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Spectroscopic and theoretical study on peramine and some pyrrolopyrazinone compounds
Vibrational Spectroscopy 49 (2009) 265–273
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Vibrational Spectroscopy journal homepage: www.elsevier.com/locate/vibspec
Spectroscopic and theoretical study on peramine and some pyrrolopyrazinone compounds A.T. Dubis a, A. Łapin´ski b,* a b
Institute of Chemistry, University of Bialystok, Al. Pilsudskiego 11/4, 15-443 Bialystok, Poland Institute of Molecular Physics, Polish Academy of Sciences, ul. Smoluchowskiego 17, 60-179 Poznan, Poland
A R T I C L E I N F O
A B S T R A C T
Article history: Received 17 June 2008 Received in revised form 8 October 2008 Accepted 8 October 2008 Available online 21 October 2008
The comparative analysis of IR and Raman spectra of peramine and its four derivatives in solid state was carried out. The harmonic vibrational frequencies, infrared intensities, and Raman scattering activities were calculated at density functional B3LYP methods with 6-311++G(d,p) basis set. For the predicted spectra, a potential energy distribution of normal modes was also calculated. For peramine derivatives the conjugation effect of pyrrole with pyrazinone ring was observed as a result of introduction of double bond. Moreover, 1H NMR analysis indicated that pyrrole protons are deshielded in comparison with the pyrrolopyrazinone model ring system. ß 2008 Elsevier B.V. All rights reserved.
Keywords: Peramine Antifeedants DFT calculations IR and Raman spectroscopy NMR spectroscopy
1. Introduction Peramine is the main secondary metabolite produced by perennial ryegrass (Lolium perenne L.) fungal endophyte [1]. This compound belongs to insect feeding inhibitors which protect the plant against grazing by insect. It is known that some other grass fungal metabolites, e.g. loritrem B and ergovaline [2], also act as antifeedant agent [3] but they are unfortunately toxic to herbivore animals such as cattle [4,5]. These fungal metabolites commonly act as neurotoxins. Among them the most interesting properties may be ascribed to peramine [6]. This compound deters feeding by insects, and has no toxic effect on mammals. Peramine is known to deter herbivores insects by attacking their taste sensors [7]. The mechanism of inhibition effect is complex, however it was found, that insects exposed to antifeedant substances, usually starved ceasing to consume leaves. Furthermore, exposure of larvae to feeding deterrent resulted in loss of their reproductive ability [8]. One can say that plants employ alkaloids as bioprotective substances which have a major impact on regulating terrestrial food webs [9]. As a consequence the peramine-infected pastures are safe for livestock grazing ryegrass. Such properties of peramine classify it to the environmental friendly insecticide. Synthetic peramine (1) and
* Corresponding author. Tel.: +48 61 869 52 79; fax: +48 61 868 45 24. E-mail address: [email protected] (A. Łapin´ski). 0924-2031/$ – see front matter ß 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.vibspec.2008.10.002
its propyl-substituted analogs 2–4 were also tested for their antifeedant effect on storage pests [10] and also showed some activities (Scheme 1). Peramine is still in the field of scientific interests and recently has been successfully determined, at trace level, in the cut plant fluid using high sensitive LCMSMS spectrometry [11]. In spite of biological importance of peramine, no attention has been given to its vibrational spectra until now. Thus, the aim of this paper is meticulous study of vibrational spectra of the title compounds, because it might allow detection of peramine related compounds in their natural environment. Peramine (1) and compounds 2–4 consist of the flat 2methylpyrrolo[1,2-a]pyrazin-1(2H)-one ring system substituted with the side chain. The three sp3CH2 groups and X moiety of the substituent can rotate, and thus one can expect a variety of structures. However, the interaction among the hydrogen or other atoms leaves certain internal rotational (dihedral) angles preferred on energetic grounds, as in the case of a small molecule. The molecules under consideration may possess a variety of structures, but certain conformations are preferred because it offers the least interaction. In case of substituted carbon chain the anti or gauche conformers are expected as an example of more general phenomenon, known as the gauche effect. Thus the relative abundances of the expected conformations decrease considerably. Nevertheless, for such complex structures, in order to state with certainty which conformer is present in the solid state, the X-ray diffraction measurements are indispensable. The crystal structure
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solvents were dried and freshly distilled. During the synthesis unexpected product 5-chloro-2-oxopentyl 1-(5-chloro-2-oxopentyl)pyrrolo-2-carboxylate (PDKE) was obtained with high yield (70%); a characterization of this compound will be described elsewhere. 1H and 13C NMR spectra were recorded using NMR Spectrometer Bruker Avance II 400 MHz using DMSO solution with TMS as an internal standard. The results of these investigations for peramine and its derivatives are presented below.
Scheme 1.
data have revealed that the flat conformation is present exclusively in the solid state. To extend our conformational consideration, the theoretical calculations were performed. The geometry optimization was performed for all investigated compounds by restricting the side chain to the rings plane (Fig. 1a) and for bent side-chain position (Fig. 1b). The results of the calculations reveal that the most stable conformation is associated with the bent arrangement of the side chain with respect to the ring’s plane. We have found that the difference in energy between these rotameric forms is rather small (less than 0.3 kcal/mol). A similar trend was obtained for compounds 2, 3, and 4. For these molecules the bent conformation is also more stable than the flat form. The transformation of the planar into bent conformation was investigated and described elsewhere in detail [12]. For complex molecular structure such as peramine many conformations are possible and designating all possible structures using theoretical methods could be very time consuming. In such cases X-ray data are necessary to avoid any mistakes. In this work the antifeedant peramine and its derivatives have been investigated by means of FT-IR, Raman, and diffuse reflectance IR spectroscopy. The quantum-mechanical calculations at DFT/6-311++G(d,p) level of theory were performed for flat conformation derived from crystallographic data. The comparison between the theoretical and experimental spectra was made for determination of the characteristic absorptions of each moiety. This is the first time such spectroscopic data are reported, to the best of our knowledge. 2. Methods 2.1. Experimental Peramine and other pyrrolopyrazinone derivatives were synthesized by the Dumas method [13]. Before the synthesis all
2.1.1. Peramine (1) (3-(1,2-dihydro-2-methyl-1-oxopyrrolo[1,2a]pyrazon-3-yl)propyl)guanidine 1 H NMR (DMSO) d ppm: 7.31 (d, 1H, Ar–H), 7.24 (s, 1H, C–H), 6.83 (d, 1H, Ar–H), 6.51 (dd, 1H, Ar–H), 3.34 (s, 3H, –CH3), 3.17 (t, 2H, –CH2–), 2.57 (t, 2H, –CH2–), 1.75 (m, 2H, –CH2–). 13 C NMR (DMSO) d ppm: 157.2 (C); 156.6 (C O); 128.1 (C); 122.5 (C); 118.7 (CH); 112.3 (CH); 109.1 (CH); 106.3 (CH); 40.3 (CH2); 29.0 (CH3); 27.3 (CH2); 27.0 (CH2). 2.1.2. 3-(3-Aminopropyl)-2-methylpyrrolo[1,2-a]pyrazin-1-(2H)one (2) 1 H NMR (DMSO) d ppm: 7.33 (dd, 1H, Ar–H), 7.23 (s, 1H, C–H), 6.81 (d, 1H, Ar–H), 6.49 (dd, 1H, Ar–H), 3.36 (s, 3H, –CH3), 2.63 (t, 2H, –CH2–), 2.57 (t, 2H, –CH2–), 1.62 (tt, 2H, –CH2–). 13 C NMR (DMSO) d ppm: 156.0 (C O); 128.8. (C); 122.3 (C); 118.1 (CH); 111.7 (CH); 108.4 (CH); 105.5 (CH); 40.8 (CH2); 31.5 (CH2); 28.5 (CH3); 27.0 (CH2). 2.1.3. 3-(3-Chloropropyl)-2-methylpyrrolo[1,2-a]pyrazin-1-(2H)one (3) 1 H NMR (DMSO) d ppm: 7.36 (dd, 1H, Ar–H), 7.28 (s, 1H, C–H), 6.83 (dd, 1H, Ar–H), 6.51 (dd, 1H, Ar–H), 3.75 (t, 2H, –CH2–), 3.38 (s, 3H, –CH3), 2.69 (t, 2H, –CH2–), 2.03 (m, 2H, –CH2–). 13 C NMR (DMSO) d ppm: 155.9 (C O); 127.4 (CH); 122.4 (C); 118.3 (CH); 111.7 (CH); 108.6 (CH); 105.9 (CH); 44.5 (CH2); 30.6 (CH2); 28.6 (CH3); 27.0 (CH2). 2.1.4. 3-Propyl-2-methylpyrrolo[1,2-a]pyrazin-1-(2H)-one (4) 1 H NMR (CDCl3) d ppm: 7.04 (m, 2H, Ar–H), 6.74 (s, 1H, C–H), 6.46 (dd, 1H, Ar–H), 3.60 (t, 2H, –CH2–), 3.38 (s, 3H, –CH3), 2.39 (t, 2H, –CH2–), 1.51 (dt, 2H, –CH2–); 0.95 (t, 3H, –CH3). 13 C NMR (DMSO) d ppm: 157.2 (C O); 128.4. (CH); 123.0 (C); 117.3 (CH); 112.0 (CH); 109.4 (CH); 105.9 (CH); 32.6 (CH2); 28.9 (CH3); 21.5 (CH2); 13.6 (CH3). 2.1.5. 2-Methyl-3,4-pyrrolo[1,2-a]pyrazin-1-(2H)-one (5) 1 H NMR (DMSO) d ppm: 6.95 (dd, 1H, Ar–H), 6.61 (dd, 1H, Ar– H), 6.13 (dd, 1H, Ar–H), 4.16 (m, 2H, –CH2–), 3.63 (m, 3H, –CH2), 2.96 (s, 3H, –CH3).
