JBCS

INTRODUCTION

The conformational analysis performed by Sachse resulted in the discovery of two conformations of cyclohexane, known as chair and boat.¹ Based on his findings, many studies have been conducted to describe the conformational preferences, electronic, steric, and dipole-dipole effects that influence the conformational equilibrium of a molecule.^2-6 Besides that, the hydrogen bond (HB) is also known to play a key role in determining the three-dimensional structure adopted by proteins, nucleic acids, and amino acids.^7-9 So, many conformational studies of amino compounds^10-13 such as amino acids have been reported.^12-16 HBs are also recognized as contributors to the spectroscopic features such as proton chemical shifts.¹⁷ Also, the HB energy can be fine-tuned by changes in the aromatic character of a molecule. HBs that increase aromaticity are strengthened, and those that reduce aromaticity are weakened.^18-19 The role of the intramolecular HB (IAHB) also have been investigated,^10,12,20,21 and recently was reported as very important for the stability of most conformers of vitamin C,²² as well as in the isotopic effect studies.²³

In previous work,²⁴ it was demonstrated that syn-1,3-diaxial steric effects favor diequatorial conformation in the equilibria of cis-3-X-cyclohexanols (X = Cl, Br, I, CH₃) and 3-X-1-methoxycyclohexanes (X = F, Cl, Br, I, CH₃). However, the presence of some substituents on the six-membered ring has shown that it is possible to promote the diaxial conformer through the IAHB. Studies of cis-3-methoxy-²⁵ and cis-3-ethoxy-cyclohexanols,²⁶ revealed that IAHBs are responsible for stabilizing the diaxial conformation, overcoming 1,3-diaxial steric interactions. Oliveira and Rittner²⁷ also have shown that the larger the size and the indutive effect of alkoxy groups, the greater the intensity of IAHB interaction through investigations of cis-3-alkoxycyclohexanols molecules.

Therefore, aiming to extend the investigations from those results obtained in previous work,²⁸ we concentrate our efforts to probe the solvent effect on the conformational equilibrium of cis-3-N-ethylaminocyclohexanol (cis-3-EACOL) and cis-3-N,N-diethylaminocyclohexanol (cis-3-DEACOL)(Figure 1), using ¹H NMR and theoretical calculations based on density functional theory (DFT) framework. The O-H···N IAHB is also investigated by theoretical calculations in the gas phase to probe the extent of its stability concerning to the size of the amino group substituent.

 

 

EXPERIMENTAL

Synthesis

Anhydrous ethylamine: 100 mL of 70% ethylamine solution was slowly dropped (ca. 2 h) onto 70 g of sodium hydroxide contained in a 250 mL three-neck round-bottomed flask, equipped with a Vigreux micro-distilling apparatus including a collecting flask cooled to -30 ºC to prevent loss of the ethylamine (b.p. 17 ºC).

Cis-3-EACOL (1): 35 mL of anhydrous ethylamine was placed in a round-bottomed flask fitted with a magnetic stirrer at -25 ºC, 2.0 g of 2-cyclohexen-1-one was added dropwise, and the reaction mixture was stirred at -25 ºC for 2 h. The excess of ethylamine was evaporated at room temperature. The product obtained (3-N-ethylaminocyclohexanone) was added dropwise to a three-necked 250-mL round-bottomed flask containing a suspension of lithium aluminum hydride (0.4 g, 0.11 mmol) in tetrahydrofuran (60 mL), with stirring, at -10 ºC and in a nitrogen atmosphere. The mixture was allowed to warm to room temperature and was stirred for one more hour. Water was added dropwise to destroy the excess lithium aluminum hydride. The organic layer was separated with diethyl ether, dried over MgSO₄, filtered, and the solvent evaporated. The compound was purified by column chromatography, using hexane:ethyl acetate 10:1 as eluent and 230-400 mesh silica gel to eliminate the 2-cyclohexen-1-ol. Next, methanol was used to obtain 2.1 g (72%) of cis-3-EACOL.

