theoretical and experimental studies of 1,3-dipolar...

Indian Journal of Chemistry Vol. 55B, November 2016, pp. 1400-1414

Theoretical and experimental studies of 1,3-dipolar cycloaddition reactions between trimethylsilylazide and citral (geranial and neral)

Sepehr Tabana & Avat (Arman) Taherpour*b,c a Chemistry Department, Science Faculty, Islamic Azad University, Arak Branch, P.O. Box 38135-567, Arak, Iran

b Department of Organic Chemistry, Faculty of Chemistry, Razi University, P.O. Box 67149-67346, Kermanshah, Iran c Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran

E-mail: [email protected]

Received 3 March 2016; accepted (revised) 5 July 2016

The [3+2] cycloaddition reactions on citral which is the mixture of geranial 1 and neral 2 isomers have been performed to obtain interesting varieties of its derivatives. The probable 1,3-dipolar cycloaddition reactions between citral mixture (1 and 2) with trimethylsilylazide (TMS), the comparison of the citral mixture in the kinetic and thermodynamic reactions, the structural studies of the 1,2,3-triazoline products, carbine reactive intermediates and transition states are investigated. The reactions are studied and discussed by B3LYP/6-31G* method. The main configurations are performed with less steric restraint effects. The HOMO and LUMO orbital levels, ∆ΕHOMO-LUMO gaps, dipole moments, Mulliken charges, thermodynamic and kinetic stabilities in vacuum are investigated for the components by the density functional theory (DFT) B3LYP/6-31G* method. The elimination reactions of N2 molecule from the 1,2,3-triazolines to produce aziridine products, the mechanisms, the biradical intermediates and the related transition states have been investigated as well by the use of B3LYP/6-31G* method. Some of the experimental results such as FT-IR, 1H NMR and GC-MS have been carried out in this study to pursue the course of the reactions.

Keywords: Citral mixture, trimethylsilylazide (TMS), [3+2] cycloaddition reaction, 1,2,3-triazoline, aziridine, reactive intermediates, DFT-B3LYP method, molecular modeling, FT-IR, 1H NMR, GC-MS

The compound with IUPAC name 3,7-dimethyl-2,6-octadienal or citral (lemonal) is a pair or a mixture of the two double bond isomer compounds Geranial and Neral. The E-isomer is known as Geranial 1 or citral-A and the Z-isomer is known as Neral 2 or citral-B. Citral was found in the oils of several plants, including lemon myrtle (90-98%), Litsea citrata (90%), Litsea cubeba (70-85%), lemongrass (65-85%), lemon tea-tree (70-80%), Ocimum gratissimum (66.5%), Lindera citriodora (about 65%), Calypranthes parriculata (about 62%), petitgrain (36%), lemon verbena (30-35%), lemon ironbark (26%), lemon balm (11%), lime (6-9%), lemon (2-5%) and orange1-7. Geranial 1 has a strong lemon odor. Neral’s 2 lemon odor is less intense, but sweeter. Citral is also used in perfumery for its citrus effect as a flavor and for fortifying lemon oil. It has also strong antimicrobial qualities1, and pheromonal effects in insects1. Citral is used in the synthesis of vitamin A, ionone, and methylionone. Citral on its own is strongly sensitizing to allergies; the International Fragrance Association (IFA) recommends that citral only be used in association with substances that prevent a sensitizing effect. Citral has been

extensively tested and has no known genotoxicity and no known carcinogenic effect, but animal tests show dose-dependent effects on the kidneys1.

Triazoline and its derivatives can be used in medicine as antibacterial, antiviral, anti-cancerous, anti-asthmatic, analgesic and anti-inflammatory drugs because of their pharmaceutical properties2. Furthermore, triazoline’s interest in 1,3-dipolar cycloadditions involving olefins as dipolarophiles and azides as 1,3-dipoles originates from the synthetic potential of these reactions which leads to the formation of five membered nitrogen containing heterocycles like 1,2,3-triazolines2.

In 1967, Scheiner reported the addition of aryl azides to unstrained olefins. Scheiner had reported that the aryl azides have been found to add to unactivated olefins, providing a convenient route to alkyl substituted triazolines3. Similarly, conjugated dienes undergo cycloaddition with azides to give S-vinyltriazoline derivatives. The electronic and steric factors that controlled the orientation of the additions accords with previously reported mechanistic considerations and were discussed by Scheiner in 1967 (Ref 3).

TABAN & TAHERPOUR: 1,3-DIPOLAR CYCLOADDITION REACTIONS

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In 1971, Broeck et al. reported the cycloaddition reactions of azides with electron-poor olefins4. The cycloaddition reactions of phenyl azide and butyl azide with mono-substituted electron-poor olefins are highly region-selective (if not region-specific) and lead to l,4-disubstituted ∆2-triazolines or products derived therefrom: aziridines, diazocompounds, pyrazolines and 1,4-trisubstituted triazolines4. As expected, the latter three products are not formed when a methyl group is introduced in the germinal position of the olefins, but ∆2-triazolines and aziridines are then obtained exclusively. In all cases studied, the 1,4-disubstituted ∆2-triazolines derived from phenyl azide only give aziridine on thermolysis, whereas those derived from alkyl azides are thermally converted into a mixture of aziridine and enamine4.

In 1976, Peterson and Arkles reported the reaction of trimethylsilyl azide (TMS) with bridged bicyclic olefins. Bridged bicyclic olefins were found to undergo facile 1,3-cycloaddition reaction with trimethylsilyl azide5. Norbornene produced cis-exo-l-trimethylsilyl-4,7-methano-3a.4,5,6,7,7a-hexahydrole, while norbornadiene formed a bi-adduct with cis-exo-stereochemistry, together with 2-trimethylsilyl-1,2,3-triazole produced by a retro Diele-Alder reaction of an intermediate mono-adduct5. Dicyclopentadiene reacted only at the norbornene position while α-pinene did not react with trimethylsilyl azide. In contrast to aryl- and sulfonyl-azide adducts of norbornene derivatives, which decompose upon heating, the present adducts were recovered unchanged after prolonged treatment at 205°C5. In 1996, the ∆2-1,2,3-triazoline anticonvulsant derivatives and novel 'built-in' heterocyclic prodrugs with a unique 'dual-action' mechanism for impairing excitatory amino acid L-glutamate neurotransmission were considered by Kadaba6. The ∆2-1,2,3-triazoline anticonvulsants are considered as representing a unique class of 'built-in' heterocyclic prodrugs where the active 'structure element' is an integral part of the ring system and can be identified only by a knowledge of their chemical reactivity and metabolism6. Investigations on the metabolism and pharmacology of a lead triazoline suggest that the triazolines function as 'prodrugs' and exert their anticonvulsant activity by impairing excitatory amino acid (EAA) L-glutamate (L-Glu) neurotransmission via a unique 'dual-action' mechanism6. While an active β-amino alcohol metabolite, from the parent prodrug acts as an N-methyl-D-aspartate (NMDA)/ MK-801 receptor antagonist, the parent triazoline