Fig. 1. Two conformations of peramine: flat (a) and bent (b) form.
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13 C NMR (DMSO) d ppm: 159.0 (C O); 124.4 (C); 123.2 (CH); 111.6 (CH); 108.8 (CH); 47.3 (CH2); 42.9 (CH2); 33.2 (CH3).
Table 1 Crystal and structure refinement for 3-(3-chloropropyl)-2-methylpyrrolo[1,2a]pyrazin-1-(2H)-one (3).
2.1.6. 5-Chloro-2-oxopentyl 1-(5-chloro-2-oxopentyl)pyrrolo-2carboxylate (PDKE) IR (KBr) n cm1: 3122, 1730, 1702, 1530, 1422, 1380, 1330, 1259, 1127, 1085, 751, 674. 1 H NMR (CDCl3) d ppm: 7.14 (m, 1H, Ar–H), 6.84 (q, 1H, C–H), 6.26 (q, 1H, Ar–H), 5.05 (s, 2H, –CH2–), 4.74 (s, 2H, –CH2), 3.60 (m, 2H, –CH2–), 2.70 (m, 4H, –CH2–); 2.10 (m, 4H, –CH2). 13 C NMR (CDCl3) d ppm: 203.7 (C O), 203.3 (C O), 160.3 (C O); 130.3 (CH); 121.0 (C); 119.4 (CH); 109.2 (CH); 67.7 (CH2); 57.9 (CH2); 44.2 (CH2); 44.1 (CH2); 36.0 (CH2); 35.4 (CH2); 25.9 (CH2); 25.8 (CH2).
Formula
C11H13ClN2O
M Crystal system Space group Unit cell dimensions (A˚)
224.68 Triclinic P 1¯ a = 7.1604(11) b = 7.3933(8) c = 10.9859 79.063(9) 71.649(11) 70.607(12) 518.33(11) 2 1.440 0.5 0.35 0.1 0.341 100(2) 0.71073 9 h 9 9 k 9 14 l 14 9616 2377 0.0132 1.123 2377 0.0279 0.0777 0.0251 0.0765 0.281 0.326
2.2. Vibrational spectroscopy The infrared spectra of 1–5 were investigated at room temperature, in KBr pellets containing dispersed compounds. The FT-IR absorption spectra were recorded in the range between 250 and 7000 cm1 with Nicolet Magna IR 550 Series II and Bruker Equinox 55 FT-IR spectrometers. These data were completed with diffuse reflectance spectra recorded in the spectral range from 400 to 7000 cm1 with a PerkinElmer 1725X FT-IR spectrometer equipped with a special accessory. The diffuse reflectance spectra were elaborated according to the Kubelka–Munk procedure. The Kubelka-Munk theory allows the prediction of spectral reflectance for a mixture of components that have been characterized by absorption K and scattering S coefficients [14], which are related to the fundamental optical coefficients for absorption e and scattering s [15]. Raman scattering of the light in the range from 50 to 4000 cm1 was investigated with a Jobin Yvon HORIBA LabRAM HR 800 confocal spectrometer with a liquid-N2-cooled charge coupled device (CCD) and two lasers: Stabilite 2017 (Ar+ ion laser) and He– Ne. The laser power of 633, 514, and 488 nm wavelength, before focusing with 100 objective was less than 8 mW. Moreover, the Raman spectra of peramine were recorded with a Renishaw System 1000 microspectrometer with excitation beam from a laser Lexel 3500 (l = 568 nm, less than 10 mW power was at the sample). Notch filters were used for stray light rejection. The position of Raman peaks was calibrated using a Si thin film as an external standard. The Raman spectra of polycrystalline samples 1–5 were recorded at room temperature in back-scattering geometry. The spectral resolution of IR and Raman spectra was 2 cm1. 2.3. X-ray data collection and structure refinement All measurements of crystalline sample 3 were performed on a KM4CCD k-axis diffractometer with graphite-monochromated Mo Ka radiation. The crystal was positioned at 62 mm from the CCD camera. 1496 frames were measured at 0.88 intervals with a counting time of 20 s. The data were corrected for Lorentz and polarization effects. Multi-scan absorption correction has been applied. Data reduction and analysis were carried out with the Oxford Diffraction programs [16]. The structure was solved by direct methods [17] and refined using SHELXL [18] and WinGX Program System [19]. The refinement was based on F2 for all reflections except those with very negative F2. Weighted R factors wR and all goodness-of-fit S values are based on F2. Conventional R factors are based on F with F set to zero for negative F2. The Fo2 > 2sðFo2 Þ criterion was used only for calculating R factors and is not relevant to the choice of reflections for the refinement. The R factors based on F2 are about twice as large as those based on F. Most of hydrogen atoms were located from a differential map and refined isotropically, except of disordered hydrogens in methyl
a (8) b (8) g (8) V (A˚3) Z Dx (Mg m3) Crystal size (mm) m (mm1) T (K) l (A˚) Index ranges
No. of data collected No. of unique data Rint Goodness-of-fit on F2 No. of parameters R1 (all data) wR2 (all data) R1 [I > 2s(I)] wR2 [I > 2s(I)] Drmin (e A˚3) Drmax (e A˚3)
group. Those were located geometrically and their positions and temperature factors were not refined. Scattering factors were taken from Tables 6.1.1.4 and 4.2.4.2 in International Tables for Crystallography [20]. A summary of crystallographic relevant data is given in Table 1. 2.4. Computational method To study the vibrational properties of peramine and its derivatives the theoretical calculations were performed with Gaussian 03 program [21] using 6-311++G(d,p) basis set at the hybrid Hartree–Fock density functional (B3LYP). These calculations were performed on stable flat conformer of pyrrolopyrazinone molecules 1–5 [12]. In all these cases the side chain lies at the same plane as the pyrrolopyrazinone ring (Fig. 1a). The initial geometry of the investigated compounds was taken from X-ray data and applied in the geometry optimization job. The results of optimizations correspond to energy minima since no imaginary frequencies were found. On the basis of optimized structures, vibrational frequencies and both infrared and Raman intensities were calculated. The computed frequencies were multiplied by a uniform factor 0.98 to obtain a good estimate of the experimental results. The scale factor used in the present work is very close to that recommended for B3LYP/6-311++G(d,p) calculations [22]. It is worth to notice that frequencies computed with a quantum harmonic oscillator approximation tend to be higher than experimental ones. The exception is the low frequencies, which are often quite far from the experimental values [23]. The potential energy distribution (PED) analysis of normal modes was used in terms of natural internal coordinates [24]. The VEDA 4.0 program (vibrational energy distribution analysis) [25] was applied in our calculations (see Electronic Supplementary Material, Tables S1– S5). The related methodology has been published elsewhere [26].
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Since only Raman scattering activities are obtained from the Gaussian calculations, the theoretical Raman intensities were calculated from scattering activities and calculated wavenumbers [27,28]. One should notice that all theoretical predictions were performed for the isolated molecules in gas phase, in which it is reasonable to assume that there is no interaction with the other molecules. The experimental spectra of peramine derivatives are recorded for solid state where the interaction between the molecules is not negligible. Nevertheless, one can find that the agreement between experimental and theoretical spectra is satisfactory. In case of peramine and its amino derivative (2), some differences between experimental and theoretical spectra are due to hydrogen bond interaction between of N–H proton donator group and proton acceptor carbonyl group. 3. Results and discussion Peramine (1) belongs to the pyrrolopyrazinone alkaloids containing 2-methylpyrrolo[1,2-a]pyrazin-1(2H)-one ring system together with a monosubstituted guanidino group [29]. This 1oxo-2,3-disubstituted structure was modified by introduction of different polarity substituent groups (compounds 2–4). Additionally, pyrrolo[1,2-a]pyrazinone (5) model ring system was also investigated in this work. The IR and Raman experimental and theoretical spectra of peramine (1) and compounds 2–4 are presented in Figs. 4–7; the results of ab initio calculations and experimental data are available in Electronic Supplementary Material. 3.1. Crystal structure of 3-(3-chloropropyl)-2-methylpyrrolo[1,2a]pyrazin-1-(2H)-one (3) Table 2 presents X-ray bond lengths and bond angles (with esd’s) of 3-(3-chloropropyl)-2-methylpyrrolo[1,2-a]pyrazin-1(2H)-one (3) molecule. The crystallographic labeling scheme and crystal packing are shown in Figs. 2 and 3, respectively. Compound 3 consists of two rings arranged in one plane and a side arm oriented in the rings’ plane. The aliphatic chain adopts a nearly planar conformation. Dihedral angle N1–C6–C9–C10 defined between the mean plane of aliphatic chain and pyrrolopyrazinone ring is 179.92(8)8 while a calculated value is 179.9968. Furthermore, it was observed that alkane chain adopts staggered arrangement in which all C–H bonds are as far away from one another as possible. It is also worth to notice that the bond lengths
Fig. 2. ORTEP plot and labeling scheme for 3-(3-chloropropyl)-2methylpyrrolo[1,2-a]pyrazin-1-(2H)-one (3). Displacement ellipsoids are drawn at the 50% probability level. Hydrogen atoms of methyl C8 group are disordered in crystal structure over two equal positions. The H8a, H8b, H8c belong to one component of disorder, while H8d, H8e, H8f to the other.
