{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T20:12:19Z","timestamp":1789503139497,"version":"build-2803163510"},"reference-count":40,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2024,12,24]],"date-time":"2024-12-24T00:00:00Z","timestamp":1734998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NASA-Exobiology","award":["80NSSC24K0679"],"award-info":[{"award-number":["80NSSC24K0679"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Using computational methods, we examine if the presence of H2S can tame the unruly formose reaction by generating a free energy map of the reaction thermodynamics and kinetics of sulfur analogs within the core cycle. With mercaptoaldehyde as the linchpin C2 species, and feeding the cycle with CH2O, selected aldol additions and enolizations are kinetically more favorable. Thione formation is thermodynamically less favored compared to aldehydes and ketones, but all these species can be connected by enolization reactions. In some sulfur analogs, the retroaldol transformation of a C4 species back into linchpin species is thermodynamically favorable, and we have found one route incorporating where incorporating sulfur selects for a specific pathway over others. However, as CH2O diminishes, the aldol addition of larger species is less favorable for the sulfur analogs. Our results also suggest that competing Cannizzaro side reactions are kinetically less favored and thermodynamically disfavored when H2S is abundant.<\/jats:p>","DOI":"10.3390\/life15010001","type":"journal-article","created":{"date-parts":[[2024,12,24]],"date-time":"2024-12-24T02:50:56Z","timestamp":1735008656000},"page":"1","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Sulfur Analogs of the Core Formose Cycle: A Free Energy Map"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2472-1887","authenticated-orcid":false,"given":"Jeremy","family":"Kua","sequence":"first","affiliation":[{"name":"Department of Chemistry & Biochemistry, University of San Diego, San Diego, CA 92110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria T.","family":"Pe\u00f1a","sequence":"additional","affiliation":[{"name":"Department of Chemistry & Biochemistry, University of San Diego, San Diego, CA 92110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha N.","family":"Cotter","sequence":"additional","affiliation":[{"name":"Department of Chemistry & Biochemistry, University of San Diego, San Diego, CA 92110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Leca","sequence":"additional","affiliation":[{"name":"Department of Chemistry & Biochemistry, University of San Diego, San Diego, CA 92110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Xavier, J.C., Hordijk, W., Kauffman, S., Steel, M., and Martin, W.F. (2020). Autocatalytic chemical networks at the origin of metabolism. Proc. Biol. Sci., 287.","DOI":"10.1098\/rspb.2019.2377"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/S0065-2318(08)60250-4","article-title":"Synthesis and Utilization of Formose Sugars","volume":"29","author":"Mizuno","year":"1974","journal-title":"Adv. Carbohydr. Chem. Biochem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/S0040-4039(01)99487-0","article-title":"On the Mechanism of the Formose Reaction","volume":"1","author":"Breslow","year":"1959","journal-title":"Tetrahedron Lett."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3720","DOI":"10.1021\/ja410886c","article-title":"Deuterium studies reveal a new mechanism for the formose reaction involving hydride shifts","volume":"136","author":"Appayee","year":"2014","journal-title":"J. Am. Chem. Soc."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"9503","DOI":"10.1021\/jo061770h","article-title":"2-Hydroxymethylboronate as a reagent to detect carbohydrates: Application to the analysis of the formose reaction","volume":"71","author":"Ricardo","year":"2006","journal-title":"J. Org. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Omran, A., Menor-Salvan, C., Springsteen, G., and Pasek, M. (2020). The Messy Alkaline Formose Reaction and Its Link to Metabolism. Life, 10.","DOI":"10.3390\/life10080125"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1038\/s41557-022-00956-7","article-title":"Environmental conditions drive self-organization of reaction pathways in a prebiotic reaction network","volume":"14","author":"Robinson","year":"2022","journal-title":"Nat. