1. Molecular Modeling: Semi-Empirical Methods C372 Introduction to Cheminformatics II Kelsey Forsythe

2. Recall Molecular Models Empirical/Molecular Modeling Neglect Electrons Semi Empirical Neglect Core Electrons Approximate/parameterize HF Integrals Ab Initio/DFT Full Accounting of Electrons

3. Huckel Theory Assumptions Assumptions Atomic basis set - parallel 2p orbitals Atomic basis set - parallel 2p orbitals No overlap between orbitals, No overlap between orbitals, 2p Orbital energy equal to ionization potential of methyl radical (singly occupied 2p orbital) 2p Orbital energy equal to ionization potential of methyl radical (singly occupied 2p orbital) The  stabilization energy is the difference between the 2p-parallel configuration and the 2p perpendicular configuration The  stabilization energy is the difference between the 2p-parallel configuration and the 2p perpendicular configuration Non-nearest interactions are zero Non-nearest interactions are zero

4. Ex. Benzene (C3H6) One p-orbital per carbon atom -  asis size = 6 One p-orbital per carbon atom -  asis size = 6 Huckel determinant is Huckel determinant is

5. Ex. Allyl (C3H5) One p-orbital per carbon atom -  basis size = 3 One p-orbital per carbon atom -  basis size = 3 Huckel matrix is Huckel matrix is Resonance stabilization same for allyl cation, radical and anion (NOT found experimentally) Resonance stabilization same for allyl cation, radical and anion (NOT found experimentally)

6. Huckel Theory Molecular Orbitals? Molecular Orbitals? # MO = #AO # MO = #AO 3 methylene radical orbitals as AO basis set 3 methylene radical orbitals as AO basis set Procedure to find coefficients in LCAO expansion Procedure to find coefficients in LCAO expansion Substitute energy into matrix equation Substitute energy into matrix equation Matrix multiply Matrix multiply Solve resulting N-equations in N-unknowns Solve resulting N-equations in N-unknowns

7. Huckel Theory Substitute energy into matrix equation: Substitute energy into matrix equation:

8. Huckel Theory Matrix multiply : Matrix multiply :

9. Huckel Theory Matrix multiply : Matrix multiply : (1) and (3) reduce problem to 2 equations, 3 unknowns (1) and (3) reduce problem to 2 equations, 3 unknowns Need additional constraint! Need additional constraint!

10. Huckel Theory Normalization of MO: Normalization of MO: Gives third equation, NOW have 3 equations, 3 unknowns. Gives third equation, NOW have 3 equations, 3 unknowns.

11. Huckel Theory Have 3 equations, 3 unknowns. Have 3 equations, 3 unknowns.

12. Huckel Theory 2p orbitals

13. Aufbau Principal Fill lowest energy orbitals first Fill lowest energy orbitals first Follow Pauli-exclusion principle Follow Pauli-exclusion principle Carbon

14. Aufbau Principal Fill lowest energy orbitals first Fill lowest energy orbitals first Follow Pauli-exclusion principle Follow Pauli-exclusion principle Allyl

15. Huckel Theory For lowest energy Huckel MO Bonding orbital

16. Huckel Theory Next two MO Non-Bonding orbital Anti-bonding orbital

17. Huckel Theory Electron Density The rth atom’s electron density equal to product of # electrons in filled orbitals and square of coefficients of ao on that atom Ex. Allyl Electron density on c1 corresponding to the occupied MO is Central carbon is neutral with partial positive charges on end carbons j=1

18. Huckel Theory Bond Order Ex. Allyl Bond order between c1-c2 corresponding to the occupied MO is Corresponds to partial pi bond due to delocalization over three carbons (Gilbert)

19. Beyond One-Electron Formalism HF method HF method Ignores electron correlation Ignores electron correlation Effective interaction potential Effective interaction potential Hartree Product- Hartree Product- Fock introduced exchange – (relativistic quantum mechanics)

20. HF-Exchange For a two electron system For a two electron system Fock modified wavefunction Fock modified wavefunction

21. Slater Determinants Ex. Hydrogen molecule Ex. Hydrogen molecule

22. Neglect of Differential Overlap (NDO) CNDO (1965, Pople et al) CNDO (1965, Pople et al) MINDO (1975, Dewar ) MINDO (1975, Dewar ) MNDO (1977, Thiel) MNDO (1977, Thiel) INDO (1967, Pople et al) INDO (1967, Pople et al) ZINDO ZINDO SINDO1 SINDO1 STO-basis (/S-spectra,/2 d-orbitals) /1/2/3, organics /d, organics, transition metals Organics Electronic spectra, transition metals 1-3 row binding energies, photochemistry and transition metals

