1. 1 Cheminformatics & Validation Molecular modelling l Introduction25-Feb (JS) l Molecular mechanics/dynamics26-Feb (NG) –Conformational analysis27, 4 & 6th Feb/March l Electronic structure methods 13-Mar (JS) –Transition states 18th & 20th Mar l Density functional theory 26-Mar (PM) –Crystalline state27 th Mar & 1 & 3 Apr

2. 2 Introduction to molecular modelling l Predicting properties of molecules, such as energy, structure, polarisability, dipole moment, etc. including reaction profiles and transition states l Focus on the application Spartan l Practical sessions: Monday afternoons 2am –Feb: 17 & 24 (NG) –Mar: 3 & 10 (JS) 17, 24 (PM) –Location: Corrib suite l Registration, usernames, passwords, etc.

3. 3 Informatics (normally Wed 9am) l World wide web (JS) –Tue March 25th l Chemical Abstracts via STN (LS) –12th & 19 th March l Beilstein CrossFire (NG) –11th March l Cambridge crystallography database (PM) –26th March & 2nd April

4. 4 Comparisons at a glance

5. 5 Molecular mechanics: Introduction l Molecular mechanics (each different force field) –eg AMBER, OPLS, BIO+, MM+ Potential energy of molecule  location of atoms l Atom types? Just elements? –eg 5 different oxygens –carbonyl, hydroxyl, carboxylic, ester or water l Parameter sets; elements parametrised l Interaction of nuclei not electrons

6. 6 Force fields Bond str.: E S = (k/2) (r - r 0 ) 2 Angle bending: E B = k  (  -  0 ) 2 Torsion: E  = V N {1+cos (n  -   )}/2 van der Waals: E NB = A IJ r  12 - B IJ r  6 Electrostatic: E E = q I q J /(  r) l H-bonding: 10-12 potential

7. 7 Applications l Geometry optimisation l Molecules with 1,000s of atoms l Organics, oligonucleotides, peptides, etc. l Metallo-organics and inorganics l Vacuum and solvent l Ground states only

8. 8 Electronic structure methods l ab initio: purely theoretical –many different approximations –Hartree-Fock, e correlation: MPn, MCSCF –basis sets: STO-3G, 6-31G(d), 6-311+G(d,p), etc l Semi-empirical: some exptal. data –many different expressions: MNDO, AM1, PM3 l Density functional theory (ab initio?) –many different –B3LYP, SVWN, etc

9. 9 Semi-empirical methods l Very large systems & 1st step for large systems l Ground state organic molecules –Calibration: parametrised –AM1: H, B/Al, C/Si/Ge, N/P, O/S, F/Cl/Br, Zn Energies E = f(x) Geometry optimisation dE/dx Frequencies d 2 E/dx 2 l Molecular orbitals (!?)

10. 10 Example Bredt’s rule: l “Elimination to give a double bond in a bridged bicyclic system always leads away from the bridgehead” l Build #2 and #3 optimise and record the energy; which is more stable? Why? Measure C=C bond lengths (  130-132 pm) Effect of increasing ring size?

11. 11 Practical: acetone Build, minimise & optimise via AM1 (H 3 C) 2 CO l Experimental data: –Heat of formation  H F = -51.9 kcal/mol –Dipole moment = 2.88 Debyes l Energy levels and MOs –Identify HOMO –View HOMO & LUMO ( Setup/Surfaces/Add/HOMO then up to Setup/Submit ) l Vibrational analysis –Identify vibrations and IR spectrum –C=O stretching vibration?

12. 12 Structure versus Energy l Hexasilabenzene can exist in several isomeric forms; Sax et al. [J. Comp. Chem. 1988, 9 :564–77] found that the prismane, isomer 2, is the most stable, do you agree (AM1)?

13. 13 Exercise: Walsh Diagrams l Walsh diagrams are useful in predicting molecular geometry. They correlate energy changes of molecular orbitals between a reference geometry, frequently of high symmetry, and a deformed structure of lower symmetry. l Sketch the water molecule, aligning it on screen; set a restraint or constraint (by clicking on ‘angle padlock’ icon) select the H–O–H angle so that the angle is forced to be say 90º. Do a geometry optimisation with AM1.

