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Solution conformations of novel redox-active cyclophane based on biindolizinequinoxaline
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Journal of Molecular Structure 889 (2008) 89–97 www.elsevier.com/locate/molstruc
Solution conformations of novel redox-active cyclophane based on biindolizinequinoxaline Alsu Balandina, Vakhid Mamedov, Shamil Latypov * Institute of Organic and Physical Chemistry, Arbuzov Street 8, Kazan 420088, Russia Received 22 December 2007; received in revised form 11 January 2008; accepted 14 January 2008 Available online 31 January 2008
Abstract A complete study of the conformational behavior of cyclopentadecaphane by DNMR and theoretical methods demonstrates that: (a) the macrocycle adopts syn-orientation of indolizine fragments; (b) internal rotation around the bonds between indolizine and quinoxaline moieties produces two strictly different structures in solution: in dominant non-symmetrical form (ca. 67%) the halves of the macrocycle are not equivalent while in the minor symmetrical form (ca. 33%) they can be superimposed by rotation. Ó 2008 Elsevier B.V. All rights reserved. Keywords: DNMR; GIAO–DFT chemical shifts; 2D NMR; 3D structure; Macrocycle; Indolizinequinoxaline
1. Introduction Biological systems use the interplay of redox and molecular recognition to regulate a wide variety of processes and transformations [1a]. Redox-active heterocycles are important to materials science and to biochemistry. Some of redox-active macrocyclic compounds have been proposed as candidates for ion transport [1b]. Therefore in recent years, there is a considerable interest in the creation of such organic based molecular devices that have the potential to function as information storage/switching systems in molecular scale computers and other applications [2]. To this end cyclophanes based on biindolizinquinoxaline moieties linked through C30 AC30 * (biindolizine linkage) bond and by oxypentane spacer seem to be a perspective redox-active ‘‘host” (Scheme 1): the combination of the electron-rich aromatic p-systems with electron-rich biindolizines leads to possibilities of p–pinteractions with potential guests such as aromatic compounds [3]; the presence of the crown ether moiety
*
Corresponding author. Tel.: +7 843 2727484; fax: +7 843 2732253. E-mail address: [email protected] (Sh. Latypov).
0022-2860/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.molstruc.2008.01.032
allows to utilize the central feature of the crown ethers – their ability to form stable and selective complexes with various inorganic and organic cations [4]. Moreover, the indolizine, quinoxaline and crown ether fragments play an important role in synthetic, therapeutic, and bioorganic chemistry. The quinoxaline derivatives show antibacterial, antiviral, anticancer, antifungal, antihelmintic, insecticidal activity [5]. Indolizines demonstrate antifungal, antimycobacterial, antiherpes and antineociceptive properties [6]. Crown ethers are found to be toxic in prokaryotic and eukaryotic cellular systems, which led to further studies on their potential for being developed as antimicrobial agents [4,7]. Over recent years there has been a trend in biochemistry towards the synthesis of extended molecular entities that are multi-component. Moreover, linked preorganized systems are of considerable intrinsic interest since they can give rise to new derivatives whose properties may be more than the ‘‘sum of the parts” [1b,7a,8]. The outcome of the operation of these systems in their use as molecular devices and/or as biologically active recognition agents in resulting supramolecular systems depends strongly on their 3D structure. Therefore the development of structure/property relationships
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Scheme 1.
Fig. 1. The principal HMBC correlations for 1 (from protons to carbons): data only for the half of the molecule are shown for clarity.
2.2. NMR spectroscopy and the knowledge of conformations and dynamics of these cyclophanes in solution is of utmost important [2e,2f,9]. Recently we reported the synthesis of diastereoisomeric triethylenglycol-bridged biindolizinequinoxaline 1 (Scheme 1) [10]. The product proved to have a reversible redox property. The chemical and isomeric structure of 1 was investigated in solid state and in solution by X-ray and NMR methods. In addition, according to our preliminary experiments at a room temperature there is extensive coalescence of signals in 1H NMR spectra of the macrocycle that may be ascribed to conformational equilibrium. In this paper we present our results of an investigation into conformational structure and dynamics of 1 in solution by a variety of experimental and theoretical NMR methods. 2. Experimental 2.1. Synthesis of compounds 2.1.1. 21,31-Diphenyl-12,42-dioxa-7,10,13-trioxa-1,4(3,1)diquinoxaline-2(2,3),3(3,2)-diindolizineacycledeaphane (1) Compound 1 was prepared according to Ref. [10]. 1H NMR (DMF, 600 MHz, 50 °C): d = 3.40 and 3.54 (4H, m, CH2-2), 3.42 (4H, m, CH2-4), 3.43 and 3.49 (4H, m, CH2-3), 3.83 and 4.02 (4H, m, CH2-1), 6.83 (2H, dd, J = 6.9, 6.7 Hz, H-60 ), 7.02 (2H, dd, J = 9.4, 6.6 Hz, H70 ), 7.14 (2H, dd, J = 7.4, 7.0 Hz, H-400 ), 7.20 (2H, ddd, J = 8.0, 5.7, 2.3 Hz, H-6), 7.25 (4H, dd, J = 7.8, 7.6 Hz, H-300 /500 ), 7.30 (2H, d, J = 7.9 Hz, H-5), 7.37 (4H, d, J = 7.6 Hz, H-200 /600 ), 7.51 (4H, m, H-7, H-8), 7.72 (2H, d, J = 8.7 Hz, H-50 , H-80 ); 13C NMR (DMF, 150.86 MHz, 50 °C): d = 42.28 (CH2-1), 67.62 (CH2-2), 70.53 (CH2-4), 70.70 (CH2-3), 112.43 (C-60 ), 114.69 (C-8), 115.26 (C-30 ), 115.44 (C-10 ), 118.46 (C-80 ), 120.15 (C-70 ), 123.30 (C-6), 125.11 (C-20 ), 125.15 (C-50 ), 126.10 (C-40 ), 128.70 (C-300 /500 ), 129.89 (C-200 /600 ), 129.99 (C-5), 130.52 (C-7), 131.42 (C-8a0 ), 133.52 (C-4a), 134.06 (C-8a), 136.01 (C-100 ), 147.98 (C-3), 154.24 (C-2); m/z = (830)M+; IR, m, cm1 (neat) (Vector-22 (Bruker)): 704, 729, 762, 1103, 1128, 1159, 1251, 1281, 1346, 1366, 1454, 1486, 1524, 1583, 1601, 1649, 2857, 2922. C52H44N 6O5.