Table 2 Experimental X-ray values of bond distances (A´˚ ), bond angles and dihedral angles (degrees) for non-hydrogen atoms of molecule 3; estimated standard deviations are given in parentheses and the labeling scheme is presented in Fig. 2. N(1)–C(1) N(1)–C(6) N(1)–C(8) C(1)–O(1) C(1)–C(7) C(2)–C(7) C(2)–C(3) C(3)–C(4) C(4)–N(2) C(5)–C(6) C(5)–N(2) C(6)–C(9) C(7)–N(2) C(9)–C(10) C(10)–C(11) C(11)–Cl(1) C(1)–N(1)–C(6) C(1)–N(1)–C(8) C(6)–N(1)–C(8) O(1)–C(1)–N(1) O(1)–C(1)–C(7) N(1)–C(1)–C(7) C(7)–C(2)–C(3) C(4)–C(3)–C(2) N(2)–C(4)–C(3) C(6)–C(5)–N(2) C(5)–C(6)–N(1) C(5)–C(6)–C(9) N(1)–C(6)–C(9) N(2)–C(7)–C(2) N(2)–C(7)–C(1) C(2)–C(7)–C(1) C(4)–N(2)–C(7) C(4)–N(2)–C(5) C(7)–N(2)–C(5) C(6)–C(9)–C(10) C(11)–C(10)–C(9) C(10)–C(11)–Cl(1) C(6)–N(1)–C(1)–O(1) C(8)–N(1)–C(1)–O(1) C(6)–N(1)–C(1)–C(7) C(8)–N(1)–C(1)–C(7) C(7)–C(2)–C(3)–C(4) C(2)–C(3)–C(4)–N(2) N(2)–C(5)–C(6)–N(1) N(2)–C(5)–C(6)–C(9) C(1)–N(1)–C(6)–C(5) C(8)–N(1)–C(6)–C(5) C(1)–N(1)–C(6)–C(9) C(8)–N(1)–C(6)–C(9) C(3)–C(2)–C(7)–N(2) C(3)–C(2)–C(7)–C(1) O(1)–C(1)–C(7)–N(2) N(1)–C(1)–C(7)–N(2) O(1)–C(1)–C(7)–C(2) N(1)–C(1)–C(7)–C(2) C(3)–C(4)–N(2)–C(7) C(3)–C(4)–N(2)–C(5) C(2)–C(7)–N(2)–C(4) C(1)–C(7)–N(2)–C(4) C(2)–C(7)–N(2)–C(5) C(1)–C(7)–N(2)–C(5) C(6)–C(5)–N(2)–C(4) C(6)–C(5)–N(2)–C(7) C(5)–C(6)–C(9)–C(10) N(1)–C(6)–C(9)–C(10) C(6)–C(9)–C(10)–C(11) C(9)–C(10)–C(11)–Cl(1)
1.3841(14) 1.4118(13) 1.4669(13) 1.2359(13) 1.4441(15) 1.3855(15) 1.4078(16) 1.3827(15) 1.3696(14) 1.3441(15) 1.3932(13) 1.5048(14) 1.3864(13) 1.5227(14) 1.5142(14) 1.8064(12) 122.83(9) 115.80(9) 121.30(9) 121.45(10) 122.64(10) 115.91(9) 106.95(9) 108.46(10) 107.42(9) 119.72(9) 120.07(9) 122.90(9) 117.03(9) 107.73(9) 119.94(9) 132.33(10) 109.43(9) 129.08(9) 121.45(9) 113.85(9) 112.62(9) 112.33(8) 177.36(9) 0.50(15) 2.26(14) 179.13(9) 0.19(12) 0.32(12) 0.91(15) 178.55(8) 0.05(15) 176.75(9) 179.54(9) 3.76(14) 0.01(11) 179.26(11) 176.03(9) 3.59(14) 3.18(18) 177.20(10) 0.33(11) 177.46(9) 0.21(11) 179.17(9) 177.77(9) 2.84(14) 178.07(10) 0.51(15) 0.60(14) 179.92(8) 176.94(8) 69.42(10)
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Fig. 3. Layered structure of 3 viewed along the b axis. Note: hydrogen atoms of methyl group are disordered in crystal structure over two equal positions.
within pyrrole ring of compound 3 are very close to the experimental values of bond distances of the pyrrole in gas phase (microwave data) [30] and to the calculated values obtained in the optimized structure [31]. The C3–C4, C4–N2, N2–C7, C7–C2 and C2–C3 bond lengths for molecule 3 are equal to 1.383, 1.369, 1.386, 1.385, and 1.408 A˚, respectively.
ing also contributes to this band. However, the observed intensity of this band is not as large as theoretically predicted (Figs. 4–7). The second prominent band was observed in the range 1608– 1624 cm1. This band is mainly due to C C stretching vibration but calculations predicts that also C O stretching contributes to this band. In the experimental spectra of compounds 3 and 4, the
3.2. Experimental and calculated frequencies related to C O and C C stretching vibrations The experimental and theoretical IR and Raman spectra of the peramine (1) and compounds 2–4 are presented in Figs. 4–7. The results of ab initio calculations for the vibrational spectra of the molecules under study and their experimental data are available as Supporting Material. Our extensive investigation of the infrared and Raman spectra of peramine and its derivatives leads to proper description of their spectroscopic properties. The most significant and valuable absorption bands appear in the region 1800–1600 cm1. These bands are mainly due to the presence of carbonyl groups, olefinic systems and scissoring vibration of NH2 group. The carbonyl group is important and its characteristic frequencies have been used to study a wide range of compounds [32]. The absorption caused by C O stretching is generally very strong, whereas the nC C bands are of variable intensity, but usually are substantially less intense than those from C O stretching vibrations. The differentiation between these two kinds of stretching modes could be provided easily by using theoretical calculations and both infrared and Raman spectra [33]. Since the Raman scattering is a function of change in polarizability of molecules, the symmetric vibrations give the most intense Raman scattering. It is in contrast to infrared absorption where dipole change gives intensity and asymmetric vibrations are intense. The positions of carbonyl nC O bands and double bond nC C bands of all analyzed here compounds are collected in Table 3. Both peramine and the other compounds 2–4 exhibited an absorption band within the range 1667–1676 cm1. According to the structural features and theoretical calculations (see Table 3), this band was thought to be mainly derived from the carbonyl group. Position of this band at the lower end of the carbonyl frequency range, implies the C O group is in conjugation with the aromatic p-electron system leading to reduced C O double bond character. Furthermore, our calculations predict that C C stretch-
Fig. 4. Absorption and diffuse reflectance spectra (upper panel) and calculated IR spectra (lower panel) of 1 (a). Experimental and calculated Raman spectra of 1 (b). Note: the level of theory was B3LYP/6-311++G(d,p), the bands are labeled as indicated in Electronic Supplementary Material—Table S1, the Raman spectra of 1 were recorded with 568 and 633 nm excitations.
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Fig. 5. Absorption and diffuse reflectance spectra (upper panel) and calculated IR spectra (lower panel) of compound 2 (a). Experimental and calculated Raman spectra of 2 compound (b). Note: the level of theory was B3LYP/6-311++G(d,p), the bands are labeled as indicated in Electronic Supplementary Material—Table S2, the Raman spectra of 2 were recorded with 514 and 633 nm excitations.
intensity of this band is about 2–3 times larger than that found for the previous band. In case of peramine (1) and compound 2 the intensities of these two bands are almost equal. On the base of the above observations one can find that bands within the spectral ranges: 1667–1676 cm1 and 1608–1624 cm1 are not simple C O or C C stretching modes, but they are the result of mixing of C O and C C stretching vibrations. Fig. 8 shows the atomic displacements of these modes; na is the mode where C O and C C double bonds are stretching ‘‘out of phase’’, whereas nb is the ‘‘in phase’’ mode. It is worth to note that experimentally observed na bands for compounds 1–4 are shifted (Dn 50 cm1) to higher frequency in comparison with model compound 5. When the carbonyl-carbon is a part of a ring system, the decrease in bond angle of two sp2 hybridized orbitals results in steric strain effects. This effect causes the shift to higher values of the frequency of absorption of the carbonyl group which contributes mainly to (a mode. For compounds 1–4 analyzed here we can say that the
Fig. 6. Absorption and diffuse reflectance spectra (upper panel) and calculated IR spectra (lower panel) of compound 3 (a). Experimental and calculated Raman spectra of 3 compound (b). Note: the level of theory was B3LYP/6-311++G(d,p), the bands are labeled as indicated in Electronic Supplementary Material—Table S3, the Raman spectra of 3 were recorded with 514 and 633 nm excitations.
behavior of carbonyl and C C stretching modes are the same in nature. 3.3. Experimental and calculated frequencies related to pyrrole ring C C stretching vibration The skeletal vibration of the pyrrole ring which involves expansion and contraction of its bonds is very sensitive to substitution [34]. The condensation of a pyrrole ring with a pyrazinone ring changes these skeletal stretching modes. The stretching of C C bonds within the pyrrole ring is observed at 1527, 1533, 1530, and 1532 cm1 for compounds 1, 2, 3, and 4, respectively. The corresponding calculated frequencies are in very good agreement with the experimental data (Table 4). The predicted Raman scattering intensities correlate well with the relative intensities observed in the Raman spectrum. A similarly good correlation was observed for IR calculated and experimental
Table 3 Experimental and calculated at B3LYP/6-311++G(d,p) theory level frequency values of the nC wavenumbers; A: the absolute IR intensities; IR: the Raman intensities [27,28].
