{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:34:14Z","timestamp":1760236454318,"version":"build-2065373602"},"reference-count":56,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2021,11,25]],"date-time":"2021-11-25T00:00:00Z","timestamp":1637798400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The concept of orthogonality between halogen and hydrogen bonding, brought out by Ho and coworkers some years ago, has become a widely accepted idea within the chemists\u2019 community. While the original work was based on a common carbonyl oxygen as acceptor for both interactions, we explore here, by means of M06-2X, M11, \u03c9B97X, and \u03c9B97XD\/aug-cc-PVTZ DFT calculations, the interdependence of halogen and hydrogen bonding with a shared \u03c0-electron system of benzene. The donor groups (specifically NCBr and H2O) were placed on either or the same side of the ring, according to a double T-shaped or a perpendicular geometry, respectively. The results demonstrate that the two interactions with benzene are not strictly independent on each other, therefore outlining that the orthogonality between halogen and hydrogen bonding, intended as energetical independence between the two interactions, should be carefully evaluated according to the specific acceptor group.<\/jats:p>","DOI":"10.3390\/molecules26237126","type":"journal-article","created":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T22:01:11Z","timestamp":1638309671000},"page":"7126","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Exploring Orthogonality between Halogen and Hydrogen Bonding Involving Benzene"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5020-5544","authenticated-orcid":false,"given":"Alessandra","family":"Forni","sequence":"first","affiliation":[{"name":"Istituto di Scienze e Tecnologie Chimiche \u201cGiulio Natta\u201d\u2014CNR, INSTM RU, Via Golgi 19, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosario","family":"Russo","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Universit\u00e0 degli Studi di Milano, INSTM RU, Via Golgi 19, 20133 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giacomo","family":"Rapeti","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Universit\u00e0 degli Studi di Milano, INSTM RU, Via Golgi 19, 20133 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7672-0720","authenticated-orcid":false,"given":"Stefano","family":"Pieraccini","sequence":"additional","affiliation":[{"name":"Istituto di Scienze e Tecnologie Chimiche \u201cGiulio Natta\u201d\u2014CNR, INSTM RU, Via Golgi 19, 20133 Milan, Italy"},{"name":"Department of Chemistry, Universit\u00e0 degli Studi di Milano, INSTM RU, Via Golgi 19, 20133 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5822-4849","authenticated-orcid":false,"given":"Maurizio","family":"Sironi","sequence":"additional","affiliation":[{"name":"Istituto di Scienze e Tecnologie Chimiche \u201cGiulio Natta\u201d\u2014CNR, INSTM RU, Via Golgi 19, 20133 Milan, Italy"},{"name":"Department of Chemistry, Universit\u00e0 degli Studi di Milano, INSTM RU, Via Golgi 19, 20133 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1351\/PAC-REC-12-05-10","article-title":"Definition of the halogen bond (IUPAC Recommendations 2013)","volume":"85","author":"Desiraju","year":"2013","journal-title":"Pure Appl. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"16789","DOI":"10.1073\/pnas.0407607101","article-title":"Halogen bonds in biological molecules","volume":"101","author":"Auffinger","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5165","DOI":"10.1021\/ja2105027","article-title":"Halogen bonding in DNA base pairs","volume":"134","author":"Parker","year":"2012","journal-title":"J. Am. Chem. Soc."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1002\/pro.2201","article-title":"Halogen bonding (X-bonding): A biological perspective","volume":"22","author":"Scholfield","year":"2013","journal-title":"Protein Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1021\/jm3012068","article-title":"Principles and applications of halogen bonding in medicinal chemistry and chemical biology","volume":"56","author":"Wilcken","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4891","DOI":"10.1021\/bi400590h","article-title":"Enthalpy\u2013entropy compensation in biomolecular halogen bonds measured in DNA junctions","volume":"52","author":"Carter","year":"2013","journal-title":"Biochemistry"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"637","DOI":"10.4155\/fmc-2017-0052","article-title":"Halogen bonding in medicinal chemistry: From observation to prediction","volume":"9","author":"Ho","year":"2017","journal-title":"Future Med. