Experimental and theoretical evaluation of trans-3-halo-2-hydroxy-tetrahydropyran conformational preferences. Beyond anomeric interaction

Abstract

Conformational isomerism in trans-3-X-2-hydroxy-tetrahydropyrans (X = F, Cl, Br, I) was investigated by NMR spectroscopy and electronic structure calculations. The compounds were synthesized, purified and identified by ¹H, ¹³C and selective TOCSY NMR spectra and by HSQC, COSY and NOESY contour maps. The geometries and conformer energies for the most stable conformers in the isolated molecules were calculated using M06-2X hybrid functional (DFT) and MP2 (ab initio) methods with the aug-cc-pVTZ basis set. Theoretical calculations taking into account the solvent effect (CHCl₃ and DMSO) were performed using the IEFPCM solvent model, M06-2X/aug-cc-pVTZ level of theory for C, H and O atoms and M06-2X/aug-cc-pVDZ-PP with pseudopotential for the iodine atom. NBO, QTAIM and NCI analyses were applied to identify which stereoelectronic interactions are responsible for their conformational preferences. The conformer stability changes in the presence of solvent. The anomeric effect does not appear to have a significant influence on the molecular conformations in these molecules.

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1. Introduction

The term conformational analysis covers two broad aspects, the determination of the molecular geometry and the conformer energies, followed by studies to determine which stereoelectronic interactions are responsible for the conformational stability.¹ Many detailed studies have investigated the conformational analysis of six-membered rings.^2–8 It has been observed that the most stable conformation of a molecule has a direct dependence on the attractive and repulsive stereoelectronic effects present in the molecular system.^7,9 This may seem obvious, but these effects are not fully understood and many controversies are found in the literature, even for simple systems.¹⁰

The same controversy is found when dealing with the origin of the anomeric effect. This is a chemical phenomenon that refers to the observed stabilization of an electronegative substituent at C2 in a pyran ring to preferably assume the axial position, rather than the equatorial position. However, the real origin of the higher stability of the axial conformation of the substituent attached to the anomeric carbon has not been determined so far.¹¹

The present study intends to evaluate which are the stereoelectronic interactions responsible for the conformational preferences in trans-3-halo-2-hydroxy-tetrahydropyrans (Fig. 1). To assess the stereoelectronic interactions present in these systems it was necessary to analyse the results from NBO (Natural Bond Orbitals),¹² QTAIM (Quantum Theory Atoms In Molecules)¹³ and NCI (Non-Covalent Interactions) topological analyses.¹⁴

Fig. 1 Structure of the studied halohydrins (halo = F, Cl, Br and I).

2. Experimental section

2.1 Nuclear magnetic resonance experiments

The solvents were commercially available and used without further purification. ¹H NMR spectra were recorded on an Avance III spectrometer operating at 600 MHz for ¹H. Measurements were carried out at 5 mm TBI probe, at temperature of 25 °C, using solutions about 10 mg cm⁻³ in different solvents. The ¹H spectra were referenced to TMS. Typical conditions for the ¹H spectra were 8 transients, a spectral width of 4.8 kHz, and 64k data points, giving and acquisition time of 4.5 s. The halohydrins of this study were fully characterized using 1D ¹H, ¹³C and selective TOCSY spectra, as well as, 2D COSY, HSQC and NOESY contour plots.

2.2 Synthesis

It is described the reaction between 3,4-dihydro-2H-pyran and the sources of fluorine, chlorine, bromine and iodine (Select-fluor, N-chlorosuccinimide, N-bromosuccinimide and periodic acid, respectively) leading to diastereoisomeric products, presenting cis and trans configuration. Both diastereoisomers will be assigned, but only the trans product will be discussed in this work. The reaction procedures were adapted according procedure described in literature for similar molecular systems.^15–18

