finding transition states algorithmically for automatic reaction mechanism generation

Computational Modeling in Chemical Engineering

.edu/comocheng

Finding Transition States Algorithmically for Automatic Reaction Mechanism GenerationPierre L. BhoorasinghRichard H. West

Can you predict TS geometries from molecular groups alone?

(this would be great)

Length of bond being broken, at TS for Hydrogen abstraction

Molecule

Length of bond being broken, at TS for Hydrogen abstraction

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3in Å with M06-2X/6-31+G(d,p)

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in Å with M06-2X/6-31+G(d,p)

You can predict TS geometries from molecular groups alone!

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You can predict TS geometries from molecular groups alone!

But...

... you gave me a distance, not a geometry.

... I gave you 15 numbers then asked you for 1.

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.

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

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)

First Annual Conference of the Combustion Energy Frontier Research

Center (CEFRC)

September 23-24, 2010

Princeton

An introduction toReaction Mechanism Generator

Automatically builds detailed kinetic models

facebook.com/rmg.mitr m g . s o u rc e f o r g e . n e t

⇌RMG

Molecules are represented as graphs

CH3CH2. C C*

Thermochemistry is often estimated by Benson group contributions

C-(C)(H)3

C-(C)2(H)2

Cb-(H)

C-(C)(Cb)(O)(H)

Reaction families propose all possible reactions with given species

bond breaking and hydrogen abstraction

intramolecularH-abstraction

•Template for recognizing reactive sites

•Recipe for changing the bonding at the site

•Rules for estimating the rate

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

Octane autoxidation has many pathways

•Some pathways go further than others.

Faster pathways are explored further

Edge requires many reaction rates

100 species1,000 reactions

Edge requires many reaction rates

100 species1,000 reactions

15,000 species180,000 reactions

Rate estimates are based on the local structure of the reacting sites.

•Hydrogen abstraction: XH + Y. → X. + YH•Rate depends on X and Y.

Rate estimation rules are organized in a tree

Part of the tree for X

Part of the tree for Y21

Ideal tree: lots of data

Typical tree: sparse data

So that was RMG...

...but what about TS geometries?

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

But a single method can apply to multiple reaction types

A B A B + C A + B C + DIntra-H migrationIntra-OH migrationBirad recombinationIntra R addition exocyclicIntra R addition endocyclic1,2 birad to alkene

Beta scissionDiels-alderRadical recombinationRadical addition

1+2/2+2 cycloadditionCyclic ether formation1,2 insertion1,3 insertion CO2/RORRadical addition COO radical recombination

H abstractionDispropotionation

Peroxyradical HO2 elimination

Want robust and user-friendly3D 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

Use RDKit’s geometry editing toolsfor atom positioning

⇌RMGMolecule

Connectivity3D

Structure

⇌RMGMolecule

Connectivity

Atoms List

st Upper limits

Lower limitsGenerate bounds matrix

Embedin 3D

⇌RMGMolecule

Connectivity

Atoms List

st Upper limits

Lower limitsGenerate bounds matrix

Atoms List

Embed in 3D

Editbounds matrix

C H H H H O O HCHHHHOOH

0 1.12 1.12 1.12 1.12 1000 1000 10001.1 0 1.86 1.86 1.86 1000 1000 10001.1 1.78 0 1.86 1.86 1000 1000 10001.1 1.78 1.78 0 1.86 1000 1000 10001.1 1.78 1.78 1.78 0 1000 1000 10003.65 2.9 2.9 2.9 2.9 0 1.33 1.043.65 2.9 2.9 2.9 2.9 1.31 0 1.973.15 2.4 2.4 2.4 2.4 1.02 1.89 0

Edit multiple distances to preciselyposition atoms involved in reactions

0 1.12 1.12 1.12 1.12 1000 1000 10001.1 0 1.86 1.86 1.86 1000 1000 10001.1 1.78 0 1.86 1.86 1000 1000 10001.1 1.78 1.78 0 1.86 1000 1000 10001.1 1.78 1.78 1.78 0 1000 1000 10003.65 2.9 2.9 2.9 2.9 0 1.33 1.043.65 2.9 2.9 2.9 2.9 1.31 0 1.973.15 2.4 2.4 2.4 2.4 1.02 1.89 0

Double-ended algorithms findtransition state estimates

Reactants

Products30

Double-ended algorithms findtransition state estimates

Reactants

Products30

Position molecules fordouble-ended searches

Best guess: just either side of TS

Method tested withsemi-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 Matrixclose to TS

Embed Matrix in

3DReaction

from RMGOptimize TS geometry

Embed Matrix in

Double-ended Search

Reactants

Products

IRCCalculation

Path analysis algorithms descendto find the reactants and products

TS search and refinement

Reaction path analysis

Compare to desired reactants & products

Embed geometry either side of TS

Get bounds matrix

Succeed

FailFail

H. .OH otherradical

otherradical

A closer look at the automatic TS search process for H abstraction

338 Reactions from the NIST Database

Get bounds matrix

Succeed

FailFail

H. .OH otherradical

otherradical

VdW collisions

Get bounds matrix

Succeed

FailFail

H. .OH otherradical

otherradical

VdW collisions

No TS at this ES level

Get bounds matrix

Succeed

FailFail

H. .OH otherradical

otherradical

VdW collisions

Get bounds matrix

Succeed

FailFail

H. .OH otherradical

otherradical

VdW collisions

Get bounds matrix

Succeed

FailFail

H. .OH otherradical

otherradical

VdW collisions

Bond perception

Species matching returned false negativesdue to incorrect bond order perception.

Observed:

Expected:

Connectthe dots

Observed:

Expected:

Connectthe dots

Perceivebond order

Observed:

Expected:

Connectthe dots

Perceivebond order

Checkvalencies

Observed:

Expected:

Connectthe dots

Perceivebond order

Checkvalencies

Observed:

Expected:

Connectthe dots

Perceivebond order

Checkvalencies

Observed:

Expected:

Get bounds matrix

Succeed

FailFail

H. .OH otherradical

otherradical

Most failures involve reactions withsmall molecules

VdW collisions

Bond perception

Small radicals need to be closer to the molecule they are abstracting from

•All abstractions by H. failed•Many with other small radicals (eg. .OH) also failed

Small radicals need to be closer to the molecule they are abstracting from

•All abstractions by H. failed•Many with other small radicals (eg. .OH) also failed

Get bounds matrix

Succeed

FailFail

H. .OH otherradical

otherradical

Learn from the successful saddle pointsto improve automatic searches

VdW collisions

Bond perception

Semi-empirical estimates used forDFT calculations

•Check semi-empirical geometry validity•Use geometry as input to DFT calculations•Check DFT geometry validity

Embed Matrix in

3DReaction

Embed Matrix in

Double-ended Search

Reactants

Products

IRCCalculation

Optimize TSgeometry at

IRC Calculation

at DFT

Trends observed in DFTsaddle point geometries

Structure method:Basis set:

M06-2X6-31+G(d,p)

Estimate geometry directly viagroup additive distance estimates

Embed Matrix in

3DReaction

Embed Matrix in

Double-ended SearchReactants

Products

IRCCalculation

Edit Bounds Matrix

for TS

Embed Matrix in

•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

Comparison of the developed methods

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

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.

Department of Chemical Engineering

finding transition states algorithmically for automatic reaction mechanism generation

h h h h h

ts geometries

automatic ts searches

radical molecule

reaction rates

molecular groups

molecule reactions

reaction families

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