{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:11:36Z","timestamp":1792789896775,"version":"4.5.0"},"reference-count":47,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T00:00:00Z","timestamp":1789862400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo","award":["1221383"],"award-info":[{"award-number":["1221383"]}],"id":[{"id":"https:\/\/ror.org\/05btm5233","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo","award":["1261636"],"award-info":[{"award-number":["1261636"]}],"id":[{"id":"https:\/\/ror.org\/05btm5233","id-type":"ROR","asserted-by":"crossref"}]},{"award":["1221383"],"award-info":[{"award-number":["1221383"]}],"id":[{"id":"https:\/\/ror.org\/05btm5233","id-type":"ROR","asserted-by":"publisher"}]},{"award":["1261636"],"award-info":[{"award-number":["1261636"]}],"id":[{"id":"https:\/\/ror.org\/05btm5233","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The conformational preferences of 2-substituted cyclic and acyclic ethers, arising from the anomeric effect, have been analyzed using the Relative Interacting Atomic Energy (RIAE) analysis within Molecular Electron Density Theory framework, using the M06-2X\/6-311G(d,p) level. Comparison of the equatorial-axial energy differences of substituted tetrahydropyrans and cyclohexanes enables the proposal of the anomeric \u03c4 index, which quantifies the excess axial stabilization of the tetrahydropyrans relative to the corresponding cyclohexane references and provides an operational estimate of the contribution associated with the O\u2013C\u2013X motif. The RIAE analysis reveals two distinct patterns in the distribution of the atomic energy contributions associated with anomeric stabilization, dominated by either intra-atomic or interatomic terms, which correlate with the period of the X atom. Accordingly, the studied compounds can be classified into two groups: Group I, comprising compounds with second-period X elements (X = N, O, and F), in which axial stabilization is dominated by favorable intra-atomic energy contributions within the basin of the anomeric carbon; and Group II, comprising compounds with third- and fourth-period X elements (X = S, Cl, and Br), in which stabilization is primarily associated with favorable interatomic energy contributions between the ether oxygen and the anomeric carbon atoms. This atomic energy-based analysis provides a complementary interpretation of the X-dependent conformational trends and identifies analogous energy contribution patterns in the cyclic and acyclic systems examined.<\/jats:p>","DOI":"10.3390\/molecules31183335","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T14:12:09Z","timestamp":1789999929000},"page":"3335","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Relative Interacting Atomic Energy Analysis of the Anomeric Effect in Cyclic and Acyclic O\u2013C\u2013X Systems"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2023-0108","authenticated-orcid":false,"given":"Luis R.","family":"Domingo","sequence":"first","affiliation":[{"name":"Independent Researcher, Av. Tirso de Molina 20, 46015 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8894-2710","authenticated-orcid":false,"given":"Mar","family":"R\u00edos-Guti\u00e9rrez","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, University of Valencia, Dr. Moliner 50, 46100 Burjassot, Spain"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6920-703X","authenticated-orcid":false,"given":"Patricia","family":"P\u00e9rez","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias, Escuela de Qu\u00edmica y Farmacia, Universidad San Sebasti\u00e1n, Campus Ciudad Universitaria, Av. del C\u00f3ndor 720, Ciudad Empresarial, Huechuraba, Santiago 8580704, Chile"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,20]]},"reference":[{"key":"ref_1","unstructured":"Carey, F.A., and Sundberg, R.J. (2008). Advanced Organic Chemistry. Part A: Structure and Mechanisms, Springer."},{"key":"ref_2","first-page":"1102","article-title":"Stability of glycosides to acid hydrolysis","volume":"37","author":"Edward","year":"1955","journal-title":"Chem. Ind."},{"key":"ref_3","unstructured":"Lemieux, R.U., and Chu, P. (1958). Abstract of Papers: 133rd National Meeting of the American Chemical Society, American Chemical Society."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1351\/pac197125030527","article-title":"Effects of unshared pairs of electrons and their solvation on conformational equilibria","volume":"25","author":"Lemieux","year":"1971","journal-title":"Pure Appl. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5019","DOI":"10.1016\/S0040-4020(01)90118-8","article-title":"Recent studies of the anomeric effect","volume":"48","author":"Juaristi","year":"1992","journal-title":"Tetrahedron"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Juaristi, E., and Cuevas, G. (1995). The Anomeric Effect, CRC Press.","DOI":"10.1055\/s-1995-3862"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"8880","DOI":"10.1002\/anie.201411185","article-title":"The Problem of Origins and Origins of the Problem: Influence of Language on Studies Concerning the Anomeric Effect","volume":"54","author":"Filloux","year":"2015","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.1139\/v65-298","article-title":"The Abnormal Conformations of Pyridinium \u03b1-Glycopyranosides","volume":"43","author":"Lemieux","year":"1965","journal-title":"Can. J. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1002\/anie.198602871","article-title":"Solvent Polarity and the Anomeric Effect","volume":"25","author":"Fuchs","year":"1986","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"9362","DOI":"10.1021\/jp001937p","article-title":"Ab Initio Study and NBO Interpretation of the Anomeric Effect in CH2(XH2)2 (X = N, P, As) Compounds","volume":"104","author":"Carballeira","year":"2000","journal-title":"J. Phys. Chem. A"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1016\/j.carres.2009.04.011","article-title":"The origin of the generalized anomeric effect: Possibility of CH\/n and CH\/pi hydrogen bonds","volume":"344","author":"Takahashi","year":"2009","journal-title":"Carbohydr. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1038\/nchem.721","article-title":"Computational evidence that hyperconjugative interactions are not responsible for the anomeric effect","volume":"2","author":"Mo","year":"2010","journal-title":"Nat. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1021\/ja00368a004","article-title":"Properties of atoms and bonds in hydrocarbon molecules","volume":"104","author":"Bader","year":"1982","journal-title":"J. Am. Chem. Soc."},{"key":"ref_14","unstructured":"Bader, R.F.W. (1994). Atoms in Molecules: A Quantum Theory, Oxford University Press."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1002\/jcc.20585","article-title":"Atoms in Molecules Interpretation of the Anomeric Effect in the O-C-O Unit","volume":"28","author":"Vila","year":"2007","journal-title":"J. Comput. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5242","DOI":"10.1021\/acs.joc.8b00707","article-title":"The Anomeric Effect: It\u2019s Complicated","volume":"83","author":"Wiberg","year":"2018","journal-title":"J. Org. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1039\/C2OB26818C","article-title":"The anomeric effect: The dominance of exchange effects in closed-shell systems","volume":"11","author":"Bauerfeldt","year":"2013","journal-title":"Org. Biomol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"084103","DOI":"10.1063\/1.3555760","article-title":"Origin of anomeric effect: A density functional steric analysis","volume":"134","author":"Huang","year":"2011","journal-title":"J. Chem. Phys."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1021\/ct0501093","article-title":"Interacting Quantum Atoms: A Correlated Energy Decomposition Scheme Based on the Quantum Theory of Atoms in Molecules","volume":"1","author":"Blanco","year":"2005","journal-title":"J. Chem. Theory Comput."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1007\/s00214-017-2113-z","article-title":"The ANANKE relative energy gradient (REG) method to automate IQA analysis over configurational change","volume":"136","author":"Thacker","year":"2017","journal-title":"Theor. Chem. Acc."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Khan, D., Duarte, L.J., and Popelier, P.L. (2022). An Interacting Quantum Atoms (IQA) and Relative Energy Gradient (REG) Analysis of the Anomeric Effect. Molecules, 27.","DOI":"10.3390\/molecules27155003"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"17613","DOI":"10.1021\/acs.joc.5c01876","article-title":"Multivariate Analysis of the Anomeric Effect: Balancing Hyperconjugation, Electrostatics, and Dispersion","volume":"90","author":"Kuhn","year":"2025","journal-title":"J. Org. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Domingo, L.R. (2016). Molecular Electron Density Theory: A Modern View of Reactivity in Organic Chemistry. Molecules, 21.","DOI":"10.3390\/molecules21101319"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"12349","DOI":"10.1021\/acs.joc.4c01297","article-title":"Understanding the Electronic Effects of Lewis Acid Catalysts in Accelerating Polar Diels-Alder Reactions","volume":"89","author":"Domingo","year":"2024","journal-title":"J. Org. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"287","DOI":"10.58332\/scirad2025v4i4a03","article-title":"Performing a Relative Interacting Atomic Energy Analysis of the Diels-Alder Reaction between Butadiene and Ethylene","volume":"4","author":"Domingo","year":"2025","journal-title":"Sci. Rad."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"A1133","DOI":"10.1103\/PhysRev.140.A1133","article-title":"Self-consistent equations including exchange and correlation effects","volume":"140","author":"Kohn","year":"1965","journal-title":"Phys. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"B864","DOI":"10.1103\/PhysRev.136.B864","article-title":"Inhomogeneous Electron Gas","volume":"136","author":"Hohenberg","year":"1964","journal-title":"Phys. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4427","DOI":"10.1139\/v69-731","article-title":"Solvation effects on conformational equilibria. Studies related to the conformational properties of 2-methoxytetrahydropyran and related methylglycopyranoside","volume":"47","author":"Lemieux","year":"1969","journal-title":"Can. J. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1063\/1.449486","article-title":"Natural population analysis","volume":"83","author":"Reed","year":"1985","journal-title":"J. Chem. Phys."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1021\/cr00088a005","article-title":"Intermolecular interactions from a natural bond orbital, donor-acceptor viewpoint","volume":"88","author":"Reed","year":"1988","journal-title":"Chem. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5397","DOI":"10.1063\/1.458517","article-title":"A simple measure of electron localization in atomic and molecular-systems","volume":"92","author":"Becke","year":"1990","journal-title":"J. Chem. Phys."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1038\/371683a0","article-title":"Classification of chemical bonds based on topological analysis of electron localization functions","volume":"371","author":"Silvi","year":"1994","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1002\/jcc.20469","article-title":"Chemical Fragments in Real Space: Definitions, Properties and Energetic Decompositions","volume":"28","author":"Blanco","year":"2007","journal-title":"J. Comput. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"34844","DOI":"10.1021\/acsomega.3c04149","article-title":"A \u201cInteracting Quantum Atoms and Multipolar Electrostatic Study of XH\u22ef\u03c0 Interactions\u201d","volume":"8","author":"Triestram","year":"2023","journal-title":"ACS Omega"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1007\/s00214-007-0310-x","article-title":"The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: Two new functionals and systematic testing of four M06-class functionals and 12 others functional","volume":"120","author":"Zhao","year":"2008","journal-title":"Theor. Chem. Acc."},{"key":"ref_36","unstructured":"Hehre, W.J., Radom, L., Schleyer, P.v.R., and Pople, J. (1986). Ab Initio Molecular Orbital Theory, Wiley."},{"key":"ref_37","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_38","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_39","unstructured":"Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Mennucci, B., and Petersson, G.A. (2017). Gaussian 16, Revision A.03, Gaussian, Inc."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2027","DOI":"10.1021\/cr00031a013","article-title":"Molecular interactions in solution: And overview of methods based on continuous distributions of the solvent","volume":"94","author":"Tomasi","year":"1994","journal-title":"Chem. Rev."},{"key":"ref_41","unstructured":"Simkin, B.Y., and Sheikhet, I.I. (1995). Quantum Chemical and Statistical Theory of Solutions\u2013Computational Approach, Ellis Horwood."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/0009-2614(96)00349-1","article-title":"Ab initio study of solvated molecules: A new implementation of the polarizable continuum model","volume":"255","author":"Cossi","year":"1996","journal-title":"Chem. Phys. Lett."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3032","DOI":"10.1063\/1.474659","article-title":"A new integral equation formalism for the polarizable continuum model: Theoretical background and applications to isotropic and anisotropic dielectrics","volume":"107","author":"Cances","year":"1997","journal-title":"J. Chem. Phys."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1002\/(SICI)1096-987X(199803)19:4<404::AID-JCC3>3.0.CO;2-W","article-title":"Geometry optimization of molecular structures in solution by the polarizable continuum model","volume":"19","author":"Barone","year":"1998","journal-title":"J. Comput. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/S0097-8485(99)00039-X","article-title":"Computational tools for the electron localization function topological analysis","volume":"23","author":"Noury","year":"1999","journal-title":"Comput. Chem."},{"key":"ref_46","unstructured":"Dennington, R., Keith, T.A., and Millam, J.M. (2016). GaussView, Semichem Inc.. version 6.1."},{"key":"ref_47","unstructured":"Keith, T.A. (2019). AIMAll, TK Gristmill Software. version 19.10.12."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/18\/3335\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T08:15:29Z","timestamp":1790151329000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/18\/3335"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,20]]},"references-count":47,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["molecules31183335"],"URL":"https:\/\/doi.org\/10.3390\/molecules31183335","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,20]]}}}