{"doi":"10.1021/acs.joc.3c02495","title":"Proton Affinity and Conformational Integrity of a 24-Atom Triazine Macrocycle across Physiologically Relevant pH","abstract":"For 24-atom triazine macrocycles, protonation of the heterocycle leads to a rigid, folded structure presenting a network of hydrogen bonds. These molecules derive from dynamic covalent chemistry wherein triazine monomers bearing a protected hydrazine group and acetal tethered by the amino acid dimerize quantitatively in an acidic solution. Here, lysine is used, and the product is a tetracation. The primary amines of the lysine side chains do not interfere with quantitative yields of the desired bis(hydrazone) at concentrations of 5–125 mg/mL. Mathematical modeling of data derived from titration experiments of the macrocycle reveals that the p K a values of the protonated triazines are 5.6 and 6.7. Changes in chemical shifts of resonances in the 1 H NMR spectra corroborate these values and further support assignment of the protonation sites. The p K a values of the lysine side chains are consistent with expectation. Upon deprotonation, the macrocycle enjoys greater conformational freedom as evident from the broadening of resonances in the 1 H and 13 C NMR spectra indicative of dynamic motion on the NMR time scale and the appearance of additional conformations at room temperature. While well-tempered metadynamics suggests only a modest difference in accessible conformational footprints of the protonated and deprotonated macrocycles, the shift in conformation(s) supports the stabilizing role that the protons adopt in the hydrogen-bonded network.","journal":"The Journal of Organic Chemistry","year":2024,"id":459162,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9514,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1285950,"name":"Zachary P. Jacobus","orcid":"0009-0009-3896-9574","position":1,"is_corresponding":false},{"id":1107408,"name":"Liam E. Claton","orcid":"0000-0002-4030-0281","position":2,"is_corresponding":false},{"id":1285951,"name":"Onofrio Annunziata","orcid":"0000-0002-6636-4750","position":3,"is_corresponding":false},{"id":1107411,"name":"Riccardo Capelli","orcid":"0000-0001-9522-3132","position":4,"is_corresponding":false},{"id":1107410,"name":"Giovanni M. Pavan","orcid":"0000-0002-3473-8471","position":5,"is_corresponding":false},{"id":418567,"name":"Eric E. Simanek","orcid":"0000-0002-3195-4523","position":6,"is_corresponding":false},{"id":1081884,"name":"Alexander J. Menke","orcid":"0000-0001-9573-7045","position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":null,"created_at":"2026-07-19T02:03:55.280882Z","pmid":"38299798","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}