3-Fluoro-2-hydroxytetrahydropyran (1). A solution of nitromethane (50 mL), water (10 mL) and 3,4-dihydro-2H-pyran (1.83 mL, 0.02 mol) was cooled at 3 °C and followed by the addition of Selectfluor (10 g, 0.03 mol). The reaction was stirred at 25 °C for 12 h. After that, the solution was refluxed (110 °C) for 1 h and concentrated under a reduced pressure to remove the nitromethane. The resulting residue was dissolved in dichloromethane (50 mL), followed by the addition of sodium bicarbonate (5%) solution. The organic layer was washed with brine, dried with magnesium sulfate and concentrated under reduced pressure. The crude product was chromatographed over SiO₂ (70–230 mesh) using a proportion of 7 : 3 hexane/ethyl acetate as eluent leading to a 41% of yield. Fluorohydrin cis: ¹H NMR (600 MHz, CDCl₃): δ (ppm) 4.93 (1H, dd, ³J_H2H3 = 1.98 and ³J_H2F = 10.92 Hz, H2); 4.56 (1H, dddd, ³J_H3H4e = 3.06, ³J_H3H4a = 7.44 and ²J_H3F = 48.43 Hz, H3); 4.02–3.96 (1H, m, H6e); 3.59–3.53 (1H, m, H6a); 2.19–2.05 (1H, m, H4e); 1.88–1.78 (2H, m, H4a and H5e) and 1.58–1.49 (1H, m, H5a). ¹³C NMR (150 MHz, CDCl₃): 92.35 (1C, d, ²J_C2F = 19.62 Hz, C2); 87.97 (1C, d, ¹J_C3F = 178.98 Hz, C3); 62.76 (C6); 25.79 (1C, d, ²J_C4F = 20.07 Hz, C4) and 21.63 (1C, d, ³J_C5F = 4.53 Hz, C5). Fluorohydrin trans: ¹H NMR (600 MHz, CDCl₃): δ (ppm) 4.97 (1H, dd, ³J_H2H3 = 3.72 and ³J_H2F = 5.82 Hz, H2); 4.37 (1H, ddt, ³J_H3H4e = 3.72, ³J_H3H4a = 6.48 and ²J_H3F = 48.19 Hz, H3); 4.02–3.96 (1H, m, H6e); 3.59–3.53 (1H, m, H6a); 2.19–2.05 (1H, m, H4e); 1.93–1.81 (2H, m, H4a and H5e) and 1.58–1.49 (1H, m, H5a). ¹³C NMR (150 MHz, CDCl₃): 93.46 (1C, d, ²J_C2F = 28.67 Hz, C2); 87.97 (1C, d, ¹J_C3F = 173.70 Hz, C3); 61.98 (C6); 25.46 (1C, d, ²J_C4F = 19.62 Hz, C4) and 21.65 (1C, d, ³J_C5F = 4.22 Hz, C5). HRMS EI⁺ (m/z): found 120.0589 [M − H⁺]; C₅H₉FO₂ requires 120.0587 g mol⁻¹.

3-Chloro-2-hydroxytetrahydropyran (2). A suspension of N-chlorosuccinimide (6.4 g, 0.05 mol) in water (10 mL) was cooled at 3 °C. A solution of 3,4-dihydro-2H-pyran (4.34 mL, 0.05 mol) in tetrahydrofuran (20 mL) was added dropwise. The reaction mixture was stirred for 3 h at 3 °C and concentrated under reduced pressure to remove the tetrahydrofuran. The resulting residue was dissolved in dichloromethane (30 mL), neutralized with a saturated solution of sodium bicarbonate and washed with water. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure. The crude products were chromatographed over SiO₂ (70–230 mesh) using a proportion of 7 : 3 hexane/ethyl acetate as eluent leading to a 33% of yield. Chlorohydrin cis: ¹H NMR (600 MHz, CDCl₃): δ (ppm) 4.91 (1H, d, ³J_H2H3 = 2.04 Hz, H2); 4.13 (1H, ddd, ³J_H3H4a = 6.78 and ³J_H3H4e = 3.72 Hz, H3); 4.05–4.01 (1H, m, H6e); 3.61–3.55 (1H, m, H6a); 2.24–2.19 (1H, m, H4e); 2.06–2.01 (1H, m, H4a); 1.93–1.81 (1H, m, H5e) and 1.58–1.52 (1H, m, H5a). ¹³C NMR (150 MHz, CDCl₃): 93.01 (C2); 63.46 (C6); 60.12 (C3); 29.44 (C4) and 22.13 (C5). Chlorohydrin trans: ¹H NMR (600 MHz, CDCl₃): δ (ppm) 4.79 (1H, d, ³J_H2H3 = 5.82 Hz, H2); 4.05–4.01 (1H, m, H6e); 3.77 (1H, ddd, ³J_H3H4a = 8.58 and ³J_H3H4e = 4.32 Hz, H3); 3.61–3.55 (1H, m, H6a); 2.37–2.32 (1H, m, H4e); 1.87–1.81 (2H, m, H4a and H5e) and 1.67–1.59 (1H, m, H5a). ¹³C NMR (150 MHz, CDCl₃): 97.24 (C2); 64.27 (C6); 58.59 (C3); 30.93 (C4) and 24.09 (C5). HRMS EI⁺ (m/z): found 136.0359 [M − H⁺]; C₅H₉ClO₂ requires 136.0291 g mol⁻¹.

