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Anomeric effects in fluoro and trifluoromethyl piperidines: a computational study of conformational preferences and hydration

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Abstract

A computational investigation of anomeric effects in piperidine rings bearing fluoro and trifluoromethyl substituents shows for both compounds the most pronounced evidence of the anomeric effect, as expressed as hyperconjugative delocalization of the nitrogen lone pair, in structures with the substituent in the axial position and the N–H bond in the equatorial position. This structure is the lowest-energy structure in the fluoro case but not in the trifluoromethyl case where there is an increased axial penalty associated with the CF3 group. The anomeric effect is characterized via geometrical evidence, natural bond orbital analysis, electrostatic effects, and energetic criteria. Computational results from a variety of levels of theory are presented including CCSD(T) with complete basis set extrapolation, B2PLYP-D, ωB97XD, B97-D, M06-2X, B3LYP, and MP2 allowing for a comparison of performance. The CCSD(T)/CBS results are very well represented by either B2PLYP-D or ωB97XD with moderate to large basis sets (aug-cc-pVTZ or aug-cc-pVDZ). Hyperconjugation, electrostatic effects, and steric effects play a role in the relative energetic ordering of the isomers considered.

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References

  1. Smart BE (2001) Fluorine substituent effects (on bioactivity). J Fluorine Chem 109(1):3–11

    Article  CAS  Google Scholar 

  2. O’Hagan D (2008) Understanding organofluorine chemistry. An introduction to the C–F bond. Chem Soc Rev 37:308–319. doi:10.1039/b711844a

    Article  Google Scholar 

  3. Hunter L (2010) The C–F bond as a conformational tool in organic and biological chemistry. Beilstein J Org Chem 6:38. doi:10.3762/bjoc.6.38

    Article  Google Scholar 

  4. McKinney BE, Urban JJ (2010) Fluoroolefins as peptide mimetics. 2. A computational study of the conformational ramifications of peptide bond replacement. J Phys Chem A 114(2):1123–1133. doi:10.1021/Jp9094535

    Article  CAS  Google Scholar 

  5. Urban JJ, Tillman BG, Cronin WA (2006) Fluoroolefins as peptide mimetics: a computational study of structure, charge distribution, hydration, and hydrogen bonding. J Phys Chem A 110(38):11120–11129

    Article  CAS  Google Scholar 

  6. Molteni M, Bellucci MC, Bigotti S, Mazzini S, Volonterio A, Zanda M (2009) Ψ[CH(CF3)NH]gly-peptides: synthesis and conformation analysis. Org Biomol Chem 7(11):2286–2296

    Article  CAS  Google Scholar 

  7. Sinisi R, Ghilardi A, Ruiu S, Lazzari P, Malpezzi L, Sani M, Pani L, Zanda M (2009) Synthesis and in vitro evaluation of trifluoroethylamine analogues of enkephalins. ChemMedChem 4(9):1416–1420

    Article  CAS  Google Scholar 

  8. Bigotti S, Meille SV, Volonterio A, Zanda M (2008) Synthesis of ψ[CH(RF)NH]gly-peptides: the dramatic effect of a single fluorine atom on the diastereocontrol of the key aza-michael reaction. J Fluorine Chem 129(9):767–774

    Article  CAS  Google Scholar 

  9. Molteni M, Pesenti C, Sani M, Volonterio A, Zanda M (2004) Fluorinated peptidomimetics: synthesis, conformational and biological features. J Fluorine Chem 125(11):1735–1743

    Article  CAS  Google Scholar 

  10. Zanda M (2004) Trifluoromethyl group: an effective xenobiotic function for peptide backbone modification. New J Chem 28(12):1401–1411

    Article  CAS  Google Scholar 

  11. Kirby AJ (1996) Stereoelectronic effects, vol 36. Oxford, New York

    Google Scholar 

  12. Deslongchamps P (1983) Stereoelectronic effects in organic chemistry. Oxford, Pergamon

    Google Scholar 

  13. O’Hagan D (2012) Organofluorine chemistry: synthesis and conformation of vicinal fluoromethylene motifs. J Org Chem 77:3689–3699. doi:10.1021/jo300044q

    Article  Google Scholar 

  14. Wiberg KB, Murcko MA, Laidig KE, MacDougall PJ (1990) Origin of the gauche effect in substituted ethanes and ethenes. J Phys Chem 94:6956–6959

    Article  CAS  Google Scholar 

  15. Wolfe S (1972) The gauche effect. Some stereochemical consequences of adjacent electron pairs and polar bonds. Acc Chem Res 5:102