Cis-3-DEACOL (2): 35 mL of diethylamine 98% was placed in a round-bottomed flask fitted with a magnetic stirrer at 25 ºC, 20 g of 2-cyclohexen-1-one was added dropwise, and the reaction mixture was stirred at 25 ºC for 15 h. Excess diethylamine was evaporated in a rotary evaporator. The product obtained (3-N, N-diethylaminocyclohexanone) was reduced by the same method used for cis-3-EACOL, replacing 3-N-ethylaminocyclohexanone by 3-N, N-diethylaminocyclohexanone, resulting in 18.5 g (52%) of cis-3-DEACOL.

NMR spectroscopy

The ¹H NMR spectra were recorded on an INOVA 500 spectrometer with probe temperature of 20 ºC, operated at 499.88 (¹H) and 125.70 MHz (¹³C) or on a Varian Gemini 300 spectrometer operating at 300.07 (¹H) and 75.45 MHz (¹³C). In all cases, SiMe₄ (TMS) was used as an internal reference. To characterize the compounds synthetized the assignment of the signals in ¹H and ¹³C NMR spectra of the cis isomers of the two compounds, were recorded at concentrations of 0.30 mol L^-1 using CDCl₃ as solvent.

Cis-3-EACOL: ¹H NMR (300 MHz, CDCl₃), d 3.80 (tt, 6.86, 3.43, 1H), 2.81 (tt, 6.69, 3.36, 1H), 2.68 (m, 2H), 1.90 (m, 1H), 1.80 (m, 1H), 1.69 (m, 1H), 1.57 (m, 1H), 1.37 (m, 2H), 1.32 (m, 2H), 1.12 (t, 7.16, 3H). ¹³C NMR (125 MHz, CDCl₃), d 68.6, 54.4, 50.1, 41.3, 34.2, 31.8, 19.2, 15.2.

Cis-3-DEACOL: ¹H NMR (500 MHz, CDCl₃), d 3.68 (tt, 9.01, 4.15, 1H), 2.63 (m, 1H), 2.58 (m, 4H), 1.92 (m, 1H), 1.82 (m, 2H), 1.66 (m, 1H), 1.49 (m, 1H), 1.36 (m, 1H), 1.30 (m, 1H), 1.27 (m, 1H), 1.02 (t, 7.16, 6H). ¹³C NMR (125 MHz, CDCl₃), d 69.7, 56.7, 43.0, 36.8, 35.1, 28.1, 20.8, 12.7.

The assessment of the solvent effect on conformational equilibria of the compounds was carried out recording the spectra at concentrations of 0.05 mol L^-1 in CCl₄, CDCl₃, C₂D₂Cl₄, CD₃CN, acetone-d₆, pyridine-d₅, and DMSO-d₆.

Computational details

The conformational search in gas phase was carried out using molecular mechanics with MM3 method using the TINKER software.²⁹ All conformer geometries were optimized in gas phase and solvent regime along the frequency calculations using the DFT M06-2X,³⁰ functional, which is recommended for an accurate description of non-covalent interactions and performed quite well for a system with dispersion and ionic HB interactions,³¹ such as for amino compounds.¹⁰ As the basis set, the triple-ζ 6-311++G(3df,3pd)³² was chosen to yield a reliable description of the orbitals. It includes diffuse functions on all atoms and supplemented by d,f-polarizations functions on heavy atoms (C, N, and O), and p,d-polarization functions on hydrogens atoms. Spin-spin coupling constant (³J_HH) were calculated in the gas phase using the B3LYP,^33-36 functional and the EPR-III,³⁷ basis set. This basis set includes s-functions with high exponentials by parametrization for a better description of the nuclear region, being a good choice for NMR parameters. In addition, it is optimized for the computation of hyperfine coupling constants by DFT methods, particularly B3LYP.^38,39 The solvent effect was represented by the continuum polarizable model SMD⁴⁰ in the optimization and NMR calculations. Note that in the SMD formalism, the solute is embedded in a cavity surrounded by a polarizable medium with the dielectric constant of specific solvent, forming the solvent reaction field. In this case, superpositions of nuclear-centered spheres form the solvent cavity and the full solute electron density is used instead of partial atomic charges definition. The calculations were performed using the Gaussian09 program package, revision D.01.⁴¹

Natural bond orbital analysis (NBO 6.0)⁴² was performed at the M06-2X/6-311++G(3df,3pd) level of theory for hyperconjugative and steric interactions (using the keyword "steric"). Topological analysis was carried out with the Quantum Theory Atoms in Molecules (QTAIM)⁴³ and Non-Covalent Interaction (NCI) methods, using the AIMALL,⁴⁴ and NCIPLOT 3.0⁴⁵ programs, respectively.