3-Bromo-2-hydroxytetrahydropyran (3). A solution of acetone (50 mL) and water (10 mL) was cooled at 10 °C, before the addition of N-bromosuccinimide (3.54 g, 0.02 mol) and 3,4-dihydro-2H-pyran (1.83 mL, 0.02 mol). The reaction was monitored by the olefin consume by TLC. The reaction mixture was concentrated under reduced pressure to remove acetone and the resulting residue was dissolved in dichloromethane and washed three times with water. The organic layer was dried with sodium sulfate and concentrated under reduced pressure. The crude products were chromatographed over SiO₂ (70–230 mesh) using a proportion of 7 : 3 hexane/ethyl acetate as eluent leading to a 53% of yield. Bromohydrin cis: ¹H NMR (600 MHz, CDCl₃): δ (ppm) 4.72 (1H, d, ³J_H2H3 = 1.86 Hz, H2); 4.28 (1H, ddd, ³J_H3H4a = 6.42 and ³J_H3H4e = 3.78 Hz, H3); 4.08–4.04 (1H, m, H6e); 3.64–3.57 (1H, m, H6a); 2.35–2.29 (1H, m, H4e); 2.16–2.11 (1H, m, H4a); 2.01–1.89 (1H, m, H5e) and 1.60–1.54 (1H, m, H5a). ¹³C NMR (150 MHz, CDCl₃): 92.83 (C2); 63.70 (C6); 54.69 (C3); 30.09 (C4) and 22.91 (C5). Bromohydrin trans: ¹H NMR (600 MHz, CDCl₃): δ (ppm) 4.86 (1H, d, ³J_H2H3 = 6.30 Hz, H2); 4.08–4.04 (1H, m, H6e); 3.88 (1H, ddd, ³J_H3H4a = 9.60 and ³J_H3H4e = 4.44 Hz, H3); 3.64–3.57 (1H, m, H6a); 2.46–2.41 (1H, m, H4e); 2.01–1.89 (1H, m, H4a); 1.81–1.76 (1H, m, H5e) and 1.70–1.63 (1H, m, H5a). ¹³C NMR (150 MHz, CDCl₃): 97.36 (C2); 64.78 (C6); 51.17 (C3); 32.13 (C4) and 25.41 (C5). HRMS EI⁺ (m/z): found 161.9682 [M − H⁺] with the loss of a water molecule; C₅H₉BrO₂ requires 179.9786 g mol⁻¹.