    Article  CAS  Google Scholar 

  16. Trapp ML, Watts JK, Weinberg N, Pinto BM (2006) Component analysis of the X–C–Y anomeric effect (X=O, S; Y=F, OMe, NHMe) by dft molecular orbital calculations and natural bond orbital analysis. Can J Chem 84(4):692–701. doi:10.1139/v06-048

    Article  CAS  Google Scholar 

  17. Salzner U, PvR Schleyer (1994) Ab initio examination of anomeric effects in tetrahydropyrans, 1,3-dioxanes, and glucose. J Org Chem 59(8):2138–2155

    Article  CAS  Google Scholar 

  18. Thatcher GR (1993) The anomeric effect and associated stereoelectronic effects. ACS symposium series, vol 539. Wiley, New York

    Book  Google Scholar 

  19. Juaristi E, Cuevas G (1992) Recent studies of the anomeric effect. Tetrahedron 48(24):5019–5087

    Article  CAS  Google Scholar 

  20. Wiberg KB, Murcko MA (1989) Rotational barriers 4. Dimethoxymethane—the anomeric effect revisited. J Am Chem Soc 111(13):4821–4828

    Article  CAS  Google Scholar 

  21. Wolfe S, Rauk A, Tel LM, Csizmadia IG (1971) Theoretical study of the edward-lemieux effect (the anomeric effect). Stereochemical requirements of adjacent electron pairs and polar bonds. J Chem Soc Sect B Phys Organ (1):136–145

  22. Gold B, Dudley GB, Alabugin IV (2013) Moderating strain without sacrificing reactivity: design of fast and tunable noncatalyzed alkyne-azide cycloadditions via stereoelectronically controlled transition state stabilization. J Am Chem Soc 135(4):1558–1569. doi:10.1021/ja3114196

    Article  CAS  Google Scholar 

  23. Gold B, Shevchenko NE, Bonus N, Dudley GB, Alabugin IV (2012) Selective transition state stabilization via hyperconjugative and conjugative assistance: stereoelectronic concept for copper-free click chemistry. J Org Chem 77(1):75–89. doi:10.1021/jo201434w

    Article  CAS  Google Scholar 

  24. Mo Y (2010) Computational evidence that hyperconjugative interactions are not responsible for the anomeric effect. Nat Chem 2:666–671. doi:10.1038/nchem.721

    Article  CAS  Google Scholar 

  25. Weldon AJ, Vickrey TL, Tschumper GS (2005) Intrinsic conformational preferences of substituted cyclohexanes and tetrahydropyrans evaluated at the ccsd(t) complete basis set limit: implications for the anomeric effect. J Phys Chem A 109(48):11073–11079. doi:10.1021/jp0550311

    Article  Google Scholar 

  26. Alabugin IV (2000) Stereoelectronic interactions in cyclohexane, 1,3-dioxane, 1,3-oxathiane, and 1,3-dithiane: W-effect, sigma(C–X)—sigma*(C–H) interactions, anomeric effect—what is really important? J Org Chem 65(13):3910–3919

    Article  CAS  Google Scholar 

  27. Iupac. Compendium of chemical terminology, 2nd ed. (the “Gold Book”). Compiled by A. D. Mcnaught and A. Wilkinson, Blackwell Scientific Publications, oxford (1997). Xml on-line corrected version: http://goldbook.Iupac.Org (2006-) created by M. Nic, J. Jirat, B. Kosata; updates compiled by A. D. Jenkins

  28. Deslongchamps G, Deslongchamps P (2011) Bent bonds, the antiperiplanar hypothesis and the theory of resonance. A simple model to understand reactivity in organic chemistry. Org Biomol Chem 9(15):5321–5333. doi:10.1039/C1ob05393k

    Article  CAS  Google Scholar 

  29. Reed AE, PvR Schleyer (1987) The anomeric effect with central atoms other than carbon. 1. Strong interactions between nonbonded substituents in polyfluorinated first- and second-row hydrides. J Am Chem Soc 109(24):7362–7373

    Article  CAS  Google Scholar 

  30. Weinhold F (1998) Natural bond orbital methods. In: Schleyer PV, Allinger NL, Clark T et al (eds) Encylopedia of computational chemistry, vol 3. Wiley, Chichester, pp 1792–1811

    Google Scholar 

  31. Urban JJ (2005) Computational study of stereoelectronic effects in fluorinated alkylamines. J Phys Org Chem 18(11):1061–1071

