The influence of steric and orbital intereactions on molecular structure in N-substituted piperidines Текст научной статьи по специальности «Химические науки»

Т 59 (11)

ИЗВЕСТИЯ ВЫСШИХ УЧЕБНЫХ ЗАВЕДЕНИЙ. Серия «ХИМИЯ И ХИМИЧЕСКАЯ ТЕХНОЛОГИЯ»

2016

IZVESTIYA VYSSHIKH UCHEBNYKH ZAVEDENIY V 59 (11) KHIMIYA KHIMICHESKAYA TEKHNOLOGIYA 2016

DOI: 10.6060/tcct.20165911.5464

Для цитирования:

Чан Динь Фиен, Шлыков С. А., Вебер П.М. Влияние стерического и орбитального взаимодействий на молекулярную структуру N-производных пиперидина. Изв. вузов. Химия и хим. технология. 2016. Т. 59. Вып. 11. С. 19-26. For citation:

Tran D. Phien, Shlykov S.A., Weber P.M. The influence of steric and orbital intereactions on molecular structure in N-substituted piperidines. Izv. Vyssh. Uchebn. Zaved. Khim. Khim. Tekhnol. 2016. V. 59. N 11. P. 19-26.

УДК 544.122.4

Чан Динь Фиен, С.А. Шлыков, П.М. Вебер

Чан Динь Фиен, Сергей Александрович Шлыков (Н)

Кафедра физической и коллоидной химии, Ивановский государственный химико-технологический университет, просп. Шереметевский, 7, Иваново, Российская Федерация, 153000.

E-mail: phientran@mail.ru, shlykov@isuct.ru (Н)

Питер М. Вебер

Химический факультет, Брауновский университет, Провиденс, Род-Айленд, США, 02912.

E-mail: peter_weber@brown.edu

ВЛИЯНИЕ СТЕРИЧЕСКОГО И ОРБИТАЛЬНОГО ВЗАИМОДЕЙСТВИЙ НА МОЛЕКУЛЯРНУЮ СТРУКТУРУ N-ПРОИЗВОДНЫХ ПИПЕРИДИНА

Конформационные свойства и молекулярная структур некоторых N-производных пиперидина, содержащих гетероатомы подгрупп Va и Via, были изучены методами квантовой химии (RnX-пиперидины, R=H или CH3; n=1: X=O или S; n=2: X=N или P). Эти соединения могут существовать в виде трех или четырех конформеров, отличающихся аксиальным и/или экваториальным положением, а также гош- и транс- или цис- и транс- ориентацией заместителей относительно пиперидинного кольца. 1,3-ди-аксиальное отталкивание влияет на аксиальное/экваториальное доминирование, в то время как орбитальное взаимодействие влияет на гош-, цис- и транс- ориентации заместителей. Гош-экваториальные конформеры более стабильны, чем другие формы в случаях RX-пиперидинов, тогда как транс-экваториальная форма более стабильна в случае RO-пиперидинов, и цис-экваториальная - в случае RS-пиперидинов. Энергетический барьер процесса азотной инверсии увеличивается в ряду P^S^N^O.

Ключевые слова: N-замещенный пиперидин, квантово-химические расчеты, конформационные

свойства, орбитальное взаимодействие, стерическое отталкивание

UDC 544.122.4

Tran D. Phien, S.A. Shlykov, P.M. Weber

Tran Dinh Phien, Sergey A. Shlykov (H)

Department of Physical and Colloidal Chemistry, Ivanovo State University of Chemistry and Technology, Sheremetevskiy ave., 7, Ivanovo, 153000, Russia E-mail: phientran@mail.ru, shlykov@isuct.ru (H)

Peter M. Weber

Department of Chemistry, Brown University, Providence, Rhode Island, 02912, US E-mail: peter_weber@brown.edu

THE INFLUENCE OF STERIC AND ORBITAL INTEREACTIONS ON MOLECULAR STRUCTURE

IN N-SUBSTITUTED PIPERIDINES

The conformational behavior and molecular structures of several N-substituted piperi-dines containing heteroatoms of the Va and Via subgroups were studied by quantum chemical (QC) calculations (RnX-piperidines, R=H or CH3; n=1: X=O or S; n=2: X=N or P). These compounds may exist as three or four conformers differing by axial and/or equatorial positions and gauche and trans or cis and trans orientation of the substituent relative to the piperidine ring. The axial/equatorial preference is strongly influenced by the 1,3-diaxial interaction, while mostly the orbital interaction governs the gauche, cis and trans orientation of the substituent. The gauche-equatorial conformers are more stable than other forms in case of R2X-piperidines, but the trans-equatorial form is most stable in the RO-, and cis-equatorial - in the RS-piperidines. The energy barrier for nitrogen inversion increases in the series P^S^N^O.