3-Iodo-2-hydroxytetrahydropyran (4). To the solution of acetonitrile (40 mL), water (12 mL), 3,4-dihydro-2H-pyran (1.83 mL, 0.02 mol) and periodic acid (5.47 g, 24 mmol) was added dropwise (during 2 h) a solution of sodium bisulfite (48 mL, 1 mol L⁻¹). After that, the mixture was stirred for further 2 h at 25 °C. The organic layer was extracted with diethyl ether (300 mL in 3 portions). The organic layer was washed with a saturated solution of sodium sulfite, dried with sodium sulfate and concentrated under reduced pressure. The crude products were chromatographed over SiO₂ (70–230 mesh) using a proportion of 6 : 4 hexane/ethyl acetate as eluent leading to 18% of yield. Iodohydrin cis: ¹H NMR (600 MHz, CDCl₃): δ (ppm) 4.43 (1H, ddd, ³J_H3H4a = 6.24, ³J_H3H4e = 3.72 Hz and ³J_H3H2 = 2.10, H3); 4.15 (1H, d, H2); 4.13–4.05 (1H, m, H6e); 3.66–3.60 (1H, m, H6a); 2.39–2.34 (1H, m, H4e); 2.15–2.08 (1H, m, H4a); 1.92–1.85 (1H, m, H5e) and 1.63–1.56 (1H, m, H5a). ¹³C NMR (150 MHz, CDCl₃): 93.31 (C2); 63.95 (C6); 37.13 (C3); 31.59 (C4) and 24.29 (C5). Iodohydrin trans: ¹H NMR (600 MHz, CDCl₃): δ (ppm) 4.90 (1H, d, ³J_H2H3 = 7.08 Hz, H2); 4.13–4.05 (1H, m, H6e); 3.99 (1H, ddd, ³J_H3H4a = 10.68 and ³J_H3H4e = 4.44 Hz, H3); 3.66–3.60 (1H, m, H6a); 2.49–2.44 (1H, m, H4e); 2.15–2.08 (1H, m, H4a); 1.72–1.65 (1H, m, H5e) and 1.63–1.56 (1H, m, H5a). ¹³C NMR (150 MHz, CDCl₃): 98.39 (C2); 65.61 (C6); 34.78 (C4); 30.80 (C3) and 27.27 (C5). HRMS EI⁺ (m/z): found 209.9531 [M − H⁺] with loss of a water molecule; C₅H₉IO₂ requires 227.9647 g mol⁻¹.

3. Computational details

In the search for the orientation of the O–H group relative to the tetrahydropyran ring, the potential energy curves were scanned using the B3LYP/cc-pVDZ level of theory and varying the C3–C2–O–H dihedral angle from 0 to 360° in 10 degree increments giving 37 possible conformations for each of the four halohydrins studied. For each conformation the C3–C2–O–H dihedral angle was fixed and the rest of the molecule was allowed to relax during the geometry optimization calculations. The geometries for the minima in the curves were then fully optimized at the MP2/aug-cc-pVTZ level of theory available in the Gaussian 09 program.¹⁹ Optimizations were also performed with solvent effect (CHCl₃ and DMSO) using the IEFPCM model, M06-2X/aug-cc-pVTZ basis set for C, H and O atoms and M06-2X/aug-cc-pVDZ-PP with pseudopotential for the iodine atom.

Theoretical values for the ³J_HH coupling constants were obtained at B3LYP functional (with 25% HF exact-exchange) employing the EPR-III basis set for the hydrogen atom, 6-311G* basis set for the iodine atom and cc-pVDZ basis set for the other atoms using Gaussian 09 program.¹⁹

Hyperconjugative interactions were evaluated using Natural Bond Orbital (NBO 5.0)²⁰ analysis as implemented in Gaussian 09, and the calculations were performed at the M06-2X/aug-cc-pVTZ level. QTAIM and NCI topological analyses were performed using the resulting wave functions obtained from the MP2/aug-cc-pVTZ optimizations. QTAIM and NCI topological analyses were carried out with the AIMALL²¹ and NCIPLOT²² programs, respectively.

4. Results and discussion

4.1 Experimental results

The reactions between 3,4-dihydro-2H-pyran and the sources of fluorine, chlorine, bromine and iodine (Select-fluor, N-chlorosuccinimide, N-bromosuccinimide and periodic acid, respectively) lead to diastereoisomeric products²³ (see spectra in ESI†), presenting cis and trans configuration, but the focus of this work was in the trans product. Selective TOCSY experiments were performed on all halohydrins under study (see spectra in ESI†) and the ¹H signals related to the trans diastereoisomer could be selected. Note that the ax–ax conformer has both the X and OH substituents in axial position, whereas the eq–eq conformer has both substituents in equatorial. Fig. 2 exemplifies the selective TOCSY experiment for the chlorohydrin (2).

