alin

V. Galasso *, B. Kovac , A. Modelli

and elucidates the empty level electronic structure of artemisinin and derivatives in the 06 eV energy range, with the support of MOcalculations and comparison with the spectra of reference molecules. Electron attachment to the lowest-lying empty r* MO, mainly local-

Plasmodium falciparum [1]. Recently, it has also been pro-ven that 1 has an antitumor activity [2]. These sesquiter-penes contain a 1,2,4-trioxane ring, and the highly

A detailed understanding of the mechanism of action of 1has previously spurred some quantum-mechanical calcula-tions on cleavage of the endoperoxide bond and principalreactions with possible sources of iron in the parasite [79].

Because the biological activity of these sesquiterpenes isclosely related to stereochemistry, thorough investigations

* Corresponding author. Tel.: +39 040 558 3947; fax: +39 040 558 3903.E-mail address: galasso@univ.trieste.it (V. Galasso).

Chemical Physics 335 (20ized on the OO bridge, occurs at an energy (1.7 eV) exceptionally low for compounds not containing third-row or heavier elements. 2007 Elsevier B.V. All rights reserved.

Keywords: Artemisinin; Ab initio and DFT calculations; Geometric and electronic structures; Vibrational frequencies; NMR chemical shifts and couplingconstants; Photoelectron and electron transmission spectra

1. Introduction

Artemisinin or qinghaosu (1) and its derivatives are themost widely used antimalarial drugs that are eectiveagainst multidrug-resistant malarial parasite strains like

reactive endoperoxide function plays a key role in theirantimalarial activity [3]. As demonstrated by ESR studies[46], reductive breaking of this bond operated by ironcomplexes generates reactive radicals, and the followingchain of reactions would nally damage the parasite.a Dipartimento di Scienze Chimiche, Universita` di Trieste, I-34127 Trieste, Italyb The Rud-er Boskovic Institute, HR-10002 Zagreb, Croatia

c Dipartimento di Chimica G. Ciamician, Universita` di Bologna, I-40129 Bologna, Italyd Centro Interdipartimentale di Ricerca in Scienze Ambientali, Universita` di Bologna, I-48100 Ravenna, Italy

Received 27 February 2007; accepted 10 April 2007Available online 21 April 2007

Abstract

The equilibrium structures of artemisinin and a selection of its derivatives (potent antimalarial drugs) have been studied with the den-sity functional theory ansatz B3LYP. Of the ve rings of the artemisinin framework, it is only the pyranose ring B that exhibits a markedconformational exibility, especially on addition of a pendant side chain at C-10. For the derivatives, the b isomer with the axial sub-stituent group is found to be energetically more stable than the a isomer with the equatorial group. The assignment of the vibrationalfundamentals has been supported by calculations on related model molecules and a normal coordinate analysis. This allows for a reliablecharacterization of the normal modes, mainly involving the peroxide linkage, in the claimed ngerprint region of 1,2,4-trioxanes. Theelectronic structures have also been studied by measuring and calculating signicant features of the NMR, photoelectron and electrontransmission spectra. In particular, a representative set of NMR chemical shifts and nuclear spinspin coupling constants, obtained withDFT formalisms, compares favourably with experiment and ts expectation in terms of stereoelectronic eects of the vicinal oxygen lonepairs. Based on ab initio outer valence Greens function calculations, a consistent interpretation of the uppermost bands in the photo-electron spectra of artemisinin and derivatives has been advanced. The top ionization energies reect a complex interaction of the variousoxygen lone pair orbitals. Electron transmission spectroscopy is applied for the rst time to compounds containing the peroxide bondA theoretical and experimentelectronic structures of artemis

a,0301-0104/$ - see front matter 2007 Elsevier B.V. All rights reserved.doi:10.1016/j.chemphys.2007.04.008study on the molecular andin and related drug molecules

b c,d

www.elsevier.com/locate/chemphys

07) 141154

of their molecular and electronic structures are, therefore,of current interest. Thus, a comprehensive insight intothe structural and spectroscopic similarities and dierencesbetween these compounds by means of experimental mea-surements and quantum-mechanical calculations seemedtimely. Here, we report on artemisinin (C15H22O5, 1),epiartemisinin (C15H22O5, 2), dihydroartemisinin(C15H24O5, 3, DHA), artemether (C16H26O5, 4), arteether(C17H28O5, 5), artesunate (C19H28O8, 6), artemisitene(C15H20O5, 7), 10-deoxo-artemisinin (C15H24O4, 8), 13-carba-artemisinin (C16H24O4, 9), and 10-deoxo-13-carba-artemisinin (C16H26O3, 10) (Fig. 1). Their conformationalpreferences are fully investigated using the density func-tional theory (DFT) formalism.

Among the various spectroscopic observables, the vibra-tional frequencies, NMR parameters, vertical ionizationenergies (Eis) and electron attachment energies (VAEs)are very ecient monitors of the complex interplay ofstructural and electronic eects operating in these mole-cules. Here, we describe measurements and calculationsof these properties, supported by the results obtained forsimple reference molecules. In particular, the vibrationalfrequencies are investigated by DFT calculations and a

O

O

O

O

AC

O

BO

O

O

O

O

1

7

8

D(E)

8a

9

1011

1213

3

45

5a6

12a12

2

142 V. Galasso et al. / Chemical PhO

O

O O

OH

O

O

O O

OR

O

O

O

O

O

O

O

O O

O

O O

O

O

O

O

4 R = Me ; 5 R = Et ;6 R = CO(CH2)2COOH

3

7 8

109Fig. 1. Formulas, ring labelling, and atom numbering of compounds110.standard normal coordinate analysis. The 1H and 13Cchemical shifts and indirect nuclear spinspin couplingconstants nJ(HH) and 1J(CH) are studied with DFT for-malisms. Photoelectron spectroscopy (PES) and electrontransmission spectroscopy (ETS) are employed to deter-mine the lled and empty electronic structures, respec-tively. The low-energy Eis, mainly associated with theoxygen lone pair orbitals and measured in the He(I) PEspectra, are analyzed by means of ab initio many-body cal-culations using the outer valence Greens function (OVGF)method. The complementary ET spectra provide theVAEs, i.e., the negative of the vertical electron anities.To our knowledge, ETS studies of peroxides have neverappeared in the literature. These data, although in thegas phase, are directly correlated with the pharmacologicalactivity of artemisinin-type drugs in the biological medium,where the mechanism is triggered by chemical reductionand cleavage of the peroxide bond [10].