 

RESULTS AND DISCUSSION

Conformational analysis

The conformational search of cis-3-EACOL and cis-3-DEACOL provided 27 and 34 rotamers, respectively. For cis-3-EACOL, 4 rotamers were diaxial (aa) and 23 diequatorial (ee), whereas for cis-3-DEACOL, 7 rotamers were aa and 27 ee. The thermal populations and Gibbs relative energies of the conformers with ΔG < 2.0 kcal mol^-1 are presented in Table 1. Those with ΔG > 2.0 kcal mol^-1 were not considered, since they comprise a very small proportion in the equilibrium.

 

 

In Figure 2 the most stable rotamers for cis-3-EACOL (1aa3 and 1ee18) and for cis-3-DEACOL (2aa7 and 2ee17) are depicted. The 1aa3 and 2aa7 rotamers showed the IAHB O₇-H₈···N₉. The substituent groups of the 1ee18 and 2ee17 rotamers were seen to be as far as possible from the ring, reducing the steric effect. Using the Gibbs energy values for the conformational equilibrium, the molar fractions of the aa and ee conformers were calculated (Table 2).

 

 

 

 

The population of aa conformation for cis-3-EACOL and cis-3-DEACOL compounds in the gas phase were 96% (ΔG = 1.80 kcal mol^-1) and 41% (ΔG = -0.22 kcal mol^-1), respectively. These results indicate that in the cis-3-EACOL, the equilibrium is shifted to the conformer aa, whereas the change to a tertiary amino group increases the 1,3-diaxial steric effect and, in turn, the conformer with diethyl groups in equatorial position predominates. It is noteworthy that the entropy term (TΔS) in Table 2 is the parameter responsible for conformational preference in the equilibria, since the enthalpy terms are very similar for both compounds. Thus, as the TΔS > 0, the repulsive interactions in aa conformer is quite significant and, therefore, there is more entropy in the ee conformer (energetically favorable to access more rotamers - freedom of movement). Although, the aa conformer seems to be more stabilized by IAHB, which decreases the entropy term for cis-3-EACOL. On the other hand, the IAHB formation must be sterically more hindered in the cis-3-DEACOL, increasing the ee conformer stability and, hence, the entropy. Several works have also addressed the role of thermodynamic terms in substituted cyclohexanes, which were brought together in a review.⁴⁶

Koch and Popelier,⁴⁷ showed that the existence of the hydrogen bond can be confirmed if it satisfies eight criteria. The topological analysis values of the 1aa3 and 2aa7 rotamers using QTAIM analysis (Figure 3) indicated that the IAHB O₇-H₈···N₉ was identified and characterized by the presence of bond path, bond critical point (BCP), and ring critical point (RCP) in both aa conformers (Figures 3a and 3a') and fulfilled all the criteria established by Koch and Popelier (see supplementary material).

 

 

NCI analysis also confirmed the presence of the IAHB O₇-H₈···N₉ for the 1aa3 and 2aa7 rotamers. The results are shown in gradient isosurfaces (Figure 3b and 3b') and reduced density gradients (RDG) versus sign(λ₂)ρ(r) (Figure 3c and 3c'). Analysis of Figures 3c and 3c' indicated the presence of IAHB O₇-H₈···N₉ in the 1aa3 and 2aa7 rotamers represented by the strong attractive interactions (peaks at -0.0292 and -0.0310 a.u., respectively). This also are in agreement with our earlier observations obtained by the QTAIM analysis. Negative peaks in Figures 3c and 3c' showed other weak attractive interactions in the 1aa3 and 2aa7 rotamers. The blue color gradients on the isosurfaces (Figures 3b and 3b') confirm the presence of highly attractive interactions between the hydrogen of the hydroxyl group (H₈) and the nitrogen atom (N₉). Positive peaks in Figures 3c and 3c' are related to the repulsive interactions between atoms (green isosurfaces) or between antibonding orbitals (red isosurfaces) for the 1aa3 and 2aa7 rotamers, respectively.

