On the molecular and electronic structure of matrine-type alkaloids

Chemical Physics 330 (2006) 457–468 www.elsevier.com/locate/chemphys

On the molecular and electronic structure of matrine-type alkaloids V. Galasso

a,*

, F. Asaro a, F. Berti a, B. Pergolese a, B. Kovacˇ b, F. Pichierri

c

a

c

Dipartimento di Scienze Chimiche, Universita` di Trieste, I-34127 Trieste, Italy b The Rud-er Bosˇkovic´ Institute, HR-10002 Zagreb, Croatia COE Laboratory, Tohoku University, IMRAM, 2-1-1 Katahira, Sendai 980-8577, Japan Received 29 June 2006; accepted 15 September 2006 Available online 20 September 2006

Abstract A systematic study of the molecular and electronic structure of the eight possible members in the trans-matrine series and of two dehydro-derivatives, sophocarpine and sophoramine, has been performed. According to density functional theory (DFT) calculations these alkaloids exhibit a variety of form and junction of the four six-membered rings and all but sophocarpine have a strong preference for one conformation. Sophocarpine is predicted to have a marked conformational flexibility at the lactamic nitrogen and to exist as a mixture of two nearly isoenergetic conformers (C/D-trans and -cis) in the gas phase or solution. The theoretical predictions are consistent with the available X-ray experimental results as well as IR and NMR evidence. The absolute configuration of the preferred conformer of each compound has been established theoretically and corroborated with the specific optical rotation calculated at the sodium D line. The conformational equilibrium of sophocarpine has also been supported by this physical property. The computed gas-phase proton affinity of matrines indicates a basicity comparable to that of other polycyclic proton sponges. The lowest-energy electronic transitions have been characterized by time-dependent DFT calculations as mainly due to excitations spanning the frontier orbitals p(NCO), n(O), n(Naminic), and p*(CO). The electronic structures have also been studied by measuring and calculating significant features of the NMR and photoelectron spectra. In particular, a representative set of NMR chemical shifts and nuclear spin–spin coupling constants, obtained with DFT formalisms, compares favourably with experiment. Notably, the stereoelectronic hyperconjugative effects on Dd(Heq/Hax) and D1J(CHeq/ CHax) of the >N–CO– groups is correctly accounted for by the theoretical results. Based on ab initio outer valence Green’s function calculations, a reliable description of the uppermost bands in the photoelectron spectra has been advanced. The splitting and sequence of the ionization energies reflect a complex interaction of the n and p chromophores.  2006 Elsevier B.V. All rights reserved. Keywords: Ab initio and DFT calculations; Structures; Optical rotatory power; NMR chemical shifts and coupling constants; Photoelectron spectra

1. Introduction Bis-quinolizidine alkaloids of matrine type represent an important class of natural products that exhibit a wide range of pharmacological activity [1–6]. Formally, the matrine skeleton contains a quinolizidinic A/B ring system fused with a quinolizidinone C/D ring system and has four stereocenters. Thus, with reference to the C/D ring junction, the two possible series of eight pairs of enantiomers can be classified as the trans and cis series. In the strict *

Corresponding author. Tel.: +39 040 558 3947; fax: +39 040 558 3903. E-mail address: [email protected] (V. Galasso).

0301-0104/$ - see front matter  2006 Elsevier B.V. All rights reserved. doi:10.1016/j.chemphys.2006.09.017

sense, due to the planar configuration of the amidic nitrogen atom, the C/D ring junction should best be referred to as quasi-trans or quasi-cis. Of these compounds, only one member of the cis series has been reported thus far in the literature [7]. On the other hand, all but two of the members of the trans series have been isolated from Sophora medicinal plants and a large number of their derivatives and related unsaturated alkaloids are also known [1,2]. However, the stereochemical properties of only a few of these compounds have been investigated by spectroscopic and X-ray diffraction measurements. In the present paper, we report on the trans series (Fig. 1), which is composed of matrine 1, allomatrine 2,

458

V. Galasso et al. / Chemical Physics 330 (2006) 457–468 O

O N

N

N

N

H

H

H H

H

H

H

H

O

O

H

H

H

H

H

H

H

H

N

N

N

N

1

2

3

4

O

O

O N

N H

H

H

H

N

H

H H

H

H

N

6

5 O

H

H

H

N

H H

H

H

N

N

7

8

O

O

14 15

N

N

N

H

16

17 5

H

H

H

N

9

10

N

4

H

N

13

D

12

11

C

H

H

2. Computational and experimental details

O N

3

2

N

O

7 6

A

1N

N

Me

Me

Me

11

12

13

B

tions. Furthermore, since the bands associated with the lowest ionization energies are sensitive to the molecular conformation, the He(I) photoelectron (PE) spectra of a number of these free bases were also measured and investigated by means of ab initio many-body calculations using the outer valence Green’s function (OVGF) method [10].

8 9

10

O

Fig. 1. Formulas, ring labelling, and atom numbering of compounds 1– 13.

sophoridine 3, isomatrine 4, isosophoridine 5, tetrahydroneosophoramine 6, 7, and 8 (the last two compounds have not yet been found in nature nor synthesized). As representative examples of dehydro-derivatives of matrine, sophocarpine 9 and sophoramine 10 are also characterized here. Because of the intimate interrelation between geometric and electronic structures, a combined experimental and theoretical investigation into the structural and spectroscopic properties of these alkaloids seemed timely. Thus, we performed calculations of the preferred conformations using the density functional theory (DFT) formalism. The optical properties of chiral molecules are of great importance. Accordingly, the optical rotation (OR) at the sodium D line was calculated by a time-dependent DFT (TD-DFT) methodology [8]. The lowest-energy electronic transitions were also characterized by TD-DFT calculations [9]. Because the NMR observables are very efficient monitors of the complex interplay of structural and electronic effects, the d(1H) and d(13C) chemical shifts and indirect nuclear spin–spin coupling constants nJ(HH) and 1J(CH) spectroscopic parameters were studied by DFT calcula-

