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Molecular geometry and optical activity of helically chiral N-nitrosamines derived from 1,2,3,4-tetrahydro- and 1,2,3,4,7,8,9,10-octahydro-1,10-phenanthroline
Tetrahedron: Asymmetry 26 (2015) 662–665
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy
Molecular geometry and optical activity of helically chiral N-nitrosamines derived from 1,2,3,4-tetrahydro- and 1,2,3,4,7,8,9,10-octahydro-1,10-phenanthroline Teresa Olszewska a,⇑, Aleksander Herman a, Artur Sikorski b a b
´ sk University of Technology, 80-233 Gdan ´ sk, Poland Department of Chemistry, Gdan ´ sk, 80-952 Gdan ´ sk, Poland Faculty of Chemistry, University of Gdan
a r t i c l e
i n f o
Article history: Received 4 April 2015 Accepted 13 April 2015 Available online 12 May 2015
a b s t r a c t X-ray crystallographic analysis of the title N-nitrosamines revealed that they assume helical conformations in the solid state. Nitrosamines 1b and 2b were resolved by inclusion crystallization with optically active diols (TADDOLs). The absolute configuration of the guest molecules in the complexes 1b3b and 2b3b was assigned as M. The optical activity of the resolved compounds is manifested by their solid state CD spectra, which showed relatively strong Cotton effects in the region of the nitrosamine n–p⁄ transition. Theoretical calculations of the electronic and CD spectra performed by classic ab initio methods predicted the correct Cotton effect signs of 1b and 2b. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction The chemistry and biological activity of N-nitrosamines are the subject of continuing interest with regard to their strong carcinogenic and mutagenic properties.1 Thus numerous experimental and theoretical investigations have been directed toward establishing their structure–activity relationship.2 Their stereochemistry has been thoroughly investigated since it is of primary importance for biological activity.3 The molecular geometry of these compounds is influenced by a partial double bond character between the adjacent nitrogen atoms, which results in restricted rotation about the N–N bond. Since the corresponding energy barrier is relatively high (23–25 kcal/mol), this rotation is very slow at ambient temperatures.4 A substitution of the nitroso group at the nitrogen atom of the secondary amines lowers their symmetry, which in the absence of any improper symmetry axis leads to molecular chirality. Owing to a weak long-wavelength absorption near 370 nm, these are attractive models for chiroptical studies.5 Thus many optically active compounds of this class have been prepared in order to correlate their optical activity with molecular geometry and also as potential chiral auxiliaries for asymmetric synthesis. Most of these compounds are derived from optically active amines but some of them owe their chirality solely to the hindered rotation about the N–N bond. In the last case, their
⇑ Corresponding author. Tel.: +48 58 3471425; fax: +48 58 3472694. E-mail address: [email protected] (T. Olszewska). http://dx.doi.org/10.1016/j.tetasy.2015.04.008 0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.
optical activity was preserved only in the solid state and upon dissolution rapid racemization occurred.
N N
R
N N
R R1
Ph2 COH
R R1
O O
H
H
Ph2COH 1a R = H 1b R = NO
2a R = R 1 = H 2b R = R 1 = NO
3a R = R1 = -(CH2 )4 3b R = R 1 = -(CH 2 )5 -
Continuing our interest on configurationally labile compounds,6,7 we turned our attention to derivatives of 1,2,3,4-tetrahydro-1,10-phenanthroline 1a and 1,2,3,4,7,8,9,10-octahydro-1, 10-phenanthroline 2a. Both parent amines are easily accessible by reduction of one or two pyridine rings of 1,10-phenanthroline.7c It is anticipated that due to a spatial proximity of the two nitrogens, a substitution of one or both of them with bulky groups should lead to helical chirality of the resulting molecules. The spectroscopic investigations of helically chiral N-nitrosamines may lead to a better understanding of the nitrosamine chromophore. Herein we describe the synthesis, structure, and a simple method of resolution of N-nitrosamines 1b and 2b by enclathration
T. Olszewska et al. / Tetrahedron: Asymmetry 26 (2015) 662–665
with chiral diol 3. The absolute configuration of the guest molecule was assigned by X-ray crystallographic analysis. We also measured the solid state CD spectra of the guest nitrosamines and compared the observed Cotton effect signs with the calculated ones with use of ab initio methods. 2. Results and discussion Amine 1a was prepared by NaBH3CN reduction of 1,10-phenanthroline in MeOH.8 The octahydro derivative 2a was obtained by the reduction of 1,10-phenanthroline with nickel–aluminum alloy in a methanolic solution of KOH as described previously.7c The N-nitrosamines 1b and 2b were prepared by nitrosation of the corresponding amines with HNO2. The diffraction quality crystals 1b and 2b were grown from CH2Cl2–heptane. In the solid state, nitrosamines 1b and 2b (the monoclinic P21/n and C2/c space groups, respectively) adopt twisted helical conformations to avoid steric N N interaction between the NO nitrogen and the neighboring piperidine N atom, with d(N N) = 2.805(3) and 2.917(3) Å, for 1b and 2b, respectively (Fig. 1a and b). In the case of 2b, its interaction causes positioning the NO groups to positions above and below the central aromatic ring. This interaction is strong enough to cause slight twisting of the central benzene ring as shown by the corresponding torsional angles of 7.5° and 7.6° in 1b and 2b, respectively. The piperidine ring in 1b as well as both rings in 2b adopt a nearly screw-boat conformation with the ring puckering parameters Q = 0.550(2) and 0.591(2) Å, h = 71.1(2) and 71.4(2)° and u = 146.5(2) and 146.1(2)°, for 1b and 2b, respectively.9 Analysis of the intermolecular interactions, which occur in the crystal packing of 1b and 2b shows that the molecules are linked by C–H O and C–H N hydrogen bonds and p–p interactions and produce layers. Since nitrosamine molecules 1b and 2b adopt helical conformations they may exist in two enantiomeric forms. An inclusion complexation with optically active hosts seems to be the method of choice for the enantiomeric resolution of compounds without additional functional groups. Chiral diols 3a,b known as TADDOLs (a,a,a0 ,a0 -tetraphenyl-1,3-dioxolane-4,5-dimethanols), easily accessible from (+)-tartaric acid,10 have been successfully used for the isolation of stereoisomers of a wide variety of compounds.6,7,11 Recently, we have been able to resolve several N-nitrosamines with chirality solely due to the hindered N–N rotation.5a,5c We found that they are also useful for 1b and 2b. We prepared the 1:1 inclusion complexes of these compounds with the host diol 3b, which gave better quality crystals than 3a by co-crystallization of equimolar amounts of the components from CH2Cl2–heptane. The complex of 1b3b crystallizes in the orthorhombic, P212121 space group with the disordered solvent molecule (methanol). The guest molecule 1b assumes essentially the same; a screw-boat conformation as in the uncomplexed form with the ring puckering parameters Q = 0.567(8) Å, h = 76.3(7)° and u = 155.2(8)°. Since the
