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Spectrochimica Acta Part A 79 (2011) 1493– 1498

Contents lists available at ScienceDirect

Spectrochimica Acta Part A: Molecular andBiomolecular Spectroscopy

j ourna l ho me page: www.elsev ier .com/ locate /saa

xperimental and theoretical assessment of the mechanism involved in theeaction of steroidal ketone semicarbazone with hydrogen peroxide

amlesh Sharmaa, Shivani B. Mishrab, Ajay K. Mishrab,∗

Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, PO Wits, 2050, South AfricaDepartment of Chemical Technology, University of Johannesburg, P.O. Box 17011, Doornfontein 2028, South Africa

r t i c l e i n f o

rticle history:eceived 18 February 2011eceived in revised form 30 April 2011ccepted 5 May 2011

a b s t r a c t

3�-Acetoxy-5�-cholestan-6-one semicarbazone 1 on reaction with hydrogen peroxide affords selectively3�-acetoxy-5�-cholestan-6-spiro-1′,2′,4′-triazolidine-3′-one 2. The structural assignment of the productwas confirmed by spectral data and elemental analysis. A free radical mechanism of the present reactionwas described successfully by calculating theoretical models of 1, A, B and 2, using DFT with B3LYP/6-31G*

eywords:teroidal triazolidinonetereoselective synthesisensity functional theoryrontier molecular orbital

basis set. It was found that the reaction undergoes through the formation of two radical intermediates andthe only one isomer of the product in which –NH–CO– group is cis with respect C5�-H, was selectivelyobtained. Frontier molecular orbital, spin electronic density, electrostatic potential and atomic chargeswere discussed.

© 2011 Elsevier B.V. All rights reserved.

ree radical reaction mechanism

. Introduction

The establishment of an efficient method for synthesizing tria-olidinones, the nitrogen-containing heterocyclic compounds haseceived great attention for drug design in the development ofharmaceutical and agricultural field. It has been reported thatriazolidinone has the ability to increase the yield of the plantood, which is contained in the plant storage organs like potatoes1]. It is also reported that triazolidinone does activate the humandrenergic receptor [2]. Krenzer has emphasized on synthesis anderbicidal activities of different type of triazolidinone [3,4]. Var-

ous research workers have adopted different approach towardshe synthesis and structural determination of triazolidinones [5–9].owever, Schantl and Gstach have reported the synthesis of tria-olidinone from arylazoalkylisocynate using Grignard reagent viaucleophilic addition [10].

In recent years, density functional theory (DFT) has become shooting star in molecular quantum mechanics for explaininghe reaction mechanisms. The main idea of DFT is to describe annteracting system of fermions via its density and not via its many-ody wave function. Thus the development of better and betterxchange-correlation functional made it possible to calculate many

olecular properties with comparable accuracies to traditional

orrelated DFT methods, with more favorable computational costs11]. According to the literature, it has been proved that DFT has

∗ Corresponding author. Tel.: +27 11 5596180; fax: +27 11 5596425.E-mail address: amishra@uj.ac.za (A.K. Mishra).

386-1425/$ – see front matter © 2011 Elsevier B.V. All rights reserved.oi:10.1016/j.saa.2011.05.005

a great accuracy in reproducing experimental data of molecularstructural properties, IR frequencies, intensities, etc. [12–14].

In continuation of our previous work on synthesis and theo-retical investigation [15–19] of biologically interesting steroidalcompounds, herein we present a novel and convenient method offormation of steroidal spiro-triazolidinone. Its structure is estab-lished by physical, elemental, spectral and computational data. Afree radical reaction mechanism of the present reaction is alsodescribed implying the density functional theory.

2. Materials and methods

2.1. General

The IR (KBr) spectrum recorded on a Perkin-Elmer 782 infraredspectrophotometer. 1H NMR spectra was recorded on a Bruker BZH-200 instrument. Chemical shifts are reported in parts per milliondownfield from tetramethylsilane. Multiplicities of proton reso-nance were designated as singlet (s) and multiplet (m). Meltingpoint reported is uncorrected. Chloroform and hydrogen perox-ide were purchased from the Aldrich Chemical Company. Lightpetroleum ether and ethyl acetate were supplied by Merck.

