Spectroscopic study of the dispiro-1,2,4,5-tetroxane (cyclohexanone diperoxide)

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Spectrochimica Acta Part A 70 (2008) 775–779

Spectroscopic study of the dispiro-1,2,4,5-tetroxane (cyclohexanone diperoxide) J.M. Romero a , N.L. Jorge a , M.E. G´omez-Vara a , A.H. Jubert b , E.A. Castro c,∗ ´ Area Fisicoqu´ımica, Facultad de Ciencias Exactas y Naturales y Agrimensura, UNNE, Campus Universitario, Av. Libertad 5400, (3400) Corrientes, Argentina b CEQUINOR, Chemistry Department, Faculty of Exact Sciences, La Plata National University, Calle 47 y 115, La Plata 1900, Buenos Aires, Argentina c INIFTA, Theoretical Chemistry Division, Suc.4, C.C. 16, La Plata 1900, Buenos Aires, Argentina a

Received 29 March 2007; received in revised form 1 September 2007; accepted 17 September 2007

Abstract The aim of this work is to present results derived from experimental IR and UV spectra and theoretical studies of DPCH, in order to get a more deeper insight on the physicochemical properties of this compound to gain a more deep knowledge of its action, helping in the design of new compounds with antimalaric effects. Experimental results are analyzed on the basis of theoretical calculations, which allow to derive suitable interpretations of spectral data. © 2007 Elsevier B.V. All rights reserved. Keywords: Dispiro-1,2,4,5-tetroxane; Artemisine; Antimalarial activity; UV and IR spectra; Theoretical study

1. Introduction Since malaria parasites are rapidly developing resistance to the most commonly used chemotherapeutic alkaloidal drugs, the antimalarial properties of nonalkaloidal compounds such as artemisinin and related endoperoxides have attracted considerable attention [1–10]. The study of the action mechanism showed the peroxide bond in artemisinin as the critical pharmacophoric functional group. This observation had led us to speculate that other cyclic peroxide systems having two peroxide groups within the same ring could also exhibit significant antimalarial activity. Among the most structurally simple class of peroxides to emerge from these studies were the dispiro-1,2,4,5-tetraoxanes (DPCH, Fig. 1) [11–13]. Tetraoxanes such as DPCH are a quite interesting set of molecules since they differ considerably in structure from artemisinin, they can be readily prepared in one step procedure from acid catalyzed substituted cyclohexanones, and besides they possess a rather good antimalarial activity, although they present a relatively low oral activity [14], a shortcoming shared in part by the semisynthetic artemisinins. ∗

Corresponding author. E-mail addresses: [email protected], [email protected] (E.A. Castro). 1386-1425/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.saa.2007.09.018

The purpose of this work is to present results derived from experimental IR and UV spectra and theoretical studies of DPCH, in order to get a more deeper insight on the physicochemical properties of this compound to gain a more deep knowledge of its action, helping in the design of new compounds with antimalaric effects. 2. Theoretical methods The conformational space for DPCH was studied using the molecular dynamics (MD) module contained in the HyperChem package [15]. Simulations were accomplished with the aid of the MM+ force field also available in that package. Different geometries for DPCH were used as starting geometries for the simulations. Those geometries were heated from 0 to 600 K in 0.1 ps. Then, the temperature was kept constant by coupling the system to a simulated thermal bath with a bath relaxation time of 0.5 ps. The time step for the simulation was 0.5 fs. After an equilibration period of 10 ps, a 500 ps-long simulation was started saving the cartesian coordinates every 10 ps. Those geometries were then optimized to an energy gradient less than ˚ −1 using the MM+ force field. 0.001 kcal mol−1 A The lowest energy conformers of the DPCH molecule obtained according to the above methodology were further stud-

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minima or saddle points on the potential energy surface of the molecule. The MEPs were calculated with the Gaussian package and their pictures were obtained with the Molekel program [19]. The electronic spectrum of DPCH was also calculated using the time dependent DFT theory as implemented in the Gaussian 98 package. The B3LYP/6-31+G(d,p) level of theory was used for this purpose. 3. Experimental Fig. 1. Optimized geometry of the dispiro-1,2,4,5-tetraoxanes (DPCH) calculated B3LYP/6-31G** level.