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"8681","DOI":"10.1021\/acs.jmedchem.7b00329","article-title":"Halogen Bonding in Nucleic Acid Complexes: Miniperspective","volume":"60","author":"Tabarrini","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4744","DOI":"10.1021\/acs.jctc.0c00431","article-title":"Halogen bonds in protein nucleic acid recognition","volume":"16","author":"Frontera","year":"2020","journal-title":"J. Chem. Theory Comput."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1942","DOI":"10.1021\/acschembio.0c00292","article-title":"Quantifying intramolecular Halogen Bonds in Nucleic Acids: A combined PDB and theoretical study","volume":"15","author":"Frontera","year":"2020","journal-title":"ACS Chem. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4253","DOI":"10.1021\/jacs.0c12470","article-title":"Halogen Bonding: An Underestimated Player in Membrane\u2013Ligand Interactions","volume":"143","author":"Nunes","year":"2021","journal-title":"J. Am. Chem. Soc."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9275","DOI":"10.1039\/D1SC02608A","article-title":"Halogen bonding in polymer science: Towards new smart materials","volume":"12","author":"Kampes","year":"2021","journal-title":"Chem. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2686","DOI":"10.1021\/ar400103r","article-title":"The Halogen Bond in the Design of Functional Supramolecular Materials: Recent Advances","volume":"46","author":"Priimagi","year":"2013","journal-title":"Acc. Chem. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3003","DOI":"10.1039\/C5TC00484E","article-title":"Halogen bonding enhances nonlinear optical response in poled supramolecular polymers","volume":"3","author":"Virkki","year":"2015","journal-title":"J. Mater. Chem. C"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5069","DOI":"10.1021\/acs.cgd.8b00529","article-title":"Toward First-Principles Design of Organic Nonlinear Optical Materials: Crystal Structure Prediction and Halogen Bonding Impact on Hyperpolarizabilities of 2-Iodo-3-hydroxypyridine","volume":"18","author":"Yushina","year":"2018","journal-title":"Cryst. Growth Des."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"28810","DOI":"10.1039\/C8CP05392H","article-title":"On molecular optical nonlinearity of halogen-bond-forming azobenzenes","volume":"20","author":"Virkki","year":"2018","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3946","DOI":"10.1039\/c3cc41227j","article-title":"Halogen-bonded liquid crystals of 4-alkoxystilbazoles with molecular iodine: A very short halogen bond and unusual mesophase stability","volume":"49","author":"McAllister","year":"2013","journal-title":"Chem. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"40237","DOI":"10.1039\/C7RA06397K","article-title":"Supramolecular control of liquid crystals by doping with halogen-bonding dyes","volume":"7","author":"Vapaavuori","year":"2017","journal-title":"RSC Adv."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1002\/chem.201802927","article-title":"The Halogen Bond: An Emerging Supramolecular Tool in the Design of Functional Mesomorphic Materials","volume":"25","author":"Wang","year":"2019","journal-title":"Chem. Eur. J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1007\/s00894-006-0130-2","article-title":"Halogen bonding: The sigma hole","volume":"13","author":"Clark","year":"2007","journal-title":"J. Mol. Model."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1002\/open.202000062","article-title":"The Origin of the \u03c3-Hole in Halogen Atoms: A Valence Bond Perspective","volume":"9","author":"Franchini","year":"2020","journal-title":"ChemistryOpen"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"19508","DOI":"10.1039\/c1cp22436k","article-title":"Halogen bonding in ligand\u2013receptor systems in the framework of classical force fields","volume":"13","author":"Rendine","year":"2011","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2564","DOI":"10.1002\/jcc.21836","article-title":"Molecular mechanical study of halogen bonding in drug discovery","volume":"32","author":"Ibrahim","year":"2011","journal-title":"J. Comput. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1021\/ct2008389","article-title":"On extension of the current biomolecular empirical force field for the description of halogen bonds","volume":"8","author":"Hobza","year":"2012","journal-title":"J. Chem. Theory Comput."