Molecular recognition, binding and catalysis are often mediated by non-covalent interactions involving aromatic functional groups. Although the relative complexity of these so-called π interactions has made them challenging to study, theory and modelling have now reached the stage at which we can explain their physical origins and obtain reliable insight into their effects on molecular binding and chemical transformations. This offers opportunities for the rational manipulation of these complex non-covalent interactions and their direct incorporation into the design of small-molecule catalysts and enzymes.
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Wolfenden, R. & Snider, M. J. The depth of chemical time and the power of enzymes as catalysts. Acc. Chem. Res. 34, 939–945 (2001)
Kirby, A. J. Enzyme mechanisms, models, and mimics. Angew. Chem. Int. Edn Engl. 35, 706–724 (1996)
Benkovic, S. J. & Hammes-Schiffer, S. A perspective on enzyme catalysis. Science 301, 1196–1202 (2003)
Biedermann, F. & Schneider, H.-J. Experimental binding energies in supramolecular complexes. Chem. Rev. 116, 5216–5300 (2016)
Schneider, H.-J. Binding mechanisms in supramolecular complexes. Angew. Chem. Int. Ed. 48, 3924–3977 (2009)
Mader, M. M. & Bartlett, P. A. Binding energy and catalysis: the implications for transition-state analogs and catalytic antibodies. Chem. Rev. 97, 1281–1302 (1997)
Knowles, R. R. & Jacobsen, E. N. Attractive noncovalent interactions in asymmetric catalysis: links between enzymes and small molecule catalysts. Proc. Natl Acad. Sci. USA 107, 20678–20685 (2010). Thought-provoking discussion of the rational implementation of attractive NCIs in asymmetric catalysis.
Davis, H. J. & Phipps, R. J. Harnessing non-covalent interactions to exert control over regioselectivity and site-selectivity in catalytic reactions. Chem. Sci. 8, 864–877 (2017)
Doyle, A. G. & Jacobsen, E. N. Small-molecule H-bond donors in asymmetric catalysis. Chem. Rev. 107, 5713–5743 (2007)
Brak, K. & Jacobsen, E. N. Asymmetric ion-pairing catalysis. Angew. Chem. Int. Ed. 52, 534–561 (2013)
Krenske, E. H. & Houk, K. N. Aromatic interactions as control elements in stereoselective organic reactions. Acc. Chem. Res. 46, 979–989 (2013)
Sinnokrot, M. O. & Sherrill, C. D. High-accuracy quantum mechanical studies of π-π interactions in benzene dimers. J. Phys. Chem. A 110, 10656–10668 (2006)
Lee, E. C. et al. Understanding of assembly phenomena by aromatic-aromatic interactions: benzene dimer and the substituted systems. J. Phys. Chem. A 111, 3446–3457 (2007)
Martinez, C. R & Iverson, B. L. Rethinking the term “pi-stacking”. Chem. Sci. 3, 2191–2201 (2012). Interesting discussion of relevance of π systems to interactions between aromatic rings
Wagner, J. P & Schreiner, P. R. London dispersion in molecular chemistry—reconsidering steric effects. Angew. Chem. Int. Ed. 54, 12274–12296 (2015). Intriguing discussion of various manifestations of London dispersion forces in molecular interactions.
Raju, R. K., Bloom, J. W. G., An, Y. & Wheeler, S. E. Substituent effects on non-covalent interactions with aromatic rings: insights from computational chemistry. ChemPhysChem 12, 3116–3130 (2011)
Tsuzuki, S., Honda, K., Uchimaru, T., Mikami, M. & Tanabe, K. Origin of attraction and directionality of the π/π interaction: model chemistry calculations of benzene dimer interaction. J. Am. Chem. Soc. 124, 104–112 (2002)
Hunter, C. A. & Sanders, J. K. M. The nature of π–π interactions. J. Am. Chem. Soc. 112, 5525–5534 (1990)
Hunter, C. A., Low, C. M. R., Vinter, J. G. & Zonta, C. Quantification of functional group interactions in transition states. J. Am. Chem. Soc. 125, 9936–9937 (2003)
Cockroft, S. L., Hunter, C. A., Lawson, K. R., Perkins, J. & Urch, C. J. Electrostatic control of aromatic stacking interactions. J. Am. Chem. Soc. 127, 8594–8595 (2005)
Cozzi, F., Cinquini, M., Annunziata, R., Dwyer, T. & Siegel, J. S. Polar/π interactions between stacked aryls in 1,8-diarylnaphthalenes. J. Am. Chem. Soc. 114, 5729–5733 (1992)
Cozzi, F. et al. Through-space interactions between face-to-face, center-to-edge oriented arenes: importance of polar-π effects. Org. Biomol. Chem. 1, 157–162 (2003)
Sinnokrot, M. O. & Sherrill, C. D. Substituent effects in π-π interactions: sandwich and T-shaped configurations. J. Am. Chem. Soc. 126, 7690–7697 (2004)
Grimme, S. Do special noncovalent π-π stacking interactions really exist? Angew. Chem. Int. Ed. 47, 3430–3434 (2008). Computational study exploring physical reality of π−π terminology.
