Supporting Information

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1 Supporting Information Wiley-VCH Weinheim, Germany

2 1 Some Studies of Noncovalent Functional Group-Arene Interactions William B. Motherwell,* Joëlle Moïse, Abil E. Aliev,* Miloslav Nič, Simon J. Coles, Peter N. Horton, Michael B. Hursthouse, Gianni Chessari, Christopher A. Hunter, Jeremy G. Vinter [ * ] Prof. W. B. Motherwell, Dr. J. Moïse, Dr. A. E. Aliev, Dr. M. Nič, Department of Chemistry, Christopher Ingold Laboratories, University College London, 20 Gordon Street, London, WC1H 0AJ, E- mail w.b.motherwell@ucl.ac.uk; a.e.aliev@ucl.ac.uk. Prof. M.B. Hursthouse, Dr. S.J. Coles, Dr. P.N. Horton, EPSRC National Crystallography Service, School of Chemistry, University of Southampton, Highfield, Southampton, SO17 1BJ. Dr. G. Chessari, Prof. C.A. Hunter, Department of Chemistry, University of Sheffield, Sheffield, S3 7HF UK. Dr. J.G. Vinter, Cresset Biomolecular Discovery, Spirella Building, Bridge Road, Letchworth SG6 4ET UK. Infrared Studies. Since infrared studies have proven to be useful for the detection of hydrogen bonds, the absorption frequencies for the hydroxyl stretching vibrations were accordingly measured for alcohols 4, 5 and 6 in a range of solvents (Table S1). Significant differences were observed between the peaks for the tertiary alcohols 5 and 6 which were sharp, concentration independent, and vibrated at lower frequencies when compared with those for the secondary alcohol 4 which displayed a multiplet of at least six overlapping peaks in the region between cm -1 in CCl 4, CHCl 3 and CS 2. These observations, when combined with the fact that the high frequency vibrations for alcohols 5 and 6 partially survive even in pyridine (with ν max at 3586 and 3687 cm -1 ), where strong solvent-solute hydrogen bonding is likely to prevail, provide strong presumptive evidence for the tertiary alcohols to form a π-facial intramolecular hydrogen bond.

3 2 Table S1. The OH stretching vibrations ν max (cm -1 ) of alcohols 4, 5 and 6. Broad peaks at frequencies lower than 3450 cm -1 were attributed to intermolecularly hydrogen bonded hydroxyls. Abbreviations used: s=sharp, m=multiplet, w=weak and br=broad. Solvent Solid state Alcohol CHCl 3 CCl 4 CS 2 Pyridine (KBr) 3606 m, 3623 m 3609 m, br 3298 br 3435w br 3479 w br 3417 w br 3586 s, 3562 s s 3595 s 3593 m 3303 br 3441 s 3587 s, s 3596 s 3595 s 3590 s 3345 br X-Ray Crystallography for 5 and 11. X-ray diffraction data were collected by means of combined φ and ω scans on a Bruker-Nonius KappaCCD area detector situated at the window of a rotating anode [λ(mo-k α ) = Å]. The structures were solved by direct methods, SHELXS-97 and refined using SHELXL-97. [1] Hydrogen atoms were included in the refinement, but thermal parameters and geometry were constrained to ride on the atom to which they are bonded. The data were corrected for absorption effects using SADABS [2]. The structure of 5 was found to be a twin and treated as two separate components refined against with a batch scale factor and therefore data were not merged. Crystal data for 5: C 18 H 18 O, Monoclinic, P2 1 /n, a = (16), b = (4), c = (19) Å, β = (12), volume = (8)Å 3, Z = 8, D c = Mg/m 3, µ = mm -1, θ max = 27.48, measured, unique (R int = 0.0) and (I>2σ(I)) reflections, R1 (obs) = and wr2 (all data) = , ρ max /ρ min = 0.450/ eå -3. Crystal data for 11: C 19 H 16 O, Monoclinic, C2/c, a = (4), b = (15), c = (5) Å, β = (3), volume = (10) Å 3, Z = 8, D c = Mg/m 3, µ = mm -1, θ max = 27.50, measured, 3201 unique (R int = ) and 2201 (I>2σ(I)) reflections, R1 (obs) = and wr2 (all data) = , ρ max /ρ min = 0.673/ eå -3. The complete crystallographic data have been deposited with the Cambridge Crystallographic Data Centre with deposition numbers CCDC & CCDC for compounds 5 and 11, respectively.