O
and nC
C
modes. Note: na, nb: calculated wavenumbers; nexp: observed
Compound
nexp (cm1)
na (cm1)
A (km/mol)
IR arbitrary units
nexp (cm1)
nb (cm1)
A (km/mol)
IR arbitrary units
1 2 3 4 5
1667 1676 1674 1673 1625
1690 1689 1691 1689 1678
444.7 432.8 441.5 436.3 387.4
21.4 22.9 23.8 19.4 66.0
1608 1616 1624 1624
1658 1659 1659 1658
114.8 128.1 116.9 123.3
231.6 268.9 285.6 262.1
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Fig. 9. Experimental 1H NMR spectrum of peramine (1).
electron density and therefore such protons are much more deshielded (Table 5, Fig. 9). They are shifted downfield in comparison with compound 5. The observed interrelation between chemical shifts and vibrational frequency changes leads to a conclusion that conjugation effect is present within these ring systems. pyr pyraz 3.4. Carbon–nitrogen nCN , nCN skeletal vibrations of pyrrolopyrazinone ring
Fig. 7. Absorption and diffuse reflectance spectra (upper panel) and calculated IR spectra (lower panel) of compound 4 (a). Experimental and calculated Raman spectra of 4 compound (b). Note: the level of theory was B3LYP/6-311++G(d,p), the bands are labeled as indicated in Electronic Supplementary Material—Table S4, the Raman spectra of 4 were recorded with 488 and 633 nm excitations.
intensities. The C C stretching vibration of pyrrole ring in compound 5 gives rise to the absorption band at 1548 cm1. One can see, that for compounds 1–4, an introduction of double bond into pyrazinone ring lowers the pyrrole C C stretching vibration in comparison with compound 5. The observed red shifts are associated with conjugation of pyrrole with pyrazinone ring and one could say that there was a reduction of these double bond characters. Additional support for such conjugation is provided by NMR spectroscopy. The pyrrole protons which are in conjunction with double bond electrons of pyrazinone ring, experience reduced
Fig. 8. Atomic displacements of C
O and C
A large majority of the carbon–nitrogen stretching vibrations of the aromatic systems appear as a medium-strong absorption in the region 1360–1250 cm1. The band is usually observed within fairly constant frequency but absorbance is a little higher than for saturated systems as a result of the increased strength of the carbon–nitrogen bond. For instance in the heterocyclic aromatic molecule nicotinaldehyde [35], a characteristic carbon–nitrogen stretching band was observed at 1391 cm1. For compounds 1–4 this band appears as a medium intensity absorption band at 1363, 1366, 1368, and 1364 cm1, respectively. For compound 5 this band was observed at much lower frequency at 1311 cm1. The presented experimental data are in good agreement with calculated frequencies (Table 4). The calculated values are: 1374, 1375, 1375, 1375, and 1317 cm1 for compounds 1, 2, 3, 4, 5, respectively. Generally speaking, any substitution in side chain (compounds 1–4) leaves the nCN pyrrole ring vibrational mode unshifted. Furthermore, it should be noted that association
C in vibrational modes: na—‘‘out-of-phase’’ and nb—‘‘in phase’’.
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Table 4 Experimental and calculated at B3LYP/6-311++G(d,p) theory level frequency values of the C–C and C–N pyrrolopyrazinone stretching modes. Mode
1 2 3 4 5
Pyrrole ring nC=C
Pyrrole ring nCN R
Pyrazinone ring nCN R
nexp
ncalc
I arbitrary units
ncalc (cm1)
I arbitrary units
ncalc
(cm1)
A (km/mol)
nexp
(cm1)
A (km/mol)
nexp
(cm1)
(cm1)
(cm1)
A (km/mol)
IR arbitrary units
1527 1533 1530 1532 1548
1532 1531 1533 1531 1544
11.1 10.8 12.2 10.9 88.5
77.5 85.9 86.1 84.3 39.7
1363 1366 1368 1364 1311
1374 1375 1375 1375 1317
15.4 36.2 19.9 20.2 129.5
19.5 32.1 123.6 116.9 46.7
1257 1257 1254 1252 1245
1271 1272 1271 1272 1258
58.0 56.9 62.6 58.6 11.5
3.0 5.2 7.9 2.5 11.5
Note: ncalc: calculated wavenumbers; nexp: observed wavenumbers; A: the absolute IR intensities; IR: the Raman intensities [27,28].
Table 5 Experimental 1H NMR chemical shift of the pyrrolopyrazinone hydrogen atoms (Fig. 9 shows the molecular structure and designations of atoms of peramine derivatives). Compound
1 2 3 5
1
H NMR shift (ppm)
Ha
Hd
Hc
Hb
3.38 3.36 3.38 2.96
6.83 6.80 6.83 6.61
6.51 6.48 5.51 6.12
7.35 7.32 7.35 6.95
of pyrrole ring with pyrazinone unsaturated system, as seen in compounds 1–4, leads to blue shift of this mode in comparison with compound 5. The presented results show that the calculations provide a good estimation of the npyraz frequency in pyrazinone ring. In CN comparison with the literature data, in particular in case of the study of crystal and vapor pyrazine [36], our calculated frequencies fit well to the previous assignments showing low intensity bands in the range 1136–1204 cm1. Furthermore, our calculations confirm the presence of another characteristic carbon nitrogen stretching band in the pyrrolopyrazinone system, which is experimentally observed at 1259 (1), 1257 (2), 1254 (3), 1252 (4), and 1245 cm1 (5). The position of this mode is comparable to ring C–N stretching vibration found previously for trimethylpyrazine [37]. Their calculated intensities are of medium values and much more intense than those observed in the range 1316– 1204 cm1. This leads to conclusion that the above-mentioned bands may show diagnostic values for analysis of pyrrolopyrazinone skeletal systems. 3.5. C–H out-of-plane bending vibrations (gC–H) The presence of unsaturation in a molecule gives rise to characteristic out of plane bending or wagging vibration of hydrogen atoms attached to sp2 carbon atom. These vibrations could be observed in the low frequency region of the spectrum in the range 900–600 cm1. In the case of pyrrolopyrazinone derivatives 1–5 the most prominent absorption bands in this region are derived from four kinds of vibrations: g CHpyrr ; g CH2 ; g ¼CH (1–5) and nC–Cl for compound 3. According to the theoretical calculations the more meaningful gCH mode of the pyrrole C–H bonds is not sensitive to the type of the side chain attached to pyrazinone ring (Table 4). The position of this band is 740, 747, 745, 743 cm1 for compounds 1, 2, 3, 4, respectively. The calculated values are: 726, 728, 728, and 726 cm1. Based on calculated and experimental data one could notice that the gCH out-of-plane bending mode for compound 5 appears at higher frequency of 746 cm1. The observed downshift for compounds 1–4 in comparison with compound 5 may be connected with conjugation of pyrrole and pyrazinone rings.
4. Conclusions Attempt has been made in the present work for the proper assignments of vibrational bands for the title compounds. The infrared and Raman spectra of peramine (1) and its four derivatives 2–4 were measured in solid state and band assignment was made on the basis of theoretical calculations at B3LYP/6-311++G(d,p) level. Comparison of the experimental spectra with the theoretical frequencies and relative intensities, led to a reliable assignment of vibrational bands for peramine and its derivatives. Calculated vibrational frequencies, IR intensities and calculated Raman intensities agree fairly well with experimental data. Any discrepancy noted between the observed and the calculated spectra may be due to the fact that calculations have been done on a single molecule in the gaseous state contrary to the experimental spectra recorded for solid state. On the basis of both FT-IR and 1H NMR spectroscopy it has been found that pyrrolopyrazinone rings are conjugated. Among the title pyrrolopyrazinones significantly less conjugated ring system has been detected for the compound 5. Besides, it has been observed that in the series of peramine derivatives 1–4 the ring modes are not sensitive to the type of substituent introduced into the side chain. Acknowledgements This work was supported by the Polish Committee for Scientific Research at the research project in 2006–2008. The X-ray measurements were undertaken in the Structural Research Laboratory at the Chemistry Department of the University of Warsaw. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.vibspec.2008.10.002. References [1] H.W. Zanhg, Y.Ch. Song, R.X. Tan, Nat. Prod. Rep. 23 (2006) 753. [2] M.J. Spierling, E. Davies, B.A. Tapper, J. Schmid, G.A. Lane, J. Agric. Food Chem. 50 (2002) 58. [3] K. Munakata, Pure Appl. Chem. 42 (1975) 57. [4] M.R. Siegel, G.C.M. Latch, M.C. Johnson, Plant Disease 69 (1985) 179. [5] J. Krauss, S.A. Harri, L. Bush, R. Hurst, L. Biglers, S. Power, C.B. Muller, Funct. Ecol. 21 (2007) 107. [6] E.N. Dubis, L.B. Brattsten, L.B. Dungan, Effects of the endophyte-associated alkaloids peramine on southern armworm microsomal cytochrome P450, in: Proceedings of the ACS Symposium Series Molecular Mechanism of Insecticide Resistance Diversity Among Insects, ACS, Washington, DC, 1992. [7] D.D. Rowan, D.L. Gaynor, J. Chem. Ecol. 12 (1986) 647. [8] K. Wyrostkiewicz, Wszechs´wiat 85 (1984) 166. [9] M. Omacini, E.J. Chaneton, C.M. Ghersa, C.B. Mulle, Nature 409 (2001) 78. [10] E. Dubis, A. Dubis, J. Nawrot, Z. Winiecki, J. Popławski, Effects of the endophyteassociated alkaloids peramine and its analogues on selected storage pests, in: Proceedings of the 1st International Conference on Insects, Insects—Chemical, Physiological and Environmental Aspects, La˛dek-Zdro´j, Poland, University of Wrocław, 1995.