23. Semi-Empirical Methods SAM1 SAM1 Closer to # of ab initio basis functions (e.g. d orbitals) Closer to # of ab initio basis functions (e.g. d orbitals) Increased CPU time Increased CPU time G1,G2 and G3 G1,G2 and G3 Extrapolated ab initio results for organics Extrapolated ab initio results for organics “slightly empirical theory”(Gilbert-more ab initio than semi-empirical in nature) “slightly empirical theory”(Gilbert-more ab initio than semi-empirical in nature)

24. Semi-Empirical Methods AM1 AM1 Modified nuclear repulsion terms model to account for H-bonding (1985, Dewar et al) Modified nuclear repulsion terms model to account for H-bonding (1985, Dewar et al) Widely used today (transition metals, inorganics) Widely used today (transition metals, inorganics) PM3 (1989, Stewart) PM3 (1989, Stewart) Larger data set for parameterization compared to AM1 Larger data set for parameterization compared to AM1 Widely used today (transition metals, inorganics) Widely used today (transition metals, inorganics)

25. What is Differential Overlap? When solving HF equations we integrate/average the potential energy over all other electrons When solving HF equations we integrate/average the potential energy over all other electrons Computing HF-matrix introduces 1 and 2 electron integrals Computing HF-matrix introduces 1 and 2 electron integrals

26. Estimating Energy Want to find c’s so that Want to find c’s so that

27. Estimating Energy

28. Complete Neglect of Differential Overlap (CNDO) Basis set from valence STOs Basis set from valence STOs Neighbor AO overlap integrals, S, are assumed zero or Neighbor AO overlap integrals, S, are assumed zero or Two-electron terms constrain atomic/basis orbitals (But atoms may be different!) Two-electron terms constrain atomic/basis orbitals (But atoms may be different!) Reduces from N 4 to N 2 number of 2-electron integrals Reduces from N 4 to N 2 number of 2-electron integrals Integration replaced by algebra Integration replaced by algebra IP from experiment to represent 1, 2-electron orbitals IP from experiment to represent 1, 2-electron orbitals

29. Complete Neglect of Differential Overlap (CNDO) Overlap Overlap Methylene radical (CH 2 *) Methylene radical (CH 2 *) Interaction same in singlet (spin paired) and triplet state (spin parallel) Interaction same in singlet (spin paired) and triplet state (spin parallel)

30. Intermediate Neglect of Differential Overlap (INDO) Pople et al (1967) Pople et al (1967) Use different values for interaction of different orbitals on same atom s.t. Use different values for interaction of different orbitals on same atom s.t. Methylene Methylene

31. Neglect of Diatomic Differential Overlap (NDDO) Most modern methods (MNDO, AM1, PM3) Most modern methods (MNDO, AM1, PM3) All two-center, two-electron integrals allowed iff: All two-center, two-electron integrals allowed iff: Recall, CINDO- Recall, CINDO- Allow for different values of  depending on orbitals involved (INDO-like) Allow for different values of  depending on orbitals involved (INDO-like)

32. Neglect of Diatomic Differential Overlap (NDDO) MNDO – Modified NDDO MNDO – Modified NDDO AM1 – modified MNDO AM1 – modified MNDO PM3 – larger parameter space used than in AM1 PM3 – larger parameter space used than in AM1

33. Performance of Popular Methods ( C. Cramer ) Sterics - MNDO overestimates steric crowding, AM1 and PM3 better suited but predict planar structures for puckered 4-, 5- atom rings Sterics - MNDO overestimates steric crowding, AM1 and PM3 better suited but predict planar structures for puckered 4-, 5- atom rings Transition States- MNDO overestimates (see above) Transition States- MNDO overestimates (see above) Hydrogen Bonding - Both PM3 and AM1 better suited Hydrogen Bonding - Both PM3 and AM1 better suited Aromatics - too high in energy (~4kcal/mol) Aromatics - too high in energy (~4kcal/mol) Radicals - overly stable Radicals - overly stable Charged species - AO’s not diffuse (only valence type) Charged species - AO’s not diffuse (only valence type)

34. Summarize Molecular Models Empirical/Molecular Modeling Neglect Electrons Semi Empirical Neglect Core Electrons Approximate/parameterize HF Integrals Ab Initio/DFT Full Accounting of Electrons HT EHT CNDO MINDO NDDO MNDO HF Completeness