Key words: N-substituted piperidine, quantum chemical calculation, conformational properties, orbital interaction, steric repulsion

INTRODUCTION

The molecular structures and conformational behaviors of saturated six-membered rings containing a heteroatom is an attractive field in chemistry. Steric repulsions and orbital interactions influence the equilibrium between axial and equatorial structures and the orientation of substituents relative to the heterocy-cles. The conformational properties of saturated heterocyclic six-membered rings were reviewed in [1]. The difference in energy between axial and equatorial conformations in six-membered saturated ring systems is mainly caused by steric repulsion caused by 1,3-syn-diaxial interactions, which are absent when a substituent is located in equatorial position. In turn, the anomeric effect stabilizes an axial form [2-4].

Piperidine and its derivatives are ubiquitous building blocks in the synthesis of organic compounds, including pharmaceuticals; nevertheless, the conforma-tional properties of N-substituted piperidines and their structures are poorly studied. The nitrogen interconver-

sion of several N-substituents was theoretically explored in [5] at the B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) level, even though the orientation of the proton in hy-droxypiperidine was not specified.

This paper continues our systematic study of the molecular structures and conformational properties of N-substituted piperidines. In recent publications, a variety of the conformations and conforma-tional preferences were described for alkyl-, alkenyl-, alkynyl- and aryl-piperidine derivatives [6-8]. The N-substituted piperidines were sorted by three groups, according to the preference of the substituent's position. We concluded that the hyperconjugation between the electron lone pair (Lp) on the nitrogen atom and the n-system of the substituents and steric repulsion influence the orientation of substituents relative to the piperidine ring [6].

In this paper, we represent results of detailed theoretical calculations performed for N-substituted piperidines in which the external substituent contains an electron lone pair. In this case, the orbital interac-

tion between the N atom of the piperidine ring and X atom of the substituent is expected to affect the conformational properties. The following N-substituted piperidines have been computed in this work: 1-amino- (H2NPi), 1-(N,N-dimethyl)amino- (Me2NPi), 1-phosphin- (H2PPÎ), 1 -dimethylphosphin- (Me2PPi), 1-hydroxy- (HOPi), 1-methoxy- (MeOPi), 1-thio-(HSPi) and 1-methylthio-piperidines (MeSPi). The axial/equatorial equilibrium is shown in Scheme 1.

P^J

Q

■N—XRn

XRn

■no

AE-EAx-EEp

R=H, CH3; n=l: X=0, S; n=2: X=N, P

Scheme 1 Схема 1

COMPUTATIONAL DETAILS

A recent benchmark study of DFT methods confirmed the general success of both M06-2X and B2PLYP-D in calculating the energies of main-group molecules [9]. Moreover, the B3LYP-D results of the monosubstituted cyclohexanes and silacyclohexane, where an empirical dispersion correction has been added, are in good agreement with the CCSD(T) results [4]. Thus, in this paper, geometry and vibrational calculations were performed with 6-311G** and cc-pVTZ basic sets by DFT, with the M06-2X and B3LYP-GD3 functionals, and with the MP2 method using the Gaussian 09 program package [10].

The potential energy surface (PES) profiles were obtained by varying the Ca-N-X-Y (X = N, P, O or S, Y = H or C) dihedral angle with a step of 10° using DFT-M062X level and the 6-311G** basis set while optimizing all other geometrical parameters. For ease of visualization, these PES profiles are plotted as the energy vs. the ф dihedral angle (Fig. 1). The ф angle is defined as ф = 180°-Z(Lp-N-X-Y) for X = O and S, and as ф = Lp-N-X-Lp for X = N, P. The Lps were placed in the plane bisecting the C-N-C bond angle of the piperidine ring and the R-X-R bond angles of substituents with X = N or P atom. Other PES profile scans, for the nitrogen inversion, were obtained by optimizing all geometric parameters at fixed CY N-X angle values with a step of 10°, and calculating at the M06-2X/6-311G** level.