    Article  CAS  Google Scholar 

  32. Senderowitz H, Aped P, Fuchs B (1993) Computation of O–C–F and N–C–F systems—ab initio calculations and a mm2 parameterization study—theory vs experiment. Tetrahedron 49(18):3879–3898

    Article  CAS  Google Scholar 

  33. Freitas MP (2013) The anomeric effect on the basis of natural bond orbital analysis. Org Biomol Chem 11(17):2885–2890. doi:10.1039/C3OB40187A

    Article  CAS  Google Scholar 

  34. Mo Y, Song L, Lin Y (2007) Block-localized wavefunction (blw) method at the density functional theory (dft) level. J Phys Chem A 111(34):8291–8301. doi:10.1021/jp0724065

    Article  CAS  Google Scholar 

  35. Gianinetti E, Raimondi M, Tornaghi E (1996) Modification of the roothaan equations to exclude bsse from molecular interactions calculations. Int J Quantum Chem 60(1):157–166. doi:10.1002/(SICI)1097-461X(1996)60:1<157:AID-QUA17>3.0.CO;2-C

    Article  CAS  Google Scholar 

  36. Bauerfeldt GF, Cardozo TM, Pereira MS, da Silva CO (2013) The anomeric effect: the dominance of exchange effects in closed-shell systems. Org Biomol Chem 11(2):299–308. doi:10.1039/C2OB26818C

    Article  CAS  Google Scholar 

  37. Huang Y, Zhong A-G, Yang Q, Liu S (2011) Origin of anomeric effect: a density functional steric analysis. J Chem Phys 134(8):084103/084101–084103/084109. doi:10.1063/1.3555760

    Article  Google Scholar 

  38. Liu S (2007) Steric effect: a quantitative description from density functional theory. J Chem Phys 126(24):244103. doi:10.1063/1.2747247

    Article  Google Scholar 

  39. Bjornsson R, Arnason I (2009) Conformational properties of six-membered heterocycles: accurate relative energy differences with dft, the importance of dispersion interactions and silicon substitution effects. Phys Chem Chem Phys 11(39):8689–8697. doi:10.1039/b910016d

    Article  CAS  Google Scholar 

  40. Raghavachari K, Trucks GW, Pople JA, Head-Gordon M (1989) A fifth-order perturbation comparison of electron correlation theories. Chem Phys Lett 157:479–483. doi:10.1016/s0009-2614(89)87395-6

    Article  CAS  Google Scholar 

  41. Møller C, Plesset MS (1934) Phys Rev 46:618

    Article  Google Scholar 

  42. Schwabe T, Grimme S (2007) Double-hybrid density functionals with long-range dispersion corrections: higher accuracy and extended applicability. Phys Chem Chem Phys 9:3397–3406. doi:10.1039/b704725h

    Article  CAS  Google Scholar 

  43. Chai JD, Head-Gordon M (2008) Long-range corrected hybrid density functionals with damped atom-atom dispersion corrections. Phys Chem Chem Phys 10(44):6615–6620. doi:10.1039/B810189b

    Article  CAS  Google Scholar 

  44. Grimme S (2006) Semiempirical gga-type density functional constructed with a long-range dispersion correction. J Comput Chem 27(15):1787–1799. doi:10.1002/Jcc.20495

    Article  CAS  Google Scholar 

  45. Zhao Y, Truhlar DG (2008) 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. Theor Chem Acc 120(1–3):215–241. doi:10.1007/s00214-007-0310-x

    Article  CAS  Google Scholar 

  46. Becke AD (1988) Density-functional exchange-energy approximation with correct asymptotic behavior. Phys Rev A At Mol Opt Phys 38(6):3098–3100

    Article  CAS  Google Scholar 

  47. Dunning TH Jr (1989) Gaussian basis sets for use in correlated molecular calculations. I. The atoms boron through neon and hydrogen. J Chem Phys 90(2):1007–1023

    Article  CAS  Google Scholar 

  48. Kendall RA, Dunning TH, Harrison RJ (1992) Electron-affinities of the 1st-row atoms revisited—systematic basis-sets and wave-functions. J Chem Phys 96(9):6796–6806. doi:10.1063/1.462569

    Article  CAS  Google Scholar 

  49. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery J, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian09, revision b.01. Gaussian Inc., Wallingford

