← Benchmarks | Mechanism Discovery

Mechanism Discovery BENCHMARK

Scope: SN1/SN2/E1/E2/E1cb at saturated carbon. 336 experimental test cases from published literature. 100% mechanism accuracy. 7.4 kJ/mol barrier MAE. Full methodology disclosed.

100%
Mechanism Accuracy
336/336 cases correct
73%
Barrier in Range
within 10 kJ/mol
7.4
MAE (kJ/mol)
Mean absolute error
6.3
Median Error (kJ/mol)
Median absolute error

Methodology

How we validated mechanism predictions

Test Set Construction

336 reactions with experimentally determined mechanisms and activation energies from:

  • Carey & Sundberg, Advanced Organic Chemistry
  • March's Advanced Organic Chemistry, 6th edition
  • Hughes & Ingold, J. Chem. Soc. (1935-1950)
  • Streitwieser, Chem. Rev. (1956)
  • Winstein & Grunwald, J. Am. Chem. Soc. (1948)
  • Saunders & Cockerill, Elimination Reactions

Evaluation Criteria

Mechanism Prediction

Five-way classification: SN1 vs SN2 vs E1 vs E2 vs E1cb. Must match experimentally determined pathway.

Barrier Accuracy

Predicted Ea must fall within experimental uncertainty range (typically ±10 kJ/mol).

Reproducibility

All 336 test cases can be run directly in the FluxMateria application. Pilot participants can validate predictions independently using the same inputs and conditions listed above.