663
configuration of the host 3b is known, the absolute configuration of the guest molecule 1b can be deduced from the X-ray structure of the complex as M. The crystal structures of 1b3b are stabilized by the intramolecular O–H O hydrogen bonds for the 3b molecule and N N contact, with d(N N) = 2.916(4) Å (Fig. 2a). An analysis of the intermolecular interactions occurring in the crystal packing of 1b and 3b shows that the adjacent molecules are linked by O–H N and C–H p hydrogen bonds and p–p interactions and produce columns (Fig. 2b). Unfortunately, the complex 2b3b does not form crystals suitable for X-ray diffraction measurements. However, the configuration of the guest molecule 2b can be assigned as M relying on the same long wavelength CD signs for both complexes. The UV–vis spectra of 1b and 2b taken in the CH2Cl2 solution revealed a weak absorption at 384 nm (e 630) and 384 (e 610), respectively, which corresponded to the forbidden n–p⁄ electronic transition of the nitrosamine chromophore and a strong one at 308 nm (e 9500) and 316 (e 7300), respectively, and can be attributed to the aromatic p–p⁄ excitation. The CD spectra of the complexes were measured in the solid state (KBr disks). They exhibit relatively strong positive Cotton effects with pronounced vibronic structure near 390 nm typical for the nitrosamine n–p⁄ transition (Fig. 3).5a,5c It is noteworthy that this region remains far outside of the absorption range of the host compound 3b. A distortion of the N-arylnitrosamine system from planarity results in the formation of the inherently chiral chromophore, the helicity of which determines the n–p* Cotton effect sign.6b Thus the observed positive CD for both complexes can be correlated with the M helicity of the guest molecules as evidenced by the C@CANAN torsional angle of 51.5° for 1b. The complex 2b3b shows an additional negative CD band centered at 325 nm. Its origin is not clear; it occurs in the region close to the aromatic p–p⁄ transition but is quite far from the region of the nitrosamine p–p⁄ excitation usually occurring near 230 nm. It is unlikely that an aromatic p–p⁄ transition is responsible for this CD since the mononitroso derivative 1b3b does not exhibit any CD at this wavelength. Thus we performed theoretical calculations of the electronic and CD spectra of 1b and 2b by classic ab initio methods. Although some DFT methods have recently been shown to give impressive results for CD spectra calculations,12 the lack of a systematic way of extending a series of calculations to approach the exact result is a major drawback of DFT. Ab initio methods have the advantage that they can be made to converge on the exact solution, when all approximations are sufficiently small in magnitude and when the finite set of basis functions tends toward the limit of a complete set. In this case, configuration interaction, where all possible configurations are included, tends to the exact non-relativistic solution of the electronic Schrödinger equation (in the Born–Oppenheimer approximation). The convergence, however, is usually not monotonic, and sometimes the smallest calculation gives the best
Figure 1. Molecular structure of compounds 1b and 2b showing the atom labeling scheme and 20% probability displacement ellipsoids.
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T. Olszewska et al. / Tetrahedron: Asymmetry 26 (2015) 662–665
Figure 2. Molecular structure of compound 1b3b showing the atom labeling scheme and 20% probability displacement ellipsoids (a) and crystal packing of the compound 1b3b. Hydrogen bonds are represented by dashed lines.
Table 1 Calculated parameters for the lowest energy transitions of N-nitrosamines 1b and 2b N N
N
O 3b
N N
N N
O 3b O
Compd
kmax (nm)
fosca
[R]b
CD k (nm) ([H])c
1b 2b
329 328 325
0.00290 0.01635 0.01905
25.1 31.7 77.8
390 (51,190)d 397 (29,580)d 325 (23,770)d
a
Oscillator strength in cgs units. Rotatory strength in 10–40 cgs units. c Molecular ellipticity in deg cm2 dmol1. d Approximate experimental values were determined by considering the weight concentration (KBr density 2.75 g cm3). b
3. Conclusion
Figure 3. CD spectra of the complexes 1b3b (---) and 2b3b (—) measured in KBr disk.
result for some spectroscopic properties. The calculations of 1b and 2b CD spectra were performed with the method implemented in ORCA version 2.8 an ab initio package13 in two steps: first the RHF with Ahlrichs-QZV Def2-QZVPP basis set structure of the reactants have been optimized with the BFGS update method up to maximal gradient tolerance <0.0001 a.u. starting from the crystallographic structures. Then single point CIS singlet calculations of the first 6 excited states were performed including CI space of dimension 60 molecular orbitals by the Davidson diagonalization method. Although the calculated transition energies are overestimated, the oscillator strengths are adequately accounted for and the calculations predict the correct CD signs (Table 1). According to these results, two oppositely signed CD bands exhibited by 2b belong to two n–p⁄ excited states that result from the interaction of two neighboring NNO systems. Nitrosamines 1b and 2b did not show any detectable CD in solution due to rapid racemization upon dissolution. The enantiomer interconversion occurs simply by piperidine ring inversion, which allows the NO group and pyridine nitrogen in 1b or the NO nitrogens in 2b to slip past each other. The corresponding energy barriers estimated using the semiempirical RM1 model14 are extremely low: 2.0 and 4.5 kcal/mol for 1b and 2b, respectively.