2. Computational and experimental details

The molecular structures of all compounds 110 werestudied with the DFT/B3LYP hybrid functional [11] byusing the 6-31G(d,p) basis set and the Gaussian-03 packageof programs [12]. Harmonic frequency calculations wereperformed for all the optimized structures to establish thatthe stationary points are minima. The vibrational charac-terization was based on the normal mode analysis per-formed according to the Wilson FG matrix method [13],using standard internal coordinates and the scaling factorsof Rauhut and Pulay [14]. Localization of the molecularorbitals (MOs) was achieved according to the PipekMezeyprocedure [15].

The relative energies were also estimated by single-pointcalculations at the ab initio MP2/6-31G(d,p) level.

The 1H and 13C NMR absolute shielding constants (rvalues) were calculated at the DFT/B3LYP level with thecontinuous set of gauge transformations (CSGT) method[16] using the 6-311+G(2d,p) basis set. The calculated mag-netic shieldings were converted into the d chemical shifts bynoting that at the same level of theory the 1H and 13C abso-lute shieldings in tetramethylsilane (TMS) are 31.25 and177.54, respectively. The indirect nuclear spinspin cou-pling constants were obtained by means of standardresponse-theory methods at the DFT/B3LYP level usingthe DZP basis set [17]. The calculation of the J tensor tookinto account all four contributions of the nonrelativisticRamsey theory [18], i.e., in addition to the Fermi-contactterm, also the diamagnetic spinorbit, paramagnetic spinorbit, and spindipole terms.

The Eis and attachment energies of 15 and referencemolecules were calculated at the ab initio level accordingto Cederbaums OVGF method [19], which incorporatesthe eects of electron correlation and reorganizationbeyond the HartreeFock (HF) approximation. The self-

ysics 335 (2007) 141154energy part was expanded up to third order and the contri-butions of higher orders were estimated by means of a

l Phrenormalization procedure. In order to calculate the self-energy part, all occupied valence MOs and the 95 (13),100 (4), and 105 (5) lowest virtual MOs were considered.The calculations were performed using the DZP basis set[17].

The He(I) PE spectra were recorded on a Vacuum Gen-erators UV-G3 spectrometer [20] with spectral resolutionof 25 meV when measured at the full width at half maxi-mum of the Ar+ 2P3/2 calibration line. The PE spectra ofthe simple reference compounds DVL (d-valerolactone)and MTP (2-methoxy-tetrahydropyran) were alsorecorded. The sample inlet temperatures required to gener-ate sucient vapour pressure were 100, 120, 100, 95, 30,and 20 C, for 1, 3b, 4b, 5b, DVL, and MTP, respectively.The energy scale was calibrated by admitting smallamounts of Ar and Xe to the sample ow.

The VAEs of 1, 3b, 4b, 5b, and the reference moleculesdi-tert-butyl-peroxide (DBP), MTP and DVL were mea-sured by means of ETS. Our experimental setup is in theformat devised by Sanche and Schulz [21] and has beenpreviously described [22]. To enhance the visibility of thesharp resonance structures, the impact energy of the elec-tron beam is modulated with a small ac voltage, and thederivative of the electron current transmitted through thegaseous sample is measured directly by a synchronouslock-in amplier. Each resonance is characterized by a min-imum and a maximum in the derivative signal. The energyof the midpoint between these features is assigned to theVAE. The spectra were obtained in the high-rejectionmode [23], and are therefore related to the nearly total scat-tering cross-section. The electron beam resolution wasabout 50 meV (fwhm). The energy scale was calibratedwith reference to the (1s12s2)2S anion state of He. The esti-mated accuracy of the measured VAEs is 0.05 or 0.1 eV,depending on the number of decimal digits reported.

Compounds 1, 3b, 4b, and 5b were prepared, puried,and identied by Alchem International Limited (NewDehli, India), and used as received.

3. Results and discussion

3.1. Molecular structures

The artemisinin molecule 1 incorporates a relativelyrigid pentacyclic framework, formed of the cyclohexanering A, the pyranose ring B, the 1,2,4-trioxane ring C,the oxepane ring D, and the 1,2-dioxepane ring E. Ringjunctions A/B, A/D, and B/C are cis, and junctions A/Eand B/D are trans. The description of the ring forms in 1and derivatives has been advanced on the basis of the val-ues of the asymmetry parameters [24,25] and conformationdiscriminators [26] calculated for each of the possible con-formations of a six- or seven-membered ring. A notableaspect is that the artemisinin derivatives 36 can assumeboth a and b conguration at C-10 [27].

V. Galasso et al. / ChemicaThe DFT structural parameters are in substantial agree-ment with the X-ray experimental values obtained for 1[28], 2 [29], 3b, 4b [27], 6a, 6b [30], and 10 [31]. A cursorysurvey of the most relevant structural features provided bythe theoretical study for 110 prompts the followingremarks.

(i) With reference to the lowest-energy conformation of1 and derivatives investigated here, all rings but Bhave one rigid conformation: chair (A), twist-boat(C and D), and twist-chair (E). The pyranose ring Bis instead the only exible component of the polycy-clic system. Indeed, it exists in half-chair form in 1and its 13-carba-derivative 9, in a sofa form in theepimer 2 and the unsaturated derivative 7, and in achair form in DHA 3 and derivatives 4, 5, 6, 8, and10. As representative examples, the DFT-optimizedstructures of 1, 2, 3a, and 3b are shown in Figs. 3and 4.

(ii) According to DFT, 1 is 1.2 kcal mol1 more stablethan its C-9 epimer 2 in the gas phase. Also the sin-gle-point MP2 calculation favours 1 over 2 by1.2 kcal mol1.

(iii) Each a and b isomer of 36 can formally adopt thechair or the twist-boat arrangement for ring B.DFT predicts a preference for the chair form overthe twist-boat in the case of both 3a and 3b, by 1.1and 5.6 kcal mol1 (0.9 and 5.7 kcal mol1 at theMP2 level), respectively, in the gas phase. Similarenergy dierences are calculated for the a and b iso-mers of artemether 4 and arteether 5. In 3b (B-chair),the axial arrangement of the OH group is stronglyfavoured by the anomeric eect. This common con-formational preference is at variance from the behav-iour shown by 10a- and 10b-aryl derivatives of DHA[32]. Indeed, the a-aryl compounds possess a chairring B with equatorial aryl group, whereas somebulky b-aryl derivatives have a twist-boat pyranosering with equatorial aryl group. This conformationalchange arises because the aryl group experiences adestabilizing 1,3-diaxial interaction with the C8C8abond in the chair conformation of the b-derivatives.