Bloom, J. W. G. & Wheeler, S. E. Taking the aromaticity out of aromatic interactions. Angew. Chem. Int. Ed. 50, 7847–7849 (2011)
Wheeler, S. E. & Houk, K. N. Substituent effects in the benzene dimer are due to direct interactions of the substituents with the unsubstituted benzene. J. Am. Chem. Soc. 130, 10854–10855 (2008)
Wheeler, S. E. & Houk, K. N. Origin of substituent effects in edge-to-face aryl–aryl interactions. Mol. Phys. 107, 749–760 (2009)
Wheeler, S. E. Local nature of substituent effects in stacking interactions. J. Am. Chem. Soc. 133, 10262–10274 (2011). Early espousal of the importance of direct interaction between substituents in tuning strengths of aromatic interactions.
Parrish, R. M. & Sherrill, C. D. Quantum-mechanical evaluation of π-π versus substituent-π interactions in π stacking: direct evidence for the Wheeler-Houk picture. J. Am. Chem. Soc. 136, 17386–17389 (2014)
Hwang, J. et al. Additivity of substituent effects in aromatic stacking interactions. J. Am. Chem. Soc. 136, 14060–14067 (2014)
Cockroft, S. L & Hunter, C. A. Chemical double-mutant cycles: dissecting non-covalent interactions. Chem. Soc. Rev. 36, 172–188 (2007) Review of an essential technique that has been used to experimentally quantify weak (<3 kcal mol−1) interactions.
Nishio, M., Umezawa, Y., Fantini, J., Weiss, M. S. & Chakrabarti, P. CH-π hydrogen bonds in biological macromolecules. Phys. Chem. Chem. Phys. 16, 12648–12683 (2014)
Tsuzuki, S., Honda, K., Uchimaru, T., Mikami, M. & Tanabe, K. The magnitude of the CH/π interaction between benzene and some model hydrocarbons. J. Am. Chem. Soc. 122, 3746–3753 (2000)
Bloom, J. W. G., Raju, R. K. & Wheeler, S. E. Physical nature of substituent effects in XH/π interactions. J. Chem. Theory Comput. 8, 3167–3174 (2012)
Asensio, J. L., Ardá, A., Cañada, F. J. & Jiménez-Barbero, J. Carbohydrate-aromatic interactions. Acc. Chem. Res. 46, 946–954 (2013)
Laughrey, Z. R., Kiehna, S. E., Riemen, A. J. & Waters, M. L. Carbohydrate-π interactions: what are they worth? J. Am. Chem. Soc. 130, 14625–14633 (2008)
Carrillo, R ., López-Rodríguez, M ., Martín, V. S & Martín, T. Quantification of a CH-π interaction responsible for chiral discrimination and evaluation of its contribution to enantioselectivity. Angew. Chem. Int. Ed. 48, 7803–7808 (2009)
Noyori, R. & Hashiguchi, S. Asymmetric transfer hydrogenation catalyzed by chiral ruthenium complexes. Acc. Chem. Res. 30, 97–102 (1997)
Yamakawa, M., Yamada, I. & Noyori, R. CH/π attraction: the origin of enantioselectivity in transfer hydrogenation of aromatic carbonyl compounds catalyzed by chiral η6-arene-ruthenium(II) complexes. Angew. Chem. Int. Ed. 40, 2818–2821 (2001)
Ma, J. C. & Dougherty, D. A. The cation–π interaction. Chem. Rev. 97, 1303–1324 (1997)
An, Y & Wheeler, S. E. Cation–π interactions. In Encyclopedia of Inorganic and Bioinorganic Chemistry (Wiley & Sons, 2011)
Dougherty, D. A. The cation-π interaction. Acc. Chem. Res. 46, 885–893 (2013)
Kennedy, C. R., Lin, S. & Jacobsen, E. N. The cation-π interaction in small-molecule catalysis. Angew. Chem. Int. Ed. 55, 12596–12624 (2016)