NMR experiments were carried out with a Bruker AVANCE-600 spectrometer (14.1 T) equipped with a pulsed gradient unit capable of producing magnetic field pulse gradients in the z-direction of 56 G cm1. All spectra were acquired in a 5-mm inverse probehead working at 600.000 MHz in 1H and 150.864 MHz in 13C experiments. Chemical shifts are reported on the d (ppm) scale and are relative to the residual 1 H and 13C signal of DMF-d7. A complete assignment of 1 was accomplished by DEPT, 2D COSY-gp, 2D HSQC-gp, 2D HMBC-gp experiments [11], using standard Bruker pulse programs (related 1D and 2D NMR spectra can be obtained in Supporting materials). The 90°-pulse widths were 7 ls and 12 ls for 1H and 13C, respectively. For 2D COSY-gp: d1(relaxation delay) = 1.5 s (T = 333 K) and d1 = 1 s (T = 213 K). For 2D HSQC-gp: d1 = 2.5 s (T = 333 K) and d1 = 1 s (T = 213 K), optimized on 1JCH = 145 Hz. For 2D HMBC-gp: d1 = 2.5 s, optimized on 1JCH = 145 Hz and nJCH = 9 Hz. For 2D NOESY-gp: d1 = 3 s, mixing time 600 ms and ROESY-gp: spin-lock time 600 ms. For DNMR spectroscopy, a standard unit calibrated using a methanol reference controlled the probe temperature; the samples were allowed to equilibrate for 15 min at each temperature before recording spectra. Line shape analysis of signals broadened by chemical exchange was carried out by WinDNMR v.7.1.6 program [12] on Pentium 4 computer. Activation parameters were calculated by Eyring equation [13]. Molecular mechanics (employing the MM2 force field) were performed with CS Chem3D Ultra 6.0 (CambridgeSoftCorp.). Chemical shifts were determined within the DFT framework using a hybrid exchange-correlation functional, B3LYP, at the 6-31G(d) level as implemented in Gaussian 98 [14]. Full geometry optimizations were done at the ab initio RHF/6-31G level. All data were referred to TMS (1H and 13C) chemical shifts that were calculated at the same conditions. All calculations were run on a Pentium 4 (CPU 2.80 GHz 512 MB RAM) computer. 3. Results and discussion The complete structure elucidation of compound 1 was carried out by variety of correlation NMR methods (2D
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Fig. 2. Schematic presentation of anti (a) and syn (b) isomers of 1.
COSY-gp, 2D HSQC-gp, 2D HMBC-gp)1 and non-empirical (GIAO DFT) chemical shift calculations [15]. The HMBC key correlations between structural fragments for compound 1 are summarized on Fig. 1. There are two isomeric forms around C30 AC30 * (indolizine linkage) bond in which 1 could exist with syn and antimutual orientations of indolizine fragments (Fig. 2). According to calculations the isomeric forms of 1 should have diagnostically valuable differences in their chemical shifts for variety of nuclei (H-5, H-50 , H-60 , C-2, C-3, C10 , C-20 , C-30 , C-50 ) [10] which can be invoked for spectrastructure correlations. Both 1H and 13C experimental chemical shifts correlates well with predicted chemical shifts for syn-isomer (R2 = 0.99 and 0.93, for 1H and 13C, respectively) while for anti-isomer these correlations are essentially worse (0.84 (1H) and 0.87 (13C)). Thus this analysis let us to conclude that in solution 1 exists as syn-isomer (Fig. 2). This finding was also supported by X-ray results in solid-state. Therefore hereinafter syn-isomer is meant for 1 unless otherwise specified. As it was mentioned above there are essential broadened almost all signals in 1H and 13C spectra of 1 at room temperature in DMSO. Particularly, for quinoxaline moiety and of CH2 groups of crown ether there are extensive broad signals in 1H spectra, probably due to the exchange process in which 1 is involved. When temperature increase (up to 323 K) almost all lines in 1H spectrum become sharp (Fig. 3). It is important to note that in resulted spectrum the geminal protons of each CH2 groups of spacer are not equivalent (see Supplementary materials). Hence the compound 1 may be in fast (in NMR time scale) notmutual exchange of the forms at least one of which is not symmetrical. In general, for 1 there might be three main conformers generated by rotation around the C20 AC3 bonds between Ind and Qx fragments (Fig. 4). In each form there is an additional conformational variety due to different geometry of the flexible spacer. One of the forms is symmetrical (SYM, Fig. 4(a)) in which two Ind and Qx fragments can be superimposed by C2 operation (rotation around the axis 1
All details can be found in Supplementary material.