In conclusion, the chirality of nitrosamines 1b and 2b can be generated by inclusion complexation with chiral diols. The guest molecules trapped in host crystal matrices are frozen in chiral conformations that can be detected by the solid state CD measurements. The helicity of the guest molecules can be determined either by X-ray crystallography or deduced from the Cotton effect sign corresponding to the lowest energy n–p⁄ electronic transition of the nitrosamino chromophore. 4. Experimental 4.1. General 1 H NMR spectra were obtained with Varian Unity Plus spectrometer at 500 MHz. CD spectra were recorded on a JASCO J-715 dichrograph. The solid state CD spectrum was taken in a freshly prepared KBr disk. A mixture of 2 mg of the sample and 200 mg of the dried KBr was ground and formed into a disk of 0.5 mm thickness and with a radius of 15 mm. The disk was rotated around the optical axis and the CD recordings were made for several positions in order to check a reproducibility of the spectrum.
4.2. N-Nitroso-1,2,3,4-tetrahydro-1,10-phenanthroline 1b To a stirred solution of 1,2,3,4-tetrahydro-1,10-phenanthroline 1a8 (1.6 g, 8.70 mmol) in 36% hydrochloric acid (4.5 mL) and water (30 mL), sodium nitrite (1.3 g, 19.1 mmol) was added in small portions over 30 min. After the addition of the last portion of sodium nitrite, the reaction mixture was stirred for one hour at room
T. Olszewska et al. / Tetrahedron: Asymmetry 26 (2015) 662–665
temperature. Next, the aqueous phase was extracted with CH2Cl2 (3 15 ml). The organic extracts were combined, washed with aqueous NaHCO3, dried over anhydrous MgSO4, and evaporated in vacuo. Recrystallization of the residue from CH2Cl2–diethyl ether afforded the product as a light brown solid: yield 1.3 g (70%); mp 137–138 °C; 1H NMR (CDCl3) d 9.00 (dd, J = 1.5 and 3.9 Hz, 1H), 8.21 (dd, J = 1.7 and 8.1 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.45 (d, J = 8.3 Hz, 2H), 7.43 (d, Hz, 1H), 4.13 (t, J = 6.6 Hz, 2H), 2.91 (td, J = 6.1 Hz, 2H), 2.10 (p, J = 6.4 Hz, 2H). UV (CH2Cl2) kmax 308 nm (e 9500), kmax 384 nm (e 630); Anal. Calcd for C12H11N3O (213.2): C, 67.59; H, 5.20; N, 19.71. Found: C, 67.41; H, 5.22; N, 19.58. 4.3. 2b
N,N0 -Dinitroso-1,2,3,4,7,8,9,10-octahydro-1,10-phenanthroline
Compound 2b was obtained from 1,2,3,4,7,8,9,10-octahydro1,10-phenanthroline 2a7c in a manner similar to that of 1b and had mp 97–98 °C (dec.). 1H NMR (DMSO-d6) d 7.27 (s, 2H), 3.76 (t, J = 6.6 Hz, 4H), 2.68 (t, J = 5.9 Hz, 4H), 1.94 (p, J = 6.3 Hz, 4H); UV (CH2Cl2) kmax 316 nm (e 7300), kmax 384 nm (e 610); Anal. Calcd for C12H14N4O2 (246.3): C, 58.53; H, 5.73; N, 19.71. Found: C, 58.35; H, 5.80; N, 19.61. 4.4. X-ray crystal structure analysis The single-crystal specimens of compounds 1b, 2b, 1b3b, were selected for the X-ray diffraction experiments at T = 295(2) K. Diffraction data were collected on an Oxford Diffraction Gemini R ULTRA Ruby CCD diffractometer with MoKa (k = 0.71073 Å) radiation for 1b, and 1b3b, and CuKa (k = 1.54184 Å) radiation for 1b. The lattice parameters were obtained by least-squares fit to the optimized setting angles of the collected reflections using CrysAlis CCD.15 Data were reduced using CrysAlis RED software15 with applying multi-scan absorption corrections (empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm). The structural resolution procedure was carried out using the SHELXS-97 package, for all compounds. The structures were solved by direct methods carrying out refinements by full-matrix least-squares on F2 using SHELXL-97 program.16 The molecule of compound 2b occupies a special position on the twofold axis. Compound 1b3b crystallized with the disordered solvent molecule (methanol) with site-occupancy factors of the disordered parts 0.5. All H atoms bound with aromatic C atoms were placed geometrically and refined using a riding model with C–H = 0.93–0.97 Å and Uiso(H) = 1.2 Ueq(C). All H–atoms bound with O–atoms 1b3b were located in a difference Fourier map and refined freely with Uiso(H) = 1.5 Ueq(O). All interactions demonstrated were fund by PLATON program.17 The programs used to prepare molecular graphics were ORTEPII,18 PLUTO-7819 and Mercury.20 Crystal data for C12H11N3O, 1b: monoclinic, space group: P21/n, a = 9.779(3), b = 7.806(4), c = 13.735(5) Å, b = 101.46(3)°, V = 1027.7(8) Å3, Z = 4, k = 0.71073 Å, T = 295 K, number of measured reflections 6419, R int = 0.0659, GOOF = 0.963, R 1 = 0.0511, wR2 = 0.1212 for 1803 independent reflections with I > 2r(I). Crystal data for C12H14N4O2, 2b: monoclinic, space group: C2, a = 9.911(2), b = 15.535(2), c = 7.853(2)Å, b = 103.44(2)°, V = 1176.1(6) Å3, Z = 4, k = 1.54184 Å, T = 295 K, number of measured reflections 10716, Rint = 0.0546, R1 = 0.0524, wR2 = 0.1512 for 1058 independent reflections with I > 2r(I).