14. 14 Example: geometry optimisation l Malonaldehyde –Simple example of intramolecular H-bonding –Cf. experimental structure with a geometry optimi- sation run –Try molecular mechanics & –Semi-empirical, PM3 –Key distance: long O...H

15. 15 The log file l Orientation of molecule l Mulliken population analysis partitions total charge among the atoms of the molecule (widely used & criticized) l Dipole moment of 1.709 –y-component of 1.709 –So points from negative O atom along Y-axis

16. 16 Portion of log file Eigenvalues(a.u.) and Eigenvectors Mol. Orbital 1 2 3 4 5 6 7 Eigenvalue -20.25158 -1.25755 -0.59385 -0.45973 -0.39262 0.58179 0.69267 S O 1 0.99422 0.23377 0.00001 -0.10404 0.00000 0.12582 0.00003 S O 1 0.02585 -0.84445 -0.00004 0.53817 0.00000 -0.82013 -0.00019 Px O 1 0.00000 0.00000 -0.61270 -0.00008 0.00000 -0.00024 0.95980 Py O 1 0.00416 -0.12284 0.00008 -0.75587 0.00000 -0.76356 -0.00023 Pz O 1 0.00000 0.00000 0.00000 0.00000 1.00000 0.00000 0.00000 S H 2 -0.00558 -0.15559 -0.44922 -0.29512 0.00000 0.76930 -0.81449 S H 3 -0.00558 -0.15560 0.44923 -0.29509 0.00000 0.76902 0.81480 EIGENVALUES(eV) -551.073608 -34.219627 -16.159496 -12.509945 -10.683656 15.831361 18.848427 NET CHARGES AND COORDINATES Atom Z Charge Coordinates(Angstrom) Mass (Mulliken) x y z 1 8 -0.330524 -0.00000774 -0.07115177 0.00000000 15.99900 2 1 0.165255 0.75813931 0.56460971 -0.00000005 1.00800 3 1 0.165271 -0.75801641 0.56471276 0.00000005 1.00800

17. 17 Open versus closed shell How to handle electron spin l Open shell (unrestricted) –odd no. of e ’s –excited states –2 or more unpaired e ’s –bond dissociation l Closed shell (restricted)

18. 18 Relative Computation Times Methylcyclohexane (7 heavy atoms) Lysergic acid (20)

19. 19 Transition states l Finding TSs (more difficult than minima) l Mathematical procedures less well developed l PE surface near TS probably “flatter” l Only good ab initio methods will work –bonds partially or fully broken l Very little quantitative data on TSs anyway l Guessing TSs –Closely-related system –Average reactant & product ( linear synchronous transit ) –Chemical intuition

20. 20 Verifying TS l Frequency normal-mode analysis l One (and one only) imaginary frequency –eg a negative frequency in the range 400-2,000 cm -1 l Check that the coordinate (corresponding to imaginary frequency) smoothly connects reactants and products by: –coordinate animation –follow the coordinate by intrinsic reaction coordinate methods

21. 21 Pyrolysis of ethyl formate l Build ethyl formate, choosing the correct geometry, minimise with AM1, save one copy as –Ethyl_formate_pBP_DNss for later & another as –Ethyl_formate_pyrolysis_AM1 for use now. l Select Reaction from Build menu (or curved arrow icon); click on bond ‘a’ then on ‘b’; then on ‘c’ & ‘d’ and finally on ‘e’ followed by Shift click on methyl H to be transferred and on the O-atom to receive it. l With all three arrows in place, click on equilibrium icon (twin arrows) at the bottom right of screen

22. 22 Transition state of ethyl formate l Result; shown on the right l Enter Calculations dialogue, specify TS geometry, semi-empirical & AM1 l Click on frequencies l Submit job, when finished examine geometry & animate imaginary (-ve) frequency l Is vibrational motion consistent with reaction? l Turn off animation by re-entering Vibrations & clicking on imaginary frequency.

23. 23 Density iso-surface l Bring up Surfaces dialogue, click on Add … select density (bond) & none from Property menu & click on OK. Repeat with potential from Property. l Submit. l Enter Surfaces & click on density completed 0.08 l Is CO bond in ethyl formate nearly fully cleaved? l Is the migrating H midway between C & O? l Click anywhere on graphic, select either Transparent or Mesh from the menu to the right of Style (bottom right) to replace opaque solid density surface by a mesh or transparent solid view l Click on density Completed 0.08 then click again l Check migrating H colour code l Is it ? –H + (blue) –H (green) or –H – (red)

24. 24 Computation of activation energy l Use “ethyl_formate_pBP_DNss” l Enter Calculations dialogue, specify single-point using the pBP/DN** DFT model, click OK & submit job. l Bring on-screen “ethyl_formate_pBP_DNss”. Enter Calculations, specify pBP/DN** but start from an AM1 structure. Submit job l When both calculations are complete, compute the activation energy from the difference between the total energies of TS and ethyl formate (use molecular properties from the Display menu) 1 atomic unit (au) = 627.51 kcal/mol l How does your value cf. with exptal. of 40-44 kcal/mol?