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Journal logoSTRUCTURAL
CHEMISTRY
ISSN: 2053-2296

Tosyl esters of cinchonidine and cinchonine alkaloids: the structure–reactivity relationship in the hydrolysis to 9-epibases

aDepartment of Chemistry, University of Podlasie, ul. 3 Maja 54, 08-110 Siedlce, Poland
*Correspondence e-mail: kar@uph.edu.pl

(Received 20 April 2011; accepted 7 July 2011; online 5 August 2011)

In the crystal structures of the diastereoisomers of O-tosyl­cinchonidine [(9R)-cinchon-9-yl 4-methylbenzenesul­fon­ate], (I), and O-tosyl­cinchonine [(9S)-cinchon-9-yl 4-methylbenzenesulfonate], (II), both C26H28N2O3S, both mol­ecules are in an anti-closed conformation and, in each case, the position of the aryl ring of the tosyl­ate system is influenced by an intra­molecular C—H⋯O hydrogen bond. The mol­ecular packing in (I) is influenced by weak inter­molecular C—H⋯O and C—H⋯π inter­actions. The crystal structure of (II) features C—H⋯π inter­actions and van der Waals forces only. The computational investigations using RHF/6–31G** ab initio and AM1 semi-empirical methods performed for (I) and (II) and their protonated species show that the conformational and energetic parameters of the mol­ecules are correlated with differences in their reactivity in hydrolysis to the corres­ponding 9-epibases.

Comment

Studies on the difference in biological activity of natural Cinchona alkaloids with respect to their structural, stereochemical and physicochemical properties have attracted much attention owing to the pharmacological inter­est in these compounds (Verpoorte et al., 1988[Verpoorte, R., Schripsema, J. & Der Leer, T. V. (1988). The Alkaloids, Vol. 34, edited by A. Brossi, pp. 331-398. San Diego: Academic Press.]). Recently, Cinchona alkaloids and their derivatives have been investigated as natural organocatalysts giving asymmetric induction in organic reactions with the formation of stereogenic centres (Song, 2009[Song, E. C. (2009). In Cinchona Alkaloids in Synthesis and Catalysis. Weinheim: Wiley-VCH.]). Transformation of natural alkaloids into pharmacologically inactive 9-epibases is known to be a two-step process: formation of sulfonate esters followed by hydrolysis in a weak acid medium (Hoffman & Frackenpohl, 2004[Hoffman, H. M. R. & Frackenpohl, J. (2004). Eur. J. Org. Chem. pp. 4293-4312.]). The first step proceeds with retention and the second one with inversion of the carbinol atom configuration. It was found that hydrolysis of O-tosyl derivatives is a good method for epimerization of C9 in the quinine, quinidine and cinchonidine cores, but is ineffective for cinchonine since its tosyl­ate converts slowly and not selectively to the corresponding 9-epi­base (Braje et al., 2000[Braje, W., Holzgrefe, J., Wartchow, R. & Hoffman, H. M. R. (2000). Angew. Chem. Int. Ed. 39, 2085-2087.]). In order to link the differences in experimental reactivity in the hydrolysis to 9-epibases with structural and energetic parameters, X-ray investigations and theoretical calculations were undertaken using cinchonidine and cinchonine tosyl­ates, (I)[link] and (II)[link], as model compounds.

[Scheme 1]

Structural analysis of the diastereoisomeric mol­ecules (I)[link] and (II)[link] confirms the retention of the original, respective, R and S configurations at atom C9 in the crystals of both tosyl­ates (Figs. 1[link] and 2[link], respectively). The geometry (bond lengths, angles and planarity) of the main Cinchona alkaloid skeleton is similar in (I)[link] and (II)[link] and the related parent structures of cinchonidine and cinchone mol­ecules (Oleksyn, 1982[Oleksyn, B. J. (1982). Acta Cryst. B38, 1832-1834.]; Oleksyn et al., 1979[Oleksyn, B., Lebioda, Ł. & Ciechanowicz-Rutkowska, M. (1979). Acta Cryst. B35, 440-444.]). Both mol­ecules adopt an anti-closed conformation, torsion angles φ1 = N1—C8—C9—O1 = 166.6 (6) and −176.7 (4)°, φ2 = N1—C8—C9—C24 = 48.4 (6) and −57.6 (6)°, φ3 = O1—C9—C24—C23 = −59.7 (4) and 50.9 (6)°, and φ4 = C8—C9—C24—C23 = 55.9 (5) and −65.7 (6)° in (I)[link] and (II)[link], respectively, which is characteristic, for example, for O-mesyl­quinidine (Braje et al., 2000[Braje, W., Holzgrefe, J., Wartchow, R. & Hoffman, H. M. R. (2000). Angew. Chem. Int. Ed. 39, 2085-2087.]) and is in contrast to an anti-open conformation observed for the parent alkaloids. The four conformers, viz. anti-closed, syn-closed, anti-open and syn-open (Caner et al., 2003[Caner, H., Biedermann, P. U. & Agranat, I. (2003). Chirality, 15, 637-645.]), of the cinchonine-type mol­ecule, showing the lowest energy, are presented in Fig. 3[link].

The orientation of the vinyl substituent in relation to the quinuclidine system is different in (I)[link] and (II)[link]: the torsion angle C2—C3—C10—C11 describing this orientation is 105.4 (13)° in (I)[link] and 175.0 (12)° in (II)[link]. The gauche conformation of the vinyl group in (I)[link] may be caused by a weak inter­molecular C10—H101⋯O3 hydrogen bond and a C11—H111⋯π inter­action (Table 1[link]). Similarly, the trans conformation of the vinyl group in (II)[link] may be a result of the weak C11—H111⋯π(quinoline) inter­molecular inter­action (Table 2[link]). The aryl ring of the tosyl group is inclined to the quinoline ring at angles of 20.24 (10) and 11.51 (13)° in (I)[link] and (II)[link], respectively, and its position is influenced by the C32—H321⋯O2 short intra­molecular contact (Tables 1[link] and 2[link]).

The hydrolysis of O-tosyl­ated mol­ecules proceeds with inversion of the C9 configuration as an SN2 attack by the nucleophilic water mol­ecule from the opposite site to the tosyl­ate leaving group in the substrate requires it to be protonated at the quinuclidine N atom. This process is favoured when the substrate mol­ecule can change from an anti-closed conformation, observed in the crystal, into a syn-open one which is optimal for the SN2 attack in the aqueous weak acid medium. It can be assumed on the basis of known reactivity that the transition state may be formed more easily in the case of cinchonidine tosyl­ate (I)[link] than in the case of cinchonine tosyl­ate (II)[link]. The theoretical calculations at the RHF SCF ab initio 6–31G** level (Bylaska et al., 2006[Bylaska, E. J. et al. (2006). NWChem. Version 5.0. Pacific Northwest National Laboratory, Richland, Washington, USA.]; Kendall et al., 2000[Kendall, R. A., Apra, E., Bernhold, D. E., Bylaska, E. J., Dupois, M., Fann, G. I., Harrison, R. J., Ju, J., Nichols, J. A., Nieplocha, J., Straatsma, T. P., Windus, T. L. & Wong, A. T. (2000). Comput. Phys. Commun. 128, 260-283.]) show that the conformations of mol­ecules (I)[link] and (II)[link] as observed in their crystals are not equi-energetic, with a difference in energy between the (I)[link] and (II)[link] con­formations of ΔE = 2.57 kcal mol−1 (1 kcal mol−1 = 4.184 kJ mol−1; single-point energy calculations). The energy minimization and full geometry optimization with initial geometries obtained from the X-ray analysis for mol­ecules (I)[link] and (II)[link] yielded a smaller difference in energy of 0.85 kcal mol−1 between the conformations of mol­ecule (I)[link] (φ1 = −178.8°, φ2 = 62.8°, φ3 = −44.0° and φ4 = 72.1°) and (II)[link] (φ1 = 174.9°, φ2 = −66.6°, φ3 = 39.8° and φ4 = −76.8°) than that reported for the single-point calculation. It is clear that these energy values do not prevent mol­ecule (II)[link] from changing from an unfavourable anti-closed conformation to a syn-open conformation as expected in the SN2 hydrolysis reaction. The calculations performed for N1-protonated mol­ecules in the syn-open conformation after energy minimization and geometry optimization [φ1 = −54.0 and 48.9°, φ2 = 179.3 and 176.4°, φ3 = 146.8 and −144.6°, and φ4 = −87.2 and 88.5° for (I)[link] and (II)[link], respectively] gave a difference in energy between the protonated (II)[link] and (I)[link] species of 0.39 kcal mol−1 and, moreover, a larger energetic profit of 1.84 kcal mol−1 after protonation of (I)[link] compared with (II)[link] with respect to the free O-tosyl­ates in an anti-closed conformation. Therefore, the different reactivity of (I)[link] and (II)[link] towards the appropriate 9-epi­bases may be related to a change in energy during protonation on the N1 atom and a change in conformation from anti-closed to syn-open during the hydrolysis process. In order to confirm this conclusion, the hydrolysis process was modelled using the N1-protonated mol­ecules of (I)[link] and (II)[link] in `crystallographic' anti-closed conformation and an anion of salicylic acid in a water environment (as an aqueous weak acid medium). The water environment was simulated by locating the alkaloid and salicylate ion in the centre of the box surrounded by 17 water mol­ecules equilibrated at 300 K and 1013 hPa (Jorgensen et al., 1983[Jorgensen, W. L., Chandrasekhar, J., Madura, J. D., Impey, R. W. & Klein, L. (1983). J. Chem. Phys. 79, 926-935.]). The energy minimization and geometry optimization of the (I)-H+–salicylate–H2O system using the semi-empirical AM1 method implemented in the HYPERCHEM package (Hypercube, 1998[Hypercube (1998). HYPERCHEM. Release 4.5. Hypercube Inc., Waterloo, Ontario, Canada.]) give mol­ecule (I)[link] an anti-open conformation (φ1 = −63.7°, φ2 = 175.4°, φ3 = −17.1° and φ4 = 102.3°) which is closely related by rotation around the C9—C24 bond to the syn-open conformation preferred for 9-epicinchonidine formation in the hydrolysis reaction (Figs. 3[link] and 4[link]a). The parallel calculation for the (II)-H+–salicylate–H2O system retains mol­ecule (II)[link] in an anti-closed conformation, unfavourable for the hydrolysis reaction (φ1 = −146.0°, φ2 = −28.5°, φ3 = 49.4° and φ4 = −65.4°) as shown in Fig. 4[link](b). Additionally, the (I)-H+–salicylate system in the gaseous phase with (I)[link] in an anti-open conformation is more energetically stable than the (II)-H+–salicylate system with (II)[link] in an anti-closed conformation with a ΔE value of 8.062 kcal mol−1. As can be seen in Fig. 4[link], the steric hindrance of the aryl ring of the tosyl­ate group and the quinoline ring can restrain the free rotation on the C24—C9 bond, making the C9 atom more accessible to nucleophilic attack by the water mol­ecule in an anti-open conformation of (I)-H+ in comparison with an anti-closed conformation of (II)-H+. The stabilizing influence of the tosyl­ate group on the conformations of (I)-H+ and (II)-H+ can result in their different behaviour in the hydrolysis reaction and their higher hydrolytic stability in comparison to O-mesyl and O-acyl Cinchona alkaloid derivatives.