The Natural Bond Orbital (NBO) analyses [11] were performed at the M06-2X/cc-pVTZ level using the Gaussian 09 built-in NBO version 3.1 package to calculate the orbital interactions.

RESULTS AND DISCUSSIONS

Energies

It is well known that the six-membered piper-idine ring is chair-like in its lowest energy conformations [1, 12]. In these compounds, the substituents, being attached to the nitrogen atom, may be located in axial or equatorial positions with reference to the pi-peridine ring.

In the PES profiles of the compounds H2NPi, Me2PPi, ROPi and RSPi, four minima were located -to two axial and two equatorial conformers. Two axial and one equatorial conformer were located for Me2NPi, and one axial and two equatorial ones for H2PPi.

The structures with torsion angle 9 = 0° are so-called cis conformers (c-Eq and c-Ax), torsion angles of 9 ~ 70-100° are the gauche conformers (g-Eq and g-Ax), and 9 = 170-180° are trans conformers (tr-Eq and tr-Ax). The molecular structures of cis and trans conformers of X=N or O, H2PPi and HSPi are of Cs symmetry equilibrium structure, and the gauche conformers of Ci symmetry. For MeSPi, the cis conformers have Cs symmetry, and the trans conformer are C1 for both axial and equatorial forms. In the case of Me2PPi, the tr-Eq conformer has Cs symmetry, while the tr-Ax form is C1. Relative total electron energies and free Gibbs energies along with predicted conformer contributions at 298 K are summarized in Tables 1 and 2.

The gauche forms of the compounds with X=N or P are more stable than the trans ones due to the steric repulsion between the two terminal groups (H or CH3) of substituents and the hydrogen atoms in the a-positions of piperidine ring.

The strong repulsion leads to the disappearance of the tr-Eq conformer of compound Me2NPi and the tr-Ax conformer of compound H2PPi. The AE = EAx-EEq values are 2.4-3.1, 4.2-5.4, 0.8-1.5 and 0,3-1.0 kcal/mol for ^NPi, Me2NPi, ^PPi and Me2PPi, respectively, where, Eq and Ax are the most stable equatorial and axial forms, see Table 1. Except for the Me2PPi, the AG values are close to the total electron energy differences. In the case of Me2PPi, the AG value is 0.8-1.0 and 1.3 kcal/mol from the DFT and MP2/6-311G** calculations, respectively.

As follows from the QC calculations for H2NPi and Me2NPi, these compounds are expected to exist in form of the g-Eq conformer in gas phase at the room temperature. In the case of R2P-piperidine, the long P-N distance, see Table 3, decreases the 1,3-diaxial repulsion, which may lead to the existence of the g-Ax conformer with a contribution of 12-21% (DFT) and 5-10%(MP2).

X

R=H

R=CH3

N M

1412103

3 6 о

4

M e,NPi

\ Axial

g-Ax

tr-A

g-Ea

O

0 -2

14 12 10

F

"3 6

о ^

■ 4

0 -2

60 90 120 Angle j, deg.

HOPi

Axial

Equatorial

c-Eq

tr-Ax tr-Eq

30 60 90 120 Angle j, deg.

150

180

14 12 10 8

Л8

"3 6 о

0 -2

HSPi

A

c-Ax/

tr-Eq

: j

30 60 90 120 Angle j, deg.

150

180

1412103 83 6-

a

" 4 20-■2-

14 12

10 j8

"3 6

Me2PPi

•Я0.6

s

"30.4

„

g~Ey

' 100 120 140 . ; . r-Ax

C -N-P-C..

a Me

Equatorial

tr-Eq

g-Eq

■ 4

MeOPi

60 90 120 Angle j, deg.

Axial

150

180

c-Eq

Equatorial Ж

tr-Ax

30

60 90 120 Angle j, deg.

0

30

14 12 10 8

ja8

"3 6 о

0 -2

60 90 120 150 180 0 30 60 90 120 Angle j, deg. Angle j, deg.