665
Crystal data for C47H49N3O6, 1b3b: orthorhombic, space group: P212121, a = 9.415(2), b = 14.417(2), c = 31.017(3) Å, V = 4210.2(8) Å3, Z = 4, k = 0.71073 Å, T = 295 K, number of measured reflections 12732, Rint = 0.0972, R1 = 0.0720, wR2 = 0.1088 for 7266 independent reflections with I > 2r(I). Crystallographic data (excluding structure factors) for the structures herein have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 1057805–1057807. Acknowledgements We are indebted to Prof. J. Frelek (IChO PAN, Warsaw) for CD measurements using her Jasco J-715 dichrograph. We also thank Dr Casimir Antczak for critical reading of the manuscript. This work was supported by the Ministry of Science and Higher Education, Grant no. NN 204 1820 36. References 1. (a) Loeppky, R. N.; Outram, J. R. N-Nitroso Compounds: Occurence and Biological Effects; IARC Scientific Publishers: Lyon, 1982; (b) N-Nitrosamines and Related N-Nitroso Compounds; Loeppky, R. N., Michejda, C. J., Eds.; American Chemical Society: Washington, DC, 1994; (c) Loeppky, R. N.; Tomasik, W.; Kerride, B. E. Carcinogenesis 1987, 8, 941. 2. Lijinsky, W. In Genotoxicology of N-Nitroso Compounds; Rao, T. K., Lijinsky, W., Epler, J. L., Eds.; Plenum Press: New York, 1984. 3. (a) Rao, C. N. R.; Bhaskar, K. R. In Spectroscopy of the Nitroso Group; Patai, S., Feuer, H., Eds.; Wiley: Chichester, 1970. Part 1, Chapter 3; (b) Challis, B. C.; Challis, J. A. In The Chemistry of Amino, Nitroso, and Nitro Compounds and Their Derivatives; Patai, F., Ed.; Wiley: New York, 1982. Supplement F, Part 2, Chapter 26. 4. Harris, R. K.; Pryce-Jones, T.; Swinbourne, F. J. J. Chem. Soc., Perkin Trans. 2 1980, 476. 5. For a review see: (a) Smith, H. E. In The Chemistry of Amino, Nitroso, Nitro, and Related Groups; Patai, F., Ed.; Wiley: Chichester, 1996. Supplement F2, Part 1, Chapter 3; (b) Połon´ski, T.; Prajer, K. Tetrahedron 1976, 32, 847; (c) Połon´ski, T.; Milewska, M. J. A.; Katrusiak, A. J. Am. Chem. Soc. 1993, 115, 11410. and Refs therein. 6. (a) Gdaniec, M.; Milewska, M. J.; Połon´ski, T. Angew. Chem., Int. Ed. 1999, 38, 392; (b) Olszewska, T.; Milewska, M. J.; Gdaniec, M.; Połon´ski, T. Chem. Commun. 1999, 1385; (c) Olszewska, T.; Milewska, M. J.; Gdaniec, M.; Małuszyn´ska, H.; Połon´ski, T. J. Org. Chem. 2001, 66, 501; (d) Szyrszyng, M.; Nowak, E.; Gdaniec, M.; Milewska, M. J.; Herman, A.; Połon´ski, T. J. Org. Chem. 2001, 66, 7380; (e) Olszewska, T.; Gdaniec, M. T. Tetrahedron: Asymmetry 2009, 20, 1308. 7. (a) Olszewska, T.; Pyszno, A.; Milewska, M. J.; Gdaniec, M. T.; Połon´ski, T. Tetrahedron: Asymmetry 2005, 16, 3711; (b) Olszewska, T.; Nowak, E.; Gdaniec, M.; Połon´ski, T. Org. Lett. 2012, 14, 2568; (c) Olszewska, T.; Sikorski, A.; Herman, A.; Połon´ski, T. Org. Biomol. Chem. 2013, 11, 7522. 8. Metallinos, C.; Barrett, F. B.; Chaytor, J. L.; Heska, M. E. A. Org. Lett. 2004, 6, 3641. 9. (a) Cremer, D.; Pople, J. A. J. Am. Chem. Soc. 1975, 97, 1354; (b) Spek, A. L. J. Appl. Crystallogr. 2003, 36, 7. 10. (a) Seebach, D.; Beck, A. K.; Imwinkelried, R.; Roggo, S.; Wonnacott, A. Helv. Chim. Acta 1987, 70, 954; (b) Toda, F.; Tanaka, K. Tetrahedron Lett. 1988, 29, 551. 11. Fogassy, E.; Nogradi, M.; Kozma, D.; Egri, G.; Palovics, E.; Kiss, V. Org. Biomol. Chem. 2006, 4, 3011. 12. Diedrich, C.; Grimme, S. J. Phys. Chem. A 2003, 107, 2524. 13. Neese, F. ORCA—an ab initio, Density Functional and Semiempirical Program Package, Version 2.8; Bonn University, 2010. 14. Rocha, G. B.; Freire, R. O.; Simas, A. M.; Stewart, J. P. J. Comput. Chem. 2006, 27, 1101. 15. CrysAlis CCD and CrysAlis RED; Oxford Diffraction Ltd: Yarnton, England, 2008. 16. Sheldrick, G. M. Acta Crystallogr., Sect. A: Fundam. Crystallogr. 2008, 64, 112. 17. Spek, A. L. Acta Crystallogr., Sect. D: Biol. Crystallogr. 2009, 65, 148. 18. Johnson, C. K. ORTEP II, Report ORNL-5138; Oak Ridge National Laboratory: Oak Ridge, TN, USA, 1976. 19. Mortherwell, S.; Clegg, S. PLUTO-78, Program for Drawing and Molecular Structure; University of Cambridge: UK, 1978. 20. Macrae, C. F.; Bruno, I. J.; Chisholm, J. A.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Rodriguez-Monge, L.; Taylor, R.; van de Streek, J.; Wood, P. A. J. Appl. Crystallogr. 2008, 41, 466.