NBO results for the most stable aa rotamers of cis-3-EACOL (1aa3) and cis-3-DEACOL (2aa7) are shown in Table 3. The orbital interactions are related to the stability of the IAHB O₇-H₈···N₉. The interactions σC₄ - H_4a → σ*C₃ - N₉ and σC₂ - H_2a → σ*C₃ - N₉ are stronger than the interactions σC₃ - N₉ → σ*C₄ - H_4a and σC₃ - N₉ → σ*C₂ - H_2a showing the electron donation to the nitrogen. The interactions σC₁₁ - H₁₆ → σ*N₉ - C₁₀ and σC₁₃ - H₂₂ → σ*N₉ - C₁₂ showed an increase in electron density on the nitrogen to cis-3-EACOL and cis-3-DEACOL, respectively.

 

 

The energy values of the interaction LP(1)N₉ → σ*O₇ - H₈ showed a higher inductive effect of nitrogen (N₉) in the cis-3-DEACOL than cis-3-EACOL. The natural localized molecular orbital (NLMO) values summarized in Table 6 showed that the exchange interaction (steric energies)⁴⁸ between the bonding orbitals is greater for cis-3-DEACOL than for cis-3-EACOL because the sum of steric energy in cis-3-DEACOL (43.32 kcal mol^-1) is higher than in cis-3-EACOL (40.94 kcal mol^-1).

 

 

 

 

 

 

The strength of the IAHB for cis-3-EACOL and cis-3-DEACOL compounds was analyzed through the values shown in Table 4. The electronic energy density H(r) in BCP is defined by Equation (1),⁴⁹ in which G(r) is the electronic kinetic energy density, which is always positive, and V(r) is the electronic potential energy density and must be negative.

The dissociation energy of IAHB was obtained by Equation (2):⁵⁰

Cis-3-DEACOL had the lowest distances between H₈···N₉ and O₇···N₉, the greatest length of the O₇-H₈ bond and angle between the O₇-H₈···N₉ atoms, the most significant displacement stretching frequency of the O₇-H₈ bond (bathochromic shift), as well as most remarkable greatest energy dissociation of the IAHB O-H···N. These results indicate that the strength of IAHB increases from cis-3-EACOL to cis-3-DEACOL compound. The positive values for ∇²ρ(r)_BCP and the negative values for H(r) (Table 4) indicate that the IAHB O₇-H₈···N₉ shows electrostatic and covalent characteristics for these compounds.⁵¹

Solvent effect on the ³J_HH

The solvent effect was evaluating in order to obtain the preference of each conformer in equilibrium for the cis isomer. However, the solvent effect is known to be very reduced for ³J_HH,⁵² and of small geometrical changes source. The ³J_H1aH2a and ³J_H1eH2e calculated for lowest in energy conformers ee and aa, found after optimization employing the SMD model to describe the solvent effect, for the most non-polar (CCl₄) and polar (DMSO) solvents are shown in Table 5. The results confirmed that the expected J values are not affected by the solvent or that the dielectric continuum model fails to promote the geometrical changes. Thus, the aa were the lowest in energy in non-polar and polar solvents. This shortcoming can be attributed, in this case, to the approach in neglecting the explicit solute-solvent interactions contributions. Therefore, the implicit solvation model correctly describes the aa conformer as more stable in non-polar solvents due to IAHB but, it wrong represents the aa as more stable in polar solvents, where solute-solvent interactions should dominate, leading to more stability of eeconformer.