Fig. 1. Lowest pathway for axial and equatorial conformers by rotating the substituent around N-X bond calculated at M06-2X/6-

311G** level; see Computational details for the ф angle definition Рис. 1. Пути минимальной энергии для аксиальных и экваториальных конформеров при вращении заместителя вокруг связи N-X, рассчитанные методом M06-2X/6-311G**; см. раздел Детали расчетов для определения угла ф

0

P

0

0

0

Table 1

Relative total electron energy, free Gibbs energy (kcal/mol) of conformer« of compounds with N and P atoms in the

substituent a

Таблица 1. Относительная полная электронная энергия, свободная энергия Гиббса (ккал/моль) конформе-_ ров соединений, содержащих атомы N и P в заместителе a_

AE AG(298K)

Conformer Я-Eq tr-Eq g-Ax tr-Ax g-Eq tr-Eq g-Ax tr-Ax

HiNPi

B3LYP-GD3 0 3.3-3.4 2.6-2.7 5.6-5.9 0 2.8-3.0 2.7-2.9 5.2-5.4

M06-2X 0 3.0-3.1 2.4-2.7 5.0-5.5 0 2.9-3.0 2.6-2.8 4.8-5.0

MP2 0 2.4-2.7 2.9-3.1 4.9-5.2 0 2.4 3.1 4.7

MeiNPi

B3LYP-GD3 0 - 4.2-4.4 7.3-7.4 0 - 4.3-4.5 7.8-7.8

M06-2X 0 - 4.5-4.8 6.0-6.1 0 - 4.5-4.8 6.6-6.7

MP2 0 - 5.4 5.1 0 - 5.6 5.8

H2PPi

B3LYP-GD3 0 5.2-5.4 0.9-1.0 - 0 4.9-5.0 1.1-1.2 -

M06-2X 0 4.9-5.1 0.8-0.9 - 0 4.5-4.5 0.8-0.9 -

MP2 0 4.8-5.1 1.2-1.5 - 0 4.6 1.7 -

Me2PPi

B3LYP-GD3 0 3.9-4.0 0.3-0.4 5.6-5.7 0 4.2-4.2 0.8-0.9 5.8-5.9

M06-2X 0 3.2-3.2 0.3-0.4 4.9-4.9 0 3.5-3.6 0.8-1.0 4.9-4.9

MP2 0 2.8-2.9 0.8-1.0 4.8-5.1 0 3.0 1.3 5.1

Note: a The intervals are given for the computations with 6-311G** and cc-pVTZ basis sets

Примечание: a Интервалы значений приведены для расчета с базисными наборами 6-311G** и cc-pVTZ

Table 2

Relative total electron energy, free Gibbs energy (kcal/mol) of conformers of the compounds with O and S atoms in

the substituent

Таблица 2. Относительная полная электронная энергия, свободная энергия Гиббса (ккал/моль) конформе-

AE AG(298K)

Conformer tr-Eq c-Eq tr-Ax c-Ax tr-Eq c-Eq tr-Ax c-Ax

HOPi

B3LYP-GD3 0 1.7-1.8 1.1-1.4 4.6-4.7 0 1.7-1.9 1.2-1.6 4.6

M06-2X 0 1.5-1.8 0.9-1.4 4.4-4.5 0 1.7-2.0 1.2-1.5 4.9-5.0

MP2 0 1.9-2.1 1.4-1.6 5.3-5.4 0 2.0-2.2 1.5-1.8 5.4-5.5

MeOPi

B3LYP-GD3 0 5.1-5.6 1.1-1.4 10.7-11.0 0 5.4-5.8 1.1-1.5 10.7-10.9

M06-2X 0 4.6-5.3 0.9-1.3 10.9-11.2 0 5.4-5.7 1.1-1.4 11.0-11.2

MP2 0 5.6-6.3 1.2-1.5 12.8-13.3 0 6.5 1.4 12.6

HSPi

B3LYP-GD3 2,6-2,7 0 3.3-3.4 1.7-1.9 2.5-2.6 0 3.4-3.5 2.0-2.1

M06-2X 2,4-2,6 0 2.9-3.2 1.8-1.9 2.5-2.7 0 2.8-3.1 2.0-2.2

MP2 2,4-2,6 0 3.4-3.5 2.2-2.7 2.2 0 3.6 2.9

MeSPi

B3LYP-GD3 1,0-1,2 0 1.8-1.9 2.4-2.5 0.6-0.7 0 1.6-1.7 2.5-2.7

M06-2X 1,2-1,3 0 1.7-1.8 3.1-3.2 0.9-1.0 0 2.0-2.1 3.0-3.2

MP2 0,7-,9 0 1.6-1.7 3.6-4.0 0.2 0 1.5 3.9

For the compounds with a P atom substituent, the MP2 method predicts the axial form to be less favorable when compared with the DFT method. On the other hand, an opposite tendency was found for 1-alkenyl- and 1-phenylpiperidines [6, 8]. In addition,

the sophistication of the basis set increases the AE = =Eax EEq values.