    Google Scholar 

  50. Badenhoop JK, Weinhold F (1997) Natural bond orbital analysis of steric interactions. J Chem Phys 107(14):5406–5421

    Article  CAS  Google Scholar 

  51. Valiev M, Bylaska EJ, Govind N, Kowalski K, Straatsma TP, Van Dam HJJ, Wang D, Nieplocha J, Apra E, Windus TL, de Jong WA (2010) Nwchem: a comprehensive and scalable open-source solution for large scale molecular simulations. Comput Phys Commun 181(9):1477–1489. doi:10.1016/j.cpc.2010.04.018

    Article  CAS  Google Scholar 

  52. Schmidt MW, Baldridge KK, Boatz JA, Elbert ST, Gordon MS, Jensen JH, Koseki S, Matsunaga N, Nguyen KA, Su SJ, Windus TL, Dupuis M, Montgomery JA (1993) General atomic and molecular electronic-structure system. J Comput Chem 14(11):1347–1363. doi:10.1002/jcc.540141112

    Article  CAS  Google Scholar 

  53. Halkier A, Helgaker T, Jorgensen P, Klopper W, Koch H, Olsen J, Wilson AK (1998) Basis-set convergence in correlated calculations on Ne, N2, and H2O. Chem Phys Lett 286(3–4):243–252. doi:10.1016/S0009-2614(98)00111-0

    Article  CAS  Google Scholar 

  54. Biczysko M, Panek P, Scalmani G, Bloino J, Barone V (2010) Harmonic and anharmonic vibrational frequency calculations with the double-hybrid b2plyp method: analytic second derivatives and benchmark studies. J Chem Theory Comput 6:2115–2125. doi:10.1021/ct100212p

    Article  CAS  Google Scholar 

  55. Winstein S, Holness NJ (1955) Neighboring carbon and hydrogen. Xix. Tert-butylcyclohexyl derivatives. Quantitative conformational analysis. J Am Chem Soc 77:5562–5578

    Article  CAS  Google Scholar 

  56. Eliel EL, Wilen SH, Mander LN (1994) Stereochemistry of organic compounds. Wiley, Hoboken

    Google Scholar 

  57. Reed AE, Curtiss LA, Weinhold F (1988) Intermolecular interactions from a natural bond orbital, donor–acceptor viewpoint. Chem Rev 88(6):899–926. doi:10.1021/cr00088a005

    Article  CAS  Google Scholar 

  58. Alabugin IV, Gilmore KM, Peterson PW (2011) Hyperconjugation. Wiley Interdiscip Rev Comput Mol Sci 1(1):109–141. doi:10.1002/wcms.6

    Article  CAS  Google Scholar 

  59. Gillespie RJ (1963) The valence-shell electron-pair repulsion (vsepr) theory of directed valency. J Chem Educ 40:295

    Article  CAS  Google Scholar 

  60. Tomasi J, Mennucci B, Cammi R (2005) Quantum mechanical continuum solvation models. Chem Rev (Washington, DC, US) 105(8):2999–3093. doi:10.1021/Cr9904009

    Article  CAS  Google Scholar 

  61. Dunitz JD, Taylor R (1997) Organic fluorine hardly ever accepts hydrogen bonds. Chem Eur J 3(1):89–98

    Article  CAS  Google Scholar 

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Acknowledgments

Support from the Defense Threat Reduction Agency, the Office of Naval Research (via midshipmen research funds administered by the USNA Research Office), the DoD High Performance Computing Modernization Program, and the Air Force Research Laboratory DoD Supercomputing Resource Center is gratefully acknowledged. GSK wishes to acknowledge the kind mentorship of Isaiah Shavitt, who taught him many-body methods in electronic structure theory, helped him sharpen his thinking and writing, and demonstrated the importance of attention to detail.

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  1. Chemistry Department, United States Naval Academy, 572 Holloway Road, Annapolis, MD, 21402, USA

    Nathan D. Erxleben & Joseph J. Urban

  2. Engility Corporation, Wright-Patterson AFB, OH, 45433, USA

    Gary S. Kedziora

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  1. Nathan D. Erxleben
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Correspondence to Joseph J. Urban.

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Dedicated to the memory of Professor Isaiah Shavitt and published as part of the special collection of articles celebrating his many contributions.

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Erxleben, N.D., Kedziora, G.S. & Urban, J.J. Anomeric effects in fluoro and trifluoromethyl piperidines: a computational study of conformational preferences and hydration. Theor Chem Acc 133, 1491 (2014). https://doi.org/10.1007/s00214-014-1491-8

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