Mecozzi, S ., West, A. P. Jr & Dougherty, D. A. Cation-π interactions in aromatics of biological and medicinal interest: electrostatic potential surfaces as a useful qualitative guide. Proc. Natl Acad. Sci. USA 93, 10566–10571 (1996)
Mecozzi, S., West, A. P. & Dougherty, D. A. Cation−π interactions in simple aromatics: electrostatics provide a predictive tool. J. Am. Chem. Soc. 118, 2307–2308 (1996)
Wheeler, S. E. & Houk, K. N. Through-space effects of substituents dominate molecular electrostatic potentials of substituted arenes. J. Chem. Theory Comput. 5, 2301–2312 (2009)
Daze, K. D. & Hof, F. The cation-π interaction at protein-protein interaction interfaces: developing and learning from synthetic mimics of proteins that bind methylated lysines. Acc. Chem. Res. 46, 937–945 (2013)
Cubero, E., Luque, F. J. & Orozco, M. Is polarization important in cation-π interactions? Proc. Natl Acad. Sci. USA 95, 5976–5980 (1998)
Tsuzuki, S., Mikami, M. & Yamada, S. Origin of attraction, magnitude, and directionality of interactions in benzene complexes with pyridinium cations. J. Am. Chem. Soc. 129, 8656–8662 (2007)
Zhong, W . et al. From ab initio quantum mechanics to molecular neurobiology: a cation-π binding site in the nicotinic receptor. Proc. Natl Acad. Sci. USA 95, 12088–12093 (1998). Classic physical organic study demonstrating relevance of cation–π interactions in biological systems.
Xiu, X., Puskar, N. L., Shanata, J. A. P., Lester, H. A. & Dougherty, D. A. Nicotine binding to brain receptors requires a strong cation-π interaction. Nature 458, 534–537 (2009)
Hughes, R. M ., Wiggins, K. R ., Khorasanizadeh, S & Waters, M. L. Recognition of trimethyllysine by a chromodomain is not driven by the hydrophobic effect. Proc. Natl Acad. Sci. USA 104, 11184–11188 (2007)
Christianson, D. W. Structural biology and chemistry of the terpenoid cyclases. Chem. Rev. 106, 3412–3442 (2006)
Morikubo, N. et al. Cation-π interaction in the polyolefin cyclization cascade uncovered by incorporating unnatural amino acids into the catalytic sites of squalene cyclase. J. Am. Chem. Soc. 128, 13184–13194 (2006)
Wendt, K. U., Poralla, K. & Schulz, G. E. Structure and function of a squalene cyclase. Science 277, 1811–1815 (1997)
Knowles, R. R., Lin, S. & Jacobsen, E. N. Enantioselective thiourea-catalyzed cationic polycyclizations. J. Am. Chem. Soc. 132, 5030–5032 (2010). Landmark example of rigorous quantification of an attractive NCI in asymmetric catalysis.
Uyeda, C. & Jacobsen, E. N. Transition-state charge stabilization through multiple non-covalent interactions in the guanidinium-catalyzed enantioselective Claisen rearrangement. J. Am. Chem. Soc. 133, 5062–5075 (2011)
Lin, S. & Jacobsen, E. N. Thiourea-catalysed ring opening of episulfonium ions with indole derivatives by means of stabilizing non-covalent interactions. Nat. Chem. 4, 817–824 (2012)
Gamez, P., Mooibroek, T. J., Teat, S. J. & Reedijk, J. Anion binding involving π-acidic heteroaromatic rings. Acc. Chem. Res. 40, 435–444 (2007)
Frontera, A., Gamez, P., Mascal, M., Mooibroek, T. J. & Reedijk, J. Putting anion-π interactions into perspective. Angew. Chem. Int. Ed. 50, 9564–9583 (2011)
Giese, M., Albrecht, M. & Rissanen, K. Experimental investigation of anion-π interactions—applications and biochemical relevance. Chem. Commun. 52, 1778–1795 (2016)
