Reaction

1
Mol Orb Reactivity Proposal
Reaction Mixture
Molecular Orbital List
Mol Orb Enumerator
Reduced Mol Orb List
Stopping Criteria Analyzer
Mol Orb Compatibility Scoring
Revised Reaction Mixture
Scored Orbital Compatibility List
Reactor Iterator
2
Reaction Mixture
100
100
10

• Reaction Conditions
• Solvent Properties
• Temperature

3
Orbital Enumerator

• Largely done for core atoms, but need extra logic
  to handle
• S,P atoms (d orbitals)
• Resonance structure enumerator
• Extended orbital chaining (e.g., E2, Sn2)
• Orbital Reactivity Proposal
• Before full combinatorial reactivity
  compatibility check, pre-filter orbital list to
  exclude those are very unlikely to react

4
Molecular Orbital List

• Filled
• sp2 O
• p CO
• Unfilled
• p CO
• s HC ? p CO

• Filled
• sp3 O
• s CO
• Unfilled
• s HO
• s CO

• Filled
• sp3 O
• sp2 O
• Unfilled
• p SO
• s HO ? p SO

5
Orbital Reactivity / Compatibility

• Core challenge (rest is mostly accounting)
• Thermodynamic Scoring
• Relative energy / stability of structures
• Reaction conditions may influence (particularly
  stabilization of ions by solvation)
• Components like bond energies, ring strain,
  entropy, aromaticity, conjugation and resonance,
  hyperconjugation, formal charges, octet rule

6
Orbital Reactivity / Compatibility

• Kinetics / Transition State Scoring
• Estimated barrier to structures to react based on
  proposed orbital interaction
• Thermodynamic basis Klopman-Salem components
  like sterics, ionic character vs. orbital
  coefficients (HOMO-LUMO energies)
• Entropy considerations (number of molecules,
  rotatable bonds)

7
Scored Orbital Compatibility List
sp2 O (reactant 1) ? s HO (reactant 3) 2 kcal
/ mol sp3 O (reactant 2) ? s HO (reactant 3) 3
kcal / mol
8
Reactor Iterator

• Orbital Interaction Applicator
• Mostly done for core orbital interactions
• Generate / translate to curved arrows
• Need to implement stereospecificity logic
• Concentration / Prevalence model
• Use reactivity scores x concentrations to
  calculate probabilities on likely mechanistic
  steps (elementary reactions)
• Apply mechanistic steps to update reaction mix,
  but limit achievable transition states by
  reaction temperature

9
Revised Reaction Mixture
97
94
1
3
6
9
10
GUI

• Input of reaction mixtures
• Output of resulting reaction mixtures
• Traceback of core mechanistic steps of major
  products
• Qualitative free energy diagrams from tracebacks
• Interactive exploration / explanation. Select
  mixtures or orbital combinations to see systems
  score report
• Systems bio style tracking of molecule
  concentrations over time (iterations)

11
Proposed Reaction Predictor

• Proposes complete arrow-pushing mechanisms,
• Including reaction intermediates and
• Electron flow schematics
• Qualitative reaction energy coordinate diagrams
• Benchmark Solve problems that human experts can
  on paper

Relative Energy
DG
DG
Reaction Coordinate