The conformational preferences of all compounds 1–10 were fully investigated with the DFT/B3LYP hybrid functional [11]. Use was made of the standard 6-31G(d,p) basis set and the Gaussian-03 suite of programs [12]. The combination of this functional, which takes into account the electron exchange-correlation effects, and the polarized basis set offers a good compromise between the size of the calculations and the accuracy of the theoretical predictions. Harmonic frequency calculations were performed for all the optimized structures to establish that the stationary points are minima. The vibrational characterization was based on the normal-mode analysis performed according to the Wilson FG matrix method [13], using standard internal coordinates and the scaling factors of Rauhut and Pulay [14]. The specific optical rotation at the sodium D line [a]D was calculated with the frequency-dependent TD-DFT method [8] using the B3LYP functional. The cc-pVDZ valence basis set [15] was augmented with 2s2p2d uncontracted diffuse functions (s exponents: 0.0624, 0.2758; p exponents: 0.0550, 0.2574; d exponents: 0.2377, 0.2787) placed at the center of mass of the molecule. Gauge-invariant atomic orbitals (GIAOs) were used to provide originindependent results. Vertical excitation energies and oscillator strengths were calculated with the TD-DFT method [9], employing the B3LYP functional and the cc-pVDZ basis set. The 1H and 13C NMR absolute shielding constants (r values) were calculated at the DFT/B3LYP level with the continuous set of gauge transformations (CSGT) method [16] using the 6-311+G(2d,p) basis set. The calculated magnetic shieldings were converted into the d chemical shifts by noting that at the same level of theory the 1H and 13C absolute shieldings in tetramethylsilane (TMS) are 31.25 and 177.54, respectively. The indirect nuclear spin–spin coupling constants were obtained by means of standard response-theory methods at the DFT/B3LYP level using the DZP basis set [17]. The calculation of the J tensor took into account all four contributions of the nonrelativistic Ramsey theory [18], i.e., in addition to the Fermi contact term, also the diamagnetic spin–orbit, paramagnetic spin– orbit, and spin–dipole terms. The vertical ionization energies were calculated at the ab initio level according to Cederbaum’s OVGF method [10], which incorporates the effects of electron correlation and reorganization beyond the Hartree–Fock approximation. The self-energy part was expanded up to third order and the contributions of higher orders were estimated by

V. Galasso et al. / Chemical Physics 330 (2006) 457–468

means of a renormalization procedure. In order to calculate the self-energy part, all occupied valence molecular orbitals (MOs) and the 95 (1–8) and 90 (9,10) lowest virtual MOs were considered. The calculations were performed using the DZP basis set [17]. Compounds 1, 3, 9, and 10 were commercial samples, whereas compounds 2 and 5 were prepared as described in the literature [19,20]. The IR spectra of solid samples in KBr pellets were obtained by using a Perkin–Elmer FT-IR RX/I spectrometer. The NMR spectra of 1, 2, 3, 5, 9, and 10 in CDCl3 solution were recorded on a Jeol Eclipse 400 spectrometer operating at 399.8 and 100.5 MHz for 1H and 13C, respectively. The 1J(CH) values were extracted from 2D (1H, 13 C)-HSQC experiments without 13C decoupling [21,22]. Spectral widths of 3600 Hz in F1 and 15,000 Hz in F2 were employed. Data matrices of 1024 · 1024 points in t1 and t2 were weighted with a Hamming function in t1 and a shifted sine-bell function in t2, and zero-filled in both dimensions prior to Fourier transformation to achieve a final digital resolution of 0.4 Hz per point in F1. The He(I) spectra were recorded on a Vacuum Generators UV-G3 spectrometer [23] with spectral resolution of 25 MeV when measured at the full width at half maximum of the Ar+ 2P3/2 peak. The sample inlet temperatures required to generate sufficient sample vapour pressure were 130, 130, 140, 140, 140, and 190 C, for 1, 2, 3, 5, 9, and 10, respectively. The energy scale was calibrated by admitting small amounts of Ar and Xe to the sample flow. 3. Results and discussion 3.1. Molecular structures A selection of the most relevant structural features provided by the DFT study for 1–8 are listed in Table 1. The description of the ring conformations has been advanced on the basis of the values of the ‘‘conformation discriminator’’ calculated for each of the possible conformations of a six-membered ring [24]. Common to all molecules 1–8 is that both the carbonyl carbon and the amidic nitrogen are perfectly planar (Ra  359); the N lone pair orbital (LPO) lies in the nodal plane of the p system and, therefore,

459

has a nearly pure p-character. The aminic nitrogen atom is instead significantly pyramidalized and strongly sp3-like in character. The main aspects of the experimental information and present theoretical analysis are summarized below. Note that the expression ‘‘cisoid’’ (‘‘transoid’’) in Table 1 denotes a junction dihedral angle larger (lower) than 15 (165). First of all, it must be pointed out that all the unsubstituted bases 1–8 have one most favourable conformer (Figs. 2–5). In particular, there are a number of feasible conformations for the still-elusive stereoisomers 7 and 8 [7]. For 7, theory predicts a strong (7.8 kcal mol1) preference for the global minimum over the second lowest-energy conformation (A(chair)/B(twist-boat)/C(twist-boat)/D(half-chair) A/B-cisoid, A/C-trans, B/C-transoid). For 8, the second favoured conformer (chair/chair/twist-boat/half-chair A/B-cisoid, A/C-cisoid, B/C-trans) is 1.8 kcal mol1 less stable than the lowest-energy conformer. Here, the interest has been restricted to the lowest-energy conformer of each compound. Ring A exhibits a chair form in all of the stereoisomers but 8, where it is a twist-boat. On the other hand, ring D is a (distorted) half-chair in all of the stereoisomers but 1, where it is a (distorted) sofa. The B/C fragment instead displays a variety of steric arrangements. For compounds 1–6, the theoretical predictions can be compared with the experimental results. Thus, it is very satisfying to remark the good agreement between the DFT geometries and corresponding X-ray structures [25–30]. At variance with matrines 1–8, the conformational situation of the enaminone sophocarpine 9 turns out to be more complex, due to a facile inversion of configuration occurring at the lactamic nitrogen. Indeed, 9 retains the same structural form of the A/B/C fragment as 1, but the conformation with the C/D-(quasi)trans ring junction (9t) is preferred by only 0.1 kcal mol1 over the (quasi)-cis ring junction (9c), depicted in Fig. 6, the barrier to interconversion being low, 2.2 kcal mol1. Geometry optimization at the DFT level was also carried out in ethanol solution with the polarizable continuum model (PCM) [31]: the energy difference is slightly raised to 0.2 kcal mol1. On this basis, one may speculate that a mixture of the 9t and 9c conformers exists in the gas phase (50:50%) and in ethanol solution

Table 1 Theoretical preferred conformations and relative energies (kcal mol1) of 1–8

1 2 3 4 5 6 7 8 a

Ring A

Ring B

Ring C

Ring D

A/B ring junction

A/C ring junction

B/C ring junction

DE

Chair Chair Chair Chair Chair Chair Chair T.-b.

Chair Chair Boat Boat Chair Chair Chair Chair

Chair Chair Boat Boat Chair Chair T.-b.a T.-b.

Sofa H.-c.a H.-c. H.-c. H.-c. H.-c. H.-c. H.-c.