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perpendicular to Ind linkage C30 AC30 * bond). Rotation of one of Qx groups (either Qx1 or Qx2) around one of the C20 AC3 bonds by ca. 180° produces non-symmetrical structure (NSYM, Fig. 4(b)), while rotation of both quinoxaline fragments (Qx1 and Qx2) theoretically should generates another symmetrical form (SYM*, Fig. 4(c)) although the last one is obviously unstable due to sterical hindrance of the Qx1 and Qx2 moieties. Thus we can conclude that in the title macrocycle two groups of conformers can be expected in solution with different orientation of quinoxaline cycles, SYM and NSYM, and some variation of fine geometry of spacer (Fig. 4). Final proof of conformational structures of 1 and their equilibrium in solution was carried out by several theoretical and NMR methods. 3.1. Calculations Initial geometries of 1 in SYM and NSYM forms were obtained by screening of the sterically allowed geometries of spacer and these structures were optimized then by molecular mechanics (MM2). Four low energy conformers both for SYM and NSYM orientations of around C20 AC3 and C20 *AC3* bonds in range of 2 kcal/mol of the lowestenergy conformer were selected for further analysis. Molecular dynamics simulations of structures 1 yielded no additional geometries, thus confirming that the MM calculations had generated all feasible low energy conformations. To confirm that the above results were not simply due to limitations of the empirical methods, we also performed ab initio calculations. The optimization of the geometry in frame of HF method produces in general similar to MM structures and energies of the conformers (Table 1, Fig. 5). Moreover, difference in dipole moments implies that some small perturbation in energies can be expected in solution. Because the energies of the SYM and NSYM forms are close, the equilibrium between them might be altered by temperature changes; the shifts in equilibrium could be followed by 1H and 13C NMR spectroscopy. Moreover, if the rate of rotamer interconversion is slow on the NMR time scale, it may be possible to distinguish conformers in which some groups are shielded from those in which they are not. The conformational equilibrium of 1 could thus be probed, and the thermodynamic parameters of this equilibrium established. It should also be possible to quantitatively correlate NMR chemical shifts with the geometric parameters of the individual conformers. 3.2. NMR results To run low temperature experiments the solution of 1 in DMF was prepared. The effects of varying the probe temperature (T) were significant (Fig. 6) as suggested by our calculations. Between 303 and 243 K the signals in 1H NMR spectra were broadened. Particularly extensive coalescence is
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Fig. 3. 1H NMR spectra of 1 in DMSO at T = 323 K.
Fig. 4. Schematically presentation of the main conformer’s geometries of 1.
observed for spacer and quinoxaline protons. Finally at 213 K the spectra represents a set of sharp multiplets and lines of different intensities, indicating that a chemical exchange process affecting these signals is slow in NMR time scale. It is particularly interesting that at 213 K for some of the well separated protons three set of signals of similar intensities are clearly observed (e.g. H-7, H-60 , H70 ). This finding led us to suppose that there are three sets
Table 1 RHF/6-31G//RHF/6-31G energies (kcal/mol) and dipole moments (D) for 1 in the stable conformations Non-symmetrical structure E, kcal/mol (l, D)
Symmetrical structure E, kcal/mol (l, D)
0 (3.99) 3.0 (2.07) 3.76 (6.99) 12.9 (5.65)
0.1 1.8 2.4 3.9
(3.88) (4.07) (4.01) (4.62)
Fig. 5. SYM (a) and NSYM (b) forms of 1.
of signals for all protons that are in slow exchange at T = 213 K. Indeed, three benzo fragments of quinoxaline, three benzo fragments of indolizine, three phenyls and three (half) oxipentene spacers were distinguished by joint analysis of 2D COSY/HSQC spectra at T = 213 K and 13C at T = 333 K (Fig. 7 and Supplementary materials). Room temperature 13C chemical shifts differ only slightly from low temperature ones for these fragments and almost equal integral intensities of three sets of signals for several protons at low temperature imply that at T = 213 K 1H NMR spectra correspond to superposition of spectra of three units equal to half of the title macrocycle 1. The two units with strong differentiating 1H and 13C chemical shifts of corresponding nuclei (e.g. C2 vs C2*, etc.) can be ascribed to non-symmetrical conformation of macrocycle (NSYM) while third unit in which two halves of the molecular are equivalent in NMR spectra can be assigned to symmetrical conformation (or set of conformation due to different geometry of spacer, SYM) in which these halves are magnetically equivalent. Thus we can conclude that we deal with two component equilibrium of the forms (or set of the forms differentiating by spacer geometry), dominant form being non-symmetrical (ca. 67%) while minor form being symmetrical with population about ca. 33%. Comparison of theoretical versus experimental chemical shifts gives an additional support to structures of minimum energy conformers (RHF/6-31G). Both semi-classical model of anisotropic shielding effects (ASE) [16] and nonempirical calculations of chemical shifts [15] predict effects of diagnostic value in the NSYM conformation while in SYM no such strong effects are expected. For example,
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Fig. 6. 1H NMR spectra of 1 in DMFA at different temperatures (solvent signals are marked by asterisks. The ‘‘s” and ‘‘n” correspond to SYM and NSYM conformers, respectively). Results of simulation exchange spectra for H-60 protons are also shown nearby with corresponding rate constants.
according to ASE calculations high field shifts in 1H due to aromatic rings have to be observed for some protons in one half of NSYM conformer (H-5 (NSYM1) – 0.52 ppm, H-8 (NSYM2) – 0.2 ppm, CH2-1 (NSYM2) – 0.5 and 1.4 ppm, respectively, for geminal protons, Fig. 8). Rest of the protons should not be notably influenced by aromatic rings. This is in qualitative agreement with remarkable high field shifts observed for these protons in one half of the molecule versus protons of another half (Fig. 8, H-5 (NSYM1) – 0.5 ppm, H-8 (NSYM2) – 0.26 ppm, CH2-1 (NSYM2) – 1.46 ppm). Moreover, the protons in non-shielded half of NSYM conformer are very similar to protons in SYM conformer. Barrier data are also in line with the above conclusion. Full line shape analysis [13] was carried out at T = 273– 233 K (Fig. 6, Eyring plot is in Supplementary materials). It was found that the experimental barrier (DH#) is ca. 2 12 kcal/mol ðDG# 243 ¼ 12:7 kcal=molÞ. To estimate the theoretical barrier of interconversion we calculated energy profile for rotation around IndAQx bond for model acycle system, 2 (Fig. 9). Full energy optimization (at the HF/631G level) except restraint around C20 AC3 bond (dihedral drive with an increment of 10°) reveals two minima, corre2 Unfortunately, full line shape calculations of three exchanging ABX spin systems (H50 , H60 , H70 ) are beyond our computational facilities. Therefore for simplicity reason each triplets were approximated by singlets and simulations were carried out for three site exchange.
