2. 2 Outline Background Objective Quantum Chemical Analysis Combinatorial Study and Data Mining Conclusion

3. 3 Pauson-Khand Reaction  Transition-metal-catalyzed/mediated [2+2+1] carbonylative cycloaddition of an alkene and an alkyne. I.U. Khand, P.L. Pauson, etc. J. Chem. Soc. Perkin Trans. 1973, 977 Javier perez-Castells, etc. Chem. Soc. Rev., 2004, 33, 32-42  More than 2000 records in Chemical Abstract Database!  Versatile and powerful methods for assembling useful and biologically interesting carbocycles!

4. 4 Diastereomers Diastereoselectivity Preference of one diastereomer over the other in chemical reaction. P. Andrew Evans, and John. E. Robinson, J. Am. Chem. Soc. 2001, 123, 4609-4610 Syn preferred!

5. 5 Why do we care about diastereoselectivity? 12 Chiral Centers: 2 12 diastereomers!!!

6. 6 Objective Construct a theoretical model that is most consistent with experimental results, using high-level computational methods. Rationalize the origin of the diastereoselectivity by combinatorial studies and data mining.

7. 7 Computational Details Density Functional Theory (DFT) is employed in the study. B3LYP/LACVP** for geometry optimization. The energies of optimized structures are reevaluated by B3LYP/cc-pVTZ(-f). Vibrational calculation is carried out for zero-point-energy (ZPE) and entropy correction. Continuum solvation model is used to correct for the solvation energy with ε=37.5 for acetonitrile. Jaguar. 5.5 ed, Schrödinger, L.L.C, Portland, OR, 1991-2003. / Becke, A. D. J. Chem. Phys. 1993, 98, 5648. / Lee, C. T.; Yang, W. T.; Parr, R. G. Phys. Rev. B. 1988, 37, 785. / Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 270. / Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 299. Wadt, W. R.;Hay, P. J. J. Chem. Phys. 1985, 82, 284. / Dunning, T. H. J. Chem. Phys. 1989, 90, 1007.

8. 8 Potential Energy Surface y

9. 9 Structural Alternatives 32 combinations!!! PES Energy

10. 10 “Classical” Approach to Proposing a Mechanism Evans, P. A. et al. J. Am. Chem. Soc. 2001, 123, 4609 Magnus, P. et al. Tetrahedron 1985, 41, 5861 Buchwald S. L. et al. J. Am. Chem. Soc. 1996, 118, 11688.

11. 11 Mechanistic Alternatives

12. 12 Reaction Energy Profiles for Four Pathways

13. 13 Reproduce experimental results ∆G‡(sol) kcal/mol ∆∆G‡(sol) kcal/mol ds (calculated) ds (experimental) α X = O226.572.25>100:1≥ 19:1 328.82 X = CE 2 225.580.999:15:1 326.57 X=TsN227.010.252:13:1 327.26 α:P. Andrew Evans, and John. E. Robinson, J. Am. Chem. Soc. 2001, 123, 4609-4610

14. 14 Diastereoselectivity of CO Dependence Path A: Low CO-Pressure: utilizing Rh(CO)Cl as the catalytically active species Path B: High CO-Pressure: utilizing Rh(CO) 2 Cl as the catalytically active species Huijun Wang, James R. Sawyer, P. Andrew Evans* and Mu-Hyun Baik*, Rhodium-Catalyzed Pauson-Khand Reaction: Computational and Experimental Evidence for the Diastereoselectivity being Dependent on the CO-Pressure

15. 15 Can We Predict New Chemistry? Our prediction!!!

16. 16 Confirmation of Our Prediction entry a Pressure (atm.) CO Ar Yield (%) b ds c 2a:3a 123123 1.00 0 0.10 0.90 0.05 0.95 82 57 47 ≥19:1 11:1 6:1 a All reactions were carried out on a 0.25 mmol reaction scale utilizing 3 mol% of [Rh(CO)2Cl]2 in xylenes at 110 °C. b Isolated yields. c Ratios of diastereisomers were determined by 400MHz 1H NMR on the crude reaction mixtures.

17. 17 Rational of diastereoselectivity under high CO pressure Partial Charge Analysis Electron-donating group -CH 3 greatly stabilizes the transition state for syn product at high CO-Pressure!

18. 18 Will electron-withdrawing group -F reverse the diastereoselectivity!? More Predictions? Path A: Low CO-Pressure: utilizing Rh(CO)Cl as the catalytically active species Path B: High CO-Pressure: utilizing Rh(CO) 2 Cl as the catalytically active species

19. 19 Combinatorial studies of various R 1 and R 2 R 1 = -H, -CH 3, -C 2 H 5, -F, -Cl, -Br, -I, -CF 3, -COOCH 3, -OOCCH 3, -NH 2,-NO 2,-C 6 H 5, -C 6 H 4 F, -C 6 F 5, -OH, -OCH 3, -CN R 2 = -H, -CH 3, -F, -CF 3

20. 20 R 1 Functionalization Syn-products are preferred!!

21. 21 R 1 Functionalization Anti-products are preferred!!

22. 22 R 2 Functionalization R 2 is not so important as R 1 in determining the diastereoselectivity.

23. 23 Quantum Computation-based Data Mining and Reaction Design New Catalytic Reactions Computational Results CombinatorialStudy Database Data Mining Question? Computer Aided Design Prediction Training set Classification Test set

24. 24 Mulliken Electronegativity The Mulliken electronegativity is related to the electron affinity EA (the tendency of an atom to become negatively charged) and the ionization potential IE (the tendency of an atom to become positively charged). R1R1 CH 2 CH 3 C6H5C6H5 OCH 3 C6H5FC6H5FCH 3 CF 3 NH 2 NO 2 COOCH 3 EN4.765.285.545.585.616.476.787.13 R1R1 HC6F5C6F5 ICH 3 COOBrOHClCNF EN7.297.57.628.138.319.119.489.6312.48

25. 25 π effect (C 6 H 5, C 6 H 4 F, C 6 F 5, NO 2, CN) σ effect (CH 3, CH 2 CH 3, CF 3, NH 2, COOCH 3, H, I, CH 3 COO, Br, OH, Cl, F) Functional Groups at R 1 Syn preferred Anti Preferred Functional Groups at R 1 π effect σ effect Unknown σ effect? Functional Groups at R 1 Yes No EN < EN(H)? Yes No Syn-PreferredAnti-Preferred

26. 26 Conclusions Computational modeling can be used in a truly predictive fashion. The diastereoselectivity of Rh-catalyzed Pauson-Khand reaction is highly dependent on the CO-pressure and R 1 functionalization. Combinatorial quantum chemical studies and data mining is a good approach for the rational catalyst design.

27. 27 Acknowledgement  Prof. Mookie Baik  Prof. P. Andrew Evans, James R. Sawyer  Prof. Gary Wiggins, Prof. Mehmet Dalkilic  Baik Group  School of Informatics  AVIDD  $$$NIH and NSF