Trans Trans Trans Trans Cisoid Cisoid Trans Trans

Cisoid Trans Trans Cisoid Cisoid Trans Trans Cis

Cisoid Trans Cis Cis Trans Cisoid Trans Trans

0 3.03 5.54 8.27 1.34 2.07 5.32 7.41

H.-c. and t.-b. stand for half-chair and twist-boat, respectively.

460

V. Galasso et al. / Chemical Physics 330 (2006) 457–468

Fig. 2. The DFT-optimized structures of 1 and 2.

Fig. 4. The DFT-optimized structures of 5 and 6.

Fig. 3. The DFT-optimized structures of 3 and 4.

Fig. 5. The DFT-optimized structures of 7 and 8.

(60:40%), assuming thermal equilibrium at 25 C. Further discussion on this point is postponed till the discussion of ORD data.

As to the dienaminone sophoramine 10, its preferred structure is closely related to that of the parent saturated base matrine 1. The theoretical geometries of 9t, 9c, and

V. Galasso et al. / Chemical Physics 330 (2006) 457–468

Fig. 6. The DFT-optimized structures of conformers 9t and 9c.

10 are in full agreement with the X-ray crystal structures established for sophocarpine monohydrate [32], 12bhydroxy-sophocarpine, and free sophoramine [33], respectively. Compounds 1–8 satisfy the stereochemical conditions for the occurrence of Bohlmann or trans bands in the vibrational spectra, albeit in different ways. These bands

461

are associated with (N–)Ca–H bonds in the antiperiplanar position towards the LPO. Thus, 1–4, 7, and 8 (Fig. 2) have three trans Ca–H bonds, whereas 5 and 6 have only one Ca–H bond. The relevant DFT frequencies are reported in Table 2 together with the available experimental data. The satisfactory correspondence between theory and experiment gives additional support to the present structural characterization. As to the C@O stretching band, it stays relatively constant along the entire series (Table 2), which reflects the similar electronic structure within the piperidinone ring D. Table 3 lists the TD-DFT/GIAO results for the specific ORs calculated for the most stable conformer of the matrines investigated. First, it must be mentioned that sizable errors in the calculated [a]D may arise from various factors: incompleteness of the basis set, inadequacy of the functional, inaccuracy of the molecular structure, and solvent effects. Despite these limitations, some useful information can still be obtained from the sign and magnitude of the theoretical [a]Ds. Indeed, assuming that the quantities calculated with inclusion of solvent effects via PCM [31] for 1–6 are consistent with the experimental results obtained in solution (within an average error of 13 units of specific rotation), it turns out that the absolute configurations of the present theoretical enantiomers (Figs. 2–5) should be (5S,6S,7R,11R)-(+)-1, (5S,6R,7R,11R)-(+)-2, (5R,6S,7R,11R)-()-3, (5R,6R,7S,11R)-(+)-4, (5R,6R,7R, 11R)-(+)-5, and (5R,6S,7R,11S)-(+)-6, respectively. Furthermore, according to the results obtained in vacuum to assign the absolute configuration, the theoretical enantiomers of the two still unknown compounds should be (5R, 6S,7S,11R)-(+)-7 and (5R,6R,7R,11S)-()-8. As to the dehydro-derivatives of 1, the structural characterization

Table 2 The stretching frequencies (cm1) of the Ca–H and C@O bonds in 1–8 1

2

3

Experimentala

Theoretical

Assignment

Experimentala

Theoretical

Assignment

Experimentala

Theoretical

Assignment

2797 2757 2742 1625

2778 2767 2747 1627

C10–H, C2–H C2–H, C10–H C6–H C@O

2806 2755 2730 sh 1633

2779 2768 2724 1629

C2–H C10–H C6–H C@O

2796 2770 sh 2747 1622

2791 2775 2750 1625

C10–H C2–H C6–H C@O

Experimentalb

Theoretical

Assignment

Experimentala

Theoretical

Assignment

Experimental

Theoretical

Assignment

2780 2760 2740 1620

2787 2771 2758 1625

C10–H C2–H C6–H C@O

2801

2810

C2–H

2811

C10–H

1622

1629

C@O

1631

C@O

Theoretical

Assignment

2794 2773 2760 1627

C2–H C10–H C6–H C@O

4

5

7

6

8

Experimental

a b

Present work. Ref. [28].

Theoretical

Assignment

2785 2772 2767 1626

C2–H C10–H C6–H C@O

Experimental

462

V. Galasso et al. / Chemical Physics 330 (2006) 457–468

Table 3 Experimental and theoretical optical rotations of 1–8 in degrees [dm Æ (g/ cm3)]1 Compound

1 2 3 4 5 6 7 8 9 10 a b c d e f g

Theory

Experiment

Enantiomer

[a]D (solvent)

[a]D (solvent)

(5S,6S,7R,11R) (5S,6R,7R,11R) (5R,6S,7R,11R) (5R,6R,7S,11R) (5R,6R,7R,11R) (5R,6S,7R,11S) (5R,6S,7S,11R) (5R,6R,7R,11S) (5S,6S,7R,11R) (5S,6S,7S)

+25.7 (H2O) +67.5 (H2O) 79.0 (H2O) +42.2 (CHCl3) +90.7 (EtOH) +52.8 (EtOH) +61.1 (vacuum) 99.7 (vacuum) 58.3f (EtOH) 134.9 (EtOH)

+38 (H2O)a +46 (H2O)b 64 (H2O)c +44 (CHCl3)d +101 (EtOH)c +72 (EtOH)e

32 (EtOH)g 98 (EtOH)g

Ref. [19]. Ref. [34]. Ref. [20]. Ref. [28]. Ref. [35]. Average weighted value. Ref. [36].

of 9 and 10 is different. Indeed, 10 is conformationally simple and assigned as (5S,6S,7S)-()-10, in agreement with experimental evidence [36]. Instead, (5S,6S,7R,11R)-()-9 is a more complicated case than the previous ones (Fig. 6). The calculated total specific rotation in ethanol is +83.3 for the quasi-trans conformer 9t and 270.7 for the quasi-cis conformer 9c. However, for an equilibrium mixture of these conformers with the ratio 60:40% (as suggested by the theoretical energy difference for ethanol solution), the calculated total specific rotation is 58.3, with sign and magnitude in agreement with the experimental value of 32 in ethanol solution [36]. This result quantitatively accounts for the conformational equilibrium of sophocarpine 9 in solution. As a final comment on the stereochemistry of matrines, it is worthwhile comparing their basicities with those of other polycyclic diamines. According to DFT calculations, monoprotonation of 1–8 occurs on the aminic N1 atom, as expected from the fact that the electron lone pair of N16 is strongly involved in the p-conjugated system N16–C@O. In particular, the protonated matrine 1 retains the conformation of the free base, in full agreement with the X-ray structure obtained for matrinium tetrachloroferrate(III) [37]. The gas-phase proton affinity (PA) was calculated at the DFT level, by taking into account the zero-point energy (weighted by the recommended factor of 0.89 [38]) and the basis set superposition error (estimated by the usual counterpoise method of Boys and Bernardi [39]). The calculated PAs – 236.4 (1), 237.3 (2), 235.8 (3), 236.3 (4), 238.1 (5), 238.0 (6), 237.8 (7), and 236.4 kcal mol1 (8) – are similar to those of a variety of proton sponges described in the literature [40,41], and predict isosophoridine 5 and tetrahydroneosophoramine 6 as the most basic alkaloids in the matrine group. These theoretical values can be correlated with the only available experimental pKa values of 7.72 (1) and 6.51 (3) [42].