(iv) For 36, the b isomer is predicted by DFT to be morestable than the a isomer by 2.2, 2.3, 2.3, and7.5 kcal mol1, respectively. (As concerns the zero-point energy dierence between the two isomers, ithas a value of 0.20.3 kcal mol1 and does not signif-icantly modify the stability order.) At the ab initioMP2 level for the DFT-optimized structures of 36,the relative preference is 2.8, 3.2, 3.3, and8.7 kcal mol1, respectively. These results corrobo-rate the empirical conclusion by Haynes et al. [30]that the exclusive formation of a-artesunate (6) inthe acylation of DHA (3) cannot be attributed tothe relative stability of the epimers but to a kineticphenomenon. For 3, the a! b interconversion, pre-sumably through an aldehydealcohol intermediate,

ysics 335 (2007) 141154 143was found to occur in solution, the rate and equilib-rium position being solvent dependent [27]. In this

respect, geometry optimization of 3a and 3b at theDFT level has also been carried out in chloroform(dielectric constant e 4.9) and methanol (e 32.63) solu-tion with the polarizable continuum model (PCM)[33]. The energy dierence between the a and b iso-mers is reduced from 2.2 kcal mol1 in the gas phaseto 1.6 in chloroform and 0.9 kcal mol1 in methanolthat is consistent with the observed equilibration rate[27].

(v) The main structural feature of artemisinin and itsderivatives is the unsymmetric endoperoxide bridge.Selected DFT structural data, together with the avail-able X-ray data, are presented in Table 1. Notably,the OO distance is of ca. 1.46 A and correspondsto a bond order index of 0.89. By comparison, thisbond length is 1.457 A in dimethyl-peroxide [34]and 1.478 A in di-tert-butyl-peroxide [35]. On theother hand, the O1C12a bond is signicantly longer

The IR and Raman techniques have been applied toprobe the vibrational modes in the 1,2,4-trioxane ring (C)of 1, especially of the endoperoxide moiety [3639]. Inthe earlier experimental studies [36,37], the OpOp vibra-tions were assigned to the bands observed at 722, 831,and 881 cm1, the lower frequency band being attributedto the OpOp stretch. Later, on the basis of the vibrationalspectra of some 1,2,4-trioxanes, both cis- and trans-fused,18O-isotopically and methyl substituted, Jeord et al. [39]recognized the two bands at 780 20 and 880 10 cm1

arising from a combination of COp and OpOp stretch-ing vibrations of the OOC entity as the ngerprint of1,2,4-trioxanes. Thus, the bands at 789 and 876 cm1 wereclassied as characteristic bands of 1 [39]. Last, Gu et al.[40,41] performed quantum-mechanical calculations on 1and empirically assigned the band at 722 cm1 to the1,2,4-trioxane ring breathing, the band at 831 cm1 totrioxane twisting, and the band at 881 cm1 to coupled

on

r(O

1.41.4

1.41.4

1.4

1.41.4

1.4

1.41.4

1.41.4

144 V. Galasso et al. / Chemical Physics 335 (2007) 141154(ca. 1.46 A) and weaker (bond order 0.73) than theO2C3 bond (ca. 1.42 A, 0.83). A peculiar aspect isthe essentially pure p nature of the peroxide bond,the formal hybridization of the oxygen atoms havingonly 5%-s in this bond. The asymmetry of the C12aO1O2C3 unit is also manifested by the valenceangles of ca. 111 at O1 and ca. 108 at O2. TheC12aO1O2C3 dihedral angle in 1 is 47.9, whereasit is slightly lower in its derivatives.

A discussion of the consequences of these structural fea-tures on some important spectroscopic properties is nowreported.

3.2. Vibrational modes

Hereafter, for the sake of simplicity, the labels Op, Oe,Ol, and Oc refer to peroxidic, ether, lactonic, and carbonyloxygen atoms, respectively.

Table 1Calculated and experimental structural parameters of endoperoxide ring (b

r(O1O2) r(O1C12a)

1 Calculated 1.460 1.455Experimentala 1.469 1.461

2 Calculated 1.462 1.457Experimentalb 1.481 1.466

3a Calculated 1.462 1.458

3b Calculated 1.463 1.459Experimentalc 1.442 1.435

4a Calculated 1.462 1.457

4b Calculated 1.462 1.459Experimentalc 1.479 1.452

5a Calculated 1.462 1.4575b Calculated 1.462 1.460a Ref. [28].

b Ref. [29].c Ref. [27].COp and OpOp stretching modes of the OOC entity.In order to obtain consistent information on the nor-

mal modes of the peroxide moiety in 1 and related mole-cules, it has been considered useful to carry out a set ofcalculations at the same level of accuracy for some repre-sentative molecules, namely dimethyl-peroxide (DMP),the secondary ozonide of ethylene (SOZ), a trans-fusedtrioxane (TFT), and a cis-fused trioxine (CFT) (Fig. 2).The theoretical COOC dihedral angle is 128.7(DMP), 48.4 (SOZ), 68.9 (TFT), and 69.2 (CFT) tobe compared to 47.9 in 1. The DFT calculations havebeen complemented with a normal coordinate analysisthat provides the potential energy distribution (PED)among the standard internal coordinates [42]. The mostrelevant results are listed in Table 2. On the whole, thetheoretical reproduction of the experimental frequenciesis fair for all these molecules. Selected results are pre-sented in Table 2, where only the most sizeable PED con-tributions are listed.

d lengths in A, angles in )

2C3) a(O1O2C3) a(O2O1C12a) s(C12aO1O2C3)

14 108.3 111.6 47.916 108.1 111.2 47.8

15 108.9 111.9 45.811 109.0 110.9 45.2

12 109.1 112.1 45.3

12 109.1 112.0 45.105 110.4 111.3 45.9

12 109.1 112.0 45.2

13 109.1 112.0 45.121 107.9 110.7 44.2

12 109.1 112.0 45.113 109.1 112.1 45.2

l PhFor DMP, it must be stressed that the present DFTresults unambiguously assigned the band at 815 cm1 tothe OpOp stretching mode. Furthermore, in contrast toprevious empirical calculations [44], no band is computedin the range 8501000 cm1 (not even for the less favouredtrans conformation). Thus, the gap between the two COpstretching modes is found to be only 13 cm1 and not121 cm1, as previously calculated [44]. For SOZ, the note-worthy aspect is the dominant OpOp character of the808 cm1 band.

