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Finding Transition States Algorithmically for Automatic Reaction Mechanism Generation
The document discusses advancements in computational modeling in chemical engineering, specifically focusing on the automatic generation of reaction mechanisms and transition state (TS) searches. It highlights the potential for predicting TS geometries from molecular groups and emphasizes the need for detailed kinetic models to enhance accuracy in energy research. The use of automated methods is portrayed as a transformative approach, enabling the characterization of complex reaction mechanisms and significantly speeding up calculations in the field of chemistry.
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Finding Transition States Algorithmically for Automatic Reaction Mechanism Generation
- 1. Computational Modeling inChemical Engineering .edu/comocheng Finding Transition States Algorithmically for Automatic Reaction Mechanism Generation Pierre L. Bhoorasingh Richard H. West 1
- 2. Can you predictTS geometries from molecular groups alone? 2 (this would be great)
- 3. Length of bondbeing broken, at TS for Hydrogen abstraction Can you predict TS geometries from molecular groups alone? 3 Radical Molecule
- 4. Length of bondbeing broken, at TS for Hydrogen abstraction !"!#$ !"!%% !"!&' !"!($ !")() !")'& !"*+$ !"*!# !")(' !")$% !"*%% !")'+ !"*+& !"*&) !"*&$ Can you predict TS geometries from molecular groups alone? 3in Å with M06-2X/6-31+G(d,p)
- 5. Can you predictTS geometries from molecular groups alone? 4 !"!#$ !"!%% !"!&' !"!($ !")() !")'& !"*+$ !"*!# !")(' !")$% !"*%% !")'+ !"*+& !"*&) !"*&$ !"#$# !"#$%!"!#$ !"#$% in Å with M06-2X/6-31+G(d,p)
- 6. You can predictTS geometries from molecular groups alone! 5 !"!#$ !"!%% !"!&' !"!($ !")() !")'& !"*+$ !"*!# !")(' !")$% !"*%% !")'+ !"*+& !"*&) !"*&$ !"#$% in Å with M06-2X/6-31+G(d,p)
- 7. You can predictTS geometries from molecular groups alone! 6 But... ... you gave me a distance, not a geometry. ... I gave you 15 numbers then asked you for 1.
- 8. Automatic Transition StateTheory (TST) would be a game-changer. •Insight and predictions require detailed kinetic models. •Error-free detailed models require automatic generation. •Automatic generation requires reasonable estimates of millions of reaction rates. •Current estimates are often unreasonable due to scarcity of data. 7
- 9. Automatic TS searchesremain an important energy research goal “An accurate description of the often intricate mechanisms of large-molecule reactions requires a characterization of all relevant transition states... Development of automatic means to search for chemically relevant configurations is the computational- kinetics equivalent of improved electronic structure methods.” - Basic Research Needs for Clean and Efficient Combustion of 21st Century Transportation Fuels. US Dept of Energy (2006) 8
- 10. Automatic TS searchesremain an important energy research goal “...transformation from by- hand calculations of single reactions to automated calculations of millions of reactions would be a game- changer for the field of chemistry, and would be a good ‘Grand Challenge’ target...” - Combustion Energy Frontier Research Center (2010) 9 First Annual Conference of the Combustion Energy Frontier Research Center (CEFRC) September 23-24, 2010 Princeton
- 11. An introduction to ReactionMechanism Generator Automatically builds detailed kinetic models facebook.com/rmg.mit rmg.sourceforge.net 10 ⇌RMG
- 12. Molecules are representedas graphs CH3CH2. C C* H H H H H = 11
- 13. Thermochemistry is oftenestimated by Benson group contributions C-(C)(H)3 C-(C)2(H)2 Cb-(H) C-(C)(Cb)(O)(H) 12
- 14. Reaction families proposeall possible reactions with given species bond breaking and hydrogen abstraction intramolecular H-abstraction 13 •Template for recognizing reactive sites •Recipe for changing the bonding at the site •Rules for estimating the rate
- 15. 14 Reaction families proposeall possible reactions with given species •Template for recognizing reactive sites •Recipe for changing the bonding at the site •Rules for estimating the rate
- 16. Octane autoxidation hasmany pathways 15
- 17. •Some pathways gofurther than others. 16
- 18. Faster pathways areexplored further A B C D E F G H A B C D E F 17
- 19. Edge requires manyreaction rates 100 species 1,000 reactions 18
- 20. Edge requires manyreaction rates 100 species 1,000 reactions 15,000 species 180,000 reactions 18
- 21. Rate estimates arebased on the local structure of the reacting sites. •Hydrogen abstraction: XH + Y. → X. + YH •Rate depends on X and Y. 19 O H O
- 22. 20 Rate estimation rulesare organized in a tree Part of the tree for X
- 23. Part of thetree for Y 21
- 24. Ideal tree: lotsof data 22
- 25. Typical tree: sparsedata 23
- 26. 24 So that wasRMG... ...but what about TS geometries?