Fig. 2 (a) Subspectrum of diastereoisomer trans of chlorohydrin (2) acquired through a selective TOCSY sequence with selection in H2; (b) spectrum of ¹H NMR for a mixture of the two diastereoisomers of chlorohydrin (2).

The analyses of 1D ¹H, ¹³C and selective TOCSY spectra together with 2D ¹H–¹H COSY, ¹H–¹³C HSQC and ¹H–¹H NOESY contour plots were crucial to assign the entire molecule (Table 1).

Table 1 Experimental values of δ_H (ppm) for fluoro-, chloro-, bromo- and iodohydrin

δH	F	Cl	Br	I
H2	4.97	4.79	4.86	4.90
H3	4.37	3.77	3.88	3.99
H4a	1.93–1.81	1.87–1.81	1.97	2.12
H4e	2.10	2.34	2.43	2.37
H5a	1.52	1.63	1.66	1.59
H5e	1.93–1.81	1.87–1.81	1.78	1.88
H6a	3.57	3.59	3.62	3.64
H6e	4.00	4.03	4.06	4.11

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Moreover, the ¹H–¹H NOESY contour plots suggested that the trans diastereoisomers are in conformational equilibrium, since the H2 shows a cross peaks (through space interaction) with H6a, H4a and H3, as exemplified for the chlorohydrin (Fig. 3). This conclusion comes from the observed correlation between H2 with H4a and H6a, which is expected to appear only in the eq–eq conformation, whereas the correlation between H3 and H2 is expected to appear only in the ax–ax conformation.

Fig. 3 The conformational equilibrium observed for the trans chlorohydrin (2).

To evaluate the conformational equilibrium, ¹H NMR spectra for compounds 1–4 were acquired in solvents of different permittivity constant (dielectric constant), and the vicinal ³J_H3H2, ³J_H3H4a and ³J_H3H4e coupling constants were measured straightforwardly from the H3 signal, which is a first-order spin system (Table 2). The solvents used were CDCl₃, C₂D₂Cl₄, acetone-d₆, CD₃CN and DMSO-d₆.

Table 2 Coupling constants J (Hz) of H3 measured in solvents with different polarity

Halogen	^3J	CDCl3	C2D2Cl4	Acetone-d6	CD3CN	DMSO-d6
Fluoro	H3H2	3.72	4.08	3.84	3.96	4.14
	H3H4e	3.72	4.08	3.84	4.50	4.14
	H3H4a	6.48	6.84	6.54	6.60	6.78
Chloro	H3H2	5.82	6.12	5.64	6.18	6.06
	H3H4e	4.32	4.32	4.26	4.32	4.32
	H3H4a	8.58	8.94	8.34	9.24	9.18
Bromo	H3H2	6.30	6.54	6.12	6.66	6.48
	H3H4e	4.44	4.44	4.32	4.44	4.38
	H3H4a	9.60	9.90	9.36	10.02	9.78
Iodo	H3H2	7.08	7.26	6.96	7.26	7.20
	H3H4e	4.44	4.44	4.38	4.44	4.38
	H3H4a	10.68	10.98	10.38	11.34	10.74

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In the analyses of the observed coupling constant values, it has to be taken into account that they are averaged values of the conformers that participate in the conformational equilibrium. The data from Table 2 suggests the preference for the eq–eq conformer increases from fluorine to iodine derivatives, since ³J_H3H4a changes from 6 Hz to 11 Hz. Also ³J_H3H4a for each halogen shows only small changes for all solvents used (Table 2), suggesting that solvent polarity does not appreciably affect the conformational equilibrium. These results indicate that the conformation equilibrium for studied compounds is dictated by halogen, instead of solvent polarity.