impairs the presynaptic release of L-Glu. Various pieces of theoretical reasoning and experimental evidence led to the elucidation of the dual-action mechanism6. In vivo and in vitro pharmacological studies of the derivatives and potential metabolities, along with a full quantitative urinary metabolic profiling of them, the β-amino alcohols as the active species are indicated6. The high anticonvulsant activity of ∆2-1,2,3-triazoline anticonvulsant derivatives may be due to its unique dual-action mechanism6.

The synthesis of some bis-heterocyclic derivatives based on 1,2,3-triazoline and a study of their antibacterial activity have been performed by Saad Jawad in 2012 (Ref 2). The results involve the isomerisation of arylazoaziridines2,3. The second synthetic route to triazolines is the 1,3-dipolar cycloaddition of diazoalkenes to Schiff bases (imines)2,6. A third route to 1,2,3-triazoline is the 1,3-dipolar cycloaddition of azides to ethylenic compounds2,7. 1,2,3-Triazolines have been used as versatile precursors of N-containing heterocycles. E. Erba and D. Sporchia2,8 synthesized 4-aminoquinazolines and 6-aminopurines from their corresponding triazolines. Triazoline can be converted into thiadiazole ring under acidic conditions2,9; they were also used in the synthesis of 1,2,3-triazoles2,10. As the antibacterial activity results of final compounds show, the derivatives exhibited moderate to high activity against both types of bacteria because the mentioned compounds contain the barbituric moiety in addition to triazoline ring while the compounds showed moderate activity against E. coli. Some of the triazole derivatives showed slight activity against S. aureus2.

The 1,3-dipolar cycloaddition, also known as the Huisgen cycloaddition, is the organic chemical reaction belonging to the larger class of cycloaddition reactions between a 1,3-dipole and a dipolarophile to form a 5-membered ring11,12. 2π-Electrons of the dipolarophile and 4π-electrons of the dipolar compound participate in a concerted pericyclic shift. IUPAC recommends the use of (3+2) for the number of involved atoms instead. A condition for such a reaction to take place is a certain similarity of the interacting HOMO and LUMO orbitals, depending on the relative orbital energies of both the dipolarophile and the dipole. Electron-withdrawing groups on the dipolarophile normally favor an interaction of the LUMO of the dipolarophile with the HOMO of the dipole that leads to the formation of the new bonds, whereas electron-donating groups on the

INDIAN J. CHEM., SEC B, NOVEMBER 2016

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dipolarophile normally favor the inverse of this interaction11-17. The Huisgen’s 1,3-dipolar cycloaddition of alkynes and azides yielding triazoles is, undoubtedly, the premier example of precyclic reactions18-23.

Sakai and Nguyen have investigated two possible electronic mechanisms for dipolar cycloaddition reactions, as: (a) depicts a spin-coupled bond breaking and bond formation, a type of biradical coupling mechanism, (b) are “heterolytic” mechanisms, where the pairs of electrons migrate to form the new bonds, with (b) differing in direction of electron flow (different arrow-pushing formalism)24-27.

The 1,3-Dipolar cycloaddition reactions of azides with terminal acetylenes and nitriles have been studied by Huisgen24,28,29. The copper-catalyzed 1,3-dipolar cycloadditions, in which copper salts have been used to catalyze the reaction between azides and terminal acetylenes24,30-32, is the main reaction of click chemistry. Sharpless et al. has reported Ruthenium-catalyzed cycloadditions between organic azides and mono- and disubstituted alkynes to afford 1,5-disubstituted and 1,4,5-trisubstituted 1,2,3-triazoles, respectively24,31. Catalysis of the reactions between nitriles and azide salts by magnesium33, zinc34 and proton35 have also been studied.

DFT calculations on the non catalyzed reactions between nitriles and azides show that the reaction follows a concerted [3+2] mechanism24,35. The results of the calculations have predicted that the barrier energies for reactions of methyl azide with electron-deficient and electron-rich nitriles range from 18 to 35 kcal mol−1, respectively. The theoretical investigations have also predicted the preference for the formation of 1,5-disubstituted adducts over 2,5-disubstituted adducts, in excellent agreement with experiment24. Theoretical methods and computational studies has played important roles in the utilization of the cycloaddition reactions in synthesis24. To perform experimentally accurate calculations, quantitative quantum mechanical (QM) methods and effective models have been applied to a wide variety of 1,3-dipolar pericyclic reactions36. The cycloaddition reactions that provide critical evaluations of the accuracy and precision of ab initio and DFT methods have been investigated24. 1,2,3 Triazoles as the products of [3+2] cycloaddition reactions are known to be relatively resilient to metabolic degradation and have known utility in several medicinal chemistry campaigns as isosteres for phenyl rings and carboxyl functionalities12-20,24,36. The triazoles may display a

wide range of biological activity as anti-HIV and antimicrobial agents, as well as selective β3 adrenergic receptor agonists and anti-allergic agents18-

21,37,38. The 1,2,3-triazole derivatives are found in herbicides, fungicides, and dyes16-23, 37,38.

The five member ring compounds, which are structurally related to isolated polycyclic acridine marine natural products38, have intriguing physical and biological properties. They are weakly basic, highly fluorescent and, because of their near planarity38, bind to DNA in an intercalative mode at high [DNA]:[ligand] ratios as evidenced by circular and linear dichroism studies38. Additionally, they stabilize DNA triple helices and are potent inducers of apoptosis (programmed cell death) in human lung and breast tumor cell lines38.