- 27. Single method notfeasible for all reaction types Intra-H migration Intra-OH migration Birad recombination Intra R addition exocyclic Intra R addition endocyclic 1,2 birad to alkene Beta scission Diels-alder Radical recombination Radical addition Peroxyradical HO2 elimination 1+2/2+2 cycloaddition Cyclic ether formation 1,2 insertion 1,3 insertion CO2/ROR Radical addition COO radical recombination H abstraction Dispropotionation 25
- 28. But a singlemethod can apply to multiple reaction types A B A B + C A + B C + D Intra-H migration Intra-OH migration Birad recombination Intra R addition exocyclic Intra R addition endocyclic 1,2 birad to alkene Beta scission Diels-alder Radical recombination Radical addition 1+2/2+2 cycloaddition Cyclic ether formation 1,2 insertion 1,3 insertion CO2/ROR Radical addition CO O radical recombination H abstraction Dispropotionation Peroxyradical HO2 elimination 26
- 29. Want robust anduser-friendly 3D representation •Internal coordinates •Alter distances and angles •Cartesian coordinates •Translate, rotate atoms •Distance geometry •Alter only distances Atom X Y Z 1 x1 y1 z1 2 x2 y2 z2 3 x3 y3 z3 4 x4 y4 z4 27
- 30. Use RDKit’s geometryediting tools for atom positioning ⇌RMG Molecule Connectivity 3D Structure 28
- 31. Use RDKit’s geometryediting tools for atom positioning ⇌RMG Molecule Connectivity Atoms List AtomsList Upper limits Lower limits Generate bounds matrix Embed in 3D 28
- 32. Use RDKit’s geometryediting tools for atom positioning ⇌RMG Molecule Connectivity Atoms List AtomsList Upper limits Lower limits Generate bounds matrix Atoms List AtomsList Embed in 3D Edit bounds matrix 28
- 33. C H HH H O O H C H H H H O O H 0 1.12 1.12 1.12 1.12 1000 1000 1000 1.1 0 1.86 1.86 1.86 1000 1000 1000 1.1 1.78 0 1.86 1.86 1000 1000 1000 1.1 1.78 1.78 0 1.86 1000 1000 1000 1.1 1.78 1.78 1.78 0 1000 1000 1000 3.65 2.9 2.9 2.9 2.9 0 1.33 1.04 3.65 2.9 2.9 2.9 2.9 1.31 0 1.97 3.15 2.4 2.4 2.4 2.4 1.02 1.89 0 Edit multiple distances to precisely position atoms involved in reactions 29
- 34. C H HH H O O H C H H H H O O H 0 1.12 1.12 1.12 1.12 1000 1000 1000 1.1 0 1.86 1.86 1.86 1000 1000 1000 1.1 1.78 0 1.86 1.86 1000 1000 1000 1.1 1.78 1.78 0 1.86 1000 1000 1000 1.1 1.78 1.78 1.78 0 1000 1000 1000 3.65 2.9 2.9 2.9 2.9 0 1.33 1.04 3.65 2.9 2.9 2.9 2.9 1.31 0 1.97 3.15 2.4 2.4 2.4 2.4 1.02 1.89 0 Edit multiple distances to precisely position atoms involved in reactions 29
- 35. C H HH H O O H C H H H H O O H 0 1.12 1.12 1.12 1.12 1000 1000 1000 1.1 0 1.86 1.86 1.86 1000 1000 1000 1.1 1.78 0 1.86 1.86 1000 1000 1000 1.1 1.78 1.78 0 1.86 1000 1000 1000 1.1 1.78 1.78 1.78 0 1000 1000 1000 3.65 2.9 2.9 2.9 2.9 0 1.33 1.04 3.65 2.9 2.9 2.9 2.9 1.31 0 1.97 3.15 2.4 2.4 2.4 2.4 1.02 1.89 0 Edit multiple distances to precisely position atoms involved in reactions 29
- 36. C H HH H O O H C H H H H O O H 0 1.12 1.12 1.12 1.12 1000 1000 1000 1.1 0 1.86 1.86 1.86 1000 1000 1000 1.1 1.78 0 1.86 1.86 1000 1000 1000 1.1 1.78 1.78 0 1.86 1000 1000 1000 1.1 1.78 1.78 1.78 0 1000 1000 1000 3.65 2.9 2.9 2.9 2.9 0 1.33 1.04 3.65 2.9 2.9 2.9 2.9 1.31 0 1.97 3.15 2.4 2.4 2.4 2.4 1.02 1.89 0 Edit multiple distances to precisely position atoms involved in reactions 29