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"7559","DOI":"10.1021\/jacs.3c00908","article-title":"Dynamic Environmental Conditions Affect the Composition of a Model Prebiotic Reaction Network","volume":"145","author":"Daines","year":"2023","journal-title":"J. Am. Chem. Soc."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e202316621","DOI":"10.1002\/anie.202316621","article-title":"Direct Analysis of Complex Reaction Mixtures: Formose Reaction","volume":"63","author":"Bris","year":"2024","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Paschek, K., Kohler, K., Pearce, B.K.D., Lange, K., Henning, T.K., Trapp, O., Pudritz, R.E., and Semenov, D.A. (2022). Possible Ribose Synthesis in Carbonaceous Planetesimals. Life, 12.","DOI":"10.3390\/life12030404"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"118558","DOI":"10.1016\/j.epsl.2023.118558","article-title":"Olivine-catalyzed glycolaldehyde and sugar synthesis under aqueous conditions: Application to prebiotic chemistry","volume":"626","author":"Vinogradoff","year":"2024","journal-title":"Earth Planet. Sci. Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1038\/s42004-020-00387-w","article-title":"Mineral-mediated carbohydrate synthesis by mechanical forces in a primordial geochemical setting","volume":"3","author":"Haas","year":"2020","journal-title":"Commun. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s11084-020-09599-5","article-title":"Plausibility of the Formose Reaction in Alkaline Hydrothermal Vent Environments","volume":"53","author":"Omran","year":"2023","journal-title":"Orig. Life Evol. Biosph."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1021\/ct401004r","article-title":"Complex Chemical Reaction Networks from Heuristics-Aided Quantum Chemistry","volume":"10","author":"Rappoport","year":"2014","journal-title":"J. Chem. Theory Comput."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6108","DOI":"10.1021\/acs.jctc.7b00945","article-title":"Context-Driven Exploration of Complex Chemical Reaction Networks","volume":"13","author":"Simm","year":"2017","journal-title":"J. Chem. Theory Comput."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1016\/j.chempr.2023.12.009","article-title":"Emergence of metabolic-like cycles in blockchain-orchestrated reaction networks","volume":"10","author":"Roszak","year":"2024","journal-title":"Chem"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"12658","DOI":"10.1021\/jp4098292","article-title":"Mapping the Kinetic and Thermodynamic Landscape of Formaldehyde Oligomerization under Neutral Conditions","volume":"117","author":"Kua","year":"2013","journal-title":"J. Phys. Chem. A"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Kua, J., Hernandez, A.L., and Velasquez, D.N. (2021). Thermodynamics of Potential CHO Metabolites in a Reducing Environment. Life, 11.","DOI":"10.3390\/life11101025"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Kua, J., and Miller, N.A. (2022). Preliminary Free Energy Map of Prebiotic Compounds Formed from CO2, H2 and H2S. Life, 12.","DOI":"10.3390\/life12111763"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Braakman, R., and Smith, E. (2013). The compositional and evolutionary logic of metabolism. Phys. Biol., 10.","DOI":"10.1088\/1478-3975\/10\/1\/011001"},{"key":"ref_21","first-page":"428","article-title":"The Beginnings of Life on Earth","volume":"83","year":"1995","journal-title":"Am. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1038\/nchem.2202","article-title":"Common origins of RNA, protein and lipid precursors in a cyanosulfidic protometabolism","volume":"7","author":"Patel","year":"2015","journal-title":"Nat. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2798","DOI":"10.1055\/a-1472-7914","article-title":"Sulfur Amino Acids: From Prebiotic Chemistry to Biology and Vice Versa","volume":"53","author":"Vallee","year":"2021","journal-title":"Synthesis-Stuttgart"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1128\/mr.52.4.452-484.1988","article-title":"Before enzymes and templates: Theory of surface metabolism","volume":"52","author":"Wachtershauser","year":"1988","journal-title":"Microbiol. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Kua, J., and Tripoli, L.P. (2024). Exploring the Core Formose Cycle: Catalysis and Competition. Life, 14.","DOI":"10.3390\/life14080933"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1021\/jp076573g","article-title":"Thermodynamics and Kinetics of Glyoxal Dimer Formation: A Computational Study","volume":"112","author":"Kua","year":"2008","journal-title":"J. Phys. Chem. A"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2997","DOI":"10.1021\/jp312202j","article-title":"Glycolaldehyde Monomer and Oligomer Equilibria in Aqueous Solution: Comparing Computational Chemistry and NMR Data","volume":"117","author":"Kua","year":"2013","journal-title":"J. Phys. Chem. A"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1139\/p80-159","article-title":"Accurate spin-dependent electron liquid correlation energies for local spin density calculations: A critical analysis","volume":"58","author":"Vosko","year":"1980","journal-title":"Can. J. Phys."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3098","DOI":"10.1103\/PhysRevA.38.3098","article-title":"Density-functional exchange-energy approximation with correct asymptotic behavior","volume":"38","author":"Becke","year":"1988","journal-title":"Phys. Rev. A"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1103\/PhysRevB.37.785","article-title":"Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density","volume":"37","author":"Lee","year":"1988","journal-title":"Phys. Rev. B"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5648","DOI":"10.1063\/1.464913","article-title":"Density-functional thermochemistry. III. The role of exact exchange","volume":"98","author":"Becke","year":"1993","journal-title":"J. Chem. Phys."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1002\/(SICI)1096-987X(199905)20:7<730::AID-JCC8>3.0.CO;2-T","article-title":"MMFF VII. Characterization of MMFF94, MMFF94s, and other widely available force fields for conformational energies and for intermolecular-interaction energies and geometries","volume":"20","author":"Halgren","year":"1999","journal-title":"J. Comput. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5950","DOI":"10.1073\/pnas.95.11.5950","article-title":"Computer simulations of enzyme catalysis: Finding out what has been optimized by evolution","volume":"95","author":"Warshel","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"8231","DOI":"10.1021\/ja0107733","article-title":"Chiral diamines 4: A computational study of the enantioselective deprotonation of Boc-pyrrolidine with an alkyllithium in the presence of a chiral diamine","volume":"123","author":"Wiberg","year":"2001","journal-title":"J. Am. Chem. Soc."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"7967","DOI":"10.1021\/ja031911m","article-title":"A computational model relating structure and reactivity in enantioselective oxidations of secondary alcohols by (-)-sparteine-Pd(II) complexes","volume":"126","author":"Nielsen","year":"2004","journal-title":"J. Am. Chem. Soc."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1039\/b601590e","article-title":"In silico evolution of substrate selectivity: Comparison of organometallic ruthenium complexes with the anticancer drug cisplatin","volume":"23","author":"Deubel","year":"2006","journal-title":"Chem. Comm."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"5316","DOI":"10.1021\/ja00536a033","article-title":"Relationship between the gas-phase entropies of molecules and their entropies of solvation in water and 1-octanol","volume":"102","author":"Wertz","year":"1980","journal-title":"J. Am. Chem. Soc."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6742","DOI":"10.1021\/ja00412a036","article-title":"Relationship between solution entropies and gas phase entropies of nonelectrolytes","volume":"103","author":"Abraham","year":"1981","journal-title":"J. Am. Chem. Soc."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"6994","DOI":"10.1021\/jp903213k","article-title":"Thermodynamics and Kinetics of Methylglyoxal Dimer Formation: A Computational Study","volume":"113","author":"Krizner","year":"2009","journal-title":"J. Phys. Chem. A"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4479","DOI":"10.1021\/jp513020y","article-title":"NMR studies of the equilibria and reaction rates in aqueous solutions of formaldehyde","volume":"119","author":"Rivlin","year":"2015","journal-title":"J. Phys. Chem. B"}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/15\/1\/1\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:58:55Z","timestamp":1760115535000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/15\/1\/1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,24]]},"references-count":40,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["life15010001"],"URL":"https:\/\/doi.org\/10.3390\/life15010001","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,24]]}}}