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy
Molecular geometry and optical activity of helically chiral N-nitrosamines derived from 1,2,3,4-tetrahydro- and 1,2,3,4,7,8,9,10-octahydro-1,10-phenanthroline Teresa Olszewska a,⇑, Aleksander Herman a, Artur Sikorski b a b
´ sk University of Technology, 80-233 Gdan ´ sk, Poland Department of Chemistry, Gdan ´ sk, 80-952 Gdan ´ sk, Poland Faculty of Chemistry, University of Gdan
a r t i c l e
i n f o
Article history: Received 4 April 2015 Accepted 13 April 2015 Available online 12 May 2015
a b s t r a c t X-ray crystallographic analysis of the title N-nitrosamines revealed that they assume helical conformations in the solid state. Nitrosamines 1b and 2b were resolved by inclusion crystallization with optically active diols (TADDOLs). The absolute configuration of the guest molecules in the complexes 1b3b and 2b3b was assigned as M. The optical activity of the resolved compounds is manifested by their solid state CD spectra, which showed relatively strong Cotton effects in the region of the nitrosamine n–p⁄ transition. Theoretical calculations of the electronic and CD spectra performed by classic ab initio methods predicted the correct Cotton effect signs of 1b and 2b. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction The chemistry and biological activity of N-nitrosamines are the subject of continuing interest with regard to their strong carcinogenic and mutagenic properties.1 Thus numerous experimental and theoretical investigations have been directed toward establishing their structure–activity relationship.2 Their stereochemistry has been thoroughly investigated since it is of primary importance for biological activity.3 The molecular geometry of these compounds is influenced by a partial double bond character between the adjacent nitrogen atoms, which results in restricted rotation about the N–N bond. Since the corresponding energy barrier is relatively high (23–25 kcal/mol), this rotation is very slow at ambient temperatures.4 A substitution of the nitroso group at the nitrogen atom of the secondary amines lowers their symmetry, which in the absence of any improper symmetry axis leads to molecular chirality. Owing to a weak long-wavelength absorption near 370 nm, these are attractive models for chiroptical studies.5 Thus many optically active compounds of this class have been prepared in order to correlate their optical activity with molecular geometry and also as potential chiral auxiliaries for asymmetric synthesis. Most of these compounds are derived from optically active amines but some of them owe their chirality solely to the hindered rotation about the N–N bond. In the last case, their
⇑ Corresponding author. Tel.: +48 58 3471425; fax: +48 58 3472694. E-mail address: [email protected] (T. Olszewska). http://dx.doi.org/10.1016/j.tetasy.2015.04.008 0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.
optical activity was preserved only in the solid state and upon dissolution rapid racemization occurred.
N N
R
N N
R R1
Ph2 COH
R R1
O O
H
H
Ph2COH 1a R = H 1b R = NO
2a R = R 1 = H 2b R = R 1 = NO
3a R = R1 = -(CH2 )4 3b R = R 1 = -(CH 2 )5 -
Continuing our interest on configurationally labile compounds,6,7 we turned our attention to derivatives of 1,2,3,4-tetrahydro-1,10-phenanthroline 1a and 1,2,3,4,7,8,9,10-octahydro-1, 10-phenanthroline 2a. Both parent amines are easily accessible by reduction of one or two pyridine rings of 1,10-phenanthroline.7c It is anticipated that due to a spatial proximity of the two nitrogens, a substitution of one or both of them with bulky groups should lead to helical chirality of the resulting molecules. The spectroscopic investigations of helically chiral N-nitrosamines may lead to a better understanding of the nitrosamine chromophore. Herein we describe the synthesis, structure, and a simple method of resolution of N-nitrosamines 1b and 2b by enclathration
T. Olszewska et al. / Tetrahedron: Asymmetry 26 (2015) 662–665
with chiral diol 3. The absolute configuration of the guest molecule was assigned by X-ray crystallographic analysis. We also measured the solid state CD spectra of the guest nitrosamines and compared the observed Cotton effect signs with the calculated ones with use of ab initio methods. 2. Results and discussion Amine 1a was prepared by NaBH3CN reduction of 1,10-phenanthroline in MeOH.8 The octahydro derivative 2a was obtained by the reduction of 1,10-phenanthroline with nickel–aluminum alloy in a methanolic solution of KOH as described previously.7c The N-nitrosamines 1b and 2b were prepared by nitrosation of the corresponding amines with HNO2. The diffraction quality crystals 1b and 2b were grown from CH2Cl2–heptane. In the solid state, nitrosamines 1b and 2b (the monoclinic P21/n and C2/c space groups, respectively) adopt twisted helical conformations to avoid steric N N interaction between the NO nitrogen and the neighboring piperidine N atom, with d(N N) = 2.805(3) and 2.917(3) Å, for 1b and 2b, respectively (Fig. 1a and b). In the case of 2b, its interaction causes positioning the NO groups to positions above and below the central aromatic ring. This interaction is strong enough to cause slight twisting of the central benzene ring as shown by the corresponding torsional angles of 7.5° and 7.6° in 1b and 2b, respectively. The piperidine ring in 1b as well as both rings in 2b adopt a nearly screw-boat conformation with the ring puckering parameters Q = 0.550(2) and 0.591(2) Å, h = 71.1(2) and 71.4(2)° and u = 146.5(2) and 146.1(2)°, for 1b and 2b, respectively.9 Analysis of the intermolecular interactions, which occur in the crystal packing of 1b and 2b shows that the molecules are linked by C–H O and C–H N hydrogen bonds and p–p interactions and produce layers. Since nitrosamine molecules 1b and 2b adopt helical conformations they may exist in two enantiomeric forms. An inclusion complexation with optically active hosts seems to be the method of choice for the enantiomeric resolution of compounds without additional functional groups. Chiral diols 3a,b known as TADDOLs (a,a,a0 ,a0 -tetraphenyl-1,3-dioxolane-4,5-dimethanols), easily accessible from (+)-tartaric acid,10 have been successfully used for the isolation of stereoisomers of a wide variety of compounds.6,7,11 Recently, we have been able to resolve several N-nitrosamines with chirality solely due to the hindered N–N rotation.5a,5c We found that they are also useful for 1b and 2b. We prepared the 1:1 inclusion complexes of these compounds with the host diol 3b, which gave better quality crystals than 3a by co-crystallization of equimolar amounts of the components from CH2Cl2–heptane. The complex of 1b3b crystallizes in the orthorhombic, P212121 space group with the disordered solvent molecule (methanol). The guest molecule 1b assumes essentially the same; a screw-boat conformation as in the uncomplexed form with the ring puckering parameters Q = 0.567(8) Å, h = 76.3(7)° and u = 155.2(8)°. Since the