In conclusion, the X-ray analysis and theoretical calculations provided the geometric, conformational and energetic parameters of the diastereoisomeric mol­ecules O-tosyl cinchonidine, (I)[link], and O-tosyl cinchonine, (II)[link], which were used to explain their different reactivity in the hydrolysis to the respective 9-epibases. It appears that the different energetic profit during protonation on the N1 atom and the different propensity to change from an anti-closed conformation in the crystal to a syn-open one favoured in the hydrolysis process can be correlated with the different reactivity of (I)[link] and (II)[link] towards 9-epibases in the SN2 hydrolysis process.

[Figure 1]
Figure 1
A view of (I)[link] showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 30% probability level. H atoms are represented as small spheres of arbitrary radii.
[Figure 2]
Figure 2
A view of (II)[link] showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 30% probability level. H atoms are represented as small spheres of arbitrary radii.
[Figure 3]
Figure 3
The four conformers of cinchonine showing the lowest energies.
[Figure 4]
Figure 4
The optimized conformations of (a) the (I)-H+–salicylate and (b) the (II)-H+–salicylate system in a water environment using the AM1 method.

Experimental

Compounds (I)[link] and (II)[link] were obtained according to the method described by Kowalik et al. (1999[Kowalik, J. T., Lipińska, T. M., Oleksyn, B. & Śliwiński, J. (1999). Enantiomer, 4, 389-410.]). The analytical data (IR, 1H NMR and 13C NMR) are in good agreement with those found by Brunner & Bügler (1997[Brunner, H. & Bügler, J. (1997). Bull. Soc. Chim. Belg. 106, 77-84.]) for (I)[link] and Kowalik et al. (1999[Kowalik, J. T., Lipińska, T. M., Oleksyn, B. & Śliwiński, J. (1999). Enantiomer, 4, 389-410.]) for (II)[link]. Crystals of both compounds suitable for X-ray diffraction analysis were grown by slow evaporation from diethyl ether–hexane (1:1 v/v) solutions.

Compound (I)[link]

Crystal data
  • C26H28N2O3S

  • Mr = 448.56

  • Orthorhombic, P 21 21 21

  • a = 9.4591 (13) Å

  • b = 10.094 (2) Å

  • c = 24.370 (4) Å

  • V = 2326.9 (7) Å3

  • Z = 4

  • Cu Kα radiation

  • μ = 1.48 mm−1

  • T = 293 K

  • 0.45 × 0.40 × 0.10 mm

Data collection
  • Kuma KM-4 four-circle diffractometer

  • Absorption correction: multi-scan (Blessing, 1995[Blessing, R. H. (1995). Acta Cryst. A51, 33-38.]) Tmin = 0.363, Tmax = 0.748

  • 3726 measured reflections

  • 3508 independent reflections

  • 1717 reflections with I > 2σ(I)

  • Rint = 0.034

  • 2 standard reflections every 100 reflections intensity decay: 0.0%

Refinement
  • R[F2 > 2σ(F2)] = 0.064

  • wR(F2) = 0.167

  • S = 1.06

  • 3508 reflections

  • 290 parameters

  • 1 restraint

  • H-atom parameters constrained

  • Δρmax = 0.30 e Å−3

  • Δρmin = −0.33 e Å−3

  • Absolute structure: Flack (1983[Flack, H. D. (1983). Acta Cryst. A39, 876-881.]), 604 Friedel pairs

  • Flack parameter: 0.00 (3)

Table 1
Hydrogen-bond geometry (Å, °) for (I)[link]

CgA, CgB and CgC are the centroids of the benzene, toluene and pyridine rings, respectively.

D—H⋯A D—H H⋯A DA D—H⋯A
C32—H321⋯O2 0.93 2.60 2.944 (9) 103
C10—H101⋯O3i 0.93 2.48 3.377 (7) 163
C11—H111⋯CgAii 0.93 2.98 3.775 (8) 144
C23—H231⋯CgBi 0.93 2.87 3.619 (5) 138
C37—H371⋯CgCiii 0.96 2.81 3.746 (7) 165
Symmetry codes: (i) [x-{\script{1\over 2}}, -y+{\script{1\over 2}}, -z+1]; (ii) [-x, y+{\script{1\over 2}}, -z+{\script{3\over 2}}]; (iii) x, y+1, z.

Compound (II)[link]

Crystal data
  • C26H28N2O3S

  • Mr = 448.56

  • Orthorhombic, P 21 21 21

  • a = 6.8350 (13) Å

  • b = 17.7364 (16) Å

  • c = 18.6632 (17) Å

  • V = 2262.5 (5) Å3

  • Z = 4

  • Cu Kα radiation

  • μ = 1.52 mm−1

  • T = 293 K

  • 0.40 × 0.10 × 0.10 mm

Data collection
  • Kuma KM-4 four-circle diffractometer

  • Absorption correction: ψ scan (North et al., 1968[North, A. C. T., Phillips, D. C. & Mathews, F. S. (1968). Acta Cryst. A24, 351-359.]) Tmin = 0.571, Tmax = 0.847

  • 2806 measured reflections

  • 2723 independent reflections

  • 1710 reflections with I > 2σ(I)

  • Rint = 0.026

  • 2 standard reflections every 100 reflections intensity decay: 0.0%

Refinement
  • R[F2 > 2σ(F2)] = 0.051

  • wR(F2) = 0.177

  • S = 1.01

  • 2723 reflections

  • 290 parameters

  • 1 restraint

  • H-atom parameters constrained

  • Δρmax = 0.45 e Å−3

  • Δρmin = −0.21 e Å−3

Table 2
Hydrogen-bond geometry (Å, °) for (II)[link]

CgD and CgE are the centroids of the pyridine and quinoline rings, respectively.

D—H⋯A D—H H⋯A DA D—H⋯A
C32—H321⋯O2 0.93 2.58 2.936 (7) 103
C22—H221⋯CgDi 0.93 2.92 3.689 (7) 141
C11—H111⋯CgEii 0.93 2.92 3.681 (7) 140
Symmetry codes: (i) [x+{\script{1\over 2}}, -y+{\script{1\over 2}}, -z+1]; (ii) [-x+1, y-{\script{1\over 2}}, -z+{\script{3\over 2}}].