Therefore, to probe the conformational changes in solution, we used the expected J values calculated in gas phase along with the experimental data. This was accomplished through the measurement of coupling constant in solvent of different polarity (³J_obs) and the molar fractions (X) for ee and aa conformers were determined through Equation (3):^53,54

The J_H1e/H2e and J_H1a/H2a are the calculated coupling constants in gas phase for the ee and aa conformers individually obtained from the weighted average over all rotamers using Equation (4), where p_Ri represented the thermal population (see supplementary material) and ³J_i the intrinsic coupling constant of rotamer i in the conformational equilibrium.

Since X_ee + X_aa = 1, the free energy difference (ΔGº) can be readily obtained from Equation (5), where R = 0.00199 kcal mol^-1 K^-1, T = 298 K and K₁ = X_ee/X_aa.

The results presented in Table 6 show that cis-3-EACOL has a very high proportion of the aaconformation in non-polar solvents (92% in CCl₄; ΔG_ee-aa = 1.48 kcal mol^-1). In polar solvents, theee conformation predominates (90% in DMSO-d₆; ΔG_ee-aa = -1.31 kcal mol^-1). These results show that in non-polar solvents, the equilibrium of cis-3-EACOL is more displaced for the aa conformation, and there is less solvation of the substituent groups. This favors the formation of the IAHB OH···N, which becomes more important than the syn-1,3-diaxial steric effect between the substituent groups and the axial hydrogens.

For cis-3-DEACOL (Table 7) the proportion of ee is 64% in CCl₄ (ΔG_ee-aa = -0.33 kcal mol^-1) and increases to 93% in pyridine-d₅ (ΔG_ee-aa = -1.55 kcal mol^-1). These results indicate that although the IAHB OH···N is present, the syn-1,3-diaxial steric effect is predominant in this equilibrium.

 

 

Comparing ³J_HH values for hydrogen H-1 in CCl₄ of cis-3-EACOL (³J_H1/H2a or ³J_H1/H6a = 4.67 Hz) and cis-3-DEACOL (³J_H1/H2a or ³J_H1/H6a = 8.70 Hz), along with the literature results for cis-3-aminocyclohexanol (7.46 Hz),⁴⁹ cis-3-N, N-dimethylaminocyclohexanol (7.50 Hz),²⁸ it was observed that for secondary amino groups, the strength of the IAHB OH···N is predominant over the steric effect. For the tertiary amino groups, which are bulkier than the secondary amino groups, the 1,3-diaxial steric effect is predominant.

Analysis of the solvent effect also showed that the ³J_HH values increase as the solvent basicity increases (SB),⁵⁵ not with the increasing dielectricconstant(ε). For example, the diequatorial conformer proportion for cis-3-EACOL in pyridine (ε= 12.40, SB = 0.58) is 81%, while in CDCN (ε = 37.50, SB = 0.29) this value is 65%.

 

CONCLUSIONS

The theoretical calculations showed that the IAHB influences the conformational equilibria of these compounds, stabilizing the aa conformer. The change from -NHC₂H₅ to the -N(C₂H₅)₂ substituent increased the strength of the IAHB due to hyperconjugative interactions and inductive effects. However, the proportion of the aa conformation decreased from 96% to 41% of cis-3-EACOL to cis-3-DEACOL compound, because the 1,3-diaxial steric effect is also strengthened. Although the implicit solvation model fails to predict the conformational changes, combining experimental NMR data in solution and computed J-couplings in gas phase, qualitative trends of conformational preference of the compounds could be described. The results indicated that the aa conformer is favored in less polar solvents (92% and 36% for cis-3-EACOL and cis-3-DEACOLin CCl₄). However, with an increase in solvent polarity, the ee conformation showed a high population in the equilibria (81% and 93% for cis-3-EACOLand cis-3-DEACOLinpyridine-d₅)_.

 

SUPPLEMENTARY MATERIAL

Electronic supplementary material associated with this article can be found at http://quimicanova.sbq.org.br, in pdf format, with free access.

 

ACKNOWLEDGMENTS

The authors thank CAPES for fellowships (P. R. B and G. J. C.). P. R. B also thanks the São Paulo Research Foundation (FAPESP) grant #2021/09687-5 for financial support. We also gratefully acknowledge CENAPAD-SP for the use of computer facilities.

 

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