3. 3�-Acetoxy-5�-cholestan-6-spiro-1′,2′,4′-triazolidine-3′-one

2

The solution of 3�-acetoxy-5�-cholestan-6-one semicarbazone1 [20] (1.05 g, 2.10 mmol) in chloroform (25 mL) was treated with

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attached to the C-6 position to avoid 1,3-diaxial interaction due toC10�–CH3, the angular methyl group. Accordingly, only one iso-mer of this reaction 2, in which –NH–CO– group is cis with respectto the C5�-H, was selectively obtained. Further, formation of this

494 K. Sharma et al. / Spectrochimi

xcess of H2O2 (30%, 4 mL) and stirred for 2.5 h at 0 ◦C. The progressf the reaction was monitored by TLC. As the reaction proceeds theolution turned yellow in color. The organic layer was separated,ried over anhydrous sodium sulfate and then evaporated to dry-ess in vacuo. The resultant crude residue was purified over silicael column (light petroleum ether–ethyl acetate; 4:1), gave the titleompound 2 (81.5% yield, mp 166–167 ◦C) as a square shaped, whiterystals. IR �max/cm−1 (KBr): 3340 (N–H), 1700 (C O), 1480 (C–N)nd 1040 (C–O). 1H NMR (200 MHz; CDCl3; Me4Si): ı 7.85 (2H, s,HCONH), 6.7 (1H, s, NH), 2.04 (3H, s, OCOCH3) and 4.24 (1H, m,1/2 18 Hz, C3�-H). Analysis. Calculated for C30H51N3O3: C, 71.81;, 10.24; N, 8.37. Found: C, 71.86; H, 10.31; N, 8.48%.

.1. Computational method

The molecules calculated in this article are 3�-acetoxy-5�-holestan-6-one semicarbazone 1, radical intermediates (A and B)nd 3�-acetoxy-5�-cholestan-6-spiro-1′,2′,4′-triazolidine-3′-one. The structure 3, where NH–CO– group is trans with respect to5�-H is also calculated. All molecules were fully optimized inrder to describe the reaction mechanism of the present reactionnd to support the stereochemistry of the product.

The lower energy conformation of all the structures wasbtained by using ab initio theory. However, the molecular calcu-ations started with the fully optimized, semiempirical PM3 levelf theory, followed by the Hartree–Fock (HF) model with minimalTO-3G basis set. The resulting wavefunction, Hessian matrix andhe geometry of molecules obtained were used to calculate HF withext level of calculation that is split-valence basis set 3-21G(*).he obtained geometry was further subjected for the calculationith higher level of basis set, HF/6-31G*. The procedure was fur-

her applied for a final calculation that is DFT with B3LYP/6-31G*ethod. The “d” polarized functions were added for carbon, oxy-

en and nitrogen atoms. Stability and feasibility of all the optimizedtructures were supported by calculating their fundamental fre-uencies and assigned as local minima (all real frequencies).

Total energy, atomic charges, electrostatic potential, spin elec-ronic density, dipole moment and frontier molecular orbitalsFMO) were calculated. The energy of highest occupied molecularrbital (HOMO) and lowest unoccupied molecular orbital (LUMO)as used for calculating the hardness as an index of molecular

eactivity [21,22]. The molecules studied in this paper were builtith Spartan’04 Windows [23], a graphical software for quantum

hemical calculations.

. Results and discussion

The synthesis of requisite 3�-acetoxy-5�-cholestan-6-spiro-′,2′,4′-triazolidine-3′-one 2 from 3�-acetoxy-5�-cholestan-6-one

cheme 1. Synthetic scheme of formation of steroidal 6-spiro-1′ ,2′ ,4′-triazolidine-′-one.

a Part A 79 (2011) 1493– 1498

semicarbazone 1 on reaction with hydrogen peroxide was accom-plished with good yield, as summarized in Scheme 1.