In general, 1,2,3-triazole formation requires harsh conditions, that is, high temperature and longer reaction times. The 1,2,3–triazole derivatives were previously produced by reaction of o-phenylenediamine, sodium nitrite and acetic acid. The conversion proceeds via diazotization of one of the amine groups17. In the original description, the examples explored showed that although these were relatively clean processes, they could take from 12 to 48 hours at high temperatures (~110°C)11. Microwave-assisted synthesis has been utilized as a powerful and effective technique to promote a group of chemical reactions18-20. Since the first publications on the use of microwave irradiation in organic chemistry, the accelerated process described have been a lure for chemists to further apply new reactions to this technology17-20. The [3+2] cycloaddition reactions under microwave irradiation and theoretical conditions were investigated for producing 1,2,3-triazoles and reported earlier11-18,38-44.

This study reports the [3+2] cycloaddition reactions on citral which is the mixture of Geranial 1 and Neral 2 isomers performed to obtain interesting varieties of its derivatives. The possible 1,3-dipolar cycloaddition reactions between citral mixture (1 and 2) with trimethylsilylazide (TMS), the comparison of the citral mixture in the kinetic and thermodynamic reactions, the structural studies of the 1,2,3-triazoline products, carbine reactive intermediates and transition states were investigated. The reactions are studied and discussed by B3LYP/6-31G* method. The calculations were performed on the main configurations with less steric restraint effects. The HOMO and LUMO orbital levels, ∆ΕHOMO-LUMO gaps, dipole moments, Mulliken charges, thermodynamic and kinetic stabilities in


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vacuum were investigated for the components by the density functional theory (DFT) B3LYP/6-31G* method. The elimination reactions of N2 molecule from the 1,2,3-triazolines to produce aziridine products, the mechanisms, the biradical intermediates and the related transition states were investigated as well by the use of B3LYP/6-31G* method. Some of the experimental techniques such as FT-IR, 1H NMR and GC-MS were used to pursue the course of the reactions which were carried out in this study.

Molecular Modeling and Computational Details The DFT-B3LYP molecular orbital calculations

were performed with the Spartan ‘10 package46. Geometries for all structures were fully optimized by means of analytical energy gradients in B3LYP levels with the 6-31G* basis sets45,46. The frequencies were scaled and used to compute the free energies (∆G

#) and the free energies changes of reaction (∆rG) at 298 K by equations:

∆G# = GTS − GReactants (Eq.-1)

∆rG = ΣGproducts − ΣGreactants (Eq.-2)

Also, rate constants were calculated with the Eyring equation, derived from transition state theory45,46:

k = KBT/h [exp(−∆G#/RT)] (Eq.-3)

The calculations on the structures of the derivatives have performed by the appropriate quantum mechanical method. In this study, the computational method employed cover DFT approaches. The structure of the diazoamine, 1,2,3-triazoline and aziridine derivatives

were optimized by DFT-B3LYP/6-31G* method. The Hartree’s energies were converted to kcal mol−1 and the relative energies were calculated. The graphs and the related tables demonstrated the appropriate data.

The Quantum chemical computations (QM) of the ground state molecular geometry, dipole moments, polarizabilities, energies HOMO and LUMO orbitals of different tautomers of the suggested molecules in vacuum were carried out at the DFT-B3LYP level of theory45,46. The structures of 1,2,3-triazoline and di-azoamine derivatives, intermediates (carbines and radicals), the transition states and the N2 eliminations from the triazolines and the di-azoamine to receive aziridine derivatives were optimized by DFT-B3LYP/6-31G* method. All of the calculations have been performed by Spartan ‘10 package45. The geometry and energy optimizations of the

molecules in different conditions leading to the energy minima46 and determination of the convergence properties of the molecules47 were first performed without any symmetry constraints43,45 using the analytical gradient methods of B3LYP46-49 by means of the standard polarized basis set; 6-31G*18,30-36. The optimized structures were then used to obtain the ground state molecular geometry parameter, dipole moments, polarizabilities, energies and frontier orbital energies (HOMO and LUMO) of the studied molecules at the same level of theory (B3LYP/6-31G*)46.

Dipole moment (µ) can be defined as the product of magnitude of charge and the distance of separation between the charges. This quantity has been found to increase with a decrease in the HOMO–LUMO energy gap of molecular systems. The total (static) dipole moment is:

µ = (µx2+µy

2+µz2)1/2 (Eq.-1)

However, it only reflects the global polarity of a molecule. For a complete molecule, the total molecular dipole moment may be approximated as the vector sum of individual bond dipole moments46-50.

Mulliken charges arise from the Mulliken population analysis50 and provide a means of estimating partial atomic charges from calculations carried out by the methods of computational chemistry, particularly those based on the linear combination of atomic orbitals molecular orbital method, and are routinely used as variables in linear regression procedures50. If the coefficients of the basis functions in the molecular orbital are Cµi for the µ'th basis function in the i'th molecular orbital, the density matrix terms are50:

Dµυ = 2Σi CµiC*υi (Eq.-2)

for a closed shell system where each molecular orbital is doubly occupied. The population matrix "P" then has terms50:

Pµυ = Dµυ,Sµυ (Eq.-3)

"S" is the overlap matrix of the basis functions. The sum of all terms of Pµυ summed over µ is the gross orbital product for orbital υ GOPυ. The sum of the gross orbital products is N- the total number of electrons50. The Mulliken population assigns an electronic charge to a given atom "A", known as the gross atom population: GAPA as the sum of GOPυ overall orbitals υ belonging to atom "A"40. The charge, QA, is then defined as the difference


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between the number of electrons on the isolated free atom, which is the atomic number ZA, and the gross atom population50:

QA = ZA − GAPA (Eq.-4)

One of the problems with this approach is the equal division of the off-diagonal terms between the two basis functions. This leads to charge separations in molecules that are exaggerated. In a modified Mulliken population analysis50, this problem can be reduced by dividing the overlap populations Pµυ between the corresponding orbital populations Pµµ and Pυυ in the ratio between the latter50. Another problem is that Mulliken charges are explicitly sensitive to the basis set choice50. This problem is addressed by Natural Population Analysis50 and other modern methods for computing net atomic charges50.