3.2. Electronic transitions From a qualitative standpoint, matrine 1 is formed by a quinolizidinone moiety fused with a quinolizidine moiety. Thus, matrine has two main chromophoric units, the amide and amino groups that are responsible for the low-lying electronic transitions. However, its n(Naminic) and n(O) orbitals are appreciably delocalized through the polycyclic r framework and the p(amidic) orbital is also perturbed by the adjacent atoms. The LUMO is mainly contributed by the p*(CO) semilocalized orbital. Furthermore, the nonplanarity of the matrine molecule markedly influences both the energy and intensity of the various electronic transitions (all symmetry allowed). The absorption spectrum of matrine in acetonitrile solution exhibits a broad band in the 200–250 nm range centered at 230 nm (emax 1100 dm3 mol1 cm1). Unfortunately, no spectrum is available in the vacuum UV region. In order to glean at least provisional information, the absorption curve was fit to a sum of two gaussian functions. The area under each component was then used to calculate the oscillator strength f for the related R absorption feature by the equation: f ¼ 4:32  109  eðmÞdm, where e(m) is the molar absorptivity [43]. Accordingly, these two features are peaked at 231 nm (e 500, f 0.0007) and 215 nm (e 950, f 0.0041). The low-lying electronic transitions calculated with the TD-DFT/B3LYP method are: p ðCOÞ 

p ðCOÞ

nðOÞð227nm;f 0:0010Þ; nðNaminic Þð204; 0:0623Þ;



r nðNaminic Þð193; 0:0261Þ;  p ðCOÞ pðamidicÞð189; 0:0750Þ: The first two predicted excitation energies are in reasonable agreement with the ‘‘experimental’’ values. (These results should be consistent with previous reports that place transition energies given by TD-DFT within approximately 0.3 eV of experimental values [9,44,45].) Theory also predicts an intruder r* n(Naminic) transition close to the strong p*(CO) p(amidic) transition. Incidentally, it is worth mentioning that the latter transition of 1 is predicted to be only slightly red-shifted relative to that observed in the absorption spectrum of the simple monocyclic amine 1-methyl-2-pyrrolidone (186 nm) [46]. The presence of the p* n and p* p bands is revealed by the circular dichroism (CD) spectrum. Indeed, (+)-matrine 1 in acetonitrile solution shows a positive Cotton effect at 200–250 nm with peaks at 215 nm (De + 5.4) and 211 nm (De + 5.8) and a negative Cotton effect below 200 nm with peaks at 195 nm (De  2.43) and 191 nm (De  2.5) [47]. The two p* n transitions should then give rise to the positive Cotton effect above 200 nm whereas the p* p transition contributes to the negative region. Remarkable correspondence is found between the experimental evidence and the optical rotatory strengths calculated for the four lowest electronic transitions in 1,

V. Galasso et al. / Chemical Physics 330 (2006) 457–468

10.47, 7.50, 3.82, and 2.00 (in 1040 esu2 cm2) in the length gauge. The TD-DFT overall picture of the absorption spectra for the matrine stereoisomers 2–8 closely resembles that of the parent compound 1, apart from some minor shifts of the bands. 3.3. NMR parameters The 13C NMR chemical shifts calculated by the DFT/ CSGT formalism together with the available experimental values are collected in Table 4. (Based on the previous structural characterization in solution, the theoretical ds of sophocarpine 9 are average weigthed values of 9t and 9c.) It must be noted that highly accurate predictions of the d observable require very large basis sets and higher orders of perturbation theory or coupled-cluster methods. However, for all available compounds, the overall agreement between theory and experiment is satisfactory. A

Table 4 Experimental and theoretical

C NMR chemical shifts relative to TMS 2

a

c d

4

Theoretical

Experimentalb

Theoretical

Experimentalb

Theoretical

Experimentalc

Theoretical

57.6 21.4 27.9 35.6 64.0 43.4 26.6 21.0 57.4 53.4 27.4 19.2 33.0 169.7 41.7

56.0 20.4 25.6 36.1 63.6 45.8 27.5 21.0 56.0 52.3 28.2 19.5 31.3 167.2 37.9

56.3 24.5 27.4 38.8 70.0 46.0 26.6 24.5 55.7 60.1 28.2 19.2 32.7 169.2 46.1

55.1 24.6 27.7 39.2 69.9 47.7 26.0 24.7 54.4 60.0 28.2 19.8 31.2 167.0 43.4

55.8 23.5 28.0 30.6 63.2 40.8 21.6 21.5 50.2 55.7 30.1 18.8 32.5 169.9 47.4

54.5 24.8 29.0 31.8 65.0 44.4 19.2 21.1 49.6 55.4 29.9 20.0 31.3 168.5 47.5

55.7 23.2 26.7 30.6 61.0 39.1 21.2 20.2 51.9 52.6 27.1 18.2 32.6 170.1 45.1

54.4 21.5 27.5 31.7 62.2 41.2 16.5 20.8 50.4 52.5 26.8 20.7 31.2 168.3 41.0

6

7

8

9

b

b

3

Experimentala

5

C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 C15 C17

comprehensive reproduction of the absolute values and main trends in the 13C NMR spectra is observed. The matrine isomers 1–8 may be regarded as derived from a different formal fusion of the quinolizidinone and quinolizidine moieties. The complex balance of the stereoelectronic interactions is manifested by some distinctive chemical shifts. Thus, the chemical shift of the carbonyl resonance changes only slightly along the series 1–8 (Dd  5), resembling the d(CO) value of the precursor half-molecule 2-quinolizidinone (experimental 169.1 [53], our theoretical value 167.6). In contrast, the positions of the apex carbon signals (C5, C6, C7, and C11) are predicted to undergo significant variations (Dd  17, 10, 13, and 8, respectively). A further notable aspect of the NMR spectra concerns the 1H resonances of the lactamic protons. Of the geminal protons, the equatorial proton is deshielded by the synperiplanar amidic group more strongly than its axial partner. The theoretical difference Dd(Heq/Hax) ranges from 2.9 in

