. Pd IV ? Ex 1: Pt 0 Pt II Pd 0 Pd II Ex 2: ME.N.I.P.E.A. Pd2.28.30.56 Pt2.29.02.13

7. Pt 0 : d 10

8. Pt II : Pt: (sp).33 d.49 s1d9s1d9 CH 3 Pt

9. Pt IV : Pt: (sp).44 d.21 Pt Cl (sp) 2 d 8 Point: Palladium wants to stay d10

11. Sparteine remains bidentate throughout oxidation /sparteine/mechanism deprotonation  -hydride elimination coordination

12. The 4-coordinate transition state:  -hydride elimimination becomes rate- determining and selectivity-determining if deprotonation reaches pre-equilibrium.  H ‡ exp(30-65°C) = 16.8 kcal  H ‡ calc(75°C) = 16.4 kcal /sparteine/mechanism/  -hydride_elimination X group (Cl - ) rests in pocket between ligand and substrate 1.61 1.30 2.09 1.62 3.11(Pd-Cl) 2.15 2.19 N N  633i cm -1

13. Woodward-Hoffmann Revisited The orbitals overlap, so we can make a strong bond and the reaction is allowed.

14. There is no way to make a second bonding M.O., thus the reaction is forbidden.

15. The d xy ’s nodal plane allows it to overlap both neighbors simultaneously. The two bonds in the reactants and products are conserved in the transition state. This is an allowed reaction.

16. Reactants Cl 2 Ti + -H D 2 Transition state (If the M-H bond in the reactants had much s- character, this wouldn’t be allowed.)

17. Implications:

18. N N And:  -Hydride Elimination N N N N

19.  -hydride Elimination X : Cl - - OAc None s exp : 20 8.8 - s calc : 17.7 7.4 1.5 Bagdanoff, Ferreira, and Stoltz, Org Let., 5,835 (2003),Ferreira,et al., Sigman et al., J. Am. Chem. Soc. 124, 8202 (2002) /sparteine/chloride_vs_acetate

20. A exp(-R1/kT) + A exp(-R2/kT) A exp(-S1/kT) + A exp(-S2/kT) S calc = S2=2.0 S1=2.8 R1=0.0kcal Predictions of s in  -hydride elimination regime are based on relative energies of four diasteriomeric transition state E ‡ sol,0K ’s: Sparteine-PdCl 2 R2=1.7 /sparteine/selectivity …… (S) paths(R) paths Factors determining s: –Which face holds X –Which site O binds to –Is X by Ph or Me

21. Transition state structures must be optimized in solvent. s observed /sparteine/selectivity A exp(-R1/kT) + A exp(-R2/kT) A exp(-S1/kT) + A exp(-S2/kT) S calc = 1,2-DCE (  =10.6) Toluene (  =2.4) Chloroform (  =4.8) Substrates

22. The Goddard Group Jason Keith William A. Goddard, III The Catalysis Group The Stoltz Group Brian Stoltz Jeff Bagdanoff (synthesis) The Stoltz Group Support NSF CHEM NSF Fellowship - J. Keith /acknowledgements