4.2 Computational results

In order to analyse the stability of the trans halohydrins a potential energy curve was acquired at the B3LYP level using cc-pVDZ basis set varying the C3–C2–O–H dihedral angle from 0° to 360° in 10° increments (Fig. 4).

Fig. 4 The potential energy curves for the trans halohydrins 1–4.

The potential energy curves (Fig. 4) provide the angles and structures for the most stable conformers for each compound. The geometry for each local minimum was re-optimized at the MP2/aug-cc-pVTZ level and the results of the most stable conformer or the minimum global of energy, that is always the dihedral angle of 180°, are summarized in Table 3.

Table 3 Electronic energies for the most stable conformer of each halohydrins with ZPE correction, applying MP2 approximation and aug-cc-pVTZ basis set for C, H and O atoms and aug-cc-pVDZ-PP with pseudopotential for the iodine atom

Halohydrins	Energy^a	ΔE^b (eq–eq − ax–ax)
a In a.u. where 1 a.u. = 627.509 kcal mol^−1.b kcal mol^−1.
F-ax–ax	−445.36572	0.0
F-eq–eq	−445.36323	1.6
Cl-ax–ax	−805.35373	0.0
Cl-eq–eq	−805.35232	0.9
Br-ax–ax	−2918.34220	0.0
Br-eq–eq	−2918.34090	0.8
I-ax–ax	−640.43731	0.0
I-eq–eq	−640.43657	0.5

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The energy values showed in Table 3 are related to the energy of the isolated molecule in vapour phase. Through these calculations the ax–ax conformer is more stable than the eq–eq by 1.6, 0.9, 0.8 and 0.5 kcal mol⁻¹ for the fluorohydrin, chorohydrin, bromohydrin and iodohydrin, respectively.

The main stereoelectronic interactions responsible for the stability of the ax–ax conformer in the vapour phase of each compound under study were evaluated through NBO, QTAIM and NCI analyses. The NBO with deletion and NBO steric analysis gave the results showed in Table 4. The NBO steric analysis give a result that is similar to the concept of steric “contact” between occupied orbitals.

Table 4 Variations of the total energy (ΔE) in vapor phase (MP2/aug-cc-pVTZ), the steric energy from the NBO-steric (ΔE_st) and of the hyperconjugative energy from the NBO-del (ΔE_hyper) and the dipole moment (μ)

Halohydrins	ΔE^a	ΔEst^a	ΔEhyper^a	μ^b
a In kcal mol^−1.b μ in debye (D).
F-ax–ax	0.0	1.6	0.0	2.05
F-eq–eq	1.6	0.0	−2.4	3.35
Cl-ax–ax	0.0	4.0	0.0	2.26
Cl-eq–eq	0.9	0.0	−4.6	3.44
Br-ax–ax	0.0	3.2	0.0	2.33
Br-eq–eq	0.8	0.0	−4.6	3.47
I-ax–ax	0.0	6.3	0.0	2.25
I-eq–eq	0.5	0.0	−4.6	3.35

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The first analysis from Tables 3 and 4 shows that the energy variation between the ax–ax and eq–eq conformers decreases in the order F > Cl > Br > I. These data indicate that the halogen size is related to the conformer stability as mentioned before. The steric repulsion energy (ΔE_st) increases from fluorohydrin to iodohydrin leading to a destabilization of the ax–ax conformer.

However, it was not possible to appoint a specific repulsive interaction responsible for this effect since the observed result is due to the sum of all interactions. Thus, considering that the halogen size is involved in the conformational behavior the interaction involving a halogen can be used to explain the observed results. In this way the interactions between σ_C3–X → σ_C2O2 and σ_C3–X → σ_C4H4a are depicted in Fig. 5 and their energies are listed in Table 5.

Fig. 5 Representation of σ_C3–Cl → σ_C2–O2 and σ_C3–Cl → σ_C4H4a repulsion interaction for the ax–ax chlorohydrin (2), respectively.