- 37. C H HH H O O H C H H H H O O H 0 1.12 1.12 1.12 1.12 1000 1000 1000 1.1 0 1.86 1.86 1.86 1000 1000 1000 1.1 1.78 0 1.86 1.86 1000 1000 1000 1.1 1.78 1.78 0 1.86 1000 1000 1000 1.1 1.78 1.78 1.78 0 1000 1000 1000 3.65 2.9 2.9 2.9 2.9 0 1.33 1.04 3.65 2.9 2.9 2.9 2.9 1.31 0 1.97 3.15 2.4 2.4 2.4 2.4 1.02 1.89 0 Edit multiple distances to precisely position atoms involved in reactions 2.0 2.1 29
- 38. C H HH H O O H C H H H H O O H 0 1.12 1.12 1.12 1.12 1000 1000 1000 1.1 0 1.86 1.86 1.86 1000 1000 1000 1.1 1.78 0 1.86 1.86 1000 1000 1000 1.1 1.78 1.78 0 1.86 1000 1000 1000 1.1 1.78 1.78 1.78 0 1000 1000 1000 3.65 2.9 2.9 2.9 2.9 0 1.33 1.04 3.65 2.9 2.9 2.9 2.9 1.31 0 1.97 3.15 2.4 2.4 2.4 2.4 1.02 1.89 0 Edit multiple distances to precisely position atoms involved in reactions 2.0 2.1 29
- 39. C H HH H O O H C H H H H O O H 0 1.12 1.12 1.12 1.12 1000 1000 1000 1.1 0 1.86 1.86 1.86 1000 1000 1000 1.1 1.78 0 1.86 1.86 1000 1000 1000 1.1 1.78 1.78 0 1.86 1000 1000 1000 1.1 1.78 1.78 1.78 0 1000 1000 1000 3.65 2.9 2.9 2.9 2.9 0 1.33 1.04 3.65 2.9 2.9 2.9 2.9 1.31 0 1.97 3.15 2.4 2.4 2.4 2.4 1.02 1.89 0 Edit multiple distances to precisely position atoms involved in reactions 2.0 2.1 2.5 2.6 29
- 40. C H HH H O O H C H H H H O O H 0 1.12 1.12 1.12 1.12 1000 1000 1000 1.1 0 1.86 1.86 1.86 1000 1000 1000 1.1 1.78 0 1.86 1.86 1000 1000 1000 1.1 1.78 1.78 0 1.86 1000 1000 1000 1.1 1.78 1.78 1.78 0 1000 1000 1000 3.65 2.9 2.9 2.9 2.9 0 1.33 1.04 3.65 2.9 2.9 2.9 2.9 1.31 0 1.97 3.15 2.4 2.4 2.4 2.4 1.02 1.89 0 Edit multiple distances to precisely position atoms involved in reactions 2.0 2.1 2.5 2.6 29
- 41. Double-ended algorithms find transitionstate estimates Reactants Products 30
- 42. Double-ended algorithms find transitionstate estimates Reactants Products 30
- 43. R P Position molecules for double-endedsearches 31
- 44. R P Best guess: justeither side of TS 32
- 45. Method tested with semi-empiricalcalculations •Two double-ended algorithms tested •QST2 at PM6 in Gaussian09 •SADDLE at PM7 in MOPAC2012 •Reaction path analysis validated the saddle points Generate Bounds Matrix Edit Bounds Matrix close to TS Embed Matrix in 3D Reaction from RMG Optimize TS geometry Generate Bounds Matrix Edit Bounds Matrix close to TS Embed Matrix in 3D Double- ended Search Reactants Products IRC Calculation 33
- 46. Path analysis algorithmsdescend to find the reactants and products R P 34
- 47. Path analysis algorithmsdescend to find the reactants and products R P 34
- 48. Path analysis algorithmsdescend to find the reactants and products R P 34
- 49. Path analysis algorithmsdescend to find the reactants and products R P 34
- 50. TS search and refinement Reaction path analysis Compare to desired reactants &products Embed geometry either side of TS Get bounds matrix Fail Succeed FailFail H. .OH other radical .OH other radical A closer look at the automatic TS search process for H abstraction 35 338 Reactions from the NIST Database