sponding to SYM and NSYM conformers of 2, and two transition states on the profile (Fig. 9) with barrier to interconversion equal to 12.4 kcal/mol. Thus good agreement between experimental and calculated barrier additionally proves that the rotation around IndAQx bond is responsible for observed extensive line shape evolution of the spectra as temperature changes. Deviation in calculated energy difference between SYM and NSYM conformations for 2 vs 1 can be well explained by short spacer restrains geometry into NSYM conformation in macrocycle. Finally, an additional support to theoretical structure was obtained from NOE’s measurements [17] at T = 213 K. Unfortunately, due to size of the molecule and low temperature the correlation time is such as xsc < 1 and therefore all NOE’s in 2D NOESY spectra are positive [11,18]. Several NOE’s are appeared due to direct dipole–dipole interactions and due to chemical (conformational) exchange as well [18]. In order to separate these effects the ROESY experiments were also carried out where these effects are of different sign. Comparative analysis of these experiments (Fig. 10) led us to reveal important indications of proposed geometry. First of all, cross-peaks due to chemical exchange can be directly distinguished from 2D ROESY spectra (e.g. H-5 (NSYM1), H-5 (NSYM2) and H-5 (SYM); H-6 (SYM) and H-6 (NSYM1), H-6 (NSYM2); H-60 (SYM) and H-60 (NSYM1), H-60 (NSYM2), Fig. 10). Then variety NOEs
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Fig. 7. Fragments of 2D HSQC spectra at T = 213 K (1D 13C spectra at T = 333 K [due to low solubility at low temperature 1D 13C spectra at T = 213 K was not measured]): low (a) and high (b) filed (13C) regions.
due to dipole–dipole interactions were assigned. The most important are ‘‘non-trivial” NOEs due to the close proxim-
ity of the protons that are not close in chemical sense (nor geminal neither vicinal) but due to folding. Thus, for exam-
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ple cross-peaks between CH2-2 (NSYM1), CH2-3 (NSYM1) and H-200 /600 , H-300 /500 (NSYM2) (Fig. 11) can be attributed to NSYM conformation. Unfortunately, as it was expected for SYM form there is no ‘‘non-trivial” effects. To sum it up, these experiments demonstrates that 1 exists in conformational exchange of its forms and one of which is NSYM with geometry leading to ‘‘non-trivial” NOE’s.
Fig. 8. Chemical shift differences (d(NSYM1) d(NSYM2)) for some asymmetric protons in NSYM conformation of 1.
3.2.1. Final remarks Stabilization of NSYM conformation, probably, is due to the p–p interactions of two Qx fragments or due to hydrogen bond between C@O and protonated NH groups (Qx). The unstability of SYM conformation is conditioned
Fig. 9. Energy profile for 2 obtained for the IndAQx bond rotation at the HF/6-31G level of theory.
Fig. 10. (a) 2D ROESY and (b) 2D NOESY spectra (sm = 0.6 s) of 1 at T = 213 K. Cross peaks due to exchange are in squares and some principal peaks due to dipole–dipole interactions are shown in ovals.
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and materials (CKP SAC) and Federal CKP for physical and chemical investigations of matter and materials (FCKP PCI) (state contracts of the Russian Federation Ministry of education and science No. 02.451.11.7036 and 02.451.11.7019). Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.molstruc. 2008.01.032. References
Fig. 11. ‘‘Non-trivial” NOE’s and their correlation with the structure of NSYM conformation.
by electrostatic repulsive interactions of carbonylic groups ˚ ). (C@OAC@O distance 3.18 A Perhaps, conformational equilibrium can be tuned by the introduction of polar group into Qx moiety or by the changing of pH solution because the protonated nitrogen well situated to interact with carbonyl group to stabilize NSYM conformer. Seems, these are the ways to rationally modify the population of the forms with different mutual orientation of chromophoric groups and it might be subject of future investigations. 4. Conclusion Thus, we can conclude that in solution the title macrocycle exists in conformational equilibrium due to rotation around indolizinie–quinoxaline linkage. In the main nonsymmetrical conformer (ca. 67%) two quinoxaline rings are non-symmetric while in minor symmetrical one (ca. 33%) these fragments are equivalent. In both conformers mutual orientation of two indolizine rings is synperiplanar. Acknowledgements Financial support from the RFBR (No. 05-03-32558-a), one of us (Sh.L.) acknowledges Russian Science Support Foundation for doctoral Grant. This investigation was carried out in NMR department of the Federal Collective Spectral Analysis Center for physical and chemical investigations of structure, properties and composition of matter