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configuration of the host 3b is known, the absolute configuration of the guest molecule 1b can be deduced from the X-ray structure of the complex as M. The crystal structures of 1b3b are stabilized by the intramolecular O–H O hydrogen bonds for the 3b molecule and N N contact, with d(N N) = 2.916(4) Å (Fig. 2a). An analysis of the intermolecular interactions occurring in the crystal packing of 1b and 3b shows that the adjacent molecules are linked by O–H N and C–H p hydrogen bonds and p–p interactions and produce columns (Fig. 2b). Unfortunately, the complex 2b3b does not form crystals suitable for X-ray diffraction measurements. However, the configuration of the guest molecule 2b can be assigned as M relying on the same long wavelength CD signs for both complexes. The UV–vis spectra of 1b and 2b taken in the CH2Cl2 solution revealed a weak absorption at 384 nm (e 630) and 384 (e 610), respectively, which corresponded to the forbidden n–p⁄ electronic transition of the nitrosamine chromophore and a strong one at 308 nm (e 9500) and 316 (e 7300), respectively, and can be attributed to the aromatic p–p⁄ excitation. The CD spectra of the complexes were measured in the solid state (KBr disks). They exhibit relatively strong positive Cotton effects with pronounced vibronic structure near 390 nm typical for the nitrosamine n–p⁄ transition (Fig. 3).5a,5c It is noteworthy that this region remains far outside of the absorption range of the host compound 3b. A distortion of the N-arylnitrosamine system from planarity results in the formation of the inherently chiral chromophore, the helicity of which determines the n–p* Cotton effect sign.6b Thus the observed positive CD for both complexes can be correlated with the M helicity of the guest molecules as evidenced by the C@CANAN torsional angle of 51.5° for 1b. The complex 2b3b shows an additional negative CD band centered at 325 nm. Its origin is not clear; it occurs in the region close to the aromatic p–p⁄ transition but is quite far from the region of the nitrosamine p–p⁄ excitation usually occurring near 230 nm. It is unlikely that an aromatic p–p⁄ transition is responsible for this CD since the mononitroso derivative 1b3b does not exhibit any CD at this wavelength. Thus we performed theoretical calculations of the electronic and CD spectra of 1b and 2b by classic ab initio methods. Although some DFT methods have recently been shown to give impressive results for CD spectra calculations,12 the lack of a systematic way of extending a series of calculations to approach the exact result is a major drawback of DFT. Ab initio methods have the advantage that they can be made to converge on the exact solution, when all approximations are sufficiently small in magnitude and when the finite set of basis functions tends toward the limit of a complete set. In this case, configuration interaction, where all possible configurations are included, tends to the exact non-relativistic solution of the electronic Schrödinger equation (in the Born–Oppenheimer approximation). The convergence, however, is usually not monotonic, and sometimes the smallest calculation gives the best
Figure 1. Molecular structure of compounds 1b and 2b showing the atom labeling scheme and 20% probability displacement ellipsoids.
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Figure 2. Molecular structure of compound 1b3b showing the atom labeling scheme and 20% probability displacement ellipsoids (a) and crystal packing of the compound 1b3b. Hydrogen bonds are represented by dashed lines.
Table 1 Calculated parameters for the lowest energy transitions of N-nitrosamines 1b and 2b N N
N
O 3b
N N
N N
O 3b O
Compd
kmax (nm)
fosca
[R]b
CD k (nm) ([H])c
1b 2b
329 328 325
0.00290 0.01635 0.01905
25.1 31.7 77.8
390 (51,190)d 397 (29,580)d 325 (23,770)d
a
Oscillator strength in cgs units. Rotatory strength in 10–40 cgs units. c Molecular ellipticity in deg cm2 dmol1. d Approximate experimental values were determined by considering the weight concentration (KBr density 2.75 g cm3). b
3. Conclusion
Figure 3. CD spectra of the complexes 1b3b (---) and 2b3b (—) measured in KBr disk.
result for some spectroscopic properties. The calculations of 1b and 2b CD spectra were performed with the method implemented in ORCA version 2.8 an ab initio package13 in two steps: first the RHF with Ahlrichs-QZV Def2-QZVPP basis set structure of the reactants have been optimized with the BFGS update method up to maximal gradient tolerance <0.0001 a.u. starting from the crystallographic structures. Then single point CIS singlet calculations of the first 6 excited states were performed including CI space of dimension 60 molecular orbitals by the Davidson diagonalization method. Although the calculated transition energies are overestimated, the oscillator strengths are adequately accounted for and the calculations predict the correct CD signs (Table 1). According to these results, two oppositely signed CD bands exhibited by 2b belong to two n–p⁄ excited states that result from the interaction of two neighboring NNO systems. Nitrosamines 1b and 2b did not show any detectable CD in solution due to rapid racemization upon dissolution. The enantiomer interconversion occurs simply by piperidine ring inversion, which allows the NO group and pyridine nitrogen in 1b or the NO nitrogens in 2b to slip past each other. The corresponding energy barriers estimated using the semiempirical RM1 model14 are extremely low: 2.0 and 4.5 kcal/mol for 1b and 2b, respectively.
