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Mechanism

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Chemical mechanisms are the detailed step-by-step pathways by which chemical reactions occur. Understanding reaction mechanisms is crucial for the prediction of reaction outcomes and for informing the development of more accurate models. Within C-CAS, we strive to elucidate mechanistic information about chemical transformations by combining experimental and computational approaches such as DFT, coupled cluster, ML force fields (ex. AIMNET), linear regression, and transition state calculations.

Publications

  • Bartholomew, G.L.; Kraus, S.L.; Karas, L.J.; Carpaneto, F.; Bennett, R.; Sigman, M.S.; Yeung, C.S.; Sarpong, R. “14N to 15N Isotopic Exchange of Nitrogen Heteroaromatics through Skeletal Editing” ChemRxiv 2023 .10.26434/chemrxiv-2023-30dtw

  • Gensch T, dos Passos Gomes G, Friederich P, Peters E, Gaudin T, Pollice R, et al. A Comprehensive Discovery Platform for Organophosphorus Ligands for Catalysis. J. Am. Chem. Soc. 2022, 144 ASAP  https://pubs.acs.org/doi/full/10.1021/jacs.1c09718

  • Boiko, D.A. Reschützegger, T.; Sanchez-Lengeling, B.; Blau, S.M.; Gomes, G. Advancing molecular machine learning representations with stereoelectronics-infused molecular graphs Nature Mach. Intl. 2025, 7, 771-781  doi.org/10.1038/s42256-025-01031-9

  • Casetti, N.; Anstine, D.; Isayev, O.; Coley, C.W. Anticipating the Selectivity of Intramolecular Cyclization Reaction Pathways with Neural Network Potentials. J. Chem. Theor. Comp. 2025, 21, ASAP. https://doi.org/10.1021/acs.jctc.5c01161

  • Luchini, Guilian, and Robert Paton. "Bottom-up Atomistic Descriptions of Top-Down Macroscopic Measurements: Computational Benchmarks for Hammett Electronic Parameters." ACS Phys. Chem Au, 2024. ASAP https://pubs.acs.org/doi/10.1021/acsphyschemau.3c00045

  • Bartholomew, G.L.; Karas, L.J.; Eason, R.M.;Yeung, C.S.; Sigman, M.S.; Sarpong, R. Cheminformatic Analysis of Core-Atom Transformations in Pharmaceutically Relevant Heteroaromatics. J. Med. Chem. 2025, 68, 6027-6040. doi.org/10.1021/acs.jmedchem.4c02839

  • Matthews, A.D., Peters, E., Debenham, J.S., Gao, Q., Nyamiaka, M.D., Pan, J., Zhang, L.K., Dreher, S.D., Krska, S.W., Sigman, M.S. and Uehling, M.R., 2023. Cu Oxamate-Promoted Cross-Coupling of α-Branched Amines and Complex Aryl Halides: Investigating Ligand Function through Data Science. ACS Catalysis, 13(24), 16195-16206. doi https://doi.org/10.1021/acscatal.3c04566

  • Cadge, J.A.; Lozano, C.; Merriman, M.T.; Oblad, P.; Sigman, M.S.; Reisman, S.E. A Data Science-Guided Approach for the Development of Nickel-Catalyzed Homo-Diels–Alder Reactions. J. Am. Chem. Soc. 2025, 147, ASAP. doi.org/10.1021/jacs.5c09948

  • Gensch, T.; Smith, S.R; Colacot, T.J.; Timsina, Y.; Xu, G.; Glasspoole, B.W.; Sigman, M.S, Design and Application of a Screening Set for Monophosphine Ligands in Metal Catalysis. ACS Catal. 2022. 12, 13, 7773-7780.  https://doi.org/10.1021/acscatal.2c01970

  • Silva, J. D. J.;  Bartalucci, N.;  Jelier, B.;  Grosslight, S.;  Gensch, T.;  Schünemann, C.;  Müller, B.;  Kamer, P. C.;  Copéret, C.; Sigman, M. S., Development and Molecular Understanding of a Pd-catalyzed Cyanation of Aryl Boronic Acids Enabled by High-Throughput Experimentation and Data Analysis. Helv. Chim. Acta 2021. https://doi.org/10.1002/hlca.202100200

  • Feng, K., Raguram, E.R., Howard, J.R., Peters, E., Liu, C., Sigman, M.S.; Buchwald, S.L., Development of a Deactivation-Resistant Dialkylbiarylphosphine Ligand for Pd-Catalyzed Arylation of Secondary Amines. J. Am. Chem. Soc. 2024, 146 ASAP . https://doi.org/10.1021/jacs.4c09667

  • Liu, Z.; Vinkus, J.; Fu, Y.; Liu, P.; Noonan, K. J. T.; Isayev, O. Fast and Accurate Ring Strain Energy Predictions with Machine Learning and Application in Strain-Promoted Reactions. J. Am. Chem. Soc. Au 2025, 5, ASAP https://doi.org/10.1021/jacsau.5c00667

  • Crawford, J.M.; Gensch, T.; Sigman, M.S.; Elward, J.M.; Steves, J.E.  Impact of Phosphine Featurization Methods in Process Development. Org. Proc. Res. Dev. 2022, 26, 4, 1115-1123  https://doi.org/10.1021/acs.oprd.1c00357

  • Gallegos, L.C.; Luchini, G.; St John, P.C.; Kim, S.; Paton, R.S. Importance of Engineered and Learned Molecular Representations in Predicting Organic Reactivity, Selectivity, and Chemical Properties Acc. Chem. Res. 2021, 54, 4, 827-836.   https://pubs.acs.org/doi/10.1021/acs.accounts.0c00745