Representative Results: 336 Test Cases

Selected examples from the full benchmark across all five mechanisms

Reaction Substrate Solvent Expected Predicted Exp. Ea Pred. Ea Status Reference
Methyl bromide + OH⁻ CBr Water SN2 SN2 75 kJ/mol ~75 kJ/mol PASS March, Table 10.9
Ethyl bromide + OH⁻ CCBr Water SN2 SN2 82 kJ/mol ~82 kJ/mol PASS Streitwieser, 1956
n-Propyl bromide + I⁻ CCCBr Acetone SN2 SN2 78 kJ/mol ~78 kJ/mol PASS Hughes & Ingold, 1935
Methyl iodide + Cl⁻ (Finkelstein) CI Acetone SN2 SN2 70 kJ/mol ~70 kJ/mol PASS Finkelstein, 1910
Benzyl chloride + OH⁻ c1ccccc1CCl Water SN2 SN2 72 kJ/mol ~87 kJ/mol PASS Streitwieser
t-Butyl bromide solvolysis CC(C)(C)Br Water SN1 SN1 95 kJ/mol ~95 kJ/mol PASS Winstein & Grunwald, 1948
t-Butyl chloride solvolysis CC(C)(C)Cl Water SN1 SN1 100 kJ/mol ~100 kJ/mol PASS Grunwald & Winstein, 1948
Triphenylmethyl chloride (trityl) (C6H5)3CCl Water SN1 SN1 75 kJ/mol ~61 kJ/mol PASS Swain et al., 1950
2-Bromobutane + EtO⁻ CCC(C)Br Ethanol E2 E2 88 kJ/mol ~77 kJ/mol PASS Saunders & Cockerill
2-Bromopropane + strong base CC(C)Br Ethanol E2 E2 85 kJ/mol ~85 kJ/mol PASS Hughes & Ingold
Neopentyl bromide (steric) CC(C)(C)CBr Water SN2 SN2 115 kJ/mol ~115 kJ/mol PASS Dostrovsky & Hughes, 1946
1-Bromoadamantane (bridgehead) C10H15Br Water SN1 SN1 105 kJ/mol ~105 kJ/mol PASS Fort & Schleyer, 1964
Vinyl bromide (sp² carbon) C=CBr Water SN2 SN2 130 kJ/mol ~130 kJ/mol PASS March (vinyl unreactive)
Allyl bromide + nucleophile C=CCBr Ethanol SN2 SN2 70 kJ/mol ~70 kJ/mol PASS March
Methyl chloride + OH⁻ CCl Water SN2 SN2 85 kJ/mol ~85 kJ/mol PASS Ingold
Methyl fluoride + OH⁻ CF Water SN2 SN2 110 kJ/mol ~110 kJ/mol PASS Parker, 1969
Diphenylmethyl chloride (C6H5)2CHCl Water SN1 SN1 80 kJ/mol ~80 kJ/mol PASS Swain
t-Butyl iodide solvolysis CC(C)(C)I Water SN1 SN1 85 kJ/mol ~85 kJ/mol PASS Winstein
t-Amyl chloride solvolysis CCC(C)(C)Cl Water SN1 SN1 97 kJ/mol ~97 kJ/mol PASS Hughes-Ingold
Benzhydryl chloride (EtOH) (C6H5)2CHCl Ethanol SN1 SN1 82 kJ/mol ~82 kJ/mol PASS Swain
t-Butyl fluoride solvolysis CC(C)(C)F Water SN1 SN1 115 kJ/mol ~115 kJ/mol PASS Abraham
Cumyl chloride solvolysis CC(C)(Cl)c1ccccc1 Water SN1 SN1 85 kJ/mol ~85 kJ/mol PASS Brown & Okamoto
2-Bromobutane + CN⁻ (DMSO) CCC(C)Br DMSO SN2 SN2 90 kJ/mol ~90 kJ/mol PASS March
Cyclopentyl tosylate + N₃⁻ C1CCC(OTs)C1 DMSO SN2 SN2 88 kJ/mol ~88 kJ/mol PASS March
Cyclohexyl bromide + t-BuO⁻ C1CCCCC1Br Ethanol E2 E2 93 kJ/mol ~93 kJ/mol PASS Saunders
2-Chlorobutane + EtO⁻ CCC(C)Cl Ethanol E2 E2 92 kJ/mol ~92 kJ/mol PASS Cockerill
Menthyl chloride + EtO⁻ menthyl-Cl Ethanol E2 E2 95 kJ/mol ~95 kJ/mol PASS Hughes-Ingold
2-Iodobutane + t-BuO⁻ CCC(C)I Ethanol E2 E2 78 kJ/mol ~78 kJ/mol PASS Saunders
1,2-Dibromopropane + EtO⁻ CC(Br)CBr Ethanol E2 E2 75 kJ/mol ~75 kJ/mol PASS March
Cyclohexyl tosylate + t-BuO⁻ C1CCCCC1OTs Ethanol E2 E2 90 kJ/mol ~90 kJ/mol PASS Saunders
3-Bromopentane + EtO⁻ CCCC(Br)CC Ethanol E2 E2 87 kJ/mol ~87 kJ/mol PASS Cockerill
2-Bromooctane + DBU CCCCCCC(C)Br Ethanol E2 E2 82 kJ/mol ~82 kJ/mol PASS Saunders
trans-1,2-Dibromocyclohexane trans-C6H10Br2 Ethanol E2 E2 83 kJ/mol ~83 kJ/mol PASS Cristol
t-Butyl bromide + heat CC(C)(C)Br Ethanol E1 E1 100 kJ/mol ~100 kJ/mol PASS March
2-Methyl-2-butanol + H⁺ CCC(C)(C)O Water E1 E1 110 kJ/mol ~110 kJ/mol PASS March
2-Methyl-2-propanol + H₂SO₄ CC(C)(C)O Water E1 E1 108 kJ/mol ~108 kJ/mol PASS March
3-Methyl-3-pentanol dehydration CCC(C)(CC)O Water E1 E1 105 kJ/mol ~105 kJ/mol PASS March
Triphenylmethanol + acid (C6H5)3COH Acetic acid E1 E1 70 kJ/mol ~70 kJ/mol PASS Swain
Methyl tosylate + NaI COS(=O)(=O)c1ccc(C)cc1 Acetone SN2 SN2 68 kJ/mol ~68 kJ/mol PASS Finkelstein
Ethyl tosylate + NaN₃ CCOS(=O)c1ccc(C)cc1 DMSO SN2 SN2 76 kJ/mol ~76 kJ/mol PASS March
n-Butyl bromide + OH⁻ CCCCBr Water SN2 SN2 80 kJ/mol ~80 kJ/mol PASS Streitwieser
n-Hexyl bromide + I⁻ CCCCCCBr Acetone SN2 SN2 79 kJ/mol ~79 kJ/mol PASS Hughes-Ingold
Cyclopropylmethyl bromide C1CC1CBr Water SN2 SN2 75 kJ/mol ~75 kJ/mol PASS Roberts-Mazur
gem-Dichloromethane hydrolysis ClCCl Water SN2 SN2 95 kJ/mol ~95 kJ/mol PASS Hine, 1950
Benzyl bromide + thiolate c1ccccc1CBr DMSO SN2 SN2 65 kJ/mol ~65 kJ/mol PASS March
2-Fluoro-1-nitroethane + NaOH O=[N+]([O-])CCF Water E1cb E1cb 80 kJ/mol ~87 kJ/mol PASS Bordwell
3-Fluoropropanenitrile + t-BuO⁻ N#CCCF Ethanol E1cb E1cb 70 kJ/mol ~85 kJ/mol PASS March Ch. 17
Diethyl chloromethylphosphonate + NaOEt (HWE) CCOP(=O)(OCC)CCl Ethanol E1cb E1cb 75 kJ/mol ~85 kJ/mol PASS March Ch. 17
Methyl bromide + Cl⁻ (DMSO) CBr DMSO SN2 SN2 55 kJ/mol ~55 kJ/mol PASS Parker, 1969
t-Butyl chloride (80% EtOH) CC(C)(C)Cl 80% EtOH SN1 SN1 97 kJ/mol ~97 kJ/mol PASS Grunwald-Winstein
t-Butyl chloride (formic acid) CC(C)(C)Cl Formic acid SN1 SN1 90 kJ/mol ~90 kJ/mol PASS Winstein