In the case of O or S heteroatoms in a substituent, the gauche form becomes a transition structure between the cis and trans conformers due to interac-

tion between the Lp on the nitrogen atom of the piperi-dine ring and the two Lps on the heteroatom of the substituents. Note that in the case of methoxycyclohex-ane and N-ethylpiperidine, in which such interactions are absents, the gauche form is most stable [2, 3, 6].

Because of steric repulsion, the trans forms of the compounds with an oxygen atom substituent are more stable than the cis forms. The AE = EAx-EEq values are from 0.9 to 1.6 kcal/mol for both ROPi compounds, and the contribution of the axial con-formers is 3-11%. The calculations show that the substitution of the hydrogen atom in the hydroxyl group by a methyl group has no influence on the energy difference between the two trans forms, axial and equatorial, see Fig.1 and Table 2. However, this substitution considerably decreases the stability of the cis conformers. Therefore the energy of the c-Ax conformer of MeOPi is less stable, by 11.0-13.3 kcal/mol, than tr-Eq. For these compounds, HOPi and MeOPi, the MP2/6-311G** method also predicts a smaller contribution of the axial conformers, compared with the DFT/6-311G** results. Changing to more sophisticated basis sets also increases the AE and AG values between tr-Eq and tr-Ax forms.

For the RSPi compounds the tendencies are somewhat different comparing with ROPis. In the case of HSPi, the cis forms are more stable than trans, and the c-Ax is less stable than c-Eq AE = 1.7-2.7 and AG = 2.0-2.9 kcal/mol. Note that in the case of HSPi, increasing the sophistication of the basis set decreases the AE value, but increases the AG value.

For MeSPi, the c-Eq conformer is more stable than tr-Eq, but the c-Ax form is less stable than tr-Ax due to strong steric repulsion; both equatorial conformers are more stable than axial ones. It is obvious from the calculations that the substitution of the hydrogen atom in the SH group by a methyl group considerably decreases the stability of the c-Ax conformer, due to an increased 1,3-diaxial repulsion. At the same time, the orbital interaction stabilizes cis forms in cases of these compounds, see section NBO analysis.

The concentration of axial conformers does not exceed 5% in the both RSPi compounds.

Nitrogen inversion

The energy barriers for the nitrogen inversion process from the Eq form to the Ax form via a planar nitrogen bond configuration of all compounds calculated at M06-2X/6-311G** level increase in the series P^S^N^O, see Table 3.

The donor property of the methyl group decreases the energy barrier. Comparing with R2NPi, the longer R-P bond distance in R2PPi decreases these values. A similar situation was found for ROPi

and RSPi. In spite of the close R-X bond distances in R2NPi and ROPi, the interaction between the two Lps on the oxygen atom and the Lp on the nitrogen atom of the piperidine ring nevertheless leads to a higher barrier in ROPi. Thus, the donor properties and the long R-X bond distance decrease the energy barrier, but the Lp-Lp interaction increases this value.

Table 3

The energy barriers, kcal/mol, of nitrogen inversion of all compounds calculated at M06-2X/6-311G** level Таблица 3. Энергетические барьеры, ккал/моль, процесса азотной инверсии всех соединений, рассчитанные методом M06-2X/6-311G**

Compound H2NPi Me2NPi H2PPi Me2PPi

g-Eq^g-Ax 9.8 7.4 2.0 0.6

Compound HOPi MeOPi HSPi MeSPi

c-Eq^-tr-Ax 13.7 9.3 5.7 4.3

tr-Eq^-c-Ax 16.6 15.2 3.7 2.9

Geometry and NBO analysis

Selected geometric parameters, natural charges and the second-order perturbation energies E(2) (donor-acceptor) of the most stable Eq and Ax con-formers of all compounds calculated at the M06-2X/cc-pVTZ level are given in Table 4.