Experimental Section The simple GC-MS, 1H NMR and FT-IR

experiments on the reaction mixture of citral mixture (Geranial 1 and Neral 2) with trimethylsilylazide (TMS) have been performed and the result of the components were extracted to investigate the theoretical pathway of the [3+2] cycloaddition reactions and N2 elimination from 1,2,3-triazoline derivatives. The derivatives were synthesized by the method that has been explained in the typical procedure. The FT-IR spectra were recorded as KBr pellets on a Shimadzu FT-IR 8400 spectrometer. The NMR spectra were determined on a 400 MHz Brüker spectrometer. The solvent for NMR recording was CDCl3. The GC and GC-MS analysis was performed on a Perkin-Elmer GC(Clarus680)-MS(Clarus-SQ8S) instrument, injector 250°C; temperature program: 70°C (1 min), then 10°C per min till 300°C on an Elite-5MS capillary column (0.25 µm thickness, 0.25 mm diameter, 30 m length). The ionization energy for mass spectra was 30 eV (Figure 1 to 9 in the text and the Supplementary data).

Typical procedure for 1,2,3-triazoline synthesis It should be noted that a limited amount of

compounds is required for the experiment. A mixture of citral mixture (1 and 2; 1.824 g, 2.05 mL, 0.012 mol) with trimethylsilylazide (TMS; 1.38 g, 1.57 mL, 0.012 mol) was made in a dried Pyrex tube. The reaction mixture was left standing 24 h after mixing. Then the reaction mixture was mixed for about 5 min at a mild air flow condition under fume

hood. The color of the final mixture was red. Then the mixture was utilized for the spectroscopy experiments.

Results and Discussion The experimental results have demonstrated the

mixture of the products, i.e. 1,2,3-triazoline, di-azoamine and aziridine derivatives at the final experimental reaction. The B3LYP/6-31G* calculations on the mechanism pathways related to the spectroscopy results are investigated and discussed here.

Figure 1 shows all of the pathways and the reactions to produce the products, intermediates and the transition states 1-15 by the use of DFT-B3LYP/6-31G* calculations. The selected structural data of the products 3-8, 15, intermediates 11-14 and the transition states 3, 4, 7, 9-12 are shown in Table I and Table II. The bond lengths (in Å) and bond angles (in °) of Geranial 1, Neral 2 and trimethylsilylazide (TMS) were demonstrated in the Supplementary data (see S1). The values of EHOMO, ELUMO and ∆EHOMO-

LUMO (in eV) for Geranial 1, Neral 2 are: {-6.14, -1.04 and 5.10} and {-6.23, -1.19 and 5.04}, respectively. The dipole moments of 1 and 2 are 3.86 and 4.59D, respectively. The stereoisomer Geranial 1 is 0.012 kcal mol−1 less stable than Neral 2. Indeed, the stability of Geranial 1, Neral 2 is almost equal (Table I).

The calculated Mulliken charges of Geranial 1, Neral 2 and trimethylsilyl azide (TMS) were demonstrated in the Supplementary data (see S2). The Mulliken charges are important to determine the pathway regio-selective process. The DFT-B3LYP/6-31G* results show that the Mulliken charges of N1, N2 and N3 are −0.501, 0.421 and −0.298 esu, respectively. The N1 has bigger electron population which is near to -Si(Me)3 group. The Mulliken charges of Cβ atoms in Cβ=C-C=O functional group are 0.201 and 0.198 for Geranial 1 and Neral 2, respectively. The Mulliken charges of Cα atoms in C=Cα-C=O functional group are −0.231 and −0.228 esu for Geranial 1 and Neral 2, respectively. So, the region-selectivity of the [3+2] cycloaddition reactions on Citral which is the mixture of Geranial 1 and Neral 2 isomers have started by attack of N1 from TMS to Cβ atoms in Cβ=C-C=O functional group to receive the 1,2,3-triazoline-TMS derivatives 3 and 4. It seems that the 1,3-dipolar cycloaddition reaction on Geranial 1 takes place better and simpler than Neral 2


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Me3Si-N3CHO

CHO

N

NNMe3Si

H

:

CHO

Me3SiN

N

NH

H2O

CHO

NN

NH

H

:

H2O

CHO

N

N

H2N

-N2

CHO

+

Geranial(1) Neral(2)

H

NN

NMe3Si

CHO

:

H2O

H

N

NNH

CHO

:

CHO

H2N

Me3Si-N3

.. CHO

H2N

.

.

Singlet Triplet

CarbeneH

N

NN

H

CHOCHO

N

NN

H

H

TSTS

-N2 -N2(more stable than Triplet)

CHO

HN

H

H

HN

CHO

.

.

.

.

In. In.

Citral

CHONH

H

BiradicalBiradical

:

(3) (5)(4)

(6) (7) (8)

(9)

(11) (12)(10)

(13)(14)

Pathway-I Pathway-I

Pathway-II Pathway-II

(15)

Figure 1 — The pathways and the reactions with the products, intermediates and the transition states (1-15). All of the studied pathways and the reactions to produce the products, intermediates and the transition states (1-15) were performed by DFT-B3LYP/6-31G* calculations.

Figure 2 — The calculated transition states (TS) of the 1,3-dipolar reactions of TMS-N3 with Geranial (1) and Neral (2) by theory (DFT) B3LYP/6-31G* method.


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Figure 3 — The reaction diagram of 1,3-dipolar cyclo-addition reactions of TMS-N3 with Citral (Geranial and Neral) to produce (3) and (4) derivatives. The product (3) is thermodynamically and kinetically more stable than (4). The energy levels were obtained by theory (DFT) B3LYP/6-31G* method.

Figure 4 — The calculated structures of the products 4,5-dihydro-5-methyl-5-(4-methylpent-3-enyl)-1-(trimethylsilyl)-1H-1,2,3-triazole-4-carbaldehyde (3) and (4) by theory (DFT) B3LYP/6-31G* method.

because of the bigger steric restraint effects in Neral 2 and the bigger Mulliken plus charges of Cβ in Geranial 2 to attract N1 atom of TMS. The results of the DFT calculations show that there are no differences at the energies and the Mulliken charges of the TMS resonance forms.

Figure 2 shows the transition states [TS]3 and [TS]4 of the 1,3-dipolar cycloaddition reactions of TMS with Geranial 1 and Neral 2 to produce 3 and 4 1,2,3-

triazoline-TMS products. The steric restraint between C6 and -SiMe3 in product 4 (from Neral 1) rather than product 3 (from Neral 2) has made the higher energy


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Figure 5 — The calculated structures of the products 4,5-dihydro-5-methyl-5-(4-methylpent-3-enyl)-1H-1,2,3-triazole-4-carbaldehyde (6) and (8) by theory (DFT) B3LYP/6-31G* method.

Figure 6 — The conversion pathways of (6), (8) and 3-amino-3-diazo-3,7-dimethyloct-6-enal (7). The structures were obtained by theory (DFT) B3LYP/6-31G* method.