- 51. TS search and refinement Reaction path analysis Compare to desired reactants &products Embed geometry either side of TS Get bounds matrix Fail Succeed FailFail H. .OH other radical .OH other radical A closer look at the automatic TS search process for H abstraction 35 VdW collisions 338 Reactions from the NIST Database
- 52. TS search and refinement Reaction path analysis Compare to desired reactants &products Embed geometry either side of TS Get bounds matrix Fail Succeed FailFail H. .OH other radical .OH other radical A closer look at the automatic TS search process for H abstraction 35 VdW collisions No TS at this ES level 338 Reactions from the NIST Database
- 53. TS search and refinement Reaction path analysis Compare to desired reactants &products Embed geometry either side of TS Get bounds matrix Fail Succeed FailFail H. .OH other radical .OH other radical A closer look at the automatic TS search process for H abstraction 35 VdW collisions No TS at this ES level 338 Reactions from the NIST Database
- 54. TS search and refinement Reaction path analysis Compare to desired reactants &products Embed geometry either side of TS Get bounds matrix Fail Succeed FailFail H. .OH other radical .OH other radical A closer look at the automatic TS search process for H abstraction 35 VdW collisions No TS at this ES level 338 Reactions from the NIST Database
- 55. TS search and refinement Reaction path analysis Compare to desired reactants &products Embed geometry either side of TS Get bounds matrix Fail Succeed FailFail H. .OH other radical .OH other radical A closer look at the automatic TS search process for H abstraction 35 VdW collisions No TS at this ES level 338 Reactions from the NIST Database Bond perception
- 56. Species matching returnedfalse negatives due to incorrect bond order perception. CH4 36 R P Observed: Expected:
- 57. Species matching returnedfalse negatives due to incorrect bond order perception. Connect the dots CH4 36 R P Observed: Expected:
- 58. Species matching returnedfalse negatives due to incorrect bond order perception. Connect the dots Perceive bond order CH4 36 R P Observed: Expected:
- 59. Species matching returnedfalse negatives due to incorrect bond order perception. Connect the dots Perceive bond order CH4 CH4 Check valencies 36 R P Observed: Expected:
- 60. Species matching returnedfalse negatives due to incorrect bond order perception. Connect the dots Perceive bond order CH4 CH4 Check valencies 36 R P Observed: Expected:
- 61. Species matching returnedfalse negatives due to incorrect bond order perception. Connect the dots Perceive bond order CH4 CH4 Check valencies Check valencies CH4 36 R P Observed: Expected:
- 62. TS search and refinement Reaction path analysis Compare to desired reactants &products Embed geometry either side of TS Get bounds matrix Fail Succeed FailFail H. .OH other radical .OH other radical Most failures involve reactions with small molecules 37 VdW collisions No TS at this ES level Bond perception