The assumed absolute stereochemistry of compound (I)[link] was confirmed by refinement of the Flack (1983[Flack, H. D. (1983). Acta Cryst. A39, 876-881.]) parameter. In the absence of Friedel pairs, the absolute configuration of compound (II)[link] was assigned from the absolute configuration of cinchonine as starting reagent in the stereoconservative synthesis. For both compounds, all H atoms were fixed geometrically and treated as riding on their parent C atoms, with C—H distances of 0.93 (aromatic), 0.96 (CH3), 0.97 (CH2) and 0.98 Å (CH), and with Uiso(H) = 1.5Ueq(C). For both molecules, C10 and C11 of the terminal vinyl group showed large displacement parameters, which result in unrealistic C10—C11 bond lengths of 1.177 (8) and 1.206 (12) Å in (I)[link] and (II)[link], respectively. An electron-density map did not reveal the alternate sites for the C10 and C11 atoms. Therefore, a DFIX restraint (SHELXL97; Sheldrick, 2008) with a target value of 1.300 (5) Å for the C10=C11 vinyl bonds in (I)[link] and (II)[link] was used.

For both diastereoisomers, data collection: KM4B8 (Gałdecki et al., 1996[Gałdecki, Z., Kowalski, A., Kucharczyk, D. & Uszyński, L. (1996). KM4B8. Kuma Diffraction, Wrocław, Poland.]); cell refinement: KM4B8; data reduction: DATAPROC (Gałdecki et al., 1995[Gałdecki, Z., Kowalski, A. & Uszyński, L. (1995). DATAPROC. Version 9.0. Kuma Diffraction, Wrocław, Poland.]); program(s) used to solve structure: SIR92 (Altomare et al., 1993[Altomare, A., Cascarano, G., Giacovazzo, C. & Guagliardi, A. (1993). J. Appl. Cryst. 26, 343-350.]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997[Farrugia, L. J. (1997). J. Appl. Cryst. 30, 565.]); software used to prepare material for publication: SHELXL97 and WinGX (Farrugia, 1999[Farrugia, L. J. (1999). J. Appl. Cryst. 32, 837-838.]).

Supporting information


Comment top

Studies on the difference in biological activity of natural Cinchona alkaloids with respect to their structural, stereochemical and physicochemical properties have attracted much attention owing to the pharmacological interest in these compounds (Verpoorte et al., 1988). Recently, Cinchona alkaloids and their derivatives have been investigated as natural organocatalysts giving asymmetric induction in organic reactions with the formation of stereogenic centres (Song, 2009). Transformation of natural alkaloids into pharmacologically inactive 9-epibases is known to be a two-step process: formation of sulfonate esters followed by hydrolysis in a weak acid medium (Hoffman & Frackenpohl, 2004). The first step runs with retention and the second one with inversion of the carbinol atom configuration. It was found that hydrolysis of O-tosyl derivatives is a good method for epimerization of C9 in quinine, quinidine and cinchonidine core, but is ineffective for cinchonine, since its tosylate converts slowly and not selectively to the corresponding 9-epibase (Braje et al., 2000). In order to link the differences in experimental reactivity in hydrolysis to 9-epibases with structural and energetic parameters, X-ray investigations and theoretical calculations were undertaken using cinchonidine and cinchonine tosylates, (I) and (II) (Scheme 1), as model compounds.

Structural analysis of the diastereoisomeric molecules (I) and (II) confirms the retention of the original, respective, R and S configuration at atom C9 in the crystals of both tosylates (Figs. 1 and 2, respectively). The geometry (bond lengths, angles and planarity) of the main Cinchona alkaloid skeleton is similar in (I) and (II) and related parent structures of cinchonidine and cinchone molecules (Oleksyn, 1982; Oleksyn et al., 1979). Strong thermal vibration of the exocyclic vinyl group results in an apparent shortening of the terminal C10—C11 bond to 1.177 (8) and 1.206 (12) Å in (I) and (II), respectively, in comparison with the expected Csp2 Csp2 bond length in C*—CHCH2 [1.299 (27) Å; Allen et al., 1987]. Both molecules adopt an anti-closed conformation with torsion angles ϕ1 = N1—C8—C9—O1 of 166.2 (4) and -176.6 (4)o, ϕ2 = N1—C8—C9—C24 of 48.1 (5) and -57.4 (5)o, ϕ3 = O1—C9—C24—C23 of -59.9 (4) and 50.8 (6)o, ϕ4 = C8—C9—C24—C23 of 55.9 (5) and -65.9 (6)o in (I) and (II), respectively, which is characteristic for e.g. O-mesyl quinidine (Braje et al., 2000) and in contrast to an anti-open conformation observed for parent alkaloids. The four conformers anti-closed, syn-closed, anti-open and syn-open (Caner et al., 2003) of the cinchonine-type molecule, showing the lowest energy, are presented in Fig. 3.

The orientation of the vinyl substituent in relation to the quinuclidine system is different in (I) and (II): the torsion angle C2—C3—C10—C11 describing this orientation is 105.4 (13)° in (I) and 175.0 (12)° in (II). The gauche conformation of the vinyl group in (I) may be caused by a weak intermolecular C10—H101···O3 hydrogen bond and C11—H111···π interaction (Table 1). Similarly, the trans conformation of the vinyl group in (II) may be a result of the weak C11—H111···π (quinoline) intermolecular interaction (Table 2). In both molecules the aryl ring of the tosyl group is inclined to the quinoline ring at an angle of 20.24 (10) and 11.51 (13)° in (I) and (II), respectively, and its position is stabilized by the C32—H321···O2 short intramolecular contact (Tables 1 and 2).

The hydrolysis of O-tosylated molecules proceeds with inversion of the C9 configuration as an SN2 attack of the nucleophilic water molecule from the opposite site to the tosylate leaving [a?] group in the substrate protonated at the quinuclidine nitrogen. This process is the most possible [favoured?] when the substrate molecule can change an anti-closed conformation, observed in the crystal, into a syn-open which is optimal for the SN2 attack in the aqueous weak acid medium. It can be assumed on the basis of known reactivity that the transition state may be formed more easily in the case of cinchonidine tosylate, (I), than in the case of cinchonine tosylate, (II). The theoretical calculations at the RHF SCF ab initio 6–31G** level (Bylaska et al., 2006; Kendall et al., 2000) show that the conformations of molecules (I) and (II) as observed in their crystals are not equi-energetically [favourbale?] with a difference of energy between the (I) and (II) conformations of ΔE = 1.45 kcal mol-1 (single-point energy calculations). Indeed, the geometry of the vinyl group obtained from the X-ray [data] is unreliable in molecules (I) and (II), but the same systematic error generated by an unrealistic bond length in the vinyl substituent during the energy calculation for both molecules makes the difference of energy reasonable. The energy minimization and full geometry optimization with initial geometries obtained from X-ray analysis for molecules (I) and (II) yielded a smaller difference of energy of 0.84 kcal mol-1 between the conformations of molecule (I) (ϕ1 = -179.2°, ϕ2 = 62.5°, ϕ3 = -44.3° and ϕ4 = 71.8°) and (II) (ϕ1 = 174.4°, ϕ2 = -67.0°, ϕ3 = 39.6° and ϕ4 = -77.0°) than that reported for the single-point calculation. It is clear that these energy values do not prevent molecule (II) from changing an unfavourable anti-closed conformation to a syn-open conformation as expected in the SN2 hydrolysis reaction. The calculations performed for N1-protonated molecules in the syn-open conformation after energy minimization and geometry optimization [ϕ1 = -54.0 and 48.9°, ϕ2 = 179.3 and 176.4°, ϕ3 = 146.8 and -144.6° and ϕ4 = -87.2 and 88.5° for (I) and (II), respectively] gave a difference of energy between the protonated, (II), and protonated, (I), species of 0.39 kcal mol-1 and, consistently, the larger energetic profit [gain?] of 1.84 kcal mol-1 after protonation of (I) than that for (II) with respect to free O-tosylates in an anti-closed conformation. Therefore, the different reactivity of (I) and (II) towards the appropriate 9-epibases may be related to a change of energy during protonation on the N1 atom and a change of conformation from anti-closed to syn-open in the hydrolysis process. In order to confirm this conclusion the hydrolysis process was modelled using the N1-protonated molecules (I) and (II) in `crystallographic' anti-closed conformation and an anion of salicylic acid in water environment (as an aqueous weak acid medium). The water environment was simulated by location of the alkaloid and salicylic acid ion in the centre of the box surrounded by 17 water molecules equilibrated at 300 K and 1013 h Pa (Jorgensen et al., 1983). The energy minimization and geometry optimization of the (I)-H+-salicylate-–H2O system using the semi-empirical AM1 method implemented in the HYPERCHEM package (Hypercube, 1998) give molecule (I) an anti-open conformation (ϕ1 = -63.7°, ϕ2 = 175.4°, ϕ3 = -17.1° and ϕ4 = 102.3°) closely related by the rotation around the C9—C24 bond to the syn-open conformation preferred for 9-epicynchonidine formation in the hydrolysis reaction (Figs. 3 and 4a). The parallel calculation for the (II)-H+-salicylate-–H2O system retains molecule (II) in unfavourable for the hydrolysis reaction anti-closed conformation (ϕ1 = -146.0°, ϕ2 = -28.5°, ϕ3 = 49.4° and ϕ4 = -65.4°) as shown in Fig. 4(b) . Additionally, the (I)-H+-salicylate- system in the gaseous phase with (I) in an anti-open conformation is more energetically stable than the (II)-H+-salicylate- system with (II) in an anti-closed conformation with a ΔE value of 8.062 kcal mol-1. As can be seen in Fig. 4, the steric hindrance of the aryl ring of the tosylate group and the quinoline ring can restrain the free rotation on the C24—C9 bond making the C9 atom more accessible to nucleophilic attack of water molecule in anti-open conformation of (I)-H+ in comparison with anti-closed conformation of (II)-H+. The stabilizing influence of the tosylate group on the conformation of (I)-H+ and (II)-H+ can result in their different behaviour in the hydrolysis reaction and higher hydrolytic stability in comparison to O-mesyl and O-acyl Cinchona alkaloid derivatives.