Lucas, X., Bauzá, A., Frontera, A. & Quiñonero, D. A thorough anion–π interaction study in biomolecules: on the importance of cooperativity effects. Chem. Sci. 7, 1038–1050 (2016)
Alkorta, I., Rozas, I. & Elguero, J. Interaction of anions with perfluoro aromatic compounds. J. Am. Chem. Soc. 124, 8593–8598 (2002)
Mascal, M., Armstrong, A. & Bartberger, M. D. Anion-aromatic bonding: a case for anion recognition by π-acidic rings. J. Am. Chem. Soc. 124, 6274–6276 (2002)
Quiñonero, D. et al. Counterintuitive interaction of anions with benzene derivatives. Chem. Phys. Lett. 359, 486–492 (2002)
Estarellas, C., Bauzá, A., Frontera, A., Quiñonero, D. & Deyà, P. M. On the directionality of anion-π interactions. Phys. Chem. Chem. Phys. 13, 5696–5702 (2011)
Hay, B. P. & Custelcean, R. Anion−π interactions in crystal structures: commonplace or extraordinary? Cryst. Growth Des. 9, 2539–2545 (2009)
Frontera, A. et al. Anion-π interactions in cyanuric acids: a combined crystallographic and computational study. Chemistry 11, 6560–6567 (2005)
Lu, T. & Wheeler, S. E. Quantifying the role of anion-π interactions in anion-π catalysis. Org. Lett. 16, 3268–3271 (2014)
Wheeler, S. E. & Bloom, J. W. G. Anion-π interactions and positive electrostatic potentials of N-heterocycles arise from the positions of the nuclei, not changes in the π-electron distribution. Chem. Commun. 50, 11118–11121 (2014)
Estarellas, C ., Frontera, A ., Quiñonero, D & Deyà, P. M. Relevant anion-π interactions in biological systems: the case of urate oxidase. Angew. Chem. Int. Ed. 50, 415–418 (2011)
Berryman, O. B., Sather, A. C., Hay, B. P., Meisner, J. S. & Johnson, D. W. Solution phase measurement of both weak σ and C–H…X− hydrogen bonding interactions in synthetic anion receptors. J. Am. Chem. Soc. 130, 10895–10897 (2008)
Dawson, R. E. et al. Experimental evidence for the functional relevance of anion-π interactions. Nat. Chem. 2, 533–538 (2010)
Zhao, Y . et al. Catalysis with anion-π interactions. Angew. Chem. Int. Ed. 52, 9940–9943 (2013). Seminal example demonstrating the possibility of exploiting anion–π interactions for catalysis.
Zhao, Y., Sakai, N. & Matile, S. Enolate chemistry with anion-π interactions. Nat. Commun. 5, 3911 (2014)
Zhao, Y., Benz, S., Sakai, N. & Matile, S. Selective acceleration of disfavored enolate addition reactions by anion–π interactions. Chem. Sci. 6, 6219–6223 (2015)
Zhao, Y., Cotelle, Y., Avestro, A.-J., Sakai, N. & Matile, S. Asymmetric anion-π catalysis: enamine addition to nitroolefins on π-acidic surfaces. J. Am. Chem. Soc. 137, 11582–11585 (2015)
Miros, F. N. et al. Enolate stabilization by anion-π interactions: deuterium exchange in malonate dilactones on π-acidic surfaces. Chemistry 22, 2648–2657 (2016)
Cotelle, Y. et al. Anion-π catalysis of enolate chemistry: rigidified Leonard turns as a general motif to run reactions on aromatic surfaces. Angew. Chem. Int. Ed. 55, 4275–4279 (2016)
Singh, S. K & Das, A. The n → π* interaction: a rapidly emerging non-covalent interaction. Phys. Chem. Chem. Phys. 17, 9596–9612 (2015). Thorough review of various manifestations of ground-state lp–π interactions.