Figure 7 — The transition states (TS) of the 1,3-dipolar reactions of H-N3 with Geranial (1) and Neral (2). The structures were calculated by theory (DFT) B3LYP/6-31G* method.

for [TS]4 than [TS]3. The distances of N1…C4 and N3…C3 in the transition states [TS]3 and [TS]4 are 2.086 and 2.109Å, respectively. The C2-C3 bond lengths in [TS]3 and [TS]4 are 1.472 and 1.480Å, respectively. Figure 3 shows the reaction diagram of 1,3-dipolar cyclo-addition reactions of TMS with the

citral mixture (Geranial and Neral) to produce 3 and 4 derivatives. The ∆G of 3 and 4 1,2,3-triazolin-TMS derivatives are 5.05 and 3.95 kcal mol−1, respectively. The ∆G

# of 3 and 4 1,2,3-triazolin-TMS derivatives are 26.46 and 46.71 kcal mol−1, respectively. So, the product 1,2,3-triazolin-TMS 3 is thermodynamically


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Figure 8 — The mass spectrum of the 1,2,3-triazoline and di-azoamine derivatives (6-8) related to the experimental part of this study. The retention times (RT) in GC-MS experiment were 8.92 (A), 17.60(B), 18.69(C) and 25.27min(D) under the spectroscopy conditions. The GC and GC-MS analysis was performed on a Perkin Elmer GC(Clarus680)-MS(Clarus-SQ8S) instrument, injector 250ºC; temperature program: 70ºC (1 min), then 10ºC per min till 300ºC on an Elite-5MS capillary column (0.25 µm thickness, 0.25mm diameter, 30m length). The ionization energy for Mass spectra was 30eV.

Figure 9 — The comparison between the 1H NMR spectrum (-CHO functional group region) of citral (Geranial 1 and Neral 2) before and after reaction with trimethylsilylazide (TMS). The NMR spectra were determined on a 400MHz Brüker spectrometer. The solvent for NMR recording was CDCl3.

and kinetically more stable than 4. The 1,2,3-triazolin-TMS derivative 3 1.10 kcal mol−1is more stable than 4 (Table I, Table II and Figures 2 and 3).

The structures of the products 4,5-dihydro-5-methyl-5-(4-methylpent-3-enyl)-1-(trimethylsilyl)-1H-1,2,3-triazole-4-carbaldehyde 3 and 4 are shown in Figure 4. The DFT-B3LYP/6-31G* calculations demonstrated that because of the 2p-3d resonance between N1 and Si atoms the hybridization of N1atoms in both 3 and 4 is sp

2. So, the

pyramidality around N1 (in comparison with sp2) in

both 3 and 4 1,2,3-triazoline-TMS derivatives are equal to zero.

The DFT-B3LYP/6-31G* calculations demonstrated that the diazoamine-TMS derivative 5 is 43.25 and 43.51 kcal mol−1 more stable than 1,2,3-triazolin-TMS derivatives 3 and 4, respectively. So, the experimental results and DFT calculations confirm that the main product of this pathway is the diazoamine-TMS derivative 5.


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Table I — The selected structural data for the real and predicted compounds and products by theory (DFT) B3LYP/6-31G* method

Selected data Bond length(Å)

Compds

Compd 3 Compd 4 Compd 5 Compd 6 Compd 7(R) Compd 7(S) Compd 8 Compd 15(SR) Compd 15(SS)

N1N2 1.363 1.365 − 1.373 − − 1.375 − − N2N3 1.254 1.256 1.142 1.251 1.142 1.142 1.253 − − N1C4 1.497 1.497 1.456 1.491 1.462 1.460 1.487 1.463 1.461 N3C3 1.481 1.488 1.308 1.492 1.310 1.308 1.495 − − C3C4 1.571 1.563 1.564 1.558 1.561 1.563 1.560 1.514 1.527 N1X7 a 1.799 1.798 1.761 1.016 1.020 1.018 1.016 1.021 1.025 C4C5 1.545 1.544 1.558 1.541 1.554 1.552 1.541 1.527 1.524 C4C6 1.539 1.541 1.535 1.539 1.535 1.539 1.539 1.520 1.519 C2C3 1.523 1.531 1.451 1.518 1.452 1.457 1.530 1.489 1.481 O1C2 1.212 1.211 1.226 1.211 1.226 1.222 1.210 1.214 1.219 C2H8 1.110 1.111 1.110 1.110 1.110 1.111 1.110 1.111 1.111 C3H9 1.100 1.093 − 1.104 − − 1.092 1.089 1.089 N1H9 − − 1.018 − 1.019 1.018 − − −

Bond angle(°) N1N2N3 114.45 114.20 − 112.33 − − 112.38 − − N2N3C3 109.72 109.42 179.18 109.26 179.13 178.71 109.36 − − N3C3C4 105.34 104.50 120.74 105.09 120.48 118.50 103.87 − − C3C4N1 98.45 98.48 109.49 96.19 110.80 113.34 96.64 59.66 59.16 C4N1N2 111.12 110.02 − 110.66 − − 109.91 − − N2N1X7 a 115.00 117.27 − 111.27 − − 111.29 − − C4N1X7 a 133.68 132.59 131.08 118.27 109.01 112.03 118.53 111.25 109.52 C2C3H8 105.76 26.78 27.65 27.35 27.63 27.78 26.69 27.12 27.28 C4N1C3 41.97 41.83 36.70 43.04 35.90 34.61 42.92 61.87 62.65 N1C3C4 39.58 39.70 33.81 40.78 33.30 32.05 40.44 58.47 58.19

Torsional angle(°) C4N1N2N3 -2.48 −7.84 − -18.71 − − −18.59 − − N1N2N3C3 177.94 −4.96 − 1.92 − − −0.20 − − N2N3C3C4 5.53 14.87 −23.52 14.30 −38.14 5.49 17.42 − − N3N2N1X7 a 173.15 175.62 − −152.33 − − −151.93 − − C3C4N1X7 a −169.15 −168.56 −84.63 154.58 51.38 58.84 156.01 101.57 99.10 C2C3C4C6 −13.55 −146.70 −169.62 −30.85 −166.64 57.95 −154.19 −0.38 149.01 O1C2C3H9 56.73 −29.39 − 86.64 − − -25.61 −17.54 −156.80 C5C4C3H9 −6.73 104.69 − −22.34 − − 99.59 −0.78 −147.27

Energy data EHOMO (eV) −6.14 −6.23 −6.00 −6.31 −6.10 −6.09 −6.39 −6.44 −6.28 ELUMO (eV) −1.04 −1.19 −1.92 −1.17 −1.99 −2.04 −1.34 −0.72 −1.01 ∆EHOMO-LUMO (eV) 5.10 5.04 4.08 5.14 4.11 4.05 5.05 5.72 5.27 Dipole moment (D) 3.86 4.59 1.82 2.82 2.03 1.88 4.31 3.88 2.49

a X=SiMe3- for Compd(s) 3, 4 and 5 and H for other predicted Compd(s). b The relative energies (in kcal mol−1) returns back to the similar and related structures.