13

1

C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 C15 C17

463

Experimental

Theoretical

Theoretical

Theoretical

Theoretical

Experimental

45.0 25.6 22.7 35.8 62.1 33.3 26.6 19.0 53.9 59.9 27.8 18.9 32.8 169.9 46.6

44.5 25.8 22.5 36.5 62.6 34.1 27.8 18.8 53.7 60.2 27.9 19.8 31.3 168.2 43.7

54.1 18.4 29.5 24.7 64.8 41.1 18.6 25.6 44.8 60.2 25.8 20.1 31.8 168.8 45.0

55.5 25.9 30.8 42.2 61.3 39.6 25.3 24.6 53.0 58.1 25.8 20.9 30.4 167.6 38.0

49.8 21.0 19.6 33.7 60.3 36.7 26.6 25.5 54.0 58.1 24.7 21.3 30.0 166.6 38.4

57.2 20.9 27.6 34.5 63.4 41.4 26.5 20.6 57.2 51.4 27.3 137.4 124.4 165.6 41.9

Ref. [49]. Present work, empirical assignment. Ref. [51]. Average weighted values.

10 b

d

Theoretical

Experimentalb

Theoretical

56.1 20.9 27.5 35.4 63.7 42.3 26.0 20.4 56.0 51.5 26.5 138.1 127.9 165.4 39.8

56.8 20.3 27.0 32.1 60.4 38.4 28.0 21.2 56.5 148.0 103.2 138.4 116.4 163.9 43.5

55.8 20.4 27.0 33.6 60.4 39.1 27.5 20.7 55.0 151.7 99.2 137.3 115.9 162.5 40.8

464

V. Galasso et al. / Chemical Physics 330 (2006) 457–468

2 to 0.3 in 4. This effect is a complex function of the torsional alignment of O@C  C–Ha and the O  Ha distance. It is satisfying to remark that the CSGT chemical shifts are in fair agreement with the experimental values determined for 1 [51], 2, 3 [50,52], 4 [51], and 5. This leads further support to the conformational characterization discussed above. In this context, it is also worth noting that in 1, for example, the geminal lactamic C–H bond lengths are ˚ for C–Heq and 1.098 A ˚ predicted by DFT to be 1.090 A for C–Hax. This sizable difference is reflected not only in the 1H NMR spectrum (signals recorded at 4.40 and 3.05 in CDCl3 solution [49]) but also in the vibrational spectrum of 1. Indeed, according to theory, the two lactamic C–H stretchings fall well apart (associated with the features observed at 2998 and 2910 cm1 in the IR spectrum of 1, the first being the highest fundamental). The DFT values of d(H), x(C–H) in cm1, and related potential energy distribution (PED in %) for systems 1–5 compare as follows:

dðHeq Þ dðHax Þ xðC–Heq Þ xðC–Hax Þ

1

2

3

4

5

4.18 2.52 3020 (94) 2909 (33)

4.45 1.57 3021 (97) 2860 (95)

3.03 2.63 2941 (34) 2915 (43)

3.36 3.08 2980 (84) 2929 (60)

4.50 2.04 3020 (97) 2864 (89)

Concerning the substituent and stereoelectronic effects on the indirect nuclear spin–spin coupling constants, owing to the large variety of nJ(XY)s, we restrict the interest on a selection of vicinal and geminal 1H–1H and one-bond 13 C–1H coupling constants. Such interproton couplings, involving lactamic and bridgehead H atoms of the matrine framework, display a well-documented conformational sensitivity [54–56]. On the other hand, an interesting manifestation of stereoelectronic factors is provided by the Per-

lin effect, that is the significant difference in 1J(CH) presented by methylenic C–H bonds adjacent to the N or O LPO in a six-membered ring [57–60]. Typically, 1J(CH) is smaller for antiperiplanar than synclinal arrangements in >N–CH2– systems. The difference between the relevant couplings for cis and trans quinolizidines is 6–9 Hz [61]. Here, in order to predict the magnitude and direction of the Perlin effect, DFT calculations were carried out on the geminal lactamic C–H bonds. The related geminal 2 J(HH)s are also affected by the orientational dependence on the N–C@O group. According to DFT/B3LYP calculations, the dominant contribution to all 1J(CH)s, 2J(HH)s, and 3J(HH)s in the matrine series is brought about by the Fermi-contact term, the non-contact contributions being comparatively small in all cases. The DFT results are presented in Tables 5 and 6. As shown in Table 5, the trans 3J(H5H17eq) is a few Hz larger than the gauche3J(H5H17ax) in all matrines but isosophoridine 5. These two interproton coupling constants are instead small and nearly equal in 5, as a consequence of the common gauche path. On the other hand, the interbridgehead couplings 3J(H5H6), 3J(H6H7), and 3J(H7H11) display a large variety of values, basically consistent with the related dihedral angles. Unfortunately, the highly overlapped resonances of these protons make their experimental determination quite difficult. Another notable result in Table 5 is the good agreement between the calculated and experimentally observed 2J(H17H17)s. As to 1J(CH)s of the lactamic system, the NMR measurements show a substantial, normal Perlin effect in all cases, that is 1J(CHeq) > 1J(CHax) (Table 5), as found previously for the related sparteine lactams [62]. The DFT calculations reproduce the available experimental values satisfactorily. In particular, the calculated D1J(CHeq/ CHax)s are in line with the larger and smaller magnitude experimentally found for 2 and 3, respectively. A noteworthy point is that the positive Perlin effect parallels the desh-

Table 5 Theoretical vicinal and geminal 1H–1H nuclear spin–spin coupling constants (Hz) of bridgehead and lactamic protons (experimental values) 1 3

J(H5H6) J(H6H7) 3 J(H7H11) 3 J(H5H17ax) 3 J(H5H17eq) 2 J(H17axH17eq) 3

3.4 3.2 8.1 10.1 4.2 12.3 6

3

J(H5H6) J(H6H7) 3 J(H7H11) 3 J(H5H17ax) 3 J(H5H17eq) 2 J(H17axH17 3

a b c d

eq)

8.8 4.6 3.1 9.4 4.5 12.7

Refs. [48,49]. Present work. Ref. [50]. Average weighted values.