ied using the density functional theory (DFT) as implemented in the Gaussian 98 package [16]. Geometry optimizations were performed using the Becke’s three parameters hybrid functional [17] with the Lee–Yang–Parr correlation functional [18], a combination that gives rise to the well known B3LYP method. The 6-31G** basis set has been used for all the atoms. The vibrational analysis was performed at the same level of theory as above for all the optimized geometries to verify whether they are local

The DPCH was prepared by methods described elsewhere [20] and its purity was checked by GC and IR analysis (KBr). Organic solvents were commercial analytical reagents purified by standard techniques. 3.1. General The synthesized DPCH was analyzed via UV and IR spectroscopic techniques. The UV visible spectrum was carried out in the 200–700 nm range (the quartz cell was 1 cm long, in a 0–2 absorbance range), in a trademark CamSpec model

Table 1 Experimental and theoretical vibrational frequencies and assignment of DPCH Calculated vibrational frequencies

Experimental vibrational frequencies

477 491

473 500

547 562 608 685 743 784 837 883 924 934 958 1039 1085 1174 1266 1365 1421 1486 1519 2869 2922 2937 2957

556 603 617 674 741 786 833 878 925 945 960 1034 1071 1153 1259 1352 1443 1493 1557 2867 2922 2938 2954

2957

3007

2959

3034

2961 2963 2991 2991

3074 3096 3126 3187

Assignment Rings deformation, wag: C30H35,36, C9H18,17, C22H26,27 ␦C3O7O14, ␦C3O6O13, deformation cyclohexanone diperoxidic ring, wag C2H1,5, ␦C2C3O6 Rings deformation Twist: C25H33,34, C30H35,36, C9H17,18, C4H10,11 ␦O14C19O13, ␦O7C3O6, twist CH2 Twist: C4H10,11, C12H20,21, C24H31,32 ␦C3O7O4, ␦C3O6O13, rings deformation, wag C25H33,34 Wag: C23H28,29, C24H31,32, C12H20,21, C2H1,5 ␯C19O14, deformation C19,22–25,30 ring, wag CH2 ␯O13O6, ␯O14O7 ␯C3O7, ␯C19O3 In phase ␯O13O6O4O7 ␯O7C3, ␯C19O14, rings deformation, CH2 wag Wag CH2 ␯C19O13, ␯C3O6, bending CH, rings deform. Twist CH2 Rings deformation, wag CH2, twist CH2 Wag CH2, C6H12 rings deformation CH bending ␦C2H1,5, ␦C8H15,16, ␦C23H28,29, ␦C22H26,27 Deformation CH2 Sym ␯C9H17,18, Sym ␯C30H35,36 Asym ␯C9H17,18, Asym ␯C30H35,36, Asym ␯C25H33,34, Asym ␯C24H31,32, Asym ␯C4H10,11, Asym ␯C12H20,21, Asym ␯C25H33,34, Asym ␯C24H31,32 Asym ␯C9H17,18, Asym ␯C30H35,36, Asym ␯C25H33,34, Asym ␯C24H31,32, Asym ␯C12H20,21, Asym ␯C4H10,11 Asym ␯C9H17,18, Asym ␯C30H35,36, Asym ␯C25H33,34, Asym ␯C24H31,32, Asym ␯C12H20,21, Asym ␯C4H10,11 Asym ␯C9H17,18, Asym ␯C30H35,36, Asym ␯C25H33,34, Asym ␯C24H31,32, Asym ␯C12H20,21, Asym ␯C4H10,11 Asym ␯C2H1,5, Asym ␯C22H26,27 Asym ␯C9H17,18 ␯ C8H15, ␯ C23H28 ␯ C8H15, ␯ C25H33

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M330 spectrophotometer. Standard solutions were employed. Infrared absorption spectra at room temperature from 1 cm diameter pellets made of the compound diluted in spectroscopic grade KB were recorded on a IR Nicolet infrared spectrometer using the diffuse reflectance technique, between 400 and 4000 cm−1 . 4. Results and discussion 4.1. IR spectrum

Fig. 2. IR spectrum of DPCH.