In conclusion, the chirality of nitrosamines 1b and 2b can be generated by inclusion complexation with chiral diols. The guest molecules trapped in host crystal matrices are frozen in chiral conformations that can be detected by the solid state CD measurements. The helicity of the guest molecules can be determined either by X-ray crystallography or deduced from the Cotton effect sign corresponding to the lowest energy n–p⁄ electronic transition of the nitrosamino chromophore. 4. Experimental 4.1. General 1 H NMR spectra were obtained with Varian Unity Plus spectrometer at 500 MHz. CD spectra were recorded on a JASCO J-715 dichrograph. The solid state CD spectrum was taken in a freshly prepared KBr disk. A mixture of 2 mg of the sample and 200 mg of the dried KBr was ground and formed into a disk of 0.5 mm thickness and with a radius of 15 mm. The disk was rotated around the optical axis and the CD recordings were made for several positions in order to check a reproducibility of the spectrum.
4.2. N-Nitroso-1,2,3,4-tetrahydro-1,10-phenanthroline 1b To a stirred solution of 1,2,3,4-tetrahydro-1,10-phenanthroline 1a8 (1.6 g, 8.70 mmol) in 36% hydrochloric acid (4.5 mL) and water (30 mL), sodium nitrite (1.3 g, 19.1 mmol) was added in small portions over 30 min. After the addition of the last portion of sodium nitrite, the reaction mixture was stirred for one hour at room
T. Olszewska et al. / Tetrahedron: Asymmetry 26 (2015) 662–665
temperature. Next, the aqueous phase was extracted with CH2Cl2 (3 15 ml). The organic extracts were combined, washed with aqueous NaHCO3, dried over anhydrous MgSO4, and evaporated in vacuo. Recrystallization of the residue from CH2Cl2–diethyl ether afforded the product as a light brown solid: yield 1.3 g (70%); mp 137–138 °C; 1H NMR (CDCl3) d 9.00 (dd, J = 1.5 and 3.9 Hz, 1H), 8.21 (dd, J = 1.7 and 8.1 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.45 (d, J = 8.3 Hz, 2H), 7.43 (d, Hz, 1H), 4.13 (t, J = 6.6 Hz, 2H), 2.91 (td, J = 6.1 Hz, 2H), 2.10 (p, J = 6.4 Hz, 2H). UV (CH2Cl2) kmax 308 nm (e 9500), kmax 384 nm (e 630); Anal. Calcd for C12H11N3O (213.2): C, 67.59; H, 5.20; N, 19.71. Found: C, 67.41; H, 5.22; N, 19.58. 4.3. 2b
N,N0 -Dinitroso-1,2,3,4,7,8,9,10-octahydro-1,10-phenanthroline
Compound 2b was obtained from 1,2,3,4,7,8,9,10-octahydro1,10-phenanthroline 2a7c in a manner similar to that of 1b and had mp 97–98 °C (dec.). 1H NMR (DMSO-d6) d 7.27 (s, 2H), 3.76 (t, J = 6.6 Hz, 4H), 2.68 (t, J = 5.9 Hz, 4H), 1.94 (p, J = 6.3 Hz, 4H); UV (CH2Cl2) kmax 316 nm (e 7300), kmax 384 nm (e 610); Anal. Calcd for C12H14N4O2 (246.3): C, 58.53; H, 5.73; N, 19.71. Found: C, 58.35; H, 5.80; N, 19.61. 4.4. X-ray crystal structure analysis The single-crystal specimens of compounds 1b, 2b, 1b3b, were selected for the X-ray diffraction experiments at T = 295(2) K. Diffraction data were collected on an Oxford Diffraction Gemini R ULTRA Ruby CCD diffractometer with MoKa (k = 0.71073 Å) radiation for 1b, and 1b3b, and CuKa (k = 1.54184 Å) radiation for 1b. The lattice parameters were obtained by least-squares fit to the optimized setting angles of the collected reflections using CrysAlis CCD.15 Data were reduced using CrysAlis RED software15 with applying multi-scan absorption corrections (empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm). The structural resolution procedure was carried out using the SHELXS-97 package, for all compounds. The structures were solved by direct methods carrying out refinements by full-matrix least-squares on F2 using SHELXL-97 program.16 The molecule of compound 2b occupies a special position on the twofold axis. Compound 1b3b crystallized with the disordered solvent molecule (methanol) with site-occupancy factors of the disordered parts 0.5. All H atoms bound with aromatic C atoms were placed geometrically and refined using a riding model with C–H = 0.93–0.97 Å and Uiso(H) = 1.2 Ueq(C). All H–atoms bound with O–atoms 1b3b were located in a difference Fourier map and refined freely with Uiso(H) = 1.5 Ueq(O). All interactions demonstrated were fund by PLATON program.17 The programs used to prepare molecular graphics were ORTEPII,18 PLUTO-7819 and Mercury.20 Crystal data for C12H11N3O, 1b: monoclinic, space group: P21/n, a = 9.779(3), b = 7.806(4), c = 13.735(5) Å, b = 101.46(3)°, V = 1027.7(8) Å3, Z = 4, k = 0.71073 Å, T = 295 K, number of measured reflections 6419, R int = 0.0659, GOOF = 0.963, R 1 = 0.0511, wR2 = 0.1212 for 1803 independent reflections with I > 2r(I). Crystal data for C12H14N4O2, 2b: monoclinic, space group: C2, a = 9.911(2), b = 15.535(2), c = 7.853(2)Å, b = 103.44(2)°, V = 1176.1(6) Å3, Z = 4, k = 1.54184 Å, T = 295 K, number of measured reflections 10716, Rint = 0.0546, R1 = 0.0524, wR2 = 0.1512 for 1058 independent reflections with I > 2r(I).