4 3 Table S2. Comparison of dihedral angles in the single crystal structure (shown below) and predicted gas-phase geometries for 5. Single molecules were used in the calculations. The heavy atom analogues of torsions φ and ψ are denoted as φ C (e.g., C14-C1-C15-C16) and ψ C (e.g., C2-C1-C15-C16). Parameters D, d and θ, used for the characterisation of the geometry of the intermolecular hydrogen bonding O-H O between 5Ut (donor) and 5Dg (acceptor) in the solid state were Å, Å and 161.2, respectively. 5Dg 5Ut φ C / ψ C / φ / ψ / ω / 5Dg, X-Ray Dg, B3LYP Dg, MMX Ut, X-Ray Ut, B3LYP Ut, MMX Vicinal J-coupling Measurements. Populations of conformers were calculated using the observed averaged coupling constants and their boundary values. The temperature

5 4 and solvent dependences of the conformer populations proved useful for the evaluation of the boundary 3 J HH values. In addition, advantage was taken of the fact that we had a series of similar compounds with varying conformational preferences, which would allow a reasonable estimate to be made. Despite its indirect nature, an advantage of the 3 J HH -based approach, especially in the case of temperature dependent population changes, is that conformer population ratios for BCNs with different functional groups can be compared at the same temperature. Since some assumptions in the estimation of the boundary coupling constants J D and J U had to be made, a realistic estimate of the introduced error is of importance. Possible errors may follow from the fact that the degree of twisting of the bridge in different compounds and conformations may differ and that electronic characteristics of the functional groups may influence the coupling constants of their neighbours. In order to assess the magnitude of these factors the corresponding dihedral angles in both conformers of various BCNs were calculated. As revealed by calculations, the force field [3] and DFT [4] geometries do not indicate any significant changes of dihedral angles φ and ψ that would be critical for 3 J HH -analysis (Table S2). The overall ranges of torsion changes on using different force fields (MMX, MM3, AMBER and OPLSA) [3] and B3LYP/6-31G(d) [4] were and 75-83, respectively. In order to validate the use of theoretically predicted gas phase geometries the single crystal structure was determined for 5 and the corresponding geometries were compared, and no significant changes of dihedral angles φ and ψ were found. In addition to the above, we also note that the present system provides an internal check inasmuch as the sum of the measured couplings 3 J AX and 3 J BX were approximately the same for the series, within ±3% for the disubstituted derivatives. This is a consequence of the fact that the changes in substituent electronegativities, as well as their orientation relative to the coupled proton pairs have only a small effect for a given series of BCNs. In this respect, we consider that the structural differences between the two conformers which could arise as a consequence of the operation of hyperconjugative effects in the ground state are minimal. [5] A similar relationship for the sum of J U and J D was found for the calculated J-couplings on using optimised molecular geometries and modified

6 5 Karplus equation. [6] The latter accounts for the dependence of 3 J HH on both dihedral angle and substituent electronegativities. Overall, this type of J-coupling prediction, rather than explicit calculations by DFT methods, proved useful. Solvent Dependence Studies. The preliminary results for some solvent dependence measurements are summarized in Table S3 below. The results for the tertiary alcohol 5 are plotted as a function of the solvent functional group H-bond parameters, α and β, in Figure S1. [7] There is a strong linear correlation with β and no obvious dependence on α. Thus solvation is dominated by interaction of the hydroxyl group with solvent hydrogen bond acceptors that can efficiently counterbalance the energies involved in the π-facial intramolecular hydrogen bond. In similar fashion, for alcohol 4, the observed trend in changes, although of the order of the measurement errors involved, was in line with increasing stabilization via solute-solvent intermolecular hydrogen bonding. Table S3. Populations of the D conformer in different solvents. Dielectric constants of solvents (ε) for the protonated solvents are also shown. Solvent ε p D (%) C 6 D CCl C 6 D C 6 D 5 CD CS CDCl C 5 D 5 N CD 3 OD CD 3 CN DMSO-d

7 6 Figure S1. Solvent dependence of the conformational equilibrium for 5. (a) Free energy differences plotted as a function of the solvent H-bond donor parameter α. (b) Free energy differences plotted as a function of the solvent H-bond acceptor parameter β. [7] References [1] G.M. Sheldrick, SHELX97: Programs for structure solution and refinement, University of Göttingen, Germany. [2] G.M. Sheldrick, SADABS. Version Bruker AXS Inc., Madison, Wisconsin, USA. [3] PCMODEL (version 8.5, Serena Software), described in: M.F. Schlecht, Molecular Modeling on the PC. Wiley-VCH, New York, [4] Gaussian 03, Revision B.05, M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, J. A. Montgomery, Jr., T. Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar, J. Tomasi, V. Barone, B.

8 7 Mennucci, M. Cossi, G. Scalmani, N. Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratchian, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P. Salvador, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W. Chen, M. W. Wong, C. Gonzalez, and J. A. Pople, Gaussian, Inc., Wallingford CT, [5] Evidence has been presented both for and against the relative importance of hyperconjugative stabilisation. For ongoing discussion see inter alia W.J. le Noble, B. Gung, Eds. Special Issue on Diastereoselection, Chem. Rev. 1999, 99, ; V.Vinkovic, K.Mlinaric-Majerski, Z Marinic, Tetrahedron Lett. 1992, 33, ; D. Kaneno, S.Tomada, Tetrahedron Lett. 2004, 45, [6] C.A.G. Haasnoot, F.A.A.M. DeLeeuw, C. Altona, Tetrahedron 1980, 36, [7] C. A. Hunter, Angew. Chem. Int. Ed. Engl. 2004, 43,