Table 1 displays the calculated and assigned frequencies of active modes in the infrared region for DPCH, at room temperatures. As it was pointed out before, the vibrational modes assignments were performed by visualization on the corresponding animation by means of the Molekel computational codes [19]. The reported theoretical values correspond to the conformer of lowest energy. The overall infrared spectrum of DPCH is shown in Fig. 2.

An inspection of the IR spectra in the regions between 617–741, 833–1085 and 878–945 cm−1 shows that the observed bands correspond to the absorption of the ␦OCO, ␦COO modes and stretchings ␯CO and ␯OO, respectively. Bands located at 878 and 925 cm−1 correspond to the ␯O13O6, ␯O14O7 and in phase ␯O13O6O4O7, respectively. Those located at 833, 925, 958, 1085 cm−1 are

Fig. 3. Frontier molecular orbitals of DPCH.

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Fig. 4. Electronic spectrum of DPCH.

assigned as ␯C19O14, ␯C3O7–␯C19O13, ␯O7C3–␯C19O14, ␯C19O13–␯C3O6 modes, respectively. From an inspection to the frontier molecular orbitals of the DPCH (Fig. 3) it is seen that the HOMO-4 is localized on the cyclohexane cycles of ␴ character, with negative charges on H20, 21, 17, 18, 27, 26, 28, 29, 35, 36 and positive charges on the H1,26 atoms; the HOMO-3 is of ␴ character on the C2, 3, 4, 8, 9, 12 atoms and O13, 6; O7, 14 atoms; the HOMO-2 is ␲ on the C–O bonds; the HOMO-1 is localized on the O6, 7, 13, 14 atoms and is of n type; the HOMO is also of n type on the same oxygen atoms and of sigma character on the C3–C8 and C19–C23; the LUMO is of ␲* character on the C–O bonds and the LUMO+1 is ␲* on the O–O bonds. The calculation of an interaction configuration that involves 15 occupied and 15 unoccupied MOs via the DFT method of the Gaussian 98 package [16] allows us to conclude that the electronic transitions, located at 217.4; 191.05; 189.59; 183.45; 168.49 and 158.05 nm of the DPCH can be mostly attributed to the configuration interaction of the transitions: HOMO2 → LUMO, HOMO → LUMO+1; HOMO → LUMO+1; HOMO-1 → LUMO+1; HOMO-2 → LUMO+1; HOMO3 → LUMO; HOMO-4 → LUMO, respectively. The electronic transitions have oscillator strength equal to 0.0016, 0.0265, 0.0004, 0.0019, 0.0041 and 0.0060, respectively. The experimental electronic spectrum is reported in Fig. 4 with a maximum at 204 nm. The transitions involved in this band are assigned above.

Fig. 5. Molecular electrostatic potential of DPCH.

static maps (MEPs) the regions of negative values account for the local minima and are site candidates for electrophilic attacks. The positive regions only possess maxima at the nuclear positions [24] indicating that there is no affinity by nucleophilic reactives. The molecular electrostatic potential of the most stable conformer of DPCH depicted in Fig. 5 shows that it has two possible sites for electrophilic attack where V(r) calculations provide insights into the order of preference. Fig. 5 shows the calculated 3D electrostatic potential contour map of DPCH. Negative regions are associated with O6, 7, 13, 14 with values around −0.1200 au, −0.0675 au. Thus, it would be predicted that the O4–O13 and O7–O14 will be the preferred sites for the electrophilic attack. On the carbon atoms a charge around −0.022 au is localized and in the center of the rings a negative charge around −0.037 au is found. Positive regions are on the Hydrogen atoms around 0.03 au indicating possible sites for nucleophilic attack.

4.2. Molecular electrostatic potential maps 5. Conclusions The electrostatic potential has been used primarily for predicting sites, relative reactivities towards electrophilic attack, in biological recognition and hydrogen bonding interactions [21–23]. The emphasis of these studies has been on negative regions of V(r). In the great majority of the potential electro-

We have described the experimental synthesis of DPCH. The UV and IR spectra were determined and the corresponding interpretation of them were performed on the basis of suitable theoretical calculations.

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