In conclusion, the X-ray analysis and theoretical calculations provided the geometric, conformational and energetic parameters of the diastereoisomeric molecules O-tosyl cinchonidine, (I), and O-tosyl cinchonine, (II), which were used to explain their different reactivity in hydrolysis to the respective 9-epibases. It appears that the different energetic profit [gain?] during protonation on the N1 atom and the different possibility to change of conformation from anti-closed in the crystal to syn-open favoured in the hydrolysis process can be correlated with the different reactivity of (I) and (II) towards 9-epibases in the SN2 hydrolysis process.

Related literature top

For related literature, see: Allen et al. (1987); Braje et al. (2000); Brunner & Bügler (1997); Bylaska et al. (2006); Caner et al. (2003); Flack (1983); Jorgensen et al. (1983); Kendall et al. (2000); Kowalik et al. (1999); Oleksyn (1982); Oleksyn et al. (1979); Song (2009); Verpoorte et al. (1988).

Experimental top

Compounds (I) and (II) were obtained by the method described by Kowalik et al. (1999) and their analytical data (IR, 1H NMR and 13C NMR) are in good agreement with those found in Brunner & Bügler (1997) for (I) and Kowalik et al. (1999) for (II). Crystals of both compounds suitable for X-ray diffraction analysis were grown by slow evaporation of diethyl ether–hexane (1:1) solutions.

Refinement top

The assumed absolute stereochemistry of compound (I) was confirmed by refinement of the Flack (1983) parameter. In the absence of Friedel pairs, the absolute configuration of compound (II) was assigned from absolute configuration of cinchonine as starting reagent in the stereoconservative synthesis. For both compounds, all hydrogen atoms were fixed geometrically and treated as riding on their parent C atoms with C—H distances of 0.93 Å (aromatic), 0.96 Å (CH3), 0.97 Å (CH2) and 0.98 Å (CH) and with Uiso(H) = 1.5Ueq(C).

Computing details top

For both compounds, data collection: KM4B8 (Gałdecki et al., 1996); cell refinement: KM4B8 (Gałdecki et al., 1996); data reduction: DATAPROC (Gałdecki et al., 1995); program(s) used to solve structure: SIR92 (Altomare et al., 1993); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997). Software used to prepare material for publication: SHELXL97 (Sheldrick, 2008) and WinGX (Farrugia, 1997) for (I); SHELXL97 (Sheldrick, 2008) and WinGX (Farrugia, 1999) for (II).

Figures top
[Figure 1] Fig. 1. A view of (I) showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level. H atoms are represented as small spheres of arbitrary radii.
[Figure 2] Fig. 2. A view of (II) showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level. H atoms are represented as small spheres of arbitrary radii.
[Figure 3] Fig. 3. The four conformers of cinchonine showing the lowest energy.
[Figure 4] Fig. 4. The optimized conformations of (a) (I)-H+-salicylate- and (b) (II)-H+-salicylate- systems in a water environment using the AM1 method.
(I) O-Tosyl cinchonidine top
Crystal data top
C26H28N2O3SDx = 1.280 Mg m3
Mr = 448.56Melting point = 407–408 K
Orthorhombic, P212121Cu Kα radiation, λ = 1.54178 Å
Hall symbol: P 2ac 2abCell parameters from 25 reflections
a = 9.4591 (13) Åθ = 19.4–34.6°
b = 10.094 (2) ŵ = 1.48 mm1
c = 24.370 (4) ÅT = 293 K
V = 2326.9 (7) Å3Prism, colourless
Z = 40.45 × 0.40 × 0.10 mm
F(000) = 952
Data collection top
Kuma KM-4 four-circle
diffractometer
1717 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tubeRint = 0.034
Graphite monochromatorθmax = 80.5°, θmin = 3.6°
ω–2θ scansh = 112
Absorption correction: multi-scan
(Blessing, 1995)
k = 112
Tmin = 0.363, Tmax = 0.748l = 311
3726 measured reflections2 standard reflections every 100 reflections
3508 independent reflections intensity decay: 0.0%
Refinement top
Refinement on F2Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: fullH-atom parameters constrained
R[F2 > 2σ(F2)] = 0.064 w = 1/[σ2(Fo2) + (0.0716P)2]
where P = (Fo2 + 2Fc2)/3
wR(F2) = 0.167(Δ/σ)max < 0.001
S = 1.06Δρmax = 0.30 e Å3
3508 reflectionsΔρmin = 0.33 e Å3
290 parametersExtinction correction: SHELXL, Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
1 restraintExtinction coefficient: 0.0085 (6)
Primary atom site location: structure-invariant direct methodsAbsolute structure: Flack (1983), 604 Friedel pairs
Secondary atom site location: difference Fourier mapAbsolute structure parameter: 0.00 (3)
Crystal data top
C26H28N2O3SV = 2326.9 (7) Å3
Mr = 448.56Z = 4
Orthorhombic, P212121Cu Kα radiation
a = 9.4591 (13) ŵ = 1.48 mm1
b = 10.094 (2) ÅT = 293 K
c = 24.370 (4) Å0.45 × 0.40 × 0.10 mm
Data collection top
Kuma KM-4 four-circle
diffractometer
1717 reflections with I > 2σ(I)
Absorption correction: multi-scan
(Blessing, 1995)
Rint = 0.034
Tmin = 0.363, Tmax = 0.7482 standard reflections every 100 reflections
3726 measured reflections intensity decay: 0.0%
3508 independent reflections
Refinement top
R[F2 > 2σ(F2)] = 0.064H-atom parameters constrained
wR(F2) = 0.167Δρmax = 0.30 e Å3
S = 1.06Δρmin = 0.33 e Å3
3508 reflectionsAbsolute structure: Flack (1983), 604 Friedel pairs
290 parametersAbsolute structure parameter: 0.00 (3)
1 restraint
Special details top