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Contents lists available at ScienceDirect
Vibrational Spectroscopy journal homepage: www.elsevier.com/locate/vibspec
Spectroscopic and theoretical study on peramine and some pyrrolopyrazinone compounds A.T. Dubis a, A. Łapin´ski b,* a b
Institute of Chemistry, University of Bialystok, Al. Pilsudskiego 11/4, 15-443 Bialystok, Poland Institute of Molecular Physics, Polish Academy of Sciences, ul. Smoluchowskiego 17, 60-179 Poznan, Poland
A R T I C L E I N F O
A B S T R A C T
Article history: Received 17 June 2008 Received in revised form 8 October 2008 Accepted 8 October 2008 Available online 21 October 2008
The comparative analysis of IR and Raman spectra of peramine and its four derivatives in solid state was carried out. The harmonic vibrational frequencies, infrared intensities, and Raman scattering activities were calculated at density functional B3LYP methods with 6-311++G(d,p) basis set. For the predicted spectra, a potential energy distribution of normal modes was also calculated. For peramine derivatives the conjugation effect of pyrrole with pyrazinone ring was observed as a result of introduction of double bond. Moreover, 1H NMR analysis indicated that pyrrole protons are deshielded in comparison with the pyrrolopyrazinone model ring system. ß 2008 Elsevier B.V. All rights reserved.
Keywords: Peramine Antifeedants DFT calculations IR and Raman spectroscopy NMR spectroscopy
1. Introduction Peramine is the main secondary metabolite produced by perennial ryegrass (Lolium perenne L.) fungal endophyte [1]. This compound belongs to insect feeding inhibitors which protect the plant against grazing by insect. It is known that some other grass fungal metabolites, e.g. loritrem B and ergovaline [2], also act as antifeedant agent [3] but they are unfortunately toxic to herbivore animals such as cattle [4,5]. These fungal metabolites commonly act as neurotoxins. Among them the most interesting properties may be ascribed to peramine [6]. This compound deters feeding by insects, and has no toxic effect on mammals. Peramine is known to deter herbivores insects by attacking their taste sensors [7]. The mechanism of inhibition effect is complex, however it was found, that insects exposed to antifeedant substances, usually starved ceasing to consume leaves. Furthermore, exposure of larvae to feeding deterrent resulted in loss of their reproductive ability [8]. One can say that plants employ alkaloids as bioprotective substances which have a major impact on regulating terrestrial food webs [9]. As a consequence the peramine-infected pastures are safe for livestock grazing ryegrass. Such properties of peramine classify it to the environmental friendly insecticide. Synthetic peramine (1) and
* Corresponding author. Tel.: +48 61 869 52 79; fax: +48 61 868 45 24. E-mail address: [email protected] (A. Łapin´ski). 0924-2031/$ – see front matter ß 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.vibspec.2008.10.002
its propyl-substituted analogs 2–4 were also tested for their antifeedant effect on storage pests [10] and also showed some activities (Scheme 1). Peramine is still in the field of scientific interests and recently has been successfully determined, at trace level, in the cut plant fluid using high sensitive LCMSMS spectrometry [11]. In spite of biological importance of peramine, no attention has been given to its vibrational spectra until now. Thus, the aim of this paper is meticulous study of vibrational spectra of the title compounds, because it might allow detection of peramine related compounds in their natural environment. Peramine (1) and compounds 2–4 consist of the flat 2methylpyrrolo[1,2-a]pyrazin-1(2H)-one ring system substituted with the side chain. The three sp3CH2 groups and X moiety of the substituent can rotate, and thus one can expect a variety of structures. However, the interaction among the hydrogen or other atoms leaves certain internal rotational (dihedral) angles preferred on energetic grounds, as in the case of a small molecule. The molecules under consideration may possess a variety of structures, but certain conformations are preferred because it offers the least interaction. In case of substituted carbon chain the anti or gauche conformers are expected as an example of more general phenomenon, known as the gauche effect. Thus the relative abundances of the expected conformations decrease considerably. Nevertheless, for such complex structures, in order to state with certainty which conformer is present in the solid state, the X-ray diffraction measurements are indispensable. The crystal structure
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solvents were dried and freshly distilled. During the synthesis unexpected product 5-chloro-2-oxopentyl 1-(5-chloro-2-oxopentyl)pyrrolo-2-carboxylate (PDKE) was obtained with high yield (70%); a characterization of this compound will be described elsewhere. 1H and 13C NMR spectra were recorded using NMR Spectrometer Bruker Avance II 400 MHz using DMSO solution with TMS as an internal standard. The results of these investigations for peramine and its derivatives are presented below.
Scheme 1.
data have revealed that the flat conformation is present exclusively in the solid state. To extend our conformational consideration, the theoretical calculations were performed. The geometry optimization was performed for all investigated compounds by restricting the side chain to the rings plane (Fig. 1a) and for bent side-chain position (Fig. 1b). The results of the calculations reveal that the most stable conformation is associated with the bent arrangement of the side chain with respect to the ring’s plane. We have found that the difference in energy between these rotameric forms is rather small (less than 0.3 kcal/mol). A similar trend was obtained for compounds 2, 3, and 4. For these molecules the bent conformation is also more stable than the flat form. The transformation of the planar into bent conformation was investigated and described elsewhere in detail [12]. For complex molecular structure such as peramine many conformations are possible and designating all possible structures using theoretical methods could be very time consuming. In such cases X-ray data are necessary to avoid any mistakes. In this work the antifeedant peramine and its derivatives have been investigated by means of FT-IR, Raman, and diffuse reflectance IR spectroscopy. The quantum-mechanical calculations at DFT/6-311++G(d,p) level of theory were performed for flat conformation derived from crystallographic data. The comparison between the theoretical and experimental spectra was made for determination of the characteristic absorptions of each moiety. This is the first time such spectroscopic data are reported, to the best of our knowledge. 2. Methods 2.1. Experimental Peramine and other pyrrolopyrazinone derivatives were synthesized by the Dumas method [13]. Before the synthesis all
2.1.1. Peramine (1) (3-(1,2-dihydro-2-methyl-1-oxopyrrolo[1,2a]pyrazon-3-yl)propyl)guanidine 1 H NMR (DMSO) d ppm: 7.31 (d, 1H, Ar–H), 7.24 (s, 1H, C–H), 6.83 (d, 1H, Ar–H), 6.51 (dd, 1H, Ar–H), 3.34 (s, 3H, –CH3), 3.17 (t, 2H, –CH2–), 2.57 (t, 2H, –CH2–), 1.75 (m, 2H, –CH2–). 13 C NMR (DMSO) d ppm: 157.2 (C); 156.6 (C O); 128.1 (C); 122.5 (C); 118.7 (CH); 112.3 (CH); 109.1 (CH); 106.3 (CH); 40.3 (CH2); 29.0 (CH3); 27.3 (CH2); 27.0 (CH2). 2.1.2. 3-(3-Aminopropyl)-2-methylpyrrolo[1,2-a]pyrazin-1-(2H)one (2) 1 H NMR (DMSO) d ppm: 7.33 (dd, 1H, Ar–H), 7.23 (s, 1H, C–H), 6.81 (d, 1H, Ar–H), 6.49 (dd, 1H, Ar–H), 3.36 (s, 3H, –CH3), 2.63 (t, 2H, –CH2–), 2.57 (t, 2H, –CH2–), 1.62 (tt, 2H, –CH2–). 13 C NMR (DMSO) d ppm: 156.0 (C O); 128.8. (C); 122.3 (C); 118.1 (CH); 111.7 (CH); 108.4 (CH); 105.5 (CH); 40.8 (CH2); 31.5 (CH2); 28.5 (CH3); 27.0 (CH2). 2.1.3. 3-(3-Chloropropyl)-2-methylpyrrolo[1,2-a]pyrazin-1-(2H)one (3) 1 H NMR (DMSO) d ppm: 7.36 (dd, 1H, Ar–H), 7.28 (s, 1H, C–H), 6.83 (dd, 1H, Ar–H), 6.51 (dd, 1H, Ar–H), 3.75 (t, 2H, –CH2–), 3.38 (s, 3H, –CH3), 2.69 (t, 2H, –CH2–), 2.03 (m, 2H, –CH2–). 13 C NMR (DMSO) d ppm: 155.9 (C O); 127.4 (CH); 122.4 (C); 118.3 (CH); 111.7 (CH); 108.6 (CH); 105.9 (CH); 44.5 (CH2); 30.6 (CH2); 28.6 (CH3); 27.0 (CH2). 2.1.4. 3-Propyl-2-methylpyrrolo[1,2-a]pyrazin-1-(2H)-one (4) 1 H NMR (CDCl3) d ppm: 7.04 (m, 2H, Ar–H), 6.74 (s, 1H, C–H), 6.46 (dd, 1H, Ar–H), 3.60 (t, 2H, –CH2–), 3.38 (s, 3H, –CH3), 2.39 (t, 2H, –CH2–), 1.51 (dt, 2H, –CH2–); 0.95 (t, 3H, –CH3). 13 C NMR (DMSO) d ppm: 157.2 (C O); 128.4. (CH); 123.0 (C); 117.3 (CH); 112.0 (CH); 109.4 (CH); 105.9 (CH); 32.6 (CH2); 28.9 (CH3); 21.5 (CH2); 13.6 (CH3). 2.1.5. 2-Methyl-3,4-pyrrolo[1,2-a]pyrazin-1-(2H)-one (5) 1 H NMR (DMSO) d ppm: 6.95 (dd, 1H, Ar–H), 6.61 (dd, 1H, Ar– H), 6.13 (dd, 1H, Ar–H), 4.16 (m, 2H, –CH2–), 3.63 (m, 3H, –CH2), 2.96 (s, 3H, –CH3).