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J.C. Burant S. Dapprich J.M. Millam A.D. Daniels K.N. Kudin M.C. Strain O. Farkas J. Tomasi V. Barone M. Cossi R. Cammi B. Mennucci C. Pomelli C. Adamo S. Clifford J. Ochterski G.A. Petersson P.Y. Ayala Q. Cui K. Morokuma D.K. Malick A.D. Rabuck K. Raghavachari J.B. Foresman J. Cioslowski J.V. Ortiz A.G. Baboul B.B. Stefanov G. Liu A. Liashenko P. Piskorz I. Komaromi R. Gomperts R.L. Martin D.J. Fox T. Keith M.A. Al-Laham C.Y. Peng A. Nanayakkara C. Gonzalez M. Challacombe P.M.W. Gill B.G. Johnson W. Chen M.W. Wong J.L. Andres M. Head-Gordon E.S. Replogle J.A. Pople, Gaussian 98, Revision A.6, Gaussian, Pittsburgh, PA, 1998. (a) J.R. Cheeseman, G.W. Trucks, T.A. Keith, J. Frisch, J. Chem. Phys. 104 (1996) 5497; (b) A. De Dios, Progr. Nucl. Magn. Res. Spectrosc. 29 (1996) 229; (c) A.A. Balandina, A.A. Kalinin, V.A. Mamedov, B. Figadere, Sh.K. Latypov, Magn. Res. Chem. 43 (2005) 816; (d) L. Galiullina, A. Nikolaev, V. Semenov, V. Reznik, Sh. Latypov, Tetrahedron 62 (2006) 7021; (e) R.M. Claramunt, C. Lopez, M.D. Santa Maria, D. Sanz, J. Elguero, Progr. Nucl. Magn. Res. Spectrosc. 49 (2006) 169; (f) I. Alkorta, J. Elguero, Tetrahedron 37 (2006) 8683; (g) C. Bassarello, G. Bifulco, P. Montoro, A. Skhirtladze, E. Kemertelidze, C. Pizza, S. Piacente, Tetrahedron 63 (2007) 148; (h) F. Blanco, I. Alkorta, J. Elguero, Magn. Res. Chem. 45 (2007) 797; (i) G. Bifulco, P. Dambruoso, L. Gomez-Paloma, R. Riccio, Chem. Rev. 107 (2007) 3744; (j) M. Barfield, Magn. Res. Chem. 45 (2007) 634; (k) V. Semenov, L. Galiullina, O. Lodochnikova, O. Kataeva, A. Gubaidullin, A. Chernova, Yu. Efremov, Sh. Latypov, V. Reznik, Eur. J. Org. Chem. (2007) 4578. (a) J.S. Waugh, R.W. Fessenden, J. Am. Chem. Soc. 79 (1957) 846; (b) C.E. Johnson, F.A. Bovey, J. Chem. Phys. 29 (1958) 1012; (c) M. Barfield, D.M. Grant, D. Ikenberry, J. Am. Chem. Soc. 97 (1975) 6956; (d) C.W. Haigh, R.B. Mallion, Progr. Nucl. Magn. Res. Spectrosc. 13 (1980) 303. (a) T.L. Hwang, A.J. Shaka, J. Am. Chem. Soc. 114 (1992) 3157; (b) T.L. Hwang, A.J. Shaka, J. Magn. Reson. B 102 (1993) 155. (a) D. Neuhaus, M.P. Williamson, The Nuclear Overhauser Effect in Structural and Conformational Analysis, VCH, New York, 1989; (b) H. Mo, T.C. Pochapsky, Progr. Nucl. Magn. Res. Spectrosc. 30 (1997) 1.
Journal of Molecular Structure 889 (2008) 89–97 www.elsevier.com/locate/molstruc
Solution conformations of novel redox-active cyclophane based on biindolizinequinoxaline Alsu Balandina, Vakhid Mamedov, Shamil Latypov * Institute of Organic and Physical Chemistry, Arbuzov Street 8, Kazan 420088, Russia Received 22 December 2007; received in revised form 11 January 2008; accepted 14 January 2008 Available online 31 January 2008
Abstract A complete study of the conformational behavior of cyclopentadecaphane by DNMR and theoretical methods demonstrates that: (a) the macrocycle adopts syn-orientation of indolizine fragments; (b) internal rotation around the bonds between indolizine and quinoxaline moieties produces two strictly different structures in solution: in dominant non-symmetrical form (ca. 67%) the halves of the macrocycle are not equivalent while in the minor symmetrical form (ca. 33%) they can be superimposed by rotation. Ó 2008 Elsevier B.V. All rights reserved. Keywords: DNMR; GIAO–DFT chemical shifts; 2D NMR; 3D structure; Macrocycle; Indolizinequinoxaline
1. Introduction Biological systems use the interplay of redox and molecular recognition to regulate a wide variety of processes and transformations [1a]. Redox-active heterocycles are important to materials science and to biochemistry. Some of redox-active macrocyclic compounds have been proposed as candidates for ion transport [1b]. Therefore in recent years, there is a considerable interest in the creation of such organic based molecular devices that have the potential to function as information storage/switching systems in molecular scale computers and other applications [2]. To this end cyclophanes based on biindolizinquinoxaline moieties linked through C30 AC30 * (biindolizine linkage) bond and by oxypentane spacer seem to be a perspective redox-active ‘‘host” (Scheme 1): the combination of the electron-rich aromatic p-systems with electron-rich biindolizines leads to possibilities of p–pinteractions with potential guests such as aromatic compounds [3]; the presence of the crown ether moiety
*
Corresponding author. Tel.: +7 843 2727484; fax: +7 843 2732253. E-mail address: [email protected] (Sh. Latypov).
0022-2860/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.molstruc.2008.01.032
allows to utilize the central feature of the crown ethers – their ability to form stable and selective complexes with various inorganic and organic cations [4]. Moreover, the indolizine, quinoxaline and crown ether fragments play an important role in synthetic, therapeutic, and bioorganic chemistry. The quinoxaline derivatives show antibacterial, antiviral, anticancer, antifungal, antihelmintic, insecticidal activity [5]. Indolizines demonstrate antifungal, antimycobacterial, antiherpes and antineociceptive properties [6]. Crown ethers are found to be toxic in prokaryotic and eukaryotic cellular systems, which led to further studies on their potential for being developed as antimicrobial agents [4,7]. Over recent years there has been a trend in biochemistry towards the synthesis of extended molecular entities that are multi-component. Moreover, linked preorganized systems are of considerable intrinsic interest since they can give rise to new derivatives whose properties may be more than the ‘‘sum of the parts” [1b,7a,8]. The outcome of the operation of these systems in their use as molecular devices and/or as biologically active recognition agents in resulting supramolecular systems depends strongly on their 3D structure. Therefore the development of structure/property relationships
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Scheme 1.
Fig. 1. The principal HMBC correlations for 1 (from protons to carbons): data only for the half of the molecule are shown for clarity.