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
S10.26610 (8)0.23628 (18)0.50781 (3)0.0584 (4)
O10.13605 (17)0.2196 (4)0.54796 (7)0.0527 (10)
O20.3885 (2)0.1817 (5)0.53325 (13)0.0792 (11)
O30.2180 (3)0.1881 (5)0.45660 (9)0.0796 (13)
N10.0247 (3)0.2361 (5)0.69153 (10)0.0606 (12)
N20.1832 (4)0.2170 (6)0.64076 (15)0.0820 (13)
C20.1152 (5)0.2772 (8)0.71136 (19)0.0762 (17)
H210.12410.25490.74990.114*
H220.18770.22940.69140.114*
C30.1385 (5)0.4302 (8)0.70376 (19)0.0769 (17)
H310.15450.47050.73980.115*
C40.0003 (5)0.4837 (7)0.68019 (16)0.0751 (15)
H410.00860.57990.67590.113*
C50.1176 (7)0.4543 (8)0.7210 (3)0.0911 (18)
H510.20550.49430.70890.137*
H520.09410.48940.75690.137*
C60.1323 (5)0.3043 (8)0.72352 (19)0.0808 (19)
H610.22500.27940.70990.121*
H620.12580.27600.76150.121*
C70.0312 (5)0.4240 (7)0.62566 (18)0.0699 (14)
H710.12240.45430.61250.105*
H720.04050.44940.59920.105*
C80.0323 (3)0.2708 (7)0.63326 (13)0.0533 (12)
H810.05270.23560.61550.080*
C90.1605 (3)0.2041 (7)0.60660 (12)0.0523 (14)
H910.24730.25060.61720.079*
C100.2653 (6)0.4535 (10)0.6688 (2)0.129 (4)
H1010.25550.42890.63220.193*
C110.3844 (8)0.5018 (11)0.6816 (3)0.174 (6)
H1110.40180.52860.71750.260*
H1120.45460.51040.65510.260*
C220.0722 (5)0.1587 (8)0.61875 (19)0.0738 (16)
H2210.00560.21120.61030.111*
C230.0636 (4)0.0230 (7)0.60731 (18)0.0612 (12)
H2310.01800.01140.59150.092*
C240.1741 (3)0.0594 (6)0.61914 (13)0.0486 (11)
C250.4215 (3)0.0725 (9)0.65689 (16)0.084 (2)
H2510.42640.16350.65110.125*
C260.5358 (5)0.0075 (11)0.6784 (3)0.109 (3)
H2610.61810.05470.68570.164*
C270.5314 (7)0.1256 (11)0.6895 (4)0.132 (4)
H2710.60900.16680.70560.198*
C280.4142 (5)0.1977 (10)0.6771 (2)0.104 (2)
H2810.41300.28790.68470.156*
C290.2941 (5)0.1380 (8)0.65287 (18)0.0695 (17)
C300.2957 (4)0.0033 (7)0.64322 (16)0.0600 (16)
C310.2856 (3)0.4081 (6)0.50317 (14)0.0527 (12)
C320.3878 (5)0.4734 (8)0.5339 (2)0.0669 (14)
H3210.44960.42660.55630.100*
C330.3952 (5)0.6107 (7)0.5302 (3)0.0787 (17)
H3310.46110.65500.55170.118*
C340.3108 (4)0.6831 (8)0.4966 (2)0.0708 (14)
C350.2132 (4)0.6138 (8)0.4643 (3)0.0728 (16)
H3510.15670.66000.43960.109*
C360.1993 (4)0.4792 (7)0.4684 (2)0.0666 (15)
H3610.13130.43550.44770.100*
C370.3242 (6)0.8314 (8)0.4920 (3)0.102 (2)
H3710.29360.87180.52560.153*
H3720.26640.86260.46230.153*
H3730.42100.85450.48520.153*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
S10.0641 (4)0.0481 (11)0.0630 (4)0.0020 (6)0.0156 (3)0.0066 (8)
O10.0558 (8)0.053 (3)0.0492 (8)0.0007 (17)0.0054 (6)0.005 (2)
O20.0639 (10)0.069 (3)0.1045 (18)0.019 (2)0.0194 (12)0.035 (3)
O30.1084 (17)0.070 (4)0.0607 (11)0.009 (3)0.0235 (12)0.013 (2)
N10.0870 (14)0.044 (3)0.0511 (11)0.004 (3)0.0104 (10)0.002 (3)
N20.109 (2)0.049 (3)0.088 (2)0.002 (3)0.0007 (18)0.011 (4)
C20.094 (2)0.059 (5)0.076 (2)0.008 (4)0.0252 (19)0.008 (5)
C30.107 (3)0.060 (5)0.0631 (19)0.014 (5)0.020 (2)0.012 (5)
C40.108 (3)0.038 (4)0.080 (2)0.006 (4)0.012 (2)0.004 (4)
C50.127 (3)0.052 (4)0.094 (3)0.026 (5)0.007 (3)0.012 (6)
C60.107 (3)0.072 (6)0.0630 (18)0.002 (5)0.0194 (18)0.009 (5)
C70.103 (3)0.037 (3)0.069 (2)0.010 (4)0.0171 (19)0.004 (4)
C80.0693 (14)0.040 (4)0.0505 (13)0.004 (3)0.0016 (10)0.004 (4)
C90.0561 (11)0.048 (4)0.0533 (14)0.005 (3)0.0005 (10)0.006 (3)
C100.122 (3)0.172 (12)0.092 (3)0.026 (7)0.019 (3)0.006 (6)
C110.158 (5)0.207 (17)0.156 (6)0.074 (9)0.029 (5)0.017 (9)
C220.091 (2)0.053 (4)0.077 (2)0.020 (4)0.006 (2)0.001 (5)
C230.0681 (16)0.042 (3)0.073 (2)0.010 (3)0.0052 (16)0.013 (4)
C240.0568 (13)0.038 (3)0.0508 (14)0.004 (3)0.0008 (11)0.000 (3)
C250.0600 (15)0.103 (7)0.088 (2)0.002 (3)0.0134 (15)0.019 (5)
C260.071 (2)0.134 (10)0.123 (4)0.014 (5)0.025 (2)0.040 (7)
C270.094 (3)0.142 (11)0.159 (6)0.038 (6)0.035 (4)0.058 (9)
C280.107 (3)0.098 (7)0.106 (3)0.030 (5)0.011 (2)0.026 (6)
C290.0788 (19)0.064 (5)0.0659 (19)0.012 (4)0.0079 (16)0.012 (4)
C300.0635 (15)0.060 (5)0.0568 (16)0.003 (3)0.0005 (13)0.009 (4)
C310.0567 (12)0.043 (3)0.0578 (14)0.002 (2)0.0101 (12)0.005 (3)
C320.0731 (18)0.060 (4)0.0677 (19)0.007 (4)0.0043 (17)0.011 (5)
C330.084 (2)0.065 (5)0.087 (3)0.008 (4)0.000 (2)0.004 (6)
C340.0757 (17)0.044 (3)0.093 (2)0.004 (3)0.0256 (19)0.013 (5)
C350.0631 (16)0.055 (4)0.101 (3)0.009 (3)0.0026 (18)0.019 (5)
C360.0586 (15)0.057 (4)0.084 (2)0.004 (3)0.0053 (15)0.019 (5)
C370.104 (3)0.051 (4)0.150 (5)0.011 (4)0.025 (4)0.011 (7)
Geometric parameters (Å, º) top
S1—O31.414 (3)C10—H1010.9300
S1—O21.424 (3)C11—H1110.9300
S1—O11.5807 (18)C11—H1120.9300
S1—C311.748 (6)C22—C231.401 (8)
O1—C91.456 (4)C22—H2210.9300
N1—C61.455 (6)C23—C241.367 (7)
N1—C81.464 (4)C23—H2310.9300
N1—C21.468 (5)C24—C301.410 (5)
N2—C221.317 (6)C25—C261.369 (7)
N2—C291.351 (8)C25—C301.420 (7)
C2—C31.571 (10)C25—H2510.9300
C2—H210.9700C26—C271.372 (12)
C2—H220.9700C26—H2610.9300
C3—C101.490 (7)C27—C281.360 (10)
C3—C41.526 (6)C27—H2710.9300
C3—H310.9800C28—C291.416 (7)
C4—C71.489 (6)C28—H2810.9300
C4—C51.523 (7)C29—C301.445 (10)
C4—H410.9800C31—C361.377 (6)
C5—C61.521 (10)C31—C321.389 (6)
C5—H510.9700C32—C331.390 (9)
C5—H520.9700C32—H3210.9300
C6—H610.9700C33—C341.357 (7)
C6—H620.9700C33—H3310.9300
C7—C81.557 (7)C34—C351.401 (7)
C7—H710.9700C34—C371.507 (9)
C7—H720.9700C35—C361.368 (9)
C8—C91.532 (5)C35—H3510.9300
C8—H810.9800C36—H3610.9300
C9—C241.498 (8)C37—H3710.9600
C9—H910.9800C37—H3720.9600
C10—C111.267 (4)C37—H3730.9600
O3—S1—O2120.8 (3)C8—C9—H91109.9
O3—S1—O1105.03 (14)C11—C10—C3129.5 (6)
O2—S1—O1108.80 (15)C11—C10—H101115.2
O3—S1—C31108.5 (2)C3—C10—H101115.2
O2—S1—C31109.0 (2)C10—C11—H111120.0
O1—S1—C31103.2 (2)C10—C11—H112120.0
C9—O1—S1119.67 (17)H111—C11—H112120.0