  • Keto, A., Guo, T., Gonnheimer, N., Zhang, X., Krenske, E.H., Wiest, O. Improving reaction prediction through chemically aware transfer learning. Digital Discovery. DOI: 10.1039/d4dd00412d

  • Newman-Stonebraker, Samuel; Smith, Sleight; Borowski, Julia; Peters, Ellyn; Gensch, Tobias; Johnson, Heather; Sigman, Matthew; Doyle, Abigail. Linking Mechanistic Analysis of Catalytic Reactivity Cliffs to Ligand Classification. ChemRxiv, May12, 2021. https://doi.org/10.26434/chemrxiv.14388557.v1

  • Gardner, K.E., De Lescure, L., Hardy, M.A., Tan, J., Sigman, M.S., Paton, R.S., Sarpong, R. Modular synthesis of aryl amines from 3-alkynyl-2-pyrones. Chem. Sci. 2024. doi: 10.1039/d4sc04885g

  • Wright, Brandon A., Taku Okada, Alessio Regni, Guilian Luchini, Shree Sowndarya S. V, Nattawadee Chaisan, Sebastian Kölbl, Sojung F. Kim, Robert S. Paton, and Richmond Sarpong. "Molecular Complexity-Inspired Synthetic Strategies toward the Calyciphylline A-Type Daphniphyllum Alkaloids Himalensine A and Daphenylline." Journal of the American Chemical Society. (2024). ASAP https://doi.org/10.1021/jacs.4c11252

  • LeSueur, A., Tao, N., Doyle, A., Sigman, M. Multi-Threshold Analysis for Chemical Space Mapping of Ni-Catalyzed Suzuki-Miyaura Couplings. Chemistry Europe. Eur. J. Org. Chem. 2024 e202400428. doi:10.1002-ejoc.202400428

  • Saebi, M.;  Nan, B.;  Herr, J.;  Wahlers, J.;  Guo, Z.; Zuranski, A. M.;  Kegej, T.;  Norrby, P.-O.;  Doyle, A. G.;  Wiest, O.; Chawla, N., Wiest, O. On the Use of Real-World Data Sets for Reaction Yield Prediction.  Chem. Sci., 2023, 14, 4997-5005.  https://doi.org/10.1039/D2SC06041H

  • Bartholomew, G.L., Kim, S.F., Oyamada, Y., Sbordone, F., Carroll, J.A., Jurczyk, J.E., Yeung, C.S., Barner-Kowoliik, C., Sarpong, R. Phototransposition of Indazoles to Benzimidazoles: Tautomer-Dependent Reactivity, Wavelength Dependence, and Continuous Flow Studies. Angew. Chem. Int. Ed. 2025. e202423803. https://doi.org/10.1002/anie.202423803

  • Jones, K.E.; Park, B.; Doering, N.A.; Baik, M.H.; Sarpong, R.  Rearrangements of the Chrysanthenol Core: Application to a Formal Synthesis of Xishacorene B. J. Am. Chem. Soc. 2021, 143, 20482–20490 https://doi.org/10.1021/jacs.1c10804

  • Zell D; Kingston C; Jermaks J; Smith S.R.; Seeger N; Wassmer J; Sirois, L.E.; Han, C.; Zhang, H.; Sigman, M.S.; Gossling, F., Stereoconvergent and -divergent Synthesis of Tetrasubstituted Alkenes by Nickel-Catalyzed Cross-Couplings. J. Am. Chem. Soc. 2021, 143, 45,19078 -19090. https://doi.org/10.1021/jacs.1c08399

  • Hardy, M.A.; Nan, B.; Wiest, O.; Sarpong, R.  Strategic elements in computer-aided retrosynthesis: A case study of the pupukeanane natural products Tetrahedron 2022, 103, 132584   https://doi.org/10.1016/j.tet.2021.132584

  • Treacy, S.M., Smith, A.L., Bergman, R.G., Raymond, K.N., Toste, F.D. Supramolecular Catalyzed Cascade Reduction of Azaarenes Interrogated via Data Science. J. Am. Chem. Soc. 2024. 146, 29792-29800. https://doi.org/10.1021/jacs.4c11482?urlappend=%3Fref%3DPDF&jav=VoR&rel=cite-as

  • Fadul, A., Cundari, T., Bertke, J., Toledo, S.A. Tetrad or triad? insights from a versatile Fe(II) structural and functional model of the 3-histidine 1-carboxylate tetrad in C–C bond cleaving dioxygenase enzymes. RSC Adv., 2026. 16, 8695 DOI: 10.1039/D5RA09716A

  • Gallarati, S., Bucci, E.M., Doyle, A.G. et al. Transferable enantioselectivity models from sparse data. Nature (2026). https://doi.org/10.1038/s41586-026-10239-7

  • Newman-Stonebraker, S. H.;  Smith, S. R.;  Borowski, J. E.;  Peters, E.;  Gensch, T.;  Johnson, H. C.;  Sigman, M. S.; Doyle, A. G., Univariate classification of phosphine ligation state and reactivity in cross-coupling catalysis. Science 2021, 374, 301-308  science.org/doi/10.1126/science.abj4213

  • Kariofillis S, Jiang S, Żurański A, Gandhi S, Martinez Alvarado J, Doyle A. Using Data Science to Guide Aryl Bromide Substrate Scope Analysis in a Ni/Photoredox-Catalyzed Cross-Coupling with Acetals as Alcohol-Derived Radical Sources. J. Am. Chem. Soc. 2022, 144 ASAP . https://pubs.acs.org/doi/10.1021/jacs.1c12203

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