2.2. NMR spectroscopy and the knowledge of conformations and dynamics of these cyclophanes in solution is of utmost important [2e,2f,9]. Recently we reported the synthesis of diastereoisomeric triethylenglycol-bridged biindolizinequinoxaline 1 (Scheme 1) [10]. The product proved to have a reversible redox property. The chemical and isomeric structure of 1 was investigated in solid state and in solution by X-ray and NMR methods. In addition, according to our preliminary experiments at a room temperature there is extensive coalescence of signals in 1H NMR spectra of the macrocycle that may be ascribed to conformational equilibrium. In this paper we present our results of an investigation into conformational structure and dynamics of 1 in solution by a variety of experimental and theoretical NMR methods. 2. Experimental 2.1. Synthesis of compounds 2.1.1. 21,31-Diphenyl-12,42-dioxa-7,10,13-trioxa-1,4(3,1)diquinoxaline-2(2,3),3(3,2)-diindolizineacycledeaphane (1) Compound 1 was prepared according to Ref. [10]. 1H NMR (DMF, 600 MHz, 50 °C): d = 3.40 and 3.54 (4H, m, CH2-2), 3.42 (4H, m, CH2-4), 3.43 and 3.49 (4H, m, CH2-3), 3.83 and 4.02 (4H, m, CH2-1), 6.83 (2H, dd, J = 6.9, 6.7 Hz, H-60 ), 7.02 (2H, dd, J = 9.4, 6.6 Hz, H70 ), 7.14 (2H, dd, J = 7.4, 7.0 Hz, H-400 ), 7.20 (2H, ddd, J = 8.0, 5.7, 2.3 Hz, H-6), 7.25 (4H, dd, J = 7.8, 7.6 Hz, H-300 /500 ), 7.30 (2H, d, J = 7.9 Hz, H-5), 7.37 (4H, d, J = 7.6 Hz, H-200 /600 ), 7.51 (4H, m, H-7, H-8), 7.72 (2H, d, J = 8.7 Hz, H-50 , H-80 ); 13C NMR (DMF, 150.86 MHz, 50 °C): d = 42.28 (CH2-1), 67.62 (CH2-2), 70.53 (CH2-4), 70.70 (CH2-3), 112.43 (C-60 ), 114.69 (C-8), 115.26 (C-30 ), 115.44 (C-10 ), 118.46 (C-80 ), 120.15 (C-70 ), 123.30 (C-6), 125.11 (C-20 ), 125.15 (C-50 ), 126.10 (C-40 ), 128.70 (C-300 /500 ), 129.89 (C-200 /600 ), 129.99 (C-5), 130.52 (C-7), 131.42 (C-8a0 ), 133.52 (C-4a), 134.06 (C-8a), 136.01 (C-100 ), 147.98 (C-3), 154.24 (C-2); m/z = (830)M+; IR, m, cm1 (neat) (Vector-22 (Bruker)): 704, 729, 762, 1103, 1128, 1159, 1251, 1281, 1346, 1366, 1454, 1486, 1524, 1583, 1601, 1649, 2857, 2922. C52H44N 6O5.
NMR experiments were carried out with a Bruker AVANCE-600 spectrometer (14.1 T) equipped with a pulsed gradient unit capable of producing magnetic field pulse gradients in the z-direction of 56 G cm1. All spectra were acquired in a 5-mm inverse probehead working at 600.000 MHz in 1H and 150.864 MHz in 13C experiments. Chemical shifts are reported on the d (ppm) scale and are relative to the residual 1 H and 13C signal of DMF-d7. A complete assignment of 1 was accomplished by DEPT, 2D COSY-gp, 2D HSQC-gp, 2D HMBC-gp experiments [11], using standard Bruker pulse programs (related 1D and 2D NMR spectra can be obtained in Supporting materials). The 90°-pulse widths were 7 ls and 12 ls for 1H and 13C, respectively. For 2D COSY-gp: d1(relaxation delay) = 1.5 s (T = 333 K) and d1 = 1 s (T = 213 K). For 2D HSQC-gp: d1 = 2.5 s (T = 333 K) and d1 = 1 s (T = 213 K), optimized on 1JCH = 145 Hz. For 2D HMBC-gp: d1 = 2.5 s, optimized on 1JCH = 145 Hz and nJCH = 9 Hz. For 2D NOESY-gp: d1 = 3 s, mixing time 600 ms and ROESY-gp: spin-lock time 600 ms. For DNMR spectroscopy, a standard unit calibrated using a methanol reference controlled the probe temperature; the samples were allowed to equilibrate for 15 min at each temperature before recording spectra. Line shape analysis of signals broadened by chemical exchange was carried out by WinDNMR v.7.1.6 program [12] on Pentium 4 computer. Activation parameters were calculated by Eyring equation [13]. Molecular mechanics (employing the MM2 force field) were performed with CS Chem3D Ultra 6.0 (CambridgeSoftCorp.). Chemical shifts were determined within the DFT framework using a hybrid exchange-correlation functional, B3LYP, at the 6-31G(d) level as implemented in Gaussian 98 [14]. Full geometry optimizations were done at the ab initio RHF/6-31G level. All data were referred to TMS (1H and 13C) chemical shifts that were calculated at the same conditions. All calculations were run on a Pentium 4 (CPU 2.80 GHz 512 MB RAM) computer. 3. Results and discussion The complete structure elucidation of compound 1 was carried out by variety of correlation NMR methods (2D
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Fig. 2. Schematic presentation of anti (a) and syn (b) isomers of 1.
COSY-gp, 2D HSQC-gp, 2D HMBC-gp)1 and non-empirical (GIAO DFT) chemical shift calculations [15]. The HMBC key correlations between structural fragments for compound 1 are summarized on Fig. 1. There are two isomeric forms around C30 AC30 * (indolizine linkage) bond in which 1 could exist with syn and antimutual orientations of indolizine fragments (Fig. 2). According to calculations the isomeric forms of 1 should have diagnostically valuable differences in their chemical shifts for variety of nuclei (H-5, H-50 , H-60 , C-2, C-3, C10 , C-20 , C-30 , C-50 ) [10] which can be invoked for spectrastructure correlations. Both 1H and 13C experimental chemical shifts correlates well with predicted chemical shifts for syn-isomer (R2 = 0.99 and 0.93, for 1H and 13C, respectively) while for anti-isomer these correlations are essentially worse (0.84 (1H) and 0.87 (13C)). Thus this analysis let us to conclude that in solution 1 exists as syn-isomer (Fig. 2). This finding was also supported by X-ray results in solid-state. Therefore hereinafter syn-isomer is meant for 1 unless otherwise specified. As it was mentioned above there are essential broadened almost all signals in 1H and 13C spectra of 1 at room temperature in DMSO. Particularly, for quinoxaline moiety and of CH2 groups of crown ether there are extensive broad signals in 1H spectra, probably due to the exchange process in which 1 is involved. When temperature increase (up to 323 K) almost all lines in 1H spectrum become sharp (Fig. 3). It is important to note that in resulted spectrum the geminal protons of each CH2 groups of spacer are not equivalent (see Supplementary materials). Hence the compound 1 may be in fast (in NMR time scale) notmutual exchange of the forms at least one of which is not symmetrical. In general, for 1 there might be three main conformers generated by rotation around the C20 AC3 bonds between Ind and Qx fragments (Fig. 4). In each form there is an additional conformational variety due to different geometry of the flexible spacer. One of the forms is symmetrical (SYM, Fig. 4(a)) in which two Ind and Qx fragments can be superimposed by C2 operation (rotation around the axis 1
All details can be found in Supplementary material.