Gallivan, J. P. & Dougherty, D. A. Can lone pairs bind to a π system? The water…hexafluorobenzene interaction. Org. Lett. 1, 103–106 (1999)
Alkorta, I., Rozas, I. & Elguero, J. An attractive interaction between the π-cloud of C6F6 and electron-donor atoms. J. Org. Chem. 62, 4687–4691 (1997)
Amicangelo, J. C., Gung, B. W., Irwin, D. G. & Romano, N. C. Ab initio study of substituent effects in the interactions of dimethyl ether with aromatic rings. Phys. Chem. Chem. Phys. 10, 2695–2705 (2008)
Ran, J. & Hobza, P. On the nature of bonding in lone pair…π-electron complexes: CCSD(T)/complete basis set limit calculations. J. Chem. Theory Comput. 5, 1180–1185 (2009)
Badri, Z., Foroutan-Nejad, C., Kozelka, J. & Marek, R. On the non-classical contribution in lone-pair-π interaction: IQA perspective. Phys. Chem. Chem. Phys. 17, 26183–26190 (2015)
Gung, B. W. et al. Quantitative study of interactions between oxygen lone pair and aromatic rings: substituent effect and the importance of closeness of contact. J. Org. Chem. 73, 689–693 (2008)
Singh, S. K., Kumar, S. & Das, A. Competition between n → π(Ar)* and conventional hydrogen bonding (N–H···N) interactions: an ab initio study of the complexes of 7-azaindole and fluorosubstituted pyridines. Phys. Chem. Chem. Phys. 16, 8819–8827 (2014)
Ao, M.-Z., Tao, Z.-q., Liu, H.-X., Wu, D.-Y. & Wang, X. A theoretical investigation of the competition between hydrogen bonding and lone pair…π interaction in complexes of TNT with NH3 . Comput. Theor. Chem. 1064, 25–34 (2015)
Egli, M & Gessner, R. V. Stereoelectronic effects of deoxyribose O4′ on DNA conformation. Proc. Natl Acad. Sci. USA 92, 180–184 (1995)
Egli, M. & Sarkhel, S. Lone pair-aromatic interactions: to stabilize or not to stabilize. Acc. Chem. Res. 40, 197–205 (2007)
Mooibroek, T. J., Gamez, P. & Reedijk, J. Lone pair–π interactions: a new supramolecular bond? CrystEngComm 10, 1501–1515 (2008)
Korenaga, T., Tanaka, H., Ema, T. & Sakai, T. Intermolecular oxygen atom…π interaction in the crystal packing of chiral amino alcohol bearing a pentafluorophenyl group. J. Fluor. Chem. 122, 201–205 (2003)
Korenaga, T., Shoji, T., Onoue, K. & Sakai, T. Demonstration of the existence of intermolecular lone pair…π interaction between alcoholic oxygen and the C6F5 group in organic solvent. Chem. Commun. 4678–4680 (2009). Rare experimental evidence of intermolecular lp–π interaction.
Gung, B. W., Xue, X. & Reich, H. J. Off-center oxygen-arene interactions in solution: a quantitative study. J. Org. Chem. 70, 7232–7237 (2005)
Pavlakos, I. et al. Noncovalent lone pair···(no-π!)-heteroarene interactions: the Janus-faced hydroxy group. Angew. Chem. Int. Ed. 54, 8169–8174 (2015)
Neel, A. J., Milo, A., Sigman, M. S. & Toste, F. D. Enantiodivergent fluorination of allylic alcohols: data set design reveals structural interplay between achiral directing group and chiral anion. J. Am. Chem. Soc. 138, 3863–3875 (2016)
Seguin, T. J. & Wheeler, S. E. Competing noncovalent interactions control the stereoselectivity of chiral phosphoric acid catalyzed ring openings of 3-substituted oxetanes. ACS Catal. 6, 7222–7228 (2016)
Raynal, M., Ballester, P., Vidal-Ferran, A. & van Leeuwen, P. W. Supramolecular catalysis. Part 1: non-covalent interactions as a tool for building and modifying homogeneous catalysts. Chem. Soc. Rev. 43, 1660–1733 (2014)
Milo, A., Neel, A. J., Toste, F. D. & Sigman, M. S. A data-intensive approach to mechanistic elucidation applied to chiral anion catalysis. Science 347, 737–743 (2015)
Buitrago Santanilla, A. et al. Nanomole-scale high-throughput chemistry for the synthesis of complex molecules. Science 347, 49–53 (2015)
Sigman, M. S ., Harper, K. C ., Bess, E. N & Milo, A. The development of multidimensional analysis tools for asymmetric catalysis and beyond. Acc. Chem. Res. 49, 1292–1301 (2016)
Wheeler, S. E., Seguin, T. J., Guan, Y. & Doney, A. C. Noncovalent interactions in organocatalysis and the prospect of computational catalyst design. Acc. Chem. Res. 49, 1061–1069 (2016)
We thank A. Milo for discussions. M.J.H. and M.S.S. thank the NSF (CHE-1361296) for financial support; A.J.N. and F.D.T. thank the NIHGMS (R35 GM118190) for financial support.
The authors declare no competing financial interests.
Reviewer Information Nature thanks S. Wheeler and J. Reek for their contribution to the peer review of this work.
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Neel, A., Hilton, M., Sigman, M. et al. Exploiting non-covalent π interactions for catalyst design. Nature 543, 637–646 (2017). https://doi.org/10.1038/nature21701
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