Fig. 1. Two conformations of peramine: flat (a) and bent (b) form.
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13 C NMR (DMSO) d ppm: 159.0 (C O); 124.4 (C); 123.2 (CH); 111.6 (CH); 108.8 (CH); 47.3 (CH2); 42.9 (CH2); 33.2 (CH3).
Table 1 Crystal and structure refinement for 3-(3-chloropropyl)-2-methylpyrrolo[1,2a]pyrazin-1-(2H)-one (3).
2.1.6. 5-Chloro-2-oxopentyl 1-(5-chloro-2-oxopentyl)pyrrolo-2carboxylate (PDKE) IR (KBr) n cm1: 3122, 1730, 1702, 1530, 1422, 1380, 1330, 1259, 1127, 1085, 751, 674. 1 H NMR (CDCl3) d ppm: 7.14 (m, 1H, Ar–H), 6.84 (q, 1H, C–H), 6.26 (q, 1H, Ar–H), 5.05 (s, 2H, –CH2–), 4.74 (s, 2H, –CH2), 3.60 (m, 2H, –CH2–), 2.70 (m, 4H, –CH2–); 2.10 (m, 4H, –CH2). 13 C NMR (CDCl3) d ppm: 203.7 (C O), 203.3 (C O), 160.3 (C O); 130.3 (CH); 121.0 (C); 119.4 (CH); 109.2 (CH); 67.7 (CH2); 57.9 (CH2); 44.2 (CH2); 44.1 (CH2); 36.0 (CH2); 35.4 (CH2); 25.9 (CH2); 25.8 (CH2).
Formula
C11H13ClN2O
M Crystal system Space group Unit cell dimensions (A˚)
224.68 Triclinic P 1¯ a = 7.1604(11) b = 7.3933(8) c = 10.9859 79.063(9) 71.649(11) 70.607(12) 518.33(11) 2 1.440 0.5 0.35 0.1 0.341 100(2) 0.71073 9 h 9 9 k 9 14 l 14 9616 2377 0.0132 1.123 2377 0.0279 0.0777 0.0251 0.0765 0.281 0.326
2.2. Vibrational spectroscopy The infrared spectra of 1–5 were investigated at room temperature, in KBr pellets containing dispersed compounds. The FT-IR absorption spectra were recorded in the range between 250 and 7000 cm1 with Nicolet Magna IR 550 Series II and Bruker Equinox 55 FT-IR spectrometers. These data were completed with diffuse reflectance spectra recorded in the spectral range from 400 to 7000 cm1 with a PerkinElmer 1725X FT-IR spectrometer equipped with a special accessory. The diffuse reflectance spectra were elaborated according to the Kubelka–Munk procedure. The Kubelka-Munk theory allows the prediction of spectral reflectance for a mixture of components that have been characterized by absorption K and scattering S coefficients [14], which are related to the fundamental optical coefficients for absorption e and scattering s [15]. Raman scattering of the light in the range from 50 to 4000 cm1 was investigated with a Jobin Yvon HORIBA LabRAM HR 800 confocal spectrometer with a liquid-N2-cooled charge coupled device (CCD) and two lasers: Stabilite 2017 (Ar+ ion laser) and He– Ne. The laser power of 633, 514, and 488 nm wavelength, before focusing with 100 objective was less than 8 mW. Moreover, the Raman spectra of peramine were recorded with a Renishaw System 1000 microspectrometer with excitation beam from a laser Lexel 3500 (l = 568 nm, less than 10 mW power was at the sample). Notch filters were used for stray light rejection. The position of Raman peaks was calibrated using a Si thin film as an external standard. The Raman spectra of polycrystalline samples 1–5 were recorded at room temperature in back-scattering geometry. The spectral resolution of IR and Raman spectra was 2 cm1. 2.3. X-ray data collection and structure refinement All measurements of crystalline sample 3 were performed on a KM4CCD k-axis diffractometer with graphite-monochromated Mo Ka radiation. The crystal was positioned at 62 mm from the CCD camera. 1496 frames were measured at 0.88 intervals with a counting time of 20 s. The data were corrected for Lorentz and polarization effects. Multi-scan absorption correction has been applied. Data reduction and analysis were carried out with the Oxford Diffraction programs [16]. The structure was solved by direct methods [17] and refined using SHELXL [18] and WinGX Program System [19]. The refinement was based on F2 for all reflections except those with very negative F2. Weighted R factors wR and all goodness-of-fit S values are based on F2. Conventional R factors are based on F with F set to zero for negative F2. The Fo2 > 2sðFo2 Þ criterion was used only for calculating R factors and is not relevant to the choice of reflections for the refinement. The R factors based on F2 are about twice as large as those based on F. Most of hydrogen atoms were located from a differential map and refined isotropically, except of disordered hydrogens in methyl
a (8) b (8) g (8) V (A˚3) Z Dx (Mg m3) Crystal size (mm) m (mm1) T (K) l (A˚) Index ranges
No. of data collected No. of unique data Rint Goodness-of-fit on F2 No. of parameters R1 (all data) wR2 (all data) R1 [I > 2s(I)] wR2 [I > 2s(I)] Drmin (e A˚3) Drmax (e A˚3)
group. Those were located geometrically and their positions and temperature factors were not refined. Scattering factors were taken from Tables 6.1.1.4 and 4.2.4.2 in International Tables for Crystallography [20]. A summary of crystallographic relevant data is given in Table 1. 2.4. Computational method To study the vibrational properties of peramine and its derivatives the theoretical calculations were performed with Gaussian 03 program [21] using 6-311++G(d,p) basis set at the hybrid Hartree–Fock density functional (B3LYP). These calculations were performed on stable flat conformer of pyrrolopyrazinone molecules 1–5 [12]. In all these cases the side chain lies at the same plane as the pyrrolopyrazinone ring (Fig. 1a). The initial geometry of the investigated compounds was taken from X-ray data and applied in the geometry optimization job. The results of optimizations correspond to energy minima since no imaginary frequencies were found. On the basis of optimized structures, vibrational frequencies and both infrared and Raman intensities were calculated. The computed frequencies were multiplied by a uniform factor 0.98 to obtain a good estimate of the experimental results. The scale factor used in the present work is very close to that recommended for B3LYP/6-311++G(d,p) calculations [22]. It is worth to notice that frequencies computed with a quantum harmonic oscillator approximation tend to be higher than experimental ones. The exception is the low frequencies, which are often quite far from the experimental values [23]. The potential energy distribution (PED) analysis of normal modes was used in terms of natural internal coordinates [24]. The VEDA 4.0 program (vibrational energy distribution analysis) [25] was applied in our calculations (see Electronic Supplementary Material, Tables S1– S5). The related methodology has been published elsewhere [26].
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Since only Raman scattering activities are obtained from the Gaussian calculations, the theoretical Raman intensities were calculated from scattering activities and calculated wavenumbers [27,28]. One should notice that all theoretical predictions were performed for the isolated molecules in gas phase, in which it is reasonable to assume that there is no interaction with the other molecules. The experimental spectra of peramine derivatives are recorded for solid state where the interaction between the molecules is not negligible. Nevertheless, one can find that the agreement between experimental and theoretical spectra is satisfactory. In case of peramine and its amino derivative (2), some differences between experimental and theoretical spectra are due to hydrogen bond interaction between of N–H proton donator group and proton acceptor carbonyl group. 3. Results and discussion Peramine (1) belongs to the pyrrolopyrazinone alkaloids containing 2-methylpyrrolo[1,2-a]pyrazin-1(2H)-one ring system together with a monosubstituted guanidino group [29]. This 1oxo-2,3-disubstituted structure was modified by introduction of different polarity substituent groups (compounds 2–4). Additionally, pyrrolo[1,2-a]pyrazinone (5) model ring system was also investigated in this work. The IR and Raman experimental and theoretical spectra of peramine (1) and compounds 2–4 are presented in Figs. 4–7; the results of ab initio calculations and experimental data are available in Electronic Supplementary Material. 3.1. Crystal structure of 3-(3-chloropropyl)-2-methylpyrrolo[1,2a]pyrazin-1-(2H)-one (3) Table 2 presents X-ray bond lengths and bond angles (with esd’s) of 3-(3-chloropropyl)-2-methylpyrrolo[1,2-a]pyrazin-1(2H)-one (3) molecule. The crystallographic labeling scheme and crystal packing are shown in Figs. 2 and 3, respectively. Compound 3 consists of two rings arranged in one plane and a side arm oriented in the rings’ plane. The aliphatic chain adopts a nearly planar conformation. Dihedral angle N1–C6–C9–C10 defined between the mean plane of aliphatic chain and pyrrolopyrazinone ring is 179.92(8)8 while a calculated value is 179.9968. Furthermore, it was observed that alkane chain adopts staggered arrangement in which all C–H bonds are as far away from one another as possible. It is also worth to notice that the bond lengths
Fig. 2. ORTEP plot and labeling scheme for 3-(3-chloropropyl)-2methylpyrrolo[1,2-a]pyrazin-1-(2H)-one (3). Displacement ellipsoids are drawn at the 50% probability level. Hydrogen atoms of methyl C8 group are disordered in crystal structure over two equal positions. The H8a, H8b, H8c belong to one component of disorder, while H8d, H8e, H8f to the other.