For the molecules investigated, the PED indicates that

O O

Me

Me

DMP

O

O

O

OO

O

Me

Me

H

H

TFT

OO

O

H

Me

Me

Me

Me

CFT

O O

DOL

OO OMeO

MTP

OO

DOX

O O

Bu

Bu

DBP SOZ

DVL

Fig. 2. Formulas of reference compounds.

V. Galasso et al. / Chemicamany of the vibrational modes become extensively coupledwith increasing molecular size. With reference to the twoclaimed ngerprints of trioxanes, the higher frequencyband (at 862 cm1 for TFT and 885 cm1 for CFT) exhib-its the stronger OpOp stretching character. However, theOpOp contribution decreases from 62% in the bicyclicTFT to 25% in the tricyclic CFT that also shows a compa-rable contribution from the COp stretching. Instead, thelower frequency band (at 785 cm1 for TFT and802 cm1 for CFT) is mainly made up of CMe and COp stretchings in TFT, whereas it is not connected withthe peroxide moiety in CFT.

The greater molecular complexity of 1 manifests itselfinto a congested vibrational pattern. Table 2 lists thePED for all of the frequencies calculated in the crucialrange 930600 cm1. An important point is that the corre-sponding vibrational modes contain an intimate mixing ofmany internal coordinates that can be hardly disentangled.However, the PED shows that the major contribution ofthe OpOp stretching is associated with the mode at883 cm1 that can be reasonably regarded as the OpOpstretching band. On the other hand, the two other suppos-edly characteristic bands [39] at 831 and 723 cm1 are scar-cely related to motions of the peroxide linkage.ysics 335 (2007) 141154 145Incidentally, it is worth mentioning that the calculatedforce constant of the OO bond is 2.51 mdyn A1 in 1 ver-sus 3.81 mdyn A1 in DMP: the apparent reversal of thestretching frequencies, 883 cm1 in 1 and 815 cm1 inDMP, arises from the quite dierent composition of therelated vibrational modes, as shown by PED in Table 2.As to the COp stretching vibrations of the endoperoxidemoiety of 1, they are predicted to correspond mainly tothe bands observed at 914 and 842 cm1. Finally, it maybe noted that the presently proposed interpretation of thevibrational spectrum of 1 diers in many respects fromthe previous ones [40,41].

Fig. 3. DFT-optimized structures of compounds 1 (top) and 2 (bottom).

l Ph146 V. Galasso et al. / ChemicaThe vibrational pattern of the artemisinin framework,mainly involving the trioxane ring C, undergoes only minorchanges on epimerization at C-9 (1! 2), hydrogenationand substitution at C-10 (36, 8), unsaturation at C-9 (7),and deoxygenation at C-10 (8). In particular, the frequencyof the band with greater OpOp stretching characterincreases with respect to 1 slightly, being calculated at886 cm1 (2), 886 cm1 (3a), 896 cm1 (3b), 922 cm1

(4a), 909 cm1 (4b), 924 cm1 (5a), 910 cm1 (5b),882 cm1 (6a), 913 cm1 (6b), 890 cm1 (7), and 917 cm1

(8). Replacement of the nonperoxidic trioxane oxygen (Oe)with a carbon atom gives rise to a similar shift (9,927 cm1; 10, 917 cm1).

Fig. 4. DFT-optimized structures of compounds 3a (top) and 3b(bottom).3.3. NMR parameters

The NMR chemical shifts were calculated using theDFT/CSGT formalism. For all molecules, the overallagreement between calculated (in the gas phase) and exper-imental (in solution) is satisfactory. The most characteristic13C chemical shifts of the molecules investigated are thoseof rings B and C (Table 3). Upon epimerization of artemis-inin 1 to epiartemisinin 2, ring B changes from half-chair tosofa form and the most aected resonance is just that of theinverted stereocentre C-9 (downeld Dd = 7). The commonconformational arrangement of the pentacyclic frameworkof 36 is reected in their similar patterns of the 13C chem-ical shifts. Of course, the acetal-type derivation of theparent 1 is accompanied by a large upeld displacementof C-10. Additional formal hydrogenation, i.e., on passingfrom 1 to 8 and 10, further lowers this resonance. On theother hand, replacement of the nonperoxidic trioxaneoxygen atom by carbon (1! 9, 10) moves the bridgeheadC-3 about 35 ppm upeld relative to 1. All of theseNMR spectroscopic features are accounted for by thepresent DFT results fairly well.

A notable aspect of the NMR spectra concerns thedowneld signal of the protons adjacent to the ether link-ages in 36. In 35, H12 resonates further downeld thanH10. Instead, the reverse situation d(H12) < d(H10) occursin 6, due to the deshielding eect of the hemisuccinyl sidechain. The experimental Dd(H12H10)s are 0.63 (3a), 0.30(3b), 1.00 (4a), 0.70 (4b) [29], 0.89 (5a), 0.62 (5b) [49],0.44 (6a), and 0.81 (6b) [30] that are reasonably repro-duced by the DFT results, 0.35, 0.34, 0.95, 0.81, 0.84, 0.71,0.44, and 0.90, respectively. Furthermore, d(H10) isslightly larger in the b-derivatives relative to the a-deriva-tives, in line with the normal stereoelectronic eect forDd(H2ax/eq) in 2-substituted tetrahydropyrans [55,56].

Concerning the substituent and conformational eectson the indirect nuclear spinspin coupling constants, owingto the large variety of nJ(XY)s, we restrict the interest on aselection of one-bond 13C1H and vicinal 1H1H couplingconstants. Indeed, such coupling constants display a wellknown sensitivity to substituent and stereoelectroniceects, see e.g. Refs. [5762]. According to the DFT/B3LYP calculations, the dominant contribution to the1J(CH)s and 3J(HH)s of the present molecules is providedby the Fermi-contact term, with the noncontact contribu-tions being comparatively small in all cases.