Table 5 Repulsive interactions energies (σ → σ), in kcal mol⁻¹, for fluoro-, chloro-, bromo- and iodohydrin for the ax–ax conformation

Interaction	F	Cl	Br	I
σC3–X → σC2O2	1.0	3.8	4.3	5.2
σC3–X → σC4H4a	1.2	5.8	6.4	6.8

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Table 4 also lists the hyperconjugative interaction energies (ΔE_hyper) obtained from NBO analysis, where it is shown that the eq–eq conformer is more stabilized by this kind of interaction. Thus, both steric and hyperconjugative energy interactions should yield a destabilization of ax–ax conformer, but this conformer shows the lowest energy. At this stage, non-covalent interactions can be invoked to explain the stabilization of ax–ax conformer.

However, which atoms should be involved in this stabilization? The isosurfaces provided by the NCI topology (Fig. 6) show that an interaction between the oxygen lone pairs from OH group and the H4 and H6 in axial orientation, as well as, the halogens lone pair with the H5 in axial orientation are responsible for the ax–ax stabilization.

Fig. 6 Plot of the reduced density gradient s and sign(λ₂)ρ; NCI isosurfaces and QTAIM image, respectively, for the compounds 1–4.

It is important to highlight that hydrogen bond O–H–X is not present among the stabilizing interactions, since, theoretically analyses (NBO, NCI and QTAIM) did not show any evidence of its existence. A recent investigation²⁴ compares the chemical shifts of the OH proton in DMSO vs. CDCl₃ to predict hydrogen bond formation through eqn (1). When A < 0.1 there is intramolecular hydrogen bond formation. The value of A for the studied compounds was 0.5 which does not represent a hydrogen bond and this agrees with the above theoretical data.

It is important to highlight that the graphics of reduced density gradients (Fig. 6) are similar in shape among ax–ax conformers and among eq–eq conformers for the halohydrins. It has been observed negative values for λ₂ in RDG, indicating an attractive interaction in the NCI plot (Fig. 6) for the ax–ax and eq–eq conformers, however for the ax–ax conformer it is observed a higher intensity, resulting in a blue interaction in the NCI surfaces. These attractive interactions are not observed in the QTAIM image as a bond critical point (BCP), since the reduced density gradient (s) does not achieve (touch) the zero value.

The stabilization of the ax–ax conformer is due to the non-covalent interactions present in the vapour phase. However in solution these interactions are reduced or vanish due to solvation which is proportional to the conformer dipole moment. This may explain why the values of the observed coupling constants (³J_H3H4a) increase from fluorine to iodine from 6 Hz to 11 Hz (Table 2), which can only be due to the preference for the eq–eq conformer. To confirm this idea, theoretical calculations, taking into account the solvent effect (CHCl₃ and DMSO), were performed and the results are showed in Fig. 7.

Fig. 7 Graphic representing the theoretical energy of eq–eq conformer in relation to the ax–ax conformer for all halohydrins without and with solvent effect (CHCl₃ and DMSO – IEFPCM). All calculations were performed with M06-2X level of theory.

Theoretical calculations with solvent effect were fundamental to prove the influence of solvent in conformer's stability. For all halohydrins the solvent favored the eq–eq conformer, for the fluorohydrin the stabilization of ax–ax conformer was 1.5 kcal mol⁻¹ in vapor phase and this value was reduced to 0.5 kcal mol⁻¹ when the solvent effect (DMSO) was included, whereas, for chloro-, bromo- and iodohydrin the eq–eq became more stable. The conformers energies taking into account the solvent effect explain the percentage obtained experimentally for the halohydrins (Table 6).

Table 6 Percentage of ax–ax conformer in the equilibrium obtained through theory (eqn (2)) and coupling constant ³J_H3H4a (eqn (3))

Solvent		Fluorohydrin	Chlorohydrin	Bromohydrin	Iodohydrin
		ax–ax	ax–ax	ax–ax	ax–ax
DMSO-d6	Eqn (2)	68%	35%	33%	30%
	Eqn (3)	60%	37%	35%	25%
CDCl3	Eqn (2)	76%	51%	45%	39%
	Eqn (3)	63%	43%	37%	26%

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The proportion of the isomers (Table 6) present in the conformational equilibrium was calculated through the eqn (2) (Boltzmann equation) and eqn (3).

where, η represents the molar fraction of a specific conformer; ΔE the energy variation between them; K_B the Boltzmann constant and T the temperature (298 K); x represents the ax–ax conformer and y the eq–eq conformer.