C6—N1—C8111.8 (4)N2—C22—C23124.3 (6)
C6—N1—C2108.7 (4)N2—C22—H221117.8
C8—N1—C2107.2 (4)C23—C22—H221117.8
C22—N2—C29116.4 (6)C24—C23—C22120.6 (5)
N1—C2—C3111.4 (5)C24—C23—H231119.7
N1—C2—H21109.3C22—C23—H231119.7
C3—C2—H21109.3C23—C24—C30117.9 (6)
N1—C2—H22109.3C23—C24—C9119.0 (4)
C3—C2—H22109.3C30—C24—C9123.1 (4)
H21—C2—H22108.0C26—C25—C30121.1 (7)
C10—C3—C4114.7 (4)C26—C25—H251119.5
C10—C3—C2109.6 (6)C30—C25—H251119.5
C4—C3—C2105.8 (4)C27—C26—C25121.4 (7)
C10—C3—H31108.9C27—C26—H261119.3
C4—C3—H31108.9C25—C26—H261119.3
C2—C3—H31108.9C28—C27—C26120.3 (7)
C7—C4—C3111.3 (5)C28—C27—H271119.9
C7—C4—C5110.9 (5)C26—C27—H271119.9
C3—C4—C5108.2 (4)C27—C28—C29121.3 (8)
C7—C4—H41108.8C27—C28—H281119.3
C3—C4—H41108.8C29—C28—H281119.3
C5—C4—H41108.8N2—C29—C28117.6 (7)
C6—C5—C4106.7 (6)N2—C29—C30123.7 (5)
C6—C5—H51110.4C28—C29—C30118.7 (6)
C4—C5—H51110.4C24—C30—C25125.7 (6)
C6—C5—H52110.4C24—C30—C29117.1 (5)
C4—C5—H52110.4C25—C30—C29117.1 (5)
H51—C5—H52108.6C36—C31—C32119.7 (6)
N1—C6—C5112.6 (5)C36—C31—S1119.6 (4)
N1—C6—H61109.1C32—C31—S1120.6 (4)
C5—C6—H61109.1C33—C32—C31118.2 (6)
N1—C6—H62109.1C33—C32—H321120.9
C5—C6—H62109.1C31—C32—H321120.9
H61—C6—H62107.8C34—C33—C32123.1 (6)
C4—C7—C8107.3 (4)C34—C33—H331118.4
C4—C7—H71110.3C32—C33—H331118.4
C8—C7—H71110.3C33—C34—C35117.2 (6)
C4—C7—H72110.3C33—C34—C37122.1 (6)
C8—C7—H72110.3C35—C34—C37120.7 (6)
H71—C7—H72108.5C36—C35—C34121.2 (6)
N1—C8—C9110.2 (4)C36—C35—H351119.4
N1—C8—C7110.6 (5)C34—C35—H351119.4
C9—C8—C7113.0 (4)C35—C36—C31120.4 (6)
N1—C8—H81107.6C35—C36—H361119.8
C9—C8—H81107.6C31—C36—H361119.8
C7—C8—H81107.6C34—C37—H371109.5
O1—C9—C24108.6 (5)C34—C37—H372109.5
O1—C9—C8104.1 (3)H371—C37—H372109.5
C24—C9—C8114.2 (4)C34—C37—H373109.5
O1—C9—H91109.9H371—C37—H373109.5
C24—C9—H91109.9H372—C37—H373109.5
O3—S1—O1—C9153.6 (5)C8—C9—C24—C2355.9 (5)
O2—S1—O1—C922.9 (5)O1—C9—C24—C30120.9 (3)
C31—S1—O1—C992.8 (5)C8—C9—C24—C30123.5 (3)
C6—N1—C2—C361.5 (6)C30—C25—C26—C272.5 (11)
C8—N1—C2—C359.5 (6)C25—C26—C27—C282.8 (14)
N1—C2—C3—C10121.6 (4)C26—C27—C28—C290.3 (13)
N1—C2—C3—C42.6 (6)C22—N2—C29—C28179.3 (4)
C10—C3—C4—C758.8 (7)C22—N2—C29—C300.3 (7)
C2—C3—C4—C762.1 (6)C27—C28—C29—N2178.6 (6)
C10—C3—C4—C5179.1 (6)C27—C28—C29—C302.3 (9)
C2—C3—C4—C560.0 (6)C23—C24—C30—C25178.2 (4)
C7—C4—C5—C657.0 (7)C9—C24—C30—C252.4 (6)
C3—C4—C5—C665.4 (7)C23—C24—C30—C290.7 (6)
C8—N1—C6—C560.9 (7)C9—C24—C30—C29179.9 (4)
C2—N1—C6—C557.2 (6)C26—C25—C30—C24177.6 (5)
C4—C5—C6—N15.3 (7)C26—C25—C30—C290.2 (7)
C3—C4—C7—C855.9 (6)N2—C29—C30—C240.8 (7)
C5—C4—C7—C864.6 (6)C28—C29—C30—C24179.8 (4)
C6—N1—C8—C973.5 (6)N2—C29—C30—C25178.5 (4)
C2—N1—C8—C9167.4 (4)C28—C29—C30—C252.5 (7)
C6—N1—C8—C752.2 (5)O3—S1—C31—C3630.4 (3)
C2—N1—C8—C766.8 (5)O2—S1—C31—C36163.9 (3)
C4—C7—C8—N18.8 (5)O1—S1—C31—C3680.6 (3)
C4—C7—C8—C9132.9 (3)O3—S1—C31—C32149.1 (3)
S1—O1—C9—C2490.4 (4)O2—S1—C31—C3215.7 (4)
S1—O1—C9—C8147.6 (4)O1—S1—C31—C3299.8 (3)
N1—C8—C9—O1166.6 (5)C36—C31—C32—C332.8 (7)
C7—C8—C9—O169.0 (5)S1—C31—C32—C33177.6 (5)
N1—C8—C9—C2448.4 (6)C31—C32—C33—C342.4 (9)
C7—C8—C9—C24172.8 (3)C32—C33—C34—C350.4 (8)
C4—C3—C10—C11130.2 (10)C32—C33—C34—C37178.0 (6)
C2—C3—C10—C11111.0 (11)C33—C34—C35—C362.9 (8)
C29—N2—C22—C230.3 (7)C37—C34—C35—C36179.5 (6)
N2—C22—C23—C240.4 (8)C34—C35—C36—C312.5 (9)
C22—C23—C24—C300.2 (7)C32—C31—C36—C350.4 (7)
C22—C23—C24—C9179.6 (4)S1—C31—C36—C35180.0 (4)
O1—C9—C24—C2359.7 (4)
Hydrogen-bond geometry (Å, º) top
CgA, CgB and CgC are the centroids of the benzene, toluene and pyridine rings, respectively.
D—H···AD—HH···AD···AD—H···A
C32—H321···O20.932.602.944 (9)103
C10—H101···O3i0.932.483.377 (7)163
C11—H111···CgAii0.932.983.775 (8)144
C23—H231···CgBi0.932.873.619 (5)138
C37—H371···CgCiii0.962.813.746 (7)165
Symmetry codes: (i) x1/2, y+1/2, z+1; (ii) x, y+1/2, z+3/2; (iii) x, y+1, z.
(II) O-Tosyl cinchonine top
Crystal data top
C26H28N2O3SDx = 1.317 Mg m3
Mr = 448.56Melting point = 447–448 K
Orthorhombic, P212121Cu Kα radiation, λ = 1.54178 Å
Hall symbol: P 2ac 2abCell parameters from 25 reflections
a = 6.8350 (13) Åθ = 9.9–19.2°
b = 17.7364 (16) ŵ = 1.52 mm1
c = 18.6632 (17) ÅT = 293 K
V = 2262.5 (5) Å3Prism, colourless
Z = 40.40 × 0.10 × 0.10 mm
F(000) = 952
Data collection top
Kuma KM-4 four-circle
diffractometer
1710 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tubeRint = 0.026
Graphite monochromatorθmax = 80.3°, θmin = 3.4°
ω–2θ scansh = 81
Absorption correction: ψ scan
(North et al., 1968)
k = 221
Tmin = 0.571, Tmax = 0.847l = 123
2806 measured reflections2 standard reflections every 100 reflections
2723 independent reflections intensity decay: 0.0%
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.051Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.177H-atom parameters constrained
S = 1.01 w = 1/[σ2(Fo2) + (0.1133P)2]
where P = (Fo2 + 2Fc2)/3
2723 reflections(Δ/σ)max < 0.001
290 parametersΔρmax = 0.45 e Å3
1 restraintΔρmin = 0.21 e Å3
Crystal data top
C26H28N2O3SV = 2262.5 (5) Å3
Mr = 448.56Z = 4
Orthorhombic, P212121Cu Kα radiation
a = 6.8350 (13) ŵ = 1.52 mm1
b = 17.7364 (16) ÅT = 293 K
c = 18.6632 (17) Å0.40 × 0.10 × 0.10 mm
Data collection top
Kuma KM-4 four-circle
diffractometer
1710 reflections with I > 2σ(I)
Absorption correction: ψ scan
(North et al., 1968)
Rint = 0.026
Tmin = 0.571, Tmax = 0.8472 standard reflections every 100 reflections
2806 measured reflections intensity decay: 0.0%
2723 independent reflections
Refinement top
R[F2 > 2σ(F2)] = 0.0511 restraint
wR(F2) = 0.177H-atom parameters constrained
S = 1.01Δρmax = 0.45 e Å3
2723 reflectionsΔρmin = 0.21 e Å3
290 parameters
Special details top