As to 1J(CH)s, we mention some illustrative examples,namely the coupling constants involving bridgehead Hatoms and bonds in ring B. Thus, in 1 and 35 (Table 4),the large 1J of the bridgehead bond C12H reects thestrong inductive eect exerted by the two adjacent oxygenatoms. Accordingly, the remarkably lower magnitudes of1J(C5aH),

1J(C8aH), and1J(C9H) are in line with the atten-

uated inductive eect at these positions.For the pairs 35(a,b), a normal manifestation of the

ysics 335 (2007) 141154stereoelectronic Perlin eect is predicted. Specically, forthe methylenic CH bonds adjacent to oxygen in a six-

ten

l PhTable 2Observed and calculated frequencies (cm1) of 1 and related peroxides (po

Observed Calculated PED and assignment

DMP

1032b 1023 68 COp a. stretch1020 1010 94 COp s. stretch815 810 73 OpOp stretch

457 82 COpOp s. bend414 398 82 COpOp a. bend

SOZ

1078d 1077 62 COe a. stretch1029 1019 64 COp s. stretch952 939 76 COe s. stretch927 912 60 COp a. stretch808 833 78 OpOp stretch737 742 27 COeC bend, 26 OpCOe bend698 704 42 COpOp bend

TFT

870f 879 10 CC stretch862 873 62 OpOp stretch843 858 11 COp stretch831 832 19 COe stretch, 15 COp stretch

821 33 CC stretch, 12 COp stretch795 778 26 CC stretch785 769 26 CMe stretch, 19 COp stretch

V. Galasso et al. / Chemicamembered ring, the axial CH bond coupling constant isgenerally smaller by 810 Hz than 1J(CHeq) [60]. As anexample, for cis-4,6-dimethyl-1,3-dioxane 1J(C2Hax) =157.4 Hz < 1J(C2Heq) = 167.5 Hz [63] (159.0 and 171.1 Hzour calculated values). With reference to the formal 1,3-dioxane segment O11C10(H,C9)OR in 35, the orienta-tion of the C10H bond is axial in the a-derivatives,whereas it is equatorial in the b-derivatives. Therefore,the calculated positive D1J(CHeq/CHax) 12 Hz betweenthe pairs a and b accounts for a normal Perlin eect. Inter-estingly, the Perlin eect D1J(CHeq/CHax) parallels thedeshielding eect Dd(Heq/Hax) as well the moderate CHlength compression (e.g. 1.109 vs. 1.099 A for C10H onpassing from 3a(Hax) to 3b(Heq)).

For the vicinal interproton coupling constants, the DFTcalculations reproduce the available experimental valuessatisfactorily. In particular (Table 5), for 1 and its deriva-tives 35(a,b), the trans 3J(H5aH6) and

3J(H5aH5proS) are afewHz larger than the gauche 3J(H8aH9) and

3J(H5aH5proR),basically consistent with the relevant dihedral angles (e.g.,177.3, 160.0, 53.4, and 44.5, respectively, in 1). On theother hand, a distinctive structural feature of the a and b iso-mers of 36 (bearing a common chair ring B) is the interpro-ton coupling constant 3J(H9H10). Indeed, the observed ratio3J(a) > 3J(b) is consistent with the trans-diaxial arrange-

672 663 33 CC stretch

a s., a., and o.o.p. stand for symmetric, asymmetric, and out-of-plane, respeb IR spectrum of the gas phase, Ref. [43].c Raman spectrum of a solid sample, Ref. [39].d Matrix IR spectrum, Ref. [45].e FTIR spectrum of a lm sample, Ref. [38].f IR spectrum of a solid sample, Ref. [39].tial energy distribution in %)a

Observed Calculated PED and assignment

CFT

896 14 OpOp stretch, 13 HCC bend885c 875 25 OpOp stretch, 22 COp stretch856 858 14 OpOp stretch, 12 CH o.o.p. bend820 812 20 CH o.o.p. bend802 779 25 CC torsion, 23 CH o.o.p. bend

1

927e 930 14 OpOp stretch, 9 COp stretch923 14 CC stretch

914 904 18 COp stretch883 886 25 OpOp stretch, 7 COe stretch856 861 16 CC stretch, 8 COe stretch842 844 26 COp stretch, 11 CC stretch831 831 14 COe stretch, 9 COp stretch

822 29 CC stretch, 8 COp stretch812 14 HCC bend

794 783 13 CC stretch772 764 35 COc o.o.p. bend723 708 31 CC stretch, 18 COe stretch696 687 14 COc o.o.p. bend, 10 CC stretch642 636 12 CC stretch, 12 CCC bend627 619 7 CCC bend

ysics 335 (2007) 141154 147ment of these protons in the a-derivatives and the cis-equa-torial-axial in the b-derivatives (the corresponding dihedralangles being 177.3 and 53.4 in the 3 isomers).

3.4. Ionization energies

Recently, Novak and Kovac [64] have measured the gasphase He(I) PE spectrum of 1 that provides valuable infor-mation on its electronic structure. From a qualitativestandpoint, the low-energy photoionizations of 1 originatefrom the two lone pair orbitals per oxygen and the bondingp(CO) orbital. In particular, distinctive features should bethe symmetric and antisymmetric combinations of the ppand pr lone pair orbitals on the peroxidic oxygen centres,yielding the n(Opp)

and n 0(Opr) pairs, respectively. How-

ever, due to the lack of symmetry in molecule 1, all the n(O)semilocalized orbitals are intimately mixed by a subtleinterplay of through-bond and through-space interactionsin the MOs of 1. Thus, the corresponding high density ofcationic states of 1 gives rise to a very congested, over-lapped band system, from which only a clear peak standsout at 9.45 eV.

Here, the experimental probing of the electronic structurethrough the analysis of the PE spectra has been extended tosome artemisinin derivatives (Fig. 5). Unfortunately,

ctively.

Table 3Experimental and calculated 13C NMR chemical shifts relative to TMS

1 2 3a 3b 4a 4b 5a 5b

Calculated Experi-mentala

Calculated Experi-mentalb

Calculated Experi-mentalc

Calculated Experi-mentalc

Calculated Experi-mental

Calculated Experi-mentald

Calculated Experi-mentale

Calculated Experi-mentalf

C3 106.3 105.3 106.1 105.1 105.3 104.3 105.1 104.0 105.2 105.1 104.1 105.2 101.2 105.1 103.9C12 93.5 93.8 93.5 93.7 91.7 91.2 88.4 87.7 91.9 88.2 87.8 91.7 91.2 88.3 87.8C12a 81.0 79.6 82.0 80.5 81.5 80.3 82.2 81.1 81.5 82.0 81.2 81.4 80.3 82.1 81.1C8a 46.0 45.1 45.2 45.5 46.3 45.4 45.5 44.4 46.3 45.8 44.6 46.2 45.4 45.5 44.5C9 32.5 33.0 39.5 40.1 33.3 34.8 31.0 30.8 32.7 31.0 30.9 32.7 32.5 31.0 30.8C10 171.9 171.5 172.1 171.1 95.7 94.7 98.7 96.2 101.0 104.0 103.4 100.1 99.8 102.9 101.7