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Crystal data for C47H49N3O6, 1b3b: orthorhombic, space group: P212121, a = 9.415(2), b = 14.417(2), c = 31.017(3) Å, V = 4210.2(8) Å3, Z = 4, k = 0.71073 Å, T = 295 K, number of measured reflections 12732, Rint = 0.0972, R1 = 0.0720, wR2 = 0.1088 for 7266 independent reflections with I > 2r(I). Crystallographic data (excluding structure factors) for the structures herein have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 1057805–1057807. Acknowledgements We are indebted to Prof. J. Frelek (IChO PAN, Warsaw) for CD measurements using her Jasco J-715 dichrograph. We also thank Dr Casimir Antczak for critical reading of the manuscript. This work was supported by the Ministry of Science and Higher Education, Grant no. NN 204 1820 36. References 1. (a) Loeppky, R. N.; Outram, J. R. N-Nitroso Compounds: Occurence and Biological Effects; IARC Scientific Publishers: Lyon, 1982; (b) N-Nitrosamines and Related N-Nitroso Compounds; Loeppky, R. N., Michejda, C. J., Eds.; American Chemical Society: Washington, DC, 1994; (c) Loeppky, R. N.; Tomasik, W.; Kerride, B. E. Carcinogenesis 1987, 8, 941. 2. Lijinsky, W. In Genotoxicology of N-Nitroso Compounds; Rao, T. K., Lijinsky, W., Epler, J. L., Eds.; Plenum Press: New York, 1984. 3. (a) Rao, C. N. R.; Bhaskar, K. R. In Spectroscopy of the Nitroso Group; Patai, S., Feuer, H., Eds.; Wiley: Chichester, 1970. Part 1, Chapter 3; (b) Challis, B. C.; Challis, J. A. In The Chemistry of Amino, Nitroso, and Nitro Compounds and Their Derivatives; Patai, F., Ed.; Wiley: New York, 1982. Supplement F, Part 2, Chapter 26. 4. Harris, R. K.; Pryce-Jones, T.; Swinbourne, F. J. J. Chem. Soc., Perkin Trans. 2 1980, 476. 5. For a review see: (a) Smith, H. E. In The Chemistry of Amino, Nitroso, Nitro, and Related Groups; Patai, F., Ed.; Wiley: Chichester, 1996. Supplement F2, Part 1, Chapter 3; (b) Połon´ski, T.; Prajer, K. Tetrahedron 1976, 32, 847; (c) Połon´ski, T.; Milewska, M. J. A.; Katrusiak, A. J. Am. Chem. Soc. 1993, 115, 11410. and Refs therein. 6. (a) Gdaniec, M.; Milewska, M. J.; Połon´ski, T. Angew. Chem., Int. Ed. 1999, 38, 392; (b) Olszewska, T.; Milewska, M. J.; Gdaniec, M.; Połon´ski, T. Chem. Commun. 1999, 1385; (c) Olszewska, T.; Milewska, M. J.; Gdaniec, M.; Małuszyn´ska, H.; Połon´ski, T. J. Org. Chem. 2001, 66, 501; (d) Szyrszyng, M.; Nowak, E.; Gdaniec, M.; Milewska, M. J.; Herman, A.; Połon´ski, T. J. Org. Chem. 2001, 66, 7380; (e) Olszewska, T.; Gdaniec, M. T. Tetrahedron: Asymmetry 2009, 20, 1308. 7. (a) Olszewska, T.; Pyszno, A.; Milewska, M. J.; Gdaniec, M. T.; Połon´ski, T. Tetrahedron: Asymmetry 2005, 16, 3711; (b) Olszewska, T.; Nowak, E.; Gdaniec, M.; Połon´ski, T. Org. Lett. 2012, 14, 2568; (c) Olszewska, T.; Sikorski, A.; Herman, A.; Połon´ski, T. Org. Biomol. Chem. 2013, 11, 7522. 8. Metallinos, C.; Barrett, F. B.; Chaytor, J. L.; Heska, M. E. A. Org. Lett. 2004, 6, 3641. 9. (a) Cremer, D.; Pople, J. A. J. Am. Chem. Soc. 1975, 97, 1354; (b) Spek, A. L. J. Appl. Crystallogr. 2003, 36, 7. 10. (a) Seebach, D.; Beck, A. K.; Imwinkelried, R.; Roggo, S.; Wonnacott, A. Helv. Chim. Acta 1987, 70, 954; (b) Toda, F.; Tanaka, K. Tetrahedron Lett. 1988, 29, 551. 11. Fogassy, E.; Nogradi, M.; Kozma, D.; Egri, G.; Palovics, E.; Kiss, V. Org. Biomol. Chem. 2006, 4, 3011. 12. Diedrich, C.; Grimme, S. J. Phys. Chem. A 2003, 107, 2524. 13. Neese, F. ORCA—an ab initio, Density Functional and Semiempirical Program Package, Version 2.8; Bonn University, 2010. 14. Rocha, G. B.; Freire, R. O.; Simas, A. M.; Stewart, J. P. J. Comput. Chem. 2006, 27, 1101. 15. CrysAlis CCD and CrysAlis RED; Oxford Diffraction Ltd: Yarnton, England, 2008. 16. Sheldrick, G. M. Acta Crystallogr., Sect. A: Fundam. Crystallogr. 2008, 64, 112. 17. Spek, A. L. Acta Crystallogr., Sect. D: Biol. Crystallogr. 2009, 65, 148. 18. Johnson, C. K. ORTEP II, Report ORNL-5138; Oak Ridge National Laboratory: Oak Ridge, TN, USA, 1976. 19. Mortherwell, S.; Clegg, S. PLUTO-78, Program for Drawing and Molecular Structure; University of Cambridge: UK, 1978. 20. Macrae, C. F.; Bruno, I. J.; Chisholm, J. A.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Rodriguez-Monge, L.; Taylor, R.; van de Streek, J.; Wood, P. A. J. Appl. Crystallogr. 2008, 41, 466.