1. 1 © David Gallagher 2002 Mount St. Helens, WA, USA, May 18, 1980 David Gallagher * Modeling Chemical Reactivity  Visualization of chemical reactivity  Kinetic & thermodynamics

2. 2 © David Gallagher 2002 Visualization of Reactivity Susceptibility to electrophilic attack? (phenol) * K. Fukui et al, J. Chem. Phys., 11. 1433-1442 (1953) ** Also, nucleophilic, radical, electrostatic potential, superdelocalizability, etc. HOMO on electron iso-density surface HOMO Largest HOMO density on para & ortho positions Partial charges Largest negative charge on para & ortho positions + - Fukui’s Frontier Density* Electrophilic susceptibility** Highest frontier density on para & ortho positions

3. 3 © David Gallagher 2002 Susceptibility to Attack *Fukui’s frontier density on electron isodensity surface Electrophilic (occupied obitals) Nucleophilic (unoccupied orbitals) Radical (all valence orbitals)

4. 4 © David Gallagher 2002 Polyester Weatherability* New methyl propane diol based Polyester introduced Competitor claims “Norrish type II” degradation mechanisms mean rapid degradation of diols with beta hydrogens under UV radiation, unlike competitor’s neopentyl based polyester HH methyl propane diol neopentyl diol

5. 5 © David Gallagher 2002 Experimental accelerated test results inconsistent with “Norrish” “Radical susceptibilty” surfaces similar for both polyesters * Published in Journal of Coatings Technology Vol. 67, No. 847, August ‘95 by Carl J. Sullivan & Charles F. Cooper, ARCO Chemical Company CAChe & Tests Disprove Claims* methyl propane polyester neopentyl polyester HH

6. 6 © David Gallagher 2002 Conrotatory sterically hindered Insights into Catalysis A. R. Pinhas, B. K. Carpenter, J.C.S. Chem. Comm., 1980, 15. tricyclo-octadiene bicyclo-octatriene X Why does iron tricarbonyl apparently catalyse this reaction? Fe(CO) 3 Disrotatory ?

7. 7 © David Gallagher 2002 Frontier MO Control of Stereochemistry Thermal reaction: most reactive electrons in HOMO Conrotatory Sterically hindered CAChe MOPAC AM1-d Disrotatory Sterically allowed Fe Iron carbonyl changes symmetry of frontier orbital (HOMO)

8. 8 © David Gallagher 2002 Improve Yield, Minimize Byproducts 83% syn 17% anti methylnitrone monofluoroallene + ? Thermodynamic control? Isomers have same H f, - No! Kinetic control? syn-product T-state is lower energy, - Yes! Why is syn lower? Visualize energy terms of T-state* *Purvis III, G. D., J. Computer Aided Molecular Design, 5 (1991) 55-80

9. 9 © David Gallagher 2002 Sterics of the Transition-state Sterics, Frontier orbitals & Electrostatics all influence transition state Sterics slightly favor anti-product: but inconsistent with experiment (17%) anti-addition (17%) syn-addition (83%) methylnitrone MFA steric hindrance?

10. 10 © David Gallagher 2002 Orbitals of the Transition-state Closest energy frontier orbitals are nitrone HOMO & MFA LUMO Frontier orbital overlap suggest both transition states equally allowed anti-addition (17%)syn-addition (83%) nitrone HOMO MFA LUMO + + + + + + + +

11. 11 © David Gallagher 2002 Electrostatic Control of Yield Anti-addition shows +/+ repulsion, syn seems energetically favored Product ratios are consistent with electrostatic control (strongest long-range) Thus, changing solvent (dielectric) or substituents could control product yield anti-addition (17%) syn-addition (83%) nitrone MFA red: +ve blue: -ve Electrostatic isopotential surfaces: proton repelled by 20 kcals on red surface. +/+

12. 12 © David Gallagher 2002 Visualization of Reactivity * K. Fukui et al, J. Chem. Phys., 11, 1433-1442 (1953) Electrostatics (AM1) partial charges (menu) electrostatics on surface electrostatic isopotential Frontier orbitals HOMO, LUMO, etc. susceptibility*, (substrate only) superdelocalizability*, (both reactants) Sterics space-filling VdW (electron isodensity) MM conformation search