6a 6b 7 8 9 10

Calculated Experi-mental

Calculated Experi-mentalg

Calculated Experi-mentalh

Calculated Experi-mentali

Calculated Experi-mentalj

Calculated Experi-mentalk

C3 105.4 105.4 104.4 106.2 105.4 105.1 103.2 78.9 78.8 78.0 78.1C13 35.3 37.3 34.8 36.8C12 91.8 89.5 88.7 93.0 93.5 92.8 91.1 70.7 71.5 67.3 67.2C12a 81.2 81.7 80.5 80.5 79.4 81.5 79.8 80.9 79.8 81.1 80.7C8a 46.3 45.2 43.8 46.8 46.1 45.8 43.9 46.8 45.7 45.1 44.1C9 30.9 30.3 29.8 131.8 130.4 27.9 26.9 32.4 33.2 27.9 28.2C10 92.1 95.0 95.2 161.9 162.8 65.3 65.2 172.9 173.4 66.4 67.1

a Ref. [46].b Ref. [29].c Ref. [47].d Ref. [48].e Ref. [49].f Ref. [51].g Ref. [30].h Ref. [52].i Ref. [53].j Ref. [54].k Ref. [31].

148V.Galasso

etal./Chem

icalPhysics

335(2007)141154

Table 4Calculated one-bond 13C1H nuclear spinspin coupling constants (Hz)

1 3a 3b 4a 4b 5a 5b1J(C5aH) 129.7 (132)

a 128.4 128.1 128.3 128.2 128.4 128.11J(C12H) 174.3 (173) 163.5 168.2 163.2 167.6 162.9 167.41J(C8aH) 130.9 (132) 130.4 128.7 130.2 128.6 130.2 128.61J(C9H) 127.9 (128) 134.2 129.9 134.0 129.4 133.7 129.51J(C10H) 157.3 169.6 154.3 166.7 154.0 166.2

a Experimental values, Ref. [46].

Fig. 5. Ultraviolet He(I) photoelectron spectra.

V. Galasso et al. / Chemical Physics 335 (2007) 141154 149unavailability of sucient amount of compounds 7 and 8precluded to record their PE spectra and gather additionalinformation on the lone pairs orbitals on the carbonylgroup. Furthermore, the PE spectrum of 3b has beenobtained with a poor resolution due to very low vapourpressure and thermal instability of this compound. On theother hand, in order to gain a more detailed assignment ofthe spectrum of 1, reference is also made to the PE spectraof some fragment molecules, DMP, DOL (1,2-dioxolane),SOZ, DOX (1,2-dioxane), DVL, andMTP (Fig. 5) that con-tain individual functional groups present in 1. The theoret-ical Eis have been obtained from the ab initio OVGFmethod. The pole strengths calculated for all investigatedphotoionization processes are larger than 0.85, whichexcludes the presence of nearby shake-up lines and thus indi-cates that the one-particle model of ionization is valid [6567]. Furthermore, with reference to OVGF results obtainedfor strained cage compounds [68], one may expect errors ofthe order of ca. 0.3 eV on vertical Eis related to oxygen lonepairs. The experimental patterns and theoretical assign-ments are reported in Table 6.

In the region of the top MOs, the following aspects ofthe electronic structure of the fragment molecules are ofspecial interest: (i) The rst Ei of peroxides DMP, DOL,DOX, and SOZ is associated with the n(Op)

MO, whichis stabilized by 0.81.0 eV in SOZ as a result of the induc-tive eect of the ether oxygen. (ii) The second Ei of perox-ides DMP, DOL, and DOX corresponds to ionization fromthe n 0(Op)

MO, and the splitting DEi1,2 is 1.9 eV (DMP),1.3 eV (DOL), and 0.2 eV (DOX). The second Ei of SOZis instead due to n(Oe) and DEi1,2 is 0.3 eV. (iii) The rstthree Eis of DVL are associated with the n(Oc), p(OCO),and n(Ol), r(CC) ionizations, respectively, the rst twoTable 5Calculated and experimental vicinal 1H1H nuclear spinspin coupling constants (Hz)

1 3a 3b 4a 4b 5a 5b3J(H8aH9) 5.2 (5.0)

a 4.7 4.9 4.7 4.8 (4.3)b 4.7 (4.3)c 4.9 (5.4)d3J(H9H10) 6.9 (9.2)

e 3.5 (3.1)b 7.1 (9.3)b 3.6 (3.4) 7.2 (9.2) 3.7 (3.6)3J(H5aH6) 8.7 (11.3) 9.0 8.9 8.9 8.9 8.9 8.9 (10.7)3J(H5aH5proS) 6.6 (6.9) 6.3 6.4 6.3 6.3 6.3 6.3 (6.5)3J(H5aH5proR) 9.1 (11.3) 9.4 9.5 9.4 9.4 9.5 9.5 (12.0)

a Experimental values, Ref. [46].b Experimental values, Ref. [27].c Experimental values, Ref. [50].d Experimental values, Ref. [51].e Experimental values from the mixture of diastereoisomeric acetals in equilibrium, Ref. [27].

l PhTable 6Vertical ionization energies (eV) and assignment

150 V. Galasso et al. / Chemicabeing split by 0.5 eV. (iv) The top two Eis of MTP aremainly due to the lone pairs localized on the lactol pyranoxygen (Opyr) and acetal oxygen (OMe), respectively. Inci-dentally, it can be noted that the present OVGF results cor-

MO Ei,calculated Ei,experimental

DMP

n(Op) 9.81 9.71a

n0(Op) 11.43 11.61

r(OpOp), r(CH) 12.53 12.58r(CH) 14.11 14.02

SOZ

n(Op) 10.80 10.67b

n(Oe) 10.85 10.96n0(Op)

12.68 12.40r(OpOp), r(COe) 13.64 13.38

DVL

n(Oc) 10.14 10.15d

p(OlCOc) 10.77 10.65n(Ol), r(CC) 11.79 11.75r(CC) 12.40 12.3

1

n(Oc,Ol) 9.18 9.45f

n(Op,Oc,Oe,Ol) 9.22r(CCOp) 9.44 9.8r(CC) 10.14r(CCOl) 10.22 10.35r(CCOp) 10.31r(OlCOc) 10.66

4a (4b)n(Opyr) 8.39 (8.48) 7.95

d

r(CCOp) 8.94 (9.01)n(Oe,Op) 9.18 (9.24)n(OMe) 9.47 (9.24) 9.45r(CC) 9.61 (9.61)r(CCOe) 9.70 (9.64)r(CH) 10.59 (10.40) 10.45a Ref. [69].b Ref. [70].c Ref. [73].d Present work.e Axial orientation of the methoxy group.f Present work and Ref. [64].g Features observed in a poorly resolved spectrum not shown in Fig. 5.