91
perpendicular to Ind linkage C30 AC30 * bond). Rotation of one of Qx groups (either Qx1 or Qx2) around one of the C20 AC3 bonds by ca. 180° produces non-symmetrical structure (NSYM, Fig. 4(b)), while rotation of both quinoxaline fragments (Qx1 and Qx2) theoretically should generates another symmetrical form (SYM*, Fig. 4(c)) although the last one is obviously unstable due to sterical hindrance of the Qx1 and Qx2 moieties. Thus we can conclude that in the title macrocycle two groups of conformers can be expected in solution with different orientation of quinoxaline cycles, SYM and NSYM, and some variation of fine geometry of spacer (Fig. 4). Final proof of conformational structures of 1 and their equilibrium in solution was carried out by several theoretical and NMR methods. 3.1. Calculations Initial geometries of 1 in SYM and NSYM forms were obtained by screening of the sterically allowed geometries of spacer and these structures were optimized then by molecular mechanics (MM2). Four low energy conformers both for SYM and NSYM orientations of around C20 AC3 and C20 *AC3* bonds in range of 2 kcal/mol of the lowestenergy conformer were selected for further analysis. Molecular dynamics simulations of structures 1 yielded no additional geometries, thus confirming that the MM calculations had generated all feasible low energy conformations. To confirm that the above results were not simply due to limitations of the empirical methods, we also performed ab initio calculations. The optimization of the geometry in frame of HF method produces in general similar to MM structures and energies of the conformers (Table 1, Fig. 5). Moreover, difference in dipole moments implies that some small perturbation in energies can be expected in solution. Because the energies of the SYM and NSYM forms are close, the equilibrium between them might be altered by temperature changes; the shifts in equilibrium could be followed by 1H and 13C NMR spectroscopy. Moreover, if the rate of rotamer interconversion is slow on the NMR time scale, it may be possible to distinguish conformers in which some groups are shielded from those in which they are not. The conformational equilibrium of 1 could thus be probed, and the thermodynamic parameters of this equilibrium established. It should also be possible to quantitatively correlate NMR chemical shifts with the geometric parameters of the individual conformers. 3.2. NMR results To run low temperature experiments the solution of 1 in DMF was prepared. The effects of varying the probe temperature (T) were significant (Fig. 6) as suggested by our calculations. Between 303 and 243 K the signals in 1H NMR spectra were broadened. Particularly extensive coalescence is
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Fig. 3. 1H NMR spectra of 1 in DMSO at T = 323 K.
Fig. 4. Schematically presentation of the main conformer’s geometries of 1.
observed for spacer and quinoxaline protons. Finally at 213 K the spectra represents a set of sharp multiplets and lines of different intensities, indicating that a chemical exchange process affecting these signals is slow in NMR time scale. It is particularly interesting that at 213 K for some of the well separated protons three set of signals of similar intensities are clearly observed (e.g. H-7, H-60 , H70 ). This finding led us to suppose that there are three sets
Table 1 RHF/6-31G//RHF/6-31G energies (kcal/mol) and dipole moments (D) for 1 in the stable conformations Non-symmetrical structure E, kcal/mol (l, D)
Symmetrical structure E, kcal/mol (l, D)
0 (3.99) 3.0 (2.07) 3.76 (6.99) 12.9 (5.65)
0.1 1.8 2.4 3.9
(3.88) (4.07) (4.01) (4.62)
Fig. 5. SYM (a) and NSYM (b) forms of 1.
of signals for all protons that are in slow exchange at T = 213 K. Indeed, three benzo fragments of quinoxaline, three benzo fragments of indolizine, three phenyls and three (half) oxipentene spacers were distinguished by joint analysis of 2D COSY/HSQC spectra at T = 213 K and 13C at T = 333 K (Fig. 7 and Supplementary materials). Room temperature 13C chemical shifts differ only slightly from low temperature ones for these fragments and almost equal integral intensities of three sets of signals for several protons at low temperature imply that at T = 213 K 1H NMR spectra correspond to superposition of spectra of three units equal to half of the title macrocycle 1. The two units with strong differentiating 1H and 13C chemical shifts of corresponding nuclei (e.g. C2 vs C2*, etc.) can be ascribed to non-symmetrical conformation of macrocycle (NSYM) while third unit in which two halves of the molecular are equivalent in NMR spectra can be assigned to symmetrical conformation (or set of conformation due to different geometry of spacer, SYM) in which these halves are magnetically equivalent. Thus we can conclude that we deal with two component equilibrium of the forms (or set of the forms differentiating by spacer geometry), dominant form being non-symmetrical (ca. 67%) while minor form being symmetrical with population about ca. 33%. Comparison of theoretical versus experimental chemical shifts gives an additional support to structures of minimum energy conformers (RHF/6-31G). Both semi-classical model of anisotropic shielding effects (ASE) [16] and nonempirical calculations of chemical shifts [15] predict effects of diagnostic value in the NSYM conformation while in SYM no such strong effects are expected. For example,
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Fig. 6. 1H NMR spectra of 1 in DMFA at different temperatures (solvent signals are marked by asterisks. The ‘‘s” and ‘‘n” correspond to SYM and NSYM conformers, respectively). Results of simulation exchange spectra for H-60 protons are also shown nearby with corresponding rate constants.