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
S10.8889 (2)0.25918 (7)0.80103 (7)0.0777 (4)
O10.8696 (5)0.20194 (18)0.73655 (17)0.0735 (8)
O20.7971 (7)0.3287 (2)0.78190 (19)0.0930 (12)
O31.0864 (6)0.2573 (2)0.8184 (2)0.0897 (10)
N10.4898 (8)0.1078 (3)0.6303 (2)0.0861 (13)
N20.6875 (9)0.3525 (3)0.5181 (3)0.0917 (14)
C20.3164 (9)0.1018 (3)0.6749 (4)0.0946 (18)
H210.20130.10140.64450.142*
H220.30830.14580.70570.142*
C30.3170 (11)0.0306 (4)0.7215 (4)0.0960 (18)
H310.22260.00540.70150.144*
C40.5216 (11)0.0035 (3)0.7159 (3)0.0931 (17)
H410.53460.04610.74890.140*
C50.5523 (12)0.0296 (4)0.6391 (4)0.102 (2)
H510.46620.07150.62840.152*
H520.68650.04600.63230.152*
C60.5068 (12)0.0371 (3)0.5894 (3)0.102 (2)
H610.61020.04210.55410.153*
H620.38530.02760.56410.153*
C70.6720 (10)0.0573 (3)0.7339 (3)0.0876 (16)
H710.80150.03530.73770.131*
H720.63990.08120.77910.131*
C80.6667 (9)0.1160 (3)0.6724 (3)0.0751 (13)
H810.77840.10600.64090.113*
C90.6831 (7)0.1977 (3)0.6986 (3)0.0689 (11)
H910.57540.20920.73150.103*
C100.2530 (15)0.0515 (5)0.7960 (5)0.135 (3)
H1010.23250.10250.80460.202*
C110.2234 (17)0.0067 (6)0.8490 (5)0.153 (4)
H1110.24170.04490.84340.229*
H1120.18380.02600.89300.229*
C220.8278 (10)0.3044 (3)0.5299 (3)0.0868 (16)
H2210.93120.30280.49750.130*
C230.8328 (8)0.2542 (3)0.5892 (3)0.0796 (13)
H2310.93890.22210.59540.119*
C240.6831 (8)0.2532 (3)0.6367 (2)0.0721 (11)
C250.3629 (8)0.3129 (3)0.6723 (3)0.0814 (13)
H2510.35140.28160.71210.122*
C260.2221 (10)0.3647 (3)0.6596 (4)0.0915 (16)
H2610.11770.36970.69120.137*
C270.2336 (11)0.4110 (4)0.5988 (4)0.105 (2)
H2710.13400.44520.58920.157*
C280.3880 (11)0.4060 (4)0.5542 (4)0.1008 (18)
H2810.39580.43800.51480.151*
C290.5370 (9)0.3533 (3)0.5664 (3)0.0781 (13)
C300.5265 (8)0.3051 (3)0.6270 (3)0.0718 (12)
C310.7531 (9)0.2174 (3)0.8694 (3)0.0764 (13)
C320.5641 (9)0.2398 (3)0.8835 (3)0.0841 (14)
H3210.50790.27860.85710.126*
C330.4580 (10)0.2048 (4)0.9369 (3)0.0924 (17)
H3310.33230.22160.94730.139*
C340.5362 (11)0.1448 (3)0.9754 (3)0.0885 (16)
C350.7259 (11)0.1250 (3)0.9617 (3)0.0929 (17)
H3510.78330.08720.98920.139*
C360.8353 (10)0.1589 (3)0.9086 (3)0.0859 (15)
H3610.96230.14290.89930.129*
C370.4185 (14)0.1059 (4)1.0331 (4)0.119 (3)
H3710.28150.11251.02370.179*
H3720.45020.12731.07890.179*
H3730.44910.05301.03340.179*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
S10.1167 (9)0.0630 (6)0.0534 (5)0.0080 (6)0.0040 (6)0.0017 (6)
O10.106 (2)0.0629 (18)0.0519 (17)0.0018 (17)0.0010 (16)0.0027 (14)
O20.160 (3)0.0551 (18)0.064 (2)0.003 (2)0.003 (2)0.0035 (16)
O30.114 (2)0.088 (3)0.067 (2)0.015 (2)0.0014 (18)0.0022 (19)
N10.133 (4)0.060 (2)0.066 (3)0.008 (2)0.016 (3)0.001 (2)
N20.136 (4)0.078 (3)0.061 (3)0.004 (3)0.009 (3)0.008 (2)
C20.106 (4)0.067 (3)0.111 (5)0.004 (3)0.011 (4)0.003 (3)
C30.120 (5)0.085 (4)0.083 (4)0.014 (3)0.007 (3)0.001 (3)
C40.146 (5)0.061 (3)0.072 (3)0.007 (3)0.008 (3)0.008 (3)
C50.153 (6)0.067 (3)0.085 (4)0.000 (3)0.003 (4)0.012 (3)
C60.162 (6)0.076 (3)0.067 (3)0.025 (4)0.002 (4)0.013 (3)
C70.123 (4)0.070 (3)0.070 (3)0.000 (3)0.011 (3)0.014 (3)
C80.114 (4)0.052 (2)0.058 (3)0.006 (2)0.003 (2)0.002 (2)
C90.088 (3)0.062 (2)0.057 (2)0.001 (2)0.006 (2)0.001 (2)
C100.183 (8)0.116 (6)0.106 (6)0.019 (6)0.037 (6)0.001 (5)
C110.196 (9)0.157 (9)0.105 (6)0.030 (8)0.023 (7)0.020 (6)
C220.127 (4)0.077 (3)0.056 (3)0.009 (3)0.012 (3)0.001 (3)
C230.110 (3)0.070 (3)0.060 (3)0.000 (3)0.006 (2)0.001 (2)
C240.105 (3)0.058 (3)0.053 (2)0.006 (2)0.002 (2)0.004 (2)
C250.107 (4)0.066 (3)0.071 (3)0.002 (3)0.001 (3)0.003 (2)
C260.115 (4)0.070 (3)0.089 (4)0.000 (3)0.001 (3)0.006 (3)
C270.112 (4)0.090 (4)0.113 (5)0.005 (3)0.007 (4)0.032 (4)
C280.123 (5)0.090 (4)0.089 (4)0.001 (4)0.001 (4)0.026 (3)
C290.109 (4)0.068 (3)0.057 (3)0.006 (3)0.002 (2)0.007 (2)
C300.105 (3)0.061 (3)0.050 (2)0.011 (2)0.006 (2)0.001 (2)
C310.109 (4)0.065 (3)0.055 (2)0.004 (2)0.003 (2)0.001 (2)
C320.120 (4)0.068 (3)0.064 (3)0.000 (3)0.006 (3)0.003 (3)
C330.121 (4)0.082 (4)0.075 (4)0.003 (3)0.014 (3)0.013 (3)
C340.137 (5)0.072 (3)0.057 (3)0.009 (3)0.013 (3)0.006 (3)
C350.146 (5)0.069 (3)0.063 (3)0.007 (3)0.007 (3)0.008 (3)
C360.116 (4)0.077 (3)0.065 (3)0.007 (3)0.007 (3)0.008 (3)
C370.182 (7)0.092 (4)0.084 (4)0.015 (5)0.044 (5)0.002 (4)
Geometric parameters (Å, º) top
S1—O31.388 (4)C10—H1010.9300
S1—O21.429 (4)C11—H1110.9300
S1—O11.580 (3)C11—H1120.9300
S1—C311.743 (6)C22—C231.420 (8)
O1—C91.460 (6)C22—H2210.9300
N1—C81.450 (8)C23—C241.355 (7)
N1—C21.452 (9)C23—H2310.9300
N1—C61.473 (7)C24—C301.423 (7)
N2—C221.303 (8)C25—C261.351 (8)
N2—C291.368 (7)C25—C301.409 (8)
C2—C31.534 (9)C25—H2510.9300
C2—H210.9700C26—C271.403 (8)
C2—H220.9700C26—H2610.9300
C3—C101.504 (10)C27—C281.347 (10)
C3—C41.527 (10)C27—H2710.9300
C3—H310.9800C28—C291.401 (9)
C4—C51.520 (9)C28—H2810.9300
C4—C71.528 (9)C29—C301.420 (7)
C4—H410.9800C31—C321.378 (9)
C5—C61.535 (9)C31—C361.389 (8)
C5—H510.9700C32—C331.379 (8)
C5—H520.9700C32—H3210.9300
C6—H610.9700C33—C341.392 (9)
C6—H620.9700C33—H3310.9300
C7—C81.548 (7)C34—C351.367 (10)
C7—H710.9700C34—C371.511 (8)
C7—H720.9700C35—C361.380 (8)
C8—C91.533 (7)C35—H3510.9300
C8—H810.9800C36—H3610.9300
C9—C241.518 (7)C37—H3710.9600
C9—H910.9800C37—H3720.9600
C10—C111.285 (5)C37—H3730.9600
O3—S1—O2120.4 (3)C8—C9—H91109.9
O3—S1—O1104.1 (2)C11—C10—C3127.3 (9)
O2—S1—O1109.1 (2)C11—C10—H101116.4
O3—S1—C31109.7 (3)C3—C10—H101116.4
O2—S1—C31108.4 (3)C10—C11—H111120.0
O1—S1—C31103.8 (2)C10—C11—H112120.0
C9—O1—S1118.4 (3)H111—C11—H112120.0
C8—N1—C2112.2 (4)N2—C22—C23124.1 (5)
C8—N1—C6107.5 (5)N2—C22—H221118.0
C2—N1—C6107.4 (5)C23—C22—H221118.0
C22—N2—C29116.7 (5)C24—C23—C22120.0 (5)
N1—C2—C3112.5 (5)C24—C23—H231120.0
N1—C2—H21109.1C22—C23—H231120.0
C3—C2—H21109.1C23—C24—C30118.5 (5)
N1—C2—H22109.1C23—C24—C9120.4 (5)
C3—C2—H22109.1C30—C24—C9121.1 (4)
H21—C2—H22107.8C26—C25—C30121.8 (5)
C10—C3—C2108.7 (6)C26—C25—H251119.1
C10—C3—C4115.3 (7)C30—C25—H251119.1
C2—C3—C4106.8 (5)C25—C26—C27120.0 (6)
C10—C3—H31108.6C25—C26—H261120.0
C2—C3—H31108.6C27—C26—H261120.0
C4—C3—H31108.6C28—C27—C26120.4 (6)
C5—C4—C7109.2 (6)C28—C27—H271119.8
C5—C4—C3108.1 (6)C26—C27—H271119.8
C7—C4—C3108.8 (5)C27—C28—C29120.8 (6)
C5—C4—H41110.2C27—C28—H281119.6
C7—C4—H41110.2C29—C28—H281119.6
C3—C4—H41110.2N2—C29—C28116.5 (5)
C4—C5—C6107.9 (5)N2—C29—C30123.9 (5)
C4—C5—H51110.1C28—C29—C30119.6 (5)
C6—C5—H51110.1C25—C30—C29117.3 (5)
C4—C5—H52110.1C25—C30—C24125.8 (5)
C6—C5—H52110.1C29—C30—C24116.9 (5)
H51—C5—H52108.4C32—C31—C36119.6 (5)
N1—C6—C5111.0 (5)C32—C31—S1121.1 (5)
N1—C6—H61109.4C36—C31—S1119.2 (5)
C5—C6—H61109.4C33—C32—C31120.1 (6)
N1—C6—H62109.4C33—C32—H321119.9
C5—C6—H62109.4C31—C32—H321119.9
H61—C6—H62108.0C32—C33—C34121.0 (6)
C4—C7—C8107.2 (5)C32—C33—H331119.5
C4—C7—H71110.3C34—C33—H331119.5
C8—C7—H71110.3C35—C34—C33117.7 (6)
C4—C7—H72110.3C35—C34—C37121.4 (7)
C8—C7—H72110.3C33—C34—C37120.9 (7)
H71—C7—H72108.5C34—C35—C36122.4 (6)
N1—C8—C9109.1 (4)C34—C35—H351118.8
N1—C8—C7110.7 (4)C36—C35—H351118.8
C9—C8—C7113.4 (4)C35—C36—C31119.1 (6)
N1—C8—H81107.8C35—C36—H361120.5
C9—C8—H81107.8C31—C36—H361120.5
C7—C8—H81107.8C34—C37—H371109.5
O1—C9—C24109.6 (4)C34—C37—H372109.5
O1—C9—C8105.5 (4)H371—C37—H372109.5
C24—C9—C8111.8 (4)C34—C37—H373109.5
O1—C9—H91109.9H371—C37—H373109.5
C24—C9—H91109.9H372—C37—H373109.5
O3—S1—O1—C9171.9 (3)C8—C9—C24—C2365.7 (6)
O2—S1—O1—C942.2 (4)O1—C9—C24—C30129.3 (5)
C31—S1—O1—C973.3 (4)C8—C9—C24—C30114.1 (5)
C8—N1—C2—C364.2 (6)C30—C25—C26—C272.0 (9)
C6—N1—C2—C353.6 (7)C25—C26—C27—C282.4 (10)
N1—C2—C3—C10135.7 (6)C26—C27—C28—C291.9 (11)
N1—C2—C3—C410.8 (7)C22—N2—C29—C28178.9 (6)
C10—C3—C4—C5173.4 (6)C22—N2—C29—C300.4 (9)
C2—C3—C4—C565.8 (6)C27—C28—C29—N2179.9 (6)
C10—C3—C4—C768.1 (7)C27—C28—C29—C300.8 (10)
C2—C3—C4—C752.7 (7)C26—C25—C30—C290.9 (8)
C7—C4—C5—C665.3 (8)C26—C25—C30—C24178.9 (5)
C3—C4—C5—C653.0 (7)N2—C29—C30—C25179.6 (5)
C8—N1—C6—C553.7 (7)C28—C29—C30—C250.3 (8)
C2—N1—C6—C567.2 (8)N2—C29—C30—C240.3 (8)
C4—C5—C6—N112.0 (9)C28—C29—C30—C24179.6 (5)
C5—C4—C7—C849.4 (7)C23—C24—C30—C25178.2 (5)
C3—C4—C7—C868.5 (6)C9—C24—C30—C252.0 (8)
C2—N1—C8—C978.3 (5)C23—C24—C30—C291.6 (7)
C6—N1—C8—C9163.8 (4)C9—C24—C30—C29178.2 (4)
C2—N1—C8—C747.2 (6)O3—S1—C31—C32150.2 (5)
C6—N1—C8—C770.6 (6)O2—S1—C31—C3217.0 (5)
C4—C7—C8—N116.6 (7)O1—S1—C31—C3299.0 (5)
C4—C7—C8—C9139.7 (5)O3—S1—C31—C3631.8 (5)
S1—O1—C9—C2490.2 (4)O2—S1—C31—C36165.0 (4)
S1—O1—C9—C8149.3 (3)O1—S1—C31—C3679.0 (5)
N1—C8—C9—O1176.7 (4)C36—C31—C32—C330.6 (8)
C7—C8—C9—O159.3 (6)S1—C31—C32—C33178.6 (4)
N1—C8—C9—C2457.6 (6)C31—C32—C33—C342.4 (9)
C7—C8—C9—C24178.4 (5)C32—C33—C34—C354.2 (9)
C2—C3—C10—C11175.4 (11)C32—C33—C34—C37179.1 (6)
C4—C3—C10—C1164.8 (14)C33—C34—C35—C364.3 (9)
C29—N2—C22—C230.3 (9)C37—C34—C35—C36179.0 (6)
N2—C22—C23—C241.7 (9)C34—C35—C36—C312.6 (10)
C22—C23—C24—C302.2 (7)C32—C31—C36—C350.7 (8)
C22—C23—C24—C9177.6 (5)S1—C31—C36—C35178.7 (5)
O1—C9—C24—C2350.9 (6)
Hydrogen-bond geometry (Å, º) top
CgD and CgE are the centroids of the pyridine and quinoline rings, respectively.
D—H···AD—HH···AD···AD—H···A
C32—H321···O20.932.582.936 (7)103
C22—H221···CgDi0.932.923.689 (7)141
C11—H111···CgEii0.932.923.681 (7)140
Symmetry codes: (i) x+1/2, y+1/2, z+1; (ii) x+1, y1/2, z+3/2.