Fig. 6. Representation of the top occupied MOsysics 335 (2007) 141154roborate the semiempirical assignment proposed in earlierphotoelectron studies on peroxides [7175].

On going from the fragment molecules to 1, one partic-ularly noteworthy point is that the original lone pair orbi-

MO Ei,calculated Ei,experimental

DOL

n(Op) 9.94 9.86b

n0(Op), r(CH) 11.31 11.13

r(CH) 12.62 12.6r(OpOp), r(CC) 12.82 12.8

DOX

n(Op) 10.17 10.17c

n0(Op) 10.28 10.35

r(CH), r(CC) 11.65r(CH) 12.46

MTP

n(Opyr) 9.83e 9.7d

n(OMe) 10.33 10.05r(CC) 10.78 10.65r(CC) 11.40 11.55

3a (3b)n(Opyr) 8.49 (8.54) (8.0)

g

r(CCOp) 9.00 (9.06)n(Op,Oe) 9.41 (9.33) (9.45)r(CC) 9.53 (9.52)r(CCOe) 9.73 (9.54)r(CC) 10.20 (10.31)r(CC) 10.74 (10.71) (11.0)

5a (5b)n(Opyr) 8.37 (8.46) 7.85

d

r(CCOp) 8.91 (8.95)n(Oe,Op) 9.15 (9.20)n(OMe) 9.44 (9.20) 9.45r(CC) 9.66 (9.59)r(CCOe) 9.66 (9.69) 9.95r(CH) 10.54 (10.35) 10.2

of 1, as supplied by HF/DZP calculations.

Koopmans theorem calculations for the evaluation ofVAEs demonstrated the occurrence of good linear correla-tions between the p* VAEs measured in a large number ofalkenes and benzenoid hydrocarbons and the correspond-ing virtual orbital energies (VOEs) of the neutral moleculesobtained with HF and MP2 calculations, using basis setswithout diuse functions [77]. This approach provided sim-ilar correlations also for the r* VAEs of a series of chloro-alkanes [82] and group 14 mixed dimers [83], although itwas shown that these empirical correlations are stronglydependent on the molecular structures and the nature ofthe r* MOs [83]. In addition, anion states associated withr* MOs generally lie at higher energy and have a shorterlifetime than those associated with p* MOs, thus giving riseto broader shape resonances. Narrow low-energy r* reso-nances were in fact observed only in compounds containingthird-row or heavier elements [84].

Within this context, in order to help in the assignmentof the ET spectra of artemisinin 1 and its saturated deriv-atives 3b5b in the 06 eV range, reference is made to therelated fragment compounds, cyclohexanone (CHN),DVL, MTP, and DBP (Fig. 7 and Table 7). Indeed, theassignment of the rst VAEs for these simple moleculesis unambiguous and also corroborated by OVGF calcula-tions with the same DZP basis set [17] employed for thecomplementary Eis. Incidentally, we note that the OVGFVAEs are systematically overestimated by about 12 eV.

l Physics 335 (2007) 141154 151tals undergo a considerable mixing, as stressed above. Asillustrative examples, the top occupied MOs of 1 are shownin Fig. 6. (Note, however, that the rst three Eis of 1reported in Table 6 correspond to the HOMO, HOMO-2,and HOMO-1, respectively.) Thus, the formal n(Op)

com-bination is not the dominant contributor to any MO of 1.Therefore, the description given in Table 6 for the MOsinvolved in the low-energy photoionizations of 1 accountsonly for their main character. However, by taking intoaccount the orbital sequence and assignment for the frag-ment molecules and the OVGF results, the present inter-pretation of the PE spectrum of 1 can be regarded asreasonably consistent. Thus, the band at 9.45 eV is associ-ated with two MOs with mainly n(Oc,Ol) and n(Op,Oc,Oe,Ol) character and the following unresolved signal at9.8 eV with a r(CCOp) MO. The prominent band systemwith onset at about 10 eV encompasses a manifold of clo-sely lying photoionizations. The feature discernible at10.35 eV may be attributed to r(CC), r(CCOl), andr(CCOp) MOs. It must be stressed that the present assign-ment of 1 diers from the previous, simple Koopmans the-orem attribution [64].

Comparison of the Eis of 1 with those of the relevantfragment molecules indicates a net destabilization of then MOs that stems from their mutual interactions withinthe polycyclic framework. On the other hand, as expected,the PE spectrum of epimer 2 is predicted to bear a closeresemblance to that of 1, consistent with the nearlyunchanged electronic structure. Instead, the acetal-deriva-tion of 1 to give 35 results in signicant changes of thespectra (Fig. 5). Indeed, the formal change of ring B froma lactonic unit in 1 to a 2-substituted tetrahydropyran moi-ety (of lactol type) in 35modies the character of the fron-tier MOs. Thus, the rst three Eis of 35(a,b) are associatedwith the n(Opyr), r(CCOp), and n(Op,Oe) MOs, and, in par-ticular, the rst band appears at lower energy than in 1.

3.5. Electron attachment energies

In gas phase collisions, an isolated molecule can tempo-rarily attach an electron of proper energy and angularmomentum into a vacant MO, the process being referredto as a shape resonance [76]. Electron transmission spec-troscopy [21] is one of the most suitable means for detect-ing the formation of these short-lived anions andelucidating the empty level electronic structure. Becauseelectron attachment is rapid with respect to nuclearmotion, temporary anions are formed with the equilibriumgeometry of the neutral molecule. The impact electronenergies at which electron attachment occurs are properlydenoted as vertical attachment energies (VAEs) and arethe negative of the vertical electron anities. Within theKoopmans theorem approximation, VAEs are equal tothe empty MO energies. A theoretical approach adequatefor describing the nature and energy of unstable anion

V. Galasso et al. / Chemicastates involves diculties not encountered for neutral orcation states [7881]. However, analyses of the use ofOn the other hand, the p*(CO) VAEs can be evaluatedFig. 7. Derivative of transmitted current as a function of electron energy.Vertical lines locate the VAEs.

l Phat the Koopmans theorem level from the HF/DZP VOEs,using the empirical relation: VAE = 1.4100 + 0.7386 VOE (eV) [77]. The scaled VOEs are reported in paren-theses in Table 7.