The comparison between the FT-IR spectrum of citral (Geranial 1 and Neral 2) before and after reaction with trimethylsilylazide (TMS) demonstrated the main changes during the process. In the FT-IR spectrum of the product the signal of 3443 and 3357cm−1 suggests the presence of –NH2 group at the final result. The appearance of the signal at 2102 cm−1

iindicated the presence of diazo (C=N=N) functional group in the product. There was no change for the signals of carbonyl group (C=O) in the two FT-IR spectra (~1667cm−1 in both the spectra). There are some changes at the O.O.P. pattern of the FT-IR spectrum under 1000 cm−1 that show the changes on the C=C of the citral molecules. All the results


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Table II — The selected structural data for the transition states [TS] by theory (DFT) B3LYP/6-31G* method

Selected data Transition States

[TS]3 [TS]4 [TS]6 [TS]8 [TS]9 [TS]10 [TS]11 [TS]12 [TS]15 [TS]15’

Bond length(Å)

N1N2 1.268 1.268 1.276 1.276 1.778 1.778 − − − − N2N3 1.179 1.179 1.171 1.172 1.251 1.251 1.174 1.174 − − N1C4 2.086 2.086 2.084 2.087 1.495 1.494 1.462 1.462 1.526 1.526 N3C3 2.109 2.109 2.207 2.204 1.801 1.801 2.116 2.116 − − C3C4 1.417 1.417 1.412 1.412 1.562 1.562 1.551 1.551 1.485 1.485 N1X7 a 1.801 1.801 1.022 1.023 1.020 1.020 1.019 1.019 1.026 1.026 C4C5 1.523 1.523 1.522 1.525 1.548 1.548 1.542 1.542 1.545 1.545 C4C6 1.521 1.521 1.520 1.518 1.534 1.534 1.529 1.529 1.531 1.531 C2C3 1.472 1.480 1.470 1.471 1.532 1.531 1.535 1.535 1.533 1.533 O1C2 1.218 1.111 1.219 1.218 1.211 1.211 1.222 1.222 1.227 1.227 C2H8 1.111 1.096 1.111 1.112 1.115 1.115 1.101 1.101 1.099 1.099 C3H9 1.088 1.088 1.087 1.088 1.093 1.093 − − − −

Bond angle(°)

N1N2N3 136.91 136.91 136.11 135.95 113.26 113.26 − − − − N2N3C3 98.60 98.60 97.14 97.33 101.54 101.54 179.68 179.68 − − N3C3C4 103.92 103.92 102.83 102.88 113.65 113.65 111.01 111.01 − − C3C4N1 99.65 99.65 100.03 99.76 99.25 99.25 104.32 104.32 72.12 72.12 C4N1N2 100.80 100.80 102.83 102.85 110.98 110.98 − − − − N2N1X7 a 120.53 120.53 112.45 112.35 111.03 118.86 − − − − C4N1X7 a 137.25 137.25 127.22 127.56 119.22 119.22 110.83 110.83 115.32 115.32 C2C3H8 26.96 25.08 26.97 26.96 26.95 24.81 25.23 25.23 24.82 24.82 C4N1C3 31.01 31.01 30.82 30.89 41.46 41.46 39.15 39.15 52.87 52.87 N1C3C4 49.34 49.34 49.15 49.35 39.29 39.29 36.52 36.52 55.01 55.01

Torsional angle(°)

C4N1N2N3 1.77 1.77 13.05 12.77 −2.25 −2.25 − − − − N1N2N3C3 −3.14 −3.14 −10.46 −8.51 7.74 7.74 − − − − N2N3C3C4 3.35 3.35 1.10 −2.28 −12.34 −12.34 65.25 65.25 − − N3N2N1X7 170.38 170.38 152.99 153.11 −137.28 141.67 − − − − C3C4N1X7 −164.03 −164.03 −139.51 −142.27 125.24 −149.44 −178.31 −178.31 −163.69 −163.69 C2C3C4C6 −2.16 −155.62 1.36 −150.02 13.36 −110.45 −61.78 57.22 111.71 111.71 O1C2C3H9 −2.83 9.23 −0.76 −0.41 24.64 −3.70 − − − − C5C4C3H9 −6.56 146.90 −4.62 158.50 18.73 142.54 − − − −

a X=SiMe3- for Comp.(s) 3, 4 and 5 and H for other predicted Compd(s). b The relative energies (in kcal mol−1) returns back to the similar and related structures.

demonstrated the reaction of TMS with the C=C adjacent to the carbonyl group in the citral mixture (Geranial 1 and Neral 2). To investigate the suggested processes see the computational part of this study (Scheme I, A and B).

In the presence of H2O (or moisture) the molecules 3, 4 and 5 have converted to derivatives 6-8, respectively (Figure 1). The pathways-I in Figure 1 show the possibility of the conversion of 4,5-dihydro-5-methyl-5-(4-methylpent-3-enyl)-1H-1,2,3-triazole-4-carbaldehyde (6 and 8) to the diazoamine derivative

7. Figure 5 shows the structures of the 4,5-dihydro-5-methyl-5-(4-methylpent-3-enyl)-1H-1,2,3-triazole-4-carbaldehyde 6 and 8 derivatives. The selected structural data related to 3-8 are shown in Table I. The DFT-B3LYP/6-31G* calculations demonstrated that 3-amino-3-diazo-3,7-dimethyl-oct-6-enal 7 is 3.52 and 4.72 kcal mol−1 more stable than 4,5-dihydro-5-methyl-5-(4-methylpent-3-enyl)-1H-1,2,3-triazole-4-carbaldehyde 6 and 8 derivatives, respectively. So, the FT-IR experimental results and DFT-B3LYP/6-31G* calculations confirm that the main product of this


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Scheme I — FT-IR spectra of citral (Geranial 1 and Neral 2) before (A) and after reaction (B) with trimethylsilylazide (TMS). The FT-IR spectra were recorded as KBr pellets on a Shimadzu FT-IR 8400 spectrometer.

pathway is the 3-amino-3-diazo-3,7-dimethyl-oct-6-enal 7. The DFT-B3LYP/6-31G* calculations demonstrated that the hybridization of N1 atoms in both 6 and 8 is sp

3 (Figure 5 and Table I). The pyramidality around N1 (sp

3) in 6 and 8 1,2,3-triazoline derivatives are 340.20° and 339.73°, respectively. The deviations of the bond angle summations around N1 (in comparison with sp

2) for 6 and 8 are 19.80° and 20.27°, respectively.