Experimental details

(I)(II)
Crystal data
Chemical formulaC26H28N2O3SC26H28N2O3S
Mr448.56448.56
Crystal system, space groupOrthorhombic, P212121Orthorhombic, P212121
Temperature (K)293293
a, b, c (Å)9.4591 (13), 10.094 (2), 24.370 (4)6.8350 (13), 17.7364 (16), 18.6632 (17)
V3)2326.9 (7)2262.5 (5)
Z44
Radiation typeCu KαCu Kα
µ (mm1)1.481.52
Crystal size (mm)0.45 × 0.40 × 0.100.40 × 0.10 × 0.10
Data collection
DiffractometerKuma KM-4 four-circle
diffractometer
Kuma KM-4 four-circle
diffractometer
Absorption correctionMulti-scan
(Blessing, 1995)
ψ scan
(North et al., 1968)
Tmin, Tmax0.363, 0.7480.571, 0.847
No. of measured, independent and
observed [I > 2σ(I)] reflections
3726, 3508, 1717 2806, 2723, 1710
Rint0.0340.026
(sin θ/λ)max1)0.6400.639
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.064, 0.167, 1.06 0.051, 0.177, 1.01
No. of reflections35082723
No. of parameters290290
No. of restraints11
H-atom treatmentH-atom parameters constrainedH-atom parameters constrained
Δρmax, Δρmin (e Å3)0.30, 0.330.45, 0.21
Absolute structureFlack (1983), 604 Friedel pairs?
Absolute structure parameter0.00 (3)?

Computer programs: KM4B8 (Gałdecki et al., 1996), DATAPROC (Gałdecki et al., 1995), SIR92 (Altomare et al., 1993), ORTEP-3 for Windows (Farrugia, 1997), SHELXL97 (Sheldrick, 2008) and WinGX (Farrugia, 1997), SHELXL97 (Sheldrick, 2008) and WinGX (Farrugia, 1999).

Hydrogen-bond geometry (Å, º) for (I) top
CgA, CgB and CgC are the centroids of the benzene, toluene and pyridine rings, respectively.
D—H···AD—HH···AD···AD—H···A
C32—H321···O20.932.602.944 (9)103
C10—H101···O3i0.932.483.377 (7)163
C11—H111···CgAii0.932.983.775 (8)144
C23—H231···CgBi0.932.873.619 (5)138
C37—H371···CgCiii0.962.813.746 (7)165
Symmetry codes: (i) x1/2, y+1/2, z+1; (ii) x, y+1/2, z+3/2; (iii) x, y+1, z.
Hydrogen-bond geometry (Å, º) for (II) top
CgD and CgE are the centroids of the pyridine and quinoline rings, respectively.
D—H···AD—HH···AD···AD—H···A
C32—H321···O20.932.582.936 (7)103
C22—H221···CgDi0.932.923.689 (7)141
C11—H111···CgEii0.932.923.681 (7)140
Symmetry codes: (i) x+1/2, y+1/2, z+1; (ii) x+1, y1/2, z+3/2.
 

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