according to ASE calculations high field shifts in 1H due to aromatic rings have to be observed for some protons in one half of NSYM conformer (H-5 (NSYM1) – 0.52 ppm, H-8 (NSYM2) – 0.2 ppm, CH2-1 (NSYM2) – 0.5 and 1.4 ppm, respectively, for geminal protons, Fig. 8). Rest of the protons should not be notably influenced by aromatic rings. This is in qualitative agreement with remarkable high field shifts observed for these protons in one half of the molecule versus protons of another half (Fig. 8, H-5 (NSYM1) – 0.5 ppm, H-8 (NSYM2) – 0.26 ppm, CH2-1 (NSYM2) – 1.46 ppm). Moreover, the protons in non-shielded half of NSYM conformer are very similar to protons in SYM conformer. Barrier data are also in line with the above conclusion. Full line shape analysis [13] was carried out at T = 273– 233 K (Fig. 6, Eyring plot is in Supplementary materials). It was found that the experimental barrier (DH#) is ca. 2 12 kcal/mol ðDG# 243 ¼ 12:7 kcal=molÞ. To estimate the theoretical barrier of interconversion we calculated energy profile for rotation around IndAQx bond for model acycle system, 2 (Fig. 9). Full energy optimization (at the HF/631G level) except restraint around C20 AC3 bond (dihedral drive with an increment of 10°) reveals two minima, corre2 Unfortunately, full line shape calculations of three exchanging ABX spin systems (H50 , H60 , H70 ) are beyond our computational facilities. Therefore for simplicity reason each triplets were approximated by singlets and simulations were carried out for three site exchange.
sponding to SYM and NSYM conformers of 2, and two transition states on the profile (Fig. 9) with barrier to interconversion equal to 12.4 kcal/mol. Thus good agreement between experimental and calculated barrier additionally proves that the rotation around IndAQx bond is responsible for observed extensive line shape evolution of the spectra as temperature changes. Deviation in calculated energy difference between SYM and NSYM conformations for 2 vs 1 can be well explained by short spacer restrains geometry into NSYM conformation in macrocycle. Finally, an additional support to theoretical structure was obtained from NOE’s measurements [17] at T = 213 K. Unfortunately, due to size of the molecule and low temperature the correlation time is such as xsc < 1 and therefore all NOE’s in 2D NOESY spectra are positive [11,18]. Several NOE’s are appeared due to direct dipole–dipole interactions and due to chemical (conformational) exchange as well [18]. In order to separate these effects the ROESY experiments were also carried out where these effects are of different sign. Comparative analysis of these experiments (Fig. 10) led us to reveal important indications of proposed geometry. First of all, cross-peaks due to chemical exchange can be directly distinguished from 2D ROESY spectra (e.g. H-5 (NSYM1), H-5 (NSYM2) and H-5 (SYM); H-6 (SYM) and H-6 (NSYM1), H-6 (NSYM2); H-60 (SYM) and H-60 (NSYM1), H-60 (NSYM2), Fig. 10). Then variety NOEs
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Fig. 7. Fragments of 2D HSQC spectra at T = 213 K (1D 13C spectra at T = 333 K [due to low solubility at low temperature 1D 13C spectra at T = 213 K was not measured]): low (a) and high (b) filed (13C) regions.
due to dipole–dipole interactions were assigned. The most important are ‘‘non-trivial” NOEs due to the close proxim-
ity of the protons that are not close in chemical sense (nor geminal neither vicinal) but due to folding. Thus, for exam-
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ple cross-peaks between CH2-2 (NSYM1), CH2-3 (NSYM1) and H-200 /600 , H-300 /500 (NSYM2) (Fig. 11) can be attributed to NSYM conformation. Unfortunately, as it was expected for SYM form there is no ‘‘non-trivial” effects. To sum it up, these experiments demonstrates that 1 exists in conformational exchange of its forms and one of which is NSYM with geometry leading to ‘‘non-trivial” NOE’s.
Fig. 8. Chemical shift differences (d(NSYM1) d(NSYM2)) for some asymmetric protons in NSYM conformation of 1.
3.2.1. Final remarks Stabilization of NSYM conformation, probably, is due to the p–p interactions of two Qx fragments or due to hydrogen bond between C@O and protonated NH groups (Qx). The unstability of SYM conformation is conditioned
Fig. 9. Energy profile for 2 obtained for the IndAQx bond rotation at the HF/6-31G level of theory.
Fig. 10. (a) 2D ROESY and (b) 2D NOESY spectra (sm = 0.6 s) of 1 at T = 213 K. Cross peaks due to exchange are in squares and some principal peaks due to dipole–dipole interactions are shown in ovals.
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and materials (CKP SAC) and Federal CKP for physical and chemical investigations of matter and materials (FCKP PCI) (state contracts of the Russian Federation Ministry of education and science No. 02.451.11.7036 and 02.451.11.7019). Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.molstruc. 2008.01.032. References
Fig. 11. ‘‘Non-trivial” NOE’s and their correlation with the structure of NSYM conformation.
by electrostatic repulsive interactions of carbonylic groups ˚ ). (C@OAC@O distance 3.18 A Perhaps, conformational equilibrium can be tuned by the introduction of polar group into Qx moiety or by the changing of pH solution because the protonated nitrogen well situated to interact with carbonyl group to stabilize NSYM conformer. Seems, these are the ways to rationally modify the population of the forms with different mutual orientation of chromophoric groups and it might be subject of future investigations. 4. Conclusion Thus, we can conclude that in solution the title macrocycle exists in conformational equilibrium due to rotation around indolizinie–quinoxaline linkage. In the main nonsymmetrical conformer (ca. 67%) two quinoxaline rings are non-symmetric while in minor symmetrical one (ca. 33%) these fragments are equivalent. In both conformers mutual orientation of two indolizine rings is synperiplanar. Acknowledgements Financial support from the RFBR (No. 05-03-32558-a), one of us (Sh.L.) acknowledges Russian Science Support Foundation for doctoral Grant. This investigation was carried out in NMR department of the Federal Collective Spectral Analysis Center for physical and chemical investigations of structure, properties and composition of matter
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