As follows from the calculations, the substitution of a hydrogen atom by a methyl group slightly changes the N-X bond distances and natural charges on the nitrogen atom of the piperidine ring. At the same time, this substitution considerably decreases the electron density on the X atoms. Comparing the molecular parameters of the both conformers of all compounds, except for Me2NPi, H2PPi and Me2PPi, one can see that the endocyclic Ca-N bond distances in g-Ax are somewhat longer than those in the g-Eq conformer, by 0.003-0.006 A. In the case of Me2PPi, the endocyclic Ca-N bond distances in g-Ax are shorter than those in g-Eq. The difference between the two Ca-N bond distances within the same conformer of compounds with nitrogen or phosphor atoms does not exceed 0.004 A.

In H2NPi and H2PPi, the 9 angle in g-Ax is larger than that in g-Eq by 8°. However, in Me2NPi and Me2PPi, the 9 angles in both gauche conformers, axial and equatorial, are almost identical. The N-N bond distance in the g-Eq form is longer than the one in g-Ax, due to steric repulsion between the substituents and CH2 groups in a-positions of the piperidine ring. Because of the higher orbital interaction energy E(2) Lp(N)^c*(N-CMe), the N-N bonds in the g-Ax form of Me2NPi is shorter than in H2NPi. For H2PPi and Me2PPi, the N-P bond in the equatorial conformer is up to 0.012 A longer than in the axial form. The NBO analysis shows that the differences AEg-Ax-g-

Eq(2) Lp(N)^Ry*(P) are 0.90 and 1.86 kcal/mol for H2PPi and Me2PPi, respectively. Thus, the orbital interaction between the Lp on the nitrogen atom of the piperidine ring and the Rydberg orbital of the P atom decreases the energy difference AE = EAx-EEq, and, therefore, stabilizes the axial conformer.

For the compounds with an oxygen atom, the N-O bond distance in the tr-Ax conformer is 0.0050.006 A longer than in tr-Eq, while the O-H (or O-CMe) bonds in both, axial and equatorial forms are identical. The orbital interaction energies E(2) (Lp(N)^ c*(O-H/CMe)) in both trans forms are equal, so that in the ROPi compounds the steric repulsion plays an important role in the axial/equatorial orientation of the substituents.

Table 4

Theoretical geometric parameters, natural charge and energy E(2) (donor-acceptor) of the most stable Eq and Ax

conformers of all compounds calculated at M06-2X/cc-pVTZ level Таблица. 4. Теоретические геометрические параметры, натуральные заряды и энергия E(2) (донор-акцептор) наиболее стабильных экваториальных и аксиальных конформеров всех соединений, рассчитанные методом

For HSPi, the orbital interaction energies E(2) (Lp(N)^-c*(S-H)) in the cis forms are higher than in the trans forms, which stabilizes the cis orientation. A similar situation was found for the equatorial conformers of MeSPi. The 1,3-diaxial repulsion in axial forms of MeSPi destabilizes the c-Ax conformer, making it less stable than tr-Ax, despite higher energy E(2) (Lp(N)^c*(S-CMe)) in c-Ax than in tr-Ax. The N-S bond distance in the c-Eq conformer of MeSPi is 0.02 A shorter than in tr-Ax. However, due to orbital interaction between Lp on the nitrogen atom of the piperidine ring and S-CMe bond in c-Eq, the latter is 0.01 A longer than in tr-Ax.

Compound HiNPi MeiNPi HiPPi MeiPPi

Conformer g-Eq g-Ax g-Eq g-Ax g-Eq g-Ax g-Eq g-Ax

Bond distance (A) and dihedral angle ф (°)

N-Cal 1.456 1.461 1.454 1.454 1.463 1.461 1.460 1.456

N-Ca2 1.457 1.463 1.459 1.459 1.459 1.460 1.457 1.455

N-X 1.419 1.422 1.421 1.414 1.713 1.705 1.715 1.703

X-H/CMe 1.023 1.018 1.455 1.456 1.432 1.429 1.855 1.854

Ф 80 88 86 87 75 83 86 86

Natural charge

N -0.306 -0.309 -0.330 -0.332 -0.764 -0.766 -0.795 -0.797

X -0.657 -0.672 -0.305 -0.307 0.540 0.531 1.008 1.007

H or CMe 0.346 0.347 -0.408 -0.401 -0.081 -0.081 -0.943 -0.943

Energy E(2) (donor-acceptor) (kcal/mol)