2

(9.5)a (12.4) (4.4) (12.6)

7.5 7.5 7.9 9.5 3.7 12.8 7 7.0 9.2 8.2 9.2 1.2 13.3

b

(9.5) (9.5) (9.5) (13.3) (3.8) (13.2)

3

4

5

8.6 9.3 8.1 11.1 (11.2)b 4.7 (4.9) 13.4 (13.6)c

4.3 9.1 3.0 11.2 3.2 12.5

4.7 8.6 7.8 3.8 1.8 13.1 (14.5)b

8

9

10

9.1 9.2 7.5 9.5 6.3 12.5

d

3.3 3.3 8.4 10.0 (13.0)b 4.2 (4.7) 12.4 (12.9)

10.5 (12.7)b 5.5 (6.8) 14.8 (14.5)

V. Galasso et al. / Chemical Physics 330 (2006) 457–468 Table 6 Theoretical one-bond

13

C–1H nuclear spin–spin coupling constants (Hz) of bridgehead and lactamic protons (experimental values)a 1

1

J(C5H5) J(C6H6) 1 J(C7H7) 1 J(C11H11) 1 J(C17H17eq) 1 J(C17H17ax)

130.1 129.6 128.9 138.4 144.1 136.8

1

2 (130.0) (133.0) (128.0) (144.5) (141.5) (135.0)

6 1

J(C5H5) J(C6H6) 1 J(C7H7) 1 J(C11H11) 1 J(C17H17eq) 1 J(C17H17ax) a

c

3

130.3 123.7 129.2 133.6 145.2 132.7

(131.0) (128.0) (131.0) (135.5) (142.0) (134.0)

7

128.9 132.2 127.4 133.6 145.7 131.7

1

b

465

127.0 129.5 129.9 136.2 143.6 142.7

(129.0) (133.0) (138.5) (138.0) (142.0)b (141.0)b

8

129.6 128.6 127.6 137.4 143.5 135.2

4

5

125.9 131.5 126.9 135.2 144.9 143.6

129.2 132.5 127.9 133.1 144.7 133.3

9

10 c

131.9 130.6 127.3 136.7 144.8 135.4

130.1 129.5 129.2 139.9 144.5 138.1

(129.0) (131.5) (128.5) (139.0) (141.5) (137.0)

(128.0) (133.5) (127.0) (135.5) (142.0) (135.5)

129.3 (130.0) 131.3 (132.0) 126.9 (128.0) 146.4 (151.0) 145.4 (143.0)

Present work. These two hydrogens are in the nodal plane of the amide group. Average weighted values.

ielding effect Dd(Heq/ Hax) as well the moderate C–H length compression. However, such magnetic properties are driven by subtle stereoelectronic interactions, as suggested by the fact that, for the present molecules, the C–H bond distance cannot be correlated with the corresponding 1 J(CH) or d(1H) in any simple way. 3.4. Ionization energies The low-energy region of the He(I) PE spectrum provides valuable probes of the electronic structure of a compound, in particular of its outer valence MOs.

The ab initio OVGF ionization energies (Eis) and assignments for compounds 1–10 are given in Table 7. The pole strengths calculated for all investigated photoionization processes are larger than 0.85, which excludes the presence of nearby shake-up lines and thus indicates that the oneparticle model of ionization is confidently valid [63]. On the whole, the correspondence between experimental data and OVGF predictions is satisfactory (Table 7). Some discrepancies between OVGF estimates and available spectroscopic data are most likely due to the limited basis set used and truncation of the particle space in the OVGF treatment.

Table 7 Vertical ionization energies (eV) and assignments MO

n(N1) p(amidic) n(O) r r

1

2

n(N1) p(amidic) n(O) p(CC) r r p

4

Ei,experimental

Ei,theoretical

Ei,experimental

Ei,theoretical

Ei,experimental

Ei,theoretical

8.05 8.58 9.23 10.09 10.61

8.05 8.60 8.95 10.0

8.25 8.42 9.30 10.06 10.58

8.2 8.45 8.97 10.1 10.6

8.21 8.29 9.30 10.23 10.50

8.0 8.4 8.9 10.15

8.15 8.34 9.21 10.29 10.47

5

n(N1) p(amidic) n(O) r r

3

Ei,theoretical

6

7

8

Ei,theoretical

Ei,experimental

Ei,theoretical

Ei,theoretical

Ei,theoretical

7.84 8.36 9.30 10.38 10.85

7.8 8.45 8.88 10.3

7.86 8.38 9.36 10.32 10.93

8.06 8.47 9.34 10.10 10.75

8.10 8.33 9.30 10.27 10.66

9t

9c

9

Ei,theoretical

Ei,theoretical

Ei,experimental

8.13 8.79 9.59 9.26 10.09 10.62 11.14

8.09 8.58 9.60 9.36 10.05 10.67 11.18

8.1 8.55 8.8 9.6 9.85

10 MO

Ei,theoretical

Ei,experimental

p(CC) n(N1) n(O) p(N16,CO) r p r

7.23 8.56 9.53 9.59 10.41 10.76 11.12

7.55 8.5 8.9 9.6 10.2

466

V. Galasso et al. / Chemical Physics 330 (2006) 457–468

The most peculiar electronic aspects of the present compounds concern the energy pattern of the photoionizations originating from the N(aminic) and O LPOs, and the bonding p(N), p(CO), and p(CC) orbitals. From a qualitative standpoint, these semilocalized orbitals are significantly mixed and energetically split by a complex balance of conjugative and inductive effects, and through-bond and through-space interactions. (See, e.g., the detailed analysis by Kirby et al. [64] on this interaction in the N–C@O unit of a representative system, 1-aza-adamantan-2-one.) In order to help in the assignment of the bands (Fig. 7 and Table 7), reference is made to the PE spectra of the related monocyclic compounds, N-methyl-piperidine (11) (8.30 eV n(N)) [62], N-methyl-piperidin-2-one (12) (8.9 [p(amidic)], 9.2 [n(O)], 11.4 [p(amidic)] eV) [65],