4.1. Spectroscopic data

Selected diagnostic bands of infrared spectrum of �-acetoxy-5�-cholestan-6-spiro-1′,2′,4′-triazolidine-3′-one 2, provided vitalinformation for determining its structure. The IR spectrum exhib-ited characteristic absorption bands at 3340 for N–H, 1480 for C–Nand 1040 cm−1 for C–O. The presence of amide carbonyl stretch-ing frequency at 1700 cm−1, which is the evidence of 5 memberedcyclic amide ring, also supports the structure 2. Besides, 1H NMRspectrum showed a two-proton broad singlet at ı 7.85 (NHCONH),a three-proton singlet at 2.04 (OCOCH3), one-proton multiplet at4.24 (C3�-H) and one-proton singlet at 6.7 (NH) (exchangeable withdeuterium). All the spectral data are in good agreement with thedesired structure 2.

4.2. Stereochemistry

The spiro-cyclization of steroidal ketone semicarbazone formsrespective spiro-1′,2′,4′-triazolidine-3′-one. It is proposed thatthere is a considerable amount of steric hindrance to the ring-closure from one side of the ring at C-6, which might be explainedon the basis that amide (–NH–CO–) group is more bulky than–NH–NH– group. Thus, the triazolidinone ring closes at C-6 bythe attack of –CO–HN• (being a radical) of semicarbazone moiety,preferably in the way that –NH–CO– group became equatorially (˛)

Fig. 1. Calculated molecular structure of 2 and 3 is shown. In structure 2, –NH–CO–group is a cis with respect to C5�-H. In structure 3, –NH–CO– group is a trans withrespect to C5�-H.

K. Sharma et al. / Spectrochimica Acta Part A 79 (2011) 1493– 1498 1495

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ig. 2. Frontier molecular orbital of 1, A, B and 2 is shown. Frontier molecular orbteroid is shown while the C–D ring system with side chain is diminished for the cl

somer is also supported by energy comparison between 2 and 3Fig. 1). It was found that structure 2 is more stable than 3 bynergy 2 kcal/mol. Indeed the atomic distance between NH and10�–CH3 is higher in 2 (2.5 A) as compared to 3 (2.4 A). Theseesults also support the concept of avoiding 1,3-diaxial interactionn 2. The obtained stereochemistry of the product 2 formation is alson good agreement with our previously reported stereochemistryf triazolidinone ring formation [15].

.3. Theoretical investigation

The oxidative cyclization of semicarbazone with hydrogen per-xide via a free radical mechanism using theoretical models 1, A, B,, calculated by B3LYP/6-31G* method of DFT was discussed.

The total energy, frontier molecular orbital, hardness and dipoleoment are summarized in Table 1. During progress of the reaction

rom starting material 1 to product 2, some molecular propertieshanged as a result of different electronic distribution, for instancehe total energy of the product was lower than the reactant by.3 kcal/mol. This implies that 2 is more stable than 1. As it is a

located exactly on the reactive part of the molecules. The A–B ring system of thef the structures.

well known fact that the lowest the energy of the molecule, thehighest the stability of the molecule.

The LUMO or a-LUMO values of all the structures 1, A, B and 2calculated were higher in energy than their respective HOMO ora-HOMO values. Thus, FMO values follow the Fukui postulate [24]that the electrons in orbital with lower energy are more susceptibleto receive the electrophilic species whereas the electrons in orbitalwith higher energy are more susceptible to receive the nucleophilicspecies.