Figure 1 and Figure 6 demonstrated the conversion pathways of 6 and 8 to 3-amino-3-diazo-3,7-dimethyl-oct-6-enal 7.

Figure 7 shows the transition states (TS) of the 1,3-dipolar cycloaddition reactions to produce 6 and 8. The selected structural data for the transition states of this process, other transition states and the intermediates are demonstrated in table S3 in the Supplementary data and Table II. The distances of


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N1…C4 and N3…C3 in the transition states [TS]6 and [TS]8 are {2.084, 2.207} and {2.087, 2.204}Å, respectively. The C2-C3 bond lengths in [TS]6 and [TS]8 are 1.470 and 1.471Å, respectively. The ∆G of 6 and 8 1,2,3-triazolin derivatives are 15.25 and 22.13 kcal mol−1, respectively. The ∆G

# of 6 and 8 1,2,3-triazolin derivatives are 22.10 and 22.20 kcal mol−1, respectively. So, the product 1,2,3-triazolin 6 is thermodynamically more stable than 8. But, 8 is a bit more kinetically labile than 6. The 1,2,3-triazolin derivative 8 with ∆G 6.88 kcal mol−1is more stable than 6.

The resonance forms of 3-amino-3-diazo-3,7-dimethyloct-6-enal 7a-c were shown in the Supplementary data (see S4). The B3LYP/6-31G* calculations demonstrated that 7a is the most stable resonance form among 7a-c. The resonance forms 7b and 7c are 2.25 and 2.04 kcal mol−1 less stable than 7a, respectively. It seems 7b is the suitable form for N2 molecule elimination from 3-amino-3-diazo-3,7-dimethyl-oct-6-enal 7 because of the simple bond order in C3-N3 and higher energy level rather than 7a and 7c. The bond lengths of C3-N3 in 7a-c are 1.308, 1.310 and 1.311Å, respectively. The calculated ∆G

# of N2 molecule elimination from 3-amino-3-diazo-3,7-dimethyl-oct-6-enal 7 by B3LYP/6-31G* calculations

is 62.76 kcal mol−1. Because of the different structures of Geranial 1 and Neral 2 to produce 3-amino-3-diazo-3,7-dimethyloct-6-enal 7, this molecule has two stereoisomers 7R (from 1) and 7S (from 2) (Table I). There are some small differences in the selected structural data. The values of EHOMO, ELUMO and ∆EHOMO-LUMO (in eV) for 7R (from 1) and 7S (from 2) are: {−6.10, −1.99 and 4.11} and {−6.09, −2.04 and 4.05}, respectively. The dipole moments of 7R and 7S are 2.03 and 1.88, respectively. The stereoisomer 7R is 2.80 kcal mol−1 more stable than 7S (Table I).

One pathway for the N2 elimination is the elimination from 6 and 8 derivatives. Figure S5 in the Supplementary data demonstrates the transition states ([TS]9 and [TS]10) of the N2 elimination from 6 and 8. The selected structural data of the [TS]9 and [TS]10 are provided in Table II. For the N2 elimination process from 6 and 8 the bond lengths N1-N2 and C3-N3 (in [TS]9 and [TS]10) increased. The bond length C3-N3 in the transition states [TS]9 and [TS]10 are: {1.778, 1.801} and {1.778, 1.801}, respectively.

The ∆G of N2 elimination reaction in 6 and 8 1,2,3-triazolin derivatives to produce bi-radical intermediates 13 and 14 ([In.]13 and [In.]14) are: 29.70

and 26.80 kcal mol−1, respectively. The ∆G# of N2

elimination reaction in 6 and 8 1,2,3-triazolin derivatives to produce bi-radical intermediates 13 and 14 ([TS]11 and [TS]12) are: 50.13 and 57.40 kcal mol−1, respectively. The B3LYP/6-31G* calculations on the bi-radical intermediates 13 and 14 ([In.]13 and [In.]14) shows that [In.]14 2.90 kcal mol−1 is more stable than [In.]13. The comparison of the ∆G

# of N2 elimination reactions show that [TS]11 is 7.27 kcal mol−1 more stable than [TS]12. So, the pathway of [TS]11 is the faster pathway to produce bi-radical intermediates 13. Figure 1 shows the bi-radical intermediates 13 and 14 to produce aziridine 15 (Table I, Table II and S3 in the supplementary data and Figure 1 and S5 and S6 in the Supplementary data).

Another pathway for the N2 elimination is the elimination from 7. The N2 molecule elimination from 3-amino-3-diazo-3,7-dimethyl-oct-6-enal 7 pathway (Figure 1) performs the “carbene” intermediates (singlet 11 [In.]11 and triplet 12 [In.]12). The B3LYP/6-31G* calculations on the carbene forms show that the singlet 11 is 22.31 kcal mol−1 more stable than triplet 12. The selected data related to the “carbene” intermediates (singlet 11 [In.]11 and triplet 12 [In.]12) is demonstrated in S3 in the supplementary data. Figure S7 in the supplementary data shows the structure of the stable carbene intermediates (singlet 11 [In.]11. One of the pathways to reach aziridine derivative is singlet 11 carbene intermediate.

