A presentation given by Prof. Richard West at the 8th International Conference on Chemical Kinetics in Seville, Spain, on 12th of July 2013. The slides were designed to accompany the oral presentation and do not quite stand alone, so please email if you have any questions.

1. Computational Modeling in Chemical Engineering
.edu/comocheng
Finding Transition States Algorithmically for
Automatic Reaction Mechanism Generation
Pierre L. Bhoorasingh
Richard H. West
1

2. Can you predict TS geometries
from molecular groups alone?
2
(this would be great)

3. Length of bond being broken, at
TS for Hydrogen abstraction
Can you predict TS geometries
from molecular groups alone?
3
Radical
Molecule

4. Length of bond being 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 predict TS geometries
from molecular groups alone?
4
!"!#$ !"!%% !"!&' !"!($
!")() !")'& !"*+$ !"*!#
!")(' !")$% !"*%%
!")'+ !"*+& !"*&) !"*&$
!"#$# !"#$%!"!#$ !"#$%
in Å with M06-2X/6-31+G(d,p)

6. You can predict TS geometries
from molecular groups alone!
5
!"!#$ !"!%% !"!&' !"!($
!")() !")'& !"*+$ !"*!#
!")(' !")$% !"*%%
!")'+ !"*+& !"*&) !"*&$
!"#$%
in Å with M06-2X/6-31+G(d,p)

7. You can predict TS 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 State Theory (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 searches remain 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 searches remain 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
Reaction Mechanism Generator
Automatically builds detailed kinetic models
facebook.com/rmg.mit
rmg.sourceforge.net
10
⇌RMG

12. Molecules are represented as graphs
CH3CH2. C C*
H
H
H H
H
=
11

13. Thermochemistry is often estimated
by Benson group contributions
C-(C)(H)3
C-(C)2(H)2
Cb-(H)
C-(C)(Cb)(O)(H)
12

14. Reaction families propose all 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 propose all 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 has many pathways
15

17. •Some pathways go further than others.
16

18. Faster pathways are explored further
A
B
C
D
E
F
G
H
A
B
C
D
E
F
17

19. Edge requires many reaction rates
100 species
1,000 reactions
18

20. Edge requires many reaction rates
100 species
1,000 reactions
15,000 species
180,000 reactions
18

21. Rate estimates are based 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 rules are organized in a tree
Part of the tree for X

23. Part of the tree for Y
21

24. Ideal tree: lots of data
22

25. Typical tree: sparse data
23

26. 24
So that was RMG...
...but what about
TS geometries?

27. Single method not feasible
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 single method 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 and user-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 geometry editing tools
for atom positioning
⇌RMG
Molecule
Connectivity
3D
Structure
28

31. Use RDKit’s geometry editing 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 geometry editing 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 H H 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 H H 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 H H 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 H H 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 H H 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 H H 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 H H 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 H H 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
transition state estimates
Reactants
Products
30

42. Double-ended algorithms find
transition state estimates
Reactants
Products
30

43. R
P
Position molecules for
double-ended searches
31

44. R
P
Best guess: just either side of TS
32

45. Method tested with
semi-empirical calculations
•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 algorithms descend
to find the reactants and products
R
P
34

47. Path analysis algorithms descend
to find the reactants and products
R
P
34

48. Path analysis algorithms descend
to find the reactants and products
R
P
34

49. Path analysis algorithms descend
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 returned false negatives
due to incorrect bond order perception.
CH4
36
R
P
Observed:
Expected:

57. Species matching returned false negatives
due to incorrect bond order perception.
Connect
the dots
CH4
36
R
P
Observed:
Expected:

58. Species matching returned false negatives
due to incorrect bond order perception.
Connect
the dots
Perceive
bond order
CH4
36
R
P
Observed:
Expected:

59. Species matching returned false 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 returned false 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 returned false 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 need to 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 need to 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 used for
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 in DFT
saddle point geometries
41
Structure method:
Basis set:
M06-2X
6-31+G(d,p)
X
Y•
H

68. Trends observed in DFT
saddle point geometries
41
Structure method:
Basis set:
M06-2X
6-31+G(d,p)
X
Y•
H

69. Trends observed in DFT
saddle point geometries
41
Structure method:
Basis set:
M06-2X
6-31+G(d,p)
X
Y•
H

70. Trends observed in DFT
saddle point geometries
41
Structure method:
Basis set:
M06-2X
6-31+G(d,p)
X
Y•
H

71. Estimate geometry directly via
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 the developed 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 Mechanism Generator 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