The hardness values remain same for 1 and A. However, there isa decrease in hardness from A to B, which is the spiro-cyclizationstep of the reaction. Hardness value is further increased from Bto 2 as the product is formed. These hardness values are in goodagreement with our previous published results of similar type oftriazolidinone molecule [16]. The structure B has the lowest hard-ness value as compared to all the molecules. In other words, B has

more softness than rest of the molecules, which implies the highreactivity of the intermediate B to proceed towards the productformation. This property fulfils the fact that according to Pearson[25], the soft molecules are more reactive than the hard molecules.

1496 K. Sharma et al. / Spectrochimica Acta Part A 79 (2011) 1493– 1498

Table 1Molecular properties of all the molecules involved in the synthesis of steroidal spiro-1′ ,2′ ,4′-triazolidine-3′-one calculated by using B3LYP/6-31G* basis set.

Steroid Total energya HOMOb LUMOb Hardnessc Dipole moment

1 −981339.461 −6.09 0.09 3.09 3.87A −980919.477 −6.46 −0.28 3.09 3.69B −980953.818 −5.19 0.46 2.82 2.822 −981344.787 −6.46 0.36 3.41 3.78

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4

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a kcal/mol.b Electron Volts (eV).c Debye.

The dipole moment (�) first decreased from 1 to B and thanncreased from B to 2. Thus the starting material 1 has higher

value than the product 2, implies more polarity of the former.ccordingly, the reactant is highly reactive and thus results into

he product formation. Similarly, dipole moment of intermediate Aas higher than intermediate B, indicates that A is more polar and

eactive and thus feasibly converts into intermediate B.The structural stability and feasibility of all the calculated

olecules were assessed by computing their harmonic normalodes of vibrations. The lowest-lying normal mode of vibration

f each of the molecule 1, A, B and 2 is of frequency at 18.25, 17.34,6.04 and 16.20 cm−1, respectively. The absence of negative (imag-

nary) frequencies indicates that all the calculated structures arehe local minima.

.3.1. Formation of radical intermediate AAn important feature of the radical formation from ketone semi-

arbazone 1 to intermediate A is the change in total energy. It

s observed experimentally that semicarbazone undergoes inter-

ediate formation due to the abstraction of hydrogen by peroxy•O2H) radical; hence A looses 420 kcal/mol of energy correspond-ng to the loss of one hydrogen atom (Table 1). This is a usual

ig. 3. Panel 1 shows electrostatic potential map of 1 and spin electronic density map off 2. Some selected electrostatic charges are labeled.

situation, as it was observed that energy diminishes when the num-ber of atoms increases [26].

There are some other characteristics of intermediate A for-mation, which can be classified into two groups: geometricand electronic features. The molecule 1 must have a reactiveNNHCONH2 group that could release H•, to be abstracted by theperoxy radical. The semicarbazone moiety 1 must have HOMO andelectrostatic potential at NH2 to release hydrogen as shown inFigs. 2 and 3, respectively. The NH2 group should have spin elec-tronic density after releasing hydrogen, due to the formation ofunpaired electron (HN•) as was exactly observed in structure A(Fig. 3).

4.3.2. Formation of cyclic radical intermediate BThe formation of intermediate B from A implies the spiro-

cyclization at C-6 carbon atom. To carry out this step of the reaction,it is necessary to have a-HOMO and spin electronic density on HN•

radical and a virtual orbital a-LUMO at C-6 on intermediate A. Theanalysis of the frontier molecular orbital in Fig. 2 shows that A hasthe frontier orbitals just on its reactive part and work in the sameway as the FMO analysis based on perturbation theory works. The

A. Panel 2 shows spin electronic density map of B and electrostatic potential map

K. Sharma et al. / Spectrochimica Acta Part A 79 (2011) 1493– 1498 1497

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ig. 4. Reaction mechanism of the formation of spiro-triazolidinone 2 from respecormation of two intermediate states A and B.

aid theory has been widely used for explaining and predicting theeactivity patters in different type of the reactions [27–29].