The results show that there are three pathways to reach the aziridine derivatives 15; (a) intera-molecular reaction of singlet carbene intermediate (11 [In.]11), (b) intera-molecular reaction of bi-radical intermediate 13 ([In.]13), and (c) intera-molecular reaction of bi-radical intermediate 14 ([In.]14). The calculated structural data of the related products, intermediates and transition states by B3LYP/6-31G* calculations are shown in Table I, Table II and S3 (in the supplementary data) and Figure 1 and Figure S5 (in the supplementary data) shows the bi-radical intermediates 13 and 14 to produce 3-methyl-3-(4-methylpent-3-enyl)aziridine-2-carbaldehyde 15 (3R,4S) and (3S, 4S). Figure S7 (in the supplementary data) shows the products of aziridine 15 (3R,4S) and (3S, 4S). Figure S8 (in the supplementary data) demonstrates the transition states ([TS]15 and [TS]15’) of the aziridines 15 formation. Figure S9 (in the supplementary data) shows the products of 3-methyl-3-(4-methylpent-3-enyl)aziridine-2-carbaldehyde 15 (3R, 4S) and (3S, 4S). The ∆G of 15 (3R, 4S) and


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(3S, 4S) production by intra-molecular reaction of singlet carbene intermediate (11 [In.]11) are: 36.65 and 38.88 kcal mol−1, respectively. The B3LYP/6-31G* calculations shows that the transition state [TS]15’ of 3-methyl-3-(4-methylpent-3-enyl)aziridine-2-carbaldehyde 15 (3S, 4S) is 8.89 kcal mol−1 more stable than 15 (3R,4S). So, the production of 15 (3S, 4S) is faster than 15 (3R, 4S). The DFT calculations show that 15 (3R, 4S) is the thermodynamic and kinetic product in the pathway (b) and (c). In accordance with the above results the reaction of “carbine” pathway is the better pathway to produce 3-methyl-3-(4-methylpent-3-enyl)aziridine-2-carbaldehyde 15 derivative.

Figure S10 (in the supplementary data) shows a diagram of the GC spectrum related to the GC-MS experiment of the product mixture in the reaction of citral mixture (Geranial 1 and Neral 2) with trimethylsilylazide (TMS). The main GC signals which appeared at 4.43, 8.29, 9.20, 17.60 and 25.37 min were investigated in accordance with the experimental and theoretical pathway results. Figure S11 (in the supplementary data) demonstrates the mass spectrum of the 3-methyl-3-(4-methylpent-3-enyl)aziridine-2-carbaldehyde 15 (A, B and C) related to the experimental part of this study. The retention times (RT) in the GC-MS experiment was 4.43, 8.29 and 9.20 min under the spectroscopy conditions. The calculation of the peak area of the GC signals demonstrated that the abundance of 6, 7 and 8 are about 80.04% (m/z 195) and for 15 is about 19.96% (m/z 167).

Figure 8 shows the mass spectrum of the 1,2,3-triazoline and di-azoamine derivatives 6-8 related to the experimental part of this study. The retention times (RT) in GC-MS experiment were 8.92 (A), 17.60(B), 18.69(C) and 25.27min (D) under the spectroscopy conditions. See the computational calculations by B3LYP/6-31G* method.

The comparison between the 1H NMR spectrum of citral (Geranial 1 and Neral 2) before and after reaction with trimethylsilylazide (TMS) shows the main changes during the process (Figure 9). Because of the 1H NMR overlapped signals especially in the aliphatic part of the mixed products, the signals of the –CHO were chosen to be investigated. Figure 9 shows the chemical shift of H-atom of the aldehyde functional groups in citral mixture (Geranial 1 and Neral 2) before the reaction with TMS. These hydrogens appeared at δ 9.9 and 10.0 as two doublets. After the reaction of citral mixture (Geranial 1 and

Neral 2) with trimethylsilylazide (TMS) the chemical shift of H-atom of the aldehyde functional groups in the mixture of the products 6 to 8 appeared at δ 9.40-9.50. In accordance with the B3LYP/6-31G* calculations in vacuum the signals at δ 9.50 and 9.45 (calcd. δ 9.72 and 9.69) were related to the H-atom of the aldehyde functional groups of 7R and 7S isomers, respectively, and the signal at δ 9.40 (calcd. δ 9.59) is for H-atom of –CHO of the mixture of 6 and 8. The percentages of the products 6 to 8 were calculated by the use of integrations. The results of the calculations show that the amounts of 3-amino-3-diazo-3,7-dimethyl-oct-6-enal (7R, 7S) and 1,2,3-triazolin derivatives (6 and 8) were almost 75.7% and 24.3% in the mixture of the final reaction and in the solvent (CDCl3;

1H NMR)condition, respectively.

Conclusion

The FT-IR, 1H NMR and GC-MS experimental results confirm the different behavior of the products of the 1,3-dipolar cycloaddition reaction of citral mixture (Geranial 1 and Neral 2) with trimethylsilylazide (TMS). The product 3-amino-3-diazo-3,7-dimethyl-oct-6-enal 7 is the main product in solid phase in accordance with the FT-IR result (Scheme I). The product of the 1,3-dipolar cycloaddition reaction i.e. 4,5-dihydro-5-methyl-5-(4-methylpent-3-enyl)-1H-1,2,3-triazole-4-carbaldehyde (6 and 8) and 3-amino-3-diazo-3,7-dimethyl-oct-6-enal 7 in liquid phase (in CDCl3 solvent) in accordance with the 1H NMR experimental results are the minor and main products, respectively. Because of the high temperature in the GC-MS experimental conditions, it is possible to determine the 3-methyl-3-(4-methylpent-3-enyl)aziridine -2-carbaldehyde 15 due to the N2 elimination as well as the other main products 6-8. The reactions were studied and discussed on the basis of the applied B3LYP/6-31G* method. The calculations were performed on the main configurations with less steric restraint effects. The HOMO and LUMO orbital levels, ∆ΕHOMO-LUMO gaps, dipole moments, Mulliken charges, thermodynamic and kinetic stabilities in vacuum are investigated for the components by the density functional theory DFT method. The elimination reactions of N2 molecule from the di-azoamine and 1,2,3-triazoline derivatives 6-8 to produce aziridine 15 products, the mechanisms, the biradical intermediates and the related transition states were investigated as well by the use of B3LYP/6-31G* method.


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Supplementary Information Additional data related to reactants, intermediates, transition states, mass spectroscopy and DFT is also available (S1 to S11).

Acknowledgement The corresponding author gratefully acknowledges

support from Theoretical and Computational Research Center of Chemistry Faculty of Razi University-Kermanshah-Iran, All the authors gratefully acknowledge support from the Medical Biology Research Center and Kermanshah University of Medical Sciences, Kermanshah.

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