- 63. Small radicals needto be closer to the molecule they are abstracting from 38 •All abstractions by H. failed •Many with other small radicals (eg. .OH) also failed
- 64. Small radicals needto be closer to the molecule they are abstracting from 38 •All abstractions by H. failed •Many with other small radicals (eg. .OH) also failed
- 65. TS search and refinement Reaction path analysis Compare to desired reactants &products Embed geometry either side of TS Get bounds matrix Fail Succeed FailFail H. .OH other radical .OH other radical Learn from the successful saddle points to improve automatic searches 39 VdW collisions No TS at this ES level Bond perception
- 66. Semi-empirical estimates usedfor DFT calculations 40 •Check semi-empirical geometry validity •Use geometry as input to DFT calculations •Check DFT geometry validity Generate Bounds Matrix Edit Bounds Matrix close to TS Embed Matrix in 3D Reaction from RMG Optimize TS geometry Generate Bounds Matrix Edit Bounds Matrix close to TS Embed Matrix in 3D Double- ended Search Reactants Products IRC Calculation Optimize TS geometry at DFT IRC Calculation at DFT
- 67. Trends observed inDFT saddle point geometries 41 Structure method: Basis set: M06-2X 6-31+G(d,p) X Y• H
- 68. Trends observed inDFT saddle point geometries 41 Structure method: Basis set: M06-2X 6-31+G(d,p) X Y• H
- 69. Trends observed inDFT saddle point geometries 41 Structure method: Basis set: M06-2X 6-31+G(d,p) X Y• H
- 70. Trends observed inDFT saddle point geometries 41 Structure method: Basis set: M06-2X 6-31+G(d,p) X Y• H
- 71. Estimate geometry directlyvia group additive distance estimates 42 Generate Bounds Matrix Edit Bounds Matrix close to TS Embed Matrix in 3D Reaction from RMG Optimize TS geometry Generate Bounds Matrix Edit Bounds Matrix close to TS Embed Matrix in 3D Double- ended SearchReactants Products IRC Calculation Generate Bounds Matrix Edit Bounds Matrix for TS Embed Matrix in 3D •Database arranged in tree structure as for kinetics •Trained on successfully optimized transition states •Direct guess much faster than double ended search •Success depends on training data
- 72. Comparison of thedeveloped methods 43 Double-Ended Searches Direct Estimates Input requirements 2 rough estimates 1 good estimate Distance specifications One rule for all Group based estimates Optimization Methods QST2, SADDLE, Surface Walking Surface Walking Computational Speed Slower Faster Small radical reactions Problematic Better Multiple conformers Problematic Possible
- 73. Contributions •Explained Reaction MechanismGenerator RMG. •Created framework to find TS geometries using RMG and RDKit for distance geometry. •Categorized reaction families, and chose H-abstraction as first target. •Implemented double-ended TS searches that work with no training data. •Identified trends in functional group contributions to TS geometries. •Implemented direct guesses based on group additive estimates, and started to train group values. 44 Departmentof Chemical Engineering