NMR at low temperatures (−80 °C) were performed in order to determine the proportion of each conformer in the equilibrium, however even at low temperatures was not possible to separate the signals of each conformer. Eqn (3) was used to this propose.

J_obs is the observed experimental coupling constant; η the molar fraction of a specific conformer; J is the calculated coupling constant of each isomer isolated (Table 7); x represents the ax–ax conformer and y the eq–eq conformer.

Table 7 Values of coupling constant (J) in Hz of each isomer isolated obtained at B3LYP/EPR-III for the hydrogen atoms

	Fluorohydrin		Chlorohydrin		Bromohydrin		Iodohydrin
	ax–ax	eq–eq	ax–ax	eq–eq	ax–ax	eq–eq	ax–ax	eq–eq
^3JH3H2	1.91	7.07	1.75	7.96	2.02	8.51	1.48	8.66
^3JH3H4e	3.51	6.42	3.18	5.97	3.48	6.27	3.03	5.77
^3JH3H4a	3.09	11.51	4.35	12.65	4.83	13.22	4.69	13.30

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Also a prevalence of the ax–ax conformation would be expected due to the anomeric effect, because for halohydrins under study the R–X–CH₂–Z fragment, where X is an electronegative atom and Z is usually an oxygen, is present. Usually, molecules with this fragment are stabilized by a specific orbital interaction delocalization, dubbed anomeric effect.^11a However, many controversies are found in the literature related to the real origin of anomeric effect. Some authors suggest that it is due to an electrostatic interaction, while others ascribe it to hyperconjugation involved in anomeric effect (Fig. 8).¹¹

Fig. 8 (a) Orbital interactions known as endo- and exo-anomeric effect respectively; (b) dipole moments for the two conformers; X represents the oxygen of the molecules under study.

Table 8 shows the energy values related to the endo- and exo-anomeric effect for the halohydrins under study (Fig. 1).

Table 8 Hyperconjugation energy values for trans diastereoisomers (kcal mol⁻¹)

Halohydrins	LP1O1 → *σC2–O2 endo	LP2O1 → *σC2–O2 endo	LP2O2 → *σC2–O1 exo
F-ax–ax	−1.1	−16.5	−14.0
F-eq–eq	−4.2	—	−14.8
Cl-ax–ax	−1.2	−16.6	−13.7
Cl-eq–eq	−4.6	—	−13.7
Br-ax–ax	−1.1	−16.7	−13.8
Br-eq–eq	−4.7	—	−13.4
I-ax–ax	−1.2	−16.3	−13.9
I-eq–eq	−4.3	—	−13.1

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The values shown in Table 8 suggest that the ax–ax conformer is more stabilized by the anomeric effect, presenting a high value for both the endo- and the exo-anomeric effects. However, it is important to remember that in the sum of all hyperconjugative interactions the eq–eq conformers have higher hyperconjugative interactions than the ax–ax conformers (Table 4). Thus, for the halohydrins under study the anomeric effect has no prevalence in the conformational stabilization.

5. Conclusion

The higher stability of the ax–ax conformer in isolated phase is due to strong non-covalent interactions. However these interactions are minimized in solution leading to a higher proportion of the eq–eq conformer in the presence of solvent. In this way, the theoretical and experimental data are in agreement. The anomeric effect does not appear to be fundamental to explain the stability of these molecules.

Acknowledgements

The authors thank a grant #2014/25903-6 and #2013/03477-2 São Paulo Research Foundation (FAPESP), for providing financial support for this research, for scholarships (to T.M.B. #2014/12776-6; R.V.V.#2012/12414, FAPESP) and also the CNPq for fellowships (to R.R. #300379/2009–9 and C.F.T. #302095/2013-6), and the Chemistry Institute of UNICAMP for the facilities.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra04968g

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