N-methyl-2-pyridone (13) (8.41 [p(O,N,CC)], 9.54 [n(O)], 10.42 [p(N,CC)] eV) [66], and other lactams [67]. In the low energy region 7–10 eV, the PE spectrum of 1 (Fig. 7) comprises two distinct bands peaked at 8.05 and 8.60 eV, with a shoulder at 8.95 eV. At 9.5 eV starts the onset of a prominent, congested band system, which is associated with the manifold of r-photoionizations. The feature due to the bonding p(CO) is hidden under this unresolved region. The first two bands are associated with the MOs n(Naminic), p(amidic), and n(O), respectively. Comparison of these Eis with those of 11 and 12 indicates a destabilization of 0.3 eV of the first three MOs, as a result of annelation. On the other hand, comparison of these Eis with those of lupanine, an isoelectronic alkaloid of sparteine-type (8.05, 8.47, and 8.92 eV) [68], reveals that these semilocalized MOs are quite slightly influenced by changing the formal fusion of the quinolizidine and quinolizidone moieties. With reference to the PE evidence collected for matrines 1–8 in Table 7, the following distinct situations are apparent. Of the outer valence MOs, the n(Naminic) MO undergoes a sizable shift along the series. Indeed, it becomes less tightly bound by 0.4 eV on passing from 2 to 5, consistent with the different steric arrangement of the ABC moiety. In contrast, the energy of the p(amidic) and n(O) MOs, localized mainly in ring D, remains virtually unchanged. Furthermore, comparison of the Eis of 1–8 with those of 9 and 10 reveals that these MOs are slightly influenced by the increased p-conjugation in ring D. The first Ei is still associated with the n(Naminic) ionization in sophocarpine 9, as in the parent matrine 1. It is instead due to the uppermost p(CC) level in sophoramine 10. Finally, it can be mentioned that the multi-peaked structure of the second band of 10, associated with the photoionizations from the n(Naminic) and n(O) MOs, resembles that shown at 9.54 eV by the n(O) band of the parent monocyclic molecule 13 [66]. Furthermore, it can be noted that the theoretical Eis of the 9t conformer do not show sufficient variation from the 9c values to allow any information on the conformational equilibrium of sophocarpine 9 in the gas phase to be confidently derived from the PE spectrum. 4. Concluding remarks

Fig. 7. Ultraviolet He(I) photoelectron spectra.

A detailed compendium of structural and spectroscopic data of matrine (1), its stereoisomers (2–8), sophocarpine 9, and sophoramine 10 has been presented. The theoretical results, obtained at the DFT and ab initio level, have provided accurate information, which makes up for the lack of experimental measurements. In particular, the equilibrium conformations of these alkaloids have been thoroughly investigated by the DFT/B3LYP method. All of these molecules but sophocarpine exhibit a strong preference for one relatively rigid conformation. Sophocarpine is instead predicted to have a marked flexibility at the lactamic nitrogen and to exist as a mixture of C/D-trans and C/D-cis conformers in the gas phase or solution. The theoretical struc-

V. Galasso et al. / Chemical Physics 330 (2006) 457–468

tural results agree fairly well with the available data of X-ray diffraction measurements. TD-DFT/GIAO calculation of the specific optical rotation has also been performed to elucidating the absolute configuration of the most stable conformer of each compound. The Boltzmann average of the specific rotation of the two conformers of sophocarpine accounts for the experimental evidence correctly. The electronic structure of the matrine-type alkaloids has been investigated with their UV, NMR, and PE spectroscopic properties. On the whole, the theoretical information is consistently correlated with experimental evidence. Thus, the low-lying electronic excited states have been characterized in terms of p* n and p* p transitions. Further, a specific set of NMR parameters, the 13C and 1 H chemical shifts and the nuclear spin–spin coupling constants nJ(HH) and 1J(CH), have been calculated with DFT formalisms. The satisfactory reproduction of the spectroscopic data corroborates the reliability of the present structural characterization. Most interestingly, the manifestation of stereoelectronic hyperconjugative effects on Dd(Heq/Hax) and D1J(CHeq/CHax) of the lactamic groups is correctly accounted for by the DFT predictions. The assignment of the low-lying bands in the He(I) PE spectra has been supported by ab initio OVGF calculations. The theoretical results indicate that the location, splitting, and sequence of these bands reflect the competing interactions among the n(Naminic), n(O), p(N,CO), and p(CC) chromophores. Acknowledgements Support from the Italian M.I.U.R. is gratefully acknowledged by V.G. and that from the Ministry of Science, Education and Sports of the Republic of Croatia by B.K.. F.P. thanks the COE project for financial support and JAERI (Kyoto) for a generous allotment of time on its ITBL computer systems. The authors are grateful to Dr. L. Zhang (The Chinese Academy of Sciences, Bejing) for providing a copy of reference [51]. References [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]

Kh.A. Aslanov, Yu.K. Kushmuradov, Alkaloids 31 (1987) 117. S. Ohmiya, K. Saito, I. Murakoshi, Alkaloids 47 (1995) 1. J.Z. Song, H.X. Xu, S.J. Tian, J. Chromatogr. A 857 (1999) 303. B.Q. Hamida, R.W. Philip, A.K. Mushtaq, Phytotherapy Res. 16 (2002) 154. T.H. Tsai, J. Chromatogr. B 764 (2001) 27. P. Ding, Y. Yu, D. Chen, Phytochem. Anal. 16 (2005) 257. B.T. Ibragimov, S.A. Talipov, Yu.K. Kushmuradov, T.F. Aripov, Khim. Prir. Soedin. 5 (1981) 597. J.R. Cheeseman, M.J. Frisch, F.J. Devlin, P.J. Stephens, J. Phys. Chem. A 104 (2000) 1039. R.E. Stratmann, G.E. Scuseria, M.J. Frisch, J. Chem. Phys. 109 (1998) 8218. L.S. Cederbaum, J. Phys. B 8 (1975) 290. A.D. Becke, J. Chem. Phys. 98 (1993) 5648. M.J. Frisch et al., Gaussian 03, Revision B.5, Gaussian Inc., Pittsburgh, PA, 2003.