Table 2 Experimental X-ray values of bond distances (A´˚ ), bond angles and dihedral angles (degrees) for non-hydrogen atoms of molecule 3; estimated standard deviations are given in parentheses and the labeling scheme is presented in Fig. 2. N(1)–C(1) N(1)–C(6) N(1)–C(8) C(1)–O(1) C(1)–C(7) C(2)–C(7) C(2)–C(3) C(3)–C(4) C(4)–N(2) C(5)–C(6) C(5)–N(2) C(6)–C(9) C(7)–N(2) C(9)–C(10) C(10)–C(11) C(11)–Cl(1) C(1)–N(1)–C(6) C(1)–N(1)–C(8) C(6)–N(1)–C(8) O(1)–C(1)–N(1) O(1)–C(1)–C(7) N(1)–C(1)–C(7) C(7)–C(2)–C(3) C(4)–C(3)–C(2) N(2)–C(4)–C(3) C(6)–C(5)–N(2) C(5)–C(6)–N(1) C(5)–C(6)–C(9) N(1)–C(6)–C(9) N(2)–C(7)–C(2) N(2)–C(7)–C(1) C(2)–C(7)–C(1) C(4)–N(2)–C(7) C(4)–N(2)–C(5) C(7)–N(2)–C(5) C(6)–C(9)–C(10) C(11)–C(10)–C(9) C(10)–C(11)–Cl(1) C(6)–N(1)–C(1)–O(1) C(8)–N(1)–C(1)–O(1) C(6)–N(1)–C(1)–C(7) C(8)–N(1)–C(1)–C(7) C(7)–C(2)–C(3)–C(4) C(2)–C(3)–C(4)–N(2) N(2)–C(5)–C(6)–N(1) N(2)–C(5)–C(6)–C(9) C(1)–N(1)–C(6)–C(5) C(8)–N(1)–C(6)–C(5) C(1)–N(1)–C(6)–C(9) C(8)–N(1)–C(6)–C(9) C(3)–C(2)–C(7)–N(2) C(3)–C(2)–C(7)–C(1) O(1)–C(1)–C(7)–N(2) N(1)–C(1)–C(7)–N(2) O(1)–C(1)–C(7)–C(2) N(1)–C(1)–C(7)–C(2) C(3)–C(4)–N(2)–C(7) C(3)–C(4)–N(2)–C(5) C(2)–C(7)–N(2)–C(4) C(1)–C(7)–N(2)–C(4) C(2)–C(7)–N(2)–C(5) C(1)–C(7)–N(2)–C(5) C(6)–C(5)–N(2)–C(4) C(6)–C(5)–N(2)–C(7) C(5)–C(6)–C(9)–C(10) N(1)–C(6)–C(9)–C(10) C(6)–C(9)–C(10)–C(11) C(9)–C(10)–C(11)–Cl(1)
1.3841(14) 1.4118(13) 1.4669(13) 1.2359(13) 1.4441(15) 1.3855(15) 1.4078(16) 1.3827(15) 1.3696(14) 1.3441(15) 1.3932(13) 1.5048(14) 1.3864(13) 1.5227(14) 1.5142(14) 1.8064(12) 122.83(9) 115.80(9) 121.30(9) 121.45(10) 122.64(10) 115.91(9) 106.95(9) 108.46(10) 107.42(9) 119.72(9) 120.07(9) 122.90(9) 117.03(9) 107.73(9) 119.94(9) 132.33(10) 109.43(9) 129.08(9) 121.45(9) 113.85(9) 112.62(9) 112.33(8) 177.36(9) 0.50(15) 2.26(14) 179.13(9) 0.19(12) 0.32(12) 0.91(15) 178.55(8) 0.05(15) 176.75(9) 179.54(9) 3.76(14) 0.01(11) 179.26(11) 176.03(9) 3.59(14) 3.18(18) 177.20(10) 0.33(11) 177.46(9) 0.21(11) 179.17(9) 177.77(9) 2.84(14) 178.07(10) 0.51(15) 0.60(14) 179.92(8) 176.94(8) 69.42(10)
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269
Fig. 3. Layered structure of 3 viewed along the b axis. Note: hydrogen atoms of methyl group are disordered in crystal structure over two equal positions.
within pyrrole ring of compound 3 are very close to the experimental values of bond distances of the pyrrole in gas phase (microwave data) [30] and to the calculated values obtained in the optimized structure [31]. The C3–C4, C4–N2, N2–C7, C7–C2 and C2–C3 bond lengths for molecule 3 are equal to 1.383, 1.369, 1.386, 1.385, and 1.408 A˚, respectively.
ing also contributes to this band. However, the observed intensity of this band is not as large as theoretically predicted (Figs. 4–7). The second prominent band was observed in the range 1608– 1624 cm1. This band is mainly due to C C stretching vibration but calculations predicts that also C O stretching contributes to this band. In the experimental spectra of compounds 3 and 4, the
3.2. Experimental and calculated frequencies related to C O and C C stretching vibrations The experimental and theoretical IR and Raman spectra of the peramine (1) and compounds 2–4 are presented in Figs. 4–7. The results of ab initio calculations for the vibrational spectra of the molecules under study and their experimental data are available as Supporting Material. Our extensive investigation of the infrared and Raman spectra of peramine and its derivatives leads to proper description of their spectroscopic properties. The most significant and valuable absorption bands appear in the region 1800–1600 cm1. These bands are mainly due to the presence of carbonyl groups, olefinic systems and scissoring vibration of NH2 group. The carbonyl group is important and its characteristic frequencies have been used to study a wide range of compounds [32]. The absorption caused by C O stretching is generally very strong, whereas the nC C bands are of variable intensity, but usually are substantially less intense than those from C O stretching vibrations. The differentiation between these two kinds of stretching modes could be provided easily by using theoretical calculations and both infrared and Raman spectra [33]. Since the Raman scattering is a function of change in polarizability of molecules, the symmetric vibrations give the most intense Raman scattering. It is in contrast to infrared absorption where dipole change gives intensity and asymmetric vibrations are intense. The positions of carbonyl nC O bands and double bond nC C bands of all analyzed here compounds are collected in Table 3. Both peramine and the other compounds 2–4 exhibited an absorption band within the range 1667–1676 cm1. According to the structural features and theoretical calculations (see Table 3), this band was thought to be mainly derived from the carbonyl group. Position of this band at the lower end of the carbonyl frequency range, implies the C O group is in conjugation with the aromatic p-electron system leading to reduced C O double bond character. Furthermore, our calculations predict that C C stretch-
Fig. 4. Absorption and diffuse reflectance spectra (upper panel) and calculated IR spectra (lower panel) of 1 (a). Experimental and calculated Raman spectra of 1 (b). Note: the level of theory was B3LYP/6-311++G(d,p), the bands are labeled as indicated in Electronic Supplementary Material—Table S1, the Raman spectra of 1 were recorded with 568 and 633 nm excitations.
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270
Fig. 5. Absorption and diffuse reflectance spectra (upper panel) and calculated IR spectra (lower panel) of compound 2 (a). Experimental and calculated Raman spectra of 2 compound (b). Note: the level of theory was B3LYP/6-311++G(d,p), the bands are labeled as indicated in Electronic Supplementary Material—Table S2, the Raman spectra of 2 were recorded with 514 and 633 nm excitations.
intensity of this band is about 2–3 times larger than that found for the previous band. In case of peramine (1) and compound 2 the intensities of these two bands are almost equal. On the base of the above observations one can find that bands within the spectral ranges: 1667–1676 cm1 and 1608–1624 cm1 are not simple C O or C C stretching modes, but they are the result of mixing of C O and C C stretching vibrations. Fig. 8 shows the atomic displacements of these modes; na is the mode where C O and C C double bonds are stretching ‘‘out of phase’’, whereas nb is the ‘‘in phase’’ mode. It is worth to note that experimentally observed na bands for compounds 1–4 are shifted (Dn 50 cm1) to higher frequency in comparison with model compound 5. When the carbonyl-carbon is a part of a ring system, the decrease in bond angle of two sp2 hybridized orbitals results in steric strain effects. This effect causes the shift to higher values of the frequency of absorption of the carbonyl group which contributes mainly to (a mode. For compounds 1–4 analyzed here we can say that the
Fig. 6. Absorption and diffuse reflectance spectra (upper panel) and calculated IR spectra (lower panel) of compound 3 (a). Experimental and calculated Raman spectra of 3 compound (b). Note: the level of theory was B3LYP/6-311++G(d,p), the bands are labeled as indicated in Electronic Supplementary Material—Table S3, the Raman spectra of 3 were recorded with 514 and 633 nm excitations.
behavior of carbonyl and C C stretching modes are the same in nature. 3.3. Experimental and calculated frequencies related to pyrrole ring C C stretching vibration The skeletal vibration of the pyrrole ring which involves expansion and contraction of its bonds is very sensitive to substitution [34]. The condensation of a pyrrole ring with a pyrazinone ring changes these skeletal stretching modes. The stretching of C C bonds within the pyrrole ring is observed at 1527, 1533, 1530, and 1532 cm1 for compounds 1, 2, 3, and 4, respectively. The corresponding calculated frequencies are in very good agreement with the experimental data (Table 4). The predicted Raman scattering intensities correlate well with the relative intensities observed in the Raman spectrum. A similarly good correlation was observed for IR calculated and experimental
Table 3 Experimental and calculated at B3LYP/6-311++G(d,p) theory level frequency values of the nC wavenumbers; A: the absolute IR intensities; IR: the Raman intensities [27,28].