Besides the FMO analysis, it was also observed that HN• rad-cal of molecule A possesses N with higher electrostatic charge−0.626) that could share charge with C-6, because of the lackf atomic charge (0.561) at C-6 as revealed in Fig. 3. Accordingly,

bond formation between nitrogen and C-6 atom occurs, whichurther reduces the C N �-bond and thus forms C–N• radical. Con-equently, changes in atomic charges are in a good support as the

bond polarization follows the present reaction mechanism.

.3.3. Formation ofˇ-acetoxy-5˛-cholestan-6-spiro-1′,2′,4′-triazolidine-3′-one 2

The cyclic intermediate B abstracts hydrogen as a radical (H•)nd thus forms steroidal spiro-1′,2′,4′-triazolidine-3′-one, the finalroduct 2. A common feature of product formation from interme-iate B to 2 is the change in total energy. It is possible to gain91 kcal/mol energy corresponding to the addition of one hydrogentom (Table 1). Due to the fact mentioned above, it could be con-ider that this step of the reaction occurs only if a-HOMO as wells spin of the electron is located on C–N• group of the interme-iate B. These properties were found exactly on the reactive parts revealed from the frontier orbital analysis and spin electronic

ensity map of structure B in Figs. 2 and 3, respectively.

Based upon the experimental and theoretical evidences, a freeadical mechanism is proposed for the formation of 3�-acetoxy-�-cholestan-6-spiro-1′,2′,4′-triazolidine-3′-one from respective

emicarbazone 1 is shown. It is proposed that this reaction undergoes through the

ketone semicarbazone using hydrogen peroxide (Fig. 4). Peroxyradical (HO2

•) induced oxidative cyclization on the semicarbazonemoiety. Abstraction of hydrogen by HO2

• initiates the reaction,causes homolytic cleavage of N–H bond. Further, abstraction of Hby heterocyclic ring of structure B, being a radical in the final stepcompletes the reaction. The required energy for fragmentation ofN–H bond in first step must be counter balanced by the energygained by formation of N–H bond in the last step of the reaction;this is found in good agreement with the energy values obtainedby computational calculations.

Comparing the results of this article with our previouslypublished work on synthesis of 3�-chloro-5�-cholestan-6-spiro-1′,2′,4′-triazolidine-3′-one [15] and 5�-cholestan-6-spiro-1′,2′,4′-triazolidine-3′-one [16], we found that in terms of synthesis, thereis no significant influence on the reaction by changing the differ-ent substituent at 3� position of steroid as the reactive part inthis reaction is present at C6 carbon atom. Nevertheless, we foundthat 3�-acetoxy group shows a very large electrostatic potential(Fig. 3), which was not found on 3�-chloro and 3�-hydrogen inprevious reports. However, substituting 3�-acetoxy at C3 positioncould have an impact on its biological activities. As the syntheticpart for the medicinal chemist is very time consuming and laborintensive, present study could be very useful to figure out which

compound will be more biologically active before synthesizing it.

All the physicochemical parameters calculated in this article:atomic charges, the total energy, dipole moment, spin electronicdensity, electrostatic potential, frontier molecular orbital and hard-

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ess, were highly supportive to provide a rational explanation of theature in which the reaction mechanism of formation of steroidalpiro-triazolidinone occurs.

. Conclusions

In summary, we have demonstrated the simple and con-enient method of preparation of 3�-acetoxy-5�-cholestan-6-piro-1′,2′,4′-triazolidine-3′-one by the oxidative cyclization ofespective steroidal ketone semicarbazone. The triazolidinone ringloses at C-6 carbon atom. The only one isomer of this reaction, inhich –NH–CO– group is cis with respect to C5�-H, was selectively

btained.The present reaction proceeds via a free radical reaction mecha-

ism, which is described successfully by using ab initio calculations.n the basis of Density Functional Theory and Frontier Molecularrbital theory, it is concluded that the reaction undergoes through

he formation of two radical intermediates. The obtained experi-ental and theoretical results could be useful for the drug design.

cknowledgments

Authors are highly thankful to the University of the Witwater-rand and University of Johannesburg for the financial support.

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