In DVL, the p*(CO) MO is destabilized by mixing withthe adjacent oxygen lone pair. This interaction causes asizeable increase of the p*(CO) VAE (1.90 eV) relative to

Table 7HF virtual orbital energies (VOEs), OVGF and experimental verticalattachment energies (VAEs) (eV), and assignment

Assignment VOE/HF VAE/OVGF VAEexperimental

CHN r*(CH) 6.74 5.67 4.2a

p*(CO) 4.16 (1.66)b 2.66 1.30

DVL r*(CH) 6.39 5.22 4.4p*(CO), n(O) 4.68 (2.05)b 3.33 1.90

MTP r*(CH3) 6.95 5.80r*(CC) 6.80 5.65 4.4

DBP r*(CH) 6.82 5.61r*(OO) 6.21 4.17 2.0

1 r*(OO) 5.38 3.78 1.76p*(CO) 4.49 (1.91)b 3.58

3b r*(OH) 6.14 5.23r*(OO) 5.84 4.24 1.7

4b r*(CH) 6.54 5.20 4.4r*(OO) 5.86 4.28 1.7

5b r*(CH) 6.40 5.17 4.3r*(OO) 5.86 4.27 1.7

a Ref. [85].b Scaled value (see text).

152 V. Galasso et al. / Chemicathat (1.30 eV) of CHN [85], in line with the eects observedin similar molecular systems [84,85]. The weaker andbroader signal centred at 4.4 eV is likely associated withelectron capture into the lowest-lying r* MOs. Consistently,the ET spectrum of the saturated derivative MTP as wellas that of cyclohexane [86] does not display distinct reso-nances at low-energy, the rst (broad) signal being locatedat 4.4 eV.

The intense rst resonance centred at 2.0 eV (fwhm1.6 eV) in the ET spectrum of the smaller peroxide DBPis associated with the r*(OO) MO. For the sake of compar-ison, the r*(OO) VAE of DBP is intermediate between thecorresponding r*(XX) VAEs of the permethylated third-row dimers CH3SSCH3 (1.04 eV) [87] and (CH3)3SiSi(CH3)3 (2.30 eV) [88]. It is worth to point out that theVAE of the r*(OO) MO of DBP is unexpectedly small.To our knowledge, r* resonances below 3.5 eV have neverbeen observed before in the ET spectra of hydrocarbonsthat do not contain third-row or heavier heteroatoms.

The ET spectra of artemisinin 1 and its derivatives 3b5b have been recorded at the maximum temperature(105 C) attainable in our apparatus. However, becauseof their low volatility, the vapour pressure achieved wastoo low to obtain an optimal attenuation of the electronbeam signal. For this reason and the weakness of r* reso-nances in compounds containing rst- and second-row ele-ments [84], the ET spectra of these compounds do not showintense features.

The ET spectrum of artemisinin 1 displays a resonanceat 1.76 eV, i.e., in the energy range where the p*(CO) reso-nance is expected. A weak and broad signal centred above4 eV is probably also present. However, it must beobserved that the width (fwhm 1.2 eV) of the rst reso-nance of 1 is signicantly larger than that (0.80 eV) ofthe corresponding signal in the spectrum of DVL. There-fore, the rst resonance of 1 should be due to the unre-solved contributions from both the p*(CO) and r*(OO)MOs. This assignment is consistent with the scaled VOEp* (CO) (1.91 eV) and the OVGF results, that predict thetwo lower energy resonances near-lying and split by only0.2 eV. This interpretation is also supported by the ETspectra of the saturated derivatives 3b5b, where the broadfeature (fwhm 1.3 eV) centred at 1.7 eV is to be ascribed totemporary electron capture into the r*(OO) LUMO. Inagreement with experiment, the HF calculations predictthe energy of the r*(OO) MO to be somewhat lower inartemisinin and its derivatives than in DBP.

Thus, the present ETS data further elucidate the rststeps of the mechanism of antimalarial activity of the drugmolecules of artemisinin type. Indeed, the malarial parasiteconsumes hemoglobin and generates a FeIIporphyrincomplex that promotes dissociative reduction of the perox-ide bond with subsequent formation of oxygen radicals[3,89], in line with the large electron-acceptor property ofthe OO bond and strongly antibonding character of ther*(OO) MO.

4. Concluding remarks

A wide investigation has been reported on structuraland spectroscopic features of artemisinin and a representa-tive selection of its derivatives, which are highly eectiveantimalarial drugs. The molecular structures have beenstudied with DFT/B3LYP calculations. The correspon-dence between theoretical results and available X-ray datais good. All molecules exhibit a marked preference for oneconformation. However, the derivatives substituted at C-10are characterized by a distinguished exibility of ring Bthat adopts dierent forms on changing the nature andposition of the pendant side chain. Furthermore, for thesederivatives, the a isomer with the equatorial substituentgroup is predicted to be energetically less stable than theb isomer with the axial group.

A consistent assignment of the vibrational modes ofartemisinin and derivatives in the ngerprint region of1,2,4-trioxanes (600900 cm1) is proposed, also byexploiting the results on related simple model moleculesand a normal coordinate analysis. Thus, the normal modewith the greater OO stretching character of each moleculehas been reliably assigned.

The electronic structures have also been investigated

ysics 335 (2007) 141154through the NMR, PE, and ETS properties, which are verysensitive to stereoelectronic eects. Thus, a specic set of

anion states generated by electron attachment to the low-

further insight into the rst steps in the antimalarial activ-

l Phity of the artemisinin drugs, which stems from reductivecleavage of the peroxide bond and consequent formationof reactive radicals.

Acknowledgements

V.G. is grateful to Alchem International (New Dehli, In-dia) for the generous gift of compounds 1, 3b, 4b, and 5b.Support from the Ministry of Science, Education andSports of the Republic of Croatia is gratefully acknowl-edged by B.K. and that of MIUR of Italy by A.M.

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154 V. Galasso et al. / Chemical Physics 335 (2007) 141154

A theoretical and experimental study on the molecular and electronic structures of artemisinin and related drug moleculesIntroductionComputational and experimental detailsResults and discussionMolecular structuresVibrational modesNMR parametersIonization energiesElectron attachment energies

Concluding remarksAcknowledgementsReferences