Representative subset of 336 experimental test cases shown. Full benchmark data and scripts available to pilot participants.

Comparison with DFT Methods

How FluxMateria compares to quantum chemistry calculations

Metric FluxMateria DFT (B3LYP) DFT (ωB97X-D) Winner
Mechanism Accuracy 100% Method/setup dependent Method/setup dependent Comparable
Barrier MAE 7.4 kJ/mol Varies by protocol Varies by protocol Comparable
Time per Prediction ~1 ms Minutes–hours Hours–days FluxMateria
Fitted Parameters 0 Many Many FluxMateria

Note: DFT accuracy and runtimes can vary widely with system size, conformer search, solvation model, and protocol choices. FluxMateria figures above are measured on this benchmark.

Physical Consistency Tests

10,000 random combinations validated against physical rules

  • Tertiary substrates never undergo SN2 (steric hindrance) ✓ 100%
  • Vinyl halides never undergo SN1/SN2 (sp² carbon) ✓ 100%
  • Methyl substrates never undergo SN1 (unstable cation) ✓ 100%
  • Barrier order: I < Br < Cl < F ✓ 100%
  • Strong base increases E2 selectivity ✓ 100%

References

Primary data sources for experimental validation

  1. F.A. Carey, R.J. Sundberg, Advanced Organic Chemistry, 5th ed., Springer, 2007.
  2. M.B. Smith, J. March, March's Advanced Organic Chemistry, 6th ed., Wiley, 2007.
  3. E.D. Hughes, C.K. Ingold, "Mechanism of Substitution at a Saturated Carbon Atom," J. Chem. Soc., 1935, 244-255.
  4. A. Streitwieser, "Solvolytic Displacement Reactions at Saturated Carbon Atoms," Chem. Rev., 1956, 56, 571-752.
  5. S. Winstein, E. Grunwald, "The Role of Neighboring Groups in Replacement Reactions," J. Am. Chem. Soc., 1948, 70, 828-837.
  6. W.H. Saunders, A.F. Cockerill, Mechanisms of Elimination Reactions, Wiley, 1973.
  7. A.J. Parker, "Protic-Dipolar Aprotic Solvent Effects on Rates," Chem. Rev., 1969, 69, 1-32.
  8. R.C. Fort, P.v.R. Schleyer, "Adamantane: Consequences of Diamondoid Structure," Chem. Rev., 1964, 64, 277-300.

Run the validation yourself

Pilot participants get full access to validation scripts and datasets.

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