467

[13] E.B. Wilson, J.C. Decius, P.C. Cross, Molecular Vibrations, McGraw-Hill, New York, 1945. [14] G. Rauhut, P. Pulay, J. Phys. Chem. 99 (1995) 3093. [15] D.E. Woon, T.H. Dunning Jr., J. Chem. Phys. 98 (1993) 1358. [16] T.A. Keith, R.F.W. Bader, Chem. Phys. Lett. 210 (1993) 223. [17] T.H. Dunning Jr., J. Chem. Phys. 53 (1970) 2823. [18] N.F. Ramsey, Phys. Rev. 91 (1953) 303. [19] P. Xiao, H. Kubo, M. Ohsawa, K. Higashiyama, H. Nagase, Y.-N. Yan, J.-S. Li, J. Kamei, S. Ohmiya, Planta Medica 65 (1999) 230. [20] K. Morinaga, A. Ueno, S. Fukushima, M. Namikoshi, Y. Iitaka, S. Okuda, Chem. Pharm. Bull. 263 (1978) 2843. [21] G. Bodenhasen, D.J. Ruben, Chem. Phys. Lett. 69 (1980) 185. [22] G. Otting, K. Wu¨thrich, J. Magn. Reson. 76 (1988) 569. [23] L. Klasinc, B. Kovacˇ, B. Rusˇcˇic´, Kem. Ind. (Zagreb) 10 (1974) 569. [24] S. Geremia, L. Vicentini, M. Calligaris, Inorg. Chem. 37 (1998) 4094. [25] B.T. Ibragimov, S.A. Talipov, G.N. Tishchenko, Yu.K. Kushmuradov, T.F. Aripov, Kristallografiya 23 (1978) 1189. [26] B.T. Ibragimov, G.N. Tishchenko, Yu.K. Kushmuradov, T.F. Aripov, Khim. Prir. Soedin. 3 (1979) 416. [27] B.T. Ibragimov, G.N. Tishchenko, Yu.K. Kushmuradov, T.F. Aripov, Khim. Prir. Soedin. 3 (1979) 355. [28] A. Ueno, K. Morinaga, S. Fukushima, Y. Iitaka, Y. Koiso, S. Okuda, Chem. Pharm. Bull. 23 (1975) 2560. [29] B.T. Ibragimov, S.A. Talipov, G.N. Tishchenko, Yu.K. Kushmuradov, Khim. Prir. Soedin. 4 (1979) 586. [30] B.T. Ibragimov, S.A. Talipov, G.N. Tishchenko, Yu.K. Kushmuradov, T.F. Aripov, S. Kuchkarov, Khim. Prir. Soedin. 4 (1979) 588. [31] V. Barone, M. Cossi, J. Tomasi, J. Chem. Phys. 107 (1997) 3210. [32] M.A. Khan, G.E. Burrows, E.M. Holt, Acta Crystallogr. Sect. C 48 (1992) 2051. [33] Atta-ur-Rahman, M.I. Choudhary, K. Parvez, A. Ahmed, F. Akhtar, M. Nur-e-Alam, N.M. Hassan, J. Nat. Prod. 63 (2000) 190. [34] K. Morinaga, A. Ueno, S. Fukushima, M. Namikoshi, Y. Iitaka, S. Okuda, Chem. Pharm. Bull. 26 (1978) 2483. [35] A. Zunnunzhanov, S. Iskandarov, S.Yu. Yusunov, Khim. Prir. Soedin. (1971) 851. [36] S. Okuda, H. Kamata, K. Tsuda, Chem. Ind. (1962) 1326. [37] Z.M. Jin, Z.G. Li, L. Li, M.C. Li, M.L. Hu, Acta Crystallogr. Sect. E 61 (2005) 2466. [38] R.F. Hout, B.A. Levi, W.J. Hehre, J. Comput. Chem. 3 (1982) 234. [39] S.F. Boys, F. Bernardi, Mol. Phys. 19 (1970) 553. [40] S.T. Howard, I.A. Fallis, J. Org. Chem. 63 (1998) 7117. [41] H. Guo, D.R. Salahub, J. Mol. Struct. Theochem. 547 (2001) 113. [42] S. Gong, X. Su, T. Bo, X. Zhang, H. Liu, K.A. Li, J. Sep. Chem. 26 (2003) 549. [43] R.S. Mulliken, C.A. Rieke, Phys. Soc. Rep. Prog. Phys. 8 (1941) 231. [44] S. Hirata, T.J. Lee, M. Head-Gordon, J. Chem. Phys. 111 (1999) 8904. [45] C.-P. Hsu, S. Hirata, M. Head-Gordon, J. Phys. Chem. A 105 (2001) 451. [46] H. Basch, M.B. Robin, N.A. Kuebler, J. Chem. Phys. 47 (1967) 1201. [47] G. Snatzke, T. Xuan, Snatzke-Spectra Collection, spectrum 12307. [48] N.C. Gonnella, J. Chen, Magn. Reson. Chem. 26 (1988) 185. [49] G.-Y. Bai, D.-Q. Wang, C.-H. Ye, M.-L. Liu, Appl. Magn. Reson. 23 (2002) 113. [50] P. Xiao, H. Kubo, H. Komiya, K. Higashiyama, Y.-N. Yan, J.-S. Li, S. Ohmiya, Phytochemistry 50 (1999) 189. [51] L. Qiao, L. Huang, C. Gao, Y. Zhao, X. Yang, L. Zhang, Beijing Yike Daxue Xuebao (J Peking Med Univ) 26 (1994) 485. [52] F.G. Kamaev, V.B. Leont’ev, Kh.A. Aslanov, Yu.A. Ustyniuk, A.S. Sadykov, Khim. Prir. Soedin. (1974) 744. [53] G.L. Milligan, C.J. Mossman, J. Aube´, J. Am. Chem. Soc. 117 (1995) 10449. [54] V.M.S. Gil, W. von Philipsborn, Magn. Reson. Chem. 27 (1989) 409. [55] M. Barfield, W.B. Smith, J. Am. Chem. Soc. 114 (1992) 1574; Magn. Reson. Chem. 31 (1993) 696; Magn. Reson. Chem. 34 (1996) 740.

468

V. Galasso et al. / Chemical Physics 330 (2006) 457–468

[56] J. San-Fabian, J. Guilleme, E. Diez, P. Lazzeretti, M. Malagoli, R. Zanasi, A.L. Esteban, F. Mora, Mol. Phys. 82 (1994) 913. [57] A.S. Perlin, B. Casu, Tetrahedron Lett. (1969) 2921. [58] V.S. Rao, Can. J. Chem. 60 (1982) 1067. [59] S. Wolfe, B.M. Pinto, V. Varma, R.Y.N. Leung, Can. J. Chem. 68 (1990) 1051. [60] E. Cuevas, E. Juaristi, J. Am. Chem. Soc. 124 (2002) 13088. [61] G. Van Binst, D. Tourwe´, Heterocycles 1 (1973) 257. [62] V. Galasso, F. Asaro, F. Berti, B. Kovacˇ, I. Habusˇ, A. Sacchetti, Chem. Phys. 294 (2003) 155.

[63] M.S. Deleuze, J. Chem. Phys. 116 (2002) 7012. [64] A.J. Kirby, I.V. Komarov, K. Kowski, P. Rademacher, J. Chem. Soc., Perkin Trans. 2 (1999) 1313. [65] L. Treschanke, P. Rademacher, J. Mol. Struct. Theochem. 122 (1985) 47. [66] M.J. Cook, S. El-Abbady, A.R. Katritzky, C. Guimon, G. PfisterGuillouzo, J. Chem. Soc. Perkin II (1977) 1652. [67] I. Novak, W. Huang, J. Phys. Org. Chem. 12 (1999) 388. [68] V. Galasso, F. Asaro, F. Berti, B. Kovacˇ, I. Habusˇ, C. De Risi, Chem. Phys. 301 (2004) 33.