13. 13 © David Gallagher 2002 Thermodynamics & Kinetics 1. Thermodynamics (heat of reaction) E products – E reactants Heats of Formation are calculated by MOPAC PM3 http://www.shodor.org/UNChem/advanced/kin/arrhenius.html Reactant E r Energy of reaction = E p – E r Product E p Activation energy E a = E t – E r T-state E t 2. Kinetics (activation energy) E transition-state - E reactants k = A*exp (-E a /R*T)

14. 14 © David Gallagher 2002 Substitution Position by Kinetics Lowest energy* transition state = fastest reaction = main product 2) Ortho: 171 Kcals 1) Para: 167 Kcals 3) Meta: 183 Kcals Br Transition states for electrophilic attack by Br+ on phenol

15. 15 © David Gallagher 2002 Urethane Polymerization Reaction Lower temperature would reduce costs and thermal decomposition R-N=C=O + CH 3 OH = RNHCOOCH 3 R Catalyst *Malwitz, N., Reaction Kinetic Modeling from PM3 Transition State Calculations, J. Phys. Chem., Vol 99, No. 15, 1995 p. 5291 R Catalyst Solvent Activation E methyl 43.7 kcal phenyl 41.3 kcal methylN(CH 3 ) 3 32.0 kcal phenylN(CH 3 ) 3 26.9 kcal phenylN(CH 3 ) 3 CH 3 OH16.7 kcal Model transition states, then calculate catalyst & solvent effects To save time & money, CAChe used to explore reaction conditions Project successful, saving many months & cost of chemicals for pilot scale

16. 16 © David Gallagher 2002 Unexpected Insights R Catalyst *Malwitz, N., Reaction Kinetic Modeling from PM3 Transition State Calculations, J. Phys. Chem., Vol 99, No. 15, 1995 p. 5291 Literature states lone-pair of trimethylamine ‘attacks’  + of carbonyl ‘C’ Modeling does NOT support this (lone pair of catalyst attaches to proton) New insight reveals alternative (or true?) mechanism

17. 17 © David Gallagher 2002 Polyurethane: “Summary” “... capable of offering insight useful toward minimizing unwanted side reactions optimizing yields suggesting reaction conditions and determining polymer composition...” *Malwitz, N., Reaction Kinetic Modeling from PM3 Transition State Calculations, J. Phys. Chem., Vol 99, No. 15, 1995 p. 5291

18. 18 © David Gallagher 2002 CPD Dimerization & Temperature *  G =  H - T  S * * * Exothermic Endothermic low temp high temp

19. 19 © David Gallagher 2002 H f RMS errors (kcal.mol -1 ) compared to experiment *Comparison of the accuracy of semiempirical and some DFT methods for predicting heats of formation, James J. P. Stewart, J Mol Model (2004) 10:6-12 MOPAC & DFT Accuracy

20. 20 © David Gallagher 2002 Strategies for locating T-States 1. Sketch a ‘guess’ 2. Modify similar TS 3. Map reaction 4. Search for saddle

21. 21 © David Gallagher 2002 Map the Reaction Screen capture with “SNAP32”, AVI movie made with “GIF Movie Gear” Diels Alder MOPAC PM3 Optimized Grid

22. 22 © David Gallagher 2002 Reactant Product 2. Copy & name it “Product” Search for Saddle (keto-enol) 1. Sketch “Reactant” with atom #s T-state 4. Copy “Reactant”, name “T-state” 3. Edit to “Product” structure 5. Experiment: Search for Saddle

23. 23 © David Gallagher 2002 Verifying the T-State 1. Refine 2. Verify (IR spectrum)

24. 24 © David Gallagher 2002 Verify Transition State 3. Do calculated bond-orders seem reasonable? “View | Pt. Chg. & Calc. Bond Order” 2. Do atom-distances seem reasonable? “Adjust | Define geometry label” 1. Single negative vibration? “Verify T-state”

25. 25 © David Gallagher 2002 Intermediates? ? ? Intrinsic Reaction Coordinate (IRC)

26. 26 © David Gallagher 2002 Reaction Path (IRC) Intrinsic Reaction Coordinate (IRC) Water-catalyzed keto-enol tautomerization, reaction path

27. 27 © David Gallagher 2002 Solvents & Radicals

28. 28 © David Gallagher 2002 Summary for locating T-States 1. Create an approximate T-state 2. Refine (consider solvents & radicals) 3. Verify (neg. vibration, bonds) 4. Check reaction path for intermediates

29. 29 © David Gallagher 2002 Safe Laboratory Practice “The purpose of computing is insight, not numbers” Amdahl “Calibrate before use!” (experiment or ab initio) Old Chemists never die… they simply fail to react