O
and nC
C
modes. Note: na, nb: calculated wavenumbers; nexp: observed
Compound
nexp (cm1)
na (cm1)
A (km/mol)
IR arbitrary units
nexp (cm1)
nb (cm1)
A (km/mol)
IR arbitrary units
1 2 3 4 5
1667 1676 1674 1673 1625
1690 1689 1691 1689 1678
444.7 432.8 441.5 436.3 387.4
21.4 22.9 23.8 19.4 66.0
1608 1616 1624 1624
1658 1659 1659 1658
114.8 128.1 116.9 123.3
231.6 268.9 285.6 262.1
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271
Fig. 9. Experimental 1H NMR spectrum of peramine (1).
electron density and therefore such protons are much more deshielded (Table 5, Fig. 9). They are shifted downfield in comparison with compound 5. The observed interrelation between chemical shifts and vibrational frequency changes leads to a conclusion that conjugation effect is present within these ring systems. pyr pyraz 3.4. Carbon–nitrogen nCN , nCN skeletal vibrations of pyrrolopyrazinone ring
Fig. 7. Absorption and diffuse reflectance spectra (upper panel) and calculated IR spectra (lower panel) of compound 4 (a). Experimental and calculated Raman spectra of 4 compound (b). Note: the level of theory was B3LYP/6-311++G(d,p), the bands are labeled as indicated in Electronic Supplementary Material—Table S4, the Raman spectra of 4 were recorded with 488 and 633 nm excitations.
intensities. The C C stretching vibration of pyrrole ring in compound 5 gives rise to the absorption band at 1548 cm1. One can see, that for compounds 1–4, an introduction of double bond into pyrazinone ring lowers the pyrrole C C stretching vibration in comparison with compound 5. The observed red shifts are associated with conjugation of pyrrole with pyrazinone ring and one could say that there was a reduction of these double bond characters. Additional support for such conjugation is provided by NMR spectroscopy. The pyrrole protons which are in conjunction with double bond electrons of pyrazinone ring, experience reduced
Fig. 8. Atomic displacements of C
O and C
A large majority of the carbon–nitrogen stretching vibrations of the aromatic systems appear as a medium-strong absorption in the region 1360–1250 cm1. The band is usually observed within fairly constant frequency but absorbance is a little higher than for saturated systems as a result of the increased strength of the carbon–nitrogen bond. For instance in the heterocyclic aromatic molecule nicotinaldehyde [35], a characteristic carbon–nitrogen stretching band was observed at 1391 cm1. For compounds 1–4 this band appears as a medium intensity absorption band at 1363, 1366, 1368, and 1364 cm1, respectively. For compound 5 this band was observed at much lower frequency at 1311 cm1. The presented experimental data are in good agreement with calculated frequencies (Table 4). The calculated values are: 1374, 1375, 1375, 1375, and 1317 cm1 for compounds 1, 2, 3, 4, 5, respectively. Generally speaking, any substitution in side chain (compounds 1–4) leaves the nCN pyrrole ring vibrational mode unshifted. Furthermore, it should be noted that association
C in vibrational modes: na—‘‘out-of-phase’’ and nb—‘‘in phase’’.
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Table 4 Experimental and calculated at B3LYP/6-311++G(d,p) theory level frequency values of the C–C and C–N pyrrolopyrazinone stretching modes. Mode
1 2 3 4 5
Pyrrole ring nC=C
Pyrrole ring nCN R
Pyrazinone ring nCN R
nexp
ncalc
I arbitrary units
ncalc (cm1)
I arbitrary units
ncalc
(cm1)
A (km/mol)
nexp
(cm1)
A (km/mol)
nexp
(cm1)
(cm1)
(cm1)
A (km/mol)
IR arbitrary units
1527 1533 1530 1532 1548
1532 1531 1533 1531 1544
11.1 10.8 12.2 10.9 88.5
77.5 85.9 86.1 84.3 39.7
1363 1366 1368 1364 1311
1374 1375 1375 1375 1317
15.4 36.2 19.9 20.2 129.5
19.5 32.1 123.6 116.9 46.7
1257 1257 1254 1252 1245
1271 1272 1271 1272 1258
58.0 56.9 62.6 58.6 11.5
3.0 5.2 7.9 2.5 11.5
Note: ncalc: calculated wavenumbers; nexp: observed wavenumbers; A: the absolute IR intensities; IR: the Raman intensities [27,28].
Table 5 Experimental 1H NMR chemical shift of the pyrrolopyrazinone hydrogen atoms (Fig. 9 shows the molecular structure and designations of atoms of peramine derivatives). Compound
1 2 3 5
1
H NMR shift (ppm)
Ha
Hd
Hc
Hb
3.38 3.36 3.38 2.96
6.83 6.80 6.83 6.61
6.51 6.48 5.51 6.12
7.35 7.32 7.35 6.95
of pyrrole ring with pyrazinone unsaturated system, as seen in compounds 1–4, leads to blue shift of this mode in comparison with compound 5. The presented results show that the calculations provide a good estimation of the npyraz frequency in pyrazinone ring. In CN comparison with the literature data, in particular in case of the study of crystal and vapor pyrazine [36], our calculated frequencies fit well to the previous assignments showing low intensity bands in the range 1136–1204 cm1. Furthermore, our calculations confirm the presence of another characteristic carbon nitrogen stretching band in the pyrrolopyrazinone system, which is experimentally observed at 1259 (1), 1257 (2), 1254 (3), 1252 (4), and 1245 cm1 (5). The position of this mode is comparable to ring C–N stretching vibration found previously for trimethylpyrazine [37]. Their calculated intensities are of medium values and much more intense than those observed in the range 1316– 1204 cm1. This leads to conclusion that the above-mentioned bands may show diagnostic values for analysis of pyrrolopyrazinone skeletal systems. 3.5. C–H out-of-plane bending vibrations (gC–H) The presence of unsaturation in a molecule gives rise to characteristic out of plane bending or wagging vibration of hydrogen atoms attached to sp2 carbon atom. These vibrations could be observed in the low frequency region of the spectrum in the range 900–600 cm1. In the case of pyrrolopyrazinone derivatives 1–5 the most prominent absorption bands in this region are derived from four kinds of vibrations: g CHpyrr ; g CH2 ; g ¼CH (1–5) and nC–Cl for compound 3. According to the theoretical calculations the more meaningful gCH mode of the pyrrole C–H bonds is not sensitive to the type of the side chain attached to pyrazinone ring (Table 4). The position of this band is 740, 747, 745, 743 cm1 for compounds 1, 2, 3, 4, respectively. The calculated values are: 726, 728, 728, and 726 cm1. Based on calculated and experimental data one could notice that the gCH out-of-plane bending mode for compound 5 appears at higher frequency of 746 cm1. The observed downshift for compounds 1–4 in comparison with compound 5 may be connected with conjugation of pyrrole and pyrazinone rings.
4. Conclusions Attempt has been made in the present work for the proper assignments of vibrational bands for the title compounds. The infrared and Raman spectra of peramine (1) and its four derivatives 2–4 were measured in solid state and band assignment was made on the basis of theoretical calculations at B3LYP/6-311++G(d,p) level. Comparison of the experimental spectra with the theoretical frequencies and relative intensities, led to a reliable assignment of vibrational bands for peramine and its derivatives. Calculated vibrational frequencies, IR intensities and calculated Raman intensities agree fairly well with experimental data. Any discrepancy noted between the observed and the calculated spectra may be due to the fact that calculations have been done on a single molecule in the gaseous state contrary to the experimental spectra recorded for solid state. On the basis of both FT-IR and 1H NMR spectroscopy it has been found that pyrrolopyrazinone rings are conjugated. Among the title pyrrolopyrazinones significantly less conjugated ring system has been detected for the compound 5. Besides, it has been observed that in the series of peramine derivatives 1–4 the ring modes are not sensitive to the type of substituent introduced into the side chain. Acknowledgements This work was supported by the Polish Committee for Scientific Research at the research project in 2006–2008. The X-ray measurements were undertaken in the Structural Research Laboratory at the Chemistry Department of the University of Warsaw. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.vibspec.2008.10.002. References [1] H.W. Zanhg, Y.Ch. Song, R.X. Tan, Nat. Prod. Rep. 23 (2006) 753. [2] M.J. Spierling, E. Davies, B.A. Tapper, J. Schmid, G.A. Lane, J. Agric. Food Chem. 50 (2002) 58. [3] K. Munakata, Pure Appl. Chem. 42 (1975) 57. [4] M.R. Siegel, G.C.M. Latch, M.C. Johnson, Plant Disease 69 (1985) 179. [5] J. Krauss, S.A. Harri, L. Bush, R. Hurst, L. Biglers, S. Power, C.B. Muller, Funct. Ecol. 21 (2007) 107. [6] E.N. Dubis, L.B. Brattsten, L.B. Dungan, Effects of the endophyte-associated alkaloids peramine on southern armworm microsomal cytochrome P450, in: Proceedings of the ACS Symposium Series Molecular Mechanism of Insecticide Resistance Diversity Among Insects, ACS, Washington, DC, 1992. [7] D.D. Rowan, D.L. Gaynor, J. Chem. Ecol. 12 (1986) 647. [8] K. Wyrostkiewicz, Wszechs´wiat 85 (1984) 166. [9] M. Omacini, E.J. Chaneton, C.M. Ghersa, C.B. Mulle, Nature 409 (2001) 78. [10] E. Dubis, A. Dubis, J. Nawrot, Z. Winiecki, J. Popławski, Effects of the endophyteassociated alkaloids peramine and its analogues on selected storage pests, in: Proceedings of the 1st International Conference on Insects, Insects—Chemical, Physiological and Environmental Aspects, La˛dek-Zdro´j, Poland, University of Wrocław, 1995.
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