Lp(N)^Ry*(X) - - - - 4.42 5.32 3.32 5.18

Lp(N)^o*(X-H/CMe) 7.56 2.36 7.54 3.15 10.10 1.60 10.45 2.84 8.09 2.61 8.53 4.36 8.00 4.23 8.38 6.02

Lp(X)^o*(N-Ca) 8.41 8.89 10.02 11.03 6.36 7.47 7.87 8.94

Compound HOPi MeOPi HSPi MeSPi

Conformer tr-Eq tr-Ax tr-Eq tr-Ax c-Eq c-Ax c-Eq tr-Ax

Bond distance (A) and dihedral angle ф (°)

N-Ca 1.459 1.464 1.458 1.464 1.462 1.465 1.461 1.466

N-X 1.426 1.432 1.422 1.427 1.696 1.693 1.695 1.713

X-H/CMe 0.960 0.960 1.410 1.410 1.358 1.357 1.817 1.806

Ф 180 180 180 180 0 0 0 180

Natural charge

N -0.179 -0.174 -0.191 -0.186 -0.607 -0.611 -0.626 -0.626

X -0.608 -0.626 -0.430 -0.447 0.184 0.178 0.396 0.344

H or CMe 0.466 0.469 -0.207 -0.204 0.063 0.063 -0.755 -0.711

Energy E(2) (donor-acceptor) (kcal/mol)

Lp(N)^Ry*(X) 0.71 0.60 0.96 0.79 4.85 5.85 4.85 5.12

Lp(N)^o*(X-H/CMe) 1.64 1.63 - - 8.31 5.37a 10.01 6.00a 9.88 4.92b 5.63 13.16c

Lp(X)^ G * (N-Ca) 3.35 3.56 3.28 3.50 3.02 4.28 4.23 3.83

Note: a - the trans forms of HSPi; b - for tr-Eq; c - for c-Ax Примечание: a - транс-формы HSPi; b - для tr-Eq; c - для c-Ax

CONCLUSION

In this study, the molecular structure and conformational properties of the several N-substituted piperidines containing heteroatoms X of the Va and Via subgroups of the type of CsHioN-X-Rn, where R = H or Me, and n = 1 or 2, were investigated by QC calculations.

These compounds may exist as three or four conformers differing by axial and/or equatorial positions and relative (gauche and trans or cis and trans) orientation of the piperidine ring and the substituent.

The 1,3-diaxial interaction strongly influences on axial/equatorial orientations. At the same time, the orbital interaction Lp(N)^c*(X-R) influences the relative gauche, cis and trans orientation of the substituent. For these compounds, the first of the two factors is stronger, making the equatorial forms more stable.

In all cases, except Me2PPi and MeSPi, the MP2 method predicts higher AE and AG values (axial-equatorial) compared to the DFT results. Increasing the sophistication of the basis set, from 6-311G** to cc-pVTZ, resulted in a lower contribution of the axial form.

According to the calculations, for the compounds containing N or P atoms, the g-Eq conformers are more stable than the other forms; the torsion angles are 9 = 80-86° for H2NPi, Me2NPi and Me2PPi and 9 = 75° for H2PPi. Except for the R2PPi, the energy difference between the most stable gauche-axial and gauche-equatorial conformers exceeds 2,4 kcal/mol, and, therefore, the contribution of the g-Eq conformer is ca. 100%.

In the case of compounds containing atoms of the VIa subgroup, the compounds with heteroatoms O and S demonstrate the opposite tendency: the tr-Eq form is more stable than c-Eq in HOPi and MeOPi, but is less stable in HSPi and MeSPi. The NBO analysis shows that the orbital interaction between the Lp on the nitrogen atom in the piperidine ring and c*(S-R) stabilizes the cis form. The contribution of axial conformer is 4-11, 1-4, 7-14 and 3-5%, for the HOPi, HSPi, MeOPi and MeSPi, respectively.

The energy barrier for the nitrogen inversion process from the equatorial to the axial conformer increases in the series P^S^N^O.

ACKNOWLEDGMENT S

The financial support of this work by the Russian Foundation for Basic Research (Grant 14-0300923) is greatly acknowledged. PMW acknowledges support by the National Science Foundation, grant number CBET-1336105.

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Поступила в редакцию (Received) 18.07.2016 Принята к опубликованию (Accepted) 03.10.2016