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1039\/C2CC37584B","article-title":"Plugging the explicit \u03c3-holes in molecular docking","volume":"49","author":"Hobza","year":"2013","journal-title":"Chem. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.cplett.2018.09.052","article-title":"Halogen bonding in the framework of classical force fields: The case of chlorine","volume":"712","author":"Franchini","year":"2018","journal-title":"Chem. Phys. Lett."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1021\/acs.jctc.8b00739","article-title":"Quadrupole Correction: From Molecular Electrostatic Potential to Free Energies of Halogen Bonding","volume":"15","author":"Titov","year":"2019","journal-title":"J. Chem. Theory Comput."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4133","DOI":"10.1021\/jacs.1c00239","article-title":"Weak yet Decisive: Molecular Halogen Bond and Competing Weak Interactions of Iodobenzene and Quinuclidine","volume":"143","author":"Otte","year":"2021","journal-title":"J. Am. Chem. Soc."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1021\/acs.cgd.8b01483","article-title":"Featuring I\u00b7\u00b7\u00b7N Halogen Bond and Weaker Interactions in Iodoperfluoroalkylimidazoles: An Experimental and Theoretical Charge Density Study","volume":"19","author":"Forni","year":"2019","journal-title":"Cryst. Growth Des."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"34287","DOI":"10.1039\/C8RA07187J","article-title":"Insight into trifluoromethylation\u2014Experimental electron density for Togni reagent I","volume":"8","author":"Wang","year":"2018","journal-title":"RSC Adv."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1515\/zkri-2018-2069","article-title":"Short is strong: Experimental electron density in a very short N\u00b7\u00b7\u00b7I halogen bond","volume":"233","author":"Wang","year":"2018","journal-title":"Z. Kristallogr. Cryst. Mater."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"11382","DOI":"10.1021\/acs.jpcb.5b03533","article-title":"Halogen Bonding and Chalcogen Bonding in 4,7-Dibromo-5,6-dinitro-2,1,3-benzothiadiazole","volume":"119","author":"Pavan","year":"2015","journal-title":"J. Phys. Chem. B"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5477","DOI":"10.1021\/cg500659c","article-title":"Characterization of Interactions Involving Bromine in 2,2-Dibromo-2,3-dihydroinden-1-one via Experimental Charge Density Analysis","volume":"14","author":"Pavan","year":"2014","journal-title":"Cryst. Growth Des."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1855","DOI":"10.1021\/cg2000415","article-title":"Halogen Bonding in 2,5-Dichloro-1,4-benzoquinone: Insights from Experimental and Theoretical Charge Density Analysis","volume":"11","author":"Hathwar","year":"2011","journal-title":"Cryst. Growth Des."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3403","DOI":"10.1021\/jp8107182","article-title":"Experimental and theoretical study of the Br\u22c5\u22c5\u22c5N halogen bond in complexes of 1,4-dibromotetrafluorobenzene with dipyridyl derivatives","volume":"113","author":"Forni","year":"2009","journal-title":"J. Phys. Chem. A"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2870","DOI":"10.1021\/acs.accounts.9b00189","article-title":"Hydrogen Bond Enhanced Halogen Bonds: A Synergistic Interaction in Chemistry and Biochemistry","volume":"52","author":"Riel","year":"2019","journal-title":"Acc. Chem. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6610","DOI":"10.1021\/jacs.6b02854","article-title":"Systematic Construction of Ternary Cocrystals by Orthogonal and Robust Hydrogen and Halogen Bonds","volume":"138","author":"Rissanen","year":"2016","journal-title":"J. Am. Chem. Soc."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"24707","DOI":"10.1021\/acs.jpcc.7b09325","article-title":"Interplay between Halogen and Hydrogen Bonds in 2D Self-Assembly on the Gold Surface: A First-Principles Investigation","volume":"121","author":"Lu","year":"2017","journal-title":"J. Phys. Chem. C"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"van Terwingen, S., Br\u00fcx, D., Wang, R., and Englert, U. (2021). Hydrogen-Bonded and Halogen-Bonded: Orthogonal Interactions for the Chloride Anion of a Pyrazolium Salt. Molecules, 26.","DOI":"10.3390\/molecules26133982"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1038\/nchem.112","article-title":"Halogen bonds as orthogonal molecular interactions to hydrogen bonds","volume":"1","author":"Voth","year":"2009","journal-title":"Nat. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4224","DOI":"10.1002\/cphc.201200605","article-title":"Halogen-Bonding Interactions with \u03c0 Systems: CCSD(T), MP2, and DFT Calculations","volume":"13","author":"Forni","year":"2012","journal-title":"ChemPhysChem"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1002\/jcc.23507","article-title":"Halogen Bonds with Benzene: An Assessment of DFT Functionals","volume":"35","author":"Forni","year":"2014","journal-title":"J. Comput. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"9071","DOI":"10.1021\/acs.jpca.6b07578","article-title":"Assesment of DFT Functionals for QTAIM Topological Analysis of Halogen Bonds with Benzene","volume":"120","author":"Forni","year":"2016","journal-title":"J. Phys. Chem. A"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6454","DOI":"10.1002\/anie.201700520","article-title":"Direct Experimental Evidence for Halogen\u2013Aryl \u03c0 Interactions in Solution from Molecular Torsion Balances","volume":"56","author":"Sun","year":"2017","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1021\/ci400539q","article-title":"Halogen Bond: Its Role beyond Drug\u2013Target Binding Affinity for Drug Discovery and Development","volume":"54","author":"Xu","year":"2014","journal-title":"J. Chem. Inf. Model."},{"key":"ref_46","first-page":"171","article-title":"The Cambridge Structural Database","volume":"B72","author":"Groom","year":"2016","journal-title":"Acta Cryst."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"084107","DOI":"10.1063\/1.3545971","article-title":"Density-functional approaches to noncovalent interactions: A comparison of dispersion corrections (DFT-D), exchangehole dipole moment (XDM) theory, and specialized functionals","volume":"134","author":"Burns","year":"2011","journal-title":"J. Chem. Phys."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"5436","DOI":"10.1021\/ct500899h","article-title":"Halogen Bonding from Dispersion-Corrected Density-Functional Theory: The Role of Delocalization Error","volume":"10","author":"Johnson","year":"2014","journal-title":"J. Chem. Theory Comput."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2823","DOI":"10.1002\/qua.22787","article-title":"Directional tendencies of halogen and hydrogen bonding","volume":"110","author":"Shields","year":"2010","journal-title":"Int. J. Quantum Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1002\/qua.25093","article-title":"Performance of Density Functional Theory on the Anisotropic Halogen\u22c5\u22c5\u22c5Halogen Interactions and Potential Energy Surface: Problems and Possible Solutions","volume":"116","author":"Liu","year":"2016","journal-title":"Int. J. Quantum Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"084106","DOI":"10.1063\/1.2834918","article-title":"Systematic Optimization of Long-Range Corrected Hybrid Density Functionals","volume":"128","author":"Chai","year":"2008","journal-title":"J. Chem. Phys."},{"key":"ref_52","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 Other Functionals","volume":"120","author":"Zhao","year":"2008","journal-title":"Theor. Chem. Acc."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2810","DOI":"10.1021\/jz201170d","article-title":"Improving the Accuracy of Hybrid Meta-GGA Density Functionals by Range Separation","volume":"2","author":"Peverati","year":"2011","journal-title":"J. Phys. Chem. Lett."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"6615","DOI":"10.1039\/b810189b","article-title":"Long-range corrected hybrid density functionals with damped atom\u2013atom dispersion corrections","volume":"10","author":"Chai","year":"2008","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.cplett.2004.07.029","article-title":"Application of 25 Density Functionals to Dispersion-Bound Homomolecular Dimers","volume":"394","author":"Johnson","year":"2004","journal-title":"Chem. Phys. Lett."},{"key":"ref_56","unstructured":"Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Petersson, G.A., and Nakatsuji, H. (2016). Gaussian 16 Rev. A.03, Gaussian, Inc."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/23\/7126\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:35:35Z","timestamp":1760168135000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/23\/7126"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,25]]},"references-count":56,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["molecules26237126"],"URL":"https:\/\/doi.org\/10.3390\/molecules26237126","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2021,11,25]]}}}